Download Boletin AMPR Vol 100 Num 3 - Asociacion Medica de Puerto Rico

B LETÍN
Asociación Médica de Puerto Rico
PERMIT No. 3007
Vol. 100 - Núm. 3 - Julio-Setiembre 2008
SAN JUAN, PR
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B LETÍN
Asociación Médica de Puerto Rico
CONTENIDO
2 JUNTA DE DIRECTORES / JUNTA EDITORA
3 MESSAGE FROM THE PRESIDENT / MENSAJE
DEL PRESIDENTE
Por Eduardo Rodríguez Vázquez, MD
5 EDITORIAL...
FROM ORGAN DONATION TO TRASPLANTATION: IT TAKES A TEAM
By: Esther A.Torres, MD
ORIGINAL ARTICLES / ARTÍCULOS ORIGINALES
7 METHADONE: AN EFFECTIVE ALTERNATIVE TO
MORPHINE FOR PAIN RELIEF IN CANCER PATIENTS ©.
By: Bernard W. Shelton, MD, Juan Deynes-Romero MD, Mari Tofani-Montalvo MD,
José Ramírez-Rivera MD, Francisco Jaume-Anselmi, MD
11 MANAGEMENT AND OUTCOME OF TRANSIENT
ISCHEMIC ATTACKS IN PONCE, PUERTO RICO ©.
By: Kenneth Geil, MD; Juan José González- Concepción, MD; Ivonne Z. JiménezVelázquez, MD, FACP, Biomaris Medina MD; Xiomara Velazco, MD
15 SEXUAL ACTIVITY AS A RISK FACTOR FOR HEPATITIS C IN PUERTO RICO©.
By: Joel De Jesús-Caraballo MD, Doris H Toro MD, FACP, Federico RodríguezPérez MD, Harry Ruiz MD, María I. Dueño MD, Mariali Álvarez, Erick Suárez-Pérez
PhD and the Gastroenterology Association of Puerto Rico
REVIEW ARTICLES / ARTÍCULOS DE REPASO
STAPHYLOCCOCUS
21 METHICILLIN-RESISTANT
AUREUS IN THE COMMUNITY ©.
By: Rosana Amador-Miranda, MD; Jorge Bertrán-Pasarell, MD , Michelle González,
MD , Ana Conde, MD
25 CONTRAST ASSOCIATED NEPHROPATHY IN THE
ELDERLY©.
By: Félix Carrillo-Alvira, MD, Carlos G Rivera-Bermúdez, Ivonne Z. Jiménez-Velázquez, MD, FACP, Cristina Ramos-Romey, MD, Juan J. González-Concepción, MD
AMONG PUERTO RICANS©.
28 ASTHMA
By: Sylvette Nazario, MD
IN THE ELDERLY©.
32 URTICARIA
By: Cristina Ramos-Romey, MD, Fernando López-Malpica, MD ,
MD, Ivonne Z. Jiménez-Velázquez, MD
Sylvette Nazario,
PORTADA
36 CONSIDERACIONES FARMACOLÓGICAS EN
EL TRATAMIENTO DE LA DEPRESIÓN
Luis Carlos Mejía Rivera MD, PhD
CASE REPORTS / REPORTE DE CASOS
42 SEVERE ANEMIA OF RAPID ONSET IN AN INMUNOCOMPROMISED HOST©.
By: Ezequiel Rivera Rodríguez, MD , Fernando Cabanillas MD
47 CALCIPHIC UREMIC ARTERIOLOPATHY COMPLICATING CHRONIC KIDNEY DISEASE©.
By: Sarahí Rodríguez-Pérez, MD, José Ramírez-Rivera, MD, MACP and Francisco
Jaume-Anselmi, MD, FACP, Axel Báez Torres, MD, FACP
51 JACCOUD’S ARTHROPATHY REVISITED©.
By: David Martínez, MD
54 SYSTEMIC LUPUS ERYTHEMATOSUS PRESENTING AS ACUTE ICTERIC HEPATITIS: A CASE REPORT©
By: Vanessa E. Rodriguez MD, Pablo Costas MD
58 SYMPOSIUM ABSTRACT
SYMPOSIUM ABSTRACTS ©.
COVER / PORTADA
64 DR. RAFAEL DEL VALLE Y RODRÍGUEZ (18471917) ©
By: Eduardo Rodríguez Vázquez, MD
CME CREDITS
64 4.0 CME© CREDITS BOLETIN VOLUME 100 NO 3,
2008.
71 SOLICITUD PRELIMINAR DE MEMBRESÍA
AMPR
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Tel.: (787) 721-6969 - Fax: (787) 724-5208
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España y Portugal
Dr. Rafael Del Valle y Rodríguez
Página 64
Vol. 100 - Núm. 3 - Julio-Setiembre 2008
Diseño Gráfico y Emplanaje realizado por el Departamento de
Prensa y Publicidad de la AMPR
E-mail: [email protected]
2
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
ASOCIACIÓN MÉDICA DE PUERTO RICO - 2008
PRESIDENTES
JUNTA DE DIRECTORES
Eduardo Rodríguez Vázquez, MD
Presidente
Ricardo Marrero Santiago, MD
Presidente Saliente
Verónica Rodríguez, MD
Secretaria
Raúl Casstellanos Bran, MD
Tesorero
Hilda Ocasio Maldonado, MD
Vicepresidente AMPR
Rolance Chavier Roper, MD
Vicepresidente AMPR
Raúl A. Jordán Rivera, MD
Vicepresidente AMPR
Arturo Arché Matta, MD
Presidente Cámara de Delegados
José I. Iglesias, MD
Vicepresidente Cámara de Delegados
Rafael Fernández Feliberti
Delegado Alterno AMA
Eladio Santos Aponte, MD
Delegado Alterno AMA
Wanda Vélez Andujar, MD
Delegado Alterno AMA
José Gerena Díaz
Presidente Distrito Este
Gustavo Cedeño Quintero, MD
Presidente Distrito Noreste
Wanda Vélez Andujar, MD
Presidente Distrito Sur
Mildred Arché Matta
Presidente Distrito Central
Verónica Rodríguez, MD
Presidente Consejo de Educación Médica Continuada
Ismael Toro Grajales, MD
Presidente Consejo Ético-Judicial
Alejandro Medina Vilar
Presidente Consejo Relaciones Públicas y Servicios Públicos
Jorge Vélez Soto, MD
Presidente Consejo Servicios Médicos
Eladio Santos Aponte, MD
Presidente Consejo Salud Pública y Bienestar Social
Natalio Debs Elías, MD
Presidente Consejo Política Pública y Legislación
Emilio Arce Ortiz, MD
Presidente Comité Asesor Presidente
Ilia E. Zayas Ortiz, MD
Presidente Instituto Educación Médica
SECCIONES DE ESPECIALIDAD
ANESTESIOLOGÍA
Carlos Estrada Gutiérrez, MD
CIRUGÍA GENERAL
José E. Silva, MD
CIRUGÍA ORTOPÉDICA
Kenneth Cintrón, MD
CIRUGÍA ESTÉTICA Y RECONSTRUCTIVA
Natalio Debs Elías, MD
CIRUGÍA TORÁCICA Y CARDIOVASCULAR
José O’Neill Rivera, MD
CIRUGÍA DE MANO
José Santiago Figueroa. MD
DERMATOLOGÍA
Luis J. Ortiz Espinosa, MD
ENDOCRINOLOGÍA
Eladio Santos Aponte, MD
MEDICINA DE FAMILIA
Marina Almenas, MD
MEDICINA FÍSICA Y REHABILITACIÓN
Miguel Berríos, MD
MEDICINA INTERNA
Ramón A. Suárez Villamil, MD
MEDICINA PREVENTIVA Y SALUD PÚBLICA
Roberto Rosso Quevedo, MD
OTORRINONARINGOLOGÍA
Charles Juarbe, mMD
PSIQUIATRÍA
Pedro Colberg, MD
NEUROCIRUJÍA
Edwin Lugo Piazza, MD
UROLOGÍA
Pedro Piquer Merino, MD
MEDICINA DE EMERGENCIA
Pablo Laureano Marti, MD
JUNTA EDITORA
Humberto Lugo Vicente, MD
Presidente
Luis Izquierdo Mora, MD
Melvin Bonilla Félix, MD
Carlos González Oppenheimer, MD
Eduardo Santiago Delpin, MD
Francisco Joglar Pesquera, MD
Yocasta Brugal, MD
Juan Aranda Ramírez, MD
Francisco J. Muñiz Vázquez, MD
Walter Frontera, MD
Mario. R. García Palmieri, MD
Raúl Armstrong Mayoral, MD
José Ginel Rodríguez, MD
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
3
Mensaje del Presidente
Message from the President
Por: Eduardo Rodríguez Vázquez, MD
Presidente Asociación Médica de Puerto Rico
Con este numero del Boletín de la Asociación Médica, dedicado a la especialidad de
medicina interna, revalidamos por tercera vez
consecutiva, una circulación de 12.000 ejemplares
impresos del mismo. Lo que una vez fue un sueño
de la Presidencia, lo hemos convertido en una realidad gracias al apoyo incondicional del Sr. Ramón
Ruiz, Presidente y Principal Oficial Ejecutivo de
Triple-S Management Corporation y de la Junta de
Directores de la Corporación.
Ha sido en el 2008 que por primera vez
Prensa Médica al igual que el Boletín Médico de
la Asociación Médica de Puerto Rico han trascendido el papel para presentarse en versión digital,
libre de costo, a través de nuestra página cibernética: asociacionmedicapr.org, accesible a todos los
médicos de Puerto Rico y del mundo.
Con ésta y otras iniciativas educativas,
como la Iniciativa de Informática Médica, nuestra
Asociación se ubica al nivel de las mejores instituciones de su clase en el panorama internacional.
Nuestra misión de brindar educación médica de
excelencia a nuestros colegas y a los estudiantes
de medicina se facilitará mediante nuestra página
cibernética, y por ello estamos diseñando cursos
para capacitar a los médicos en el uso de las computadoras y la Internet.
Tanto el Boletín Médico como Prensa Médica brindarán exámenes con créditos en educación médica continuada en sus versiones impresa
y digital. Estos exámenes estarán acreditados localmente por el Tribunal Examinador de Médicos
de Puerto Rico (TEM) y a nivel de Estados Unidos
por el American Council of Continuing Medical
Education (ACCME).
Además, estamos en el proceso de que las
conferencias ofrecidas en las jornadas científicas
auspiciadas por la Asociación Médica se publiquen con sus respectivos exámenes de educación
médica continuada en versiones impresa y digital.
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
De esta forma, los médicos que no asistieron a las
jornadas podrán obtener la educación y sus respectivos créditos. Hasta ahora hemos ofrecido 31
créditos de educación médica continuada, libre de
costo, en las jornadas científicas auspiciadas por la
Asociación.
Por otra parte, nos llena de profunda satisfacción poder aseverar que tanto el Boletín como
Prensa Médica son las únicas dos revistas médicas en Puerto Rico que se distribuyen a todos los
médicos sin costo alguno y en versiones impresa
y digital. Entendemos que éstos son los mejores
vehículos en que pueden anunciarse las compañías farmacéuticas, las aseguradoras médicas y el
comercio en general. Los médicos deberían también aportar su granito de arena, anunciándose en
cualquiera de las revistas así como en la página
cibernética de la Asociación. Es la mejor manera
de comunicar los mensajes a sus colegas.
Debemos estimular a todos los distritos
y secciones de especialidad de la Asociación, así
como a otras organizaciones médicas (como asociaciones, academias y sociedades) a utilizar nuestros
recursos para anunciar sus actividades, congresos,
cursos, etc. De igual forma, debemos invitar a todos estos grupos médicos a que auspicien nuestro
Instituto de Educación Médica, acreditado por el
TEM y el ACCME, ya que mediante éste podrán
acreditar sus actividades de educación.
El ejemplo de Triple-S que, consecuentemente, durante todos estos años, nos ha apoyado
en nuestra agenda de educación médica continuada para los médicos de Puerto Rico y por ende,
así contribuyendo a mejorar la salud del nuestro
Pueblo, debería ser emulado por todos. Es por eso
que le reiteramos nuestro agradecimiento públicamente.
La Asociación Médica es de ustedes, y
es de ustedes el camino a elegir.
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
5
Editorial...
FROM ORGAN DONATION TO TRASPLANTATION:
IT TAKES A TEAM
By: Esther A.Torres, MD
Associate Medical director LifeLink of Puerto Rico
Professor/Chair Department of Medicine, UPR School of Medicine
Transplantation is the treatment of choice
for end-stage kidney, liver, heart and lung disease, intestinal failure and type I diabetes with renal
failure. Approximately 100,000 persons are in the
United Network for Organ Sharing (UNOS) waiting list in the United States and Puerto Rico, and
the list grows by the hour.1 Yet, only 28,358 were
transplanted in 2007 and many die while waiting.
Puerto Rico has active transplant centers for kidney, heart and pancreas. About 4,000 persons are
estimated to have chronic kidney disease in Puerto
Rico and the transplant waiting list hovers close to
400. 1,2
Transplantation of an organ can not be
achieved without a donor, and living donors are
few and limited to certain organs. A gift of life,
offered by the relatives of someone who died, accounts for most transplants in the United States
and Puerto Rico. This altruistic choice can only
be made possible by the dedicated work of a team
of people who believe in helping miracles happen.
As physicians, we may sometime find ourselves
called to be part of this team.
The first step in the path that ends in the
act of transplanting a new organ is taken by a person so remote from the recipient that he or she may
have never seen or known someone in a waiting
list or a transplanted patient. The recognition of
imminent death in a patient with a neurologic catastrophic injury is the trigger for that first step.
Health care workers, be they physicians or nurses,
must be educated to recognize this and act upon
this medical assessment. The diagnosis of brain
death, made possible by the able medical management of this patient, allows the organ procurement
organization (OPO) to proceed with the next steps
in the process leading to transplantation. Grieving
families receive compassionate care, clear communication, and time and space to accept death
and consider the gift of donation. Cultural and
religious beliefs must be recognized and respected. The opportunity to consider donation and the
comfort of giving life to others and making sense
of an unexpected and untimely death are central to
the process.
Once a wish for donation has been expressed, the focus turns to assuring the safety of the
recipients, by assessing the health of the donor and
donated organs and protecting them from harm
until they can be transplanted. The system for organ allocation, managed by UNOS, ensures that a
fair allocation is made, taking into consideration
the community from which donation is obtained,
the medical need for the waiting patients, and the
compatibility of the match.
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
Finally, suitable organs are recovered by trained
surgeons, transported to the transplant center, and
for the most part, transplanted successfully, giving
new life to sick people. The process is not complete until the grieving family of the donor has received the comfort of knowing a successful outcome
of their gift.
Since 1994, LifeLink of Puerto Rico has
recovered organs from 812 donors, resulting in
2,075 transplants.3 Current statistics place Puerto
Rico among the foremost countries in the world
in cadaveric donation, at a rate of more than 30
donors per million populations, well above most
of the states of the USA. Our culture is a generous one, and public education campaigns, as well
as media exposure of prominent donors and recipients, have resulted in one of the highest consent
rates of the nation and the frequent occurrence of
relatives expressing the wish to donate even before death is formally declared. Still, our transplant
programs are in need of more donors, as are the
thousands of patients, including Puerto Ricans, in
waiting lists across the nation.
How can we, as physicians, then, become
part of the team that leads to transplantation? As
counselors of our patients, we have the opportunity to discuss organ donation as part of the endof-life decisions that can and should be decided
and expressed beforehand. We can allay fears and
assure our patients that a decision to donate after
death will never result in denial of medical care to
preserve life. As practicing physicians, we have to
learn to recognize imminent death and futility of
medical treatment. It is our duty to declare death as
it is to protect life. It is our professional mandate
to communicate humanely and effectively with the
families of our patients, even when we may feel
that our efforts have failed to sustain life. It is our
obligation to respect the relative’s right to consider donation as a final altruistic act in the name of
their deceased relative. A few of us may be directly
involved in donor management, and even fewer
highly specialized physicians will have the task
of retrieving donated organs and/or transplanting
them into waiting recipients. But all of us, when
given the opportunity, can be part of the miracle of
transplantation.
Let us then, as professionals, educate ourselves about organ donation and transplantation,
and given the opportunity, become part of the team
that results in transplantation. To serve humanity is
our calling and our oath. To be part of the miracle
of life is our reward.
1. www.optn.org/data, accessed Oct 4, 2008
2. www.paho.org/english/gov/ce/spp/spp39-06-e.pdf, accessed Oct
5,2008
3. LifeLink of Puerto Rico, 2008
:FD@E>JFFE
Copyright © 2008 Daiichi Sankyo, Inc. and Eli Lilly and Company. All Rights Reserved. PG51957 Printed in USA. June 2008.
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
7
Original Articles - Artículos Originales
METHADONE: AN EFFECTIVE ALTERNATIVE
TO MORPHINE FOR PAIN RELIEF IN CANCER
PATIENTS
Bernard W. Shelton, MD*, Juan Deynes-Romero MD*, Mari Tofani-Montalvo
MD*, José Ramírez-Rivera MD, Francisco Jaume-Anselmi, MD*
ABSTRACT
Pain management is a central issue in the
care of cancer patients in hospice services. Morphine is at present the first line opioid recommended. But when morphine is used in large doses,
especially in renal patients, an active metabolite
of morphine, morphine-6-glucoronide, may cause
delirium and myoclonus and sometimes antagonize the analgesic effect of morphine. Both fentanyl
and methadone have some potential advantages
over morphine since they are longer-acting and
have no active metabolites. However, large doses
of fentanyl or long-acting morphine are expensive
while methadone has an extremely low cost. We
present our retroactive comparative observations
in 50 cancer patients. Methadone was found to be
as effective as morphine, transdermal fentanyl and
common combinations of other opioids in controlling the types of cancer pain presented by patients
in a hospice in the Northwestern Region of Puerto Rico. The use of methadone on elderly patients
with cancer pain as first line therapy is growing
in European and North-American hospices. Hospitals should add methadone to their therapeutic
armamentarium and physicians should develop
skills to use this long acting opioid.
Key words: methadone, pain, cancer, hospice
INTRODUCTION
The effective control of cancer pain is a
challenge to patients, their families and the physicians who care for them. This is even more
pronounced if the pain is of the neuropathic variety where treatment is traditionally refractory.
Comfort care measures often mean large doses of
long-acting morphine or transdermal fentanyl (1,
2). However, accumulating metabolites of morphine may cause delirium or myoclonus especially in
the elderly and those with renal impairment (3).
Also, these long acting formulations are expensive. In the hospice setting, effective but more economical methods of pain control are sought.
We present here a comparative observation on 50
patients treated with morphine, fentanyl and other
opioids or with oral methadone alone.
METHODS
The charts of 76 patients admitted with
cancer pain for more than 10 days between September 1, 2003 and September 30, 2004 to the
Hospicio de la Paz in the North Western region of
Puerto Rico, were reviewed.
The charts were divided into three groups.
Charts of 18 patients who were initially treated
with other opioid and who were subsequently
switched to methadone as their only analgesic was
labeled as Group 1A1 and 1A2. Charts of 17 patients who received only methadone as the only
opioid pain medication were categorized as Group
2. The charts of 15 patients treated with other
analgesics with the exclusion of methadone were
identified as Group 3.Excluded from analysis were
26 patients: 18 received methadone concomitant
with other opioids, 3 were discharged or died in
less than 10 days, 3 were unable to swallow and 2
received methadone for less than 7 days.
Because Group 1 consisted of patients
who were once using other opioids but were subsequently switched entirely to methadone as their
only analgesic, it was possible to compare the observations made while on other analgesics (1A1),
with observations made while receiving methadone as their only analgesic (1A2)
The assessment of the intensity of pain
was taken from a tabulation on a 10-point scale
in the nurses’ records obtained before the patient
was changed from other opioids to methadone, or
when methadone was initiated as their first and
only analgesic, and subsequently on the third, seventh and tenth day of treatment, when the final
assessment as to the effectiveness of treatment was
made. The exact origin of the pain was not identified.
From the * Department of Medicine, Hospital de la Concepción, San Germán, PR 00683
Address reprints to: Francisco Jaume-Anselmi, MD, FACP - Carretera#2, Kmo 174.3, Barrio Caín Alto, San Germán, PR 00683. E-mail: <frjaume@
coqui.net.> Presented in part at the annual meeting of the American College of Physicians in the Caribe Hilton Hotel, San Juan, Puerto Rico on
February 17, 2005
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
8
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
Figure 1: Trend of pain
intensity among the
three groups of patiens
during the initial 10day period of observation. Groups 1A2 and
2 were on methadone
alone while Group
3 was on mixture of
opioids including fentanyl patch, morphine
and others. All recorded an improvement
with treatment. Group
2 patiens receiving methadone seems to have
had an earlier and more
complete relief of pain.
Pain was considered to be controlled between 0-1 on a 10-point scale. Mild pain was taken
as 2-3 and moderate pain as 4-5. Levels of 6 and
above were considered to represent severe or uncontrolled pain.
In patients initially treated with methadone, a starting dose of 5 mg bid was adopted. The
5 mg dose was increased to three or four times
a day as needed and additional dose increments
were made on an eight to 12 hour basis. Costs of
the various opioids used were obtained on a wholesale basis from the local pharmacy. The actual
daily cost was based on the average daily dosage
of opioids required to achieve effective analgesia,
and was tabulated and compared for each patient
in each group.
The side effects of the opioids, as well as
their tolerability were obtained from the notes of
the seven visiting nurses. The nurses’ preference
of analgesics was obtained by means of an eightpoint questionnaire.
Data analysis was performed using the
maple math program and calculated student’s t-test
for paired means to determine the statistical significance of the response to treatment. Response
to treatment was compared between Group 2 (those only using methadone) and Group 3 patients
(using a variety of opioid analgesics). Response
to treatment and cost was also compared between
Group 1A1 (patients while on other opioid combination) and Group 1A2 (the same patients when
switched to methadone alone). A level of significance was considered acceptable at the p value of
0.05. A 95 % confidence interval was calculated
using the Microsoft excel statistic data analysis.
RESULTS
The following cancers were represented:
colon, stomach, breast, prostate, ovarian, gall
bladder, urinary bladder, leukemia, lung, esophagus, uterine and brain. Most men were suffering
from metastatic prostatic disease (32%). Breast
cancer predominated among the women (42%).
Cancer of the colon was present in 16 % of the total group. The average ages of the groups 1, 2 and
3 were 64.1 yrs (SD 10.1), 65.8 yrs (SD 11.1) and
67.5 yrs (SD 10.1) respectively.
Five of seven nurses indicated a preference to an analgesic used. Four of these five chose
methadone citing better tolerability and ease of
administration. The secondary effects of nausea
(42%) and constipation (28%) as reported in the
nurses’ notes and questionnaires were present in
the same proportion in all patients. No one in this
group experienced respiratory failure, myoclonus
or delirium. No one had to be discontinued from
either methadone or the other opioids.
The pain relief obtained with each method
of treatment is shown in Figure 2. The pain severity on the initial day of observation for groups
1, 2 and 3 were 4.8 (SD 1.9; 95 % CI of 3.9-5.7),
4.6 (SD 2.0; 95 % CI of 3.0-4.0) and 4.4 (SD 1.3;
95% CI of 3.7-5.1) respectively. Forty four percent
of group 1 patients had severe pain initially, while
41% of group 2 and 53% of group 3 had severe
pain.
At day 7, 82.8% of patients in the group
receiving methadone (Group 2) had achieved pain
control (mean of 0.88 SD 1.83) compared to 66 %
of patients who had been switched to methadone
(Group 1A2) (mean of 1.4 SD1.9).
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
Cost in dollars
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
25
Daily Cost of Pain Control
20
18.61
22.98
The average cost of opioids for the 18 patients in
Group 1 was $18.61 /day while using other opioids
but $ 0.61 (sixty one cents)/day by the 10th day
while using methadone.
Patients initiated on methadone (Group 2)
obtained relief at an average cost of $0.57 daily in
sharp contrast to the estimated average daily cost
of $22.98 for patients on a mixture of other opioids
(Group 3).
15
10
DISCUSSION
5
0
9
0.61
0.57
Group 1A1
Group
Group 2
(before
1A2 (after (methadone
starting meonly)
thadone) starting methadone)
Group 3
(common
mixture of
opioids)
Grouping
Figure 2: Mean cost of the daily dose of opioids required for pain control in the four study groups at the 10th
day of observation.
This difference was not significant. Only 60% of
patients receiving other opioids (Group 3) had
achieved pain control (mean of 1.6 SD 2.1) by the
seventh day of treatment.
By the 10th day, 88 % of group 2 patients,
66% of Group 1A2 patients and 67% of Group 3
patients had achieved pain control. The remaining
patients estimated their pain levels as mild (2-3).
The response to treatment for all patients within
the 10 day period was found to be statistically significant (p <0.0001).
Pain control by the 10th day among Group
2 patients was achieved using methadone at an
average dose of 19.40 mg/day while Group 1A2
patients required an average dose of 24.16 mg/day.
This difference was not found to be statistically
significant.
Methadone was successful in controlling cancer pain at a fraction of the costs of other
opioids (see Figure 2).
Regardless of the type of medication used,
most patients in our study achieved an acceptable
control of pain within the 10-day observation span.
Breakthrough pain was treated promptly with the
target drug or other drugs. The intention was to
achieve effective pain control however possible.
The use of long acting oral methadone by the hospice was found convenient for the staff and for the
patient, and much less expensive.
Perhaps, because of more advanced disease or because of more aggressive and refractory
neuropathic pain, the patients who were switched
from other opioids to methadone (Group 1A2) required a higher daily dose to control their pain than
those who were initially treated with methadone
(Group 2). Interestingly, patients who were taking
commonly prescribed combinations of long acting
opioids with short-acting rescue doses (Group 3)
achieved less pain control than those receiving
methadone alone and at a greater cost.
Methadone has similar analgesic efficacy
and tolerability at four weeks compared to morphine. In one recent randomized double blind study
where 49 patients were initiated on methadone and
54 on morphine, more than 75% of the patients in
each group reported a 20% or more reduction in
pain intensity (5). In another study, 17 patients
who were treated with more than 300 mcg/hr of
transdermal fentanyl, in which 41% had uncontrolled pain and 60% with neurotoxic side effects
were switched to oral methadone as their only
analgesic. The results showed that opioid rotation
was fully or partially effective in 80% of patients
with somatic pain. Delirium was reversed in 80%
and myoclonus in 100% of the patients (6).
Table 1: Wholesale cost of drugs used to control paint in 3 groups
Drug (mg)
$ Cost per Unit
$ Cost per Month
Fentanyl TD /100 mcg/hr (5 patches)
62.38
623.18
MS. Long acting 60 mg tabs
4.67
280.79
Tramadol /acetaminophen 37.5/325
1.49
134.10
Acetaminophen and oxycodone 325/5
1.16
104.00
hydromorphone 4mg
1.00
90.00
Acetaminophen/codeine 300/30
0.68
61.20
Methadone 10 mg tabs
0.25
14.40
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
10
The conversion of morphine and fentanyl
to methadone is not straightforward because of the
high individual variability in the pharmacokinetics
of methadone (7, 8). Patients in high doses of other
opioids may achieve effective pain control with
modest doses of methadone. Besides the expected
opioid agonism, methadone exhibits N-methyl-D
aspertate antagonism and monoaminergic effects
(9). An initial equivalency of 15 mg of long acting
morphine to 5 mg of methadone is reasonable. Recently, success with rapid switching of fentanyl to
methadone with an initial fixed ratio of 20:1 has
also been reported, but no relationship was found
between the final opioid dose and the original dose
of fentanyl (10).
The duration of analgesia following a single dose of methadone is approximately 6-8 hours.
This is very short compared to the half-life of methadone which is approximately 24 hours. This
initial brevity of the analgesic effect relative to
the long half life is a result of the drug’s rapid absorption-distribution phase. With repeated dosing,
methadone accumulates in the tissues and the plasma concentration is sustained by this peripheral reservoir. For this reason, and because of its rapid
gastric absorption, small doses of methadone may
be used for breakthrough pain. In 3 of six patients
in which pain intensity was assessed every 10 minutes during 37 discrete episodes of breakthrough
pain the onset of relief started 10 minutes after an
oral rescue dose and patients were moderately to
completely satisfied (11). Because of its incomplete cross-tolerance to morphine, methadone may be
increased to the point of controlling pain; intolerable side effects of other opioids limit more readily
their dose escalation.
Because of the potential risk of cumulative toxicity, uncertain knowledge of its pharmacokinetics, and the common misconception that its
use is under the exclusive control of the government for treating drug addiction, methadone has
not been extensively studied in large clinical trials.
There are no financial incentives for pharmaceuticals to study its advantages or disadvantages or to
promote its use.
It is not marketed to physicians. But the growing
use in North America for cancer pain has led the
College of Physicians of Ontario to establish guidelines for its use (12), and in depth articles have
been recently published in clinical practice journals (13, 14)
Methadone is listed in schedule II of the
controlled substances act. Since 1976 all physicians with the standard Drug Enforcement Agency
registration are allowed to prescribe the drug for
analgesia. We believe that hospices and hospitals
should add methadone to their armamentarium and
physicians should be encouraged to develop the
needed skills to use this long-acting opioid. Methadone is a useful and inexpensive addition to the
analgesic armamentarium.
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
+ SOCIOS
+ SERVICIO
Asóciate y asocia
Clínicas Multifásicas
Educación Médica Continuada
Eventos Culturales
La Asociación Médica de Puerto Rico
ha desarrollado, este año, una intensa actividad. Un total de 37 eventos entre Clínicas Multifásicas de Salud (12), Jornadas
Científicas de Educación Médica Continuada (7), Conferencias (6), Series de cine
(7), Conciertos y eventos culturales. El Bo
letín científico editado en 12.000 ejemplares que se distribuyen gratuitamente a
todos los medicos y estudiantes. Un nuevo
web site, portal médico que ofrece diversas
herramientas de utilidad para los profesionales de la salud.
El próximo año planeamos continuar
creciendo y aumentando las actividades
para beneficio de la clase médica.
Por tal, aumentar la cantidad de
miembros de la Institución es de crucial
importancia.
Ayúdanos en esta iniciativa para
seguir creciendo y ofreciéndote más y mejores servicios. Asóciate y Asocia.
Informes y formas de suscripcion:
www.asociacionmedicapr.org
Boletín de la AMPR
Teléfono (787) 721-6969
REFERENCES
1.
Cancer Pain Relief: Report of a WHO expert Committee.
Geneva, Switzerland. World Health Organization, 1996.
2.
Ripamonti C, Zecca E, Bruera E: An Update of the Clinical Use of Methadone for Cancer Pain. Pain 1997; 70:109-115.
3.
Mancini, I. MD; Lossignol, Dominique A. MD; Body, JJ.
Opioid switch to oral methadone in cancer pain. Curr Opin Oncol 12:
308-313, July 2000.
4.
Bruera E, Sweeney C: Methadone uses in cancer patients
with pain. A review.
J Palliat Med. 2002; 5: 127-138.
5.
Bruera E, Palmer JL, Boenjak S, et al. Methadone versus
morphine as a first-line strong opioid for cancer pain: a randomized,
double-blind study; J Clin Oncol. 2004; 22:185-192.
6.
Benítez-Rosario MA, Feria M, Salinas-Martín A, Martínez-Castillo LP, et al. Opioid switching from transdermal fentanyl
to oral methadone in patients with cancer pain. Cancer. 2004; 101:
2866-73.
7.
Tse DM, Sham MM, Ng DK, Ma HM. An ad libitum schedule for conversion of morphine to methadone in advanced cancer
patients: an open uncontrolled prospective study in a Chinese population. Palliat Med 2003; 17: 206-11.
8.
Cherny N, Ripamonti C, Pereira J, et al. Strategies to manage the adverse effects of oral morphine: An evidence-based report
for the expert working group of the European Association of Palliative Care Network, J Clin Oncol. 2001; 19: 2542-54.
9.
Lynch M E. A review for the use of methadone in the
treatment of noncancer pain. Pain Res Manag. 2005; 10:133-44.
10.
Mercadante S, Ferrera P, Vilari P and Casuccio A. Rapid
switching between trans-dermal fentanyl and methadone in cancer
patients. J Clin Oncol 2005; 23: 5229-34.
11.
Fisher K, Stiles C, Hagen NA. Characterization of the
early pharmacodynamic profile of oral methadone for cancer-related
breakthrough pain: a pilot study. J Pain Symptom Manage. 2004;
28:619-25.
12.
Methadone for Pain Guidelines College of Physicians and
Surgeons of Ontario 2004. Access on line:www.cpso.on.ca/publications methpain.htm
13.
Tooms JD, Krall LA. Methadone treatment for pain states.
Am Fam Physician 2005; 71:1353-8.
14.
Soares LG. Methadone for cancer pain: what have we
learned from clinical studies? Am J Hosp Palliat Care. 2005 MayJun; 22(3):223-7.
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
11
MANAGEMENT AND OUTCOME OF TRANSIENT
ISCHEMIC ATTACKS IN PONCE, PUERTO RICO
Kenneth Geil, MD*; Juan José González- Concepción, MD**; Ivonne Z. JiménezVelázquez, MD, FACP**, Biomaris Medina MD***; Xiomara Velazco, MD***
ABSTRACT
Background: Approximately 240,000
transient ischemic attacks (TIA’s) are diagnosed
every year in USA. Recent studies have shown
that 4-20% will have a stroke within 90 days after a TIA, half in 2 days. Objectives: To determine
morbidity and assess outcome at 72 hours of patients with TIA’s arriving at the Emergency Room
(ER) of San Lucas Hospital, Ponce, PR. Methodology: Medical records of all patients evaluated at
ER in 2006 with neurological symptoms for < 24
hours, and outcome for next 72 hrs were reviewed.
Anticoagulation given and timeframe between
initial symptoms and diagnostic neurologic workup was also recorded. Results: 53/182 records reviewed met inclusion criteria. 45% males, 55%
females, median age of 62 years (Range 53-90).
All received antithrombotic drugs at ER. HeadCT performed upon arrival in 100%, only 57% of
Echocardiograms and Carotid-Doppler done in 24
hrs. Conclusion: No patients developed stroke or
death related to TIA in 72 hours.
Key Words: Transient Ischemic Attacks / Elderly
/ Stroke
INTRODUCTION
It is well known that chest pain could be
a symptom of myocardial infarction and therefore
most patients with chest pain seek medical attention quickly. However, the same does not happen
with patients having rapid onset of neurological
deficits such as dysarthria, weakness of one side
of the body, facial palsy or numbness. Sometimes
symptoms last only a few minutes and disappear
without apparent sequelae, giving the patient a
false sense of security, making them believe that
the event was insignificant. The truth is that these
patients carry a high risk of developing a stroke.
About 15% of patients experiencing stroke
report a history of Transient Ischemic Attack (TIA)
(1). According to the American Heart Association (AHA) and the American Stroke Association
(ASA), stroke is defined as neurological symptoms lasting more than 24 hours, whereas transient
ischemic attack is defined as neurological deficits
lasting less than 24 hours, although most of the
time they resolve in less than one hour. The cause of both events is related to the abrupt discontinuation of cerebral perfusion caused by emboli,
thrombosis, atherosclerotic infarction, hypercoagulable states, and/or infarcts of undetermined
cause (2). Other predisposing factors are diabetes,
hypertension, and dyslipidemia.
About 240,000 TIA’s are diagnosed every
year in the United States of America (USA), and
about 70,000 in the United Kingdom. Patients with
TIA’s are generally unstable, with recent studies
showing that 4-20% will have a stroke within 90
days after a TIA, half within the first 2 days (3).
The faster the diagnosis and treatment, the better
the prognosis. The ABCD score predicts the stroke
risk in seven days following a TIA. A score of four
or greater may justify a 24 hour admission in USA,
solely on the basis of a greater opportunity to administer early thrombolytic therapy if a subsequent
stroke occurs in the hospital as opposed to at home
(3).
The National Stroke Association (NSA)
guidelines for the management of TIA’s recommend:
- A brain CT-scan, carotid Doppler and
2-D Echocardiogram in all patients with acute
neurological deficits.
- To start adequate anticoagulation as soon
as possible to reduce the recurrence of another
neurological event (category 4).
- To perform an endarterectomy in patients
with evidence of carotid artery stenosis between
70 to 99%, in the first 2-4 weeks of symptoms (category 1) (4).
Rothgell, et al (6), found that early initiation of existing treatments after TIA or minor
stroke was associated with an 80% reduction in the
risk of early recurrent stroke. The cost of disability
in a patient after a stroke is more than the cost of
a diagnostic work up, but the most important consideration is the well-being and independence of
the patient if the occurrence of a disabling stroke
could be prevented.
*From the Veterans Healthcare Center, Geriatrics and Extended Care, San Juan, PR, the ** Internal Medicine Department, Geriatric Medicine Program, University of Puerto Rico Medical Sciences Campus, San Juan, PR, and the ***Internal Medicine Department, San Lucas Episcopal Hospital,
Ponce, PR.
Address reprints to: Juan J. González-Concepción, MD, Department of Medicine, Geriatric Medicine Program, PO Box 365067, San Juan, PR
00936-5067. Fax 787-754-1739, e-mail: < [email protected]>.
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
12
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
OBJECTIVES
EXCLUSION CRITERIA
# OF PATIENTS
A retrospective study was done:
Symptoms for more than
•
24 hrs prior to ER arrival
55
Diagnosis of seizures
5
Meningitis
1
Syncope
7
Stroke 42
Intoxication
1
Hemorrhagic Stroke
1
Brain death
1
Neuropathy
1
Migraine
3
Trigeminal neuralgia
1
Hypoglycemia
1
Psychiatric illness
1
Acute Coronary Syndrome
3
TOTAL EXCLUDED
129
•
To determine the frequency of transient ischemic attacks (TIA’s) arriving at the Emergency
Room of Hospital Episcopal San Lucas, Ponce, PR.
To assess outcome (stroke, death) at 72 hours
and compare to published literature.
METHODOLOGY
Following IRB approval, the medical
charts of all patients that arrived from 1/1/06 to
12/31/06 to the Medical Emergency Department
in San Lucas Episcopal Hospital, Ponce P.R. with
neurological symptoms lasting less than 24 hours
were reviewed. The sample was collected using
the ICD-9 codes for transient ischemic attacks, namely 435.9, 435, 435.1, and 437.
The medical record was also evaluated
for the next 72 hours after the presentation of the
initial neurological symptoms. Age, hypertension,
diabetes mellitus, symptoms for more than 10 minutes, speech difficulty, and motor difficulty were
gathered from the chart. We also recorded the antithrombotic drug selected for treatment, and the timeframe between initial symptoms and diagnostic
neurologic work up (Head CT scan, Carotid Doppler, and a 2-D echocardiogram), as recommended by the NSA for the management of TIA’s at
ER. We evaluated if the imaging study performed
(Brain CT/ MRI) showed evidence of recent infarction.
Inclusion Criteria:
►
Neurological symptoms that recover in <
24 hrs.
►
Patients must arrive to ER with a primary
neurological complaint.
Exclusion criteria (see Table 1):
►
Permanent neurological symptoms or lasting > 24 hrs.
►
CT scan with evidence of cerebral hemorrhage or neoplasm.
►
Neurological deficits associated with an
infectious process, such as meningitis, toxoplasmosis, or herpes virus infection, among others.
►
Evidence of hypoglycemia or seizures.
►
sion.
Acute neurological deficits during admis-
Table 1: Amount of patients excluded from the study.
Most of them were excluded because patients did not
meet the criteria of transient ischemic attack according
to the American Stroke Association.
RESULTS
Of the 182 records reviewed, only 53 met
the inclusion criteria. The sample was composed
of 45% males and 55% females, the median age
was 62 years (Range: 53-90). Hypertension was
present in about 77.4% of the affected patients, followed by diabetes mellitus in 47.2% of patients
(see Figure 1). Speech disturbances and motor
deficits were the most common neurological complaints in the patient that arrived to the ER (see
Figure 2 &3). All patients studied received antithrombotic drugs in the ER. The antithrombotic
drugs preferred by ER physicians were aspirin and
clopidogrel. None of the patients received Dypiridamole/aspirin as secondary prevention of stroke.
An interesting finding was the use of Lovenox in
nineteen patients without clear evidence of atrial
fibrillation or acute coronary symptoms. There is
no indication for Lovenox in TIA or stroke as per
literature reviewed, and the risk of hemorrhagic
transformation seems to be higher when used.
A Head CT scan was performed upon
arrival to ER in 100% of cases, but only 57% 2D
Echocardiograms and carotid dopplers were done
in a 24 hour period. A carotid doppler was not
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
Frequency
FIG. 1: COMORBIDITIES
41
50
25
13
HTN
DM
20
8
7
1
0
FIG. 2: NEUROLOGIC DEFICITS
DYSL
HTN + DM
HTN+DM+DYSL
Disease
< 1 HR
6
< 24 HR
0
1
Time
MOTOR
SENSORY
OR+ SENSORY
FIGURE 4: DIAGNOSTIC STUDIES
Number of patients
Percentage
100
3
SPEECH+MOT
Figure 2: The most common neurological
symptom
OR
was slurred speech, followed by motorSPEECH+MOT
weakness.
FIG. 3: DURATION OF SYMPTOMS
94
SPEECH
28 30
1
Symptoms
NONE
Figure 1: Co-morbidities presented in the studied group.
Hypertension was present in 41 of the patients. 20 of the
patients had Diabetes mellitus and hypertension.
50
59 55
100
50
0
60
40
20
0
53
HEAD CT
26
23
23
0
ADMISSION
4 7
24 HR
0
8
48 HR
15
0
0
NONE
CAROTID
DOPPLER
2D ECHO
Time after onset of symptoms
Figure 3: The neurological symptoms lasted more than
one hour, but less than 24 hour in 94% of the patients.
Recent studies have demonstrated a correlation between
the duration of symptoms. The lesser the neurological
deficit, the greater the risk for stroke recurrence.
Figure 4: Brain CT was performed on all patients, but
only 57% of 2D Echocardiograms and carotid dopplers
were done in a 24 hour period.
performed in 28% of the cases during the admission (see Figure 4). These studies will reduce the
chance of endarterectomy, which is most effective
for stroke prevention if performed within the first
two weeks of the last neurovascular event.
DISCUSSION
In the next 72 hours after admission, none
of the patients developed recurrence of stroke.
These findings did not correlate with similar studies performed, probably because the sample
was too small for such comparison. However, all
patients were admitted on antithrombotics such
as clopidrogel, aspirin, dypiridamole/aspirin, or
coumadin, which have demonstrated high efficacy
in primary and secondary stroke prevention (see
Figure 5).
Number of
patients
FIG 5: TREATMENT GIVEN AFTER NEUROLOGIC
DEFICIT
50
32
ASA
28
4
0
0
19
Anticoagulant
PLAVIX
COUMADIN
AGGRENOX
LOVENOX
Figure 5: The preferred antithrombotic was aspirin,
followed by clopidogrel and coumadin. None of the
patients was on aggrenox although it can be used as primary or secondary prevention. Lovenox was used in 19
patients even though there is no approved indication for
the use of heparin in stroke.
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
Evidence has shown the importance of
the time interval between diagnosis and treatment
in patient’s morbidity and mortality, therefore
we evaluated the timing in where the diagnostic
work up was performed. Studies recommended
in the National Stroke Association Guidelines for
the management of TIA include a brain Computerized Tomography, carotid Doppler, and a 2-D
echocardiogram. All of them should be performed
in the emergency room or during the first 24 hour
after the beginning of symptoms. In our study all
patients had a brain CT upon arrival to ER, therefore all of them received this benefit that might
be of benefit if a thrombolytic is considered. The
major deficiency found was performing a carotid
Doppler in a 24 hour period. In fact, about 28% of
the patients were discharged without performing
a carotid Doppler. This omission can reduce the
chance of endarterectomy in a 2-week interval
period to avoid stroke recurrence. Although all of
the 2D-echocardiograms were performed, 43% of
these studies were done more than 24 hours later.
A delay in performing a 2D echocardiogram may
increase the risk of stroke recurrence if there is a
non-detected cardiac thrombi, especially in patients with history of atrial fibrillation.
Recent studies have demonstrated a significant increase risk (4 to 20%) of developing a
stroke in a 90 days period after a TIA.
14
Half of strokes happen in high risk patients the
next 48 hours after a TIA. We did not demonstrate these findings in our study. According to the
American College of Chest Physicians, AHA and
ASA, anticoagulation treatment is the mainstay of
treatment. All the patients in the study received
the benefit of anticoagulation. If we compare these
findings with the literature revised and similar studies, we could conclude that the absence of stroke
recurrence in the study group may be due to early
anticoagulation.
RECOMMENDATIONS
1.
To continue follow up after 7
days and 90 days should give more information
about the outcomes, since the risk of stroke is still
latent for about one year after the first symptoms.
2.
Compare the outcome in patients
with complete neurologic work up in 24 hours after the initial symptoms versus patients in where
neurologic work up was delayed.
3.
Determine the ABCD score of
the patient upon arrival to ER to compare the
outcome according to the initial score.
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
pacientes en SE del HSL con síntomas neurológicos por < 24 horas y en 72 horas desde 1/1/200631/12/2006 fueron revisados. Anticoagulantes administrados y tiempo trascurrido entre síntomas
y estudios diagnósticos fueron registrados. Resultados: 53/182 con criterios de inclusión. 45%
masculinos y 55% femeninos; edad promedio - 62
años (53-90). Todos recibieron anticoagulantes en
SE. CT de cabeza se realizó en 100%, pero sólo
57% de Ecocardiogramas y Doppler Carotídeos
fueron realizados en 24 horas. Conclusión: Ningún paciente desarrolló un evento cerebrovascular
o muerte en 72 horas.
Technology
In
Physician
REFERENCES
1.
S. Claiborne, MD, MPh, R. Daryl, MD, S. Warren, MD,
MPh (Dec. 2000) Short-term Prognosis After Emergency Department Diagnosis of TIA. Vol 284, No.22: 2901-2906.
2.
Sacco R. MD, MS. FAHA, FAAN, Adams R., MD,
FAHA, Albers G. MD, et al. (Feb. 2006) Stroke. Journal of the
American Heart Association, Vol. 37, No. 2: 577-617.
3.
S. Claiborne, P. Rothwell, Mai N. Nguyen-Huynh, et al
(Jan. 2007) Validation and refinement of scores to predict very early
stroke risk after transient ischaemic attack. Lancet. Vol 369: 283292.
4.
Claiborne, MD, PhD, Mai N. Nguyen-Huynh, MD,
Schwarz, M., BS, et al. (2006) National Stroke Association Guidelines for the management of transient ischemic attacks. Ann Neurol.
60: 301-313.
5.
Gladstone, D. (Jan. 2005) Toward an emergency response
to transient ischemic attacks. Vol. 117. No. 1. Postgraduate Medicine.
6.
Rotwell PM, Giles MF, Chandratheva A, et al. (Oct.
2007). Effect of urgent treatment ischaemic attack and minor stroke
on early recurrent stroke: a prospective population-based sequential
comparison. Lancet.
7.
S. Claiborne, MD, MPh (Nov. 2005) Transient Ischemic
Attack: A Dangerous Harbinger and an Opportunity to Intervene.
Seminars in Neurology. Vol. 25. No. 4: 362-370.
8.
Albers, G., MD; P. Amarenco, MD; Donald, J., MD, et
al. (2004) Antithrombotic and thrombolytic therapy for ischemic
stroke;Chest 126 (3): September: 483-512.
RESUMEN
Aproximadamente 240,000 ataques isquémicos temporeros (TIA’s) se diagnostican en Estados Unidos anualmente. Estudios recientes han
demostrado que 4-20% de estos pacientes desarrollarán un accidente cerebrovascular en los próximos 90 días, la mitad en 2 días. Objetivo: Determinar frecuencia de eventos cerebrovasculares y
evaluar progreso en 72 horas subsiguientes en sala
de emergencia (SE), Hospital San Lucas (HSL),
Ponce, PR. Metodología: Expedientes médicos de
Iniciativa de Informática
Médica de la AMPR
Jaime Claudio Villamil, MD
Director
Conscientes de la gran necesidad y oportunidad de promover la capacitación en
informática de salud tanto a médicos
como a pacientes, la AMPR propone este
esfuerzo pedagógico para fomentar el
uso de las tecnologías de información.
Entérese y obtenga los informes completos en:
www.asociacionmedicapr.org
Seccion Recursos Profesionales
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
15
SEXUAL ACTIVITY AS A RISK FACTOR FOR
HEPATITIS C IN PUERTO RICO
Joel De Jesús-Caraballo MD*, Doris H Toro MD*, FACP, Federico RodríguezPérez MD*, Harry Ruiz MD*, María I. Dueño MD*, Mariali Álvarez**, Erick
Suárez-Pérez PhD*** and the Gastroenterology Association of Puerto Rico
ABSTRACT
Background: Hepatitis C (HCV) is a blood
born infection that affects millions of people worldwide. Although IV drug use (IVDU) and blood
transfusions have been clearly defined as transmission risk factors for HCV, the role of sexual
transmission is still not clearly defined. Aims: To
define the role of sexual transmission among Puerto Ricans HCV+ patients, and to determine if there
is an association between sexual, and non-sexual
risk factors, genotypes and viral load. Methods:
A cross-sectional epidemiological IRB approved
study was performed among patients with HCV+
enrolled from Nov-2001 to May-2002. The Puerto Rico Gastroenterology Association sponsored
this study. Five hundred subjects completed a riskfactor study questionnaire. Blood samples were
drawn to determine HCV genotype and viral load.
Results: A male predominance was found (68%).
Most patients (70%) were between 45-65 years old.
The most common genotype was 1 (82%). Reported sexual risk factors were: sex with a drug user
(30.3%), multiple sexual partners (>10) (28.9%),
sex with an HCV infected partner (9.0%), and homosexuality (8.3%). Most common non-sexual
risk factors were: blood transfusion (30.2%) and
intravenous drug use (IVDU) (46.8%). Illicit drug
users (IDU) reported having sex at a younger age
(15.5 y/o), than those non-IDU (18.9 y/o) p=0.015.
IDU reported both, a higher frequency of homosexual encounters than non-IDU (10.8% vs. 1.5%)
p<0.0001, as well as having sex with another IDU
(47.8% vs. 11.3%) p<0.0001. Those patients who
reported sex with an HCV infected partner and
were non-IDU had fewer partners than those who
were IDU (1-2 vs. >20 partners) p<0.001. As a
group, homosexuals had sex at a younger age, had
multiple partners (> 20) and a higher proportion
of sex with IVDU. After adjusting for age, gender, and risk factors, no significant association was
found between genotype and sexual variables. The
difference noted between groups in viral load had
no statistical significance. Conclusions: Our data
supports that sexual risk factors are common in
HCV infected patients. High risk sexual practices
such as early sexual intercourse, homosexuality
and multiple sexual partners are the most common
in patients with hepatitis C with use of illicit drugs
as a risk factor also.
The role of sexual transmission in this group cannot be clearly established. No significant relationship was found between genotype, viral load and
sexual transmission. Patients with illegal drug use
(IDU) showed significant difference from non
users in regard to the age of the first sexual intercourse, the number of sexual partners and the practice of sex with other illicit drug users or partners
of the same sex. When parenteral transmission is
excluded, practicing sex with a HCV infected partner was the only identified risk factor in 6.5% of
the studied population.
Index words: hepatitis C, sexual transmission, viral load
INTRODUCTION
Hepatitis C infection (HCV) is the most
common chronic infection in the United States,
with an estimated 2.7 million Americans infected
(1). Although it is most commonly acquired by
percutaneous exposure to infected blood, other
less efficient modes of transmission such as perinatal and sexual transmission have been studied.
(2-4)
The role of sexual activity in HCV transmission is still a subject of debate. Epidemiologic
evidence indicates that this disease can be transmitted by sexual means although less efficiently
than hepatitis B or human immunodeficiency virus
(HIV) (5). Some studies have identified several
high-risk sexual variables that may affect HCV
transmission (6-13). These variables may include:
higher number of sexual partners, exposure to an
infected sex partner, history of sexually transmitted disease, and sex with an intravenous drug user
(IVDU).
Several studies in stable heterosexual monogamous couples suggest that transmission is
extremely low (average 1.5%, range 0%-4.4%) (913). For those subjects with high-risk sexual practices (multiple sexual partners), anti-HCV prevalence were higher (11%-27%) than the prevalence
in sexual contacts of persons without high-risk
behavior (0%-7%) (5). Some investigators have
postulated that there is a relationship between the
From the *Gastroenterology Department, VA Caribbean Healthcare System, San Juan P.R., the **University of Puerto Rico School of Medicine, and
the ***Department of Biostatistics and Epidemiology, Graduate School of Public Health, University of Puerto Rico, San Juan, P.R.
Address reprints to: Doris H. Toro, MD - VA Caribbean Healthcare System, Casia Street #10, San Juan Puerto Rico, 00921-3201. Tel: (787)-6413669. Fax: (787)-641-4561. Email: <[email protected]>
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
16
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
sero-prevalence of anti-HCV positivity in spouses
and the length of marriage, especially in those with
more than 20 years of marriage (10). Japanese studies have reported an increase of 50% in HCV antibodies and 90% on positive HCV RNA titers for
each decade of marriage.
STUDY DESIGN
In the United States, the estimated seroprevalence for HCV may vary depending on sexual
preferences. HCV-infected partners who are long
term monogamous carry a 2.3% risk of getting
infected while those with risky sexual practices,
such as sex workers, males having sex with men
(MSM), and multiple sexual partners have a 4-6%
risk. (13) Recently, some reports showed a low
prevalence of HCV transmission in subjects with
homosexual activity (sex same sex). HIV or impaired immune status appears to increase the risk
of sexual transmission among this subpopulation.
Still it is unclear and a subject of debate, why subjects with higher risk of STD may have low risk of
sexual transmission of hepatitis C. (14)
2.
Determine the relationship between genotype, and viral load with sexual risk
factors.
Subsequent studies have found that there
are well-defined differences of HCV transmission
between gender types, with a three-fold increased
risk of transmission among females. These suggest
that male-to-female transmission is more efficient.
In spite of HCV-RNA has been isolated in semen
(13), researchers have found that HCV viral loads
collected in semen and genitalia are characterized
by low titers of the virus (8). This can be a reason for less effective HCV transmission than other
sexually transmitted conditions. No difference of
transmission has been found between the sexual
practice preferences (i.e. vaginal, oral, anal) or the
frequency of sexual contact rate per month.
In regards to hepatitis C sub-variables
(genotype and viral load), the available recent data
suggest, that elevated viral load may increase the
risk of sexual transmission. No evidence has been
found to favor any HCV genotype. Failure to characterize anti-HCV in concordant couples (antibody concordant couples) may limit most of the
recent published studies. Sero-prevalence studies
using genotypes and sequence analysis (E2 region)
may help in estimating antibody among concordant
couples with less degree of error (13). This method
suggests that in United States, the transmission for
heterosexual monogamous couples remains close
to 2.7%.
HCV constitutes an important public
health problem in Puerto Rico. Epidemiological studies about the magnitude and extension
of the disease in the island are limited.
The main purpose of the study is to clearly define sexual factors for transmission of HCV in
Puerto Ricans, and the relationship with viral
load and genotype.
Objectives of the study are the following:
1.
Identify sexual risk factors among
HCV infected patients in Puerto Rico
Study relevance:
•
To define the role of sexual transmission
among Puerto Ricans infected patients with Hepatitis C virus (HCV) and to determine the relationship between sexual and non sexual risk factors,
genotype and viral load.
METHODS
A cross section epidemiologic study was
performed in chronic HCV patients diagnosed by
ELISA, RIBA or PCR from 1990 to 2002. Patients
were recruited from November 2001 to May 2002.
Physician’s member of the Gastroenterology Association of Puerto Rico referred the patients by
making initial interview and screening. Patients
that accepted to participate in the study were referred to the Gastroenterology Section of the corresponding Veterans Affairs Medical Center (Ponce,
Mayaguez, or San Juan) until 500 patients were
enrolled. The study was approved by the San Juan
VA Institutional Review Board.
Inclusion Criteria
Exclusion criteria
- Patient within 21-65 - HIV or other viral hepayears old.
titis infections.
- Chronic Hepatitis C
diagnosed from 1990 - Antiviral therapy at least and thereafter.
six months before study.
- HCV diagnosed by - History of organ transELISA or RIBA.
plant.
- Legally competent.
Definition
•
•
IVDU- intravenous drug user
IDU- illicit drug use (includes cocaine snorting, marihuana, heroine, cocaine and others)
STD- sexually transmitted disease
Sample Size
•
•
•
The patient sample was taken from the hepatitis C
prevalence study (N=509). The data was collected
between Nov-2001 and May-2002. The estimate
of required participants was calculated based on a
4.5% prevalence of HCV with a 96% confidence
level.
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BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
Reported Risk Factors for
HCV Transmission
40
30
a. Demographic Characteristics
A total of 500 patients were enrolled from
November 2001 to October 2002 at different locations of Puerto Rico. Half (49.8%) of the study
population lived in the northeast (metropolitan region) Puerto Rico, while the rest of the subjects
were distributed in the south /southwest and west/
northeast regions. Study population was composed mostly of males (68%), between ages of 45-65
yrs old. Around 25% of subjects were veterans, of
which 99.1% (112/113) were males.
b. Risk Factors
i.
Non-sexual
In the studied group the most common reported non-sexual HCV-related risk factors were:
blood transfusion (30.2%) and intravenous drug
use (IVDU) (46.8%). Other common risk factors
among subjects were: body piercing [females
92.4% (146/158) males 28.9% (98/342)], tattooing
22% (110/500), syringe/needles accidents 12.7%
(62/490), and hemodialysis 1% (5/500). It is important to mention that 75.5% of the patients report a history of surgery. (see Figure 1).
ii.
12.7
9
10
1
Sex with
infected HCV
partner
Needle injury
Blood
transfusion
0
N= 500
Figure 1: Reported global risk factors for Hepatitis C
infection.
Age at First Sexual Intercourse and
Use of Illicit Drugs
20
18
16
14
12
Years 10
8
6
4
2
0
18.86
15.54
18.86
15.54
Users
Non users
Use of Illicit Drugs
p<.015
Figure 2: Patient with illegal drug use (IDU) reported
having sexual intercourse at a younger age (15.54) than
those without illegal drug use (non-IDU) (18.86)
Reported Sexual Risk Factors
40
Percent
RESULTS
22
20
Statistical Methods
Descriptive statistic analyses were used
for sexual risk factors. Chi-square analysis, crosstabs, and Spearman chi-square were used to determine any statistic association. Frequency among
risk factors and sub-population were estimated.
SPSS for Windows was used for data analysis. A p
< 0.05 was considered statistically significant.
30.2
Hemodialysis
Percent
Data was collected from written questionnaire formulated for Prevalence study. Blood samples were sent to Ponce Medical School of Medicine Laboratory. Roche Amplicor method was
used for PVR-HCV test, and LIPA was used for
genotype.
46.8
50
Data Collection
Tattooing
The patient sample was taken from the hepatitis C prevalence study (N=509). The data was
collected between Nov-2001 and May-2002. The
estimate of required participants was calculated
based on a 4.5% prevalence of HCV with a 96%
confidence level.
17
(>10 partners) 28.9% (145/479), sex with an HCV
infected partner 9.0% (32/352), and same sex relationship 8.3% (29/349) (see Figure 3).
IVDA
Sample Size
30
30.3
28.9
20
9
10
0
141/465
145/479
32/352
8.3
29/349
Sex with a drug user
Multiple sexual partners >10
Sex with an HCV infected partner
Homosexual
Sexual
Reported sexual risk factors in this study were divided as follow: sex with a drug user (i.e. cocaine,
heroin) 30.3% (141/465), multiple sexual partners
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
Figure 3: Reported sexual risk factors were: Sex with a
drug user (30.3%), Multiple sexual partners > 10 partners (28.9%), Sex with an HCV infected partner (9.0%),
and Homosexual (8.3).
18
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
The majority of the patients with higher
risk practices such as IDU, had an increased number of sexual partners as compared to those nonIDU (see Figure 2). These results reach significance by chi-square correlation, and indicate that IDU
were probably more prone to develop high risk
sexual practices than non-IDU.
Data analysis of those patients with illegal
drug use (IDU), indicate that they usually started
having sex at a younger age (15.54 y/o) than those
non-IDU (18.86 y/o p= .015) (see Figure 2). The
IDU and non-IDU groups differ in the rate of homosexual activity (10.8% vs. 1.5% p<.001), and
having sex with a drug user (47.8% vs. 11.3%
p<.001). However, there was no significant difference among those IDU’s having sex with an HCV
infected partner (6.9% vs. 6.5%) p>.05, and (see
Figure 4). Those patients who reported having sex
with an HCV infected partner as a risk factor and
were non-IDU, had more stable sexual practice
(1-2 partners) than those with IDU (>20 partners)
p< .001 (see Figure 5).
Patients with partners of the same sex had
a significant lower mean age for the first sexual intercourse (14.6 y/o) than other studied subpopulations (p<.01). Furthermore, they had a higher risk
sexual profile, including multiple sexual partners
(>20 partners- 41.4%), and a higher frequency of
sex with IVDU (62.1%). A low prevalence of having known sexual partners with HCV (6.9%) as a
risk factor.
c. Genotypes
The most common genotype was 1
(82%). When a correlation between genotype
and sexual risk factors, was done only those
with multiple sexual partners (p=0.049), and
sex with an infected partner (p=0.018) reached
statistical significance. After readjustment for
age, gender and risk factors, no significant
association was found between genotype and
sexual variables.
d. Viral load
The mean viral load in subjects practicing
sex with an infected partner was found to be higher
(13 million IU/ml) than in those without this risk
factor (3.9 million IU/ml), but when variance was
considered, the statistical significance was lost
(from p.001 to p>0.05).
No significant differences was found in
the viral load of IVDU and the non-IVDU group
in relation to having sex with an infected partner
(p>0.05).
DISCUSSION
Data from recent studies supports sexual
transmission as a common risk factor for HCV
transmission (13). Although the risk of transmission through sexual contact appears to be low,
high-risk sexual practices are a common behavior
and may contribute to the total burden of this disease.
There are differences among HCV sexual
transmission rate from country to country. This variability may be in some way related to cultural
and local sexual practices. Therefore, the precise
rate of transmission may vary depending on the
group of subjects studied, and it is characteristics,
the laboratory techniques used and/or study design
limitations. Data of sexual transmission in sexual
couples infected with hepatitis C range from 0 to
24%, with an estimated rate of transmission for
Figure 4: Differences between sexual risk factors and
Illegal drug use (IDU)
Figure 5: Patients having sex with an infected HCV
partner
Sexual Risk Factors and
Use of Illicit Drugs
Sex with an HCV infected partner
60
p<.001
40
30
p<.001
20
Users
Non-user
p>0.05
10
0
Percent
Percent (%)
50
80
70
60
50
40
30
20
10
0
Non-user
Users
1 to 2
N= 29
Homosexual
N= 34
Sex HCV+
Sexual Risk Factors
N = 34
Sex IDU
3 to 5
6 to 9
10 to 19
Number of Sexual Partners
>20
N=32
Spearman correlation p<.001
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BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
monogamous heterosexual couples in USA between 2.0 to 4.8% described at USA (13).
Our study reveals similar findings to available published data in regard to sexual and parenteral risk factors. General non-sexual risk factors
related to HCV transmission in our population
were similar to worldwide reports, in which illicit
drug use (46.8%) and blood transfusions (30.2%)
were the most common parenteral mode of HCV
transmission. As expected, the parenteral route
still represents the most common risk factor for infection with HCV in this Hispanic subpopulation.
There have been several known sexual
factors highlighted over years which are related to
high-risk sexual practices including sex with professional sex workers (prostitutes), multiple sexual
partners, promiscuous homosexual men, STD and
sex with an infected HCV individual among others
(13).
After studying reported sexual factors for
transmissions among our study subjects, we found
several variables that may promote HCV transmission. These variables were: sex with an infected
individual, promiscuous homosexual practice,
multiple sexual partners and sex with an IDU. We
found that those patients having same sex partners
appeared to have a high risk sexual profile with
more number of sexual partners >20(40.4%), early
sexual experiences (14.6 y/o) and more likely to
had sex with a drug user.
An important variable that appears to enhance high risk sexual behavior in these subjects
was the use of illicit drugs. Those individuals
with IDU experienced more premature sexual encounters, had more sexual partners, more sexual
encounters with an infected individual, and were
more prone to engage in promiscuous homosexual
activity, not only increasing their risk of getting
infected by parental route, but also by sexual activity when compared with other patients. Therefore, the role of sexual transmission among patients
with hepatitis C and active illegal drug use cannot
be clearly separated; making it difficult to clearly
determine the risk of getting sexually infected in
this group of patients.
High hepatitis C viral titers have been implicated with an enhanced mother to infant transmission as well as increased men to female rate
of transmission (men-female ratio 3 times higher),
nevertheless in our study no correlation was found
between sexual transmission and hepatitis C viral
titers. In this study the differences in values failed
to reach statistical significance after variance was
considered. In the same way, there was no relationship between the risk of getting infected by sexual
contact and the hepatitis C genotypes.
After excluding potential parenteral
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
19
routes of HCV transmission such as blood transfusions, IDU’s, needle injuries, tattooing, and other,
sexual transmission for HCV patients in our population was 6.5%. This is similar with existing data
from CDC, in which risk of getting infected by
sex is estimated between 2 to 4% using complex
analysis of hepatitis C genetic sequence.
Our study has some limitations, since we
used information provided by the subjects based on
a questionnaire, and may be probably overestimating the risk of sexual transmission. Other limitations include the study design (cross-section study,
questionnaire-based), failure to characterize antiHCV concordant couple infection, and to exclude specific co-variables that enhance transmission
(STD’s). Although less important, the fact of an
unequal distribution of recruited patients (49.8%
from metropolitan area) is also a limitation.
Despite these limitations, the study is the
first of its kind in Puerto Rico in which sexual factors in HCV transmission are studied. Therefore, it
may provide valuable information for the design
and development of additional studies. Our study
suggests that although the incidence of transmission appears to be low, HCV may be acquired from
an infected individual by sexual contact. It appears
that high-risk sexual practices such as multiple
sexual partners, sex with an infected partner and
sex with a drug user may predispose to HCV transmission.
Current recommendations regarding
sexual contact provided on the last consensus review for HCV (2002), suggest that long-term monogamous relationships need not to change their
sexual practices, but couples may reduce risk of
transmission by considering barrier methods (15).
Barrier methods or abstinence should be recommended for HCV-infected patient with multiple or
short term sexual partners, and for couples engaged on sexual practices that might traumatize genital mucosa.
Sex partners or patients enrolled on high
risk sexual practices should use barriers methods or
abstinence as a preventive tool. Health care providers should strongly recommend serology analysis
for HCV among patients having sex with infected
individuals. Even though sexual behavior appears
to play an important role for HCV transmission in
our population, the parenteral route continues to be
the most common risk factor. Additional studies
will need to use special genetic analysis to precisely confirm viral transmission by sexual contact.
REFERENCES
1.
Alter, M. Epidemiology of Hepatitis C. Hepatology
1997; 26(3),S1:634
2.
Alter, M. Prevention of Spread of Hepatitis C. Hepatology Nov 2002: S93
20
3.
Boonyarad V, Chutaputti A, et al. Interspousal transmission of hepatitis C in Thailand. J Gastroenterol. Jan 2003;
38(11):1053-9
4.
Dienstag, J. Sexual and Perinatal Transmission of Hepatitis C. Hepatology 1997;26(3):S166.
5.
Briggs M, Baker C, Hall R, et al. Prevalence and Risk
Factors for Hepatitis C Virus Infection at an Urban Veterans Administration Medical Center. Hepatology 2001;34(6):1200-5
6.
Caporaso N. Spread of Hepatitis C virus infection within
families. Journal of Viral Hepatitis 1998;5:67-72.
7.
Consensus Development Panel. National Institutes of
Health Consensus Development Conference Statement: Management of Hepatitis C: 2002-June 10-12, 2002. Hepatology
2003;36:S3-S20.
8.
Leruez-Ville M, Kunstmann J, et al. Detection of Hepatitis C virus in the Semen of Infected Men. The Lancet 2000;356:42
9.
Kao JH, Liu CJ, Chen W, Lai MY, Chen DS. Low incidence of hepatitis C
virus transmission between spouses: a prospective study. J Gastroenterol Hepatol 2000;15:391-395.
10.
Vandelli C, Renzo F, Romano L, et al. Lack of evidence
of sexual transmission of hepatitis C among monogamous couples:
Results of a 10-year prospective follow-up study. Am J Gastroenterol. 2004;99: 855-9.
11.
Marincovich B, Castilla J, del Romero J, et al. Absence
of hepatitis C virus in a prospective cohort of heterosexual serodiscordant couples. Sex Transm Infect. 2003; 79(2):160.
12.
Stroffolini T, Lorenzoni U, et al. Hepatitis C virus
infection in spouses: sexual transmission or common exposure to the
same risk factors? Am J Gastroenterol. 2001;96(11):3138-41.
13.
Terrault N. Sexual activity as a risk factor for hepatitis C.
Hepatology 2002;36: S99-105
14.
Bollepalli S, Mathieson K, Jasiurkowski B et al. A
comparison of risk factors for HCV-mono-infection, HIV-monoinfection, and HCV/HIV-co-infection in a community setting. Dig
Dis Sci. 2008 Feb;53(2):517-21.
15.
Workowski K, Levine W, et al. Sexually Transmitted Diseases Treatment Guidelines 2002. Morbidity and Mortality weekly
Report. CDC. May 2002; 51(6).
RESUMEN
La hepatitis C es una infección del torrente sanguíneo que afecta a millones de personas en el mundo.
A pesar de que el uso intravenoso de substancias
ilícitas (USI) y las transfusiones de sangre han sido
claramente definidas como factores de contagio, el
papel de la transmisión sexual todavía no esta claramente definida. PROPÓSITO: Definir el papel
de la transmisión sexual entre pacientes puertorriqueños infectados con hepatitis C, y determinar si
hay una asociación entre factores de riesgo sexual,
no-sexual, genotipo y la carga viral. MÉTODOS:
Se realizo un estudio transversal aprobado por el
comité de investigación entre pacientes con hepatitis C durante el periodo de Noviembre del 2001 a
Mayo del 2002. La Asociación de Gastroenterología de Puerto Rico auspicio este estudio. Quinientos (500) pacientes completaron un cuestionario de
factores de riesgos a través de diversas regiones
de Puerto Rico. Se tomaron muestras de sangre
para determinar el genotipo y la carga viral de los
sujetos. RESULTADOS: Se encontró una predominancia de pacientes masculinos (M=68%). La
mayoría de los pacientes (80%) se encontraban entre las edades de 45-65 años de edad. El genotipo
de hepatitis C mas común lo fue el tipo 1 (82%).
Los factores sexuales reportados fueron: sexo con
un usuario de drogas (30.3%), múltiples parejas
sexuales (>10) (28.9%), sexo con un paciente infectado con hepatitis C (9.0%), y homosexualidad
(8.3%). Los factores mas comunes no-sexuales
fueron: transfusiones de sangre (30.2%) y uso de
sustancias ilícitas (46.8%).
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
Los sujetos con uso de sustancias ilícitas (USI) reportaron un contacto sexual a una edad mas temprana (15.5 años), que los no-usuarios de drogas
(18.9 años) p=0.015. Aquellos con uso de sustancias ilícitas reportaron una frecuencia mas alta de
homosexualidad (10.8% vs. 1.5%) p<.0001, así
como tener contacto sexual con una pareja con
USI (47.8% vs. 11.3%) p<.0001 en comparación
con los no usuarios. Aquellos sujetos que reportaron sexo con un paciente portador de la hepatitis C y fueron no usuarios de sustancias ilícitas
tuvieron un menor numero de parejas sexuales en
comparación con los usuarios de drogas (1-2 vs.
>20 parejos) p< .001. Como grupo los sujetos
con contacto homosexual, tuvieron sexo a una
edad mas temprana, un mayor número de parejos
sexuales (>20) y una proporción mas alta de sexo
con usuarios de drogas. Después de ajustar para la
edad, género, y factores sexuales, no se encontró
una asociación estadísticamente significativa entre
los genotipos de hepatitis C y los factores sexuales. No hubo una significancia estadístico entre
los grupos estudiados y la carga viral de la hepatitis C. CONCLUSIÓN: La información recopilada
en nuestro estudio sustenta el principio de que los
factores sexuales son muy comunes en los pacientes infectados con hepatitis C. Los factores de alto
riesgo como contacto sexual a una edad temprana,
homosexualidad, y múltiples parejas sexuales son
comunes en estos pacientes. El papel de la transmisión sexual por tanto es muy difícil de definir en
este grupo de pacientes. No se estableció ninguna relación significativa entre los genotipos, carga viral y transmisión sexual para la hepatitis C.
Los pacientes con uso de substancias ilícitas (USI)
demostraron una diferencia significativa contra
los no usuarios en relación a la edad del primer
contacto sexual, el número de parejas sexuales,
y la práctica de sexo con usuarios de drogas ilícitas o parejas del mismo sexo. Cuanto excluimos la
transmisión parenteral en este estudio, se encontró
que solamente el 6.5% de los sujetos reportaron el
factor sexual como único mecanismo para contraer
la enfermedad.
Tres obras de
incalculable
valor
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21
Review Articles - Artículos de Repaso
METHICILLIN-RESISTANT STAPHYLOCCOCUS
AUREUS IN THE COMMUNITY
Rosana Amador-Miranda, MD *; Jorge Bertrán-Pasarell, MD *,
Michelle González, MD *, Ana Conde, MD *
ABSTRACT
Methicillin-resistant Staphylococcus aureus (MRSA) has become a major nosocomial
pathogen worldwide since the 1960’s. For decades the bacteria was almost exclusively associated with healthcare settings. However, community
outbreaks have emerged in the 1990’s and since
then the prevalence of MRSA infections is rapidly
increasing in the community.
Community-acquired MRSA (CA-MRSA) differs from healthcare-associated MRSA
(HA-MRSA) in terms of its epidemiological, clinical, and bacteriological characteristics. Reports
of outbreaks caused by CA-MRSA are usually
related to “closed populations”. Most outbreaks
have been linked with a single-clone strain and
affected individuals are otherwise healthy with no
known risk factors for acquisition of the bacteria.
The spectrum of disease caused by CA-MRSA has
changed in recent years and new syndromes vary
from minor skin and soft tissue infections to rapidly overwhelming and often fatal infections. Also,
CA-MRSA differs from the nosocomial strain regarding the bacteriologic characteristics which include different antimicrobial susceptibility profiles
and the presence of certain virulence factors and
exotoxins.
Because CA-MRSA is generally not multidrug resistant, good therapeutic options are still
available. To provide an effective therapy is necessary to first have the clinical suspicion. Therefore,
physicians should be aware of the clinical and epidemiological characteristics of this emergin infection in the community.
Key Words: Community-Acquired Methicillin Resistant Staphyloccocus aureus (CA-MRSA), Panton -Valentine Leukocidin (PVL).
INTRODUCTION
Methicillin-resistant Staphylococcus aureus (MRSA), also known as oxacillin-resistant
Staphylococcus aureus (ORSA), has become a
major nosocomial pathogen worldwide since it
first appeared in 1961 (1). In the United States
most hospitals report that up to 60% of Staphylococcus aureus are resistant to methicillin (2).For
decades MRSA was almost exclusively associated
with healthcare settings. However community outbreaks of MRSA, the first one reported in 1980,
have emerged in the 1990’s and since then the prevalence of MRSA infections is rapidly increasing
in the community.
Reports of outbreaks caused by community-acquired MRSA (CA-MRSA) continue to appear
around the world, mostly in “closed populations”
such as military facilities, athletic teams, prisons,
IV drug users, and Native Americans (1). Most
outbreaks have been linked with a single-clone
strain and, of concern is that affected individuals
are otherwise healthy with no known risk factors
for MRSA acquisition (3). Thus far, populations
at risk for CA-MRSA include children in daycare
centers, soldiers, prisoners, homeless persons, IV
drug users, and men who have sex with men (see
Table 1) (1, 4). Several factors have been identified as probable contributors to infection outbreaks
such as poor hygiene, crowding, and sharing infected equipment or clothing. Although the anterior
nares are the primary reservoir of Staphylococcus
aureus, individuals may be colonized at other body
sites (eg, throat, skin, axilla, and perineum). Nasal
colonization of MRSA has been identified as a risk
factor for infection in healthcare settings; however
more data are needed to establish the association
between MRSA colonization and infection in the
community (4).
Table 1: Risk Factors for CA-MRSA infection
Athletes (particularly contact sports)
Soldiers
Prisons inmates
Day-care center contacts of hospitalized patients with MRSA
infections
Children
Household contacts of a patient with proven CA-MRSA infection
Intravenous drug users
Native AmericansPacific Islanders
Men who have sex with men
Adapted from: Daum RS. N Engl J Med 2007; 357: 380-390.
* From the Department of Internal Medicine, Infectious Diseases Program, UPR School of Medicine, San Juan, PR.
Address reprints to: Jorge Bertran-Pasarell MD - Director, Infectious Diseases Program, University of Puerto Rico school of Medicine, P.O. Box
365067, San Juan, PR 00936-5067. E-mail <[email protected]>
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The incidence and prevalence of CA-MRSA is difficult to establish due to the lack of accepted criteria that define “community-acquired”.
Interestingly, CA-MRSA differs from healthcareassociated MRSA (HA-MRSA) in terms of its epidemiological, clinical, and bacteriological characteristics (see Table 2).
The most frequent clinical manifestations include
skin and soft tissue infections, specifically furuncles (“boils”), carbuncles (coalesced masses of
furuncles), and abscesses (Figure 1) (4).
Table 2: Differences between CA-MRSA and HAMRSA
Characteristic
CA-MRSA
HA-MRSA
Clinical presentation
Respiratory tract,
Skin and soft tissue urinary tract, and
bloodstream infections
infections
Epidemiology
Outbreaks in closed Outbreaks
in
populations
healthcare cenFew clones
ters Polyclonal
Age
Younger
Older
Non-white
White
Race/ethnicity
Antibiotic
ceptibility
sus- Multiple classes of Few classes of
antibiotics
antibiotics
Genotypic cha- SCCmec type IV
racteristics
PVL present
SCCmec type I,
II, III
PVL absent
Adapted from: Diederen, Klutmans. J Ifect. 2006;52:157168.
Figure 1 - Left thigh abscess and associated cellulitis caused by CA- MRSA.
These infections may present as mild and superficial but, in some cases, may produce deeper softtissue abscesses requiring surgical incision and
drainage in conjunction with intravenous antibiotic therapy (Figure 2).
Most authorities agree that CA-MRSA refers to
an MRSA infection with onset in the community
in an individual with no established MRSA risk
factors (5). The CDC Active Bacterial Core Surveillance Program defined a “CA-MRSA case” as
a patient with an MRSA infection and no history
of recent hospitalization nor surgery, residence in
a long-term care institution within the year of infection, dialysis within the previous year, presence invasive medical devices, hospitalization > 48
hours before MRSA culture, nor previous MRSA
infection or colonization. Factors that should guide physicians to suspect CA-MRSA are listed in
Table 3.
Table 3: When to suspect CA-MRSA?
- previously healthy
- young
- no recent hospital or healthcare exposure
- primary skin infections (furuncles, impe
tigo, abscesses, or cellulitis)
- ethnic minority
- low socioeconomic status
Adapted from: Eady, Cove. Curr Opin Infect Dis. 2003; 16:103-124.
As opposed to HA-MRSA, the spectrum
of disease caused by CA-MRSA has changed in recent years. New syndromes are appearing that vary
from minor skin infections to rapidly overwhelming and fatal infections.
Figure 2 - Extensive tissue destruction caused by
CA-MRSA, on upper back. Courtesy of Dr. Sonia
Saavedra
Skin infections with a necrotizing center are increasingly seen in emergency departments and are
commonly confused with spider bites by both patients and clinicians in U.S. centers (6). Less frequently, CA-MRSA has been associated with severe and invasive infections, many of which can be
fatal. These include necrotizing pneumonia, sepsis
syndrome, meningitis, pyomyositis and osteomyelitis, necrotizing fasciitis, and disseminated infecVol.: 100 - Núm 3 - Julio-Setiembre 2008
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
tions with septic emboli (4, 6). A recently recognized presentation is the pelvic syndrome in children, which consists of septic arthritis of the hips,
pelvic osteomyelitis, pelvic abscesses, and septic
pelvic-vein thrombophlebitis (6). This syndrome
is associated with high rates of morbidity and mortality.
In addition to the clinical characteristics,
CA-MRSA strains differ from HA-MRSA in the
bacteriologic characteristics, which include genetic elements, antimicrobial susceptibility profiles,
and the presence of certain virulence factors and
exotoxins. Studies on genetic typing and susceptibility testing confirm that CA-MRSA strains are
genetically and phenotypically different from HAMRSA (1). These differences are in part attributable to a different type of the gene complex known
as the staphylococcal cassette chromosome mec
type IV (SCCmec type IV), which contains the
methicillin-resistant gene. In contrast to HA-MRSA isolates, which are typically resistant to multiple classes of antimicrobial agents, the majority
of CA-MRSA isolates show susceptibility to most
antibiotics other than beta-lactams (the antibiotic
class that includes penicillins and cephalosporins)
(4). CA-MRSA strains also posses specific virulence factors that may enhance the ability to initiate
infection in intact skin, directly cause lesions, and
facilitate local spread. Of particular importance is
the gene that codes for Panton-Valentine leukocidin (PVL), which is a potent toxin that lyses leukocytes and mediates tissue necrosis. PVL is rarely
found in HA-MRSA, but is commonly present in
the USA300 strain, which appears to cause the majority of CA-MRSA cases in the United States (2).
PVL-positive strains are highly virulent and have
been associated with necrotic skin lesions and severe necrotizing pneumonia in both children and
adults (7, 8).
Because CA-MRSA is generally not multidrug resistant, good therapeutic options are still
available. Most strains remain susceptible to more
classes of antibiotics (eg, clindamycin, fluoroquinolones, tetracyclines, and trimethoprim-sulfamethoxazole) than the nosocomial strain. These
antimicrobial agents have been used for empiric
treatment of skin and soft tissue infections associated to CA-MRSA; however controlled trials
are still needed to determine optimal therapy. The
importance of incision and drainage of focal purulent lesions as part of the management has been
clearly established (9). In fact, it may be sufficient
in otherwise healthy patients who present with
cutaneous abscesses and no systemic manifestations of infection (4). Serious or fulminant infections should be treated with intravenous antibiotics known to be effective against HA-MRSA (eg,
vancomycin, linezolid, daptomycin, tygecycline).
CA-MRSA and HA-MRSA infections have been
well established. Physicians, in general, should be
aware of these differences since they warrant different preventive and therapeutic strategies.
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
23
REFERENCES
1. Fowler, VG. The changing epidemiology of MRSA-from hospital
to community. MRSA Update newsletter. Spring 2006, Vol. 2 Issue
1.
2. Barlett, J. Evolving epidemiology of MRSA. MRSA: The pharmacologic basis for selecting appropriate therapy. Monograph from
experts meeting during the 44th Annual Meeting of the IDSA in Toronto. Oct.12, 2006.
3. Rybak, MJ, et al: Community associated methicillin-resistant Staphylococcus aureus: a review. Pharmacotherapy. 2005; 25(1):74-85.
4. Gorwitz, RJ, Jernigan DB, Powers JH, Jernigan JA, and participants
in the CDC-convened experts’ meeting on management of MRSA in
the community. Strategies for clinical management of MRSA in the
community: Summary of an experts’ meeting convened by the Center
for Disease Control and Prevention. March 2006.
5. Fridkin SK, et al. Methicillin-resistant Staphylococcus aureus disease in three communities. N Engl J Med. April 2005; 352(14):14361444.
6. Moellering RC. Rationale for New Treatments for MRSA. From
the monograph “Confronting MRSA: What’s on the horizon?” based on a symposium held September 27, 2006 during the American
Society for Microbiology’s 46th Annual ICAAC, in San Francisco,
California.
7. Pankey, GA. Resistance trends and MRSA pneumonia. MRSA Update newsletter June 2006. Volume 2, Issue 2.
8. Lina G, et al. Involvement of Panton-Valentine leukocidin producing Staphylococcus aureus in primary skin infections and pneumonia. Clin Infect Dis 1999; 29:1128-1132.
9. Ruhe JJ, et al. Community-onset methicillin-resistant Staphylococcus aureus skin and soft tissue infections: impact of antimicrobial
therapy on outcome. Clin Infect Dis 2007; 44:777-784.
10. Daum, R.S. Skin and Soft-Tissue Infections Caused by Methicillin-Resistant Staphylococcus aureus. N Engl J Med 2007;357; 380390.
11. Mongkolrattanothai K, et al. Severe Staphylococcus aureus infections caused by clonally related community-acquired methicillinsusceptible and methicillin-resistant isolates. Clin Infect Dis 2003;
37: 1050-1058.
RESUMEN
La bacteria Staphylococcus aureus resistente a meticilina (MRSA) se ha convertido en un
patógeno nosocomial de gran importancia a nivel
mundial desde los 1960’s. Por décadas, el MRSA
ha estado asociado exclusivamente al ambiente de
hospital o nosocomial. Sin embargo, han surgido
brotes de infecciones por cepas de MRSA adquiridas en la comunidad durante los 1990’s y desde
entonces la prevalencia ha ido en aumento.
Existen diferencias importantes entre el
MRSA adquirido en la comunidad (CA-MRSA)
y las cepas de hospital (HA-MRSA) con respecto a las características epidemiológicas, clínicas y
bacteriológicas. Muchos de los brotes que se han
reportado en la comunidad ocurren en poblaciones
o grupos cerrados, se asocian a una sóla cepa, y
los individuos afectados son usualmente saludables, sin factores de riesgo aparentes para adquirir la bacteria. Las manifestaciones clínicas varían
desde infecciones leves en la piel y sus estructuras
asociadas hasta el desarrollo de infecciones diseminadas y fatales. CA-MRSA también se diferencia de las cepas nosocomiales en los perfiles de
susceptibilidad a antibióticos y la presencia de
ciertos factores de virulencia y exotoxinas.
Al presente, hay varias alternativas terapéuticas en el manejo de las infecciones por
CA-MRSA. Para proveer un tratamiento efectivo
primero debemos tener la sospecha clínica. Por
consiguiente, los profesionales de la salud debemos estar alerta y conocer las características clínicas y epidemiologícas relacionadas a esta infección emergente en la comunidad.
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
25
CONTRAST ASSOCIATED NEPHROPATHY
IN THE ELDERLY
Félix Carrillo-Alvira, MD*, Carlos G Rivera-Bermúdez, ** Ivonne Z.
Jiménez-Velázquez, MD, FACP*, Cristina Ramos-Romey, MD*, Juan J.
González-Concepción, MD*.
ABSTRACT
Contrast medium studies have become an
important tool for management and diagnosis in
many medical specialties. As we age, the need for
such studies increase in presence of multiple comorbidities as coronary artery disease and diabetes
mellitus. Nephropathy induced by iodine contrast
medium is an important complication of radiological procedures, most common in the aged, and
a potentially preventable one. For this reason, the
understanding and prevention of contrast associated nephropathy is of prime importance to prevent
morbidity and mortality in the geriatric population.
Key Words: contrast nephropathy, elderly, renal
failure.
INTRODUCTION
Aging goes beyond wrinkles, dry skin
or gray hair. It is a complex process where the
function of every single organ is affected. Kidney
function declines after age 40 at a mean rate of
approximately 1% per year, with the rate of decline accelerating in the later years. Glomerular
filtration rate (GFR) declines as a consequence of
a decrease in kidney size and renal blood flow and
a decrease in functioning nephrons (1). These age
related alterations and tendency for co-morbidities
and polypharmacy in the elderly population, predisposes them to the nephrotoxic effects of contrast agents.
Contrast induced nephropathy (CIN) is a
recognized complication after coronary angiography and intervention, and has been associated with
prolonged hospitalization and adverse clinical
outcomes (2). Contrast media accounts for 10% of
all causes of in-hospital acquired renal failure (3).
Risk factors are older age, Diabetes Mellitus, preexisting renal dysfunction, diabetic nephropathy,
and decreased effective circulating volume, concurrent use of nephrotoxic drugs, dehydration, and
large contrast volume (4). The reported incidence
of radio-contrast induced nephropathy varies widely, ranging from zero to over 50 percent (5).
Nephropathy induced by iodine contrast
medium is an important complication of radiological procedures and a potentially preventable one.
CIN is most commonly defined as an acute impairment of renal function manifested by an absolute increase in the serum creatinine of at least 0.5
mg per deciliter (44.2umol per liter) or by relative increase of at least >25 percent from base-line
value (6). Clinically, patients with CIN typically
present with an acute rise in serum creatinine 24 to
48 hours after contrast study. The serum creatinine
usually peaks three to 5 days after the onset of renal
failure and returns to baseline within 7 to 10 days
(7). Although the renal failure is often non-oliguric, oliguria may be seen. In patients with normal
base line renal function the risk is negligible. The
presence of renal insufficiency in a diabetic patient
results in a dramatic rise of the incidence of CIN
as high as 10 to 40%. Advanced renal insufficiency
is the worst clinical scenario for CIN since 50% or
more of the patients develop the syndrome (8).
The kidney is the main route of elimination of Iodinated Contrast Media (ICM), with less
than 1% excreted extra-renal. The elimination
half-life following intra-vascular administration in
patients with normal renal function is approximately 2 hours, and 75% of the administered dose is
excreted in the urine within 4 hours. In patients
with renal impairment and reduced GFR the excretion of ICM is prolonged and can last for several
weeks (9). Alterations in renal hemodynamics and
direct tubular toxicity (secondary to increase of
renal free-radical production (10) are considered
the primary factor in the pathogenesis of contrastmedia associated nephropathy (11). It has been
speculated that such renal failure occurs because
of the vulnerability of the renal medullary circulation to stimuli that disrupt the balance between the
high metabolic needs of the tubular segments of
the renal medulla and their hypoxic environment
(12). This balance is normally maintained by the
interplay between vasodilators and vasoconstrictor
influences, mediated by the activity of nitric oxide,
prostaglandin, and endothelin systems within the
medulla (2).
The introduction of the contrast media into
the vascular system causes water from the body
tissue (cells) to move into the vascular system in
an attempt to equalize concentration (osmosis).
The blood vessels dilate in an attempt to compensate from the increased fluid volume.
*From the Internal Medicine Department, Geriatric Medicine Program, and the **Internal Medicine Department, Nephrology Section**, University
of Puerto Rico, Medical Sciences Campus, San Juan, PR.
Address reprints to: Ivonne Z. Jiménez-Velázquez, MD, FACP, Department of Medicine, Geriatric Medicine Program, PO Box 00936-5067, San
Juan, PR 00936-5067. Fax 787-754-1739, e-mail: < [email protected]>.
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
26
Sometimes the fluid shift may be too dramatic for
the vessels to handle and the fluid actually extravasates into the surrounding tissue. The rapid fluid
movement, especially water, throughout the vascular system is believed to contribute to pain associated with vessel dilation, flushing, and damage to the vascular endothelium, red cell changes,
nausea, vomiting and dehydration. The osmotic
effect can cause the arteries of the kidneys to expand. When they enlarge, vasoconstrictors are released to compensate for the artery expansion. The
vasoconstrictors compress the arteries resulting in
a rapid opening and closing action of those blood
vessels. The result of this action is a diminished
blood supply to the kidney which can lead to total
shut down of the kidneys (12).
When contrast agents are indicated, risks
vs. benefits should always be considered in older
patients and/or high-risk patients. There are three
generations of contrast agents, the earliest being
non-ionic hyperosmolar agents with high incidence of CIN. The most recent agents are isosmolar
dimeric, non ionic iodinated contrast agent which
have resulted in significantly fewer nephrotoxic
effect in high risk patient undergoing arteriography
when compare with the two previous generations
of contrast agents (13). There have been many attempts for prevention of contrast media associated
nephropathy without any remarkable results, and
protocols for prevention vary from institution to
institution. Studies have been performed using dopamine (14), mannitol (15), furosemide (15), atrial
natriuretic peptide (16), mixed endothelium antagonist and calcium channel blockers with adverse
effects or no benefit. Only intravenous hydration
with saline has been shown repeatedly to provide
effective and safe prophylaxis for CIN in patients
undergoing percutaneous coronary intervention
(PCI) (17).
Many studies have evaluated the administration of acetylcysteine (N-AC) as a preventive
measure for CIN since many studies have reported
a risk reduction for CIN of up to 50% (2). N-AC
has been found to reduce free radicals, increase
the expression of nitric oxide synthetase (thus improving blood flow) and to promote pathways that
lead to repair and survival whenever cells are under
oxidant stress. However, other studies including
prospective trials and evaluation of the data in several meta-analyses have reported less substantial
and even non-significant results (18-22). Although
the results are conflicting, recent studies suggest a
dose-dependent effect of N-AC, suggesting that a
higher dose could be needed in high-risk patients
(17).
One of the most recent strategies to prevent CIN is the use of rapid hydration with sodium
bicarbonate and high dose of N-AC for emergency
PCI. The rational for bicarbonate use is based on
the fact that an acidic environment promotes free
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
radical formation, and hydration with bicarbonate
should be more effective. It is also postulated that
rapid bicarbonate infusion, with subsequent volume expansion, could stimulate diuresis, diluting
contrast medium and preventing tubuloglomerular
feedback. It is important to note that the incidence
of pulmonary edema in patients treated with bicarbonate was similar to that of patients treated with
normal saline and N-AC (17). Recent studies have
found that the combination of sodium bicarbonate and N-AC is more effective in preventing CIN
than treatment N-AC with normal saline and saline
infusion alone (17, 24).
Although, CIN usually is self limited and
is most of the time a reversible form of acute renal
failure, renal function and potentially nephrotoxic
medications should be evaluated prior to any contrast study in geriatric patients and other high risk
populations (25). The administration of oral N-AC
as a preventive measure for CIN for high-risk patients has been challenged by recent evidence, but
still there is a potential benefit especially in view
of the low cost and low toxicity associated with its
use. Adequate hydration with isotonic fluids, the
use of isosmolar contrast agents and lower doses
of contrast should be used as standard preventive
measures. Recent studies have shown a superior
renoprotective effect of bicarbonate therapy over
normal saline and N-AC. There is still much debate and ongoing research to determine the most
effective strategy to prevent CIN. Nevertheless,
opportunities for positive impact are present if
high-risk patients are identified and institutional
protocols established which will improve patient
care; reduce hospital stay, hospital costs and reduction of morbidity and mortality.
REFERENCES
1. Pompei P, Murphy J, eds. Geriatrics Review Syllabus: A Core Curriculum in Geriatrics Medicine, 6th Edition, New York: American
Geriatrics Society, 2006.
2. Kay Jay, Wing Hing, Tak Mao Chan, Sin Kai Lo. Acetylcysteine for
Prevention of Acute Deterioration of Renal Function Following Elective Coronary Angiography and Intervention. JAMA 2003, 289:553558.
3. Briguori C, Airoldi F, et al. Renal Insufficiency Following Contrast Media Administration Trial (REMEDIAL). Circulation,
2007;115:1211-1217.
4. Solomon R, Natarajan M, Doucet S. Cardiac angiography in renal
impaired patients (CARE Study). Circulation, 2007;115:3189-3196.
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
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5. Rudnick MR, Kesselheim A, Goldfarb S. Contrast-induced nephropathy: how it develops, how to prevent it. Cleve Clin J Med.
2006 Jan;73(1):75-80, 83-7.
6. Aspelin P, Pierre A, Fransson S, Strasser R. Nephrotoxic Effect in
High Risk Patients Undergoing Angiography. New Engl J Med 2003;
348:491-499 F.
7. Palevsky P. Acute Renal Failure. Nephrology Self-Assessment Program, 2003;Vol 2, No. 2.
8. Parfrey PS; Griffiths SM; Barrett BJ; et al. Contrast material-induced renal failure in patients with diabetes mellitus, renal insufficiency, or both. A prospective controlled study. N Engl J Med 1989;
320(3):143-9.
9. Morcos S, Thomsen H. Adverse reaction to iodinated contrast media. Eur Radiol, Vol 11 1267-1257.
10. Barkis GL, Lass N, Gabber AO, Jones JD, Burnett JC Jr. Radiocontrast medium-induced declines in renal function: a role for oxygen
free radicals. Am J Physiol, 1990; 258:F115-F120.
11. Mueller C, Buerkle G, Buettner H. Prevention of Contrast MediaAssociated Nephropathy. Arch Intern Med, 2002; Vol 162.
12. Brezis M, Rosen S. Hypoxia of the renal medulla—its implications for disease. N Engl J Med 1995;332:647-655.
13. Sandler M. Carl. Contrast Agents Induced Acute Renal Failure
Dysfunction-Is Iodixanol the Answer? N Engl J Med, 2003;348:551553.
14. Abizaid AS, Clark CE, Mintz GS, et al. Effects of dopamine and
aminophilline on contrast-induced acute renal failure after coronary
angioplasty in patients with preexisting renal insufficiency. Am J Cardiol, 1999;83:260-263.
15. Solomon R, Werner C, Mann D, D’Elia J, Silva P. Effect of saline,
mannitol and furosemide to prevent acute decrease in renal function
induced by radiocontrast agents. N Engl J Med, 1994;331:14161420.
16. Kurnik BR, Allgren RL, Genter FC, et al. Prospective study of
atrial natriuretic peptide for the prevention of radiocontrast-induce
nephropathy. Am J Kidney Dis 1998;31:674-680.
17. Recio-Mayoral A, et al. The reno-protective effect of Hydration with Sodium Bicarbonate Plus N-AC in Patients Undergoing
Emergency Percutaneous Coronary Intervention. J Am Coll Cardiol,
2007;49(12):1283-8.
18. Birck R, Krzossok S, Markowetz F, Schnulle P, van der Woude
FJ, Braun C. Acetylcysteine for prevention of contrast nephropathy:
meta-analysis. Lancet, 2003;362(9384):598-603.
19. Alonso A, Lau J, Jaber BL, Weintraub A, Sarnak MJ. Prevention
of radiocontrast nephropathy with N-acetylcysteine in patients with
chronic kidney disease: a meta-analysis of randomized, controlled
trials. Am J Kidney Dis, 2004;43(1):1-9.
20. Pannu N, Manns B, Lee H, Tonelli M. Systematic review of the
impact of N-acetylcysteine on contrast nephropathy. Kidney Int, 2004
Apr;65(4):1366-74.
21. Liu R, Nair D, Ix J, Moore DH, Bent S. N-acetylcysteine for the
prevention of contrast-induced nephropathy. A systematic review and
meta-analysis. J Gen Int Med, 2005;20(2):193-200.
22. Seyon Rajamalar RN, Jensen L, et al. Heart and Lung
2007;36(3).
23. Ozcsn E, Guneri S, et al. Sodium bicarbonate, N-AC, and saline for prevention of radiocontrast-induced nephropathy. Am Heart J,
2007;154:539-44.
24. Brendan J Barrett, M. B., and Patrick S Parfrey. Preventing Nephropathy by Contrast Medium. N Engl J Med, 2006;354:379-386.
25. Weisbord SD, Hartwig KC, Sonel AF, et al. The incidence of
clinically significant contrast-induced nephropathy following nonemergent coronary angiography. Catheter Cardiovasc Interv 2008
Jun 1;71(7):879-85.
PRESORT STANDARD
U.S. POSTAGE
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
10.500 Ejemplares
Gratuitos
RESUMEN
Los estudios de contraste se han convertido
en una herramienta importante para el diagnóstico
y manejo en muchas del las especialidades médicas. A medida que envejecemos, la necesidad de
estos estudios aumenta en presencia de múltiples
co-morbilidades como enfermedad coronariana y
diabetes melitus. La nefropatía inducida por medios de contraste es una importante complicación
de los procedimientos radiológicos, más común en
el adulto mayor y potencialmente prevenible. Por
esta razón, la comprensión y prevención de nefropatía asociada a contraste es de suma importancia
para la disminución de morbilidad y mortalidad en
la población geriátrica.
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
12.000 Ejemplares
Gratuitos
Informes:
Teléfono: (787) 721-6969 Fax: (787) 724-5208
Email:[email protected]
28
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
ASTHMA AMONG PUERTO RICANS
Sylvette Nazario, MD *
ABSTRACT
Puerto Ricans have one of the highest asthma prevalence, morbidity and mortality in the
world. Genetic, socioeconomic and environmental
factors have been hypothesized to account for these elevated figures. The article discusses published
articles on asthma among Puerto Ricans.
Index words: asthma, Puerto Ricans
Asthma demographics among Puerto Ricans
Puerto Ricans living in the USA present
consistently elevated asthma prevalence compared
to other racial and ethnic groups in USA. NHANES II reported that 11.26% of Puerto Rican children living in United States suffer from asthma, the
highest prevalence of physician diagnosed asthma
in the survey (1). Rose et al. using data from the
1998 through 2000 US National Health Interview
Surveys, analyzed asthma prevalence among US
adults. They found that unlike US adults who reported that 8.9% ever been diagnosed with asthma,
Puerto Ricans had 17.0% (2). MMWR reiterated in
2004, that 11.5% of Puerto Rican children living in
US suffered from asthma. According to the National Health Interview Service for 2005, among all
racial and ethnic groups, Puerto Ricans have the
highest rate of lifetime asthma (3). We were 95%
more likely than whites to have been diagnosed
with asthma; and had the highest current asthma
rates, 125% higher than non-Hispanic whites, and
80% higher than non-Hispanic blacks (4).
Asthma mortality is consistently elevated among
Puerto Ricans living in the United States as well.
MMWR reported that subjects living in the northeastern part of the USA, where a high proportion
of Puerto Ricans reside, had significantly higher
asthma mortality than other regions of the USA,
even after correcting for sex, age and race (3). According to the National Center for Health Statistics
from 1990 to 1995, Puerto Ricans had the highest
asthma mortality rate (40.9 per million) of all ethnic groups in the mainland United States (5). According to statistics from 2003-05, Puerto Ricans
were the most likely to die from asthma and had
asthma death rate 360% higher than non-Hispanic
white people (4). Puerto Ricans had 2.5 higher asthma mortality rate than in the United States from
1980-98, with 8.1 deaths per million inhabitants as
reported by the Puerto Rico Department of Health
statistics. (6).
Asthma prevalence rates among Puerto
Ricans living in the island are also elevated. Loyo
et al reported in a survey conducted among 1,467
elementary and 1,334 high school students in a
northern town in Puerto Rico that 46 and 24%
respectively suffered asthma (7). BRFSS in 2000
reported a lifetime asthma prevalence of 15.8%
among Puerto Ricans in the island and among those 39.86% still had asthma (8).
Asthma morbidity is elevated in the Puerto Rico. Perdomo et al reported that 46% of asthmatics had at least one visit to the emergency
department in the last year and 20% had at least
one hospitalization. Seven percent of children lost
2 school weeks for asthma per year (8).
Beside elevated prevalence, morbidity and
mortality, asthma among Puerto Ricans is more severe than other ethnic groups. Gonzalez-Bouchard
et al compared Puerto Rican and Mexican asthmatic 8-40 years of age and their parents. Puerto Ricans had higher asthma morbidity with 163% increased risk of emergency department visits, 94%
increased risk of hospitalizations for asthma and
7.3% less bronchodilator response in FEV1 than
Mexicans. Overall Puerto Rican asthmatics had a
more severe asthma when evaluating symptoms,
pulmonary function and morbidity (9).
Genetics
The high prevalence of asthma among
Puerto Ricans living in the island and in the United
States suggests a genetic component. Since Puerto
Ricans represent an admixture of three different
races (Spaniards, Black and indigenous) genetic
analysis has been complicated. Several genes related to inflammatory markers and bronchodilator
response has been studied among Puerto Ricans
including ADAM-33, endotoxin receptor, prostanoid DR receptor and beta agonist receptor polymorphisms (10-13).
Choudhry et al evaluated beta agonist receptor polymorphisms among a cohort of Puerto
* From the Division of Allergy and Immunology, UPR School of Medicine, Medical Science Campus, San Juan, PR.
Address reprint requests to: Sylvette Nazario MD, Director of the Division of Allergy and Immunology, U.P.R. School of Medicine, Medical Science
Campus, San Juan, P.R. 00936. <[email protected]>
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
Rican asthmatics characterized by spirometry before and after albuterol inhalation. She reported
the existence of the Arg Arg variant on position 16
which has been linked to tachyphylaxis and lowered respiratory function in other ethnic groups,
which may have implications in understanding our
increased asthma severity and poor bronchodilator
response (13). However, the clinical significance
of this variant in our population must to be evaluated.
Choudhry et al also evaluated polymorphisms in CD14, the endotoxin receptor and the
association to asthma. Subjects with asthma with
the GG or GC genotypes who were exposed to
tobacco had mean baseline FEV1 (% predicted)
values 8.6% lower than subjects not exposed to it
(p=0.03). The lowest IgE levels were in those subjects with the TT genotype and who were exposed
to ETS regardless of ethnicity. The study was a
pioneer at demonstrating and interaction between
variants of endotoxin receptor gene and environmental tobacco exposure on respiratory function
and IgE levels. (11).
Atopy, manifested as increased IgE levels,
has been studied in Hispanics and African Americans. Naqvi et al compared the IgE levels of Hispanic and African American asthmatics using 100
IU/ ml as a cut off. Subjects with higher IgE had
lower pulmonary functions, higher hospitalization
rates and were more likely Hispanic than African
American (14). The study suggests the important
role of allergies in asthma among Puerto Ricans.
No association with asthma among Puerto
Ricans were found with polymorphism of ADAM33, a marker for increased bronchial responsiveness, nor PTGDR, a molecule involved in T cell
chemotaxis, airway hyperreactivity and eosinophil
infiltration, previously associated to asthma in
other populations (10, 12). More recently, Galanter et al described an association of asthma with
polymorphism in the gene ORMDL3, in Mexicans
and blacks but just a trend among Puerto Ricans.
ORMDL3 is a protein with a trans membrane domain of unknown function which has been linked
to asthma by positional cloning in white subjects
(15).
Thus, inflammatory and atopic markers
have been associated to asthma in Puerto Ricans.
Future studies are necessary to clarify the clinical
relevance of these polymorphisms and how they
may help to screen or treat asthmatics.
Environmental
Environmental factors including allergen
and irritant exposure, tobacco and pollution are associated to asthma exacerbations. Data suggesting
that environmental factor play an important role in
asthma among Puerto Ricans is derived from the
29
study by Cohen et al. He compared asthma prevalence among Puerto Ricans living in the Bronx,
USA and in the island. Even after adjusting for socioeconomic factors, tobacco exposure and prematurity, Puerto Ricans in the island had 27% higher
likelihood of suffering from asthma and had 47%
higher likelihood of hospitalization than Puerto
Ricans living in the mainland (16).
Let’s examine each of these environmental factors. EPA monitors of particulate matter,
carbon monoxide, nitric and sulfur dioxide levels
throughout the island do not exceed acceptable
annual national standards (17). However, Suro et
al compared large particulate matter concentration
in urban and rural areas in Caguas and noted that
urban areas had higher particulate than rural areas,
sometimes exceeding acceptable standard levels
(18). The clinical relevance of these variations is
suggested in a study by Loyo et al. She conducted
a nested case-control study to evaluate if proximity
to air pollution point sources was associated with
increased risk of asthma attacks in Cataňo, an industrial town on the northern side of Puerto Rico.
Risk of asthma attack was increased 35% if residing near a grain mill, 44% if close to a petroleum
refinery, 23% for an asphalt plant, or 28% for a
power plant (all p's < 0.05). Residence near major
air emissions sources (>100 tons/year) increased
asthma attack risk by 108% (p < 0.05) (19)
Outdoor allergens are associated to asthma exacerbations. In San Juan, outdoor air samples are collected on a daily basis and spore counts
reported. A predominance of mold spores is identified throughout the year in Puerto Rico (20). The
clinical effect of such elevated spore counts is not
known but elevated spore counts has been related
to asthma symptoms in other populations.
The indoor environment is also of crucial
importance in asthma. Celedón et al evaluated asthmatic Puerto Rican Children in Hartford. They
identified that sensitivity to cockroach and mites
were more likely among Puerto Ricans, in spite
low level of mite exposure in their homes (21).
Ramsey and Celedón reported a direct relationship
between the number of allergen sensitivities and
asthma severity (22). Findley et al reported a high
exposure to rats or mice on a self administered
school survey administered to parents of Puerto
Rican children living in East Harlem (23).
Thus environmental factors including exposure to pollutants, indoor and outdoor allergens
seem to play a role in asthma among Puerto Ricans. Further studies are needed to examine the
relative importance of each of these factors.
Socioeconomic factors and health care utilization
A clue of the importance of socioeconomic
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
30
factors in asthma morbidity among Puerto Ricans
is suggested by Nazario et al. She compared parent
report of asthma prevalence and morbidity among
children attending private or public schools in the
island. The latter was used as a surrogate for lower
socioeconomic status. In spite similar asthma prevalence, children attending public schools had higher school absenteeism, hospitalization and emergency department visits than children attending
private schools (24).
Socioeconomic factor includes healthcare
utilization, access to care, quality of care, acculturation and psychosocial factors, which may affect
asthma morbidity. Cohen et al evaluated health
care utilization patterns among Puerto Rican children in Hartford, CT. Compared to African Americans, Puerto Rican children were more likely to
have outpatient asthma visits (31% more likely) in
spite similar prescriptions for bronchodilators and
ED visits and shorter hospital length of stay (25).
Montealegre et al evaluated treatment for acute asthma at the Emergency Department. He reported
that 72.1% received inhaled short acting beta agonists, 84.1% received oral or intravenous steroids,
only 64.8% received a follow up appointment and
5.3% where referred to a specialist. The study suggests areas of improvement in the acute management of asthma exacerbations, which may explain
(26).
Psychosocial factors have also been related to asthma, including depression and more
recently exposure to violence. Feldman et al reported an association between asthma in children
and depression and anxiety in a household based
survey of 1886 medically indigent children (27).
Cohen et al reported the association between physical or sexual abuse and suffering from asthma,
healthcare and asthma medication use in a population based house hold survey in San Juan and Caguas (28).
Choudhry et al evaluated the relationship
between racial admixture, asthma prevalence and
socioeconomic status among Puerto Ricans. Using
135 asthmatic families in Puerto Rico and 156
controls, she reported that at lower SES, European
ancestry was associated with increased risk of asthma, whereas African ancestry was protective. In
families with higher SES, African ancestry increased the asthma risk (29). The study undermines
that genetic and socioeconomic factors interplay
in asthma among Puerto Ricans.
Similarly, environmental and socioeconomic factors interplay in asthma. Prematurity has
also been linked to asthma in other populations.
Gorman et al examined the role of prematurity
in a cohort of Puerto Rican children living in the
US. She found that socioeconomic status and the
cleanliness of the home environment were related
to asthma for term, but not preterm, children (30).
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
Thus, socioeconomic factors also play a
role in elevated asthma rates among Puerto Ricans. Evidence of the interplay between genetic,
environmental and socioeconomic factors has accumulated.
CONCLUSIONS
Puerto Ricans suffers one of the highest
asthma prevalence, morbidity and mortality in the
world. Moreover asthma is more severe and with
poorer bronchodilator response. Several risk factors has been associated to asthma severity including being born and living in Puerto Rico, sensitivity to cockroaches and, increased IgE. A pattern of
increased use of emergency department and office
visits for asthma has been recognized, concomitant
to suboptimal asthma care. A complex interaction
of genetic, environmental and socioeconomic factors is involved in our elevated asthma prevalence,
morbidity and mortality. A multi prong approach is
essential to reduce the disease burden and improve
our health outcome.
REFERENCES
1. Carter-Pokras O.D., Gergen P.J., Reported asthma among Puerto
Rican, Mexican-American, and Cuban children, 1982 through 1984.
Am J Public Health. 1993; 83: 580-582.
2. Rose D, Mannino DM, Leaderer BP. Asthma Prevalence among US
Adults, 1998–2000: Role of Puerto Rican Ethnicity and Behavioral
and Geographic Factors. American Journal of Public Health. 2006;
96(5):880-8.
3. Centers for Disease Control and Prevention. Asthma prevalence
and control characteristics by race/ethnicity–United States, 2002.
MMWR Morb Mortal Wkly Rep. 2004; 53:145-148.
4. CDC. Asthma prevalence, health care use, and mortality, 2002.
Hyattsville, MD: US Department of Health and Human Services,
CDC, National Center for Health Statistics; 2004.Available at http://
www.cdc.gov/nchs/products/pubs/pubd/hestats/asthma/asthma.htm.
5. Homa D.M., Mannino D.M., Lara M., Asthma mortality in US
Hispanics of Mexican, Puerto Rican, and Cuban heritage, 1990–1995.
Am J Respir Crit Care Med. 2000; 161 : 504-509.
6.Bartololmei Diaz J. Epidemiological Profile of asthma in Puerto
Rico. At http://www.salud.gov.pr/Programas/ProgramaMadresNinosAdolecentes/Documents/Informe%20Vigilancia%20Asma.pdf.
7. Loyo N, Orengo JC, Serrano-Rodríguez RA. Childhood asthma
prevalence in northern Puerto Rico, the Rio Grande, and Loíza experience. J Asthma. 2006 Oct;43(8):619-24.
8. Perez- Perdomo R, Perez Cardona C, Disdier Flores O, Cintron Y.
Prevalence and correlates of asthma in the Puerto Rican population:
Behavioral Risk Factor Surveillance System, 2000. J Asthma.2003;
40(5):465-74.
9. González Burchard E, Ávila PC, Nazario S, Casal J, Torres A, Rodríguez-Santana JR, et al. Lower Bronchodilator Responsiveness in
Puerto Rican than in Mexican Subjects with Asthma. American Journal of Respiratory and Critical Care Medicine. 2004; 169: 386-392.
10. Lind DL, Choudhry S, Ung N, Ziv E, Avila PC, Salari K, Ha C,
Lovins EG, Coyle NE, Nazario S, et al. Adam33 is not associated
with asthma in Puerto Rican or Mexican populations. Am J Respir
Crit Care Med. 2003;168:1312-1316.
11. Choudhry, S., Avila, P. C., Nazario, S., Ung, N., Kho, J., Rodríguez-Santana, J. R., Casal, J., Tsai, H. J., Torres, A., Ziv, E., Toscano,
M., Sylvia, J. S., Alioto, M., Salazar, M., Gómez, I., Fagan, J. K.,
Salas, J., Lilly, C., Matallana, H., Castro, R. A., Selman, M., Weiss,
S. T., Ford, J. G., Drazen, J. M., Rodriguez-Cintron, W., Chapela, R.
(et al)
CD14 tobacco gene-environment interaction modifies asthma severity and immunoglobulin E levels in Latinos with asthma. American
Journal of Respiratory and Critical Care Medicine. 2005;172 ( 2):
173-182.
12. Tsai YJ, Choudhry S, Kho J, Beckman K, Tsai HJ, et al. The PTGDR gene is not associated with asthma in 3 ethnically diverse populations. J Allergy Clin Immunol. 2006; 118(6): 1242-8.
13. Choudhry S, Ung N, Avila PC, Ziv E, Nazario S, Casal J, Torres
A, Gorman JD, Salari K, Rodriguez-Santana JR, et al. Pharmacogenetic
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
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differences in response to albuterol between Puerto Ricans and Mexcans with asthma. Am J Respir Crit Care Med 2005;171: 563-570.
14. Naqvi M, Thyne S, Choudhry S, Tsai H, Navarro D, Castro R, Nazario S, Rodriguez-Santana J, Casal J, Torres A, et al. Ethnic-specific
differences in bronchodilator responsiveness among African Americans, Puerto Ricans, and Mexicans with asthma. J Asthma 2007; 44:
639-648.
15. Galanter J, Choudhry S, Eng C, Nazario S, Rodríguez-Santana JR,
Casal J, Torres-Palacios A, Salas J, Chapela R, Watson HG, Meade
K, LeNoir M, Rodríguez-Cintrón W, Avila PC, González Burchard
E. ORMDL3 Gene Is Associated with Asthma in Three Ethnically
Diverse Populations. American Journal of Respiratory and Critical
Care Medicine 2008; 177: 1194-1200.
16. Cohen RT, Canino GJ, Bird HR, Shen S, Rosner BA, Celedón JC.
Area of Residence, Birthplace, and Asthma in Puerto Rican Children.
Chest 2007; 131(5): 1331-8
17. Junta de Calidad Ambiental. Indice de calidad ambiental, Estado
Libre Asociado de Puerto Rico. http://www.prtc.net/~jcaaqs/Index.
html#Escalas%20del%20Indice%20Ambiental
18. Suro-Maldonado R., A. González & A. Rivera-Rentas. Air quality, particulate matter, and geographic characterization in a potential
asthma prone region of eastern central Puerto Rico. In Air Pollution
XIV.WIT press, 2006.
19. Loyo-Berríos NI, Irizarry R, Hennessey JG, Grant Tao X, Matanoski G. Air Pollution Sources and Childhood Asthma Attacks
in Cataño, Puerto Rico. American Journal of Epidemiology
2007;165(8):927-35.
20. National Allergy Bureau Aeroallergen Network at http://www.
aaaai.org/nab/index.cfm
21. Celedón JC, Sredl D, Weiss ST, et al. Ethnicity and skin test
reactivity to aeroallergens among asthmatic children in Connecticut.
Chest 2004; 125:85–92
22. Ramsey CD, Celedón JC, Sredl DL, Weiss ST, Coutier MM. Predictors of disease severity in children with asthma in Hartford, Connecticut. Pediatr Pulmonol. 2005; 39(3):268-75.
23. Findley S, Lawler K, Bindra M, Maggio L, Penachio MM,
Maylahn C. Elevated Asthma and Indoor Environmental Exposures
Among Puerto Rican Children of East Harlem. Journal of Asthma
2003;40(5): 557 – 569.
24. Nazario S, Casal J ; Torres-Palacios A; Rodriguez W ; Delamater
A; Applegate E. B; Piedimonte G ; Wanner A. Parent-reported asthma in Puerto Rican children. Pediatric Pulmonology 2004; 37 (5):
453-460.
25. Cohen RT, Celedón JC, Hinckson VJ, Ramsey CD, Wakefield
DB, Weiss ST, Cloutier MM. Health-care use among Puerto Ricans
and African Americans children with asthma. Chest 2006; 130(2):
463-71.
31
26. Montealegre F, Bayona M, Chardon D, Treviño F. Age, gender and seasonal patterns of asthma in emergency departments of
southern Puerto Rico. P R Health Sci J. 2002 ;21 (3):207-12 .
27. Feldman JM, Ortega AN, McQuaid EL, Canino G. Comorbidity
Between Asthma Attacks and Internalizing Disorders Among Puerto Rican Children at One-Year Follow-Up Psychosomatics 2006;
47:333–339.
28. Cohen RT, Canino GJ, Bird HR, Celedon JC. Violence, Abuse,
and Asthma in Puerto Rican Children. Am J Respir Crit Care Med.
2008; 178(5):453-9.
29. Choudhry S. González Burchard, Luisa N. Borrell, Hua Tang, Ivan
Gomez, Mariam Naqvi, Sylvette Nazario, Alfonso Torres, Jesus Casal, Juan Carlos Martinez-Cruzado, Elad Ziv, Pedro C. Avila, William
Rodriguez-Cintrón and Neil J. Risch. Ancestry–Environment Interactions and Asthma Risk among Puerto Ricans . American Journal of
Respiratory and Critical Care Medicine 2006; 174(10): 1088-1093.
30. Gorman B, Landale N.Premature Birth and Asthma Among
Young Puerto Rican Children .Population Research and Policy Review. 2005; 24(4): 335-358.
RESUMEN
Los Puertorriqueños sufren de una de las
prevalencias, morbilidades y mortalidades por
asma más altas en el mundo. Más aun, el asma es
más severa y con menor respuesta a broncodilatadores. Varios factores de riesgos se han asociado a
severidad de asma entre los puertorriqueños incluyendo nacer y vivir en Puerto Rico, sensitización a
las cucarachas y niveles altos de IgE. Se ha identificado un patrón de uso marcado de sala de emergencia y de visitas a oficinas de médicos por asma,
concomitante a un cuidado subóptimo en sala de
emergencia. Por lo tanto, factores genéticos, ambientales y socioeconómicos están envueltos en la
alta prevalencia, morbilidad y mortalidad de asma.
Un acercamiento multidisciplinario es esencial
para reducir la carga de la enfermedad y mejorar
nuestro estado de salud.
Participe en los eventos
culturales de la
Asociación Médica
La Asociación Médica de Puerto Rico
realiza múltiples eventos culturales de
interés general.
Series de cine, conferencias, noches
de bohemia, conciertos y eventos institucionales se suman a las jornadas
científicas regulares.
Entérese de nuestra interesante agenda visitando nuestro web site www.
asociacionmedicapr.org
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
32
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
URTICARIA IN THE ELDERLY
Cristina Ramos-Romey, MD *, Fernando López-Malpica, MD **, Sylvette
Nazario, MD**, Ivonne Z. Jiménez-Velázquez, MD *
ABSTRACT
Urticaria is a common disorder affecting
approximately 15-25% of the population at some
point in their life. We can assume that with the advancement of medical therapeutics, which have in
turn prolonged the duration of life, the incidence of
drug induced urticaria will increase in the geriatric
population. Other common causes that need to be
considered are allergy, autoimmune conditions and
stress. Urticaria is characterized by transient pruritic wheals or erythematous patches on the skin. The
signs and symptoms usually resolve in less than 24
hrs, leaving no residual scar or discoloration. Generally, the etiology of urticaria remains unknown
in 75-90% of patients. In this article we discuss
pathogenesis, clinical presentation, and treatment
of urticaria in the elderly. A complete medical evaluation and age appropriate screening should be
performed in all elderly patients in a primary care
setting. We should also weigh risk versus benefits
of each prescribed medication to decrease morbidity and improve the quality of life.
Key Words: Urticaria, elderly, drug sensitivity,
food sensitivity.
INTRODUCTION
Every day more primary care physicians
evaluate patients with multiple allergic conditions,
including urticaria. Due to the demographic shift
occurring in the United States the number of geriatric patients suffering from allergic conditions
is also expected to rise.
point in their lives (2). Studies have found that
urticaria is among the ten most common dermatologic diagnoses made by general practitioners
and internists, comprising 2.3% of dermatological
cases seen by internists (3). It is characterized by
transient pruritic wheals or erythematous patches
on the skin. The symptoms usually resolve in less
than 24 hrs, leaving no residual scar or pigmentary change. Generally, the etiology of urticaria
remains unknown in 75-90% of patients (2).
Acute urticaria, lasting less than 6 weeks is more common and its incidence is higher in
the pediatric population. Chronic urticaria (CU)
is defined as daily or almost daily recurrence of
wheals lasting more than 6 weeks. Angioedema,
or submucosal and subcutaneous tissue swelling,
coexists with urticaria in approximately 40% of
patients.
Urticaria has been considered to be a minor disorder but it severely impairs quality of life
at the same level as psoriasis and atopic dermatitis
(4). This disorder can be intensely pruritic, interfere with sleep, daily activities and social interaction (5). Furthermore, available treatment may not
be effective in all patients (6). Since the cause in
many cases is not identified, it can be a very frustrating condition for both the patient and the physician. Healthcare costs of chronic idiopathic urticaria (CIU) have been compared to those of other
skin diseases such as vitiligo and bullous disease
(7).
PATHOGENESIS
The dramatic increase in the geriatric population that has occurred in the 20Th century,
which is expected to continue to increase, has
brought significant change and concerns to the
medical system (1). This population is of special
concern due to the prevalence of co-morbid conditions, physiological changes, and use of polypharmacy. As limited publications exist on urticaria
in the elderly, the aim of this paper is to review
the clinical manifestations, treatment, and medical
implications of this widespread condition.
Urticaria is mediated by cutaneous mast
cells activation in the superficial dermis, which
due to IgE or non-IgE mediated activation, lead to
the release of histamine and other vasoactive substances. Several mechanisms have been proposed to
explain the pathophysiology of chronic idiopathic
urticaria. In 30-50% of patients there is evidence
of autoantibodies that directly activate histamine
releasing mast cells or basophils (8). Other mechanisms include abnormalities of basophils and
abnormalities in the coagulation cascade (9).
Urticaria is a common disorder affecting
approximately 15-25% of the population at some
The causative agent of urticaria varies depending on its chronicity, and the age of the
From the *Internal Medicine Department, Geriatrics Program, University of Puerto Rico Medical Sciences Campus, San Juan, and the **Rheumatology, Allergy and Immunology Division, Internal Medicine Department, University of Puerto Rico Medical Sciences Campus, San Juan, PR.
Address reprint requests to: Ivonne Z. Jiménez-Velázquez, MD, FACP, Department of Medicine, Geriatric Medicine Program, PO Box 365067, San
Juan, PR. 00936-5067. Fax 787-754-1739, E-mail: [email protected].
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
patient. In patients with acute urticaria; drugs, insect bites and food allergens are likely suspects
(10). Some causes of chronic urticaria are known
to exist in which a specific agent or stimuli has
been identified as a precipitant factor. An example are physical urticarias that present as wheals
triggered by a specific physical stimulus, such
as: stroking, delayed pressure, cholinergic stimuli, cold exposure, solar exposure and very rarely,
contact with water. Other examples are drug reactions, food reactions, inhalants, bacterial and parasitic infections, internal diseases, malignancies
and autoimmune diseases (11).
There is conflicting evidence associating
urticaria with malignancy, some studies have suggested causal relationship, but other recent studies
have not found any supporting data (11). In a study
by Karakelides, patients with history of CU had a
higher incidence of Monoclonal Gammopathy of
Unknown Significance (MGUS) when compared
to the general population. Patients older than 56
years of age, diagnosed with CU and MGUS, had
also a higher incidence of hematologic malignancies as compared to younger patients (12). An association has been established between acquired
angioedema associated C1-esterase inhibitor and
lymphoproliferative disorders (13).
Autoimmune diseases such as thyroid
autoimmunity, vitiligo and others have also been
associated with an increased risk of chronic idiopathic urticaria (CIU). Multiple studies have demonstrated statistically increased levels of thyroid
microsomal antibodies and antithyroglobulins
in patients with CIU as compared with healthy
euthyroid controls.
Euthyroid patients have shown clinical
improvement of urticaria with thyroid replacement
therapy (14-18). Due to the significant evidence of
the association between thyroid autoimmunity and
CIU thyroid autoantibodies are recommended as
part of the medical evaluation. It is not clear if
these autoantibodies are a marker of patients with
autoimmune predisposition or if they are pathogenic by themselves. Further studies are being conducted to clarify this issue.
33
PATIENT EVALUATION
The evaluation of patients presenting with
urticaria should include a complete medical history including review of symptoms, detailed medication review, including prescription, non-presciption and other herbal or natural remedies, personal
and family history of atopy, previous adverse drug
reactions, as well as travel history. No further workup is generally needed in cases of acute urticaria.
On the other hand, in patients with chronic
urticaria, specifically at this age group, other medical conditions must be ruled out. A physical examination and a basic laboratory workup consisting
of complete blood count, urinalysis, erythrocyte
sedimentation rate, ANA, antithyroglobulin, and
antimicrosomal antibodies, liver function tests and
creatinine levels is indicated. There is no evidence
to support further extensive laboratory evaluation,
unless suggested by medical history or physical
examination.
Skin biopsies are not recommended, unless lesions are painful, individual lesions fail to
resolve in 24 hours, or leave hyperpigmentation as
they resolve. In these circunstances, a punch biopsy of the skin may be useful to differentiate urticaria from urticarial vasculitis (10).
The evaluation of urticaria in the geriatric population must focus on a detailed medical
history with special emphasis on medications and
exclusion of underlying medical conditions. Additional studies must be directed by positive findings
during the initial evaluation. Polypharmacy which
is commonly seen in geriatric patients, may frequently cause adverse drug reactions and unwanted side-effects (see Table 1).
Adverse drug reactions account for millions of hospital admissions yearly and are believed to be a major problem in terms of morbidity
and mortality.
Anti-hypertensive
medications
Recently, it has been described that the
frequent use of medications that decrease gastric
acid production may affect gastrointestinal allergen digestion and absorption, increasing sensitization risk.
Antibiotics
Stress may commonly affect dermatologic disorders, as a predisposing, participating or
perpetuating factor. It is generally accepted that
traumatic life experiences and stress may trigger
or maintain episodes of urticaria in some patients.
Multivitamins
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
(Ace-Inhibitors, Angiotensin Receptor Blockers)
(penicillins,sulfonamides,
tetracyclines)
Anti-inflammatory (aspirin non steroidal antiagents
inflammatory drugs)
Table 1: Medications commonly used by elderly
patients that produce Urticaria.
34
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
In a recent study drug-induced urticaria
was one of the most common adverse drug reactions in hospitalized patients. They found the
greatest diversity of adverse clinical reactions in
patients over 60 years, most probably due to polypharmacy-related, drug interactions and decreased medication clearance (19).
Drug induced urticaria may occur as a single phenomenon or as part of a generalized reaction. In a retrospective analysis of drug induced urticaria and angioedema by Nettis et al, they found
a consistent increase in the incidence of drug related urticaria over the years. Non-steroidal antiinflammatory drugs (NSAIDS) were involved in
the majority of cases, followed by antimicrobial
agents. These results are in agreement with other
similar studies.
The authors conclude that this rise in drug induced
urticaria and other adverse drug reactions may be
a result of the development of new drug therapies
and multiple drug regimens (20).
Dykewicz also reports on angioedema secondary to angiotensin-converting enzyme (ACE)
inhibitors, which is more commonly reported in
black patients, and may be intermittent in nature,
even after prolonged use of the medication making its diagnosis even more difficult (43).
TREATMENT
The treatment of physical urticaria consists of avoidance of precipitant factors. If history
suggests a triggering factor, an exposure challenge may be performed, taking appropriate medical
precautions.
If food is considered as a possible cause,
a stepwise elimination diet may also be effective
(see Table 2). All patients should be oriented to
avoid precipitating agents such as NSAID’s, alcohol and warm temperatures.
Seafood
Nuts
Eggs
Tomatoes
Chocolate
Berries
Milk
Colorants
Citrics
Pork
Table 2: Foods that may produce Urticaria
Currently the mainstay therapy for CU is
H1 blockers. Non-sedating H1 blockers are preferred due to the high tolerability and minimal side
effects. Multiple studies have shown that cetirizine
has superior efficacy than other new H1 blockers
(21,22). Desloratadine which contains the active
metabolite of loratadine has been shown to produce improvement of pruritus, and on the number and
size of wheals versus patients treated with placebo. Improvement was observed with the first dose
and results maintained during a 6-week treatment
period (23, 24).
A similar study of patients with CIU
showed improvement of quality of life scores with
desloratadine treatment (22). Although H1 receptor antagonists have demonstrated variable efficacy
rates they have all proved to be superior to placebo
in multiple studies (21-28). Treatment with first
generation antihistamines (i.e. diphenhydramine,
chlorpheniramine) should be avoided in geriatric
patients due to their wider profile of adverse side
effects such as sedation, increased risk of falls,
cognitive impairment, and urinary retention.
Patients who do not respond to H1 blockers may benefit from short courses of oral corticosteroids. Due to the known adverse effects of
systemic corticosteroids, patients should receive
the lowest effective dose, while avoiding long
term therapy to avoid immunesupression and further loss of bone density, already frequent in this
age group (11). Elderly patients treated with corticosteroid therapy should be monitored for other
possible adverse effects such as: peptic ulcers,
elevation of blood pressure, intraocular pressure,
blood glucose level and mood changes.
Studies have demonstrated good tolerability and adequate safety profile of these medications, without any increased risk of QT prolongation. These mediations have not been found to
cause cognitive or psychomotor dysfunction in
healthy individuals (28-31). Although these side
effects have not been found to be clinically significant we must consider that geriatric patients
are in most cases excluded from clinical research.
Particular considerations in the geriatric population limit the extrapolation of these results to the
geriatric practice.
Certain physiologic changes occur during
aging such as: decreased creatinine clearance, decreased hepatic metabolism, and changes in distribution, that increase the concentration and number of intermediate and potentially sensitizing or
adverserly-interacting metabolites of medications.
Therefore, we should not assume that these potential side effects are not clinically significant in this
age group.
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BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
CONCLUSIONS
We can assume that with the advancement of medical therapeutics, which has in turn
prolonged the life expectancy, the incidence of
drug induced urticaria will increase in the geriatric population. The presentation of chronic urticaria in elderly patients should not be overlooked.
CU may be the initial clinical manifestation of a
serious systemic illness or adverse drug reaction
and a complete medical history and evaluation as
mentioned above, is indicated. Age appropriate
screening should be performed in all patients in a
primary care setting. We should also weigh risks
versus benefits of each prescribed medication to
decrease morbidity and improve quality of life.
REFERENCES
1.Pompei P, Murphy J, eds. Geriatrics Review Syllabus: A Core Curriculum in Geriatrics Medicine, 6th Edition, New York: American
Geriatrics Society, 2006.
2.Liutu M, Kalimo K, et al. Etiologic aspects of chronic urticaria. Int
J of Dermatology 1998; 37:515-519.
3.Feldman S, Fleisher A, et al. Most common dermatologic problems
identified by internists, -1990-1994. Arch Intern Med 1998; 158: 726730.
4.Grob JJ, Revuz J, et al. Comparative study of the impact of chronic
urticaria, psoriasis and atopic dermatitis on the quality of life. Br J
Dermatol 2005; 152: 289-295.
5.O’Donnell BF, Lawlor F, et al. The impact of chronic urticaria on
the quality of life. Br J Dermatol 1997;136(2):197-201.
6.Kozel M, Mekkes J, et al. The Effectiveness of a history based diagnostic approach in chronic urticaria and angioedema. Arch Dermatol
1998; 34:1575-1580.
7.Delong LK, Culler SD, et al. Annual direct and indirect health care
costs of chronic idiopathic urticaria: a cost analysis of 50 nonimmunosuprressed patients. Arch Dermatol 2008;144(1):102-103.
8.Kaplan, AP. Chronic urticaria: Pathogenesis and treatment. J Allergy Clin Immunol 2004;114:465.
9.Kikuchi Y, Kaplan A. Mechanisms of autoimmune activation of basophils in chronic urticaria. J Allergy Clin Immunol 2001;107(6):10561062.
10.Varadarajulu S. Urticaria and angioedema; Postgraduate Medicine
2005;117(5):25-31.
11.Kozel M, Sabroe R. Chronic Urticaria: Aetiology, Management and Current and Future Treatment Options. Drugs 2004; 64
(22):2515-2536.
12.Karakelides M, Monson KL, et al. Monoclonal gammopathies
and malignancies in patients with chronic urticaria: Int J Dermatol
2006;45(9):1032-1038.
13.Sigutgeirsson B. Skin disease and maliganancy: an epidemiological study. Acta Derm Venereol Suppl 1992; 178:1-110.
14.O’Donnell BF, Francis DM, et al. Thyroid autoimmunity in chronic urticaria. Br J Dermatol 2005;153:331-335.
15.Verneuil l, Leconte C, et al. Association between chronic urticaria and thyroid autoimmnunity: a prospective study involving 99 patients. Dermatology 2004;208:98-103.
16.Palma-Carlos AG. Chronic urticaria and thyroid auto-immunity.
Allerg Immunol 2005;37(4):143-146.
17.Cebeci F. Association between chronic urticaria and thyroid autoimmunity. Eur J Drematol 2006;16(4):402-405.
18.Gaig P, Garcia-Ortega P, et al. Successful treatment of chronic urticaria associated with thyroid autoimmunity. J Investig Allergol Clin
Immunol 2000;10(6):342-345.
19.Jenerowicz D, Czarnecka-Operacz M, et al. Drug-related hospital
admissions- an overview of frequency and clinical presentation. Acta
Pol Pharmacy 2006;63(5): 395-399.
20.Nettis E, Marcandrea, G, et al. Retrospective analysis of druginduced urticaria and angioedema: a survey of 2287 patients
Immunopharmacology and Immunotoxicology 2001; 23(4):585-595.
21.Loratadine and cetrizine in the treatment of chronic urticaria. J Eur
Acad Dermatol Venereol 1994;3(2)148-152.
22.Grod JJ, Auquier P, et a. Quality of life in adults with chronic
idiopathic urticaria receiving desloratadine: a randomized, doubleblinded, multicenter, placebo-controlled study. J Eur Acad Dermatol
Venereol 2008; 22:87-93.
23.DuBuske L. Desloratadine for Chronic Idiopathic Urticaria: a review for clinical efficacy. Am J Clin Dermatol 2007;8(5):271-283.
24.Ortonne J, Grob J, et al. Efficacy and safety of desloratadine in
adults with chronic idiopathic urticaria: a randomized, double-blind
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
35
, placebo-controlled, multicenter trial. Am J Clin Dermatol 2007;
8(1):37-42.
25. Murdoch D, Goa KL, et al. Desloratadine: an update of its efficacy
in the management of allergic disorders. Drugs 2003;63(19):2051-77
26. Ring J, Hein R, et al. Once-daily desloratadine improves the signs
and symptoms of chronic idiopathic urticaria: a double-blind, randomized, placebo controlled study. Int J Dermatology 2001; 40(1):726.
27. Paul E, Berth-Jones J, et al. Fexofenadine hydrochloride in the
treatment of chronic idiopathic urticaria: a placebo controlled, parallel group, dose-ranging study. J Dermatol Treat 1998; 9:143-149.
28. Nelson HS, Reynolds R, et al. Fexofenadine is safe and effective
for treatment of chronic idiopathic urticaria. Ann Allergy Asthma Immunol 2000; 84(5):517-522.
29. Hindmarch I, Shamsi Z, et al. An evaluation of the effects of highdose fexofenadine on the central nervous system: a double-blind, placebo-controlled study in healthy volunteers. Clin Exp Allergy 2002;
32(1): 133-139.
30. Gandon JM, Allain H, et al. Lack of effect of single and repeated
doses of levocetrizine, a new antihistamine drug, on cognitive and
cognitive and psychomotor functions in healthy volunteers. Br J Clin
Pharmacol 2002; 54(1):51-58.
31. Vester JC, Volkerts ER, et al. Acute and subchronic effects of levocetrizine and diphenydramine on memory functioning, psychomotor
performance, and mood. J Allergy Clin Immunol 2003; 111(3):623627.
32. Tanus T, Atkins P, et al. Comparison of serum histamine-releasing
activity and clinical manifestations in chronic idiopathic urticaria.
Clinical and Diagnostic Laboratory Immunology 1996;3(1):135-137.
33. Chung HS, Kwang HL, et al. Heat Contact Urticaria. Yonsei Medical Journal 1996;37(3):230-235.
34. Kim G. Primary (idiopathic) cold urticaria and cholinergic urticaria. Dermatology Online Journal 10(3):13.
35. Asero R, Tedeschi A, et al. Activation of the tissue factor pathway
of blood coagulation in patients with chronic urticaria. J Allergy Clin
Immunol 2007;119:750-10.
36. Greaves M. Pathophysiology of chronic urticaria. Int Arch Allergy Immunol 2002;127:3-9.
37. Shipley D, Ormerod A. Drug-induced urticaria. Am J Clin Dermatol 2001;(3):151-158.
38. Grattan C. Aspirin sensitivity and urticaria. Clinical and Experimental Dermatology 2003;28:123-127.
39. Bircher A, Poliklinik A, et al. Drug-induced urticaria and angioedema caused by non-IgE mediated pathoomechanisms. European
Journal of Dermatology 1999;9(8):657-653.
40. Asero R. Intolerance to nonsteroidal anti-inflammatory drugs
might precede by years the onset of chronic urticaria. J Allergy Clin
Immunol 2003;111(5):1095-1098.
41. Zembowicz A, Mastalerz L, et al. Histological spectrum of cutaneous reactions to aspirin in chronic idiopathic urticaria. J Cutan
Pathol 2004;31:323-329.
42. Fiszenson-Albala F, Auzeria V, et al. A 6-month prospective survey of cutaneous drug reactions in a hospital setting. British Journal
of Dermatology 2003;149:1018-1022.
43. Dykewicz Mark S. Cough and Angioedema from AngiotensinConverting Enzyme Inhibitors: New Insights into Mechanisms and
Management. Cough and Angioedema from Angiotensin-Converting
Enzyme Inhibitors: New Insights into Mechanisms and Management.
Curr Opin Allergy Clin Immunol 4(4):267-270, 2004.
RESUMEN
La urticaria es un desorden común que
afecta aproximadamente un 15-20% de la población en algún momento de su vida. Podemos asumir que con los avances en la terapia médica, que
a su vez han prolongado la expectativa de vida, la
incidencia de urticaria aumentará en la población
geriátrica. La urticaria se caracteriza por ronchas
elevadas, pruríticas y rojizas que se desaparecen
en menos de 24 horas, sin dejar cicatriz o cambios
de color en la piel. En el 75-90% de los pacientes
la etiología es desconocida. En este artículo discutimos la patogénesis, la presentación clínica y
el tratamiento de la urticaria en pacientes geriátricos. Una evaluación médica completa y dirigida
por grupo de edad, debe llevarse a cabo en todo
paciente geriátrico como parte de su cuidado primario. Debemos sopesar los riesgos y beneficios
de cada medicamento recetado para disminuir la
morbilidad y mejorar la calidad de vida.
36
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
Consideraciones Farmacológicas en el
Tratamiento de la Depresión
Luis Carlos Mejía Rivera MD, PhD *
Hasta no hace mucho tiempo, el trastorno depresivo era conceptualizado como situacional o exógeno, que ocurría como una reacción a
los estresores de la vida y presumiblemente una
falta de “neurobiología”; este panorama ha cambiado. Existe actualmente evidencia científica de
que cuando alguien encuentra criterios de depresión mayor, existe una neurobiología subyacente,
con cambios en la estructura y en la función de
áreas cerebrales clave en la regulación de las emociones y la cognición. El ambiente también juega un papel en depresión, justo como lo tiene en
hipertensión arterial y otras condiciones médicas.
Ahora también sabemos que la depresión no es tan
benigna como una vez se pensó, y en los estudios
clínicos solo un 25 – 40 % de los pacientes alcanzan remisión. Aun más preocupante, es la evidencia creciente de que la enfermedad es progresiva y
se hace cada vez más difícil de tratar en el tiempo.
Después de varios episodios depresivos, estos recurren espontáneamente en ausencia de factores
precipitantes.
Este es nuestro modelo de pensamiento
actual para explicar la progresión de la patología
celular en el cerebro de los pacientes con depresión. Una combinación de factores ambientales
y genéticos, desde estadíos muy tempranos de la
condición, conducen a elevaciones en los niveles
de glucocorticoides y a reducciones en los factores
neurotróficos, que derivan en daño de las células
gliales. La glía suple glucosa a las neuronas y las
protege de la excitotoxicidad mediada por glutamato, facilita la reparación y la supervivencia de
las neuronas por sintetizar y liberar factores neurotróficos. Así, la pérdida de las células gliales
genera una reacción en cascada que culmina en
injuria neuronal progresiva. En resumen, “vulnerabilidades genéticas” interactúan con el estrés,
el dolor crónico y otras comorbilidades médicas,
para desembocar en disregulaciones neuroendocrinas, reducción en el soporte trófico, cambios en
la estructura y en la función de ciertos circuitos
neuronales, que conllevan a cambios celulares en
regiones cerebrales definidas, especialmente la
corteza prefrontal y el hipocampo. Clínicamente,
esto se traduce en manifestaciones emocionales,
cognoscitivas y físicas.
El modelo farmacodinámico clásico del bloqueo
de la recaptación de monoaminas de los antidepresivos, ha sido mejorado con la hipótesis neurotrófica que sostiene que el mecanismo de acción
inicial conduce, en última instancia, a cambios de
neuroplasticidad que se oponen a los correlatos
celulares y funcionales descritos. Nuevos modelos farmacológicos de depresión nos están dando
esperanza de que algunos aspectos de la patofisiologia de la depresión pudieran ser detenidos, lentificados, o potencialmente prevenidos.
¿Y qué significa todo esto clínicamente?
La remisión sintomática de la depresión, manejando todos los síntomas, incrementa la probabilidad
de detener la progresión de la enfermedad. Evidentemente, la capacidad de lograr esta loable meta
requiere la selección de una terapia farmacológica
con las dosis y la duración del tiempo adecuados.
Que se consideren las comorbilidades médicas y
psiquiátricas, los tratamientos concomitantes, evitando así interacciones farmacológicas relevantes. Que la terapia sea individualizada, evitando
la práctica del patrón prescriptivo monotemático.
El mismo medicamento antidepresivo no encaja
en el cerebro de todos los pacientes y existe gran
variabilidad biológica en la respuesta a un mismo
medicamento. Esta variabilidad biológica en la
respuesta, cuyas fuentes son complejas, algunas
farmacodinámicas y otras farmacocinéticas, justifican la disponibilidad de un mayor número de
opciones en nuestro arsenal terapéutico. Las mejor
entendidas son las fuentes de variabilidad farmacocinética debidas a diferencias en la velocidad
de biotransformación enzimática, y a diferencias
en la afinidad por la glicoproteína-p, esta bomba
de eflujo de la barrera hemato-encefálica, que remueve fármacos del cerebro minando su llegada al
blanco molecular de acción. Fármacos cada vez
menos influenciados tanto por variaciones en la
capacidad catalítica de las enzimas, como por esta
tendencia a ser expulsados del cerebro, podrían aumentar las posibilidades de remisión.
En fin, es necesario que eduquemos a los
pacientes y a la sociedad en general sobre la depresión y su neurobiología en aras de reducir el
estigma aún prevalente y frenar la actitud nihilista
frente a las terapias antidepresivas.
REFERENCIAS
1. Fales CL, et al. Biol Psychiatry. 2008;63:377-384.
2. Gatt JM, et al. J Integr Neurosci. 2007;6:75-104.
3. Siegle GJ, et al. Biol Psychiatry. 2007;61:198-209.
4. Rajkowska G, et al. CNS Neurol Disord Drug Targets. 2007;6:219233.
5. Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific
Basis and Practical Applications. 3rd ed. 2008.
6. Warden D, et al. Curr Psychiatry Rep. 2007;9:449-459
* Profesor asociado de Farmacología Clínica, Escuela de Medicina San Juan Bautista, Puerto Rico. Email: <[email protected]>
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
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42
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
Case Reports/Reporte de Casos
SEVERE ANEMIA OF RAPID ONSET IN AN
INMUNOCOMPROMISED HOST
Ezequiel Rivera Rodríguez, MD *, Fernando Cabanillas MD *
ABSTRACT
We describe a case of pure red cell aplasia developing within two months after kidney
transplant in a patient who was actively receiving
immunosuppression. His hemoglobin was 9.5 g/
dL and his reticulocyte count was 0%. WBC and
platelet counts were normal and a bone marrow
showed hypercellularity with normal myelocytic
and megakaryocytic elements. The erythrocytic
series was completely absent except for an increased number of giant proerythronormoblasts with
cytoplasmic vacuolization. The titers for IgG and
IgM for Parvovirus were negative. However, DNA
PCR for Parvovirus B19 was positive. After receiving IV human immunoglobulin, the patient’s hemoglobin increased in 4-6 weeks to 13.1 g/dL and
his reticulocyte count became normal. The cause
of his anemia was attributed to Parvovirus B19.
Parvovirus B19 should be considered as a cause of
unexplained progressive anemia in this setting and
in any immunosuppressed patient. The reticulocyte count, bone marrow picture and PCR for DNA
for Parvovirus B19 are essential for diagnosis.
Key words: anemia, inmunocompromised host
CASE HISTORY
This 40-year-old Puerto Rican male with
end-stage renal disease secondary to polycystic
kidney disease and arterial hypertension underwent
cadaveric kidney transplantation on July 9, 2006.
The patient had been on peritoneal dialysis for two
years prior to transplantation, and at the time of
transplantation his hemoglobin was 13 g/dL and he
had never received erythropoietin.
He was discharged fifteen days later on
July 24, 2006 after an initial postoperative course
which required medical supervision at the intensive care unit for aspiration pneumonia secondary to
postanesthetic vomiting.
He was treated at the intensive care unit
with antibiotics, including a short course of 48
hours of IV ganciclovir. This was followed by ganciclovir 250 mg p.o. daily until 07-24-06. He spent
three days in the intensive care unit being stabilized, from July 9, 2006 to July 12, 2006, and on the
fourth day was transferred to the ward, where he
was started on immunosuppressive medications,
including rabbit antithymocyte globulin 75 mg IV
from July 9, 2006 to July 14, 2006 followed by
50 mg IV until 07-16-06, prednisone 30 mg q.6h.
p.o. decreased slowly until at the time of discharge
he was on prednisone 10 mg b.i.d., mycophenolate
mofetil 500 mg p.o. t.i.d., sirolimus 2 mg p.o. daily
and trimethoprim sulfamethoxazole.
His hospital course was otherwise uneventful except for a postoperative decrease in his
hemoglobin to 8.8 g/dL one day post surgery, attributed to blood loss. The rest of his hemogram was
normal. He had received one dose of Aranesp 200
mg (Darbepoeting) on 07-12-06. At the time of
discharge, his laboratory studies were within normal limits and his hemoglobin improved to 11.1
g/dL. His hemoglobin continued to drop until 55
days post transplantation, at which time his hemoglobin was 7.5 g/dL. At this time he was started on
erythropoietin but he received only two doses, and
was transfused with two units of packed RBCs.
Post transfusion his hemoglobin was 9.5 g/dL and
his reticulocyte count was 0%.
An hematology consult was requested
on 09-08-06, at which time a peripheral smear
showed normocytic normochromic RBCs, no polychromatophilia, WBC and platelet counts were
within normal limits and a bone marrow was characterized by hypercellularity with normal myelocytic and megakaryocytic elements. The erythrocytic series was completely absent except for an
increased number of giant proerythronormoblasts
with cytoplasmic vacuolizations (Figures 1-2).
The erythropoietin was stopped and the patient
was treated immediately with human immune gamma globulin at a dose of 400 mg/kg IV daily x 5
* From the section of Hematology-Oncology, Auxilio Mutuo Cancer Center, San Juan, PR. Address reprints to: Ezequiel Rivera Rodriguez MD,
Section of hematology-Oncology, Auxilio Mutuo Hospital, San Juan, PR
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
43
Figure I
Oil immersion view of giant proerythroblast with marked cytoplasmic vacuolization (see yellow arrow) as
is typical of pure red cell aplasia induced by Parvovirus B-19.
Figure II
High
power
view of marrow
showing
vacuolated giant
proerythroblasts
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
44
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
days from Sept 21, 2006 to Sept 26, 2006. At the
same time, his immunosuppression was decreased
to prednisone 7.5 mg per day, mycophenolate 250
mg t.i.d. and tacrolimus 2 mg p.o. b.i.d.
Laboratory analysis showed negative IgM
titers for Epstein-Barr virus and for cytomegalovirus. It also showed a positive titer for IgG for
EBV and for CMV. The titers for IgG and IgM for
Parvovirus were negative. However, the PCR for
DNA for Parvovirus B19 was positive. After receiving the IV human immune globulin, the patient’s
hemoglobin increased, in a matter of 4-6 weeks, to
13.1 g/dL and his reticulocyte count became normal.
DISCUSSION
Chronic refractory anemia is an uncommon disorder characterized by severe anemia, low
reticulocyte count and almost complete absence of
erythroid precursors in the bone marrow, all other
series being normal. Pure red cell aplasia may be
rarely congenital (Blackfan-Diamond syndrome)
but usually is idiopathic. It may also be associated
to thymoma, myelodysplasia, lymphoma, leukemias, autoimmune diseases secondary to recombinant erythropoietin especially in patients with
renal failure, drugs such as phenytoin and Chloromycetin and viral infections. Of these viral infections, most notable is Parvovirus B19.(1-5)
Pure red cell aplasia has been lately associated to antibodies against erythropoietin; this has
occurred mostly in Europe, associated to a particular type of recombinant erythropoietin not used
in the United States of America and Puerto Rico
(Eprex). Fewer than 10 cases have been described
among patients exposed either to Epogen (Erythropoieting) manufactured and marketed by Amgen,
or Procrit marketed by Ortho Biotech. Only two
cases have been described and confirmed with the
use of darbepoetin alfa, also produced and marketed by Amgen. Pure red cell aplasia does not occur unless the patient has been on erythropoietin
therapy for at least 3-4 weeks and typically occurs
6-8 months after exposure to this medication(6-9).
This plus other factors discussed below make it
unlikely that darbepoetin was the cause of this
patient’s pure red cell aplasia.
Parvovirus B19 is a recognizable cause
of pure red cell aplasia, mostly in patients who
are immunosuppressed or who have hematologic disorders associated to hemolytic crisis(4, 5,
9-11). The basis of erythroid trophism is the tissue
distribution of the B19 cellular receptor globoside (blood group Pag), mostly in erythroid cells
and mostly in proerythronormoblasts. If the patient is immunosuppressed, the virus infects the
proerythroblasts, giving it the characteristic bone
marrow picture associated with Parvovirus B19 of
giant proerythronormoblasts with cytoplasmic va-
cuoles and cytoplasmic hyaline material similar to
what we used to see with chloramphenicol toxicity
(see photograph II). This, in turn, would lead to either cell lysis of the infected cell and/or maturation
arrest of the erythroid series(2, 3, 9, 12). Parvovirus B19 causes diverse clinical conditions, depending on the immunologic status of the host and/or
associated disorders (13, 14). See Table I.
Table #1
RANGE OF PARVOVIRUS B19 MANIFESTATIONS BY HOST
Healthy individuals
Asymptomatic infection
Erythema infectiosum
Arthropathy
Thrombocytopenia
Transient aplastic crisis
Neurologic disease
Myocarditis
Hepatisis
Vasculitis
Nephritis
Pregnant women
Miscarriage
Congenital anemia
Intrauterine fetal death
Non-immune hydrops fetalis
Individuals with increased red blood cell turnover
Transient aplastic crisis
Immunocompromised hosts
Chronic pure red cell aplasia
Virus-associated hemophagocytic syndrome
Transient pure red cell aplasia
Parvovirus B19 belongs to the subfamily
Parvoviridae, genus Erythrovirus. It is the only
accepted member of the Erythrovirus genus and
the only Parvovirus known to be pathogenic in
humans. There are three documented modes of
B19 transmission: (1) Most individuals develop it
through respiratory fomites, (2) vertical transmission can cause congential infection from women
who become infected during pregnancy, which
would lead then to fetal hydrops fetalis, and (3)
vertical transmission with blood and blood products(12, 15-17).
The usual course of Parvovirus infection
is complete resolution in 3-4 weeks unless the
patient is immunocompromised, in which case
infection may last for many years (11). The accepted treatment in an immunocompromised host
is human immune globulin 400 mcg/kg x 5 days,
or even less days; sometimes patients require a
second or even chronic human immune globulin
administration, depending on the underlying immunologic disorder. In patients with immunosuppressive therapy, decreasing the dose of immunosuppressants may have an additive therapeutic
effect(3, 10, 18).
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
Table 1 (cont.)
Cardiovascular
Neurologic
Acute congestive
Heart failure
Brachial plexus
abnormalities
Myocarditis
Sensorineural abnor malities
Pericardial
effusions
Meningitis/encephalo
pathy
Pericarditis
Seizures
Cutaneous
Ocular
Gianotti-Crosti syn- Conjunctivitis
drome (papular acrodermatitis of
childhood and papulovesicular acrolated síndrome)
Papular-purpuric Ophthalmoplegia
gloves and socks
syndrome
Vascular purpura
Renal
Acute renal failure
Acute renal failure
Erythema nodosum Nephrotic syndrome
Erythema multiforme
Collapsing Glomeru
lopathy transplanted Kidney with allograft
failure
Livedo reticularis
Respiratory
Fifth disease
Acute chest syndrome in sickle cell disease
Hematologic
Pleural effusions
Hemophagocytic
síndrome
Aplastic anemia
(not transient)
Autoimmune hemo-
lytic anemia
Pneumonia
Rheumatic
Autoimmunity and immune mediated
inflammation
Chronic neutropenia Juvenile rheumatoid arthritis
Thrombocytopenia Rheumatoid arthritis
purpura
Transient erythro-
blastopenia of
childhood
Systemic lupus erythe
matosus
Juvenile rheuma- toid arthritis
Chronic pure red
cell aplasia
Vasculitis
*Modified and reproduced with permission from: Jordan, JA. Clinical
manifestations and pathogenesis of human parvovirus B19 infection.
In: UpToDate, Waltham, MA, 2007. Copyright 2007 UpToDate, Inc.
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
45
Diagnostic testing depends on the patient’s
immune status. In immunocompetent hosts, acute
infections may be appropriately diagnosed by serologic testing of B19-specific IgM and IgG. For
immunosuppressed patients, nucleic acid amplification testing by PCR for B19-specific DNA is
considered the test of choice. B19-specific DNA
can be detected for months or even years after infection occurs(18-21).
This patient didn’t have Parvovirus B19
specific IgG or IgM antibodies, arguing against
latent infection in the patient; there is a possibility that the infection came from the transplanted
organ, however, the most probable explanation is
that the patient acquired the infection at some time
after transplantation.
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1991; 28 (4): 275.
2. Fisch P, Handgretinger R, Schaefer HE. Pure red cell aplasia. Br J
Haematol 2000; 111 (4): 1010.
3. Frickhofen N, Chen ZJ, Young NS, Cohen BJ, Heimpel H,
Abkowitz JL. Parvovirus B19 as a cause of acquired chronic pure red
cell aplasia. Br J Haematol 1994; 87 (4): 818.
4. Brown KE, Young NS. Parvovirus B19 infection and hematopoiesis. Blood Rev 1995; 9 (3): 176.
5. Kurtzman G, Young N. Viruses and bone marrow failure. Baillieres
Clin Haematol 1989; 2 (1): 51.
6. Casadevall N, Nataf J, Viron B, et al. Pure red-cell aplasia and
antierythropoietin antibodies in patients treated with recombinant
erythropoietin. N Engl J Med 2002; 346 (7): 469.
7. Rossert J, Casadevall N, Eckardt KU. Anti-erythropoietin antibodies and pure red cell aplasia. J Am Soc Nephrol 2004; 15 (2): 398.
8. Eid AJ, Brown RA, Patel R, Razonable RR. Parvovirus B19 infection after transplantation: a review of 98 cases. Clin Infect Dis 2006;
43 (1): 40.
9. Boven K, Stryker S, Knight J, et al. The increased incidence of pure
red cell aplasia with an Eprex formulation in uncoated rubber stopper
syringes. Kidney Int 2005; 67 (6): 2346.
10. Plentz A, Hahn J, Holler E, Jilg W, Modrow S. Long-term parvovirus B19 viraemia associated with pure red cell aplasia after allogeneic bone marrow transplantation. J Clin Virol 2004; 31 (1): 16.
11. Kurtzman G, Frickhofen N, Kimball J, Jenkins DW, Nienhuis AW,
Young NS. Pure red-cell aplasia of 10 years’ duration due to persistent
parvovirus B19 infection and its cure with immunoglobulin therapy.
N Engl J Med 1989; 321 (8): 519.
12. Young NS, Brown KE. Parvovirus B19. N Engl J Med 2004; 350
(6): 586.
13. Moreux N, Ranchin B, Calvet A, Bellon G, Levrey-Hadden H.
Chronic parvovirus B19 infection in a pediatric lung transplanted patient. Transplantation 2002; 73 (4): 565.
14. Nguyen QT, Sifer C, Schneider V, et al. Novel human erythrovirus
associated with transient aplastic anemia. J Clin Microbiol 1999; 37
(8): 2483.
15. Saldanha J, Minor P. Detection of human parvovirus B19 DNA
in plasma pools and blood products derived from these pools: implications for efficiency and consistency of removal of B19 DNA durin
manufacture. Br J Haematol 1996; 93 (3): 714.
16. Virus taxonomy update. The International Committee on Taxonomy of Viruses. Arch Virol 1993; 133 (3-4): 491.
17. Brown KE. Variants of B19. Dev Biol (Basel) 2004; 118: 71.
18. Jordan JA. Identification of human parvovirus B19 infection in
idiopathic nonimmune hydrops fetalis. Am J Obstet Gynecol 1996;
174 (1 Pt 1): 37.
19. Heegaard ED, Schmiegelow K. Serologic study on parvovirus
b19 infection in childhood acute lymphoblastic leukemia during chemotherapy: clinical and hematologic implications. J Pediatr Hematol
Oncol 2002; 24 (5): 368.
20. Nguyen QT, Wong S, Heegaard ED, Brown KE. Identification and
characterization of a second novel human erythrovirus variant, A6.
Virology 2002; 301 (2): 374.
21. Cassinotti P, Burtonboy G, Fopp M, Siegl G. Evidence for persistence of human parvovirus B19 DNA in bone marrow. J Med Virol
1997; 53 (3): 229
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BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
Acknowledgement:
The authors thank Dr. Luis Lozada Munoz for
his collaboration in reproducing the bone marrow
photographs.
RESUMEN
Describimos un caso de aplasia pura de células
rojas desarrollado dos meses después de un trasplante de riñón en un paciente que recibió inmunosupresión. La hemoglobina del paciente era 9.5g/
dl, el contaje de reticulocitos fue de 0%, las células
blancas y las plaquetas mostraban un contaje normal, los resultados de la medula ósea mostraban
hipercelularidad con elementos normales de células mielociticas y megakariociticas. Las series
eritrociticas estaban completamente ausentes excepto por un aumento en proeritronormoblastos gigantes con vacuolas en su citoplasma. Los títulos
para imunoglobulinas IgG y IgM para Parvovirus B19 fueron negativos. Sin embargo, el “DNA
PCR” para Parvovirus B19 fue positivo. Después
de recibir imunoglobulina humana intravenosa la
hemoglobina del paciente aumentó en 4-6 semanas
a 13.1g/dl y el contaje de reticulocitos se normalizo. La causa de la anemia del paciente se atribuye al Parvovirus B19. Parvovirus B19 debería ser
considerado como una causa idiopática de anemia
progresiva en este caso de hecho un factor a considerar en cualquier paciente imunosuprimido. El
contaje de reticulocitos, la biopsia de médula ósea
y el “DNA PCR” para Parvovirus B19 son esenciales para el diagnóstico.
¿Por qué celebrar la Convención de
Estudiantes de Medicina?
Puerto Rico posee cuatro escuelas de medicina acreditadas por la Association of American
Medical Colleges, alrededor de 1,200 estudiantes
cursan su formación médica cada año en estas instituciones. Sin embargo, no es hasta ahora que se
logra establecer una asociación que reúna a este
grupo de jóvenes talentosos comprometidos con
la salud del País. La Asociación de Estudiantes de
Medicina de Puerto Rico surge con la iniciativa de
brindar a sus miembros un organismo que desarrolle sus intereses académicos, profesionales y sociales. Para emprender nuestra visión, la AEMPR
planifica la Primera Convención de Estudiantes de
Medicina de Puerto Rico que se celebrará del 3 al
5 de abril de 2009 en el hotel Ponce Hilton. Allí se
desarrollará un foro académico para el intercambio
de ideas entre estudiantes y facultativos en un ambiente de confraternización. Además, se cultivará
una tradición de pensamiento colectivo que promueva la unificación de la futura clase médica.
Esta inciativa es apoyada por los Decanos,
Consejos Estudiantiles y miembros de la Facultad Médica de las respectivas escuelas de medicina: Recinto Ciencias Médicas de la UPR, Ponce
School of Medicine, Universidad Central del Caribe y la Escuela de Medicina San Juan Bautista.
Esperamos la asistencia de más de 800 estudiantes
y 200 facultativos que participarán en la discusión
de temas que afectan significativamente la práctica
de la medicina, pero que no forman parte de los
currículos académicos de nuestras escuelas.
3 al 5 de abril del 2009
Contaremos con la presencia de distinguidos galenos cuya trayectoria exitosa los convierten en
recursos invaluables en los temas que integran el
programa de conferencias: El Desarrollo de Puerto
Rico como Centro para la Investigación Mundial,
la Falta de Talleres y Programas de Residencia en
Puerto Rico, La Reforma de Salud, Panel sobre la Impericia Médica, Medicina Comunitaria, Éxodo Médico, Planificación Financiera para
Médicos y Medicina Alternativa, entre otros. Para
el beneficio de nuestros facultativos varias de estas
conferencias serán acreditadas como Educación
Médica Continua. Además, ofreceremos una Feria
de Residencias y culminaremos con una Asamblea
Estudiantil para seleccionar a la nueva directiva y
así vincular la responsabilidad de los estudiantes
de medicina con la salud de Puerto Rico.
Estamos comprometidos con nuestro propósito, esperamos el apoyo económico del Gobierno, de los profesionales, de las asociaciones
e industrias relacionadas a la salud para encaminarnos en esta misión. La Primera Convención de
Estudiantes de Medicina de Puerto Rico iniciará
un proceso novel en el desarrollo profesional de
los futuros médicos de la Isla al hacerlos partícipes, desde temprano en su formación, de aquellos
problemas que afectan profundamente la salud de
nuestra Isla.
Cordialmente,
Luis A. Tarrats Ortolaza
[email protected]
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
47
CALCIPHIC UREMIC ARTERIOLOPATHY COMPLICATING
CHRONIC KIDNEY DISEASE
Sarahí Rodríguez-Pérez, MD *, José Ramírez-Rivera**, MD, MACP and Francisco
Jaume-Anselmi***, MD, FACP, Axel Báez Torres, MD, FACP****
ABSTRACT
Calcific uremic arteriolopathy is a rare and
devastating disorder characterized by diffuse calcification of medium size arterioles and occasionally affects patients with chronic kidney disease.
A 62-year-old woman with diabetes mellitus, arterial hypertension and moderate to severe chronic
kidney disease was admitted to the hospital with
multiple, non painful, necrotic, hemorrhagic and
purulent chronic open wounds ranging from 1 cm
to 3 cm of diameter in the medial and posterior aspects of both lower extremities. Sensation to light
touch and vibration were absent in the lower extremities. Biopsy of a one of the lesions showed fat
necrosis and extensive dystrophic calcific deposits
in the subcutaneous fat and the wall of small arterioles, consistent with systemic calcific uremic
arteriolopathy. Once the lesions ulcerate and grow
proximally survival is unlikely.
Index words: calciphic, uremic, arteriolopathy,
chronic, kydney
INTRODUCTION
Calcific uremic arteriolopathy is a rare
and devastating disorder characterized by diffuse
calcification of medium size arterioles. It usually occurs in patients with an elevated calcium/
phosphate product. At risk are particularly patients
with end-stage renal disease in chronic hemodyalisis; but occasionally it is seen in patients with long
standing chronic kidney disease.
CASE REPORT
A 62-year-old woman with diabetes mellitus, arterial hypertension and moderate to severe
chronic kidney disease since five years before admission was admitted to the hospital with multiple
chronic open wounds in the medial aspect of lower
legs developed in recent weeks. Her daily medications were captopril 50 mg daily, verapamyl 240
mg daily, spironolactone 25 mg daily, rosiglitazone 8 mg daily and Insulin N 50 units twice a day.
Her temperature was 36.6°C, pulse 65/
min, respirations 22/min, blood pressure was
220/100 mm Hg, weight 234 pounds and height
5’5’’ (BMI 38). She looked chronically ill. The
heart had a regular rhythm. There were bilateral
basilar crackles. There was +3 leg edema and multiple, non painfull, necrotic, hemorragic and purulent chronic open wounds ranging from 1 cm to 3
cm of diameter in the medial and posterior aspects
of both calves and thighs. Sensation to light touch
and vibration was absent.
The admission white blood-cell count was
12,200, hemoglobin 10.5 g/dL, hematocrit 31.2%,
and platelets 577,000/m³. The glucose was 227 mg/
dL, BUN 50 mg/dL, creatinine 3.6 mg/dL, Ca 8.4
mg/dL and PO4 6.9 mg/dL. The calculated creatinine clearance was 27 ml/hr. Urinalysis showed
protein >300 mg/dL. The intact parathyroid hormone was 143 pg/mL.
Five days after the admission the BUN
rose to 62 mg/dL and the creatinine to 4.4 mg/
dL; and hemodialysis was started. The chronic
open wounds increased in size, growing toward
the medial aspect of thighs (Fig.1). Biopsy of one
of the lesions showed fat necrosis and extensive
dystrophic calcific deposits in the subcutaneous
fat and the wall of small arterioles, consistent with
systemic calcific uremic arteriolopathy (Fig. 2).
Amputation was advised, but the patient refused.
She was discharged to continue with ambulatory
hemodialysis. She died three months later of septic
shock.
DISCUSSION
Calcific uremic arteriolopathy is a disorder characterized by arteriolar calcification in the
dermis, leading to painful, red nodules that progress to ulcerative lesions with necrotic centers
and well defined borders. The lesions occur distally in the lower extremities, or proximally in the
inner thighs, buttocks or abdomen. In 1962, Hans
Selye described skin ulcers secondary to dermal
calcifications as calcifilaxis; and for some time
this disorder has been incorrectly labeled with this
name.
From the Department of Medicine of La Concepción Hospital: *Resident PGYII, La Concepción Hospital, **Director in Clinical Investigation,
La Concepción Hospital, ***Internal Medicine Program Director, La Concepción Hospital, ****Pathology Department and Medical Laboratory
Director, La Concepción Hospital. Presented in part in the Associates Meeting of the American College of Physicians, Intercontinental Hotel, San
Juan, Puerto Rico, October 28, 2006
Address reprint requests to: Francisco Jaume-Anselmi, MD, FACP - Coral 21 Vista Verde, Mayaguez, PR 00682 Tel.: 787 892 0102 Fax: 787 831
1037. E-mail: <[email protected]>
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
48
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
Figure 1. View of the medial aspect of the left leg. The chronic open wounds have well defined
borders with violaceous and black scars. The white material is sylvadene cream.
Figure 2. Biopsy of the subcutaneous tissue with a medium size arteriole. There are dystrophic
calcific deposits in the adventicia (arrow), with necrosis of the surrounding fat tissue (hematoxylin-eosin, original magnification x100).
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
Calcific uremic arteriolopathy does not exclusively occur in end-stage renal disease patients,
it can also develop before chronic hemodialysis is
required. The mortality rate of calcific uremic arteriolopathy ranges from 45% to 65%, and increases
to 80% with proximal distribution and once ulceration develops (1,2). Risk factors include female
gender, Caucasian race, obesity, renal disease and
hypoalbuminemia.
Historically, increase parathyroid hormone (PTH) as a key risk factor lead to recommendations of parathyroidectomy in patients with the disorder; however, recent studies have demonstrated
that hyperphosphatemia is the most prominent risk
factor (3).
Elevated calcium and phosphate are proposed to induce vascular calcification in two ways:
The elevated phosphate increases phosphorus uptake and the elevated calcium increases the synthesis of the Sodium – Phosphorus co-transporter.
This leads to increase intracellular concentration
of phosphorus. Elevated intracellular phosphorus
induces a phenotypic modulation of the vascular
smooth muscle cell through up-regulation of osteogenic genes. The stimulated vascular smooth
muscle cell behaves as an osteoblast. It produces
osteocalcin, osteoponting and alkaline phosphatase, a competent extracellular matrix for mineralization. In addition the increase activity of the
co-transporter increases the Ca/P loading of matrix
vesicles and promotes the nucleation of minerals
within the extracellular matrix. The elevated Ca
and PO4 increase the Ca/PO4 product increasing
the growth of apatite crystals in the extracellular
matrix. These two mechanisms together contribute
to calcific deposition within the extracellular space
of the muscular layer of the skin vessels (Diagram
1)(4).
The occurrence of calcific uremic arteriolopathy is frequently precipitated by a specific
event, such as local skin trauma and/or injections.
The most common clinical presentation includes
very painful nodules on the lower extremities, abdomen, buttocks, or thighs. These nodules often
rapidly progress to growing ulcerative lesions that
may become infected and lead to sepsis and death.
Unfortunately peripheral vascular disease as well
as diabetic neuropathy may coexist, and this can
obscure the initial presentation.
The gold standard procedure for diagnosis is a biopsy of the borders of the open wounds
showing calcified arterioles.
Calcific uremic arteriolopathy was once
thought to occur only in patients in chronic hemodialysis, but the incidence of this disorder is
increasing in patients with chronic kidney disease
stage 3 and 4. This increase is in part due to the
practice of treating severe hyperparathyrodism
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
49
with calcium-based phosphate binders and vitamin
D analogs (5).
The optimal treatment for this disorder is
prevention: aggressive control of hyperphosphatemia and maintaining the Ca x P04 product below
55 is essential. Non calcium-containing phosphate
binders and strict monitoring should be employed
to prevent the metabolic circumstances in which
calcific uremic arteriolopathy develops (6).
Given the high mortality of calcific uremic arteriolopathy, an early diagnosis is imperative. As soon as the disease is suspected, vitamins
D analogs must be discontinued and the frequency of the dialysis should be increased (7). The Ca
x P04 product and hyperphosphatemia should be
aggressively controlled. Once the lesions ulcerate
and grow proximally chances of of survival is unlikely.
Pathogenesis
Vascular Smooth Muscle Cell
(VSMC)
Minerals
Elevated
Ca and PO4
Na
P
P
Matrix vesicle
Collagen
Ca/P
Ca/P loading of
Phenotypic
Matrix vesicles
modulation
•Osteocalcin
•Osteopontin
•Alkaline phospatase
Matrix Mineralization
Elevated
CaxPO4 product
CM Giachelli. Vascular calcification mechanisms. J AM Soc Nephrol 2004. 15; 2959 – 2964.
Diagram 1. Possible roles of Ca and PO4 on vascular calcification
REFERENCES
1.
Coates T, Kirkland GS, Dymock RB, et al. Cutaneous necrosis from
calcific uremis arteriolopathy. AM J Kidney Dis
1998; 32: 384-391.
2.
Fine, A, Zacharias, J. Calciphylaxis is usually non-ulcerating: Risk factors, outcome and therapy. Kidney Int 2002; 61:2210.
3.
Lim, SP, Batta, K, Tan, BB. Calciphylaxis in a patient with
alcoholic liver disease in the absence of renal failure. Clin Exp Dermatol 2003; 28:34.
4.
CM Giachelli. Vascular calcification mechanisms. J AM
Soc Nephrol 2004. 15; 2959-2964.
5.
Price, PA, Williamson, MK, Nguyen, TM, Than, TN.
Serum levels of the fetuin-mineral complex correlate with artery calcification in the rat. J Biol Chem 2004; 279:1594.
6.
Ahmed S, O’Neill KD, Hood AF, et al. Calciphylaxis is
associated with hyperphosphatemia and increase osteopontin expression by vascular smooth muscle cells. Am J Kidney Dis 37: 12671276, 2001.
7.
Don, BR, Chin, AI. A strategy for the treatment of calcific uremic arteriolopathy (calciphylaxis) employing a combination of
therapies. Clin Nephrol 2003; 59:463.
50
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
RESUMEN
La arteriolopatía urémica calcificante es
un desorden raro y devastador caracterizado por
calcificación difusa de las arteriolas de pequeño y
mediano calibre que puede afectar pacientes con
enfermedad renal crónica. Una mujer de 62 anos
de edad con diabetes mellitus, hipertensión arterial y enfermedad crónica renal fue admitida al
hospital con múltiples heridas abiertas crónicas,
purulentas, necróticas y hemorrágicas, de 1 a 3 cm
de diámetro en el aspecto medial y posterior de la
porción distal de las extremidades inferiores. La
sensación al tacto y a la vibración estaba ausentes
en ambas extremidades. Biopsia de una de las lesiones demostró extensos depósitos de calcio en el
tejido subcutáneo y en las paredes de las arteriolas
de pequeño calibre, consistente con la arteriolopatía urémica calcificante. La arteriolopatía urémica calcificante puede desarrollarse antes de que la
hemodiálisis sea necesaria. Isquemia a los tejidos
perfundidos por estas arteriolas pueden provocar
necrosis e infecciones fatales. Una vez las lesiones
se desarrollan la supervivencia es poco probable.
Publique su trabajo
en una de nuestras
prestigiosas publicaciones
Circulación 10.500 ejemplares Circulación 12.000 ejemplares
Las colaboraciones deben ser remitidas en formato
impreso y digital (CD) a:
Prensa Medica / Boletin AMPR
P.O. Box 9387
San Juan, PR 00908-9387
Informes: [email protected]
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
51
JACCOUD’S ARTHROPATHY REVISITED
David Martínez, MD*
ABSTRACT
Jaccoud’s arthropathy is a chronic, non
erosive, rheumatoid-like deformity of the hands
associated with rheumatic fever and systemic lupus erythematosus (SLE). This deforming arthropathy may present difficulties in differentiating
SLE from rheumatoid arthritis (RA). We present
a case of a 43-year-old woman who was initially
diagnosed with Sjögren’s syndrome and rheumatoid arthritis (RA), and several years later, with
SLE. The diagnosis of RA was based mainly on
the presence of hands deformities. On evaluation
she had reducible hands deformities and had no
radiographic evidence of joint destruction; thus joint deformities were not consistent with RA but to
Jaccoud’s arthropathy associated with SLE. Here,
we revisit Jaccoud’s arthropathy and highlight the
importance of a careful joint examination in the
assessment of rheumatic diseases.
Index words: Jaccoud’s deformities, systemic lupus erythematosus
INTRODUCTION
In 1869 a French physician, Francois Sigismond Jaccoud (1830-1913), described an unusual
form of arthritis occurring after several attacks of
rheumatism in a 29-year-old man with endocarditis (1). The young man developed ulnar deviation
and subluxation of the metacarpophalangeal joints
of the second, third, fourth and fifth fingers. The
toes were also affected. It was considered a form
of rheumatism following acute rheumatic fever.
E.G.L. Bywaters is credited of being the
first one to associate the deformities described by
Jaccoud with those seen in some patients with systemic lupus erythematosus (SLE) (2). These deformities are similar to those observed in patients
with rheumatoid arthritis (RA), but in contrast,
Jaccoud’s deformities are usually reducible and are
not associated with ankylosis or joint erosions.
Thirty years ago our resident physicians
were very familiar with Jaccoud’s deformities as
they were frequently seen, particularly in patients
with rheumatic fever. Jaccoud’s was a familiar
name; nowadays we rarely see a case. Here, we
present a case of a 43-year-old woman with SLE
and Jaccoud’s arthropathy who was initially misdiagnosed as having RA. This case report exemplify that a careful joint examination is critical in
reaching an accurate diagnosis of rheumatic diseases.
CASE REPORT
In November 2006 our service was consulted to evaluate a 43-year-old pregnant woman
who had history of multiple autoimmune rheumatic disorders. She had RA, SLE and Sjogren’s
syndrome (SS) for more than 20 years. She was
first diagnosed with SS after complaining of dryness of eyes and mouth. The diagnosis of SS was
confirmed by minor salivary gland biopsy. Few
years later, she was diagnosed with RA after developing deformities in both hands and having a positive rheumatoid factor. She was treated only with
low-dose prednisone. Five years before admission
she was diagnosed with SLE after presenting malar rash, photosensitivity, thrombocytopenia, oral
ulcers, and positive ant-nuclear, anti-Smith and
anti-dsDNA antibodies. She was continued on
glucocorticoids but at higher doses. In 2005 she
had intrauterine death of twins. Antithrombin-3
deficiency was found. Anticardiolipin antibodies
and lupus anticoagulant tests were negative. Afterwards, she developed premature ovarian failure
but she became pregnant again after in-vitro fertilization.
One week before admission she developed arterial hypertension, suprapubic discomfort
and vaginal blood spotting. She was treated with
alpha methyldopa and bed rest. Fetal sonogram
was compatible with a 15 weeks fetus with a heart
rate of 169 beats per minute. She was admitted due
to severe hypertension, headaches, marked proteinuria, and pleural effusions. On admission she was
using methylprednisolone 12 mg daily, alpha methyl dopa 250 mg twice a day, enoxaparin sodium
40 mg subcutaneous twice daily, prenatal multivitamins, ferrous sulfate 325 mg daily and folic acid
400 mcg daily.
On physical examination the temperature
From the *Department of Medicine,,Division of Rheumatology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico
Address reprints to: David Martínez, MD - Professor of Medicine, Division of Rheumatology, University of Puerto Rico Medical Sciences Campus,
PO Box 365067, San Juan, PR 00936-5067. Tel. 787-758-2525, ext. 1825. Fax: 787-764-6839. E-mail: [email protected]
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
52
was 36°C, blood pressure was 173/92 mm Hg,
pulse was 84/min and respiratory rate was 20/min.
She had dry eyes and mouth. She presented ulnar
deviation of the metacarpophalangeal joints with
subluxation of the second, third, fourth and fifth
fingers bilaterally, Z deformity of the thumbs and
bilateral swan neck deformities of the first, second
, and fifth fingers, She had pes planus, hallus valgus and hammer toes bilaterally. Strikingly, hands
deformities were reducible and no ankylosis or
subcutaneous nodules were present. There were no
signs of inflammation. Breath sounds were diminished in both lung bases. The rest of the physical
examination was unremarkable.
The white blood cell count was 5.7 x
103/ cu mm, Hgb was 9.5g/dl, platelets count was
206,000/ cu mm, erythrocyte sedimentation rate
by Westergreen method was 69 mm/hr and the CReactive protein was positive at 1:2. Direct and
indirect Coombs tests were negative. Reticulocyte count was normal. Prothrombin time, partial
thromboplastin time, and international normalized
ratio were within normal limits. Serum blood urea
nitrogen, creatinine and liver function tests were
normal. Albumin was decreased at 2.1g/dl. Urine
analysis showed proteinuria (>300mg) with negative sediment. A 24-hr urine collection showed a
total protein of 2,363 mg and normal creatinine
clearance at 105 ml/min. Urine culture was negative. HIV-1 and VDRL tests were negative. Anti
dsDNA antibodies were elevated at 1:320. Anti-Ro
and anti-La antibodies were both elevated at >100
EU/ml (positive>20). Serum levels of complements C3 and C4 were normal.
Echocardiogram showed a normal left
ventricular systolic function and normal ejection
fraction (70%) with no pericardial effusion and no
chamber dilatation. Renal ultrasound was compatible with parenchymal renal disease. Hands x-rays
showed no erosions.
She was managed aggressively with antihypertensive medications and pulse methylprednisolone (1 g) followed by high-dose prednisone
(1 mg/kg/day). Three days after admission she
had intrauterine death for which she underwent
dilatation and curettage. Afterwards, she improved markedly; her blood pressure normalized and
proteinuria resolved. A 24-hr urine collection after
delivery showed a total protein of 123 mg. Also, a
chest computed tomography done two days after
the obstetric procedure showed only small bilateral pleural effusions.
DISCUSSION
Jaccoud’s arthropathy is an uncommon joint deformity associated with rheumatic fever and SLE
(3). Our patient presented classical findings of
Jaccoud’s arthropathy. In fact, she had nine points
of the Jaccoud’s arthropathy index where a sco
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
re exceeding 5 points is used for establishing the
diagnosis (3). This index includes ulnar drift, swan
neck deformities, boutonnière deformities and
Z deformity of the thumb. However, our patient
posed a diagnostic challenge as she was initially
diagnosed with Sjögren’s syndrome which itself
has been associated with Jaccoud’s arthropathy (4).
Furthermore, she had a positive rheumatoid factor
which together with the presence of polyarthritis
and joint deformities raised the possibility of RA.
Indeed, the clinical appearance of lupus and RA
synovitis in early stages of disease is very similar (5). In addition, hands deformities may appear
early in SLE (5). As in our case, the latter patients
have a greater frequency of sicca syndrome and
rheumatoid factor positivity (5).
By the time we evaluated our patient the
diagnosis of SLE was already established based on
clinical and serologic criteria. The main question
was whether she also had RA, the so called rhupus
syndrome (6). After a detailed joints examination
we concluded she had reducible hand deformities
consistent with Jaccoud’s arthropathy as seen with
SLE. X-rays of the hands done afterwards showed
no erosions confirming the initial assessment. In
fact, it has been suggested that polyarthritis without
erosive changes after two years of disease should
prompt the diagnosis of SLE rather than RA (7).
On the other hand, the coexistence of RA and SLE
is diagnosed when bone erosions typical or RA are
present (8). Magnetic resonance imaging may help
to distinguish Jaccoud’s arthropathy from RA as it
can disclose RA erosions missed by conventional
radiology (9). It can also show soft tissue pathologic alterations characteristic of SLE.
The prevalence of Jaccoud’s arthropathy
in SLE (lupus hands) has been reported between 4
% and 25 % (10, 11). Although the hands show the
most striking clinical findings the foot may also
be involved (lupus foot) with hallus valgus and/
or subluxation of the metatarsophalangeal joints
with hammer toes (12). In addition, flexion contracture of the elbows has been described (13). The
arthropathy seems to involve all joints with the
main clinical manifestations in the hands and feet
as their ligaments, tendons and periarticular soft
tissues are more prone to the clinical evident deformities. The diagnosis of Jaccoud’s arthropathy
is still clinical (reversible joint deformities) as no
specific diagnostic criteria have been established.
However, some attempts for diagnosis have been
proposed (14, 15).
Deformities of Jaccoud’s arthropathy may
be impressive but the joints themselves are relatively well preserved (2). Contrary to RA where
inflammatory joint damage causes joints deformities, the pathogenic mechanisms in Jaccoud’s arthropathy are not well established. Several possibilities have been considered including capsulitis
and muscular imbalance (10), laxity of ligaments
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BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
(16), ulnar displacement of the extensor tendons
after capsular distension (17), ligaments and tendon pathology (9) and joint hypermobility (18).
Dr. Jaccoud himself considered that the deformities were related to contractures of the palpable
cords in the palmar aponeurosis (1). These deformities have been identified in many rheumatologic conditions as well as in nonrheumatic diseases
(14). Pathological specimens show mild synovitis
without pannus formation (10). Thus, it seems that
various mechanisms may play a role leading to the
final joint deformities.
In summary, our case demonstrates that
SLE may be misdiagnosed as RA, particularly
when Jaccoud’s arthropathy is present. Careful joint examination may reveal reducible deformities
and the absence of bony ankylosis. X rays typically shows no erosions even when the rheumatoid
factor is positive. In case of clinical uncertainty,
magnetic resonance could be helpful to elucidate
the diagnosis. Some patients may have RA and
SLE but the vast majority of patients we see have
one disease or the other. Making a correct early
diagnosis is of paramount importance in patient’s
management and outcome.
REFERENCES
1.
Jaccoud FS. Sur une forme de rhumatisme chronique.Lecons de clinique Medicale faites a l’Hopital de la Charite.
Paris:Delahaye,1869:598-616.
2.
Bywaters E.G.L Relationship between heart and joint disease including “rheumatoid heart disease” and chronic post-rheumatic arthritis (type Jaccoud). Brit. Heart J.,1950,12,101-131.
3.
Spronk PE, ter Borg EJ, Kallenberg CGM. Patients with
systemic lupus erythematosus and Jaccoud’s arthropathy clinical subset with an increased C reactive protein response? Ann Rheum Dis
1992; 51:358-61.
4.
Ballard M, Meyer O, Adle-Biassette H, Grossin M.
Jaccoud’s arthropathy with vasculitis and primary Sjogren’s syndrome A new entity. Clin Exp Rheumatol. 2006;24:S102-3.
5.
Alarcon-Segovia D, Abud-Mendoza C, Diaz-Jouanen E,
Iglesias A, De los Reyes V, Hernandez-Ortiz J. Deforming arthropathy of the hands in systemic lupus erythematosus. J Rheumatic. 1988;
15:65-69.
6.
Fernandez A, Quintana G, Matteson EL, Restrepo JF,
Rondon F, Sanchez A, Iglesias A. Lupus arthropathy: historical evolution from deforming arthritis to rhupus. Clin Rheumatol.2004; 23;
523-26.
7.
Bywaters E.F.L. Classification criteria for systemic lupus
erythematosus, with particular reference to lupus-like syndrome. Proc
R Soc Med 1967;60:463-4.
8.
Satoh M, Ajmani A, Akizuki M. What is the definition
for coexistent rheumatoid arthritis and systemic lupus erythematosus?
{letter}. Lupus 1994;3:137-8.
9.
Ostendorf B, Scherer A, Specker C, Modder U, Schneider
M, Jaccoud’s arthropathy in systemic lupus erythematosus: Differentiation of deforming and erosive patterns by magnetic resonance imaging. Arthritis Rheum 2003;48:157-65.
10.
Bywaters E.G.L .Jaccoud’s syndrome. A sequel to the joint involvement of systemic lupus erythematosus. Clin Rheum Dis
1975;1:125-48.
11.
Russel AS, Pery JS, Rigal WM, Wilson GL. Deforming
arthropathy in systemic lupus erythematosus. Ann Rheum Dis 1974;
33:204-9.
12.
Morley KD, Leung A, Rynes RI. Lupus foot. BMJ 1982;
284:557-8.
13.
Esdaile JM, Daroff D, Rosenthal L, Gutowsko A. Deforming arthritis in systemic lupus erythematosus .Ann Rheum Dis
1981;40:124-6.
14.
Murphy WA, Staple TW. Jaccoud’s art14.Ballard M,
Meyer O, Adle-Biassette H, Grossin M. Jaccoud’s arthropathy with
vasculitis and primary Sjogren’s syndrome A new entity. Clin Exp
Rheumatol. 2006;24:S102-3.
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
53
15.
Villaumey J, Arlet J, Avouac B. Diagnostic criteria and
new etiologic events in the arthropathy of Jaccoud: a report of 10
cases. Clin Rheumatol Pract. 1986;4:156-75.
16.
Bleifield CJ, Inglis AE: The hands in systemic lupus
erythematosus .J Bone Joint Surg 1974;56A:1207-15.
17.
Zvaiter N.J. Chronic post-rheumatic-fever (Jaccoud’s)
arthritis. New England J.Med.,1962,267,10-14.
18.
Caznoch CJ, Esmanhotto L ,Silva MB, Skare TL. Pattern
of joint involvement in patients with systemic lupus erythematosus
and its association with rheumatoid factor and hypermobility. Rev
Bras Reum. 2006; 46:261-65.
Acknowledgements:
Dr. Judith Román for translating Dr. Jaccoud’s original article and Dr. Luis Vilá for reviewing the
manuscrit.
RESUMEN
La artritis de Jaccoud es una deformidad
de las manos parecida a la observada en las manos
de pacientes con artritis reumatoide. Esta deformidad crónica, no erosiva, se asocia mayormente al
lupus sistémico eritematoso y a la fiebre reumática. Los pacientes con lupus sistémico eritematoso
y la deformidad de Jaccoud pueden diagnosticarse
erróneamente como artritis reumatoide. Se presenta el caso clínico de un paciente de lupus sistémico
eritematoso con deformidad de Jaccoud. Se repasan los criterios diagnósticos de la condición enfatizando la importancia de un examen detallado
de las coyunturas para poder hacer un diagnostico
preciso.
54
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
SYSTEMIC LUPUS ERYTHEMATOSUS PRESENTING AS
ACUTE ICERIC HEPATITIS: A CASE REPORT
Vanessa E. Rodriguez MD*, Pablo Costas MD**
ABSTRACT
Liver involvement in systemic lupus
erythematosus (SLE) is infrequent. The coexistence of SLE and autoimmune hepatitis is rare
(1.3-1.7%). We report a case of a 27 year old female with no history of systemic illnesses or alcohol abuse that presented with acute hepatitis
with jaundice, abdominal pain, and increased liver
function tests. Viral markers were negative. ANA
was strongly positive. Patient was suspected to
have SLE but no definite diagnosis made. She remained asymptomatic for 9 years but then she had
recurrence of hepatitis. She also presented with
malar rash, arthritis, and proteinuria. At that time a
liver biopsy showed autoimmune hepatitis. Other
tests which confirmed SLE included a positive antidsDNA, positive antismith antibody and decreased complement levels. She was started on prednisone 40 mg with mild improvement of symptoms
and transaminase values, but when azathioprine
100 mg was added a marked improvement in liver
function tests was observed. After a year in azathioprine she remained with SLE in remission. To
our knowledge this is the third reported case and
the first in the Western Hemisphere of jaundice as
the initial presentation of SLE.
Key words: systemic, lupus, erythematosus, acute,
icteric, autoimmune, hepatitis
INTRODUCTION
Systemic lupus erythematosus (SLE) is a
multisystemic autoimmune disorder characterized
by circulating autoantibodies that are deposited in
the vascular beds of all the organs. These deposited autoantibodies initiate an inflammatory response that damages the organ. SLE can affect any
organ in the body, but the joints, skin and kidney
Date
AST (U/L)
ALT (U/L)
are most frequently affected. Liver involvement is
notoriously uncommon in SLE and often of little
clinical significance (1). From 2.5-29% of patients
with SLE have increased liver transaminases (2,3),
and 25-50% will develop abnormal transaminases
at some point during their illness. The most common causes of increased transaminases in SLE are
viral infections and drugs (4).
Autoimmune hepatitis (AIH) is a self-perpetuating hepatic inflammation of unknown cause
characterized by the presence of liver associated
autoantibodies. It is a distinct clinicopathological
entity from SLE, although the two may coexist (5).
A scoring system developed by the International
Autoimmune Hepatitis Group Report (IAHGR)
uses clinical, laboratory and histologic data to establish a “definite” or “probable” diagnosis of AIH
(6).
We present a case of a patient with acute
hepatitis that led to a diagnosis of SLE. The patient
fulfilled the criteria for the diagnosis of AIH. To
our knowledge, this is the third reported case of
acute icteric hepatitis as the first clinical presentation of SLE, and the first in the Western Hemisphere.
CASE REPORT
A 42 year old woman with no history of
systemic illness presented in December 1991 at
age 27 with acute onset of tiredness, right upper
quadrant pain, nocturnal fevers, diarrhea, and
jaundice. There were no prodromal symptoms. She
was hospitalized and laboratory data showed elevated levels of aspartate aminotransferase (AST)
1105 U/L, alanine aminotransferase (ALT) 895
U/L, gamma glutamyltransferase (GGT) 243 U/L
and bilirubin 5.3 mg/dl (Table 1). There was no
1991 1998 Mar-2006 May-2006 June-2006 Aug-2006 June-2007
1105 217
246
229
60
55
57
895
449
136
414
214
78
87
Table 1: Results of liver transaminases.
From the *Rheumatology Section, Internal Medicine Department, UPR School of Medicine, and the **Department of Gastroenterology and Liver
Diseases Section, Internal Medicine Department, UPR School of Medicine.
Address reprints to: Vanessa E. Rodríguez , MD, Division of Rheumatology, Department of Medicine, Medical Sciences Campus, University of
Puerto Rico, Division of Rheumatology, E-mail: <[email protected]>
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
55
history of alcohol abuse, blood transfusion, or
use of prescribed or “natural” medications. There was no family history of liver disease. Testing
for hepatitis A IgM, hepatitis B surface antigen,
and hepatitis B core antibody IgM were negative.
Subsequent testing for hepatitis C antibody was
negative. Abdominal sonogram was negative for
cholelithiasis or bile duct dilatation. Antinuclear
antibody (ANA) test was positive in high titers
(1:2560 speckled pattern), and antismooth muscle
(ASMA), antimicrosomal and antimitochondrial
(AMA) antibodies were all negative. Jaundice resolved without specific treatment, and patient was
discharged.
Outpatient evaluation by a rheumatologist
revealed arthralgias and a positive ANA. Systemic
lupus erythematosus was suspected but there was
no malar rash, discoid rash, oral ulcers, leucopenia,
thrombocytopenia, anemia, pleuritis, pleural effusion, pericardial effusion, microhematuria, proteinuria, psychosis or seizures. Hydroxychloroquine
400 mg daily was prescribed which she continued
from 1992 until 2000. No further episode of jaundice or abdominal pain.
Figure 1: Mild portal inflammation with extension of mononuclear
inflammatory infiltrate to the zone 1 hepatocytes – interface hepatitis
(arrow)
Testing done in 1998 revealed a positive
double stranded DNA (dsDNA) at 1:320, and a
positive antiSmith (Sm) at 1:50. At that time AST
217 U/L, ALT 449 U/L, C3 89 mg/dl, C4 15 mg/dl,
and creatinine .8 mg/dl.
In 2000 she recurred with right upper quadrant pain and elevated liver enzymes. A cholecystectomy and liver biopsy were performed. The
gallbladder did not contain gallstones. The liver
histology showed mild portal inflammation, mild
interface hepatitis, and occasional spotty necrosis
(Fig 1 and 2). Mild periportal fibrosis with rare
porto-portal septae were also present. Prednisone
10 mg and ursodiol 300 mg daily were started with
improvement in symptoms.
Figure 2: Inflammatory infiltrate within the hepatic acinus – spotty
necrosis (arrow)
In 2006 patient presented with malar rash,
arthritis of the hand joints, alopecia, tiredness, and
right upper quadrant pain. Laboratories revealed
white blood cells 8,500/ul, hemoglobin 13.1 gm/
dl, platelets 163,000 , creatinine 0.8 mg/dl, AST
136 U/L, ALT 246 U/L, ANA positive 1:640 nucleolar pattern, and antidsDNA positive (75 AU/
ml). Other tests included: anti-SSA (Ro) positive,
anti-SSB (La) negative, normal complement C3
100 mg/dl, low complement C4 16 mg/dl, anticardiolipin IgG, IgM, and IgA all negative, anti β-2
glycoprotein IgG and IgM negative but IgA 28 U/
ml positive. Tests for hepatitis A, B and C were
negative. Prednisone dose was increased to 20 mg
daily.
tories had also improved with AST 55 U/L, ALT
414 U/L and ALT 229 U/L and proteinuria appeared
for the first time (protein 1,020 mg in 24 hour urine collection). Prednisone was increased to 40 mg
daily, and 4 weeks later there was marked reduction in AST 60 U/L and unchanged ALT 214 U/L.
Patient continued with severe fatigue and persisted
with high dsDNA (392 AU/ml) and low C4. Since
she continued with active disease azathioprine 50
mg daily was started. Corticosteroid induced diabetes developed and prednisone was decreased to
30 mg. Three weeks later azathioprine was increased to 100 mg daily. After six weeks of azathioprine therapy, the patient reported feeling much better
with increased appetite, no arthralgias or arthritis,
no malar rash and no fatigue. Labora78 U/L, antidsDNA 122 AU/ml, normal complements C3 108
mg/dl and C4 20 mg/dl and decrease in proteinuria
(325 mg in 24 hr urine collection).
One month later antidsDNA increased to
401 AU/ml, liver transaminases increased to AST
A year after starting azathioprine, the patient did not have any clinical complaints and
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
56
serology revealed SLE in remission: a negative
dsDNA 34 AU/ml, normal complement levels C3
112 mg/dl and C4 24 mg/dl, and mildly elevated
liver enzymes AST 57 U/L and ALT 870 U/L. Proteinuria persisted (494 mg in 24 hr urine collection).
DISCUSSION
Hepatic manifestations of SLE are uncommon. Several investigators have reported a prevalence of 2.5-29% in several case series (2,3). The
most common manifestations are hepatomegaly
and increased liver function tests (1, 2).
Causes of liver abnormalities in SLE include steatosis, autoimmune hepatitis (as a result
of SLE or coexistent type I autoimmune hepatitis),
autoimmune cholangiopathy, nodular regenerative
hyperplasia, coexistent viral hepatitis (11% in one
Spanish study)(7), Budd-Chiari syndrome (lupus
anticoagulant), and drugs, especially NSAIDS and
methotrexate (8).
Jaundice is rare in SLE, and is usually
due to hemolytic anemia (4). A study done by our
group and presented in abstract form at the ACG
Annual Meeting in 2001 (9) found a 7% (18/243)
prevalence of persistently elevated ALT (two measurements at least 4 weeks apart). Liver biopsy in
three patients revealed hepatitis C, non-alcoholic
fatty liver disease (NAFLD), and non-specific triaditis. No case of autoimmune hepatitis was detected.
Although liver involvement in SLE is rare,
it can lead up to liver failure and death (4,10). All
of the mortalities reported had liver cirrhosis and
chronic liver disease (4). Two cases of SLE and
acute liver failure from Japan responded to corticosteroids (10).
Most causes of acute liver disease in our
patient were reasonably excluded. There was no
history of alcohol use or prescription or non-prescription drugs. Viral serologies for hepatitis A, B
and C were negative. Liver biopsy excluded biliary tract disease, NAFLD, vascular, granulomatous, metabolic, neoplastic and infiltrative disease.
Although other viral etiologies were not excluded
(such as EBV and CMV), the recurrence of elevated transaminases over several years makes this
diagnosis unlikely.
Our patient fulfills the criteria for definite
autoimmune hepatitis (AIH) according to the International Autoimmune Hepatitis Group Report
(6), with a score of 18 (a score of >17 considered
definite AIH). The favorable criteria for diagnosis
in this case include female gender, predominant
AST, high ANA titers, negative viral markers, negative alcohol and drug intake, liver histology, and
presence of other autoimmune disorders.
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
Coexistence of SLE and AIH is rare. Several series document 1.3%-1.7% prevalence of AIH
in SLE (11, 12). Although the term “lupoid hepatitis” coined in 1956 by Mackay (13) to describe
patients with hepatic inflammation and positive
LE cell prep has led to significant confusion, it is
now recognized that SLE and AIH are two distinct
clinicopathologic disorders that may coexist, as is
true of most autoimmune diseases.
A case series by Tojo et al reported five
patients with AIH and SLE overlap (5). Two of the
5 patients presented jaundice and AIH years before
the diagnosis of SLE. In these cases, as in our case,
the ACR criteria for the diagnosis of SLE were fulfilled years after the episode of jaundice.
Some authors have questioned the validity
of the International Autoimmune Hepatitis Group
Report in patients with SLE, especially with negative ASMA (14). Our patient falls in this group.
Interestingly, she developed RUQ pain during two
of the SLE exacerbations, suggesting that liver inflammation may be sign of SLE activation. This
has been suggested by other authors (15). Whether
the subsequent acute hepatic symptoms in our patient were caused by SLE reactivation or AIH flare
is uncertain, since the diagnostic criteria for AIH
were not applied.
In summary, we reported a patient who
presented acute hepatitis and jaundice compatible
with acute AIH, who several years later fulfilled
the criteria for SLE. To our knowledge, this is the
third reported case, and the first in the Western Hemisphere, of jaundice as the initial presentation of
SLE.
REFERENCES
1.
Youssef W, Tavill A. Connective tissue diseases and the
liver. J Clin Gastroenterol 2002; 345-349.
2.
Abraham S, Begum S, Isenberg D. Hepatic manifestations
of autoimmune rheumatic diseases. Ann Rheum Dis 2004; 63: 123129.
3.
Miller M, Urowitz M, Gladman D, Blendis L. The liver in
systemic lupus. Q J Med 1984; 211: 401-409.
4.
Chi Lu M, Jen Li K, Chou Hsieh S, Han Wu C, Li Yu C.
Lupus related advanced liver involvement as the initial presentation
of systemic lupus erythematosus. J Microbiol Immunol Infect 2006;
39: 471-475.
5.
Tojo J, Ohira H, Abe K, et al. Autoimmune hepatitis accompanied by systemic lupus erythematosus. Internal Medicine 2004;
43: 258-262.
6.
Alvarez F, Berg PA, Bianchi FB, et al. International autoimmune hepatitis group report: review of criteria for diagnosis of
autoimmune hepatitis. J Hepatol 1999; 31: 929-938.
7.
Ramos-Casals M, Font J, Garcia-Carrasco M, et al. Hepatitis C virus infection mimicking systemic lupus erythematosus: study
of hepatitis C virus infection in a series of 134 Spanish patients with
systemic lupus erythematosus. Arth Rheum 2000; 43: 2801-2806.
8.
Orchards T, Summerfield J: The liver in systemic disease:
In : Friedman LS, Keeffe EB. Eds. Handbook of Liver Disease, 2nd
Ed, Philadelphia, Elsevier, 2004: 286.
9.
Rios M, Cruz M, Rodriguez VE, Costas PJ. Causes of increased liver enzymes in patients with systemic lupus erythematosus.
American College of Gastroenterology 66th Annual Meeting, Las Vegas, October 2001, poster presentation p368.
10.
Atsumi T, Sagawa A, Jodo S, et al. Severe hepatic involvement without inflammatory changes in systemic lupus erythematosus:
report of two cases and review of the literature. Lupus 1995; 4: 225228.
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
57
11.
Runyon BA, LaBrecque DR, Anuras S. The spectrum of
liver disease in systemic lupus erythematosus. Report of 33 histologically-proved cases and review of the literature. Am J Med 1980; 69:
187-194.
12.
Irving KS, Sen D, Tahir H, Pilkington C, Isenberg DA. A
comparison of autoimmune liver disease in juvenile and adult populations with systemic lupus erythematosus – a retrospective review of
the cases. Rheumatology (Oxford) 2007; 46: 1171-1173.
13.
Mackay IR, Taft LI, Cowling DC. Lupoid hepatitis and
the hepatic lesions of systemic lupus erythematosus. Lancet 1959; 1:
65-69.
14.
Iwai M, Harada Y, Ishii M, et al. Autoimmune hepatitis in
a patient with systemic lupus erythematosus. Clin Rheumatol 2003;
22: 234-236.
15.
Gibson T, Myers AR. Subclinical liver disease in systemic
lupus erythematosus. J Rheumatol 1981; 8: 752-759.
RESUMEN
Envolvimiento hepático en lupus sistémico eritematoso (LE) es infrecuente. La coexistencia de lupus y hepatitis autoinmune es rara (1.31.7%). Reportamos el caso de una mujer de 27
años de edad sin historial médico previo ni abuso
de alcohol que presentó una hepatitis aguda con
ictericia, dolor abdominal, y aumento de las enzimas hepáticas. Los marcadores de hepatitis virales estaban ausentes. El ANA estaba presente en
títulos altos. Se sospechó LE pero no se hicieron
pruebas confirmatorias. La paciente permaneció
asintomática por 9 años y luego tuvo una recidiva
de la hepatitis. También presentó erupción malar,
artritis y proteinuria. En este momento se le realizó una biopsia de hígado la cual reveló hepatitis
autoinmune. Otros laboratorios que confirmaron la
presencia de LE incluyeron un anticuerpo contra
doble hebra de DNA (dsDNA), y complementos
bajos. Se comenzó en prednisona 40 mg y tuvo
una mejoría leve en la elevación de transaminasas, pero al añadir azatioprina 100 mg la paciente tuvo una reducción marcada en la elevación de
transaminasas hepáticas. Después de un año de
tratamiento con azatioprina la paciente sigue en
remisión del LE. Este es el tercer caso reportado y
el primero en el hemisferio occidental de ictericia
como la manifestación inicial de LE.
Serigrafía
por
José Alicea
José Alicea nació en 1928 en
Ponce, Puerto Rico. Entrenado
como pintor, comenzó su actividad
como diseñador gráfico en 1957,
bajo la tutoría de Lorenzo Homar.
En 1967 fue nombrado Profesor de
Imprenta y fundó la Escuela GráPuerfica del Instituto de Cultura Puer
torriqueña.
De venta en la Asociación Médica
de Puerto Rico
(787) 721-6969
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PUERTO RICO
Jornadas Científicas
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58
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
2008 Internal Medicine Clinical Research Symposium
May 27, 2008
Department of Medicine
University of Puerto Rico School of Medicine
Research Oral Presentation
TITLE: Surveillance for Dysplasia in Patients
with Ileal Pouch-Anal Anastomosis for Ulcerative
Colitis: An Interim Analysis.
Jorge D. Meléndez Hernández MD^, Carlos Jiménez-Huyke MD^,
Kathia Rosado MD, Carmen González-Keelan, MD‡, Juan J. Lojo
MD†, Esther A. Torres MD^
^Department of Internal Medicine, †Department of Surgery, ‡Department of Pathology, University of Puerto Rico School of Medicine,
San Juan, Puerto Rico.
ABSTRACT
Purpose: The risk of developing cancer in
the ileal pouch of patients who have surgery for
ulcerative colitis has not been defined. Some have
found dysplasia within the pouch mucosa to be quite rare. Although some investigators suggest that
pouch surveillance should be based on the results
of previous histological assessments, there are no
current guidelines for endoscopic surveillance of
patients who have undergone IPAA for ulcerative
colitis. The aim of our study was to investigate that
risk and identify crucial time intervals to guide
ileoanal pouch surveillance.
Methods: Endoscopy of the ileal pouch
was performed in all consenting patients at 3, 6
and/or 12 months after their IPAA became functional. Pouch biopsies were taken to assessevidence
of dysplasia. Biopsies were evaluated by two pathologists using Riddel’s criteria to ensure standardized interpretation. Interim data analysis using
descriptive statistics is reported here.
Results: Thirty eight patients have entered
the study. The average patient age at 3, 6 and 12
months of surveillance were 39.1 (SD, 12.0; range,
21-67 years), 36.8 (SD, 12.7; range 19-68 years)
and 39.1 years (SD, 12.2; range, 22-77 years) respectively. Average disease length was 8.2 years
(SD, 6.6; range, 0.7-27.8 years). Ten of 38 cases
(26 %) had colonic dysplasia prior to IPAA surgery. Dysplasia within the pouch was reported
in only one patient, 6 months after IPAA became
functional. This patient demonstrated no evidence
of dysplasia on further surveillance at 12 months
or statistical divergence by age, duration of disease
or history of colonic dysplasia prior to IPAA. No
significant subgroup of patients with pouch dysplasia was identified to calculate cumulative risk
or to perform comparative statistical analysis.
Conclusion: At this moment, long-term
follow up of IPAA should precede any attempt to
support routine surveillance. However, the finding
of dysplasia early after surgery underscores the
importance of early pouch surveillance in our population, at least until definite predisposing variables are identified.
First Award Research Oral Presentation
TITLE: Disease Activity and Damage in Puerto
Ricans with Rheumatoid Arthritis: Impact of Public and Private Health Insurance Systems
Tania C. González-Rivera, MD, Yesenia C. Santiago-Casas, MD,
Lesliane E. Castro-Santana, MD, Grissel Ríos, MD, David Martínez,
MD, Vanessa Rodríguez, MD, Rafael González-Alcover, MD, Angel
M. Mayor, MD, MS, and Luis M. Vilá, MD.
Department of Medicine, Division of Rheumatology, University of
Puerto Rico School of Medicine, San Juan, Puerto Rico
ABSTRACT
Objective: To determine the disease activity and damage in rheumatoid arthritis (RA) pa-
tients who received their healthcare either througha
private fee-for-service system or a publicly-funded
managed-care system in Puerto Rico.
Methods: A cross-sectional study was
conducted in 181 patients with RA (per American
College of Rheumatology classification criteria).
Demographic parameters, health-related behaviors, cumulative clinical manifestations, disease
activity (per Disease Activity Score, DAS-28),
comorbid conditions, functional status (per Health
Assessment Questionnaire, HAQ) and pharmacologic profile were determined at study visit. Data
were examined using univariable and multivariable analyses.
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
Results: The mean (SD) age of the study population was 57.4 (13.4) years; 149 (82.8%) were
women. The mean (SD) disease duration was 11.0
(9.4) years. Forty-seven patients had the public
health insurance whereas 134 patients had the private health insurance. RA patients having the public health insurance were more likely to have joint deformities/contractures (72.3% vs. 49.3%, p=
0.006), extra-articular manifestations (80.9% vs.
58.2%, p= 0.005), myocardial infarctions (13.0%
vs. 3.0%, p= 0.019), and higher DAS-28 [4.3 (1.7)
vs. 3.3 (1.5), p= < 0.001) and HAQ scores [1.37
(0.78) vs. 0.99 (0.79), p= 0.006] than those who
had private health insurance. Patients having the
public insurance were less likely to use biologic
agents (27.7% vs. 48.5%, p=0.013). These differences remained significant on multivariable
analyses. No differences were found for age, gender, disease duration, health-related behaviors,
other comorbidities, and the use of traditional disease modifying anti-rheumatic drugs and glucocorticoids among study groups.
Conclusions: RA patients having the public health insurance in Puerto Rico present more
joint damage, extra-articular manifestations, greater disease activity, myocardial infarcts and poorer
functional status. Efforts should be undertaken to
curtail the gap of health disparities in RA.
59
Research Oral Presentation
TITLE: Syncope in Puerto Rico: The Cardiovascular Center of Puerto Rico and the Caribbean
Hospital Experience.
Juan C. Lopez-Mattei, MD; Pablo I Altieri, MD; Jose Hernandez,
BSc; Yolanda Figueroa, MD
ABSTRACT
Syncope is defined as a transient loss of
consciousness with an inability to maintain postural tone that is followed by spontaneous recovery. Syncope is a prevalent disorder, accounting
for 1-3% of emergency department visits and up
to 6% of hospital admissions in the United States.
The medical records of patient admitted during
the years 1999-2005 at the Cardiovascular Center
of Puerto Rico and the Caribbean were reviewed.
The characteristics of this population and the etiologies of syncope were analyzed. One hundrede
and sixty-eight patients were identified with a
primary diagnosis of syncope. A specific etiology
was identified in 77.5% of the population studied
whereas 22.6% had an unknown or unidentifiable
cause. Cardiac syncope was diagnosed in 60.8%
of the evaluated patients. Other diagnosis and risk
factors in the studied population were identified.
Second Award Research Oral Presentation
TITLE: The influence of candidate genes on the
response of sibutramine treatment for weight loss
in overweight and obesity
Vazquez Roque M*, Camilleri M*, Carlson P*, Clark MM†, Stephens
D*, and Zinsmeister AR‡. *C.E.N.T.E.R., Mayo Clinic, Rochester,
MN †Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN.‡Department of Health Sciences Research, Division
of Biostatistics, Mayo Clinic, Rochester, MN.
ABSTRACT
Background: Sibutramine is a noradrenergic (NE) and serotonergic (5-HT) reuptake inhibitor approved for the treatment of obesity. Prior
studies suggest that genetic variations in phenylethanolamine N-methyltransferase (PNMT) and
GNβ3 influence the weight loss response to sibutramine. Aim: To assess the influence of candidate NE and 5-HT genes on weight loss in response to sibutramine or placebo treatment in healthy
overweight and obese individuals.
Methods: Forty-eight healthy overweight
and obese participants were randomly assigned to
receive placebo or sibutramine, 15 mg daily, for 12
weeks.
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
Venous blood DNA was analyzed for SERT-P (SLC6A4), α-2 MspI, PNMT and GNβ3 C825T genotypes. All participants also received structured behavioral therapy for weight management. Separate
ANCOVA models were used to assess each candidate gene’s associations with weight loss.
Results: The SLC6A4 genotype had a significant influence on the effect of sibutramine on
the change in weight (p=0.024). Subjects with SLC6A4 LS/SS (heterozygous/short) genotype had
an average weight loss of 6.1±1.0 kg on sibutramine compared to 0.1±0.9 kg average weight increase on placebo. In contrast, for subjects with the
homozygous SLC6A4 LL (long) genotype, weight
was similar in both treatment groups; 3.3±1.8 kg
in placebo compared to 3.9 ± 1.6 kg in the sibutramine group. There were no significant associations of treatment with the α-2a MsPI, PNMT, and
GNβ3 genotypes.
Conclusions: Genetic modulation of endogenous serotonin reuptake may explain, in part,
the variation in the weight reduction observed with
sibutramine. This may provide guidance on selection of patients for this pharmacological treatment
of obesity.
60
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
Research Oral Presentation
acade mic hospitals in PR in 2007.
TITLE: Age as a deciding factor in the consideration of futility for a medical intervention in patients
with similar clinical severity of illness among Internal Medicine physicians
Dulce M. Cruz-Oliver MD (Associate),1 Marytere Melendez-Rosario MS MPH,2 Wilfredo E. De
Jesus-Monge MD (Associate),1 and Jesus MunizGonzalez MD
1Department of Medicine, University of Puerto Rico School of Medicine, San Juan, PR, 2Department of Biostatistics and Epidemiology, University of Puerto Rico Graduate School of Public
Health, San Juan, PR
The instrument was an anonymous questionnaire that explored their knowledge and attitudes towards medical futility and their consideration of age as a factor in deciding if a medical
intervention is futile or not. In this questionnaire
we compared pairs of patient scenarios with similar clinical severity and treatment, but different
age. Two hundred and one physicians were enrolled: 154 physicians in training (107 residents and
47 fellows) and 47 physicians in practice. The data
was evaluated using frequency distribution and
analyzed with Chi square test and Fisher Exact
test.
ABSTRACT
Results: For any pair of patient’s scenarios with similar medical interventions and similar
clinical severity of illness, 15% of the physicians
considered the intervention as futile in the elderly
as compared to the non-elderly (p<0.0001). There
was no difference in the analysis by physician’s
experience, 15% of physicians in training and
16% of physicians in practice considered the intervention as futile in the elderly (p = 0.9944).).
This tendency was preserved when compared by
clinician’s academic level, 14% of residents, 17%
of fellows and 16% of attendings (p = 0.8505).
Introduction: Physicians face daily the
situation of deciding if a standard medical therapy or procedure (intervention) is futile (useless) or
not, when choosing end of life care for elderly
patients. The most accepted definition for medical
futility is an intervention that will not benefit the
patient in achieving a specific therapeutic goal. In
2006 the elderly population (individuals with age
65 years-old and more) comprised approximately
1 out of 10 individuals. In the United States it was
estimated at 12.4% of the total population and in
Puerto Rico (PR) they comprised 12.9% of the total
population. Many physicians take into account age
to categorize a treatment as futile. The hypothesis
is that Internal Medicine (IM) physicians consider
a medical intervention as futile more commonly in
the elderly patients as compared to the non-elderly
patients despite both groups having similar clinical
severity of illness.
Method: This is a cross-sectional study of voluntary IM physicians in training (residents and fellows) and in practice (attendings) from four
Conclusion: A minority of IM physicians
considers a medical intervention as futile in the
elderly patients as compared to the non-elderly
patients despite both groups having similar clinical severity of illness. The similar consideration
between physicians in training and in practice
may be explained by a learn-by-example method
of learning in medical education. A limitation of
the study is that not all participants answered all
questions in the instrument. In conclusion, a small
fraction of IM physicians considers a medical intervention as futile in the elderly.
Third Award Research Oral
Title: Epidemiology of Thyroid Cancer in Puerto
Rico
Mariela Nieves-MD, Ana M. Lugaro-MD, Margarita Ramirez-VickMD, FAAP
ABSTRACT
Background: Thyroid cancer accounts
for 1% of all malignancies and is one of the fastest
increasing cancers in the United States. With the
majority of these cancers diagnosed at an early stage, patients can receive appropriate treatment and
live longer. There is no epidemiological data for
this cancer in our population.
This study aims to report the epidemiology of
this cancer type in Puerto Rico between 1987 and
2003.
Methods: Using the Central Cancer Registry of Puerto Rico database (CCRPR), we identified the thyroid cancer patients diagnosed from
January 1, 1987, to December 31, 2003. Overall
gender-specific and age-specific incidence and
mortality rates were calculated. All rates are per
100,000 and age-adjusted to the 2000 PR standard
population. Also Annual Percent Changes (APC)
were calculated using weighted least squares method.
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
Results: 2,360 cases of thyroid carcinoma
were identified. Age adjusted incidence rate increased from 2.4 per 100,000 to 5.9 per 100,000
and the APC was 5.9% in the 16 year study period.
Analysis of gender specific incidence rates showed
increases from 3.6 and 1.1 per 100,000 in 1987 to
9.6 and 1.8 per 100,000 in 2003 with APCs of 6.0%
and 5.4% among females and males respectively.
Age adjusted mortality rate decreases from 0.4 per
100,000 to 0.3 per100,000 with APC of -1.2. Age
specific mortality rate increases significantly after
age 70.
Conclusion: As expected, the incidence of
thyroid cancer in Puerto Rico has increased over
this 16-year period (1987-2003) by 2.4 folds. The
mortality rate had remained stable with less than
1 per 100,000. Studies addressing changes in risk
factors or medical practices among diagnosis of
thyroid cancer could answer why the incidence of
thyroid cancer is increasing.
Research Oral Presentation
Title: Analysis of Heart Failure Management at
the Heart Failure & Transplantation Clinics of the
Cardiovascular Center of Puerto Rico and the Caribbean
Omar Segarra-Alonso,MD; Hilton Franqui-Rivera,MD; Héctor Banchs-Pieretti,MD
ABSTRACT
Introduction: Heart failure is a common
clincal síndrome representing the end- stage of a
number of different cardiac diseases, resulting
from any structural or functional cardiac disorder
that impairs the ability of the ventricle to fill with
or eject blood. There has been much debate regarding the role of specialized Hearth Failure Clinics.
Do these clinics improve quality of care? What
about patient’s quality of life?
Purpose: To describe the experience with
heart failure patients at the Heart Failure & Transplantation Clinics of the Cardiovascular Center of
Puerto Rico and the Caribbean (CCPRC).
Methods: A total of 244 records from
the Heart Failure & Transplantation Clinics of the
CCPRC extending over a period of 2000 to 2006
were retrospectively analyzed. New York Heart
(NYHA) Functional Classification, left ventricular
ejection fraction (LVEF), re-hospital frequency,
death and transplantation were monitored at 3,6,
and 12 months after initial referral to our clinic.
Results: After 12 months, there was significant improvement in NYHA functional class
with 82.3% of patients in Class I or II vs. 17.7% in
Class III or IV (p<0.01); this trend began to appear
during the first three months of care.
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
61
In average, LVEF increased from 21.3% to 41.8%
(p<0.01), with 25.82% of patients reaching LVEF
over 50%. There was also a reduction in both
systolic and diastolic left ventricular dimensions,
suggesting a partial reversal of myocardial remodeling. Re-hospitalization rates decreased from
62.7% within one months prior to referral to our
clinics to 2.9% (p<0.01) at 12 months; this trend
was appreciated immediately after referral.
Conclusions: Probably because of proficiency and evidence-based practices, referral to
a specialized clinic such as the Heart Failure &
Transplantation Clinics of the CCPRC improve
multiple parameters of patient’s well being. Early
referral to specialized clinics should be considered.
Research Oral Presentation
Title: Treatment Outcomes of Peg-interferon and
Ribavirin in a Government Sponsored Clinic for
an Underserved Hispanic Population with Chronic
Hepatitis C
Johanna Iturrino, MD, Carlos J. Sánchez, MD, Adelaida Ortiz MD,
Carlos J. Romero MD, Vanessa Velázquez MD, Pablo Costas MD,
Esther A. Torres, MD
ABSTRACT
Background: Hispanics with hepatitis C
(HCV) have a lower response to interferon-based
therapy in comparison to other populations. A pilot
clinic was established at the University of Puerto
Rico for the treatment of HCV in the governmentinsured population. The aim of this study is to describe the outcomes and treatment response to peginterferon and ribavirin in treatment-naïve patients
enrolled in this government-sponsored clinic.
Methods: A retrospective analysis to investigate the treatment outcome with weight based peg-interferon-alfa-2b and ribavirin in patients
with chronic HCV enrolled during 2003-2005.
Descriptive statistics were reported. Continuous
variables were summarized as means and standard
deviations. Frequency distributions and percents
were used for categorical variables. Statistical
analysis was performed using STATA.
Results: 155 (105 M: 50 F, mean age 42.2)
patients were started in treatment, with 72.4% of
them being genotype 1. Only fifty-nine of these
patients (38.1%) completed treatment. End of
treatment response (ETR) was observed in 30/59
(50.8%). Sustained viral response (SVR) was
seen in 19/59 (32.2%) of patients who completed treatment. Intended-to-treat analysis showed
a 12.3% (19/155) SVR. The only predictor of
SVR was a diagnosis of HCV within 5 years of
treatment onset (p=0.026). Although no association was found between HCV genotype and SVR
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
62
(p=0.192), those patients with genotype 2 and 3
were found to have a better chance of completing
treatment (p=0.009).
Conclusion: SVR to Peg-interferon and
Ribavirin seems to be lower in our population.
The high rate of incomplete treatment surpasses
the previously reported rates in U.S. Latinos and
Caucasians. Further studies should explore reasons for higher treatment discontinuation in our
population.
Research Oral Presentation
Title: Seroprevalence of Viral Hepatitis Markers
in the Liver Transplant Clinic of the University of
Puerto Rico, Medical Sciences Campus
Miguel de Varona, MD, Nicole Rassi, Mariely
Nieves Plaza, MS, Esther A. Torres, MD
ABSTRACT
Background: Chronic viral hepatitis is
the leading cause of liver transplantation in the
world. Approximately 8% of liver transplants are
due to acute liver failure and acute infections with
hepatitis A and/or B are among the etiologies. Hepatitis A/B vaccination is recommended for all patients with chronic liver disease and it is important
to know how successful we have been in promoting this vaccination.
Methods: A retrospective analysis of
medical records from patients enrolled in the Liver Transplant Clinics of the University of Puerto
Rico, Medical Sciences Campus since 1999 was
performed.
Charts were reviewed following a random list of
medical records numbers. A total of 242 records
were reviewed until a sample size of 100 was obtained. Records without regarding age, gender,
etiology of liver disease, risk factors, co-morbidities, and viral hepatitis serological markers was
retrieved and a descriptive analysis was made.
Results: The most common etiology of
chronic liver disease was hepatitis C (47%) followed by chronic ethanolism (33%) and cryptogenic cirrhosis (20%). Seventy six percent (76%)
of patients were immunized against hepatitis A virus either by vaccination or past infection. Only
12% of patients were vaccinated against hepatitis
B. A total of 57% were never exposed nor vaccinated against hepatitis B. Thirteen percent (13%)
showed evidence of past hepatitis B infection, 2%
were chronic hepatitis B carriers and 16% showed
isolated hepatitis B core IgG antibody.
Conclusion: As expected, viral hepatitis continues to be the most common etiology of
chronic liver disease. Vaccination against viral
hepatitis (A and B) in patients with chronic liver
disease is of the utmost importance. According to
the data obtained, a significant amount of patients
is still not immunized against these preventable
viral infections. The year in which the vaccines
were developed, the requirement of administering
the vaccines at birth, and the “lost-to-follow-up”
patients are among the possible explanations for
the results obtained. It is very important to recall
and emphasize the need of hepatitis A and B vaccination among chronic liver disease patients.
Clínicas de Salud Multifásicas
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salud:
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gratuito para la
comunidad
Informes: (787) 721-6969
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
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64
Cover - Portada
Dr. Rafael del Valle y Rodríguez
(1847-1917)
Por: Eduardo Rodríguez Vázquez, MD
Presidente Asociación Médica de Puerto Rico
¿Quereís que ausculte, señora?
¿No temeis que a mis oídos
Lleguen todos los latidos
Que el corazón atesora?
Estos versos componen la primera estrofa del poema Ausculto tomado del libro Poesías
Completas del Dr. Rafael del Valle y Rodríguez,
publicado póstumamente por su hijo, el Ingeniero
Rafael del Valle Zeno, en la Imprenta La Primavera, en 1921.
El Dr. Rafael del Valle cuya fotografía incluímos en la portada de esta edición, es uno de
los médicos puertorriqueños que más se destacó
en el siglo XIX, no sólo en la medicina, sino en la
literatura, el periodismo y la política. Este ilustre
médico aguadillano, contemporáneo de los doctores Agustin Sthal y Martin Corchado, cursó la instrucción primaria en su pueblo natal y prosiguió
los estudios de bachillerato en el Instituto Civil de
Segunda Enseñanza, en San Juan de Puerto Rico.
Español, del Hospital Municipal de San
Juan(edificio que hoy alberga el Museo de Arte
de Puerto Rico) y varios puentes en la isla.
Es en Arecibo, en 1879, que publica versos por primera vez en Puerto Rico. Estos fueron
recogidos en una antología de poetas arecibeños
titulada Notas Perdidas editada por Alejandro Salicrup. En 1884 publica un libro: Poesías, prologado por Aniceto Valdivia, famoso escritor cubano.
Durante estos años recibió la condecoración del
“Mérito militar” por servicios prestados en una
epidemia de viruelas.
Realizó sus estudios universitarios en Barcelona obteniendo el título de Licenciado en Medicina y Cirugía el 26 de junio de 1869, a los 22 años
de edad, doctorándose en el 1870 en la facultad
de medicina de Madrid. Fue uno de los primeros
puertorriqueños, junto al Dr. Martin Corchado
de Isabela, que trabajaron bajo la tutela del sabio
francés Luís Pasteur en su Instituto en Paris. A su
regreso a Puerto Rico, en el 1871, ejerció la medicina en diferentes pueblos como: Aguada, Aguadilla y Arecibo. Radicóse en este último, donde casó
con la distinguida dama Micaela Zeno Gandia,
hermana de nuestro ilustre médico novelista: Manuel Zeno Gandia. La pareja procreó varios hijos,
entre ellos: Micaela, que se destacó en la pintura
como una de las discipulas preferidas del pintor
Francisco Oller. Dos de sus hijos, Rafael y Carlos,
se distinguieron como ingenieros y contratistas.
Estos tuvieron unas de las firmas de ingeniería más
prestigiosas en la isla de Puerto Rico en las primeras décadas del siglo 20. Entre sus obras de arquitectura e ingeniería más conocidas figuran: los
edificios del Hospital Auxilio Mutuo, del Casino
Sus ideas liberales autonomistas le causaron problemas con el régimen absolutista, que
prevalecía en la isla de Puerto Rico. Esto provocó
el tener que exiliarse en el 1891 a Caracas, la capital de Venezuela. Fue colaborador del general
revolucionario Joaquín Crespo, quien derrocó al
presidente Andueza Palacios, al este querer continuar más tiempo en el poder de lo establecido
por la constitución Venezolana. Fue comisionado
por la junta revolucionaria del General Palacios a
comprar armas y municiones en la isla de Trinidad, siendo capturado a su regreso y aprisionado
en la célebre Rotonda, donde permaneció por tres
meses. Luego del triunfo de la revolución, el Dr.
Del Valle fue el primer preso en ser liberado por
el triunfante General. A raíz de sus actos heroicos
se convirtió en su secretario particular consejero y médico de familia. Ocupó numerosos cargos
en sus años venezolanos, entre estos: Fundador y
director del Periodíco oficial “El Derecho” diplomático en Colombia, presidente de la Junta Centralde Aclimatación y Perfecionamiento Industrial
y colaborador de los principales periódicos de Venezuela.
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
65
Desde el exilio, a través de la prensa Venezolana,
continuó atacando al gobierno Español en Puerto
Rico. Durante esos años fue nombrado miembro
de la Academia de Medicina de Caracas, de la
Acedemia Nacional de la Lengua y condecorado
con la medalla del “Busto del Libertador” y con la
cinta de la Legión de honor de Francia.
Volvió a Puerto Rico en 1899, luego de
la Guerra Hispanoamericana, radicándose en la
capital San Juan, donde se activó en los procesos
políticos locales. Fundó, junto a Luís Muñoz Rivera y otros, el Partido Unionista. Con la creación
de la Ley Foraker en 1902, fue nombrado miembro del Consejo Ejecutivo en varias ocasiones. En
1905, nombrado por el presidente Teodoro Roosevelt, y luego, en el 1909; siendo su presidente
pro-tempore varias veces. Fue Comisionado de
Instrucción y presidió, en 1912, la Comisión para
proteger la tarifa del azúcar.
Además de destacarse en la poesía, dejó
dos novelas, Lucila y De la forma al fondo, publicadas en 1897. En 1899 edita un ensayo biográfico
sobre el patriota cubano Antonio Maceo. La defensa de la memoria de este héroe revolucionario
le había costado a su colega y compueblano, el Dr.
Agustin Sthal, el destierro en Santo Domingo, República Dominicana, un año antes (en 1898). En
Puerto Rico fue miembro de la Academia Antillana de la Lengua, fundada por José de Diego y
de la Asociación Médica de Puerto Rico. Fundó
el Instituto Microbiológico de San Juan, siendo su
primer director e investigador cientifico. De este
Instituto se originó, posteriormente, el Instituto de
Medicina Tropical.
El Dr. Rafael del Valle y Rodiguez ocupa
un sitial de honor en la Galería de Médicos Célebres de la Asociación Médica de Puerto Rico.
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
66
BIBLIOGRAFIA
A. OBRAS DE RAFAEL DEL VALLE RODRIGUEZ
Del Valle Rodríguez, R. “Poesías”. Prólogo por D. Aniceto Valdivia.
Imp. Salicrup y Cia., Arecibo, PR
1884 p.205
Del Valle Rodríguez, R. “Lucila” y “De la forma al fondo”. Caracas,
1897, p. 232.
Del Valle Rodríguez, R. “Maceo”. Club Betances. Editorial Caracas,
Caracas, PR, 1897.
Del Valle Rodríguez, R. “Maceo”. Club Betances. Imp. Sucesión J.J.
Acosta, San Juan, PR, 1899, p.12
Del Valle Rodríguez, R. “Al Rev. Padre Nazario: ¿Son los Indios Descendientes de los Hebreos?”
PRI, 5 de octubre de 1912 num. 136
Del Valle Rodríguez, R. “Por la Literatura Portorriqueña”. Carta a D.
Virgilio Dávila. PRI, 29 marzo de
1913, num. 161
Del Valle Rodríguez, R. “Poesías Completas del Doctor Rafael del
Valle”. La Primavera, San Juan, PR, 1921. pp. 42-43.
B. ESTUDIOS SOBRE RAFAEL DEL VALLE RODRÍGUEZ
Arana Soto, S. “Valle y Rodríguez, Rafael del”, Diccionario de Médicos Puertorriqueños. San Juan,
PR. 1963. Imprenta de Aldecoa, España. pp. 319-325
Arana Soto, S. “Valle y Rodríguez Rafael”, Catálogo de Médicos de
PR. De Siglos Pasados. San
Juan, PR. 1966. Imprenta de Aldecoa, España. pp. 438-439
Asenjo, C. “De la vida íntima: Dr. Rafael Del Valle Rodríguez”. PRI.,
5 de octubre de 1912, num. 136.
Asenjo, C. “Puertorriqueños Ilustres del Pasado”, Almanaque Puertorriqueño, 1917-1918, p. 55
Asenjo, C. “Puertorriqueños Ilustres del Pasado”, Almanaque Puertorriqueño, 1945, Pp. 125-126
Astol, E. “Hombres del Pasado”, El Libro de Puerto Rico. San Juan,
PR. 1923. El Libro Azul Publishing
pp. 1004-1006
Cadilla de Martínez, M. Alturas Paralelas. San Juan. Imp. Venezuela,
1941. pp. 5-80
Daubón, J. “Rafael del Valle Rodríguez”. Cosas de Puerto Rico. Segunda serie. San Juan, PR., 1905,
p.153
Matos Bernier, F. (Fray Justo, seudo.): “Dr. Rafael Del Valle Rodríguez”. Cromos Ponceños. Ponce, PR
1896, p. 105
Matos Bernier, F. “Isla de Arte”. San Juan, Imprenta La Primavera,
1907, Pp. 226-228
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
Rivera de Álvarez, J. “Valle Rodríguez, Rafael del (1947-1917)”,
Diccionario de Literatura
Puertorriqueña Tomo segundo Volumen II. San Juan, PR.1974. Instituto de Cultura Puertorriqueña. Pp1575-1576.
Rivera de Álvarez, J. Diccionario de Literatura Puertorriqueña, UPR
Ediciones de la Torre. 1955. Pp.
478-480
Ruiz Arnau, R. “Elogio del Dr Rafael del Valle Rodríguez”. Boletín
Asociación Médica de Puerto Rico,
Año XIII num. 117 Pp. 136 Diciembre de 1917
The Representative Men of Porto Rico. “Rafael del Valle y Rodríguez”. New York. 1910. F.E. Jackson &
Son. p 22
.C. BIBLIOGRAFIA GENERAL
Asenjo, C. “Puertorriqueños Ilustres del Pasado”, Almanaque Puertorriqueño, años de 1945 a 1955
Cruz Monclova, L. Historia de Puerto Rico (siglo XIX). Vol. I UPR
Editorial Universitaria 1952 pp. 691,
876, 877, 936, 948
Diccionario Enciclopédico Hispanoamericano, 1939, Suplemento
Gómez Tejera, C. La Novela en Puerto Rico: Apuntes para su Historia. San Juan, 1947, P. 76
Gontán, J.A. Historia Político-Social de Puerto Rico. San Juan, Editorial Esther.1945. P 161
Martínez Acosta, Carmelo: Desfile de Combatientes, San Juan, 1939,
Págs. 37, 38, 40, 41, 43-44, 47, 49,
51-53.
Panigua, R. Puerto Rico Roll of Honor. San Juan, Cantero Fernández
y Cia., 1918, p. 85
Quevedo Báez, M. Historia de la Medicina y Cirugía de Puerto Rico.
Vol. I. Asoc Med PR, 1946. P.376.
Quevedo Báez, M. Historia de la Medicina y Cirugía de Puerto Rico.
Vol. II, Asoc Med PR, 1949. Pp. 40,
142, 269, 271, 347-348.
Rivero Méndez, A. Crónica de la Guerra Hispanoamericana en Puerto
Rico. Madrid, 1922, Pp. 19, 1427
Rodríguez Vázquez, E. 2008. “La medalla del cuarto centenario de la
colonización cristiana de la isla de
Puerto Rico”, Numiexpo’08.San Juan, PR. pp. 7-15
Rosa Nieves, C. La Poesía en Puerto Rico. México, 1943, pp. 59,
138-139
Sáez, A. El Teatro en Puerto Rico (notas para su historia). San Juan,
1950, P. 93
Sapiens. Enciclopedia Ilustrada de la Lengua Castellana, Editorial
Sopena, Argentina, Buenos Aires,
1949
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
67
4.0 CME Credits Boletin Volume 100 No 3, 2008
Instructions:
To obtain CME four (4) credits AMA 1, you should read and study the following articles and be able to answer the
questions correctly. After answering the questions below fill in your personal information, cut and send with a check
for $20.00 payable to: Asociacion Medica de Puerto Rico.
You can answer this test on-line with PayPal payment in our web site www.asociacionmedicapr.org
Questions related to article “Methadone: An
Effective Alternative to Morphine for Pain Relieve in Cancer Patients” by Bernard W. Sheldon,
et al.
1. Which of the following statements is correct?
(A) A disadvantage of methadone is its short acting effect.
(B) Methadone is effective for pain control, has similar side effects and is tolerated as well as other
opioids.
(C) Morphine does not cause delirium.
(D) disadvantage of methadone is its active metabolites.
2. What is the advantage of methadone over other
opioids?
(A) It is long acting and is less well tolerated as
compared with other opioids
(B) It is long acting and has active metabolites
(C) It is long acting, has no active metabolites and
is inexpensive.
(D) It is long acting causing delirium and myoclonus
3. Which of the following opioids may cause delirium and myoclonus?
(A) Codeine
(B) Fentanyl
(C) Methadone
(D) Morphine
Questions relate to article “Management and
Outcome of Transient Ischemic Attacks in Ponce, Puerto Rico” by Kenneth Geil et al.
4. The National Stroke Association (NSA) recommend to perform an endarterectomy in patients
with carotid artery stenosis between 70 to 99%.
The best time to do this procedure is:
(A) in 3 months after the initial neurological deficit
(B) in 2 to 4 weeks after the initial neurological
deficit.
(C) Not yet recommended
(D) In 2 to 4 weeks if the patient does not respond
to medical treatment.
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
5. All of the above antithrombotic and / or antiplatelet are indicated in the management of transient
ischemic attack and stroke, except:
(A) aspirin
(B) clopidogrel
(C) Cenoxaparin
(D) aspirin/ long acting dipyridamole
6. Choose the correct statement about the ABCD
score:
(A) The ABCD score predicts the stroke risk in seven days following a transient ischemic attack.
(B) The ABCD score predicts the stroke risk in ninety days following a transient ischemic attack.
(C) The ABCD score is not useful in predicting the
risk of stroke, but determine if the patient requires
in hospital treatment.
(D) The ABCD score is the best parameter to start
tPA.
Questions related to article “- Sexual Activity as
a Risk Factor for Hepatitis C in Puerto Rico Joel
De Jesús-Caraballo et al.
7. Which of the following sexual behaviors is the
least likely to be associated to a higher hepatitis C
transmission rate?
(A) Higher number of sexual partners
(B) Males having sex with men
(C) History of sexually transmitted disease
(D) Sex with an intravenous drug user (IVDU)
(E) Long term monogamous sex
8. Which of the following risk factors for HCV
transmission is the commonest risk factor for
transmission in the evaluated population:
(A) blood transfusion
(B) syringe/needle accident (work related)
(C) IV drug abuse
(D) body piercing
(E) sex
9. Which of the following is the HCV sexually
transmission rate in the Puerto Rico population
when others risk factors are excluded:
(A) 10%
(B) 6.5%
(C) less than 1%
(D) 20%
68
Questions related to article “Asthma among
Puerto Ricans” by Sylvette Nazario.
10. Which of the following is a correct statement?
(A) Puerto Ricans have higher asthma prevalence
and mortality than Americans.
(B) Puerto Ricans have lower asthma mortality
than White Americans.
(C) Asthma prevalence and mortality is similar
among all Hispanics.
(D) Puerto Ricans, although having higher asthma
mortality rate than Americans, have lower prevalence.
(E) In spite elevated prevalence, asthma severity
among Puerto Ricans is lower than among other
ethnic groups in the United States.
11. Which of the followings has been associated
to increased asthma likelihood among Puerto Ricans?
(A) ADAM-33
(B) Lower IgE
(C) prostanoid DR receptor polymorphisms
(D) polymorphism in the gene ORMDL3
(E) none of the above
12. Which of the following is true?
(A) A single gene has been identified that accounts
for our increased asthma prevalence.
(B) Increased air pollution exposure explains our
increased asthma prevalence and morbidity.
(C) Socioeconomic factors play a role in our elevated asthma morbidity.
(D) Most asthma care is conducted by specialist in
the island.
(E) Most asthmatics visit regularly their doctor for
their care rather than relying on the Emergency
Department.
Questions from article: “Methicillin-Resistant
Staphylococcus Aureus in the Community” by
Rosana Amador-Miranda et al.
13. Which of the following is associated to Community-Associated MRSA infections?
(A) Infections that are acquired by persons who
have not been recently hospitalized (within one
year).
(B) Usually manifested as skin infections.
(C) Occurs in healthy people.
(D) Genotype differ from those of Hospital-Associated strains.
(E) All of the above
14. Risk factors associated to Community-Associated MRSA infections include which of the following?
(A) Prison inmates
(B) Children in day-care centers
(C) Athletes
(D) Men who have sex with men.
(E) All of the above
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
15. Most Strains of Community-Associated MRSA
are susceptible to the following antibiotics EXCEPT for?
(A) Vancomycin (Vancocin)
(B) Clindamycin (Cleocin)
(C) Trimethropin-Sulfamethoxazole (Septra/Bactrim)
(D) Amoxicillin-clavulanate (Augmentin)
Questions from article “Urticaria in the Elderly”
by Cristina Ramos-Romey et al.
16. Urticaria is mediated by
(A) mast cells
(B) endothelial cells
(C) muscle cells
(D) histamine release
(E) a and d
17. Skin punch biopsy is indicated in urticartia in
all of the following conditions EXCEPT when:
(A) lesions are non-tender
(B) individual lesions fail to resolve in 24 hours
(C) hyperpigmentation occurs
(D) hypopigmentation occurs
(E) melanoma suspicion
18. Most common cases of reported drug-induced
urticaria occurs with:
(A) aspirin
(B) acetaminophen
(C) Demerol
(D) non-steroidal anti-inflammatory agents
(E) antimicrobials
Questions from article “Severe Anemia of Rapid Onset in an Inmmunocompromised Host” by
Ezequiel Rivera Rodríguez et al.
19. Diagnostic finding in the Bone Marrow of Patients with Red Cell Aplasia secondary to parvovirus B19 includes:
(A) Aplasia Red Cell Series
(B) Hypoplastic Bone Marrow
(C) Erythocrytic Hyperplasia
(D) Large vacuolated pro normoblasts
20. The treatment of choice pure red cell aplasia
secondary to parvovirus B19
(A) Immunosupression
(B) Blood Transfussions
(C) Observation
(D) IV Human Globulin
21. Most important diagnostic lab test for a parvovirus B19 in an immunosupressed
(A) IgG serology for parvovirus B19
(B) IgM serology for parvovirus B19
(C) DNA for parvovirus by PCR
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
69
4.0 CME Credits Boletin Volume 100 No 3, 2008
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Vol.: 100 - Núm 3 - Julio-Setiembre 2008
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
70
OFICINAS ADMINISTRATIVAS SUBSCRIPCIONES Y ANUNCIOS
Asociación Médica de Puerto Rico
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Vol.: 100 - Núm 3 - Julio-Setiembre 2008
BOLETÍN - ASOCIACIÓN MÉDICA DE PUERTO RICO
71
Asociación Médica de Puerto Rico
P.O. Box 9387
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#
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USTED PUEDE OBTENER ESTE FORMULARIO, INSTRUCCIONES PARA MEMBRESÍA Y PAGO CON
TARJETA DE CRÉDITO O PAYPAL EN NUESTRO WEB SITE www.asociacionmedicapr.org
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
B LETÍN
ASOCIACIÓN MÉDICA DE PUERTO RICO
• Instrucciones para los Autores*
• Instructions to Authors*
• Manuscrito
• Manuscripts
El “Boletín” acepta para su publicación artículos relativos a medicina y cirugía y las
ciencias afines. ¡Igualmente acepta artículos especiales y correspondencia que pudiera ser
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manuscrito.
El artículo, si se aceptara, será con la condición de que se publicara únicamente en la revista.
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autores que sigan las siguientes instrucciones:
El manuscrito completo, incluyendo las leyendas y referencias deberán estar escritos en
maquinilla a doble espacio; por un sólo lado de cada página, en TRIPLICADO y con amplio
margen (ARTÍCULO DEBERÁ SER ACOMPAÑADO POR UN “CD”). En página separada
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artículo, nombre de la revista, año, volumen, páginas. Por ejemplo: Villavicencio R: Soplos
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childhood, 3d. Ed., New York, MacMillan, 1978: 789
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autor(es) del capítulo y el título del mismo. Por ejemplo: Olley PM: Cardiac arrythmias; In:
Keith ID, Rowe RD, Vlad P Eds. Heart disease in infancy and childhood,
3d Ed., New York, MacMillan, 1978: 275-301
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volume, pages. For example: Villavicencio R.: Soplos inocentes en pediatría. Bol Asoc Med
P Rico 198 1; 73: 479 87. If there are more than 7 authors list only 3 and add et al.
2. For books when the authors of the cited chapter is at the same time the editor: Surname
and initials of author(s), title, edition, city, publishing house, ~ear and page. For example:
Keith JD, Rowe RD, Vlad P: Heart disease in infancy and childhood, 3d Ed., New York,
MacMillan, 1978: 789
3. For chapter in book when the author of the chapter is not one of the Olley PM: Cardiac
arrythmias: In: Keith JD, Rowe RD, Vlad P. Eds. Heart disease in infancy and childhood, 3d
Ed. New York, MacMillan, 1978, 275-301
• Letters to the Editor
Will be published at the discretion of the Editorial Board. They should be typewritten doublespaced, should not exceed 500 words nor more than five references.
ARTICLES SHOULD BE ACCOMPANIED WITH A "CD" *The above 'Instructions to
Authors" are according to the format required by the international Committee of Medical
Journal Editors in its “Uniform Requirements for Manuscripts Submitted to Biomedical
Journals”.
Vol.: 100 - Núm 3 - Julio-Setiembre 2008
indications 2
Efficacy across
safety data in
moderate to severe
rheumatoid
arthritis (RA)1
biologic by
rheumatologists3†
patients with psoriatic arthritis. ENBREL can be used in combination with MTX in
patients who do not respond adequately to MTX alone.
ENBREL is indicated for reducing signs and symptoms in patients with active
ankylosing spondylitis.
ENBREL is indicated for the treatment of adult patients (18 years or older) with
chronic moderate to severe plaque psoriasis who are candidates for systemic
therapy or phototherapy.
References: 1. Data on file, Amgen. 2. Enbrel® (etanercept) Prescribing Information, Immunex Corporation, Thousand Oaks, Calif. March 2008.
3. Data on file, Wyeth Pharmaceuticals, Inc.
† Based on SDI patient claims data for September 2007 for biologic agents approved for moderate to severe RA.
*Based on estimated number of patient-years from 1998 through August 2007. Estimated number of patient-years is calculated by region based on
the number of ENBREL units distributed and an estimated average dose.
Please see Important Safety Information and Brief Summary of Prescribing Information on adjacent pages.
ENBREL is indicated for reducing signs and symptoms, inducing major clinical
response, inhibiting the progression of structural damage, and improving physical
function in patients with moderately to severely active RA. ENBREL can be
initiated in combination with methotrexate (MTX) or used alone.
ENBREL is indicated for reducing signs and symptoms of moderately to severely
active polyarticular juvenile idiopathic arthritis (JIA) in patients ages 2 and older.
ENBREL is indicated for reducing signs and symptoms, inhibiting the progression
of structural damage of active arthritis, and improving physical function in
Adult ENBREL patient since 1997
Your experience matters
Confidence to prescribe
patient-years of
experience worldwide
across indications1*
1.3 Million
Debra C.
collective clinical
experience1
15 Years of
More than
More than
More than
9 Years of
1 prescribed
#
Instituto de Educación Médica de
Puerto Rico
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