CED
Clinical dermatology • Concise report
Clinical and Experimental Dermatology
Pernicious anaemia presenting as hyperpigmentation W. Y. Tham,1 C. C. Oh2 and H. Y. Koh2 Departments of 1Internal Medicine and 2Dermatology, Singapore General Hospital, Singapore, Singapore doi:10.1111/ced.12600
Summary
An adult East Asian woman presented macules on her oral mucosal surfaces, hypoguesia and loss of weight. This was severe vitamin B12 deficiency secondary to
Vitamin B12 deficiency should be considered as a differential diagnosis in a patient who presents with hyperpigmentation. The required investigations and the other possible causes of acquired hyperpigmentation in an adult will also be discussed briefly.
Report A 51-year-old Chinese woman presented with a 4-month history of pigmentation on her oral mucosa, palms and soles. This was associated with unintentional weight loss of 20 kg and development of hypoguesia in the past 4 months. She also had numbness of her hands but not her feet. Her bowel function was normal. She had a history of hyperthyroidism (had previously been taking carbimazole, and was now on thyroxine replacement) and hypertension, which had been controlled on enalapril since 2006. She denied taking any health supplements, and was not on a restricted or vegetarian diet. On examination, multiple hyperpigmented macules of different shades of black and grey were seen on the patient’s oral mucosa, palms and soles (Fig. 1a). Enalapril was changed to losartan and amlodipine, but the hyperpigmentation persisted. In view of the increased pigmentation and unexplained weight loss, the patient was investigated for Addison disease, but both her renal panel and synacthen tests were normal. Her thyroid function tests Correspondence: Dr Oh Choon Chiat, Department of Dermatology, 20 College Road, Academia, Singapore 169856, Singapore E-mail: [email protected] Conflict of interest: the authors declare that they have no conflicts of interest. Accepted for publication 9 September 2014
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Clinical and Experimental Dermatology (2015) 40, pp626–628
with sudden onset of hyperpigmented palms and soles, in association with found to be associated with underlying pernicious anaemia.
were also normal. Fasting blood glucose was 4.5 mmol/L (normal range 3.9–6.0 mmol/L). Tumour markers including carcinoembryonic antigen, CA19–9, CA125 and a-fetoprotein were unremarkable. VDRL (Veneral Disease Reference Laboratory) tests for sexually transmitted disease were negative. Complete blood count revealed macrocytosis (mean cell volume 109.6 fL; normal range 78–98 fL), which was associated with a low serum vitamin B12 level of < 37 pmol/L (normal range 145–637 pmol/L). Peripheral blood film showed mainly normocytic red blood cells with slight macrocytosis; white blood cells and platelets were otherwise normal. Tests for antiparietal cell and anti-intrinsic factor antibodies were positive. Oesophagogastroduodenoscopy and colonoscopy detected gastritis at the antrum and fundus. Biopsy of a gastric polyp showed hyperplastic regenerative changes and intestinal metaplasia, while biopsy of a hyperpigmented macule on the patient’s sole showed features of an intradermal naevus. A diagnosis of vitamin B12 deficiency secondary to pernicious anaemia was made. The patient was started on intramuscular cyanocobalamin injections three times per week for 1 week, followed by once a week for a month. She would subsequently receive monthly cyanocobalamin injections, which are expected to be lifelong. A review at 2 months showed that the patient had regained her taste and put on 5 kg in weight, and her hyperpigmentation had started to resolve (Fig. 1b). The numbness in her hands also started to improve. In evaluating a patient presenting with unexplained focal hyperpigmentation involving the palms, soles and oral mucosa, investigation should focus on
ª 2015 British Association of Dermatologists
Pernicious anaemia presenting as hyperpigmentation W. Y. Tham et al.
(a)
(b)
Figure 1 (a) Hyperpigmentation before treatment; (b) improvement of pigmentation after treatment.
presence of medication history, any family history of inheritable disorders and a systemic review of symptoms for conditions beyond the skin. Physical examination should be directed towards the distribution of the lesions, blood pressure, and signs of thyroid disease or hypocortisolism. The differential diagnoses for this pattern of hyperpigmentation can be divided into inherited and acquired causes. The inherited causes that should be considered include Peutz–Jeghe and Laugie–Hunziker syndromes. The former was unlikely in this case, given the age of presentation and the absence of family history. Although Laugier–Hunziker syndrome is a differential diagnosis that should be considered, the patient had associated loss of weight and hypoguesia, therefore other causes of hyperpigmentation had to be excluded. Systemic diseases known to be associated with similar hyperpigmentation include endocrinological disorders, especially Addison disease. These should be excluded by reviewing the relevant symptoms in the patient’s history and by appropriate investigations, including thyroid function tests, fasting glucose levels, and adrenocorticotropic hormone stimulation (synacthen) tests. These results were within normal limits in our case. However, this patient was found to have severe vitamin B12 deficiency. Vitamin B12 deficiency more
ª 2015 British Association of Dermatologists
commonly presents with macrocytic anaemia, neurological symptoms and other gastrointestinal symptoms such as glossitis. However, there have been reports since the 1900s of hyperpigmentation associated with vitamin B12 deficiency.1–5 The first documented association between pernicious anaemia and hyperpigmentation was by Aitken in 1909.6 Common sites of hyperpigmentation include the palmar and plantar surfaces, intertriginous areas, oral mucosa, and regions exposed to pressure, such as the elbows and knees, the extensor surfaces of finger and toe joints, and new scars.7 There are several hypotheses about how vitamin B12 deficiency results in hyperpigmentation. The most commonly accepted theory is that vitamin B12 deficiency causes a depletion in intracellular-reduced glutathione, resulting in an increase in tyrosinase, which subsequently leads to the stimulation of melanocytes to secrete melanin.8 Another hypothesis is that there is a deficit in the transfer of melanin from the melanocytes to the keratinocytes, resulting in pigment incontinence. However, in their case of vitamin B12 deficiency with hyperpigmentation, Mori et al.9 did not observe a defect of melanin transfer under electron microscopy. The hyperpigmentation improves within weeks following correction of the deficiency, with complete resolution in a few months, as noted in other case reports.3–5 A study conducted by Demir et al.7 on 57
Clinical and Experimental Dermatology (2015) 40, pp626–628
627
Pernicious anaemia presenting as hyperpigmentation W. Y. Tham et al.
children found that there was complete resolution in 86.66% of patients after 3 months of treatment for vitamin B12 deficiency. The response to treatment is said to be related to the duration of symptoms. Causes of vitamin B12 deficiency can be due to problems anywhere along the absorption pathway. This can be due to decreased intake such as with a vegetarian diet, or as a consequence of decreased acid production in the gut due to medication or postgastrectomy. Other possible causes include pernicious anaemia such as in our patient, ileal disease such as Crohn disease, or malabsorption seen in blind loop syndrome or coeliac disease, among others. The cutaneous manifestations of vitamin B12 deficiency that have been described also include vitiligo, stomatitis and hair changes. In summary, vitamin B12 deficiency should be considered as a differential diagnosis in the evaluation of a patient who presents with hyperpigmentation. If vitamin B12 deficiency is present, the underlying cause for this problem needs to be investigated, and the patient should receive appropriate treatment.
Learning points Vitamin B12 levels should be checked in a
patient presenting with focal hyperpigmentation. The underlying cause for vitamin B12 defi-
ciency needs to be investigated and managed accordingly.
628
Clinical and Experimental Dermatology (2015) 40, pp626–628
In most cases, there is resolution of the hyper-
pigmentation with correction of the vitamin B12 deficiency.
References 1 Cook BA. A vitamin B12 deficiency syndrome allied to sprue. Indian Med Gaz 1944; 79: 429–37. 2 Baker SJ, Johnson S, Ignatius H et al. Hyperpigmentation of the skin: a sign of vitamin B12 deficiency. Br Med J 1963; 1: 1713–15. 3 Agrawala RK, Sahoo SK, Choudhury AK, Mohanty BK, Baliarsinha AK. Pigmentation in vitamin B12 deficiency masquerading Addison’s pigmentation: a rare presentation. Indian J Endocr Metab 2013; 17: S254–6. 4 Kannan R, Ng MJM. Cutaneous lesions and vitamin B12 deficiency. Can Fam Physician 2008; 54: 529–32. 5 Hoffman CF, Palmer DM, Papadopoulos D. Vitamin B12 deficiency: a case report of ongoing cutaneous hyperpigmentation. Cutis 2003; 71: 127–30. 6 Aitken J. Pernicious anaemia with pigmentation of the skin and buccal mucous membrane. Br Med J 1909; 1: 1349–51. 7 Demir N, Dogan M, Koc H et al. Dermatological findings of vitamin B12 deficiency and resolving time of these symptoms. Cutan Ocul Toxico. 2014; 33: 70–3. 8 Lee SH, Lee WS, Whang KC et al. Hyperpigmentation in megaloblastic anaemia. Int J Dermatol 1988; 27: 571–5. 9 Mori K, Ando I, Kukita A. Generalized hyperpigmentation of the skin due to vitamin B12 deficiency. J Dermatol 2001; 28: 282–5.
ª 2015 British Association of Dermatologists
Clinical dermatology • Concise report
Clinical and Experimental Dermatology
Pernicious anaemia presenting as hyperpigmentation W. Y. Tham,1 C. C. Oh2 and H. Y. Koh2 Departments of 1Internal Medicine and 2Dermatology, Singapore General Hospital, Singapore, Singapore doi:10.1111/ced.12600
Summary
An adult East Asian woman presented macules on her oral mucosal surfaces, hypoguesia and loss of weight. This was severe vitamin B12 deficiency secondary to
Vitamin B12 deficiency should be considered as a differential diagnosis in a patient who presents with hyperpigmentation. The required investigations and the other possible causes of acquired hyperpigmentation in an adult will also be discussed briefly.
Report A 51-year-old Chinese woman presented with a 4-month history of pigmentation on her oral mucosa, palms and soles. This was associated with unintentional weight loss of 20 kg and development of hypoguesia in the past 4 months. She also had numbness of her hands but not her feet. Her bowel function was normal. She had a history of hyperthyroidism (had previously been taking carbimazole, and was now on thyroxine replacement) and hypertension, which had been controlled on enalapril since 2006. She denied taking any health supplements, and was not on a restricted or vegetarian diet. On examination, multiple hyperpigmented macules of different shades of black and grey were seen on the patient’s oral mucosa, palms and soles (Fig. 1a). Enalapril was changed to losartan and amlodipine, but the hyperpigmentation persisted. In view of the increased pigmentation and unexplained weight loss, the patient was investigated for Addison disease, but both her renal panel and synacthen tests were normal. Her thyroid function tests Correspondence: Dr Oh Choon Chiat, Department of Dermatology, 20 College Road, Academia, Singapore 169856, Singapore E-mail: [email protected] Conflict of interest: the authors declare that they have no conflicts of interest. Accepted for publication 9 September 2014
626
Clinical and Experimental Dermatology (2015) 40, pp626–628
with sudden onset of hyperpigmented palms and soles, in association with found to be associated with underlying pernicious anaemia.
were also normal. Fasting blood glucose was 4.5 mmol/L (normal range 3.9–6.0 mmol/L). Tumour markers including carcinoembryonic antigen, CA19–9, CA125 and a-fetoprotein were unremarkable. VDRL (Veneral Disease Reference Laboratory) tests for sexually transmitted disease were negative. Complete blood count revealed macrocytosis (mean cell volume 109.6 fL; normal range 78–98 fL), which was associated with a low serum vitamin B12 level of < 37 pmol/L (normal range 145–637 pmol/L). Peripheral blood film showed mainly normocytic red blood cells with slight macrocytosis; white blood cells and platelets were otherwise normal. Tests for antiparietal cell and anti-intrinsic factor antibodies were positive. Oesophagogastroduodenoscopy and colonoscopy detected gastritis at the antrum and fundus. Biopsy of a gastric polyp showed hyperplastic regenerative changes and intestinal metaplasia, while biopsy of a hyperpigmented macule on the patient’s sole showed features of an intradermal naevus. A diagnosis of vitamin B12 deficiency secondary to pernicious anaemia was made. The patient was started on intramuscular cyanocobalamin injections three times per week for 1 week, followed by once a week for a month. She would subsequently receive monthly cyanocobalamin injections, which are expected to be lifelong. A review at 2 months showed that the patient had regained her taste and put on 5 kg in weight, and her hyperpigmentation had started to resolve (Fig. 1b). The numbness in her hands also started to improve. In evaluating a patient presenting with unexplained focal hyperpigmentation involving the palms, soles and oral mucosa, investigation should focus on
ª 2015 British Association of Dermatologists
Pernicious anaemia presenting as hyperpigmentation W. Y. Tham et al.
(a)
(b)
Figure 1 (a) Hyperpigmentation before treatment; (b) improvement of pigmentation after treatment.
presence of medication history, any family history of inheritable disorders and a systemic review of symptoms for conditions beyond the skin. Physical examination should be directed towards the distribution of the lesions, blood pressure, and signs of thyroid disease or hypocortisolism. The differential diagnoses for this pattern of hyperpigmentation can be divided into inherited and acquired causes. The inherited causes that should be considered include Peutz–Jeghe and Laugie–Hunziker syndromes. The former was unlikely in this case, given the age of presentation and the absence of family history. Although Laugier–Hunziker syndrome is a differential diagnosis that should be considered, the patient had associated loss of weight and hypoguesia, therefore other causes of hyperpigmentation had to be excluded. Systemic diseases known to be associated with similar hyperpigmentation include endocrinological disorders, especially Addison disease. These should be excluded by reviewing the relevant symptoms in the patient’s history and by appropriate investigations, including thyroid function tests, fasting glucose levels, and adrenocorticotropic hormone stimulation (synacthen) tests. These results were within normal limits in our case. However, this patient was found to have severe vitamin B12 deficiency. Vitamin B12 deficiency more
ª 2015 British Association of Dermatologists
commonly presents with macrocytic anaemia, neurological symptoms and other gastrointestinal symptoms such as glossitis. However, there have been reports since the 1900s of hyperpigmentation associated with vitamin B12 deficiency.1–5 The first documented association between pernicious anaemia and hyperpigmentation was by Aitken in 1909.6 Common sites of hyperpigmentation include the palmar and plantar surfaces, intertriginous areas, oral mucosa, and regions exposed to pressure, such as the elbows and knees, the extensor surfaces of finger and toe joints, and new scars.7 There are several hypotheses about how vitamin B12 deficiency results in hyperpigmentation. The most commonly accepted theory is that vitamin B12 deficiency causes a depletion in intracellular-reduced glutathione, resulting in an increase in tyrosinase, which subsequently leads to the stimulation of melanocytes to secrete melanin.8 Another hypothesis is that there is a deficit in the transfer of melanin from the melanocytes to the keratinocytes, resulting in pigment incontinence. However, in their case of vitamin B12 deficiency with hyperpigmentation, Mori et al.9 did not observe a defect of melanin transfer under electron microscopy. The hyperpigmentation improves within weeks following correction of the deficiency, with complete resolution in a few months, as noted in other case reports.3–5 A study conducted by Demir et al.7 on 57
Clinical and Experimental Dermatology (2015) 40, pp626–628
627
Pernicious anaemia presenting as hyperpigmentation W. Y. Tham et al.
children found that there was complete resolution in 86.66% of patients after 3 months of treatment for vitamin B12 deficiency. The response to treatment is said to be related to the duration of symptoms. Causes of vitamin B12 deficiency can be due to problems anywhere along the absorption pathway. This can be due to decreased intake such as with a vegetarian diet, or as a consequence of decreased acid production in the gut due to medication or postgastrectomy. Other possible causes include pernicious anaemia such as in our patient, ileal disease such as Crohn disease, or malabsorption seen in blind loop syndrome or coeliac disease, among others. The cutaneous manifestations of vitamin B12 deficiency that have been described also include vitiligo, stomatitis and hair changes. In summary, vitamin B12 deficiency should be considered as a differential diagnosis in the evaluation of a patient who presents with hyperpigmentation. If vitamin B12 deficiency is present, the underlying cause for this problem needs to be investigated, and the patient should receive appropriate treatment.
Learning points Vitamin B12 levels should be checked in a
patient presenting with focal hyperpigmentation. The underlying cause for vitamin B12 defi-
ciency needs to be investigated and managed accordingly.
628
Clinical and Experimental Dermatology (2015) 40, pp626–628
In most cases, there is resolution of the hyper-
pigmentation with correction of the vitamin B12 deficiency.
References 1 Cook BA. A vitamin B12 deficiency syndrome allied to sprue. Indian Med Gaz 1944; 79: 429–37. 2 Baker SJ, Johnson S, Ignatius H et al. Hyperpigmentation of the skin: a sign of vitamin B12 deficiency. Br Med J 1963; 1: 1713–15. 3 Agrawala RK, Sahoo SK, Choudhury AK, Mohanty BK, Baliarsinha AK. Pigmentation in vitamin B12 deficiency masquerading Addison’s pigmentation: a rare presentation. Indian J Endocr Metab 2013; 17: S254–6. 4 Kannan R, Ng MJM. Cutaneous lesions and vitamin B12 deficiency. Can Fam Physician 2008; 54: 529–32. 5 Hoffman CF, Palmer DM, Papadopoulos D. Vitamin B12 deficiency: a case report of ongoing cutaneous hyperpigmentation. Cutis 2003; 71: 127–30. 6 Aitken J. Pernicious anaemia with pigmentation of the skin and buccal mucous membrane. Br Med J 1909; 1: 1349–51. 7 Demir N, Dogan M, Koc H et al. Dermatological findings of vitamin B12 deficiency and resolving time of these symptoms. Cutan Ocul Toxico. 2014; 33: 70–3. 8 Lee SH, Lee WS, Whang KC et al. Hyperpigmentation in megaloblastic anaemia. Int J Dermatol 1988; 27: 571–5. 9 Mori K, Ando I, Kukita A. Generalized hyperpigmentation of the skin due to vitamin B12 deficiency. J Dermatol 2001; 28: 282–5.
ª 2015 British Association of Dermatologists
