Download Pernicious Anemia

Grand Rounds
4/16/15
Ashish Sharma
PGY-4 Gastroenterology Fellow
Mentor- Maya Balakrishnan,MD
Case presentation
• 54 y/o Hispanic female was brought in by her
family after recurrent falls.
• She felt progressively feeling weak for at least
2 months.
• She had persistent nausea/vomiting, post
prandial fullness, inability to tolerate PO and a
30 lb. wt. loss over 2 months.
Case presentation
• She reported tingling sensation of fingers and
tows, “felt funny on the bottom of foot”, “not
able to feel pressure”, and “walked like a
robot”.
• She denied any hematochezia, hematemesis
or melena.
Case presentation
• PMH/PSH - None
• Family history – thyroid disorder and lupus in her
daughters
• Social history – works as a cleaner, denied
ETOH/smoking/illicit drugs
• Medications - None
Case presentation - Exam
• Vitals – Afebrile, P – 65, BP- 86/47, RR- 15, Pulse Ox – 99%
on RA, BMI -22
• Exam –
GEN: NAD
HEENT: mild icterus, OP clear
CV: RRR, soft systolic murmur
CHEST: CTAB
ABD: + BS, soft, mild periumbilical tenderness with no
guarding or rebound, non distended
EXT: No edema
NEURO: Rhomberg positive, otherwise non focal and intact
Case presentation - Labs
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CBC - WBC 3; Hb 5.6; PLT 96; MCV 115
CMP – Chemo 8 normal, TB 4, DB 0.8, other LFTs normal
Coagulation profile – normal; TSH - normal
B12 – 187, Folate – 15, Ferritin – 434, Iron Sat – 37%
Reticulocyte count – 1% (low)
LDH – 3670 (high), Haptoglobin < 32
Coomb’s test - negative
Homocysteine – 13.2 (ULN 10.7)
Methylmalonic acid (MMA) – 35437( ULN 378)
Intrinsic factor ab - Neg
Parietal cell ab - 48.7 (ULN 24.9)
Case presentation – Peripheral smear
Macrocytosis, + tear drops, Dysmorphic RBC, +
hypersegmented neutrophil, early granulocyte
progenitors, + platelet (normal morphology)
Case presentation - EGD
Atrophic stomach body
Normal stomach body
Case Presentation - Pathology
Atrophic stomach body
Normal stomach body
No H. pylori seen on immunohistochemical stains
Case Presentation - Pathology
Intestinal Metaplasia
Synaptophysin staining
Diagnosis
• Pernicious Anemia - Pernicious anemia (PA) is a
macrocytic anemia that is caused by vitamin B12
deficiency, as a result of intrinsic factor deficiency
(which is caused by an autoimmune corpus restricted
atrophic gastritis)
Clinical Questions
• Background- Epidemiology, clinical presentation
and diagnosis of PA
• Is there a relationship between H pylori and PA?
• Gastric cancer in PA - Incidence & role of surveillance
Epidemiology
• PA is an uncommon disease
• Primarily a disease of the Caucasians, however there
are recent reports of occurrence in Blacks, Latin
Americans and Asians
• Incidence - 9 cases/100k per year; and about 0.13%
of population is affected in high risk groups
• Up to 1.9 % of persons > 60 years may have
undiagnosed PA
• F: M- 2:1 per older data, but newer data shows no
difference in gender distribution
Pedersen AB. Morbidity of pernicious anaemia.
Incidence, prevalence, and treatment in a Danish county.
Acta Med Scand 1969
Carmel R. Prevalence of undiagnosed pernicious anemia in
the elderly. Arch Intern Med 1996
Clinical presentation
• Mean age of
presentation
is 59-62 years
• General symptoms - weakness, asthenia,
decreased mental concentration, headache and
with chest pain/palpitations in elderly.
Edith Lahner. Pernicious anemia: New insights from a gastroenterological
point of view. World J Gastroenterol 2009
Clinical presentation
• GI symptoms – dyspepsia (up to 28% patients)
• Neurological symptoms - paresthesia,
unsteady gait, clumsiness, and in some cases,
spasticity (up to 19% patients)
• Association with other autoimmune disorders
Edith Lahner. Pernicious anemia: New insights from a gastroenterological
point of view. World J Gastroenterol 2009
Diagnostic algorithm
Edith Lahner. Pernicious anemia: New insights from a gastroenterological
point of view. World J Gastroenterol 2009
Clinical Questions
• Background- Epidemiology, clinical
presentation and diagnosis of PA
• Is there a relationship between H pylori and
PA?
• Gastric cancer in PA - Incidence & role of
surveillance
PA and H pylori
• PA was primarily understood as an autoimmune condition
occurring in a genetically predisposed individual –
clustering with other autoimmune conditions, presence of
auto-antibodies, HLA- DR restriction
• In recent years, H pylori (infectious etiology) is thought to
be implicated in the pathogenesis of PA
• Mechanism ? -Molecular mimicry between H+/K+-ATPase
and H pylori antigens likely resulting in loss of
immunological tolerance in a genetically predisposed
individual
Amedei A. Molecular mimicry between Helicobacter pylori antigens
and H+, K+ --adenosine triphosphatase in human gastric
autoimmunity. J Exp Med 2003
PA and H pylori
Reasons for this association –
- H pylori serology positive in upto 50% of PA patients
- H pylori found in upto 30% of stomach biopsies of PA
patients
- PA (initially defined as corpus restricted atrophic
gastritis), also involves antrum in upto 50% cases, with
atrophic antrum gastritis seen in upto 30% cases
- Serology positive for H pylori antigens - Cag A and Vac A
Annibale B. CagA and VacA are immunoblot markers of past Helicobacter
in upto 50% patients
pylori infection in atrophic body gastritis. Helicobacter 2007
Fong TL. Helicobacter pylori infection in pernicious anemia: a prospective controlled
study. Gastroenterology 1991
PA and H pylori
Edith Lahner. Pernicious anemia: New insights from a gastroenterological
point of view. World J Gastroenterol 2009
PA and H pylori
• Therefore, pathogenesis of PA may be a
autoimmune and/or infectious (H pylori
related)
PA and H pylori
Importance of H pylori
association with PA?
- May be a prognostic factor in
gastric neoplasia in PA
-
Study by Rugge et al. 4/562 PA
confirmed patients had gastric
neoplastic epithelial lesions (all
were OLGA stage III or IV, and
all had H pylori association).
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116/562 PA patients (9/10 PA
patients treated for H pylori)
studied prospectively with
EGD/biopsy over a mean of 54
months developed NO gastric
epithelial neoplasia.
Rugge et al. Autoimmune gastritis: histology phenotype
and OLGA staging. Aliment Pharmacol Ther 2012
Clinical Questions
• Background- Epidemiology, clinical
presentation and diagnosis of PA
• Is there a relationship between H pylori and
PA?
• Gastric cancer in PA - Incidence & role of
surveillance
Gastric cancer and PA
There is a 7 fold increase in RR of gastric cancer in PA patients
Vannella et al. Systematic review: gastric cancer incidence in pernicious
Anaemia. Aliment Pharmacol Ther 2013;
Gastric cancer and PA - ASGE
guidelines 2006
• ASGE states that risk for gastric cancer in PA
patients in US population is low (about 1.2%,
close to average population risk)
• Recommends at least one EGD after diagnosis
of PA (risk is highest within 1st yr of diagnosis)
• Guidelines for gastric cancer surveillance in
intestinal metaplasia/dysplasia should
probably be applicable to PA patients as well
ASGE guideline: the role of endoscopy in the surveillance of premalignant
conditions of the upper GI tract GASTROINTESTINAL ENDOSCOPY Volume 63
Gastric cancer and PA
• Given that there are no guidelines for
surveillance, an individualized approach needs to
be adopted.
• In patients with gastric symptoms, pre-neoplastic
lesions (on index EGD), age >50 yr at diagnosis,
family h/o gastric cancer, high risk ethnicity
(Asian/Hispanic) and H pylori associated PA may
be considered for gastric cancer surveillance
Back to our patient
• Patient had remarkable improvement in her
fatigue and asthenia with Vitamin B12 injections.
Hb and B12 levels improved. LDH and MMA
decreased, and reticulocyte index increased
• Neurological symptoms did not reverse
• Repeat EGD done with mapping biopsies in 3
months, showed extensive intestinal metaplasia.
Will repeat EGD in 4 years with mapping biopsies
for reasons mentioned before
• Will monitor for iron deficiency
• Will obtain H pylori IgG for prognostication
Take home points
• PA is an uncommon cause of anemia resulting from
autoimmune atrophic body gastritis; presents in 5th or 6th
decade of life, mostly commonly with general anemia
symptoms
• H pylori plays role in pathogenesis of PA via mechanism of
molecular mimicry. This relationship may have prognostic
significance for gastric neoplasia in PA
• From the data shown, there is increased risk of gastric
cancer in PA patients compared to average population.
However there are no guidelines yet to support
surveillance.
Take home points
• Per ASGE at least one EGD is warranted after
diagnosis of PA (preferably within 1 yr), to
screen for neoplastic or pre-neoplastic lesions.
Thereafter, surveillance should be
individualized.
Thankyou!