Localised Skin Hyperpigmentation as a Presenting Symptom of Vitamin B 12 Deficiency Complicating Chronic Atrophic Gastritis

Vitamin B12 deficiency is common in developing countries and should be suspected in patients with unexplained anaemia or neurological symptoms. Dermatological manifestations associated with this deficiency include skin hyper- or hypopigmentation, angular stomatitis and hair changes. We report a case of a 28-year-old man who presented to the Sultan Qaboos University Hospital in Muscat, Oman, in November 2013 with localised hyperpigmentation of the palmar and dorsal aspects of both hands of two months' duration. Other symptoms included numbness of the hands, anorexia, weight loss, dizziness, fatigability and a sore mouth and tongue. There was no evidence of hypocortisolaemia and a literature search revealed a possible B12 deficiency. The patient had low serum B12 levels and megaloblastic anaemia. An intrinsic factor antibody test was negative. A gastric biopsy revealed chronic gastritis. After B12 supplementation, the patient's symptoms resolved. Family physicians should familiarise themselves with atypical presentations of B12 deficiency. Many symptoms of this deficiency are reversible if detected and treated early.

A clinical examination revealed a diffuse brownishblack discolouration on both the palmar and dorsal aspects of both hands which was more pronounced at the distal and proximal interphalangeal joints [Figure 1A & B].There was ulceration on both sides of the tongue with angular stomatitis.No abnormal pigmentation was found on any other site of the skin or on the buccal mucosa.On neurological examination, the patient was unable to feel a 10 g monofilament on either hand; however, he could feel vibration on the hands and his proprioception was intact.The patient had brisk reflexes in the upper limbs but diminished reflexes in the lower limbs.The plantar reflexes were equivocal and Romberg's test results were negative.The rest of the physical examination was normal.Serum cortisol and adrenocorticotropic hormone levels were normal, ruling out Addison's disease.A complete blood count showed macrocytosis with megaloblastic features, although his haemoglobin level was normal [Figure 2].
The patient's B 12 and folate levels were subsequently assessed; his B 12 level was found to be significantly low [Table 1].As B 12 plays a pivotal role in many metabolic pathways, further metabolic work-up showed high levels of both methylmalonic acid and homocystiene.Multiple biopsies from an endoscopy were consistent with a fungal infection at the lower end of the oesophagus and chronic gastritis including focal intestinal metaplasia without any evidence of   In addition, malabsorption of B 12 has been associated with long-term (>4 years) use of histamine type 2 receptor antagonists and proton-pump inhibitors. 5f these potential causes of B 12 deficiency, the only one applicable to this patient was the possibility of inadequate IFA production by the stomach due to histologically-proven chronic atrophic gastritis.
Amarapurkar et al. reported that there was no statistically significant difference in haematological, biochemical and histological parameters in IFApositive and IFA-negative gastritis. 6These may be part of the spectrum for the same disease, with H. pylori as the agent responsible for initiating the process.It has been reported that patients who are IFA-negative are classified as chronic atrophic gastritis cases. 6In the current patient, the associated Candida infection at the lower part of the oesophagus may also be explained by a B 12 deficiency, as vitamin B group deficiencies have been reported as one of the causes for a Candida albicans infection. 7][10][11][12] The pigmentation observed in the current patient differs from these reported cases in that it was localised only to the hands, which may possibly be due to an early diagnosis of the condition.Kannan et al. described a similar case of B 12 deficiency where the patient presented over a short period of time (1.5 months) with localised hyperpigmented macular lesions on the dorsum of the middle phalanges of both feet. 3rom the current case, it is obvious that skin signs and symptoms, specifically hyperpigmentation, can precede the typical neurological signs and symptoms of B 12 deficiency.Mori et al. proposed that skin hyperpigmentation can be an important clue in diagnosing B 12 deficiency and that dermatologists need to be familiar with the clinical appearance of this disorder. 10The mechanism of hyperpigmentation is not well understood.It has been suggested that the lack of B 12 causes depletion in intracellular glutathione levels which normally inhibit tyrosinase activity in melanogenesis; the lack of this inhibitor would lead to an increase in melanogenesis. 13 Mori et al. reported   Helicobacter pylori [Figure 3].The duodenal biopsy also revealed mild chronic inflammation and focal villous blunting.An autoimmune work-up was negative, including antiparietal cell, intrinsic factor antibody (IFA), transglutaminase and anti-gliadin antibody tests.A skin biopsy of the hyperpigmented lesions showed dermal vessels with mild lymphocytic cuffing and ectatic capillaries.
The patient was prescribed 1,000 µg of intramuscular B 12 every day for one week, followed by the same dose once a week for four weeks and then once a month for two months.Following the treatment, the patient underwent remarkable symptomatic improvement.His skin pigmentation completely normalised within eight weeks of treatment with B 12 [Figure 1C & D].
Written informed consent was obtained from the patient for publication of this case report and the accompanying images.

Discussion
Vitamin B 12 deficiency was considered to be the cause of localised hyperpigmentation in the reported patient, due to the fact that the hyperpigmentation disappeared following the normalisation of serum B 12 levels with treatment.The most common causes of B 12 deficiency are either a strict vegetarian diet or malabsorption of B 12 due to inadequate gastric production or defective functioning of IFA. 1,2Other causes include a gastrectomy, surgical resection of the terminal ileum, bacterial overgrowth of the small intestine, diverticulitis, coeliac disease, Crohn's disease, chronic alcoholism, human immunodeficiency virus, Diphyllobothrium infestation, giardiasis and medications such as metformin and colchicine.that the dominant mechanism of hyperpigmentation due to B 12 deficiency is not a defect in melanin transport but rather an increase in melanin synthesis. 10

Conclusion
B 12 deficiency should be considered as an underlying cause of unexplained hyperpigmentation.In the current case, a patient presented with localised hyperpigmentation of the palmar and dorsal aspects of both hands which resolved rapidly after B 12 supplementation.It is essential for family physicians to familiarise themselves with atypical presentations of B 12 deficiency, as early detection and adequate treatment of the condition can prevent neurological complications.

Figure
Figure 1A-D: Diffuse brownish-black hyperpigmentation on the (A) dorsal and (B) palmar aspects of both hands at presentation.Improved (C) dorsal and (D) palmar hyperpigmentation was noted after vitamin B 12 supplementation.

Figure 2A &
Figure 2A & B: May-Grünwald-Giemsa stain at x40 magnification showing blood cell morphology (A) before and (B) after treatment with vitamin B 12 .

Figure 3 :
Figure 3: Haematoxylin and eosin stain of a gastric biopsy sample from the antrum showing crypt disarray and moderate chronic inflammation of the lamina propria with foci of intestinal metaplasia (arrow) at x100 magnification.Inset: Periodic acid-Schiff-alcian blue stain showing foci of intestinal metaplasia with alcianophilic mucinous cells at x400 magnification.

Table 1 :
Summary of haematological, biochemical and other investigation results for the current patient with localised skin hyperpigmentationLocalised Skin Hyperpigmentation as a Presenting Symptom of Vitamin B 12 Deficiency Complicating Chronic Atrophic Gastritis e422 | SQU Medical Journal, August 2015, Volume 15, Issue 3 1,2