10.30.07 Pernicious Anemia Vavalle

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Pernicious AnemiaMorning Report

John Paul Vavalle, MDOctober 30, 2007


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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.


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Pernicious Anemia

Historical View First described in 1849 by Thomas Addison

Austin Flint linked that anemia to the stomachin 1860.

Named pernicious anemia shortly thereafter.

No longer pernicious as pathophysiologybetter understood and simple treatmentsavailable.


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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).


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B-12 Physiology

Normal B-12 absorption: Dietary B-12 binds to R factor in saliva and gastric

juices.

In duodenum, pancreatic enzymes promotedissociation from R factor and binding to IntrinsicFactor (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 endocytosisand metabolized into two coenzymes: adenosyl-Cbland methyl-Cbl.


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Folate/B12 DNA Synthesis


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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 HCand MMA is elevated (Sn 94% Sp 99%). Presence of neurological deficits may also indicate B-

12 def.


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Pernicious Anemia

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

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

Atrophic glossitis Achlorhydria (lack of HCl in gastric juice) Elevated serum bilirubin and LDH reflective of

increased RBC breakdown due to ineffectiveerythropiesis.


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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.


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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 gastrin-producing cells. This leads to achlorhydria and high serumgastrin levels.

Type B: Involves fundus, body, and antrum Usually associated with H.pylori infection.

The progression of Type A chronic atrophic gastritisto gastric atrophy and clinical anemia is likely to span20 30 years.


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Pernicious Anemia

Schilling Test Stage I

Give 1mcg of radiolabeled B-12 orally, followed by1000 mcg of B- 12 IM one hour later to flush anyabsorbed radiolabeled B-12 from tissues. A 24-hrurine is collected to determined how much

radiolabeled B-12 is excreted. Normal is 8-35%.


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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 inP.A., but not intestinal malabsorption.


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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.


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Pernicious Anemia

Treatment IM B-12 at 1000 mcg daily for one week, then

1000 mcg weekly for one month, then 1000mcg every month for one year indefinitely. No harm in overtreatment. Inexpensive,

non-toxic and excess is excreted in urine.


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Pernicious Anemia

Response to Treatment Reticulocytosis in 3-4 days

Rise in Hgb concentration within 10 days andnormalization in 8 weeks as well as correctionof 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 increasedpotassium use in hematopoiesis.


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References

Toh BH, van Driel IR, Gleeson PL. Perniciousanemia. NEJM. 1997. 337:1441-1448.

Schrier SL. Diagnosis and treatment of B12 andfolic acid deficiency. UpToDate online. Accessed 5/8/06

Schrier SL. Physiology of vitamin B12 and folicacid deficiency. UpToDate online.

Schrier SL. Etiology and clinical manifestations of vitamin B12 and folic acid deficiency. UpToDateonline. Accessed 5/8/06

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10.30.07 Pernicious Anemia Vavalle