Download file (Porphyria: Patient Case / Disease

Nick Wytiaz
University of Pittsburgh
APPE – LifeCare Hospital
June 13, 2011
[email protected]
PATIENT CASE / DISEASE-STATE DISCUSSION
Dx/CC: Major depression disorder w/out psychotic features / “my family doesn’t care about me”
HPI: MS is a 54yo WM admitted to Sharon Regional Hospital CCU 5/9/11 sp intentional
demeraol OD (#40 – 100mg tabs). Cleared medically and transferred to LifeCare on 5/14/11 for
further psychiatric evaluation.
PMH: CVA (2009), acute intermittent porphyria (dx ~1995), polysubstance abuse, EtOH abuse,
lower back pain/right-side weakness, requiring 4-prong cane to ambulate, bipolar disorder?
FH: Lives with wife at home
SH:
+ smoking (2ppd x37yrs), + substance abuse (THC, cocaine), narcotic dependant x20yrs
(off narcotics x1wk), EtOH abuse?
Supervisor at Midas Muffler x16ys, lost job after missing work days prior to porphyria dx
Allergies: NKDA
Home Medications (4/11):
Meperidine 100mg PO Q6H PRN
Oxycodone IR 30mg PO Q4H PRN
Citalopram 20mg PO daily
Clopidogrel 75mg PO daily
Compazine 10mg PO PRN
Omeprazole 20mg PO daily
Simvastatin 40mg PO HS
Baclofen 40mg PO TID
Tizanidine 4mg PO TID
Admission Medications (5/13/11):
Baclofen 40mg PO TID
Citalopram 20mg PO daily
Clopidogrel 75mg PO daily
Lamotrigine 25mg PO QIW
Lansoprazole 30mg PO daily
Lidocaine 5% patch daily
Milk of Mag 30mL PO daily PRN
Nicotine gum 2mg PO Q1H PRN
Maalox 30mL PO Q6H PRN
Tramadol 50-100mg PO QID PRN
Trimethobenzamide 300mg PO Q8H PRN
Nicotine 21mg patch daily
Simvastatin 40mg PO HS
Trazodone 50mg PO HS
Theravite 1 tablet daily
Acetaminophen 650mg PO Q4H PRN
Benztropine 1mg PO Q2H PRN
Bisacodyl 10mg PO/PR daily PRN
Clonidine 0.1mg PO Q6H PRN
Dicyclomine 20mg PO Q8H PRN
Ibuprofen 800mg PO Q8H PRN
Loperamide 2mg PO Q4H PRN
Lorazepam 1mg IM/PO PRN
PE / ROS (5/17/11):
Gen: No wt loss/gain despite poor appetite, depressed mood, anxiety at times
Skin: clear
HEENT: No problems
Pulm: Hx resp infxn, wheezing, COPD
GI: Hx IBS, diarrhea; sharp pain in stomach, n/v
Neuro: MMSE = 30/30, GDS = 25/30 (severe)
Muscoskeletal: low back pain
Vitals: Ht/Wt - 5’11” / 126lbs
Date
T (oF)
5/17
98.1
5/20
97.5
5/22
97.7
5/25
97.7
5/26
98.5
5/27
98.3
5/28
97.7
5/29
97.6
5/30
97.7
Current Medications:
Medication
Dose
Scheduled
Baclofen
20mg
Citalopram
40mg
Clopidogrel
75mg
Guar Gum Powder 8 oz
Lansoprazole
30mg
BP (mmHG)
152/96
106/74
170/60
98/60
90/66
98/52
108/68
110/60
100/68
HR (bpm)
76
76
74
80
60
80
64
60
68
Route
Schedule
Indication
Start-Stop
PO
PO
PO
PO
PO
TID
Daily
Daily
BID
Daily
Muscle Spasm
Depression
CVA
Diarrhea / IBS
Stress Ulcer
Prophylaxis
Back Pain
Smoking Cessation
Health Maintenance
Depression / Sleep
5/13-6/1
5/24-6/1
5/13-6/1
5/20-6/1
5/13-6/1
Mild-Mod Pain
(Scale 1-4)
EPS
Constipation
BP>140/95, HR>95
Abdominal Pain
Mild-Mod Pain
(Scale 1-4)
Diarrhea
Anxiety
Upset Stomach /
Constipation
Constipation
Nicotine Craving
Mod-Severe Pain
(Scale 5-10)
Mod-Severe Pain
(Scale 4-10)
Nausea / Vomiting
5/13-6/1
Lidocaine patch
Nicotine patch
Theravite
Trazodone
PRN
Acetaminophen
5%
21mg
1 tablet
75mg
Transdermal
Transdermal
PO
PO
Daily
Daily
Daily
Daily
650mg
PO
Q4H
Benztropine
Bisacodyl
Clonidine
Dicyclomine
Ibuprofen
1mg
10mg
0.1mg
20mg
800mg
PO
PO/PR
PO
PO
PO
Q2H
Daily
Q6H
Q8H
Q8H
Loperamide
Lorazepam
Maalox
2mg
1mg
30mL
PO
IM/PO
PO
Q4H
Q4H
Q6H
Milk of Magnesium 30mL
Nicotine gum
2mg
Oxycodone
30mg
PO
PO
PO
Daily
Q1H
Q4H
Tramadol
PO
QID
PO
Q8H
50-100mg
Trimethobenzamide 300mg
RR (bpm)
22
18
20
20
18
16
16
20
20
5/15-6/1
5/15-6/1
5/13-6/1
5/27-6/1
5/13-6/1
5/13-6/1
5/13-6/1
5/13-6/1
5/13-6/1
5/13-6/1
5/13-6/1
5/13-6/1
5/13-6/1
5/13-6/1
5/20-6/1
5/13-6/1
5/13-6/1
Labs:
Normal Range
5/14 5/17 5/23
Na
136-145 mEq/L
141
141
140
K
3.5-5.0 mEq/L
3.9
4.0
4.2
Cl
98-107 mEq/L
106
106
105
CO2
21-31 mEq/L
28
26
26
Glucose
70-99 mg/dL
110
112
101
BUN
5-20 mg/dL
14
13
19
SCr
0.5-1.4 mg/dL
1.0
1.0
1.0
Protein
6.4-8.2 g/dL
6.6
7.3
6.3
Albumin
3.5-5.0 g/dL
3.3
3.7
3.1
TBili
<1.0 mg/dL
0.3
0.4 <0.1
Alk Phos
50-136 IU/L
123
127
105
AST
15-37 IU/L
14
13
10
ALT
30-65 IU/L
28
33
26
Ca
8.5-10.1 mg/dL
9.0
9.2
Mg
1.8-2.4 mg/dL
2.0
TC
<200 mg/dL
158
Trigs
40-220 mg/dL
70
LDL
<130 mg/dL
94
HDL
>45 mg/dL
50
WBC
3.8-10.6 x109
7.2
6.9
7.2
RBC
4.13-5.57 x1012 4.43 4.64 4.09
Hgb
12.9-16.9 g/dL 15.2 15.6 13.8
Hct
42-51 % 43.7 45.6 40.7
Platelets
156-369 x109
181
238
233
Porphyrins Interpretive Guide
Porphyria Disorder
Porphyrins – Random Urine
Normal Range
5/23
Coproporphyrins
23-130 mcg/g creat
87.6
Pentaphorphyrin
<1.7 mcg/g creat
Heptaphorphyrin
< 4.6 mcg/g creat
2.8
Urophorphyrins
<22.0 mcg/g creat
13.7
Total Pophyrins
31-139 mcg/g creat 104.1
Aminolevulinic Acid
<1.8 mg/g creat
2
Porphyrins Expected* Elevated Urine
D-aminolivulinic Acid
Acute Intermittent
None
+
ALA Dehydratase Deficiency
None
+
Congenital Erythropoietic
Uro, Copro
Erythropoietic Protoporphyria
None
Hepatoerythropoietic
Uro, Heptacarboxyy
Hereditary Coproporphyria
Copro, Pentacarboxy +/Porphyria Cutanea Tarda
Uro, Heptacarboxy
Variegate
Copro, Pentacarboxy +/*Patients with hereditary forms of porphyria usually will present with profound elevations of
these anlytes (> 5-fold) during acute episodes. Moderates elevations (<3-fold) are more often due
to medications or environmental factors.
THE PORPHYRIAS
Background / Pathogenesis:
Porphyrias are a group of rare, hereditary disorders, in which the heme biosynthesis pathway is
altered. Heme, a prosthetic group consisting of an iron atom in the center of a large heterocyclic
organic ring (porphyrin), is an important component of hemoglobin and can also be found in
myoglobin. Normally, heme is made in a multi-step process which also results in the production
of porphyrins via multiple reactions within the heme synthesis pathway.
While many different forms of porphyria (at least eight) have been identified, all share the
common feature of porphyrins or porphyrin precursor accumulation in the body. The enzyme
deficiencies and subsequent chemical build-ups are specific to the various types of porphyrias as
seen on the following figure from a James and Hift review article:
Enzymatic defects are believed to predispose affected persons to various factors that may trigger
acute attacks. These exacerbating factors include drugs, such as barbiturates, hydantoins,
rifampin, progestins, steroid hormones, and other P450 inducers. Dietary restrictions, alcohol,
smoking, and other acute illnesses or stress may also trigger acute attacks. All of these
exacerbating factors either increase the demand for hepatic heme or impair the negative feedback
loop responsible for inhibiting additional heme synthesis. As a result, heme synthesis continues
unchecked and the concentration of pathway intermediates increase with respect to the specific
inherited partial enzymatic deficiency.
The porphyrias, even when taking into account all forms, are rare diseases, afflicting fewer than
200,000 people in the US. According to European studies, the prevalence of the most common
porphyria, porphyria cutanea tarda (PCT), is 1 in 10,000, the most common acute porphyria,
acute intermittent porphyria (AlP), is about 1 in 20,000, and the most common erythropoietic
porphyria, erythropoietic protoporphyria (EPP), is estimated at 1 in 50,000 to 75,000. Congenital
erythropoietic porphyria (CEP) is extremely rare with prevalence estimates of <1 in 1,000,000.
Only 6 cases of ALAD-deficiency porphyria (ADP) are documented.
Signs / Symptoms:
While symptoms usually vary significantly depending on the type of porphyria, they generally
result mostly from effects on either the nervous system or the skin.
Effects on the nervous system occur most often in the acute porphyrias (AIP, ADP, HCP and
VP) and present as neurovisceral symptoms such as abdominal pain/cramping (followed by
vomiting and constipation), seizures, mental disturbances, or muscle pain / weakness . Chronic
porphyrias are most often associated with skin manifestations. Cutaneous symptoms range from
the chronic, blistering lesions seen with PCT to the acute, non-blistering photosensitivity
(redness, swelling, pain) common in EPP.
Additional signs of an acute attack may include, discolored urine (red or brown), significant drop
or increase in blood pressure, severe electrolyte imbalances, tachycardia, and shock.
Diagnosis:
A complete personal and family history is the first step in the diagnosis of the porphyrias. While
not definitively diagnostic in of itself, such a work-up may reveal telltale signs and symptoms as
previously discussed (i.e. recurrent episodes of abdominal pain, photosensitivity). Severe stress,
starvation, "crash" dieting, alcohol excess or infections may also provide clues since these events
often trigger acute porphyric attacks.
After family and personal history, laboratory testing, especially at or near the time of symptoms,
is used to confirm a diagnosis of porphyria. However, since many of the symptoms of porphyria
are nonspecific, the group of diseases is often mistaken for other, more common diseases which
present with similar symptoms. Thus, laboratory testing for porphyria is often not considered
until much later, delaying the diagnosis of porphyria or even causing it to be missed altogether.
In order to avoid this problem, porphyria must be considered early on when patients first present
with compatible signs and symptoms and should be ruled out via laboratory testing.
The most common tests used for acute porphyrias are measurements of porphyrin precursors and
porphyrins in red blood cells (erythrocytes), blood plasma, urine and feces. Measuring enzyme
levels in cells and identifying genetic mutations in DNA is useful for confirmation and for family
studies, especially in chronic porphyrias. The key to diagnosis is rapid and simple testing for
increased porphobilinogen (PBG) in the urine. In all cases of acute porphyria, with the exception
of ALA dehydratase deficiency, PBG levels are generally markedly increased (20–200 mg/dL
with a typical reference range of 0–4 mg/dL). If PBG is increased, second-line testing including
erythrocytic PBG deaminase levels, urinary, fecal, and plasma porphyrin levels can help establish
the specific porphyrin disorder. The table presented previously in the Labs section, shows
additional second-line urine tests useful in this further differentiation.
After diagnosing the presence and type of porphyria via labs, DNA studies can identify the
disease-causing mutation(s) in the defective gene. Patients and family members with acute
porphyria can undergo mutational analysis to pinpoint the causative defect.
Treatment / Prevention / Follow-Up:
Treatment options depend on the type of porphyria and focus on symptomatic management and
steps to prevent future acute attacks. Common approaches include:








Identification and removal of exacerbating factors: drugs, alcohol, toxins, chemicals
Nutritional supplementation: at least 300 grams glucose/day
Frequent neurologic status review (specifically, watch for paresis of respiration muscles)
Monitor / treat for hypoventilation, hyponatremia, or hypomagnesemia
Intravenous heme: 3–4 mg/kg/day for 3–5 days
Pain managment: merperidine, morphine, oxycodone
Nausea/vomiting: phenothiazines (prochlorperazine, chlorpromazine), trimethobenzamide
Tachycardia / Hypertension: propranolol, nadolol, clonidine
The most effective therapy for the acute attack is hemin. This treatment is specific, because it
corrects the deficiency of regulatory heme in the liver and down-regulates ALAS. Glucose
loading has a similar effect, but is much less potent and effective and should be used only for
mild attacks. Panhematin® (Lundbeck) is the only hemin therapy available in the US and is
FDA-approved for treating acute porphyrias.
For long-term treatment and prevention of future episodes, harmful drugs should be stopped
immediately and avoided in porphyric patients. Information on such medications can be found in
regularly updated, searchable databases at the APF (www.apfdrugdatabase.com/) and EPI
websites (www.drugs-porphyria.org).
Patient education, genetic counseling, medic alert bracelets, and consultation with a porphyria
expert for additional advice and follow-up are recommended after recovery from an acute attack.
Despite these precautions, some patients may develop chronic symptoms, including chronic pain
syndrome and severe depression with an increase risk of suicide. In these cases, patients require
careful supportive management in order to control and, ultimately, improve their symptoms.
PATIENT CASE (CONTINUED)
Assessment / Plan:
MS was receiving psychiatric evaluation and treatment following recovery from intentional
Demerol overdose. Upon admission to Lifecare, he presented with depression, social problems
(substance abuse), and family concerns (wife threatening to leave). Physically, he complained of
a sharp, severe abdominal pain (8-10), nausea / vomiting, and mild constipation – symptoms
consistent with his AIP.
To further assess, a consult was requested on 5/16 to evaluate the history of the porphyria and
update special treatment recommendations. In addition, pharmacy was consulted on 5/17 to
review medications in order to identify drugs which may exacerbate porphyria. After conducting
a literature search of all the patient’s medications and their effects on porphyria, three drugs were
found to be potentially unsafe in those with porphyria. Lamotrigine, simvastatin, and tramadol
were each identified via chick embryo liver studies to cause porphyrin accumulation, which may
precipitate or exacerbate acute porphyria attacks. Based on the results of the literature review,
pharmacy recommended the following:

Discontinuation of tramadol and consideration of alternative analgesic agents (opiods)

Discontinue simvastatin

Lamotrigine, which was discontinued on 5/17, should not be restarted
Hematology replied to the consult on 5/23 and agreed with pharmacy’s recommendations and the
suggested changes were made to the patient’s medication regimen. They also requested a urine
porphobilinogen and delta-aminolevulinic acid and advised the patient to eat regular meals,
maintaining adequate carbohydrate intake.
Even prior to changes in his medications, the patient’s symptoms began to improve. On 5/19, he
was no longer vomiting and his appetite returned. MS stated that he “felt a lot better” and was
becoming more social with patients on the floor, playing cards and board games. Patient also
admitted to behavioral health personnel that he stopped taking his some of his medications
(citalopram and lamotrigine) a few days prior to his suicide attempt. He then stated that he now
“realizes that they help and will take them again.” While his mood was improving, he still
complained of stomach pain (8-10) and some problems ambulating.
On 5/20, changes in the patient’s medications were made per pharmacy recommendations and
oxycodone 30mg PO Q4H was started to control stomach pain. The physician was hesitant to
prescribe a narcotic due to MS’s history of dependence / abuse; however it was the best means to
control his pain. MS stated that he “would not abuse oxycodone.” Physical therapy (PT) 2x/week
for 3 weeks was also ordered to help MS regain his gait. In addition, citalopram was increased to
40mg PO daily on due to some continued depression.
MS continued to improve clinically in the days following changes to his medication regimen. He
confirmed that his pain was controlled and the he “felt a lot better, 110% better with oxycodone.”
His depression also appeared to be controlled with the higher dose of citalopram as he
continually reported feeling “not at all depressed” and in a “good mood”. MS was discharged on
6/1 with the plan to continue his current drug regimen and PT 2x / week for 2 weeks.
References:
American Porphyria Foundation. Porphyria: diagnosis and treatment options. PowerPoint.
2010. Accessed 1-7 June 2011 via http://www.porphyriafoundation.com/for-healthcareprofessionals/additional-resources#physician_kit
Anderson KE, Bloomer, JR Bonkovsky HL, et al. Recommendations for the diagnosis and
treatment of the acute porphyrias. Ann Intern Med. 2005; 142:439-450
Bonkovsky HL. Neurovisceral porphyrias: what a hematologist needs to know. Hematology Am
Soc Hematol Educ Program. 2005:24-30. Available online at
http://asheducationbook.hematologylibrary.org/cgi/content/full/2005/1/24#T1B
James MFM and Hift RJ. Porphyrias. Br J Anaesth. 2000; 85:143-53. Accessed via
http://bja.oxfordjournals.org/content/85/1/143.full
Puy H, Gouya L, Deybach JC. Porphyrias. Lancet 2010; 375:924. Accessed via
http://www.porphyrie.net/articles/deybach_2010.pdf
Wiley JS, Moore MR. Heme biosynthesis and its disorders: porphyrias and sideroblastic
anemias. In: Hoffman R, Benz EJ Jr., Shattil SJ, et al, eds. Hoffman Hematology: Basic
Principles and Practice. 5th ed. Philadelphia, Pa: Churchill Livingstone Elsevier; 2008:38.
UpToDate (electronic). Accessed 1-7 June 2011 via http://www.uptodate.com/contents
/porphyrias-an- overview?source=search _result& selected Title=1%7E82