Pernicious Anemia

Morning Report
John Paul Vavalle, MD October 30, 2007

Pernicious Anemia
Epidemiology:
Most common cause of vitamin B12 def. About 2% of people over 60 have undiagnosed pernicious anemia Most common in whites of Northern European ancestry. Average age of diagnosis is approx 60. Under age 30, it is usually associated with other autoimmune dz. Of 729 subjects 4.1% prevalence in C & AA women and 2.1% incidence in C & AA men.

Pernicious Anemia
Historical View
First described in 1849 by Thomas Addison Austin Flint linked that anemia to the stomach in 1860. Named pernicious anemia shortly thereafter. No longer pernicious as pathophysiology better understood and simple treatments available.

Megaloblastic Anemia
Anemia with macrocytic red cells (MCV > 100 fL) Low-normal absolute reticulocyte count BM shows intense erythroid hyperplasia w/

abnormal morphology. Macroovalocytes and occasional megaloblasts can be seen. Hypersegmented PMN ( > 5% w/ 5 or more lobes or > 1% w/
6 or more lobes.)

A result of impaired DNA synthesis due to def. in

Folate and/or vitamin B12 (cobalamin).

Megaloblastic Anemia

Megaloblastic Anemia

Megaloblastic Anemia

B-12 Physiology
Normal B-12 absorption:
Dietary B-12 binds to R factor in saliva and gastric juices. In duodenum, pancreatic enzymes promote dissociation from R factor and binding to Intrinsic Factor (IF) IF-B12 complex taken up by ileal receptor cubilin. Released into plasma bound to transcobalamines TC I, II, or III. Enters cells through receptor mediated endocytosis and metabolized into two coenzymes: adenosyl-Cbl and methyl-Cbl.

Folate/B12 DNA Synthesis

Megaloblastic Anemia
Initial work-up
Check serum B-12, folate (serum or red cell), TSH, Reticulocyte panel, CBC, Fe panel, Social Hx, Neuro exam. MCV predictive of b-12/folate def. B-12 level < 200 pg/mL is 95-100% Sp for def If serum B-12 and folate levels are equivocal, check serum HC and MMA levels. In folate def, only HC is elevated (Sn 86%, Sp 99%). In B-12 def, both HC and MMA is elevated (Sn 94% Sp 99%). Presence of neurological deficits may also indicate B12 def.

Pernicious Anemia
Clinical Features:
Megaloblastic anemia Serum B-12 def Chronic atrophic gastritis Neurologic manifistations (paresthesias, numbness,

Atrophic glossitis Achlorhydria (lack of HCl in gastric juice) Elevated serum bilirubin and LDH reflective of increased RBC breakdown due to ineffective erythropiesis.

weakness, memory loss, personality changes, ataxia, loss of vibration and position sense, psychosis megaloblastic madness)

Pernicious Anemia
Pathophysiology
Autoantibody to IF Two types:
Type I blocks attachment of B-12 to IF Type II blocks B-12-IF complex to ileal receptor

Present in up to 70% of patients with P.A. and Sn approaches

100%.

Autoantibody to gastric parietal cells Directed against the H/K-ATPase on cell membrane Leads to decline in # of parietal cells and IF production Leads to chronic atrophic gastritis and gastric atrophy. Found in 90% of patients with pernicious anemia.

Pernicious Anemia
Chronic Atrophic Gastritis
Type A (autoimmune): The type involved in P.A. (due to autoantibodies) Involves the fundus and body which contain acid-secreting

parietal cells and spares the antrum which contains gastrinproducing cells. This leads to achlorhydria and high serum gastrin levels.

Type B: Involves fundus, body, and antrum Usually associated with H.pylori infection. The progression of Type A chronic atrophic gastritis to gastric atrophy and clinical anemia is likely to span 20 30 years.

Pernicious Anemia
Schilling Test
Stage I Give 1mcg of radiolabeled B-12 orally, followed by
1000 mcg of B-12 IM one hour later to flush any absorbed radiolabeled B-12 from tissues. A 24-hr urine is collected to determined how much radiolabeled B-12 is excreted. Normal is 8-35%.

Pernicious Anemia
Schilling Test
Stage II Done only if Stage I is abnormal. Repeat Stage I, except with the addition of added
oral IF which should normalize B-12 absorption in P.A., but not intestinal malabsorption.

Pernicious Anemia
Schilling Test
Many false pos and neg results Not commonly used Not readily available in many places Less sensitive test checking HC and MMA to detect B-12 def. Only recommended when anti-IF antibodies are normal.

Pernicious Anemia
Treatment
IM B-12 at 1000 mcg daily for one week, then 1000 mcg weekly for one month, then 1000 mcg every month for one year indefinitely. No harm in overtreatment. Inexpensive, non-toxic and excess is excreted in urine.

Pernicious Anemia
Response to Treatment
Reticulocytosis in 3-4 days Rise in Hgb concentration within 10 days and normalization in 8 weeks as well as correction of MCV. Fall of serum LDH levels within 2 days Hypersegmented PMN disappear in 10-14 days Must watch closely for severe hypokalemia during early response due to marked increased potassium use in hematopoiesis.

References
Toh BH, van Driel IR, Gleeson PL. Pernicious

anemia. NEJM. 1997. 337:1441-1448. Schrier SL. Diagnosis and treatment of B12 and folic acid deficiency. UpToDate online. Accessed 5/8/06 Schrier SL. Physiology of vitamin B12 and folic acid deficiency. UpToDate online. Schrier SL. Etiology and clinical manifestations of vitamin B12 and folic acid deficiency. UpToDate online. Accessed 5/8/06