Subclinical cobalamin deficiency.

PURPOSE OF REVIEW: This review focuses on recent developments and controversies in the diagnosis, consequences, and management of subclinical cobalamin deficiency (SCCD), which affects many elderly persons. RECENT FINDINGS: Diagnosis of SCCD depends exclusively on biochemical tests whose individual limitations suggest that combinations of tests are needed, especially in epidemiologic research. The causes of SCCD are unknown in more than 60% of cases, which limits prognostic predictions and identification of health consequences. After years of varying, often inconclusive associations, new clinical trials suggest that homocysteine reduction by high doses of folic acid, cobalamin, and pyridoxine may reduce progression of structural brain changes and cognitive impairment, especially in predisposed individuals. The causative or contributory roles, if any, of SCCD itself in cognitive dysfunction require direct study. If the findings are confirmed, high-dose supplementation with three vitamins will probably be more effective than fortification of the diet. SUMMARY: The story of SCCD, which is severalfold times more common in the elderly than clinical cobalamin deficiency but also differs from it in arising only infrequently from severe malabsorption and thus being less likely to progress, continues to evolve. Preventive benefits need to be confirmed and expanded, and will require fuller understanding of SCCD pathophysiology, natural history, and health consequences.

Mandatory fortification of the food supply with cobalamin: an idea whose time has not yet come.

The success of folic acid fortification has generated consideration of similar fortification with cobalamin for its own sake but more so to mitigate possible neurologic risks from increased folate intake by cobalamin-deficient persons. However, the folate model itself, the success of which was predicted by successful clinical trials and the known favorable facts of high folic acid bioavailability and the infrequency of folate malabsorption, may not apply to cobalamin fortification. Cobalamin bioavailability is more restricted than folic acid and is unfortunately poorest in persons deficient in cobalamin. Moreover, clinical trials to demonstrate actual health benefits of relevant oral doses have not yet been done in persons with mild subclinical deficiency, who are the only practical targets of cobalamin fortification because >94% of persons with clinically overt cobalamin deficiency have severe malabsorption and therefore cannot respond to normal fortification doses. However, it is only in the severely malabsorptive disorders, such as pernicious anemia, not subclinical deficiency, that neurologic deterioration following folic acid therapy has been described to date. It is still unknown whether mild deficiency states, which usually arise from normal absorption or only food-bound cobalamin malabsorption, have real health consequences or how often they progress to overt clinical cobalamin deficiency. Reports of cognitive or other risks in the common subclinical deficiency state, although worrisome, have been inconsistent. Moreover, their observational nature proved neither causative connections nor documented health benefits. Extensive work, especially randomized clinical trials, must be done before mandatory dietary intervention on a national scale can be justified.

Efficacy and safety of fortification and supplementation with vitamin B12: biochemical and physiological effects.

Long known as an uncommon but serious medical disorder requiring medical management, vitamin B12 deficiency is now seen to be common worldwide, but it is in a quite different form than traditionally envisioned. Most of the newly recognized deficiency is subclinical in nature, its health impact and natural history are uncertain, and its prevalence has been greatly inflated by also including persons with "low-normal" vitamin B12 levels, few of whom are deficient. The spread of folic acid fortification has also introduced concerns about folate's potentially adverse neurologic consequences in persons with undetected vitamin B12 deficiency. Fortification with vitamin B12 may prove more complicated than fortification with folic acid, however, because the bioavailability of vitamin B12 is limited. Bioavailability for those who need the vitamin B12 the most is especially poor, because they often have malabsorption affecting either classical intrinsic factor-mediated absorption or food-vitamin B12 absorption. Moreover, new evidence shows that many elderly persons respond poorly to daily oral doses under 500 microg (1 microg = 0.74 nmol), even if they do not have classical malabsorption, which suggests that proposed fortification with 1 to 10 microg may be ineffective. Those least in need of vitamin B12 usually have normal absorption and are thus at greatest risk for whatever unknown adverse effects of high-dose fortification might emerge, such as the effects of excess accumulation of cyanocobalamin. Studies are needed to define the still unproven health benefits of vitamin B12 fortification, the optimal levels of fortification, the stability of such fortification, interactions with other nutrients, and any possible adverse effects on healthy persons. The answers will permit formulation of appropriately informed decisions about mandatory fortification or (because fortification may prove a poor choice) about targeted supplementation in subpopulations with special needs for additional vitamin B12, such as vegetarians, nursing mothers, and the elderly.

Mild hyperhomocysteinemia in adult patients with sickle cell disease: a common finding unrelated to folate and cobalamin status.

Homocysteine has associations with both vitamin insufficiency and vascular complications, and its status is therefore of interest in sickle cell disease (SCD). However, information is limited, especially in adults. We studied plasma total homocysteine (tHcy) and three of its major modifiers, cobalamin, folate, and creatinine, in 90 adult patients with SCD and 76 control subjects. The patients had higher tHcy levels than did controls (P = 0.03) and had elevated tHcy more often (20% vs. 3%, P = 0.0005). None of the hyperhomocysteinemic patients had low cobalamin or folate levels; on the contrary, patients with SCD had high folate levels more often than control subjects (32% vs. 7%; P < 0.0001). Although serum creatinine values were lower in SCD patients than in control subjects (P = 0.03), high levels also tended to occur more often (8% vs. 1%; P = 0.054). Most importantly, creatinine levels correlated significantly with tHcy (P < 0.0001) and logistic regression analyses showed creatinine to be the only significant predictor of high tHcy levels in SCD (P = 0.01). Our results show that hyperhomocysteinemia affects 20% of adults with SCD despite routine folate supplementation and is independent of folate and cobalamin status. Creatinine was the major identifiable influence on tHcy, but renal insufficiency explained only 4 of the 18 elevated tHcy levels. Longitudinal studies will be needed to determine whether the frequent hyperhomocysteinemia of SCD influences the vascular complications in SCD. If reducing tHcy becomes advisable, then interventions other than folate therapy will be needed.

Update on cobalamin, folate, and homocysteine.

Three topics affecting cobalamin, folate, and homocysteine that have generated interest, activity, and advances in recent years are discussed. These are: (I). the application of an expanded variety of tools to the diagnosis of cobalamin deficiency, and how these affect and are affected by our current understanding of deficiency; (II). the nature of the interaction between homocysteine and vascular disease, and how the relationship is affected by vitamins; and (III). the improved understanding of relevant genetic disorders and common genetic polymorphisms, and how these interact with environmental influences. The diagnostic approach to cobalamin deficiency now allows better diagnosis of difficult and atypical cases and more confident rejection of the diagnosis when deficiency does not exist. However, the process has also become a complex and sometimes vexing undertaking. Part of the difficulty derives from the lack of a diagnostic gold standard among the many available tests, part from the overwhelming numerical preponderance of patients with subclinical deficiency (in which isolated biochemical findings exist without clinical signs or symptoms) among the cobalamin deficiency states, and part from the decreased availability of reliable tests to identify the causes of a patient's cobalamin deficiency and thus a growing deemphasis of that important part of the diagnostic process. In Section I, Dr. Carmel discusses the tests, the diagnostic issues, and possible approaches to the clinical evaluation. It is suggested no single algorithm fits all cases, some of which require more biochemical proof than others, and that differentiating between subclinical and clinical deficiency, despite their overlap, may be a helpful and practical point of departure in the evaluation of patients encountered in clinical practice. The arguments for and against a suggested expansion of the cobalamin reference range are also weighed. The epidemiologic data suggest that homocysteine elevation is a risk factor for vascular and thrombotic disease. In Section II, Dr. Green notes that the interactions of metabolism and clinical risk are not well understood and a causative relationship remains unproven despite new reports that lowering homocysteine levels may reduce vascular complications. Genetic and acquired influences may interact in important ways that are still being sorted out. The use of vitamins, especially folate, often reduces homocysteine levels but also carries potential disadvantages and even risks. Folate fortification of the diet and supplement use have also markedly reduced the frequency of folate deficiency, and cobalamin deficiency is now the more common deficiency state, especially among the elderly. Although genetic disorders are rare, they illuminate important metabolic mechanisms and pose diagnostic challenges, especially when clinical presentation occurs later in life. In Section III, Drs. Rosenblatt and Watkins use selected disorders to illustrate the subject. Imerslund-Gräsbeck syndrome, a hereditary disorder of cobalamin absorption at the ileal level, demonstrates genetic heterogeneity. Finnish patients show mutation of the gene for cubilin, the multiligand receptor for intrinsic factor. Surprisingly, Norwegian and other patients have been found recently to have mutations of the AMN (amnionless) gene, mutations that are lethal in mice at the embryonic stage. Two disorders of cobalamin metabolism, cblG and cblE, are now known to arise from mutations of the methionine synthase and methionine synthase reductase genes, respectively. These disorders feature megaloblastic anemia and neurologic manifestations. The folate disorder selected for illustration, methylenetetrahydrofolate reductase (MTHFR) deficiency, paradoxically causes neurological problems but no megaloblastic anemia. This rare deficiency is the most common inborn error of folate metabolism. It is distinct from the very common MTHFR gene polymorphisms, mutations that cause mild to moderate reductions in MTHFR activity but no direct clinical manifestations. The MTHFR polymTHFR polymorphisms, especially the 677C-->T mutation, may contribute to vascular and birth defect risks, while reducing the risk of certain malignancies, such as colon cancer. These polymorphisms and those of genes for other enzymes and proteins related to cobalamin, folate, and homocysteine metabolism may be important role players in frequent interactions between genes and the environment.