Sultan Qaboos University Med J, August 2015, Vol. 15, Iss. 3, pp. e420–423, Epub. 24 Aug 15. doi: 10.18295/squmj.2015.15.03.019. Submitted 29 Dec 14 Revision Req. 9 Mar 15; Revision Recd. 10 Mar 15 Accepted 30 Mar 15 Vitamin B12 deficiency is common among individuals in developing countries.1 Its prevalence is often underestimated as it is believed to occur only in strict vegetarians and patients with pernicious anaemia.1 However, vitamin B12 deficiency should be suspected in all patients with unexplained anaemia or neurological symptoms.2 Various dermatological manifestations associated with B12 deficiency are skin hyper- or hypopigmentation, angular stomatitis and hair changes.3 Hyperpigmentation as the primary presenting symptom of B12 deficiency is rarely reported in the literature.4 The case reported below describes a 28-year-old Omani man who presented with brownish-black hyperpigmentation on both hands, which proved to be due to a B12 deficiency caused by chronic atrophic gastritis. Case Report A 28-year-old Omani male presented to Sultan Qaboos University Hospital (SQUH) in Muscat, Oman, in November 2013 with hyperpigmentation of both hands. Two months later he developed severe numbness in both hands to the extent that he could no 1Department of Family Medicine & Public Health, Sultan Qaboos University Hospital; 2Department of Pathology, College of Medicine & Health Sciences, Sultan Qaboos University, Muscat, Oman; 3Department of Family Medicine, Oman Medical College, Sohar, Oman *Corresponding Author e-mail: nafisa77@squ.edu.om تغيري موضعي لصبغة اجللد إىل اللون الداكن نتيجة لنقص فيتامني ب12 بسبب التهاب مزمن باملعدة كوثر الشافعي، نفي�سه سمري، ريتو لكتاكيا، روبن ديفد�سون، اأحمد الوائلي، منى املعمرية، حممد ال�سافعي abstract: 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. Keywords: Vitamin B12 Deficiency; Hyperpigmentation; Atrophic Gastritis; Case Report; Oman. أو ال�سبب جمهول الدم فقر من يعانون الذين املر�سى عند به ال�ستباه وينبغي النامية البلدان يف �سائع ب12 فيتامني نق�س امللخ�ص: أعرا�س ترتبط باجلهاز الع�سبي. املظاهر اجللدية املرتبطة بهذا النق�س ت�سمل زيادة اأو نق�سان �سبغة اجللد، التهاب جوانب الفم وتغيري يف ال�سعر. نعر�س حالة لرجل يبلغ 28 �سنة قدم إىل م�ست�سفى جامعة ال�سلطان قابو�س يف نوفمرب 2013 وهو ي�سكو من زيادة �سبغة اجللد يف راحة وظهر يديه ملدة �سهرين. كما كان ي�سكو من خدر يف اليدين، فقدان ال�سهية و الوزن، الدوخة، إعياء واأمل بالفم والل�سان، وك�سف الفح�س اأنه ل يوجد لدى هذا املري�س نق�س يف الكورتيزون ولكن البحث يف الأدبيات الطبية ك�سف احتمال نق�س فيتامني ب12. واأثبتت نتيجة الفح�س نق�س هذا الفيتامني و فقر الدم �سخم اخلاليا عند املري�س. ومل يكن لديه نق�س يف العامل امل�ساعد على امت�سا�س فيتامني ب12. كما اأثبت فح�س خزعة املعدة التهاب مزمن باملعدة. اختفت كل اأعرا�س املري�س بعد اإعطائه فيتامني ب12. لذلك نن�سح باأن يتعرف اأطباء الأ�رسة على الأعرا�س النادرة لنق�س فيتامني ب12. الكثري من اأعرا�س نق�سان فيتامني ب12 قابلة للرتاجع إذا �سخ�س هذا النق�س وعولج مبكرا. مفتاح الكلمات: نق�س فيتامني ب12؛ زيادة �سبغة اجللد؛ التهاب املعدة ال�سموري؛ تقرير حالة؛ عمان. Localised Skin Hyperpigmentation as a Presenting Symptom of Vitamin B 12 Deficiency Complicating Chronic Atrophic Gastritis Kawther El-Shafie,1 *Nafisa Samir,1 Ritu Lakhtakia,2 Robin Davidson,1 Ahmed Al-Waili,1 Muna Al-Mamary,1 Mohammed Al-Shafee3 online case report Kawther El-Shafie, Nafisa Samir, Ritu Lakhtakia, Robin Davidson, Ahmed Al-Waili, Muna Al-Mamary and Mohammed Al-Shafee Online Case Report | e421 longer carry objects. On further enquiry, he reported symptoms of glossitis and angular stomatitis for the preceding two weeks. He had lost 10 kg within one month (with an initial weight of 86 kg) and was experiencing anorexia, feelings of excessive fatigability and dizziness. His past medical, medication and dietary history was unremarkable. There was no previous history of fever, epigastric pain, diarrhoea, steatorrhea, diabetes mellitus, tuberculosis or use of any over-the-counter medications. A clinical examination revealed a diffuse brownish- black 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 B12 and folate levels were subsequently assessed; his B12 level was found to be significantly low [Table 1]. As B12 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 Figure 1A–D: Diffuse brownish-black hyperpigmen- tation on the (A) dorsal and (B) palmar aspects of both hands at presentation. Improved (C) dorsal and (D) palmar hyperpigmentation was noted after vitamin B12 supplementation. Figure 2A & B: May-Grünwald-Giemsa stain at x40 magnification showing blood cell morphology (A) before and (B) after treatment with vitamin B12. Table 1: Summary of haematological, biochemical and other investigation results for the current patient with localised skin hyperpigmentation Investigation Value Normal range Haemoglobin 12.2 g/dL 11.5–15.5 g/dL Mean corpuscular volume 115 fL ↑↑ 78–96 fL Red cell distribution width 17.2% ↑ 11.5–16.5% C-reactive protein 2 mg/L 0–8 mg/L Vitamin B12 75 pmol/L ↓↓ 133–675 pmol/L Folate 20.4 mmol/L 7.0–45.1 mmol/L Cortisol at 10 am 422 nmol/L 185–624 nmol/L Adrenocorticotropic hormone at 8 am 98 ug/L 24–336 ug/L Homocysteine plasma 36 µmol/L ↑↑ <15 µmol/L Methylmalonic acid 3.4 µmol/L ↑↑ <0.5 µmol/L Anti-deamidated gliadin antibody 1gA and immunoglobulin G 1 µ/mL 0–25 µ/mL Transglutaminase antibody immunoglobulin A 1 µ/mL 0–20 µ/mL Human immunodeficiency virus serology Negative Negative Localised 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 In addition, malabsorption of B12 has been associated with long-term (>4 years) use of histamine type 2 receptor antagonists and proton-pump inhibitors.5 Of these potential causes of B12 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 IFA- positive and IFA-negative gastritis.6 These 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.6 In the current patient, the associated Candida infection at the lower part of the oesophagus may also be explained by a B12 deficiency, as vitamin B group deficiencies have been reported as one of the causes for a Candida albicans infection.7 Pigmentation in B12 deficiency can also masque- rade as pigmentation due to Addison’s disease.4,8‒12 There are few reported cases of vitamin B12 deficiency in which mucocutaneous lesions predate other manifestations.4,8‒12 In these cases, the skin changes were characterised by Addisonian brownish-black hyperpigmentation which affected more than one area of the body, including sun-exposed sites, such as the palmar and dorsal aspects of the hands and feet and the knuckles, flexures, tongue, oral mucosa, palmar creases, nails and gluteal region.4,8‒12 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 B12 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.3 From the current case, it is obvious that skin signs and symptoms, specifically hyperpigmentation, can precede the typical neurological signs and symptoms of B12 deficiency. Mori et al. proposed that skin hyperpigmentation can be an important clue in diagnosing B12 deficiency and that dermatologists need to be familiar with the clinical appearance of this disorder.10 The mechanism of hyperpigmentation is not well understood. It has been suggested that the lack of B12 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 intramus- cular B12 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 B12 [Figure 1C & D]. Written informed consent was obtained from the patient for publication of this case report and the accompanying images. Discussion Vitamin B12 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 B12 levels with treatment. The most common causes of B12 deficiency are either a strict vegetarian diet or malabsorption of B12 due to inadequate gastric production or defective functioning of IFA.1,2 Other 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 immunodefi- ciency virus, Diphyllobothrium infestation, giardiasis and medications such as metformin and colchicine.1,2 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. Kawther El-Shafie, Nafisa Samir, Ritu Lakhtakia, Robin Davidson, Ahmed Al-Waili, Muna Al-Mamary and Mohammed Al-Shafee Online Case Report | e423 that the dominant mechanism of hyperpigmentation due to B12 deficiency is not a defect in melanin transport but rather an increase in melanin synthesis.10 Conclusion B12 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 B12 supplementation. It is essential for family physicians to familiarise themselves with atypical presentations of B12 deficiency, as early detection and adequate treatment of the condition can prevent neurological complications. References 1. Allen LH. How common is vitamin B-12 deficiency. Am J Clin Nutr 2009; 89:693S‒6S. doi: 10.3945/ajcn.2008.26947A. 2. Hvas AM, Nexo E. Diagnosis and treatment of vitamin B12 deficiency: An update. Haematologica 2006; 91:1506–12. 3. Kannan R, Ng MJ. Cutaneous lesions and vitamin B12 deficiency: An often-forgotten link. Can Fam Physician 2008; 54:529–32. 4. Jithendriya M, Kumaran S, P IB. Addisonian pigmentation and vitamin B12 deficiency: A case series and review of the literature. Cutis 2013; 92:94–9. 5. Allen LH. Causes of vitamin B12 and folate deficiency. Food Nutr Bull 2008; 29:S20–34. 6. Amarapurkar DN, Amarapurkar AD. Intrinsic factor antibody negative atrophic gastritis: Is it different from pernicious anaemia? Trop Gastroenterol 2010; 31:266–70. 7. Akpan A, Morgan R. Oral candidiasis. Postgrad Med J 2002; 78:455–9. doi: 10.1136/pmj.78.922.455. 8. Agrawala RK, Sahoo SK, Choudhury AK, Mohanty BK, Baliarsinha AK. Pigmentation in vitamin B12 deficiency masquerading Addison’s pigmentation: A rare presentation. Indian J Endocrinol Metab 2013; 17:S254–6. doi: 10.4103/2230- 8210.119591. 9. Hoffman CF, Palmer DM, Papadopoulos D. Vitamin B12 defi- ciency: A case report of ongoing cutaneous hyperpigmentation. Cutis 2003; 71:127–30. 10. Mori K, Ando I, Kukita A. Generalized hyperpigmentation of the skin due to vitamin B12 deficiency. J Dermatol 200l; 28:282–5. doi: 10.1111/j.1346-8138.2001.tb00134.x. 11. Cherqaoui R, Husain M, Madduri S, Okolie P, Nunlee-Bland G, Williams J. A reversible cause of skin hyperpigmentation and postural hypotension. Case Rep Hematol 2013; 2013:680459. doi: 10.1155/2013/680459. 12. Srivastava N, Chand S, Bansal M, Srivastava K, Singh S. Reversible hyperpigmentation as the first manifestation of dietary vitamin B12 deficiency. Indian J Dermatol Venereol Leprol 2006; 72:389–90. doi: 10.4103/0378-6323.27766. 13. Niiyama S, Mukai H. Reversible cutaneous hyperpigmentation and nails with white hair due to vitamin B12 deficiency. Eur J Dermatol 2007; 17:551–2. doi: 10.1684/ejd.2007.0285. http://dx.doi.org/10.3945/ajcn.2008.26947A http://dx.doi.org/10.1136/pmj.78.922.455 http://dx.doi.org/10.4103/2230-8210.119591 http://dx.doi.org/10.4103/2230-8210.119591 http://dx.doi.org/10.1111/j.1346-8138.2001.tb00134.x http://dx.doi.org/10.1155/2013/680459 http://dx.doi.org/10.4103/0378-6323.27766 http://dx.doi.org/10.1684/ejd.2007.0285