Nutritional Cobalamin Deficiency

 Vegetarian diets can be classified as lactovegetarian, ovovegetarian, lacto-ovovegetarian, or vegan, respectively, if they include dairy products, eggs, dairy products and eggs, or no animal products at all. However, all these vegetarian diets contain insufficient amounts of cobalamin. Therefore, all vegetarians are in various stages of progressive cobalamin depletion and moving inexorably toward cobalamin deficiency. This warrants early supplementation with cobalamin.

In addition, the vast majority of those living in resource-limited countries subsist on a relatively monotonous diet that is intrinsically low in animal-source foods (that are more expensive than plant based diets). Although not strictly considered vegetarians, such individuals are better classified as “near-vegetarians” and should also be supplemented with cobalamin. Cobalamin deficiency has been widely reported among 45% of Northern Chinese women, and in up to 85% of Indian adolescents and 65% of newborns. In Pakistan, among those with megaloblastic anemia (hemoglobin < 8 g/dL), nearly 80% had cobalamin deficiency. Surprisingly, even those consuming “Mediterranean diets” that are rich in fruits and vegetables but low in animal-source protein are at risk for cobalamin deficiency; among 180 pregnant women, cobalamin deficiency was found in 72% of mothers and 41% of babies.

The fetus is dependent on the mother’s cobalamin stores for a sufficient quota of cobalamin at birth; a close correlation exists between low maternal serum and breast milk cobalamin concentrations and cobalamin insufficiency in the infant. Therefore when mothers do not consume sufficient amounts of animal source foods, they themselves are at risk for nutritional cobalamin deficiency, and their infants will have smaller stores of the vitamin at birth. Although the dictum is that infants should be exclusively breastfed for the first 6 months of life, a large percentage of mothers in resource-limited countries had evidence of cobalamin deficiency. For example, three-quarters of a cross section of 366 pregnant urban women in South India had cobalamin deficiency. So there is an imperative to raise these values in women and in babies. An important series of studies has shown that treatment of the mother during pregnancy or even the infant shortly after delivery will promptly reverse preexisting cobalamin deficiency.

Cobalamin-deficient infants can present with a spectrum of clin 0ical findings, ranging from feeding difficulties and refusal of both breast milk and complementary food by regurgitation (which results in further failure to thrive) to motor and social retardation, reflecting a developmental delay. The child is persistently drowsy and rarely sits up or makes eye contact. There may be lemon-tint jaundice with hypotonia, insufficient head control, and delayed spontaneous turning. There can be brownish-black areas of hyperpigmentation in the dorsal fingers and toes as well as over the medial thighs, arms, and axillae (which usually resolve within 3 months of therapy). Evidence of megaloblastic anemia may be masked with superim posed iron deficiency. If left untreated, there is growth retardation with reduced height and weight, and reduced head circumference with cranial MRI showing delayed myelination and frontoparietal cortical atrophy in affected infants; these can also be reversed within 3 months of cobalamin replacement. Treatment results in a dramatic increase in alertness and responsiveness of the child, who is now miraculously transformed into a normal child who, within a few days, rolls over spontaneously, makes eye contact with its mother, and is much more interested in the surroundings. Any previous abnormal movements (tremors, chorea, or myoclonus) may regress but transiently return within a few days to affect the face or tongue; however, these will resolve in 2 to 3 months. Cobalamin deficiency often resurfaces during wartime, which invariably leaves women and their infants malnourished.

Infants in the West fed a macrobiotic diet (vegan-like with occasional servings of fish) must be rapidly replenished with full doses of cobalamin before switching to a cobalamin-rich diet. Otherwise, up to 20% continue to have low cobalamin status, which can lead to impaired psychomotor functioning well into youth and later adolescence with compromise in faculties related to reasoning, abstract thinking, and learning ability.

When children in resource-limited settings grow up on the same monotonous diet as their parents, they are at risk for combined cobalamin, folate (and iron) deficiency. This problem of vertical intergenerational transfer of a deficient “bank balance” of minerals and micronutrients from one generation to another has been documented in all resource-limited countries. These affected children with preexisting depleted stores of cobalamin, folate (and iron), and imminent deficiency, who are the unwitting victims of circum stance, limp on through life with cognitive dysfunction and lower intelligence quotient and emotional intelligence (when compared with their better nourished counterparts in resource-rich countries). When they move on into adolescence and (often premature) young motherhood, they pass on their deficient “bank balances” vertically to the next generation and so the cycle continues ad infinitum. The number of such affected individuals worldwide is probably in the hundreds of millions.

Longitudinal studies from the West among women who apparently consume a balanced nonvegetarian diet confirm that pregnancy places an additional stress on the mother’s cobalamin stores and can lead to metabolic evidence of cobalamin deficiency. This can negatively affect their breastfed infants’ cobalamin status at 6 weeks; indeed, over two-thirds of Norwegian infants of otherwise healthy mothers had a metabolic profile consistent with cobalamin deficiency, which reverted to normal after cobalamin replenishment. Among infants with only minor developmental delays and feeding difficulties (regurgitation) and biochemical evidence of cobalamin deficiency, those treated with cobalamin responded with significant clinical benefit, a fact that underscores the importance of cobalamin in postnatal neurodevelopment. Thus it is likely that many more breastfed infants in the West probably need cobalamin supplements early in life, as do their mothers in preparation for pregnancy.

Intragastric Events Leading to Cobalamin Malabsorption

Inadequate Dissociation of Cobalamin From Food Protein

Dietary cobalamin is bioavailable only after proteolytic digestion of food by gastric acid and pepsin. Failure to release cobalamin from food protein can lead to food-cobalamin malabsorption and frank cobalamin deficiency despite the presence of IF.

Congenital Intrinsic Factor Deficiency

Congenital IF deficiency arising from mutations in gastric IF, resulting in complete loss of IF, can be transmitted as an autosomal recessive trait and expressed in homozygotes by the age of 2 years as severe megaloblastic anemia (less than 100 cases reported). Dysfunctional IF may lead to only a mild abnormality in binding to cobalamin and result in a delayed presentation into the second decade.

Loss or Atrophy of Gastric Oxyntic Mucosa

 IF deficiency, which arises from atrophy of gastric parietal (oxyntic) mucosal cells, can be caused by total or partial gastrectomy (bariatric surgery); by autoimmune destruction, as observed in adult Addisonian pernicious anemia or, rarely, in a similar disease in children (juvenile pernicious anemia); and after destruction of gastric mucosa by caustic (lye) ingestion.

Total gastrectomy invariably leads to cobalamin deficiency in about 5 years (range, 2 to 10 years); indeed, longitudinal follow-up revealed that all 176 patients developed cobalamin deficiency within 4 years, with earlier clinical presentations occurring in those with lower cobalamin status preoperatively. This condition is often associated with iron deficiency, warranting routine prophylactic cobalamin and parenteral iron replacement.

By contrast, after partial gastrectomy, the degree of cobalamin deficiency depends on the size of the remaining gastric remnant. Cobalamin deficiency eventually develops in 10% to 20% of patients at 8 years with a minority (about 5%) developing overt clinical manifestations from a combination of decreased IF secretion, hypochlorhydria, intestinal bacterial overgrowth of cobalamin-consuming organisms, and iron deficiency. It is more common in Billroth II than in Billroth I surgery, and in subtotal than in partial gastrectomy. Morbidly obese patients treated surgically with gastric bypass also have more food-cobalamin malabsorption than patients treated with vertical banded gastroplasty. Even after laparoscopic Roux-en-Y gastric bypass, and despite oral multivitamin supplementation, iron deficiency was seen in one-half of patients and cobalamin deficiency seen in one-quarter at 3 years; therefore all such patients need prophylactic cobalamin and parenteral iron.

Absent Intrinsic Factor Secretion and Pernicious Anemia

 A common cause of cobalamin malabsorption is pernicious anemia, an autoimmune disease in which the fundamental defect is atrophy of the gastric (parietal cell) oxyntic mucosa that eventually leads to the complete absence of IF and hydrochloric acid secretion (Fig. 1). The autoimmune gastritis (leading to chronic atrophic gastritis) associated with pernicious anemia involves the fundus and body of the stomach, and the histologic appearance of the gastric mucosa (infiltration with plasma cells and lymphocytes) is strongly reminiscent of autoimmune lesions. Because cobalamin is absorbed only by binding to IF and uptake by ileal IF-cobalamin receptors, the net consequence is severe cobalamin malabsorption leading to cobalamin deficiency.

Fig1. HISTOLOGIC FEATURES OF STOMACH IN PERNICIOUS ANEMIA COMPARED TO NORMAL. The normal gastric mucosa (A) is contrasted to that seen in pernicious anemia (B), in which there is atrophy of gastric glands, intestinal metaplasia with goblet cells, and loss of parietal cells (not visible at this magnification).

The annual incidence of pernicious anemia is approximately 25 new cases per 100,000 persons older than 40 years. Although the average age of onset is about 60 years, pernicious anemia is no respecter of age, race, or ethnic origin. The predisposition to devel oping pernicious anemia may have a genetic basis, but neither the mode of inheritance nor the initiating events or primary mechanism is precisely understood. There is a positive family history for about 30% of patients, among whom the risk for familial pernicious anemia is 20 times as high as in the general population; about 20% of siblings of patients are projected to develop pernicious anemia by the age of 90 years, and pernicious anemia has developed concordantly in identical twins. There is a significant association of pernicious anemia with other autoimmune diseases, including Graves disease (30%), Hashimoto thyroiditis (11%), vitiligo (8%), Addison disease, idiopathic hypoparathyroidism, primary ovarian failure, myasthenia gravis, type 1 diabetes mellitus, and adult hypogammaglobulinemia.

Autoimmune gastritis progresses over decades to atrophic body gastritis and pernicious anemia. Serum anti-IF antibodies are highly specific (100%) for pernicious anemia, but the sensitivity is only about 50%. Earlier, the clinical use of anti-parietal cell antibodies was limited because of low specificity. This necessitated use of additional surrogate markers (high serum gastrin and low pepsinogen I levels) that reflected loss of acid- and IF-secreting parietal (oxyntic) cells. However, newer enzyme-linked immunosorbent assays (ELISA) for anti-parietal cell antibodies, which are directed against gastric H+/K+ ATPase, are 30% more sensitive than previous (immunofluorescence) assays. A reanalysis of the clinical utility of combining anti-IF and newer anti-parietal cell antibody tests to noninvasively diagnose pernicious anemia points to this approach as very promising. Thus among 81 patients with biopsy-proven atrophic body gastritis and pernicious anemia, combining anti-IF antibodies (37% sensitivity; 100% specificity) with newer anti-parietal cell antibodies (sensitivity 91%; specificity 90%) significantly increased their diagnostic performance for pernicious anemia, yielding overall 73% sensitivity while maintaining 100% specificity.

Juvenile pernicious anemia can manifest in the second decade with severe cobalamin deficiency in conjunction with many of the associated endocrinopathies and autoantibodies observed in adults.

Undiagnosed pernicious anemia is common among free-living elderly persons (over 60 years of age) who have only minimal clinical manifestations of cobalamin deficiency (i.e., 1.9% of a Southern California survey population had unrecognized and untreated pernicious anemia). The prevalence was 2.7% in women and 1.4% in men, but 4.3% of the African American women and 4.0% of the women of European descent had pernicious anemia.

Abnormal Events in the Small Bowel Lumen

 Insufficient Pancreatic Protease

About 30% of patients with severe pancreatic insufficiency fail to degrade R proteins, which will lead to impaired transfer of cobalamin from R protein to IF. Pancreatic extract will normalize cobalamin malabsorption.

Inactivation of Pancreatic Protease

 Pancreatic protease can be inactivated by massive gastric hypersecretion arising from a gastrinoma in Zollinger-Ellison syndrome.16 The continued low pH of the luminal contents reaching the ileum may also perturb interaction of the IF-cobalamin complex with IF-cobalamin receptors (which requires a pH above 5.4).

Usurpation of Luminal Cobalamin

The near-sterile condition of the small bowel is maintained by a combination of the mechanical cleansing action of peristalsis and the chemical action of gastric acid. Disorders conducive to relative stasis, impaired motility, and hypogammaglobulinemia are predisposing factors that favor colonization by bacteria. Many of these bacteria can take up free cobalamin, but not IF-bound cobalamin. However, if colonization extends proximally to the locus at which IF and cobalamin interact, significant cobalamin may be usurped before it can bind to IF. This cobalamin malabsorption can be corrected to some extent by a 7- to 10-day course of antibiotic therapy.

Approximately 3% of individuals infested with the fish tapeworm Diphyllobothrium latum, which avidly usurps cobalamin for growth, can develop frank cobalamin deficiency. Humans become infected when they eat partially cooked or raw fish containing plerocercoids, which develop into adult worms in the jejunum in about 6 weeks, growing to a length of 10 m, with up to 4000 proglottids; when these worms lay eggs, the life cycle is repeated. After ova have been identified in the stools, expulsion of the worms by oral praziquantel (10 to 20 mg/kg as a single dose) and cobalamin replenishment is curative.

Disorders of Ileal Intrinsic Factor–Cobalamin Receptors or Mucosa

 Absence of Intrinsic Factor–Cobalamin Receptors

 The distal ileum has the greatest density of IF-cobalamin receptors. Disease or removal of only 1 to 2 feet of terminal ileum by resection or bypass reduces ileal IF-cobalamin receptor numbers for interaction with IF-cobalamin, resulting in cobalamin malabsorption.

Defective Intrinsic Factor–Cobalamin Receptors or Post-Intrinsic Factor–Cobalamin Receptor Defects

 Imerslund-Gräsbeck syndrome is a term used collectively for a heterogeneous group of congenital (autosomal recessive) disorders in children arising from biallelic mutations (in 80% of cases) involving either the CUBN or AMN genes that constitute the functional IF-cobalamin receptor (i.e., cubam). This results in selective cobalamin malabsorption. Children present between 3 and 10 years of age with megaloblastic anemia and neurologic presentations with low serum cobalamin levels associated with mild, persistent, benign proteinuria (in 90% of cases). Because renal cubam also participates in renal tubular absorption of albumin, this explains the proteinuria in Imerslund-Gräsbeck syndrome. Diagnosis requires analysis of mutational status of gastric IF, CUBN, and AMN genes.

Drug-Induced Defects

Long-term use of H2 antagonists and/or proton pump inhibitors may interfere with the eventual handover of food-cobalamin to IF, especially in those with preexisting borderline cobalamin stores. Long term treatment with metformin can interfere with IF-cobalamin binding to ileal IF-cobalamin receptors (cubam) and increases risk for cobalamin deficiency over time, warranting replacement therapy. Cholestyramine, colchicine, and neomycin probably also impair transepithelial transport of cobalamin.

Disorders of Plasma Cobalamin Transport

 Polymorphism or absence of TCI can be associated with low cobalamin levels, but the MMA and homocysteine levels are normal. By contrast, either deficiency or defective TCII can present with meg aloblastic anemia in infancy; these conditions can nevertheless be associated with normal cobalamin levels (because TCI, which binds over 75% of serum cobalamin, is normal). However, there will be metabolic evidence of cobalamin deficiency that can be reversed by daily or biweekly injections of 1 mg of cobalamin, which ensures passive cobalamin delivery into cells. Rare mutations in the gene for the TCII receptor (CD320) have also been identified.

Disorders of Intracellular Cobalamin Use

Congenital Metabolic Defects of Cobalamin Metabolism: Cobalamin Mutants A to J

 Given the multitude of chaperones or transporters involved in escorting cobalamin intracellularly to their destination to function as coenzymes for methionine synthase and methylmalonyl-CoA mutase, it is not difficult to envision that there would invariably be rare inborn errors of cobalamin metabolism where one of these escorts or trans porters is missing. The combination of megaloblastic anemia with increased levels of homocysteine or MMA, or both, in serum and urine despite normal cobalamin and folate levels should suggest an inborn error of cobalamin metabolism. The inherited defects of cobalamin use are heterogeneous and are empirically defined as cobalamin mutations A to J (cblA to cblJ). These infants must be differentiated from those with nutritional cobalamin deficiency who could have similar clinical features. Patients suspected of having an inborn error of metabolism should be evaluated by experts who have published extensively on this topic.

Functional Cobalamin Deficiency After Nitrous Oxide Exposure

 Nitrous oxide (N2O) inactivates coenzyme forms of cobalamin by oxidizing the fully reduced cob(I)alamin to cob(III)alamin; this results in a state of functional intracellular cobalamin deficiency. This syndrome was first identified in patients with tetanus given nitrous oxide for up to 6 days. Subsequently, persons exposed to nitrous oxide for open heart surgery and through chronic (recreational, accidental, or occupational) exposure have been recognized as being at high risk for developing megaloblastosis and cobalamin-deficient neuromyelopa thy. Megaloblastosis develops within 24 hours and lasts less than 1 week after a single exposure. Severe neurologic deficits have been reported after prolonged intraoperative exposure to nitrous oxide in patients with unsuspected or even borderline cobalamin deficiency. The neurologic syndrome is usually seen with chronic intermittent exposure. (See box on Subclinical Cobalamin Deficiency.)

SUBCLINICAL COBALAMIN DEFICIENCY

The entity of subclinical cobalamin deficiency is present when there is biochemical evidence for cobalamin deficiency, reflected by a low cobalamin value (and increased methylmalonic acid and homocysteine) but without overt clinical manifestations. Although dependent on the population studied, the frequency of (silent) sub clinical cobalamin deficiency in the United States is suspected to be 10 times higher than classic (overt) cobalamin deficiency that is found in 1%–2% of the population. Many elderly persons may have various symptoms consistent with aging (including fatigue, cognitive changes, lower quality-of-life measures, and subtle symptoms of neuropathy) that cannot be directly attributed to cobalamin deficiency, despite the fact that these very symptoms are often seen in symptomatic cobalamin deficiency. Often this triggers testing with a serum cobalamin test, and a borderline result that can either spontaneously revert to normal, or minimally fluctuates above or below the cutoff value, or remains stable without change over many years; this in turn generates a new set of problems, including the need to label this entity and thereby make clinical decisions.

Although some experts do not feel obliged to treat, preferring to wait for overt symptoms, others feel ethically bound to treat even without overt clinical manifestations; the latter position is based on the fact that such clinical manifestations can be very subtle and are detected only by sophisticated neurophysiologic or imaging studies (which are both expensive and impractical in routine clinical practice). In support of earlier therapy in this clinical setting, there is compelling clinical evidence that combined B-vitamin supplementation to reduce homocysteine can reduce brain atrophy and both cognitive and clinical decline.

Therefore, after first replenishing potentially depleted cobalamin stores with parenteral cobalamin therapy, oral supplementation for up to 6 months on and 6 months off can normalize cobalamin status in most patients as an alternative to continuous therapy. A key factor in such decisions is the benefit in avoiding progressive brain dysfunction and relatively low cost of cobalamin (and lack of side effects).

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Clinical Manifestations of Iron Overload

Pathobiology of Acquired Iron Overload

Thyroid Disease in Pregnancy

Hypothyroidism

Hyperthyroidism

Clinical Manifestations of Iron Deficiency

Thyroid Imaging: nuclear Medicine Techniques - Thyroiditis

Thyroid Imaging: nuclear Medicine Techniques - Thyrotoxicosis

Pathobiology of Iron Deficiency

Outcome and Prevention of Infectious Diseases

Serum and Tissue Thyroid Hormone concentrations in NTI

Microorganism Entry, Invasion, and Dissemination: The Host’s Perspective