Causes of Deficiency

The classic disease, pernicious anemia, is caused by defective intrinsic factor production by parietal cells, leading to malabsorption. These patients may have demonstrable circulating antibodies to parietal cells or lymphocytic infiltrations of the gastric mucosa, suggesting an underlying autoimmune disorder. Another common cause of malabsorption is food-cobalamin malabsorption (Dali-Youcef and Andres, 2009). Under some clinical settings, the normal digestive process fails to release cobalamin from food or intestinal transport protein. Cobalamin remains bound and cannot be absorbed even in the presence of available intrinsic factors. Predisposing factors include atrophic gastritis and hypochlorhydria, and malabsorption may be seen with Helicobacter pylori infection, gastrectomy or other gastric surgeries, intestinal bacterial overgrowth, and prolonged use of H₂ antagonists, proton pump inhibitors, or biguanides (e.g., metformin). Patients with human immunodeficiency virus (HIV) are often observed to have a low serum cobalamin level, usually with normal homocysteine and methylmalonic acid. The significance of this association is unknown.

People who abuse nitrous oxide may develop a clinical syndrome of myeloneuropathy indistinguishable from that of cobalamin deficiency. The mechanism appears to be an interference with the cobalamin-dependent conversion of homocysteine to methionine. The other pathway, conversion of methylmalonyl co-A to succinyl co-A, is unaffected by nitrous oxide. Prolonged exposure to nitrous oxide is necessary to produce neurological symptoms in normal individuals. By contrast, patients who are already deficient in cobalamin may experience neurological deficits after only brief exposures during general anesthesia. Symptoms appear subacutely after surgery and resolve quickly with cobalamin treatment (Singer et al., 2008).

Clinical Features

The onset of symptoms is insidious, with paresthesias in the hands or feet experienced by most patients. Weakness and unsteadiness of gait are the next most frequent complaints. The Lhermitte sign may be present. Cerebral symptoms such as mental slowing, depression, confusion, delusions, and hallucinations are common, and occasionally patients present with only cognitive or psychiatric symptoms. Many patients also complain of dyspepsia, flatulence, altered bowel habits, or other GI symptoms.

On examination, signs of both peripheral nerve and spinal cord involvement may be present, although either can be affected first or disproportionately. Loss of vibration or joint position sense in the legs is common. If impaired position sense is severe, the Romberg sign may be present. Motor impairment, if present, results from pyramidal tract dysfunction and is most severe in the legs, ranging from mild clumsiness and hyperreflexia to spastic paraplegia and extensor plantar responses. Tendon reflexes are variably affected depending on the degree of pyramidal and peripheral nerve involvement. Visual impairment occasionally is encountered and may antedate other manifestations of vitamin deficiency; ophthalmological examination reveals bilateral visual loss, optic atrophy, and centrocecal scotomata. Brainstem or cerebellar signs, chorea, autonomic insufficiency, or even reversible coma may rarely occur.

Laboratory Studies

Serum assays of vitamin B₁₂ and cobalamin-dependent metabolites provide direct measures of cobalamin homeostasis, although there are important limitations (Solomon, 2005). Blood cobalamins are bound to two transport proteins, transcobalamin and haptocorrin. The cobalamin bound to transcobalamin, known as holotranscobalamin, is the fraction that is available to tissues, although it accounts for only 10% to 30% of the serum level measured by standard laboratory methods. Serum levels are influenced by conditions that affect the concentrations of these transport proteins. Myeloproliferative and hepatic disorders may raise the concentration of haptocorrin and cause a falsely normal serum level. A misleadingly high serum level also may result from the presence of an abnormal cobalamin-binding protein. In contrast, pregnancy and contraceptives may give falsely low measurements in the absence of deficiency. Folate deficiency also causes a falsely low cobalamin serum level that corrects after folate replacement. These confounding factors diminish the sensitivity and specificity of the commonly used assay of total serum cobalamin in the diagnosis of deficiency state. Although measurement of holotranscobalamin is better in theory, available data suggest that its diagnostic accuracy is approximately equivalent to that of total serum cobalamin (Miller et al., 2006).

Homocysteine and methylmalonic acid are precursors of cobalamin-dependent biochemical reactions. These metabolites accumulate during deficiency state. Measuring these metabolites is useful in settings of nitrous oxide abuse and in inherited metabolic disorders in which cobalamin-dependent pathways are impaired despite normal serum level. Homocysteine and methylmalonic acid assays are also useful when the cobalamin concentration is in the lower range of normal, between 200 and 350 pg/mL. Homocysteine level should be measured either at fasting or after an oral methionine load. The blood sample should be refrigerated immediately after collection because the level increases if whole blood is left at room temperature for several hours. Elevated levels of homocysteine and methylmalonic acid are not specific for cobalamin deficiency, as there are many other causes of increase in these metabolites (Box 57.1). In cobalamin-deficient patients, these levels typically normalize within 2 weeks of treatment.

In patients with autoimmune gastritis and intrinsic factor deficiency, antibodies against parietal cell and intrinsic factor may be elevated. Anti–parietal cell antibodies are nonspecific and are present in other autoimmune endocrinopathies as well as occasional normal individuals. Anti–intrinsic factor antibodies are less sensitive (50%–70%) but are specific for pernicious anemia. Elevated serum gastrin level is a marker of atrophic gastritis and hypochlorhydria and is a sensitive (up to 90%) but nonspecific indicator of pernicious anemia. The Schilling test measures intestinal cobalamin absorption using radiolabeled cobalamin and intrinsic factor but has fallen out of favor, in part because the labeled cobalamin is not readily available. In food-cobalamin malabsorption, the routine Schilling test is normal, but a modified Schilling test using protein-bound cobalamin may show impaired absorption.

The classic hematological manifestation of pernicious anemia is a macrocytic anemia. Erythrocyte or bone marrow macrocytosis or hypersegmentation of polymorphonuclear cells may be present without anemia. Hematological abnormalities may be absent at the time of neurological presentation and are thus insufficiently sensitive for use in diagnosis.

Because most patients present with clinical features suggesting a myelopathy or encephalopathy, imaging studies are necessary to exclude structural causes. Results of magnetic resonance imaging (MRI) may be normal, or T2-signal abnormalities may be seen in the lateral or posterior columns in patients with subacute combined degeneration (Kumar and Singh, 2009) (Fig. 57.1). Both gadolinium enhancement and spinal cord swelling have been described. Patients with encephalopathy or dementia often have multiple foci of T2 signal abnormalities in the deep white matter that may become confluent with disease progression. Radiographic improvement is seen within a few months after initiation of treatment. Nonspecific abnormalities of electroencephalography, as well as visual and somatosensory evoked responses, are present in most patients with neurological abnormalities. Nerve-conduction studies show small or absent rural nerve sensory potentials in approximately half of patients, providing evidence for an axonal polyneuropathy.

Fig. 57.1 Vitamin B₁₂ deficiency myelopathy. Gadolinium-enhanced, T1-weighted cervical and upper thoracic magnetic resonance image showing marked enhancement of posterior cord of a 30-year-old African-American woman wheelchair-bound due to an 18-month history of progressive myelopathy; vitamin B₁₂ level: 60 pg/mL.

(Courtesy Dr. R. Laureno.)

Pathology

The term subacute combined degeneration of the spinal cord describes the pathological process seen in this disorder. Microscopically, spongiform changes and foci of myelin and axon destruction are seen in the white matter of the spinal cord. The most severely affected regions are the posterior columns at the cervical and upper thoracic levels (Fig. 57.2). Pathological changes also are seen commonly in the lateral columns, whereas the anterior columns are involved in only a small number of the advanced cases. The pathological findings of the peripheral nervous system are those of axonal degeneration, but in some cases there is evidence of demyelination. Involvement of the optic nerve and cerebral white matter also occurs.

Fig. 57.2 Subacute combined degeneration of the spinal cord in vitamin B₁₂ deficiency. Demyelination and loss of axons are more widespread in posterior than in lateral columns (Weigert stain).

(Courtesy Dr. Michael F. Gonzales.)

Treatment

Recommendations for treatment of cobalamin deficiency vary widely. A typical regimen uses intramuscular daily injections of 1000 µg for the first week, followed by weekly 1000 µg injections for 1 month, and monthly injections thereafter. These parenteral doses provide quantities considerably higher than the body requirement. There is no evidence that overdosing can speed neurological recovery, but high doses of cobalamin appear to be safe. Oral supplementation at 1000 µg daily has also been used with some success, even in patients with suspected malabsorption, although close monitoring is necessary to ensure adequacy of treatment.

With proper treatment, serum levels of homocysteine and methylmalonic acid return to normal in about 2 weeks. Neurological improvement is more delayed and may be incomplete. Most of the symptomatic improvement occurs during the first 6 to 12 months of therapy. The need for early diagnosis and treatment is underscored by the observation that remission correlates inversely with the time lapse between onset of symptoms and initiation of therapy.

Causes of Deficiency

Absorption of folate occurs in the jejunum and to a lesser extent the ileum. Chronic alcoholism is an important cause of folate deficiency. Folate deficiency also may complicate small-bowel disease (e.g., sprue, Crohn disease, ulcerative colitis). Other populations at risk are pregnant women and patients receiving anticonvulsant drugs that interfere with folate metabolism. Sulfasalazine, methotrexate, triamterene, and oral contraceptives also may cause folate deficiency. Intrathecal methotrexate, in particular, causes a leukoencephalopathy associated with marked elevation of homocysteine levels in the cerebrospinal fluid (CSF).

Clinical Features

The majority of patients with laboratory evidence of folate deficiency do not have overt neurological findings. The classic syndrome of folate deficiency is similar to subacute combined degeneration seen in cobalamin deficiency. Presenting symptoms are limb paresthesias, weakness, and gait unsteadiness. These patients have megaloblastic anemia, impaired position and vibration sense, pyramidal signs, and possibly dementia. Chronic folate deficiency may result in mild cognitive impairment or increased stroke risk in adults, and in increased frequency of neural tube defects in babies born to folate-deficient mothers. Since 1998, the U.S. Food and Drug Administration mandates fortification of grain products with folate. The level of supplement, on the average, increases the dietary folate intake of adults by 100 mg/day.

Serum homocysteine is an important surrogate marker for folate metabolism, although there are other causes of elevated homocysteine levels. Hyperhomocysteinemia is a risk factor for vascular diseases and venous thrombosis. For cerebrovascular disease, the association is strongest for multi-infarct dementia and white-matter microangiopathy, but there is little or no association with cardioembolic or large-artery disease. Even a modestly increased serum level, in the range of 15 to 20 mmol/L, engenders a recognizable increase in vascular risk. On the other hand, it is as yet unclear whether folate supplementation can provide any reduction in vascular adverse outcomes.

Although low folate level is present in many elderly asymptomatic people, the prevalence seems to be higher in the psychiatric and Alzheimer disease populations. Moreover, a low folate level appears to correlate with depression and cognitive impairment. Even in healthy older adults, a low folate level is associated with subtle deficits in neuropsychological test performance.

Clinical observations in two inborn errors of metabolism reinforce our understanding of the role of homocysteine in neurological diseases. Hereditary deficiency of cystathionine β-synthase leads to hyperhomocysteinemia and hyperhomocysteinuria. The homozygous form presents with markedly elevated homocysteine levels, mental retardation, premature atherosclerosis, and seizures. Heterozygous individuals have milder elevations of homocysteine and also have increased risk of vascular disease. A much more common condition is a C-to-T substitution at codon 677 in the gene coding for N5, N10-methylenetetrahydrofolate reductase (MTHFR). Some 5% to 10% of the white population are homozygotes for this C677T mutation. These individuals have mildly elevated homocysteine levels and increased risk of vascular disease.

Laboratory Studies

Plasma and erythrocyte folate levels may be measured directly. Erythrocyte level is generally more reliable than plasma level because it is less affected by short-term fluctuation in intake. Serum homocysteine is increased in folate deficiency. Its measurement is discussed in Laboratory Studies under Vitamin B₁₂ Deficiency in this chapter.

Treatment

In patients with documented folate deficiency, the initial dose is usually 1 mg of folate several times per day, followed by a maintenance dose of 1 mg/day. For acutely ill patients, parenteral doses of 1 to 5 mg may be given. Even with oral doses as high as 15 mg/day, there is no substantiated report of toxicity. In women of childbearing potential with epilepsy, daily folate supplementation of 0.4 mg or more is recommended as prophylaxis against neural tube defects.