Pernicious Anemia Clinical Presentation

Updated: May 16, 2022
  • Author: Srikanth Nagalla, MD, MS, FACP; Chief Editor: Emmanuel C Besa, MD  more...
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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 neurologic 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

Individuals with pernicious anemia often tolerate the anemia well, and many are ambulatory with hematocrit levels in the mid-teens. However, the cardiac output is usually increased when hematocrit levels fall below 20%, with associated accerations in heart rate. Congestive heart failure and coronary insufficiency can occur, most particularly in patients with preexisting heart disease.

Gastrointestinal symptoms

Approximately 50% of patients with pernicious anemia develop atrophic glossitis, presenting with a smooth tongue that may be painful and beefy red, with loss of papillae that is usually most marked along the edges of the tongue. These patients report burning or soreness, most particularly on the anterior third of the tongue, 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. [14]

Neurologic symptoms

The most common neurologic symptoms in vitamin B12 deficiency include paresthesias, weakness, clumsiness, and an unsteady gait. The last two symptoms are exacerbated in dark environments due to the loss of visual cues that patients often rely on, in concert with the loss of proprioception. 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 (subacute combined degeneration).

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. So-called megaloblastic madness—delusions, hallucinations, outbursts, and paranoid schizophrenic ideation—is less common. 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. [15] 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. [16]

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. [17]


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 feature 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 in 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.