Grand Rounds4/16/15

Ashish SharmaPGY-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

• 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

Normal stomach body

Atrophic stomach body

Case Presentation - Pathology

Atrophic stomach body Normal stomach body

No H. pylori seen on immunohistochemical stains

Case Presentation - PathologySynaptophysin stainingIntestinal Metaplasia

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 inthe 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 gastroenterologicalpoint 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 gastroenterologicalpoint of view. World J Gastroenterol 2009

Diagnostic algorithm

Edith Lahner. Pernicious anemia: New insights from a gastroenterologicalpoint 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 antigensand H+, K+ --adenosine triphosphatase in human gastricautoimmunity. J Exp Med 2003

PA and H pyloriReasons 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 in upto 50% patients

Annibale B. CagA and VacA are immunoblot markers of past Helicobacter pylori infection in atrophic body gastritis. Helicobacter 2007Fong TL. Helicobacter pylori infection in pernicious anemia: a prospective controlledstudy. Gastroenterology 1991

PA and H pylori

Edith Lahner. Pernicious anemia: New insights from a gastroenterologicalpoint 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 pyloriImportance 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).

- 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 perniciousAnaemia. 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!