_~CME credit article
`
`Pernicious anemia
`Early identification to prevent permanent sequelae
`
`Anand B. Kamad, MD Agnes Krozser-Hamati, MD
`
`Preview
`Because pernicious anemia is easily treated, early diagnosis
`is essential to prevent permanent neurelogic deficits. Labora-
`tory tests include a complete blood cell count, determination
`of the serum cobalamin level, and the Schilling test, in which
`radiolabeled vitamin B12 is used to demonstrate a lack of in-
`trinsic factor. Therapy gives rapid relief but usually must be
`continued for life.
`
`Pernicious anemia was uniformly
`fatal tmtil 1934, when two Boston
`physicians, George Richards Minot
`and William Parry Murphy, were
`awarded the Nobel Prize in medi-
`cine for demonstrating the efficacy
`of a diet rich in liver for treating the
`disease. William Bosworth Castle’s
`classic series of experiments at
`Boston City Hospital established
`that a lack of gastric intrinsic factor
`(due to achylia gastrica) was a hall-
`mark of the disease. The vital in-
`gredient in liver (extrinsic factor)
`was later shown to be vitamin B12
`(cobalamin).
`
`Charat~ristics
`Adult-onset pernicious anemia is
`relatively common among persons
`of northern European descent
`who are older than age 50. (The
`annual incidence of new cases is
`100/1 million population.) How-
`ever, the disorder affects virtually all
`racial and ethnic groups and is
`slightly more common in women.
`A steep rise in incidence in older
`age-groups suggests that atrophic
`gastritis and pernidous anemia
`
`are a consequence ofepithdial
`aging.’
`With florid disease, manifesta-
`tions consist of megaloblastic ane-
`mia, gastric atrophy followed by
`generalized epithelial atrophy, and
`neuropsychiatric abnormalities
`from subacute combined degenera-
`tion of the spinal cord and brain.
`The clinical expression of the disor-
`der is variable; for example, pro-
`gression of anemia may not parallel
`that of epithelial atrophy or neu-
`ropathy, and patients without ane-
`mia may have severe nervous sys-
`tem involvement. The reason for
`predominance of neurologic or
`hematologic dysfunction in indi-
`vidual patients remains uncertain.
`MEGALOBLASTIC ANEMIA--
`The two distinctive deformities of
`blood cells in pernicious anemia
`are (1) hypersegmentation ofneu-
`trophils and (2) macro-ovalocytosis
`(the presence of large, egg-shaped
`red cells, or macro-ovalocyres). Al-
`though the volume ofmacro-
`ovalocytes is about twice normal,
`red ceils vary in size and shape, so
`the average mean corpuscular vol-
`
`ume in patients with severe anemia
`falls in the range of110 to 140 fL.
`Severe anemia may be accompa-
`nied by moderate leukopenia and,
`less often, by severe thrombocy-
`topenia. Morphologic characteris-
`tics of the bone marrow indude
`marked nuclear-cytoplasmic dys-
`synchrony in both erythroid and
`myeloid cells; the nuclear chro-
`matin acquires an unevenly speck-
`led pattern that gives it a "sliced
`salami" appearance.2
`GASTRIC a_TROPH¢ Atrophy
`of the gastric mucosa, which is the
`initial lesion ofpernidous anemia,
`affects the proximal two thirds of
`the stomach. Endoscopic biopsy
`reveals a thin mucosa with sparse
`glands surrounded by infiltrates of
`lymphocytes and plasma cells. Be-
`cause cobalamin deficiency affects
`all exfoliating cell populations, at-
`rophy of the tongue, lips, skin, and
`enteric and vaginal mucosa may be
`seen.
`NEUROPSYCHIATRIC ABNOR-
`MALITIES~Subacure combined
`degeneration of the spinal cord and
`brain is the characteristic neuro-
`pathic disorder caused by cobala-
`min deficiency: Symmetric wast-
`ing of hands and feet and loss
`of vibration sense in the lower ex-
`tremities are caused by patchy de-
`myelination of the dorsal and lat-
`eral columns of the spinal cord. In
`cases of severe untreated cobala-
`min deficiency; optic neuropathies
`and central nervous system abnor-
`continued
`
`VOL 91/NO 2/FEBRUARY 1, 1992/POSTGRADUATE MEDICINE , PERNICIOUS ANEMIA
`
`231
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`In cases of severe untreated cobalamin
`deficiency, optic neuropathies and
`central nervous system abnormalities
`may be seen.
`
`Megaloblastic
`Vitamin B12 deficiency
`Folic acid deficiency
`
`Normoblastic
`Alcohol
`Reticulocytosis
`Myelodysplastic syndromes
`Hypothyroidism
`Chronic liver disease
`Anticancer drugs (eg, hydroxyurea
`[Hydrea])
`
`*Mean corpuscular volume > 94 fL.
`
`Normal pregnancy
`
`Partial gastrectomy
`
`Folate deficiency
`
`Iron deficiency
`
`Severe atrophic gastritis
`
`Strict vegetarianism
`
`Urinary excretion of radiolabeled
`vitamin B12 (%)
`Without IF With IF
`
`>8
`
`<8
`
`<8
`
`>8
`
`>8
`
`>8
`
`<8
`
`_>8
`
`Normal
`
`Pernicious anemia
`
`Malabsorption
`
`Food-bound malabsorption
`
`IF:, intrinsic factor.
`
`17-year period at two New York
`hospitals, found that pernidous
`anemia was the most common un-
`derlying cause of the cobalamin
`deficiency. The most frequent
`symptoms were paresthesias and
`ataxia, whereas the most common
`objective findings were diminished
`vibratory sensation and proprio-
`ception in the lower extremities. A
`variety of other symptoms and
`signs were seen, including muscle
`weakness, diminished reflexes,
`spasdcity; urinary and fecal inconti-
`nence, orthostatic hypotension,
`dementia, psychoses, and mood
`disturbances. Multiple neurologic
`syndromes were seen in a single pa-
`tient.
`The hematocrit was normal in
`27% of the patients, and the mean
`corpuscular volume was normal in
`23%. In most of the patients, care-
`ful review of blood smears and
`bone marrow aspirates revealed
`subtle morphologic evidence of
`megaloblastic changes. All patients
`responded to cobalamin therapy,
`and recovery was complete in
`47%. The scope ofneurologic
`residua after treatment was strongly
`related to the extent and duration
`of symptoms before therapy.
`
`malities ranging from conf~ion to
`dementia may be seen.
`Recent studies3’4 indicate that
`neurologic disorders encountered
`in current clinical practice are less
`
`severe than in the past and are
`highly responsive to therapy. Heal-
`ton and associates,+ describing their
`experience with neurologic disor-
`ders in 143 patients seen over a
`
`l~horamry diagnosis
`A complete blood cell count, deter-
`mination of the serum cobalamin
`level, and the Schilling test aid in
`the diagnosis of pernicious anemia.
`
`232
`
`PERNICIOUS ANEMIA * VOL 91/NO 2/FEBRUARY 1, 1992/POSTGRADUATE MEDICINE
`
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`
`The Schilling test
`can be used to
`demonstrate a lack of
`intrinsic factor and
`confirm the diagnosis of
`pernicious anemia.
`
`COMPLETE BLOOD COUNT--
`Macrocytosis may be the first sign
`of the disease; however, the dif-
`ferential diagnosis of macrocytosis
`is extensive (table 1). The appear-
`ance of the blood film is of little
`hdp in early cases, and the white
`blood cell and platelet counts do
`not change until anemia is severe.
`In the absence of changes in the
`blood, examination of bone mar-
`row aspirate is the only other way
`ofidentifi/ing megaloblastosis.
`When megaloblastic changes are
`confirmed, the patient is catego-
`rized as having megaloblastic rather
`than normoblastic macrocytosis?
`SERUM COBALAMIN LEVEL All
`patients who have cobalamin deft-
`ciency have a low serum vitamin
`B12 level, although cobalamin defi-
`ciency is not the only cause. Low
`serum cobalamin levels in the pres-
`ence of normal vitamin B12 tissue
`stores (false-positives) are common
`(table 2). The serum vitamin B12
`level is just one piece of evidence
`that needs to be fitted into the rest
`of the clinical picture. The presence
`of megaloblasfic hematopoiesis ac-
`companied by a low serum vitamin
`B12 level is not sufficient proof of
`pernicious anemia; lack of gastric
`intrinsic factor must be established
`as the cause of these changes?
`SCHn.~.~G TEST This absorp-
`tion test uses radiolabeled vitamin
`B12 to show that lack of intrinsic
`factor is the cause of a low serum
`
`What causes pernicious anemia?
`
`Pernicious anemia, which is characterized by megaloblastic hemato-
`poiesis and/or neuropsychiatric abnormalities, is due to vitamin B12
`(cobalamin) deficiency resulting from severe atrophic gastritis.
`Megaloblastic hematopoiesis is due to cytologic deformities caused
`by malfimction ofcobalamin-dependent enzymes (the latter are vi-
`tal for DNA synthesis). The mechanism for neurologic abnormali-
`ties seen with cobalamin deficiency remains unknown.
`Over 90% of patients with pernicious anemia have serum anti-
`bodies (IgG) to parietal cell cytoplasm, and over 75% have de-
`tectable antibodies (polyclonal IgG or IgA) to intrinsic factor in the
`serum, saliva, and gastric juice. Anti-parietal cell antibodies may
`simply be evidence of a response to parietal cell damage by other
`agents. The absence of intrinsic factor antibodies in about 25% of
`patients and evidence that these antibodies appear after, rather than
`before, gastric atrophy argue against an initiating role. Thus, as
`yet, the pathogenetic role of these antibodies has not been firmly
`established.
`
`cobalamin level. Impaired absorp-
`tion of vitamin B12 that is corrected
`by repeating the test with added in-
`trinsic factor (table 3) implies a lack
`of intrinsic factor and confirms the
`diagnosis of pernicious anemia.
`The test is usually done by measur-
`ing radioactivity in a 24-hour urine
`specimen, and incomplete collec-
`tion of urine (especially in a very
`elderly patient) may cause a false-
`positive or false-negative result; this
`is more common in outpatients
`than inpatients. Measurement of
`plasma radioactivity 8 to 10 min-
`utes after the start of the Schilling
`
`test has been found to be as reliable
`as measurement in a complete
`urine specimen?
`A normal result on the Schilling
`test in patients with a low serum
`cobalamin level indicates food-
`bound cobalamin malabsorption.
`This condition has stimulated
`the widespread use of a "food"
`Schilling test (or egg-yolk cobala-
`min absorption test), in which the
`ingested cobalamin is derived from
`eggs produced by hens injected
`with radiolabeled cobalamin. Mal-
`absorption of food-bound cobala-
`min can cause a variety ofneuro-
`continued
`
`VOL 91/NO 2/FEBRUARY 1, 1992/POS3GRADUATE MEDICINE ¯ PERNICIOUS ANEMIA
`
`233
`
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`
`

`
`Oral cobalamin is available to treat patients
`with pernicious anemia, but the lowest effective
`dose has not been established.
`
`Oral cobalamin is available and
`has been shown to be effective
`(large doses are absorbed indepen-
`dently of intrinsic factor); however,
`present data are not sufficient to
`establish the lowest effective oral
`dose for the majority of patients.7’8
`Patients receiving oral cobalamin
`therapy should be closely moni-
`tored.
`The hematologic response to
`therapy is rapid, with brisk teticu-
`locytosis that reaches a peak 5 to 6
`days after initiation of therap$ In
`the patients observed by Healton
`and assodates,3 some evi&nce of
`response was always seen during
`the first 3 months of treatment. As
`noted, in patients with neurologic
`syndromes, the amount of im-
`provement over baseline neurologic
`status is inversely related to both
`hematocrit level and duration of
`symptoms.
`
`Smnnlary
`
`Pernidous anemia can be confi-
`dendy diagnosed in a patient
`who has megaloblastic hemato-
`poiesis, low serum cobalamin
`level, and impaired vitamin B~2
`absorption correctable by ad-
`ministering intrinsic factor. Re-
`cent studies suggest that neuro-
`logic disorders in patients with
`pemidous anemia are less severe
`than in the past, highly respon-
`continued
`
`Anand B. Karnad, MD
`Agnes Krozser-Hamati, MD
`Drs Karnad (left) and Krozser-Hamati (right) are assistant professors of medicine, division
`of hematology-oncology, department of interna! medicine, James H. Quillen College of
`Medicine, East Tennessee State University, Johnson City. The division focuses on clinical
`research in hematologic abnormalities in elderly patients, with a strong emphasis on
`geriatric oncology.
`
`psychiatric manifestations; there-
`fore, low cobalamin levels in the
`presence of normal results on the
`Schilling test should not be dis-
`missed without performing a test
`for malabsorption of food-bound
`cobalarnin.6
`
`Treatment
`In treating pernicious anemia, the
`basic regimen of first administering
`
`parenteral cyanocobalamin at a
`slow rate to replenish reserves and
`then administering 1,000 Dg intra-
`muscularly in monthly mainte-
`nance doses for life is well known.
`The optimal dose and frequency
`of maintenance therapy are not
`yet well established. There is no
`evidence that hydroxycobalamin
`(AlphaRedisol) is superior to cyano-
`cobalamin.
`
`234
`
`PERNICIOUS ANEMIA * VOL 91/NO 2/FEBRUARY 1, 1992/POSTGRADUATE MEDICINE
`
`Sandoz Inc. IPR2016-00318
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`
`

`
`sive to therapy, and seen in the
`absence of anemia and macrocy-
`tosis. A low serum cobalamin
`level in the absence of anemia,
`particularly in a patient with a
`neurologic disorder, should not
`be ignored, m.
`
`Earn credit on this article.
`
`__~ See CME Quiz.
`
`Address for correspondence: Anand B.
`Karnad, MD, Division of Hematology-
`Oncology, Department of Internal
`Medicine, PO Box 70622, James H.
`Quillen College of Medicine, Fast Ten-
`nessee State University, Johnson City,
`TN 37614-0622.
`
`1. JandlJH. Blood: textbook of hematology.
`Boston: Little, Brown, 1987:161
`2. Jandl JH. Blood: pathophysiology. St Louis:
`Mosby-Year Book, 1991:108
`3. Healton EB, Savage DG, Bmst JC, et al.
`Neurologic aspects of cobalamin deficiency.
`Medicine 1991;70(4):229-45
`4. BeckWS. Neuropsychiatric consequences of
`cobalamin defidency. Adv Intern Med 1991 ;36:
`33-56
`5. Chanarin I. How to diagnose (and not misdi-
`agnose) pernicious anaemia. Blood Rev 1987;
`1(4):280-3
`6. Cannel R, Sinow RM, Siegel ME, et al. Food
`cobalamin malabsorption occurs frequently in pa-
`tients with unexplained low serum cobalamin lev-
`els. Arch Intern Med 1988;148(8):1715-9
`7. Lederle FA. Oral cobalamin for pernicious
`anemia: medicine’s best kept secret? JAMA
`1991;265(i):94-5
`8. HathcockJN, Troendle GJ. Oral cobalamin
`for treatment of pernicious anemia. (Editorial)
`JAMA 1991;265(1):96-7
`
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