Megaloblastic Anemia Differential Diagnoses

Updated: Jul 17, 2021
  • Author: Srikanth Nagalla, MD, MS, FACP; Chief Editor: Emmanuel C Besa, MD  more...
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Diagnostic Considerations

Conditions that can cause a megaloblastic anemia include the following:

  • Vitamin B12 insufficiency
  • Pernicious anemia
  • Lack of absorption of B12 complexes in the terminal ileum (eg, from small bowel bacterial overgrowth, pancreatic exocrine insufficiency, tapeworm, familial factors, drugs, ileal bypass, ileal enteritis, celiac disease)
  • Folic acid deficiency
  • Thiamine-responsive megaloblastic anemia syndrome (TRMA)
  • Inherited defects of cobalamin transport and metabolism

By definition, pernicious anemia refers specifically to vitamin B12 deficiency resulting from a lack of production of intrinsic factor (IF) by parietal cells in the stomach. This can be due to autoantibodies directed against the parietal cells, removal of parietal cells by bariatric surgery or gastrectomy, or destruction of parietal cells by gastric disease or alcohol abuse.

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. [16]

Vitamin B12 absorption is a complex process, and other causes of vitamin B12 deficiency exist. Pernicious anemia must be differentiated from other disorders that interfere with the absorption and metabolism of vitamin B12 and produce cobalamin deficiency, with the development of a macrocytic anemia and neurologic complications. It is very important to distinguish between vitamin B12 and folate deficiencies since the treatment of the former with folate can lead to the progression of neurological impairment. See Overview/Etiology.

Other potential causes of macrocytosis (eg, liver disease, hypothyroidism, copper deficiency, hemolytic anemia) should be considered in the differential diagnosis. Copper deficiency can present as normocytic, microcytic, or macrocytic anemia. Patients with copper deficiency presenting with macrocytic anemia and myeloneuropathy could be misdiagnosed as having vitamin B12 deficiency. 

Occasionally, the morphologic changes in hematopoietic cells of patients with megaloblastic anemia are extremely bizarre and can be misinterpreted as neoplasia, such as acute leukemia or myelodysplasia.

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 B12 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. [17]  

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. [18]

The anemia in TRMA is corrected with pharmacologic doses (50-100 mg/day) of thiamine (vitamin B1). However, the red cells remain macrocytic. [19]

Inherited defects of cobalamin transport and metabolism

Three hereditary disorders affect absorption and transport of cobalamin, and another seven alter cellular use and coenzyme production. Clinical onset of these disorders usually occurs in infancy and childhood.

The three disorders of absorption and transport are transcobalamin II (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. [20]

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, caused by 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.

Differential Diagnoses