ABSTRACT
Vitamin B12 deficiency presents usually with hematologic, gastrointestinal, neurologic, and less commonly, psychiatric, cardiovascular, and dermatological manifestations. A 20-year-old female presented with palmoplantar hyperpigmentation, accentuated over creases and knuckles. She also had intertriginous, perioral/intraoral hyperpigmentation, and gray, thin, lustreless hair. She consumed nonvegetarian diet occasionally.
Histopathology revealed increased pigmentation of stratum malpighii. Hemoglobin, vitamin B12, and folate levels were reduced; RBC indices, deranged and parietal cell antibodies, weakly reactive. Pernicious anemia was diagnosed; the patient responded to intramuscular cobalamin injections. Review of Indian and global cases/case series of this deficiency with mucocutaneous presentation iterates knuckle hyperpigmentation to be its prime clinical marker. However, the nonvegetarians comprising a majority of participants in case series from India of vitamin B12 deficiency presenting with hyperpigmentation is confounding and necessitates reassessment with larger future studies. Moreover, increased awareness of the mucocutaneous signs—often nonspecific, subtle, or asymptomatic—of this widely pervasive deficiency among Indians may facilitate prompt management and rectify underreporting.
Keywords: Knuckle hyperpigmentation, vitamin B12 deficiency, vegan, mucocutaneous hyperpigmentation
Introduction
Vitamin B12 deficiency has been reported to present with skin (pallor, hyperpigmentation, vitiligo), mucosal (glossitis, angular stomatitis), and hair (dry, brittle, thin, lustreless, prematurely gray) involvement less commonly as compared to hematologic, neurologic, psychiatric, gastrointestinal, and cardiovascular. Knuckle hyperpigmentation is virtually considered surrogate marker. These mucocutaneous signs are often nonspecific, subtle, or asymptomatic, thereby not only resulting in delayed diagnosis perpetuating morbidity eventuating into major health issues[1,2] but also contributing to the paucity of reported cases with mucocutaneous presentations from India. We report one such case—16th from India—and tabulate the 6 case series reported to date from India with a brief review thereof
Case Report
A 20-year-old unmarried female who partook nonvegetarian diet occasionally presented with complaints, since 8 months, of progressive palmoplantar hyperpigmentation accentuated over palmar creases and dorsae of feet/hands, especially over knuckles. Axillae, groins, perioral skin, and intraoral—buccal, sublingual, palatal, and labial—mucosae also revealed patchy hyperpigmentation (Fig. 1). She acknowledged experiencing fatigue, episodic painful oral ulcerations, loose motions, excessive fall of hair, and loss of weight (3 kg) during the preceding 4 months. She denied history of fever, postural hypotension, seizures, polyuria, polydypsia, polyphagia, chronic cough, evening rise in temperature, or any drug intake. Skin, conjunctivae, and nails showed gross pallor. Hair were gray, thin, dry, brittle, and lustreless (Fig. 1).
Hematological parameters and folate/vitamin B12 levels were abnormal (Table 2). Serum ACTH, cortisol, blood sugar, electrolytes, liver/renal function tests, ultrasonography, and stool examination were all normal. Parietal cell antibody was weakly positive. Skin (left toe) histopathology revealed increased pigmentation in stratum spinosum and basale (Fig. 2). Upper gastrointestinal (GI) endoscopy revealed atrophic gastric mucosa with scalloped duodenal folds. Bone marrow aspirate had erythroid hyperplasia of dimorphic pattern, predominantly megaloblastic. Diagnosed as a case of pernicious anemia, the patient was administered 1 ml, containing 2500 mcg, vitamin B12, and 0.7 mg folate intramuscular injections—initial 5, alternate days, subsequent 5 days, weekly, and thereafter, monthly— supplemented with daily oral iron and multivitamins. Follow-up after 1 month revealed appreciable regression of physical symptoms and after 9 months, freedom from oral ulcers and loose motions, weight gain of 3 kg, and near normal pigmentation, hair (Fig. 3) as well as hematological profile, and vitamin levels (Table 2).
Discussion
Vitamin B12 is sourced from meat, poultry, and dairy products as it lacks endogenous synthesis.[1] Its approximate daily requirement, as well as loss (mainly in urine/feces) of 1–3 μg in adults constitutes∼0.1% of body stores. Hence, even if supplies are completely cut off, body stores (2–3 mg) would suffice for 3 to 4 years. Dietary cobalamin gets bound to salivary haptocorrin and on digestion by trypsin in the duodenum gets free to bind to the intrinsic factor. Within the enterocytes of the terminal ileum, the intrinsic factor gets destroyed and cobalamin transported by transcobalamin into the portal circulation is taken up by the liver—mainly bound to haptocorrin, a smaller percentage to transcobalamin II with a negligent amount circulating as free cobalamin.[3]
Globally, the prevalence of vitamin B12 deficiency increases with age, being around 6% in people aged <60 years, and closer to 20% in those >60 years in United Kingdom and the United States. The estimate of this deficiency among adults across Latin America is∼40% and as high as 70% in India.[4]
Prevalence of vitamin B12 deficiency is considered higher in vegans and vegetarians.[4] However, majority of the participants in three out of the six case series from India (North Bengal, Maharashtra, and Puducherry) as also our patient consumed nonvegetarian diet (Table 1).
Autoimmune destruction of parietal cells as in pernicious anemia causes deficiency of intrinsic factor decreasing absorption of cobalamin. Malabsorption can also result from gastrectomy, ileal resection, pancreatic insufficiency, diseases such as celiac/Crohn, and long-term intake of proton pump inhibitors, H2 receptor antagonists,biguanides, and so on.[1] The likely etiology in our patient appears to be dietary insufficiency with concurrent presence of parietal cell antibodies.
Vitamin B12 deficiency may commonly present with megaloblastic anemia, anorexia, weight loss, fatigue, orthostatic hypotension, paraesthesias, and subacute combined degeneration of spinal cord.[1,5] Less commonly, mucocutaneous presentations, usually Addisonian-like hyperpigmentation over knuckles, palms/soles—diffuse/ symmetric, or few scattered macules can occur. Pallor, glossitis, gray hair, and localized/diffuse depigmentation can also occur. Glossitis can initially be linear and cause red, painful tongue with atrophy of the filiform papillae (Hunter glossitis).[6] Occasionally, B12 deficiency has been implicated as a cause of myocardial infarction, stroke, retinal hemorrhages, mood disorders, dementia, psychosis, and depression.[1]
Three hypotheses proposed regarding pathophysiology of B12 deficiency-induced hyperpigmentation are first, decrease in reduced form of glutathione increasing the activity of tyrosinase; second, defective melanin transfer between melanocytes and keratinocytes; and finally, disturbed melanin distribution due to megaloblastic changes in the keratinocytes.[7] As this hyperpigmentation often resembles that seen in Addison disease, hypocortisolemia should be ruled out.[8] The usual improvement of mucocutaneous findings within weeks with complete resolution in a few months following correction of this deficiency motivates patients’ compliance to maintain adequate dietary/pharmacologic intake.[6] Our patient remains asymptomatic and on oral supplementation.
Conclusion
The surprising rarity of reported cases of vitamin B12 deficiency among Indians, despite its purported wide prevalence, is not only indicative of the difficulty to decipher its initial—often trivial, asymptomatic, or even nonspecific—signs and symptoms but also suggests possible lack of awareness. Hence, increased index of suspicion of cutaneous clues, most characteristically of the virtually surrogate knuckle hyperpigmentation, may help early diagnosis and prompt management of such cases, thereby decreasing preventable morbidity. Well- designed, larger, multicentric, clinico-epidemiologic, and etiological studies are necessary, especially regarding the dietary aspects.
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