Vitamin B12 is one of the most common vitamin deficiencies, yet there is no consensus for a cut-off point for cobalamin or for folate, holotranscobalamin, methylmalonic acid, and homocysteine. A recent review article showed that serum cut-off points for deficiency in journal articles widely ranged: for cobalamin 100–350 pmol/L, holotranscobalamin 20–50 pmol/L, methylmalonic acid 0.210–0.470 lmol/L, homocysteine 10–21.6 lmol/L, and folate 3.7–15.9 nmol/L. Additionally, cobalamin pseudo-deficiency (low cobalamin serum levels but no true deficiency) can rarely be caused by a transcobalamin deficiency. In this case, determining levels of methylmalonic acid and homocysteine would reveal this pseudodeficiency, and treatment with cobalamin therapy would be unnecessary. Another way to test for cobalamin deficiency is by measuring methylmalonic acid in the urine, which has been shown to be a reliable laboratory marker in newborns.
Findings of decreased serum cobalamin, elevated methylmalonic acid or elevated homocysteine can be used to make a diagnosis of vitamin B12 deficiency (Fig. 2). One study of 406 patients with known vitamin B12 deficiency showed that 98.4 % of patients had elevated serum methylmalonic acid levels and 95.9 % had elevated serum homocysteine levels (defined as three standard deviations above the mean). When both methylmalonic acid and homocysteine levels are used for diagnosis, there is a sensitivity of 99.8 %. In this study, 28 % of the patients had normal hematocrit levels and 17 % had normal mean corpuscular volumes, thus hematological manifestations of the cobalamin deficiency were not yet observed. When evaluating laboratory values, one must also consider that folate deficiency can elevate homocysteine and falsely lower serum vitamin B12 levels. Additionally, renal disease can elevate methylmalonic acid.
Cobalamin is a co-factor for the enzymes homocysteine methyltransferase and methylmalonyl-CoA mutase. This facilitates the conversion of homocysteine, folic acid, and methylmalonyl-CoA to methionine and succinyl-CoA. CoA coenzyme A
The prevalence of cobalamin deficiency is difficult to assess since under-diagnosis is likely and subclinical disease is considered common. Cobalamin deficiency is rarely due to inadequate intake, although it can occasionally be seen in strict veganism. It is typically a result of malabsorption (from sprue, enteritis, or infection with Diphyllobothrium latum), pernicious anemia (with a decrease in gastric intrinsic factor), surgical resection of the terminal ileum (often with Crohn's disease), or overgrowth of intestinal bacteria. It can also be seen in infants from a mother with vitamin B12 deficiency, which can lead to failure to thrive and other developmental problems. A very common cause of cobalamin deficiency is the widespread use of gastric acid-blocking agents, especially in the aging population.
The normal variation in cobalamin and folate levels has been tied to various genetic loci in different populations. The gene products are involved in the pathways of cobalamin uptake and metabolism. Genetic defects in the intracellular processing of cobalamin have been classified into nine complementation groups. These mutations result in methylmalonic aciduria, homocystinuria, or a combination of the two, with devastating results. Currently, there is widespread newborn screening for homocysteine and methylmalonate, highlighting the importance of identifying and treating these patients early. The most recently described mutation involves the adenosine triphosphate (ATP)-binding cassette transporter ABCD4, which is involved in the release of cobalamin from lysosomes into the cytoplasm. While the other mutations result in severe phenotypes with little appreciable skin findings, this mutation has been reported to produce a phenotype of skin pigmentation. In one case, a 14-year-old boy presented with hyperpigmentation alongside neurologic abnormalities, while another case demonstrated diffuse progressive skin pigmentation in the absence of neurological or cardiovascular complications in a 12-year-old girl.
A very rare cause of cobalamin deficiency is the recreational abuse of nitric oxide gas. In one case report, a patient presented with skin hyperpigmentation after abusing nitrous oxide for 2 years, and was found to also have myeloneuropathy of the posterior and lateral columns, a low serum vitamin B12 level, and an elevated serum homocysteine level.
Extracutaneous clinical manifestations of cobalamin deficiency vary widely. Hematological manifestations include megaloblastic macrocytic anemia with hypersegmented polymorphonuclear cells and pancytopenia. Neurological findings may include paresthesias, peripheral neuropathy, and combined systems disease with demyelination of dorsal columns and corticospinal tract. Psychiatric changes include irritability, personality change, mild memory impairment, dementia, depression, and psychosis. There have been numerous reports of cobalamin deficiency presenting with delusions of parasitosis, so an evaluation of the serum cobalamin and folate should be considered. Other manifestations include a possible increased risk of myocardial infarction and stroke as well as infertility. Some of these manifestations can be attributed to the elevated levels of homocysteine and methylmalonic acid seen with cobalamin deficiency.
Am J Clin Dermatol. 2015;16(1):27-33. © 2015 Adis Springer International Publishing AG