A nurse is assessing a client who is at risk for the development of pernicious anemia

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)

• 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)

Pernicious anemia is the most common cause of severe vitamin B12 deficiency worldwide and is due to autoimmune destruction of parietal cells and/or intrinsic factor. 

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 due to genetic abnormalities that result in failure to secrete IF or production of defective IF. 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, such patients 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.

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.

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]

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]

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

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]