Pernicious anemia
BASIC INFORMATION
Pernicious anemia is an autoimmune disease resulting from antibodies against intrinsic factor and gastric parietal cells. Pernicious anemia is the classic presentation of vitamin B12 deficiency. Lack of intrinsic factor, a glycoprotein that is secreted by the gastric mucosa and that is necessary for absorption of vitamin B12 in the terminal ileum, is responsible for pernicious anemia. Hereditary intrinsic factor deficiency is very rare. It follows an autosomally recessive pattern of inheritance and manifests early in childhood. Consanguinity of the parents is common. Intrinsic factor deficiency in the adult form of pernicious anemia is caused by atrophic gastritis. Although in a high percentage of the adult population, signs of atrophic gastritis can be found upon biopsy, only a small proportion develops pernicious anemia.
SYNONYMS
Megaloblastic anemia resulting from vitamin B12 deficiency
EPIDEMIOLOGY & DEMOGRAPHICS
• Increased incidence in females and older adults (diagnosis is unusual before age 35 yr)
• The overall prevalence of undiagnosed PA over age 60 yr is 1.9%
• Prevalence is highest in women (2.7%), particularly in black women (4.3%)
• Increased incidence of autoimmune disease (e.g., type 1 DM, Graves’ disease, Addison’s disease), Helicobacter pylori infection
Megaloblastic anemia resulting from vitamin B12 deficiency
EPIDEMIOLOGY & DEMOGRAPHICS
• Increased incidence in females and older adults (diagnosis is unusual before age 35 yr)
• The overall prevalence of undiagnosed PA over age 60 yr is 1.9%
• Prevalence is highest in women (2.7%), particularly in black women (4.3%)
• Increased incidence of autoimmune disease (e.g., type 1 DM, Graves’ disease, Addison’s disease), Helicobacter pylori infection
PHYSICAL FINDINGS & CLINICAL PRESENTATION
Clinical Findings. The classic triad is weakness, burning tongue, and paresthesia. The lingual mucosa is atrophic (Fig. 3.10) and the sense of taste becomes weak. These clinical symptoms are known as Hunter glossitis. In addition, patients complain of loss of appetite, weight loss, vomiting, flatulence, abdominal discomfort, and fever. In the nervous system, demyelination with consequent axonal disruption can affect all parts, but typically it predominates in the dorsal and lateral tracts of the spinal cord. Normally, the peripheral nerves are less susceptible to this process, but can still be involved. Possibly, this is a secondary degeneration due to loss of proximal fibers. These changes manifest as dysesthesia, paresthesia, gait disturbance, and reduced position sense. The Romberg test becomes positive. Cerebral symptoms of cognitive and emotional types are possible. Accompanying autoimmune diseases of the thyroid with pathologic TSH values were observed in almost half of the patients with pernicious anemia.
Clinical Findings. The classic triad is weakness, burning tongue, and paresthesia. The lingual mucosa is atrophic (Fig. 3.10) and the sense of taste becomes weak. These clinical symptoms are known as Hunter glossitis. In addition, patients complain of loss of appetite, weight loss, vomiting, flatulence, abdominal discomfort, and fever. In the nervous system, demyelination with consequent axonal disruption can affect all parts, but typically it predominates in the dorsal and lateral tracts of the spinal cord. Normally, the peripheral nerves are less susceptible to this process, but can still be involved. Possibly, this is a secondary degeneration due to loss of proximal fibers. These changes manifest as dysesthesia, paresthesia, gait disturbance, and reduced position sense. The Romberg test becomes positive. Cerebral symptoms of cognitive and emotional types are possible. Accompanying autoimmune diseases of the thyroid with pathologic TSH values were observed in almost half of the patients with pernicious anemia.
Fig. 3.10 Hunter glossitis in pernicious anemia in a 75-yearold woman.
• Mucosal pallor, glossitis
• Peripheral sensory neuropathy with paresthesias initially and absent reflexes in advanced cases
• Loss of joint position sense, pyramidal or long track signs
• Possible splenomegaly and mild hepatomegaly
• Generalized weakness and delirium/dementia
ETIOLOGY
• Antigastric parietal cell antibodies in >70% of patients, antiintrinsic factor antibodies in >50% of patients
• Atrophic gastric mucosa
DIAGNOSIS
DIFFERENTIAL DIAGNOSIS
The blood count shows macrocytic anemia. Leukocytopenia and thrombocytopenia are possible. The blood smear is characterized by macro-ovalocytosis, anisocytosis, poikilocytosis, and hypersegmented neutrophils (Fig. 3.1.e). Usually the level of lactate dehydrogenase (LDH) is elevated. The serum vitamin B12 level is diminished. In the case of borderline values, a functional deficiency of vitamin B12 can be identified by measuring the serum homocysteine level. For this determination, blood must be drawn strictly from a fasting patient, because the value increases after food intake. The serum homocysteine level is also elevated in folic acid deficiency. To discriminate between these two states, the serum level or 24-hour urinary excretion of methylmalonic acid may be measured, because this value increases only in the case of vitamin B12 deficiency. The bone marrow displays increased erythropoiesis, which is macroblastic. Antibodies to parietal cells are found significantly more frequently in patients with pernicious anemia. However because of their high prevalence in normal individuals (9.2% of men and 22.3% of women over 55 years of age) they are not specific. Antiintrinsic- factor antibodies have a high specificity. They are found in less than 1% of healthy persons. Therefore, in spite of their poor sensitivity (only 56% of patients with pernicious anemia are positive), they are useful in the diagnostic work-up. If anti-intrinsic factor antibodies are positive in a patient with vitamin B12 deficiency, then a diagnosis of pernicious anemia is established. In the case of a negative test result, pernicious anemia is not excluded. The vitamin B12 urinary excretion test (Schilling test), demonstrates defective absorption caused by intrinsic factor deficiency. Radioactively labeled cyanocobalamin is given orally to a patient, vitamin B12 uptake into tissues is blocked by a concomitant intramuscular dose of 1000 mg cobalamin, and the amount of radioactivity excreted in the urine after 24 hours is measured. Values below 8% are considered pathologic. Upon administration of the same dose, together with intrinsic factor, this value becomes normal in cases of endogenous intrinsic factor deficiency. Other causes of vitamin B12 malabsorption (Tab. 3.4) are not reversible by addition of intrinsic factor. The Schilling test requires normal renal function and careful collection of the urine over 24 hours.
• Nutritional vitamin B12 deficiency
• Malabsorption
• Chronic alcoholism (multifactorial)
• Chronic gastritis related to H. pylori infection
• Folic acid deficiency
• Myelodysplasia
• Peripheral sensory neuropathy with paresthesias initially and absent reflexes in advanced cases
• Loss of joint position sense, pyramidal or long track signs
• Possible splenomegaly and mild hepatomegaly
• Generalized weakness and delirium/dementia
ETIOLOGY
• Antigastric parietal cell antibodies in >70% of patients, antiintrinsic factor antibodies in >50% of patients
• Atrophic gastric mucosa
DIAGNOSIS
DIFFERENTIAL DIAGNOSIS
The blood count shows macrocytic anemia. Leukocytopenia and thrombocytopenia are possible. The blood smear is characterized by macro-ovalocytosis, anisocytosis, poikilocytosis, and hypersegmented neutrophils (Fig. 3.1.e). Usually the level of lactate dehydrogenase (LDH) is elevated. The serum vitamin B12 level is diminished. In the case of borderline values, a functional deficiency of vitamin B12 can be identified by measuring the serum homocysteine level. For this determination, blood must be drawn strictly from a fasting patient, because the value increases after food intake. The serum homocysteine level is also elevated in folic acid deficiency. To discriminate between these two states, the serum level or 24-hour urinary excretion of methylmalonic acid may be measured, because this value increases only in the case of vitamin B12 deficiency. The bone marrow displays increased erythropoiesis, which is macroblastic. Antibodies to parietal cells are found significantly more frequently in patients with pernicious anemia. However because of their high prevalence in normal individuals (9.2% of men and 22.3% of women over 55 years of age) they are not specific. Antiintrinsic- factor antibodies have a high specificity. They are found in less than 1% of healthy persons. Therefore, in spite of their poor sensitivity (only 56% of patients with pernicious anemia are positive), they are useful in the diagnostic work-up. If anti-intrinsic factor antibodies are positive in a patient with vitamin B12 deficiency, then a diagnosis of pernicious anemia is established. In the case of a negative test result, pernicious anemia is not excluded. The vitamin B12 urinary excretion test (Schilling test), demonstrates defective absorption caused by intrinsic factor deficiency. Radioactively labeled cyanocobalamin is given orally to a patient, vitamin B12 uptake into tissues is blocked by a concomitant intramuscular dose of 1000 mg cobalamin, and the amount of radioactivity excreted in the urine after 24 hours is measured. Values below 8% are considered pathologic. Upon administration of the same dose, together with intrinsic factor, this value becomes normal in cases of endogenous intrinsic factor deficiency. Other causes of vitamin B12 malabsorption (Tab. 3.4) are not reversible by addition of intrinsic factor. The Schilling test requires normal renal function and careful collection of the urine over 24 hours.
• Nutritional vitamin B12 deficiency
• Malabsorption
• Chronic alcoholism (multifactorial)
• Chronic gastritis related to H. pylori infection
• Folic acid deficiency
• Myelodysplasia
Fig. 3.1.e Megalocytosis in pernicious anemia with typical, large elliptoid cells and a hypersegmented neutrophil.
WORKUP
• The clinical presentation of pernicious anemia varies with the stage. Initially, patient may be asymptomatic. In advanced stages, patients may present with impaired memory, depression, gait disturbances, paresthesias, and complaints of generalized weakness.
• Investigation consists primarily of laboratory evaluation.
• Endoscopy and biopsy for atrophic gastritis may be performed in selected cases.
• Diagnosis is crucial because failure to treat may result in irreversible neurologic deficits.
LABORATORY TESTS
• CBC generally reveals macrocytic anemia and leukopenia with hypersegmented neutrophils.
• MCV is generally significantly elevated in the advanced stages.
• Reticulocyte count is low/normal.
• Falsely low serum cobalamin levels can occur in patients with severe folate deficiency, in patients using high doses of ascorbic acid, and when cobalamin levels are measured following nuclear medicine studies (radioactivity interferes with cobalamin RIA measurement).
• Falsely high normal levels in patients with cobalamin deficiency can occur in severe liver disease or chronic granulocytic leukemia.
• The absence of anemia or macrocytosis does not exclude the diagnosis of cobalamin deficiency. Anemia is absent in 20% of patients with cobalamin deficiency, and macrocytosis is absent in >30% of patients at the time of diagnosis. It can be blocked by concurrent iron deficiency or anemia of chronic disease and may be masked by thalassemia trait.
• Schilling test is abnormal in part I; part II corrects to normal after administration of intrinsic factor.
• Laboratory tests used for detecting cobalamin deficiency in patients with normal vitamin B12 levels include serum and urinary methylmalonic acid level (elevated), total homocysteine level (elevated), intrinsic factor antibody (positive).
• An increased concentration of plasma methylmalonic acid (P-MMA) does not predict clinical manifestations of vitamin B12 deficiency and should not be used as the only marker for diagnosis of B12 deficiency.
• Additional laboratory abnormalities can include elevated LDH, direct hyperbilirubinemia, and decreased haptoglobin.
• The clinical presentation of pernicious anemia varies with the stage. Initially, patient may be asymptomatic. In advanced stages, patients may present with impaired memory, depression, gait disturbances, paresthesias, and complaints of generalized weakness.
• Investigation consists primarily of laboratory evaluation.
• Endoscopy and biopsy for atrophic gastritis may be performed in selected cases.
• Diagnosis is crucial because failure to treat may result in irreversible neurologic deficits.
LABORATORY TESTS
• CBC generally reveals macrocytic anemia and leukopenia with hypersegmented neutrophils.
• MCV is generally significantly elevated in the advanced stages.
• Reticulocyte count is low/normal.
• Falsely low serum cobalamin levels can occur in patients with severe folate deficiency, in patients using high doses of ascorbic acid, and when cobalamin levels are measured following nuclear medicine studies (radioactivity interferes with cobalamin RIA measurement).
• Falsely high normal levels in patients with cobalamin deficiency can occur in severe liver disease or chronic granulocytic leukemia.
• The absence of anemia or macrocytosis does not exclude the diagnosis of cobalamin deficiency. Anemia is absent in 20% of patients with cobalamin deficiency, and macrocytosis is absent in >30% of patients at the time of diagnosis. It can be blocked by concurrent iron deficiency or anemia of chronic disease and may be masked by thalassemia trait.
• Schilling test is abnormal in part I; part II corrects to normal after administration of intrinsic factor.
• Laboratory tests used for detecting cobalamin deficiency in patients with normal vitamin B12 levels include serum and urinary methylmalonic acid level (elevated), total homocysteine level (elevated), intrinsic factor antibody (positive).
• An increased concentration of plasma methylmalonic acid (P-MMA) does not predict clinical manifestations of vitamin B12 deficiency and should not be used as the only marker for diagnosis of B12 deficiency.
• Additional laboratory abnormalities can include elevated LDH, direct hyperbilirubinemia, and decreased haptoglobin.
TREATMENT
NONPHARMACOLOGIC THERAPY
Avoid folic acid supplementation without proper vitamin B12 supplementation.
ACUTE GENERAL Rx
Traditional therapy of a cobalamin deficiency consists of IM injections of vitamin B12 1000 mg/wk for the initial 4 to 6 wk followed by 1000 mg/mo IM indefinitely. When hematologic parameters have returned to normal range, intranasal cyanocobalamin may be used in place of IM cyanocobalamin. The initial dose of intranasal cyanocobalamin (Nascobal) is one spray (500 mg) in one nostril once per week. Monitor response and increase dose if serum B12 levels decline. Consider return to intramuscular vitamin B12 supplementation if decline persists.
CHRONIC Rx
Parenteral vitamin B12 1000 mg/mo or intranasal cyanocobalamin 500 mg/wk
DISPOSITION
Anemia generally resolves with appropriate treatment. Neurologic deficits, if present at diagnosis, may be permanent.
NONPHARMACOLOGIC THERAPY
Avoid folic acid supplementation without proper vitamin B12 supplementation.
ACUTE GENERAL Rx
Traditional therapy of a cobalamin deficiency consists of IM injections of vitamin B12 1000 mg/wk for the initial 4 to 6 wk followed by 1000 mg/mo IM indefinitely. When hematologic parameters have returned to normal range, intranasal cyanocobalamin may be used in place of IM cyanocobalamin. The initial dose of intranasal cyanocobalamin (Nascobal) is one spray (500 mg) in one nostril once per week. Monitor response and increase dose if serum B12 levels decline. Consider return to intramuscular vitamin B12 supplementation if decline persists.
CHRONIC Rx
Parenteral vitamin B12 1000 mg/mo or intranasal cyanocobalamin 500 mg/wk
DISPOSITION
Anemia generally resolves with appropriate treatment. Neurologic deficits, if present at diagnosis, may be permanent.
Table 3.4 Causes of macrocytic anemia
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