Pernicious Anemia 

Updated: Feb 18, 2019
Author: Srikanth Nagalla, MBBS, MS, FACP; Chief Editor: Emmanuel C Besa, MD 

Overview

Practice Essentials

The term “pernicious anemia” is an anachronism—it dates from the era when treatment had not yet been discovered, and the disease was fatal—but it remains in use for megaloblastic anemia resulting from vitamin B12 deficiency due to lack of intrinsic factor (IF).[1] Impaired IF production can occur in adults due to autoimmune destruction of parietal cells, which secrete IF. Gastrectomy can significantly reduce the production of IF. A rare congenital autosomal recessive disorder can result in deficiency of IF without gastric atrophy.

Several conditions other than impaired Intrinsic Factor production can cause a megaloblastic anemia such as: folic acid deficiency, altered pH in the small intestine, and lack of absorption of B12 complexes in the terminal ileum. Thus, pernicious anemia must be differentiated from other disorders that interfere with the absorption and metabolism of vitamin B-12 (see DDx and Workup).

The following goals are the most important in establishing care for patients with pernicious anemia:

  • To establish that the patient has cobalamin deficiency

  • Treat with cobalamin.  Higher doses of cobalamin are administered in patients with B12-related mental or neurological impairment.

  • If there is evidence for folic acid deficiency but pernicious anemia remains a possibility, treat with both folic acid and cobalamin until pernicious anemia has been ruled out. The reason is that folic acid restores blood counts but does not prevent the development of subacute combined system degeneration in patients with pernicious anemia.

  • Monitor therapy to confirm that that therapy has been effective

  • Administration of adequate quantities of cobalamin for the remainder of the patient's life

  • Periodic evaluation to rule out gastric carcinoma

For further discussion, see Treatment and Medication.

Go to Anemia, Iron Deficiency Anemia, and Chronic Anemia for complete information on these topics.

Pathophysiology

Classic pernicious anemia is caused by the failure of gastric parietal cells to produce sufficient IF (a gastric protein secreted by parietal cells) to permit the absorption of adequate quantities of dietary vitamin B-12. Other disorders that interfere with the absorption and metabolism of vitamin B12 can produce cobalamin deficiency, with the development of a macrocytic anemia and neurologic complications.

Cobalamin is an organometallic substance containing a corrin ring, a centrally located cobalt atom, and various axial ligands (see the image below).

Pernicious anemia. The structure of cyanocobalamin Pernicious anemia. The structure of cyanocobalamin is depicted. The cyanide (Cn) is in green. Other forms of cobalamin (Cbl) include hydroxocobalamin (OHCbl), methylcobalamin (MeCbl), and deoxyadenosylcobalamin (AdoCbl). In these forms, the beta-group is substituted for Cn. The corrin ring with a central cobalt atom is shown in red and the benzimidazole unit in blue. The corrin ring has 4 pyrroles, which bind to the cobalt atom. The fifth substituent is a derivative of dimethylbenzimidazole. The sixth substituent can be Cn, CC3, hydroxycorticosteroid (OH), or deoxyadenosyl. The cobalt atom can be in a +1, +2, or +3 oxidation state. In hydroxocobalamin, it is in the +3 state. The cobalt atom is reduced in a nicotinamide adenine dinucleotide (NADH)–dependent reaction to yield the active coenzyme. It catalyzes 2 types of reactions, which involve either rearrangements (conversion of l methylmalonyl coenzyme A [CoA] to succinyl CoA) or methylation (synthesis of methionine).

The basic structure known as vitamin B12 is solely synthesized by microorganisms, but most animals are capable of converting vitamin B12 into the two coenzyme forms, adenosylcobalamin and methylcobalamin. The former is required for conversion of L- methylmalonic acid to succinyl coenzyme A (CoA), and the latter acts as a methyltransferase for conversion of homocysteine to methionine.

When either cobalamin or folate is deficient, thymidine synthase function is impaired. This leads to megaloblastic changes in all rapidly dividing cells because DNA synthesis is diminished. In erythroid precursors, macrocytosis and ineffective erythropoiesis occur.

Severe neurological impairment, usually subacute combined system degeneration, occurs in cobalamin deficiency. However, vitamin B12 deficiencies can also present as peripheral neuropathy, psychosis, or leukoencephalopathy. Cobalamine neurological disorders can occur independently of hematological manifestations of pernicious anemia. The biochemical impairment in neurological degeneration may differ from hematological changes.[2]

Dietary cobalamin is acquired mostly from meat and milk and is absorbed in a series of steps, which require proteolytic release from foodstuffs and binding to IF. Subsequently, recognition of the IF-cobalamin complex by specialized ileal receptors—cubilin receptors—must occur for transport into the portal circulation to be bound by transcobalamin II (TCII), which serves as the plasma transporter.

The cobalamin-TCII complex binds to cell surfaces and is endocytosed. The transcobalamin is degraded within a lysozyme, and the cobalamin is released into the cytoplasm. An enzyme-mediated reduction of the cobalt occurs with either cytoplasmic methylation to form methylcobalamin or mitochondrial adenosylation to form adenosylcobalamin.

Defects of these steps produce manifestations of cobalamin dysfunction. Most defects become manifest in infancy and early childhood and result in impaired development, mental retardation, and a macrocytic anemia. Certain defects cause methylmalonic aciduria and homocystinuria. See the image below.

Pernicious anemia. Inherited disorders of cobalami Pernicious anemia. Inherited disorders of cobalamin (Cbl) metabolism are depicted. The numbers and letters correspond to the sites at which abnormalities have been identified, as follows: (1) absence of intrinsic factor (IF); (2) abnormal Cbl intestinal adsorption; and (3) abnormal transcobalamin II (TC II), (a) mitochondrial Cbl reduction (Cbl A), (b) cobalamin adenosyl transferase (Cbl B), (c and d) cytosolic Cbl metabolism (Cbl C and D), (e and g) methyl transferase Cbl utilization (Cbl E and G), and (f) lysosomal Cbl efflux (Cbl F).

Pernicious anemia probably is an autoimmune disorder with a genetic predisposition. The disease is more common than is expected in families of patients with pernicious anemia, and it is associated with human leukocyte antigen (HLA) types A2, A3, and B7 and type A blood group.

Antiparietal cell antibodies occur in 90% of patients with pernicious anemia but in only 5% of healthy adults. Similarly, binding and blocking antibodies to IF are found in most patients with pernicious anemia. A greater association than anticipated exists between pernicious anemia and other autoimmune diseases, including thyroid disorders, type 1 diabetes mellitus, ulcerative colitis, Addison disease, infertility, and acquired agammaglobulinemia. An association between pernicious anemia and Helicobacter pylori infections has been postulated but not clearly proven.

Cobalamin deficiency may result from dietary insufficiency of vitamin B12; disorders of the stomach, small bowel, and pancreas; certain infections; and abnormalities of transport, metabolism, and utilization (see Etiology). Deficiency may be observed in strict vegetarians.[3] Breastfed infants of vegetarian mothers also are affected. Severely affected infants of vegetarian mothers who do not have overt cobalamin deficiency have been reported.

Meat and milk are the main source of dietary cobalamin. Because body stores of cobalamin usually exceed 1000 µg and the daily requirement is about 1 µg, strict adherence to a vegetarian diet for more than 5 years usually is required to produce findings of cobalamin deficiency.

Classic pernicious anemia produces cobalamin deficiency due to failure of the stomach to secrete IF (see the image below).

Pernicious anemia. Cobalamin (Cbl) is freed from m Pernicious anemia. Cobalamin (Cbl) is freed from meat in the acidic milieu of the stomach where it binds R factors in competition with intrinsic factor (IF). Cbl is freed from R factors in the duodenum by proteolytic digestion of the R factors by pancreatic enzymes. The IF-Cbl complex transits to the ileum where it is bound to ileal receptors. The IF-Cbl enters the ileal absorptive cell, and the Cbl is released and enters the plasma. In the plasma, the Cbl is bound to transcobalamin II (TC II), which delivers the complex to nonintestinal cells. In these cells, Cbl is freed from the transport protein.

In adults, pernicious anemia is associated with severe gastric atrophy and achlorhydria, which are irreversible. Coexistent iron deficiency is common because achlorhydria prevents solubilization of dietary ferric iron from foodstuffs. Autoimmune phenomena and thyroid disease frequently are observed. Patients with pernicious anemia have a 2- to 3-fold increased incidence of gastric carcinoma.

Etiology

Cobalamin deficiency may result from the following:

  • Inadequate dietary intake (ie, vegetarian diet)

  • Atrophy or loss of gastric mucosa (eg, pernicious anemia, gastrectomy, ingestion of caustic material, hypochlorhydria, histamine 2 [H2] blockers)

  • Functionally abnormal IF

  • Inadequate proteolysis of dietary cobalamin

  • Insufficient pancreatic protease (eg, chronic pancreatitis, Zollinger-Ellison syndrome [ZES])

  • Bacterial overgrowth in intestine (eg, blind loop, diverticula) - bacteria compete with the body for cobalamin

  • Diphyllobothrium latum (fish tapeworm) competes with the body for cobalamin

  • Disorders of ileal mucosa (eg, resection, ileitis, sprue, lymphoma, amyloidosis, absent IF-cobalamin receptor, Imerslünd-Grasbeck syndrome, ZES, TCII deficiency, use of certain drugs)

  • Disorders of plasma transport of cobalamin (eg, TCII deficiency, R binder deficiency)

  • Dysfunctional uptake and use of cobalamin by cells (eg, defects in cellular deoxyadenosylcobalamin [AdoCbl] and methylcobalamin [MeCbl] synthesis)

An increased incidence of pernicious anemia in families suggests a hereditary component to the disease. Patients with pernicious anemia have an increased incidence of autoimmune disorders and thyroid disease, suggesting that the disease has an immunologic component. For example, pernicious anemia may occur together with autoimmune thyroid disease, type 1A diabetes mellitus, alopecia, vitiligo, and chronic atrophic gastritis in type III polyglandular autoimmune (PGA) syndrome—one of a rare group of disorders also known as autoimmune polyendocrine syndromes (APS) and polyglandular failure syndromes.[4] Type III PGA occurs in adults.

Children who develop cobalamin deficiency usually have a hereditary disorder, and the etiology of their cobalamin deficiency is different from the etiology observed in classic pernicious anemia. Congenital pernicious anemia is a hereditary disorder in which an absence of IF occurs without gastric atrophy. Other gastric conditions that cause cobalamin deficiency are gastrectomy, gastric stapling, and bypass procedures for obesity and extensive infiltrative disease of the gastric mucosa. Usually, these conditions are associated with a decreased ability to mobilize cobalamin from food rather than a malabsorption of cobalamin; thus, a patient may exhibit a normal finding on a Schilling test (stage I).

Pancreatic insufficiency can produce cobalamin deficiency. Nonspecific R binders chelate cobalamin in the stomach, making it unavailable for binding to IF. Pancreatic proteases degrade the R binders and release the cobalamin so that it can bind IF. The cobalamin-IF complex is formed so that it can bind ileal receptors that enable uptake by absorptive cells. Thus, patients with chronic pancreatitis may have impaired absorption of cobalamin.

Cobalamin deficiency is also reported in ZES. The mechanism is believed to be due to the acidic pH of the distal small intestine, which hinders the cobalamin-IF complex from effectively binding to the ileal receptors.

Disorders of the ileum cause cobalamin deficiency as a consequence of the loss of the ileal receptors for the cobalamin-IF complex. Thus, surgical loss of the ileum and diseases such as tropical sprue, regional enteritis, ulcerative colitis, and ileal lymphoma interfere with cobalamin absorption.

Genetic defects of the ileal receptors for IF (ie, Imerslünd-Grasbeck syndrome) and hereditary transcobalamin I (TCI) deficiency produce cobalamin deficiency from birth and are usually discovered early in life.

Many drugs impair cobalamin uptake in the ileum but are rarely a cause of symptomatic vitamin B12 deficiency, because they are not taken for long enough to deplete body stores of cobalamin. Such agents include nitrous oxide, cholestyramine, para -aminosalicylic acid, neomycin, metformin, phenformin, and colchicine.

The clinical manifestations of inherited defects of cobalamin transport and metabolism are usually observed in infancy and childhood. Thus, they are discussed only briefly in this article.

Three hereditary disorders affect absorption and transport of cobalamin, and another seven alter cellular use and coenzyme production. The three disorders of absorption and transport are TCII deficiency, IF deficiency, and IF receptor deficiency. These defects produce developmental delay and a megaloblastic anemia, which can be alleviated with pharmacologic doses of cobalamin. Serum cobalamin values are decreased in the two IF abnormalities but may be within the reference range in TCII deficiency.

The seven abnormalities of cellular use, commonly denoted by letters A through G, can be detected by the presence or absence of methylmalonic aciduria and homocystinuria. The presence of only methylmalonic aciduria indicates a block in conversion of methylmalonic CoA to succinyl CoA and results in either a genetic deficit in the methylmalonyl CoA mutase that catalyzes the reaction or a defect in synthesis of its CoA cobalamin (cobalamin A and cobalamin B deficiency).

The presence of only homocystinuria results either from poor binding of cobalamin to methionine synthase (cobalamin E deficiency) or from producing methylcobalamin from cobalamin and S adenosylmethionine (cobalamin G deficiency). This results in a reduction in methionine synthesis, with pronounced homocystinemia and homocystinuria.

Methylmalonic aciduria and homocystinuria occur when the metabolic defect impairs reduction of cobalamin III to cobalamin II (cobalamin C, cobalamin D, and cobalamin F deficiency). This reaction is essential for formation of both methylmalonic acid and homocystinuria.

Early detection of these rare disorders is important because most patients respond favorably to large doses of cobalamin. However, some of these disorders are less responsive than others, and delayed diagnosis and treatment are less efficacious.

Abnormalities in the intestinal lumen may produce cobalamin deficiency. Individuals with blind intestinal loops, stricture, and large diverticula may develop bacterial overgrowth, which sequesters dietary cobalamin for their metabolic needs. Tapeworm infestation with Diphyllobothrium latum occurs from eating poorly cooked lake fish that are infected and causes cobalamin deficiency because the parasites have a high requirement for cobalamin.

Epidemiology

The adult form of pernicious anemia is most prevalent among individuals of either Celtic (ie, English, Irish, Scottish) or Scandinavian origin. In these groups, 10-20 cases per 100,000 people occur per year.

Pernicious anemia is reported less commonly in people of other racial backgrounds. Although the disease was once believed to be rare in Native American people and uncommon in black people, its incidence in these groups now appears to be higher than previous estimates suggested. Indeed, it is now apparent that pernicious anemia occurs more commonly in all racial and ethnic groups than was previously recognized.

Age-, sex-, and race-related demographics

Adult pernicious anemia usually occurs in people aged 40-70 years.[5] Among white people, the mean age of onset is 60 years, whereas it occurs at a younger age in black people (mean age of 50 y), with a bimodal distribution caused by increased occurrence in young black females. Congenital pernicious anemia usually manifests in children younger than 2 years.

A female predominance has been reported in England, Scandinavia, and among persons of African descent (1.5:1). However, data in the United States show an equal sex distribution.

Whereas the disease originally was believed to be restricted primarily to whites of Scandinavian and Celtic origin, recent evidence shows that it occurs in all races. In general, the prevalence of pernicious anemia is probably underestimated, due to the complexity of the diagnosis.[6]

Prognosis

The disease is called pernicious anemia because it was fatal prior to the discovery that it was a nutritional disorder. The megaloblastic appearance of cells led many to speculate that it was a neoplastic disease. The response of patients to liver therapy suggested that a nutritional deficiency was responsible for the disorder. This became obvious in clinical trials once vitamin B12 was isolated.

Currently, early recognition and treatment of pernicious anemia provide a normal, and usually uncomplicated, lifespan. Delayed treatment permits progression of the anemia and neurologic complications. If patients are not treated early in the disease, neurological complications can become permanent. Severe anemia can cause congestive heart failure or precipitate coronary insufficiency.

Although vitamin B12 therapy resolves the anemia, it does not cure the atrophic gastritis, which can progress to gastric cancer.[7] The incidence of gastric adenocarcinoma is 2- to 3-fold greater in patients with pernicious anemia than in the general population of the same age. Presently, periodic gastroscopy and/or barium roentgenographic studies are not advocated in patients with treated pernicious anemia who are asymptomatic, because such screening has not been demonstrated to prolong lifespan.

A population-based, case-control study using the Surveillance, Epidemiology, and End Results (SEER)–Medicare database found that elderly persons with pernicious anemia were not only at significantly increased risk for noncardia gastric adenocarcinoma (odds ratio [OR] 2.18) and gastric carcinoid tumors (OR, 11.43), they were also at increased risk for the following[7] :

  • Tonsillar cancer (OR, 2.00)
  • Hypopharyngeal cancer (OR, 1.92)
  • Esophageal squamous cell carcinoma (OR, 2.12)
  • Small intestinal cancer (OR, 1.63)
  • Liver cancer (OR, 1.49)
  • Myeloma (OR, 1.55)
  • Acute myeloid leukemia (OR, 1.68)
  • Myelodysplastic syndrome (OR, 2.87)

Chan et al, in a longitudinal study of 199 intrinsic factor antibody (IFA)-positive and 168 IFA-negative Chinese patients from the period between 1994 and 2007,[8] found that despite a good hematologic response to therapy, both groups had an unsatisfactory neurologic response, and newly diagnosed hypothyroidism was found during follow-up. In addition, newly diagnosed cancers were also found (24 in IFA-positive patients, seven in IFA-negative patients), of which 20% were gastric cancer.[8]

For the IFA-positive patients with a cancer, mean survival was 64 months; for those without a cancer, it was 129 months. Mortality was 31% in this group, in which cancer-related deaths represented 37% of the total.[8] For the IFA-negative patients with a cancer, mean survival was 36 months. For those without a cancer, it was 126 months. Mortality was 21% in this group, in which cancer-related deaths represented 14% of the total.

Chan et al concluded that although Chinese patients treated for pernicious anemia have a good survival period, the risk of gastric carcinomas is increased. Furthermore, IFA-positive patients had a higher risk of developing all types of cancers and cancer-related deaths than did IFA-negative patients.[8]

Patient Education

Lifelong compliance in obtaining adequate vitamin B12 by injection (or possibly orally) is necessary to avoid relapse of pernicious anemia.

For patient education resources, see the Blood and Lymphatic System Center, as well as Anemia.

 

Presentation

History

The onset of pernicious anemia usually is insidious and vague. The classic triad of weakness, sore tongue, and paresthesias may be elicited but usually is not the chief symptom complex. Typically, medical attention is sought because of symptoms suggestive of cardiac, renal, genitourinary, gastrointestinal, infectious, mental, or neurological disorders, and the patient is found to be anemic with macrocytic cellular indices.

General symptoms

Weight loss of 10-15 lb occurs in about 50% of patients and probably is due to anorexia, which is observed in most patients. Low-grade fever occurs in one third of newly diagnosed patients and promptly disappears with treatment.

Cardiac symptoms

The anemia often is well tolerated in pernicious anemia, and many patients are ambulatory with hematocrit levels in the mid-teens. However, the cardiac output is usually increased with hematocrits less than 20%, and the heart rate accelerates. Congestive heart failure and coronary insufficiency can occur, most particularly in patients with preexisting heart disease.

Gastrointestinal symptoms

Approximately 50% of patients have a smooth tongue with loss of papillae. This is usually most marked along the edges of the tongue. The tongue may be painful and beefy red. Occasionally, red patches are observed on the edges of the dorsum of the tongue. Patients may report burning or soreness, most particularly on the anterior third of the tongue. These symptoms may be associated with changes in taste and loss of appetite.

Patients may report either constipation or having several semisolid bowel movements daily. These symptoms have been attributed to megaloblastic changes of the cells of the intestinal mucosa.

Nonspecific gastrointestinal (GI) symptoms are not unusual and include anorexia, nausea, vomiting, heartburn, pyrosis, flatulence, and a sense of fullness. Rarely, patients present with severe abdominal pain associated with abdominal rigidity; this has been attributed to spinal cord pathology. Venkatesh and colleagues report the case of a patient who presented with epigastric pain, diarrhea, and vomiting and was found to have thrombosis of the portal, superior mesenteric, and splenic veins due to hyperhomocysteinemia secondary to pernicious anemia.[9]

Neurologic symptoms

Neurologic symptoms can be elicited in patients with pernicious anemia. The most common of these are paresthesias, weakness, clumsiness, and an unsteady gait. The last two symptoms become worse in darkness because they reflect the loss of proprioception in a patient who is unable to rely upon vision for compensation. These neurologic symptoms are due to myelin degeneration and loss of nerve fibers in the dorsal and lateral columns of the spinal cord and cerebral cortex.

Neurologic symptoms and findings may be present in the absence of anemia. This is more common in patients taking folic acid or on a high-folate diet.

Older patients may present with symptoms suggesting senile dementia or Alzheimer disease; memory loss, irritability, and personality changes are commonplace. Megaloblastic madness is less common and can be manifested by delusions, hallucinations, outbursts, and paranoid schizophrenic ideation. Identifying the cause is important because significant reversal of these symptoms and findings can occur with vitamin B12 administration.

While neurologic symptoms usually occur in the elderly, they can rarely occur in the young.[10] Kocaoglu et al reported a case of vitamin B12 deficiency and cerebral atrophy in a 12-month-old infant whose development had slowed since 6 months of age; the infant was exclusively breastfed and his mother was a long-time vegetarian. Neurologic recovery began within days after the infant received an intramuscular cobalamin injection.[11]

Genitourinary symptoms

Urinary retention and impaired micturition may occur because of spinal cord damage. This can predispose patients to urinary tract infections.

Symptoms of thrombotic complications

A study of four patients revealed that pernicious anemia can lead to hyperhomocysteinemia that is significant enough to lead to venous thrombosis, even in the absence of any other risk factors for thromboembolism.[12]

Physical Examination

The finding of severe anemia in an adult patient whose constitutional symptoms are relatively mild and in whom weight loss is not a major symptom should arouse suspicion of pernicious anemia.

Typically, patients with pernicious anemia are described as having a stereotypic appearance: they have a lemon-yellow waxy pallor with premature whitening of the hair, and they appear flabby, with a bulky frame that is generally incongruent with the severe anemia and weakness. It should be remembered, however, that whereas this characterization is useful in patients of northern European descent, it is less helpful among patients of other ethnic groups (who, as noted, are more commonly affected than was once believed).

The following signs may be noted:

  • Low-grade fever and mild icterus are commonplace but are usually mild and easily missed

  • A beefy, red, smooth tongue may be observed

  • In patients with dark complexions, blotchy skin pigmentation may be observed

  • Tachycardia often is present and may be accompanied by flow murmurs

  • Abnormal mentation and deterioration of vision and hearing may be observed

  • With severe anemia, dyspnea, tachypnea, and evidence of congestive heart failure may be present

  • Retinal hemorrhages and exudates may accompany severe anemia

  • The liver may be enlarged in association with congestive heart failure

  • A splenic tip is palpable in about 20% of patients

Neurologic assessment

A careful neurologic assessment is important. All megaloblastic disorders can give rise to hematologic and epithelial manifestations, but only cobalamin deficiency causes neurologic deficits. Neurologic findings may occur in the absence of anemia and epithelial manifestations of pernicious anemia, making it more difficult to identify the etiology. If left untreated, they can become irreversible.

Suspect pernicious anemia in all patients with recent loss of mental capacities. Somnolence, dementia, psychotic depression, and frank psychosis may be observed, which can be reversed or improved by treatment with cobalamin. Perversion of taste and smell and visual disturbances, which can progress to optic atrophy, can likewise result from central nervous system (CNS) cobalamin deficiency.

A history of either paresthesias in the fingers and toes or difficulty with gait and balance should prompt a careful neurologic examination. Loss of position sense in the second toe and loss of vibratory sense for a 256-Hz tuning fork, but not for a 128-Hz fork, are the earliest signs of posterolateral column disease. If untreated, this can progress to spastic ataxia from demyelinization of the dorsal and lateral columns of the spinal cord.

 

DDx

Diagnostic Considerations

By definition, pernicious anemia refers specifically to vitamin B-12 deficiency resulting from a lack of production of intrinsic factor (IF) in the stomach. However, vitamin B-12 absorption is a complex process, and other causes of vitamin B-12 deficiency exist. Pernicious anemia must be differentiated from other disorders that interfere with the absorption and metabolism of vitamin B-12 and produce cobalamin deficiency, with the development of a macrocytic anemia and neurologic complications.

Go to Anemia, Iron Deficiency Anemia, and Chronic Anemia for complete information on these topics.

Thiamine-responsive megaloblastic anemia syndrome (TRMA) is an autosomal recessive disorder characterized by megaloblastic anemia, progressive sensorineural hearing loss, and diabetes mellitus. Onset of megaloblastic anemia occurs between infancy and adolescence. Vitamin B-12 and folic acid levels are normal. On bone marrow examination, affected individuals have megaloblastic changes with erythroblasts often containing iron-filled mitochondria (ringed sideroblasts). Molecular genetic testing will show biallelic pathogenic variants in SLC19A2.[13]  

Uncommonly, variable ocular anomalies may be present in TRMA. One case report describes symmetric bull's eye maculopathy and other ocular findings consistent with cone-rod degeneration.[14]

The anemia in TRMA is corrected with pharmacologic doses (50-100 mg/day) of thiamine (vitamin B1) . However, the red cells remain macrocytic.[13]

Other conditions to be considered include the following:

  • Cestode infection
  • Neurologic disorders
  • Senility

Pernicious anemia may rarely be associated with liver disease (eg, primary biliary cholangitis, autoimmune hepatitis, interferon-treated hepatitis C). Yan et al report two cases of pernicious anemia in patients with cryptogenic cirrhosis, in both of whom the neuropsychiatric symptoms of pernicious anemia were initially attributed to hepatic encephalopathy.[15]

Differential Diagnoses

 

Workup

Approach Considerations

The workup for pernicious anemia may include the following:

  • Peripheral blood smear
  • Indirect bilirubin and lactate dehydrogenase assays
  • Evaluation of gastric secretions
  • Serum cobalamin, folic acid, methylmalonic acid, and homocysteine assays
  • Schilling test (no longer available in most medical centers)
  • A clinical trial of vitamin B12
  • Bone marrow aspiration and biopsy

Peripheral Blood Smear

The peripheral blood usually shows a macrocytic anemia with a mild leukopenia and thrombocytopenia. The mean cell volume (MCV) and mean cell hemoglobin (MCH) are increased, with a mean corpuscular hemoglobin concentration (MCHC) within the reference range (see the image below). The leukopenia and thrombocytopenia usually parallel the severity of the anemia.

Peripheral smear of blood from a patient with pern Peripheral smear of blood from a patient with pernicious anemia. Macrocytes are observed, and some of the red blood cells show ovalocytosis. A 6-lobed polymorphonuclear leucocyte is present.

The peripheral smear shows oval macrocytes, hypersegmented granulocytes, and anisopoikilocytosis. In severe anemia, red blood cell inclusions may include Howell-Jolly bodies, Cabot rings, and punctate basophilia. The macrocytosis can be obscured by the coexistence of iron deficiency, thalassemia minor, or inflammatory disease.

Indirect Bilirubin and Serum Lactate Dehydrogenase

The indirect bilirubin level may be elevated because pernicious anemia is a hemolytic disorder associated with increased turnover of bilirubin. The serum lactate dehydrogenase (LDH) concentration usually is markedly increased. Hemolysis is intramedullary.

Increased values for other red blood cells, enzymes, and serum iron saturation also are observed. The serum potassium, cholesterol, and skeletal alkaline phosphatase often are decreased.

Evaluation of Gastric Secretions

Total gastric secretions are decreased to about 10% of the reference range. Most patients with pernicious anemia are achlorhydric, even with histamine stimulation. Intrinsic factor (IF) is either absent or markedly decreased.

Serum Cobalamin

Serum cobalamin reference ranges may vary slightly among different laboratories, but are generally from 200–900 pg/mL. Values of 180-250 pg/mL are considered bordeline, while less than 150 pg/mL is considered diagnostic of vitamin B12 deficiency.

The serum cobalamin level is low in patients with pernicious anemia. However, it may be within the reference range in certain patients with other forms of cobalamin deficiency, such as some inborn areas of cobalamin deficiency, transcobalamin II (TCII) deficiency, and cobalamin deficiency due to nitrous oxide.

Conversely, serum cobalamin levels may be low in patients with no clinical or identifiable metabolic abnormality.[16]  Causes of falsely low serum cobalamin levels inclue the following:

  • Pregnancy
  • Oral contraceptives and hormone replacement therapy
  • Multiple myeloma
  • Transcobalamin I (TCI) deficiency
  • Severe folic acid deficiency
  • Ascorbic acid in high doses

Serum cobalamin levels can be in the low reference range in patients with clinical vitamin B12 deficiency. In these cases, elevated levels of methylmalonic acid and total homocysteine can confirm the diagnosis.[17] Screening of older individuals has shown that 10-20% have low serum cobalamin levels, and half of these patients have increased levels of homocysteine and methylmalonic acid, indicating a tissue cobalamin deficiency.

 

Serum Folic Acid, Methylmalonic Acid, and Homocysteine

A serum folic acid assay is useful for ruling out folic acid deficiency. The reference range is 2.5-20 ng/mL. Blood should be drawn before patients have a single hospital meal since food can restore serum folic acid levels to normal. Red blood cell folic acid level is not influenced by food. (For more information, see Megaloblastic Anemia and Folic Acid Deficiency).  

A significantly decreased serum cobalamin level along with a typical clinical presentation, a characteristic peripheral smear, and an increased indirect bilirubin and LDH level is sufficient evidence for the diagnosis of a megaloblastic anemia.

Serum methylmalonic acid and homocysteine tests are important confirmatory tests but are not first-line tests. Elevated serum methylmalonic acid and homocysteine levels are found in patients with pernicious anemia. They probably are the most reliable test for cobalamin deficiency in patients who do not have a congenital metabolism disorder (see the table below). In the absence of an inborn error of methylmalonic acid metabolism, methylmalonic aciduria is a sign of cobalamin deficiency.

Table 1. Serum Methylmalonic Acid and Homocysteine Values Used in Differentiating Between Cobalamin and Folic Acid Deficiency (Open Table in a new window)

Patient Condition

Methylmalonic Acid

Homocysteine

Healthy

Normal

Normal

Vitamin B12 deficiency

Elevated

Elevated

Folate deficiency

Normal

Elevated

Intrinsic Factor Antibodies

Intrinsic factor (IF) antibodies, type 1 and type 2, occur in 50% of patients with pernicious anemia and are specific for this disorder. Therefore, they can be used to confirm the diagnosis.

In one case report, the presence of IF antibodies was used to diagnose cobalamin deficiency in a patient with severe leukoencephalopathy. Interestingly, serum vitamin B12, homocysteine, and methylmalonic acid levels were normal. The patient responded to intense cobalamin therapy.[18]

Parietal cell antibodies occurs in 90% of patients with pernicious anemia. However, these antibodies are not specific for pernicious anemia.

Schilling Test

The Schilling test measures cobalamin absorption by assessing increased urine radioactivity after an oral dose of radioactive cobalamin. The test is useful in demonstrating that the anemia is caused by an absence of IF and is not secondary to other causes of cobalamin deficiency (see the table below). It is also useful for identifying patients with classic pernicious anemia, even after they have been treated with vitamin B12. The Schilling test is no longer available in most medical centers.

Table 2. Schilling test results (Open Table in a new window)

Patient Condition

Stage I

No Intrinsic Factor

Stage II

Intrinsic Factor

Stage III

Antibiotic

Stage IV

Pancreatic Extract

Healthy

Normal

Pernicious anemia

Low

Normal

Bacterial overgrowth

Low

Low

Normal

Pancreatic insufficiency

Low

Low

Low

Normal

Defect in ileum

Low

Low

Low

Low

The test is performed by administering 0.5-2.0 mCi of radioactive cyanocobalamin in a glass of water to patients who have fasted. Two hours later, the patient is injected with 1 mg of unlabeled vitamin B12 to saturate circulating transcobalamins. A 24-hour urine sample is collected, and the radioactivity in the specimen is measured and compared to a standard.

Specimens with less than 7% excretion represent abnormal findings and indicate that poor absorption of the oral test dose occurred. If abnormal low values are obtained, a stage II Schilling test is performed. In this test, 60 mg of active hog IF is administered with the oral test dose to determine if this enhances the absorption of vitamin B12. If poor absorption of vitamin B12 is normalized, the patient presumably has classic pernicious anemia.

If poor absorption is observed in a stage II test, other causes of vitamin B12 malabsorption must be sought. Performance of a stage I Schilling test after 5 days of tetracycline therapy is used to exclude a blind loop as the etiology for cobalamin deficiency (stage III). Similarly, if administration of trypsin or pancreatic enzyme with the radiolabeled test dose corrects the absorption of vitamin B12, pancreatic disease (stage IV) should be suspected.

False-positive Schilling test results are observed in patients with incomplete 24-hour urine collections or renal insufficiency. False-positive results are also observed when inactive IF is used. Finally, false-positive results may occur because of neutralization of the IF in the stage II test by any IF antibodies in the stomach and severe ileal megaloblastosis.

Occasionally, cobalamin deficiency and a normal stage I Schilling test result are observed. Patients with these findings can absorb vitamin B12 in the fasting state, but not when it is presented with food. Adding the radiolabeled vitamin B12 to egg white and testing the absorption usually reveals this cause of cobalamin deficiency.

Clinical Trial of Vitamin B12

Intramuscular (IM) administration of 1000 µg of vitamin B12 can be used as a clinical trial for suspected cobalamin deficiency. Subjectively, patients who are cobalamin deficient usually begin to experience a marked sense of well-being within 24 hours after administration. Objectively, administration of cobalamin produces a marked reticulocytosis, which reaches its maximal level 5-7 days after the injection; correction of the anemia occurs in about 3 weeks (see the image below).

Response to therapy with cobalamin (Cbl) in a prev Response to therapy with cobalamin (Cbl) in a previously untreated patient with pernicious anemia. A reticulocytosis occurs within 5 days after an injection of 1000 mcg of Cbl and lasts for about 2 weeks. The hemoglobin (Hgb) concentration increases at a slower rate because many of the reticulocytes are abnormal and do not survive as mature erythrocytes. After 1 or 2 weeks, the Hgb concentration increases about 1 g/dL per week.

Bone Marrow Aspiration and Biopsy

Bone marrow aspiration and biopsy can provide complementary information, with the aspirate revealing the numerical and cytological features of marrow cells, while the biopsy shows the spatial relationships between cells and the overall marrow structure. [19] The bone marrow biopsy and aspirate specimens usually are hypercellular and show trilineage differentiation. Erythroid precursors are large and often oval (see the image below).

Bone marrow aspirate from a patient with untreated Bone marrow aspirate from a patient with untreated pernicious anemia. Megaloblastic maturation of erythroid precursors is shown. Two megaloblasts occupy the center of the slide with a megaloblastic normoblast above.

The nucleus is large and contains coarse motley chromatin clumps, providing a checkerboard appearance. Nucleoli are visible in the more immature erythroid precursors. An imbalance in the rate of maturation of the nucleus relative to the cytoplasm exists, leading to disassociation between the maturity of the nucleus and the hemoglobinization of the orthochromic megaloblastic normoblasts.

Giant metamyelocytes and bands are present, and the mature neutrophils and eosinophils are hypersegmented. Imbalanced growth of megakaryocytes is evidenced by hyperdiploidy of the nucleus and the presence of giant platelets in the smear. Lymphocytes and plasma cells are spared from the cellular gigantism and cytoplasmic asynchrony observed in other cell lineages.

The bone marrow histology in cobalamin deficiency is similar to that in folic acid deficiency. Significant changes in the histology have been observed within 12 hours after appropriate treatment is initiated. The megaloblastic changes due to cobalamin deficiency can be reversed by pharmacologic doses of folic acid. However, folic acid therapy may worsen the neurologic consequences of cobalamin deficiency, despite the hematologic improvement.

 

Treatment

Approach Considerations

The following goals are the most important in establishing care for patients with pernicious anemia:

  • To establish that the patient has cobalamin deficiency

  • If there is evidence for folic acid deficiency but pernicious anemia has not been ruled out, treat with both folic acid and cobalamin until pernicious anemia has been ruled out. The reason is that folic acid restores blood counts but does not prevent the development of subacute combined system degeneration in patients with pernicious anemia.

  • To determine the cause of the failure to absorb cobalamin (This goal is somewhat controversial. Not all hematologists work to establish the precise cause of low vitamin B12 levels. The nuclear medicine tests are expensive and cumbersome, and as a result, many hematologists simply proceed to treatment once a differential diagnosis of a low vitamin B12 state is established.)

  • To treat the patient with adequate doses of cobalamin

  • To confirm the diagnosis by documenting that specific therapy is effective

  • To ensure administration of adequate quantities of cobalamin for the lifespan of the patient

Once therapy is started, hospitalization is necessary only for patients with severe life-threatening anemia. It may be required until patients develop an adequate hematologic response.

Patients whose cobalamin deficiency is due to underlying diseases involving the intestine or pancreas may require additional therapy. Examples of additional therapy are surgical correction of anatomic abnormalities of the gut that produce small bowel bacterial overgrowth, or the treatment of fish tapeworm anemia or pancreatitis. Elderly patients who also have hypokalemia should receive oral potassium supplements, to prevent severe hypokalemia and possible arrhythmias.

Go to Anemia, Iron Deficiency Anemia, and Chronic Anemia for complete information on these topics.

Cobalamin Therapy

Vitamin B12 is available for therapeutic use parenterally as either cyanocobalamin or hydroxocobalamin.[20] The two forms are equally useful in the treatment of vitamin B12 deficiency, and both are nontoxic (except for rare allergic reactions). Theoretical advantages exist to using hydroxocobalamin because it is retained better in the body and is more available to cells; however, both chemical forms of cobalamin provide prompt correction.

Cobalamin is available in a solution for injection in doses ranging from 100 to 1000 µg. Most of the injected doses in excess of 50 µg are rapidly excreted in the urine. Thus, when therapy is started, repeated doses are recommended in order to replenish body stores.

A number of regimens have been recommended. One regimen begins with daily subcutaneous administration for the first week. If significant reticulocytosis confirms that therapy is successful, doses are then administered twice weekly for another 4-5 weeks. After this period, 100 µg can be administered monthly by subcutaneous or intramuscular injection. Lifetime compliance is necessary. An alternative regimen involves weekly injections of 1000 µg of vitamin B12 for 5-6 weeks, followed by monthly injections.

Cobalamin deficiency–related neurological impairment can vary in clinical presentation, including acute combined system degeneration, peripheral neuropathy, and psychosis. These neuropathies should be treated more aggressively.

Response should be monitored by reticulocyte counts, lactic dehydrogenase (LDH), and an appropriate rise in hemoglobin levels. LDH levels decrease and hemoglobin levels increase by about 1 g/dL/wk. A rise in LDH might indicate a relapse.

Limited studies have shown that adequate therapy can be maintained after the initial parenteral loading doses through oral ingestion of 250-1000 µg of vitamin B12 daily. Even with a total absence of intrinsic factor (IF), about 1% of an oral dose is absorbed, and the daily requirement for vitamin B12 is 1 µg/d. A study by Zhang and colleagues found evidence that using orally ingested soy protein isolate (SPI) nanoparticles as a carrier can improve the intestinal transport and absorption of vitamin B12.[21]

The oral route may be necessary in the rare patients who have allergic reactions to parenteral administration, or in patients receiving anticoagulant or antiplatelet agent therapy, in whom intramuscular injections are contraindicated.[22] If this route is used, obtain serum cobalamin measurements at periodic intervals to ensure that adequate quantities of cobalamin have been absorbed. Oral cobalamin therapy should not be used in patients with neurologic symptoms.

A randomized, placebo-controlled trial of oral cobalamin therapy in 50 patients with borderline serum vitamin B12 levels (125-200 pg/mL) and nonspecific symptoms compatible with subtle vitamin B12 deficiency found that after 1 month, serum methylmalonic acid (MMA) levels were corrected more often in patients receiving oral cobalamin than in those receiving placebo. However, the benefit to the MMA level disappeared after 3 additional months without cobalamin therapy.[23]

A study found that oral cobalamine was more effective than parenteral therapy in some circumstances.[23]

Blood Transfusions

Transfusions are rarely required in patients with a megaloblastic anemia that is due to vitamin B12 deficiency. The likelihood of obtaining a dramatic response to cobalamin therapy within a few days of initiating treatment makes it unnecessary to subject the patient to the hazards of blood transfusion.

Usually, mild-to-moderate congestive heart failure secondary to anemia abates with bed rest and low-dosage diuretic therapy. However, if the congestive heart failure is severe or the patient has coronary insufficiency, transfusion of packed red blood cells may be necessary.

Transfuse the blood slowly because patients who are transfused for severe anemia often develop circulatory overload. For this reason, low-dose diuretic therapy is often employed with transfusion.

Dietary Measures and Activity Restriction

People who are strict vegetarians and, most particularly, people who do not consume eggs, milk, or meat can develop cobalamin deficiency. Counsel these people to either change their dietary habits or remain on supplementary vitamin B-12 therapy for their lifetime. An oral tablet of 100-200 µg taken weekly should provide adequate therapy.

Patients with severe anemia should curtail strenuous physical activity until they develop an adequate hematologic response after treatment.

Prevention

Because an increased familial incidence of pernicious anemia exists, family members should be aware that they are at greater risk of developing this disease and should seek medical attention promptly if they develop anemia or mental and neurologic symptoms. Monitor siblings and children of patients with a hereditary abnormality of cobalamin deficiency for evidence of the specific defect in cobalamin transport or metabolism.

Determine whether cobalamin deficiency is the etiology in patients who recently developed evidence of mental deterioration.

Prophylactically treat patients with cobalamin when they have undergone total gastrectomy, bypass procedures for weight reduction, ileectomy, pancreatectomy, or when they have atrophic gastritis or chronic inflammatory disease of the ileum.

Strict vegetarians should continue supplementary cobalamin, particularly during pregnancy and while nursing a newborn infant.

Elderly people are at risk for developing pernicious anemia due to achlorhydria. Therefore, serum vitamin B-12 levels should be checked. If low or if cobalamin deficiency is suspected, they should be treated with vitamin B-12 supplementation.

Consultations and Long-Term Monitoring

A consultation with a neurologist may be desirable in patients with unusual neurologic manifestations. Such consultation is most useful in patients without a macrocytic megaloblastic anemia.

Outpatient follow-up of patients with pernicious anemia is required to ensure that they have responded to therapy with cobalamin and that they continue to receive cobalamin on a regular basis for the remainder of their lives. Most patients can be taught to self-administer cobalamin subcutaneously so that they can minimize their visits to the physician.

 

Medication

Medication Summary

Vitamin B12 is available for therapeutic use parenterally as either cyanocobalamin or hydroxocobalamin.[20] Both are equally useful in the treatment of vitamin B12 deficiency, and they are nontoxic (except for rare allergic reactions). Theoretical advantages exist to using hydroxocobalamin because it is retained better in the body and is more available to cells; both chemical forms of cobalamin provide prompt correction.

Vitamins

Class Summary

Cobalamin is an essential vitamin. The inability to absorb adequate quantities of the vitamin from the diet leads to hematologic and neurologic complications.

Cyanocobalamin (CaloMist, Ener-G, Nascobal)

Deoxyadenosylcobalamin and hydroxocobalamin are active forms of vitamin B12 in humans. Microbes, but not humans or plants, synthesize vitamin B12. Vitamin B12 deficiency may result from intrinsic factor (IF) deficiency (pernicious anemia), partial or total gastrectomy, or diseases of the distal ileum.

Cyanocobalamin may be administered either intramuscularly (IM) or subcutaneously (SC). At the initiation of therapy, large daily doses are administered in order to replenish body stores with cobalamin.

With certain hereditary defects of cobalamin, metabolism doses of cobalamin (eg, 1000 µg SC every week) may be required to obtain a response.

Hydroxocobalamin

Deoxyadenosylcobalamin and hydroxocobalamin are active forms of vitamin B12 in humans. Vitamin B12 synthesized by microbes but not humans or plants. Vitamin B12 deficiency may result from intrinsic factor deficiency (pernicious anemia), partial or total gastrectomy, or diseases of the distal ileum. This agent is used to treat conditions caused by altered cobalamin metabolism that may cause secondary carnitine deficiency (ie, cobalamin C deficiency).

Multivitamins (MVI-12, Cernevit-12)

Multivitamins are used as dietary supplements.

 

Questions & Answers

Overview

What is pernicious anemia?

What conditions cause pernicious anemia?

What are the treatment options for pernicious anemia?

What is the pathophysiology of pernicious anemia?

What is the role of cobalamin deficiency in the pathophysiology of pernicious anemia?

What is the role of genetics in the pathogenesis of pernicious anemia?

What is the prevalence of antiparietal cell antibodies in patients with pernicious anemia?

What causes cobalamin deficiency in the pathophysiology of pernicious anemia?

What are common comorbidities of pernicious anemia in adults?

What causes cobalamin deficiency in pernicious anemia?

What is the etiologic role of genetics in pernicious anemia?

What causes cobalamin deficiency in children with pernicious anemia?

What is the etiologic role of pancreatic insufficiency in pernicious anemia?

What is the etiologic role of Zollinger-Ellison syndrome (ZES) in pernicious anemia?

Which disorders of the ileum may lead to pernicious anemia?

Which genetic disorders affect cobalamin transport and metabolism resulting in pernicious anemia?

What is the role of abnormalities of cellular use in the etiology of pernicious anemia?

What is the role of the intestinal lumen in the etiology of pernicious anemia?

What is the prevalence of pernicious anemia?

How does the incidence of pernicious anemia vary by age?

How does the incidence of pernicious anemia vary by sex?

What are the racial predilections of pernicious anemia?

What is the prognosis of pernicious anemia?

Which malignancies are associated with pernicious anemia?

How do intrinsic factor antibodies (IFA) affect the prognosis of pernicious anemia patients?

What is included in patient education for pernicious anemia?

Presentation

What is the initial presentation of pernicious anemia?

What are the general symptoms of pernicious anemia?

What are the cardiac symptoms of pernicious anemia?

What are the GI symptoms of pernicious anemia?

What are the neurologic symptoms of pernicious anemia?

What are the genitourinary symptoms of pernicious anemia?

What are the symptoms of thrombotic complications in pernicious anemia?

What is the typical appearance of patients with pernicious anemia?

What are the physical findings suggestive of pernicious anemia?

What is included in the neurologic assessment of pernicious anemia?

DDX

How is pernicious anemia defined?

What is thiamine-responsive megaloblastic anemia syndrome (TRMA) and how is it diagnosed?

Which conditions should be considered in the differential diagnosis of pernicious anemia?

What are the differential diagnoses for Pernicious Anemia?

Workup

What is included in the workup of pernicious anemia?

Which peripheral blood smear findings indicate pernicious anemia?

Which indirect bilirubin and serum lactate dehydrogenase findings suggest pernicious anemia?

Which gastric secretions findings suggest pernicious anemia?

What is the role of serum cobalamin measurement in the workup of pernicious anemia?

How are serum folic acid, methylmalonic acid, and homocysteine values used to differentiate folic acid deficiency from pernicious anemia?

What is the role of intrinsic factor (IF) antibodies in the diagnosis of pernicious anemia?

What is the role of the Schilling test in the workup of pernicious anemia?

How is administration of vitamin B12 used in the diagnosis of pernicious anemia?

What is the role of bone marrow aspiration and biopsy in the workup of pernicious anemia?

Treatment

What are the goals of treatment for pernicious anemia?

When is inpatient care indicated in the treatment of pernicious anemia?

What is the role of cobalamin therapy in the treatment of pernicious anemia?

What is the efficacy of cobalamin therapy for pernicious anemia?

What is the role of blood transfusions in the treatment of pernicious anemia?

Which dietary and activity modifications are required for the treatment of pernicious anemia?

How is pernicious anemia prevented?

Which specialist consultations are needed for the treatment of pernicious anemia?

What is included in long-term monitoring of pernicious anemia?

Medications

Which medications are used for the treatment of pernicious anemia?

Which medications in the drug class Vitamins are used in the treatment of Pernicious Anemia?