Rapid Improvement in Dermatitis after Zinc Supplementation in a Patient with Crohn's Disease DOUGLAS C. HEIMBURGER, M.D., F.A.C.P., TSUNENOBU TAMURA, M.D., ROBERT D. MARKS, M.D. Birmingham,Alabama
he essentiality of zinc for humans was established more than 25 years ago [1,2]. It is involved in reacT tions of over 150 metalloenzymes that participate in a
the entire body except the head and neck (Figure 1). Healing necrolytic erosions were present over bony prominences such as the patellae. Laboratory values wide variety of metabolic processes and plays an im- a r e listed in Table I. Notably decreased were levels of portant role in the metabolism of proteins and nucleic serum albumin and plasma zinc, copper, iron, ~-caroacids [2,3]. Zinc deficiency can occur in the presence of tene, ascorbate, retinol-binding protein (RBP), and poor intake, malabsorption, chronic renal failure, cir- testosterone. Not listed in Table I are a mildly elevatrhosis of the liver, and sickle cell disease, and its der- ed bilirubin level and elevated lactate dehydrogenase matologic manifestations include poor wound healing, and aspartate aminotransferase activities. Barium hyperkeratosis, hyperpigmentation, progressive bul- contrast studies and computed tomography showed lous-erythematous dermatitis, and alopecia. To aid in partial obstruction of the distal ileum because of a recognizing dermatitis due to zinc deficiency in clini- possible mass. Examination of biopsied skin specical medicine, we describe a patient with Crohn's dis- mens from the neck and abdomen revealed changes ease in whom dermatitis secondary to zinc deficiency consistent with malnutrition, such as zinc deficiency. resolved rapidly with zinc supplementation. These included an irregular psoriasiform epidermal hyperplasia with mild acanthosis, confluent parakeraCASE REPORT tosis, dilated superficial blood vessels, and neutrophil A 58-year-old white man was admitted to the Bir- infiltration of the acanthotic epidermis and parakeramingham Veterans Administration Medical Center on totic areas. Periodic acid-Schiff stain was negative for October 27, 1988, with diarrhea, anorexia, weight loss, fungi. and a rash. In 1984, he first began to experience watery Diagnosed with kwashiorkor and presumed zinc dediarrhea, two to 15 times per day, and anorexia, nau- ficiency, the patient was treated with nasogastric sucsea, and vomiting. Radiologic studies revealed dilata- tion and total parenteral nutrition including dextrose, tion and thickening of the small bowel wall. Small amino acids (Aminosyn®, Abbott Laboratories, North bowel biopsy revealed nonspecific duodenal inflam- Chicago, Illinois), lipid emulsion (Liposyn II ®, Abbott mation. In 1986, he was given a presumptive diagnosis Laboratories, North Chicago, Illinois), maintenance of Crohn's disease and was treated with corticoste- doses of 12 vitamins (MVI-12 ®, Armour Pharmaceutiroids and nutritionally complete liquid supplements, cal Co., Tarrytown, New York), and zinc, copper, manwith resultant weight gain and improvement in diar- ganese, and chromium (MTE-4 ® Concentrate, Lyrhea. However, he apparently discontinued the ste- phoMed Inc., Melrose Park, Illinois). In addition, he roids, and inpatient treatment was required in 1987 received supplemental intravenous zinc, bringing his because of weight loss, steatorrhea (23 g stool fat/day), total zinc intake to 16 mg/day. No topical therapy was and edema. Once again, his symptoms improved sub- applied. Within three to four days, the rash had ceased stantially. to progress, and after two weeks it had substantially The patient did not return for further care until the resolved (Figure 2). The patient's serum albumin levpresent admission. During the interim, he had discon- el increased only slightly, but the plasma and erythrotinued all of his medications and nutritional supple- cyte zinc, RBP, and testosterone concentrations inments. He gave a history of continued diarrhea, steat- creased markedly (Table I). Because of unremitting small bowel obstruction, on orrhea, anorexia, and weight loss of 18 kg during the four months before the current admission. Progressive December 14, the patient underwent exploratory lapaedema, malaise, easy bruising, and a new scaling pru- rotomy, with resection of 18 cm of narrowed terminal ritic erythematous rash had developed over the previ- ileum. The mucosal surface of the resected segment ous four to five weeks. At the time of hospitalization, was diffusely nodular. Histologic findings included sehe had clinical and radiologic evidence of intestinal vere chronic inflammation of the mucosa with lymobstruction, and a presumptive diagnosis of Crohn's phocytic and eosinophilic infiltration and blunting of the villi, all of which are consistent with Crohn's disdisease was made. The patient weighed 65 kg, with anasarca. He had a ease. generalized reticulated blanchable erythema with focal overlying hyperpigmented retained scale involving C O M M E N T S The low plasma and erythrocyte levels of zinc, which increased to normal after zinc therapy, together with the prompt response of the skin lesions and the serum From the Departments of Nutrition Sciences (DCH, TT) and Medicine (DCH, RDM), Universityof Alabamaat Birmingham, Birmingham, Alabama. RBP level, strongly suggests that this patient's skin This work was supported by Public Health Service Grant POl-CA28103, lesions were caused by zinc deficiency. Although apawarded by the National Cancer Institute, Department of Health and Human Services. Requestsfor reprints should be addressed to Douglas C. proximately 80% of plasma zinc is bound to albumin, Heimburger, M.D., F.A.C.P., Department of Nutrition Sciences, University the greater increase in plasma zinc than in serum albuof Alabamaat Birmingham, Birmingham, Alabama35294. Manuscriptsubmin after treatment excludes the possibility that the mitted April 7, 1989, and accepted in revisedform August 7, 1989. low zinc level was only caused by hypoalbuminemia. January 1990 The American Journal of Medicine Volume88
71
DERMATITIS IN ZINC DEFICIENCY / HEIMBURGER ET AL
Figure 1. Skin of the patient's abdomer and knee (inset) on November 3, 1988 before zinc treatment.
TABLE I Laboratory Values Test Serumalbumin(g/L) Serumcalcium(mmol/L) Serumalkalinephosphatase(U/L) Wholebloodhemoglobin(g/L) Plasmazinc (#mol/L) Erythrocytezinc (pmol/L) Plasmacopper(#mol/L) Serumceruloplasmin(mg/L) Plasmairon (pmol/L) Plasmaretinol (#mol/L) Plasmaretinol-bindingprotein (rag/L) Plasma/~-carotene(#mol/L) Plasmavitamin B12 (pmol/L) Plasmafolate (nmol/L) Erythrocytefolate (nmol/L) Plasmaascorbate(pmol/L) Plasmatestosterone(nmol/L)
Normal Range
November3, 1988
November18, 1988
40-60 2.20-2.58 30-120 136-172 1].5-18.5 >100 11.0-22.0 200-350 14-32 0.35-1.75 30-60 1.47-4.34 150-750 4-22 550-2,200 30-] 10 14.0-28.0
15 1.78 179 131 3.7 106 6.9 150 6.4 0.52 15 0.47 900~ 6.8 698 22 1.0
19 1.82 90 105 13.5 211 11.8 210 15.8 2.27 52 0.35 ---127 5.5
* A vitamin B12injection was administeredseveraldays prior to measurementof the level.
Figure 2. Skin of the patient's abdomen on November 18, 1988, after 14 days of zinc treatment.
72
January 1990 The American Journal of Medicine Volume 88
DERMATITIS IN ZINC DEFICIENCY / HEIMBURGER ET AL
The dermatologic findings are not pathognomonic for zinc deficiency and could have been caused in part by kwashiorkor or by deficiencies of essential fatty acids, biotin, or vitamin A. However, the resolution of these lesions was more rapid than would be expected in kwashiorkor. The development of the skin lesions before the use of parenteral nutrition makes deficiency of essential fatty acids or biotin less likely, since virtually all reports of these deficiencies are in patients treated with parenteral nutrition devoid of the respective nutrient. The initially low plasma retinol level can be explained in large part by the low level of RBP, and the increase in plasma retinol was commensurate with the increase in RBP during the initial two weeks of treatment. Serum levels of RBP are closely associated with zinc status, being low in zinc deficiency and responding promptly to zinc supplementation [5]. The fact that the increase in RBP was proportionally greater than that in albumin may be a combined effect of zinc supplementation and of the more rapid synthesis rate of RBP [6]. The serum level of testosterone increased markedly after zinc supplementation. This is consistent with observations in zinc-deficient patients with sickle cell disease [7]. However, the level remained below the normal range, possibly because the time interval was too short to observe a full response of testosterone production to zinc therapy. Normally, alkaline phosphatase levels are low in zinc deficiency and increase after supplementation [7,8]. However, with the initial elevation of other liver tests, the increased activity of serum alkaline phosphatase may have been due to liver dysfunction. Zinc deficiency is reported to be present in 35% to 45% of patients with stable Crohn's disease [9]. The mechanisms involved in the development of zinc deficiency in these patients may be a combination of long-
term intestinal malabsorption, excessive intestinal loss of endogenous zinc due to diarrhea, and low dietary intake [9]. The patient reported herein had prolonged uncontrolled Crohn's disease and poor dietary intake for a few months before the current admission. Despite the presence of zinc deficiency in a relatively high proportion of patients with Crohn's disease, most clinicians and medical students may not be adequately trained to identify its dermatologic manifestations. Prompt recognition and more aggressive and routine supplementation of zinc may improve the symptoms in these patients.
ACKNOWLEDGMENT We gratefully acknowledgeLarry Boots, Ph.D., for measuringtestosterone levels, and Jo-David Fine, M.D., for reviewing the manuscript.
REFERENCES 1. PrasadAS, MialeA Jr, FaridZ, StandsteadHH, Schubert AR: Zinc metabolism in patients with the syndrome of iron deficiencyanemia, hepatosplenomegaly,dwarfism and hypogonadism. J Lab Clin Med 1963; 61: 537-549. 2. Halsted JA, Smith JC Jr, Irwin MI: A conspectus of research on zinc requirements of man. J Nutr 1974; 104: 345-378. 3. Hambidge KM, Casey CD, Krebs NF: Zinc. In: Mertz W, ed. Trace elements in human and animal nutrition, ed 5, vol 2. Orlando, Florida: AcademicPress, 1986; 1-137. 4. Fine JD, Wise TG, Falchuck KH: Zinc in cutaneous disease and dermatologic therapeutics. In: Moschella SL, ed. Dermatology update--reviews for physicians. New York: Elsevier, 1982; 299-312. 5. McClainCJ: Zinc metabolism in malabsorptionsyndromes. J Am Coil Nutr 1985; 4: 49-64. 6. Latimer JS, McClain CJ, Sharp HL: Clinical zinc deficiency during zinc-supplemented parenteral nutrition. J Pediatr 1980; 97: 434-437. 7. PrasadAS, AbbasiAA, RabbaniP, DuMouchelleE: Effect of zinc supplementation on serum testosterone level in adult male sickle cell anemia subjects. Am J Hematol 1981; 10: 119-127. 8. ArakawaT, TamuraT, IgarashiY, SuzukiH, SandsteadHH: Zinc deficiency in two infants during total parenteral alimentation for diarrhea. Am J Clin Nutr 1976; 29: 197-204. 9. Hendricks KM, Walker WA: Zinc deficiency in inflammatory bowel disease. Nutr Rev 1988; 46: 401-408.
January 1990 The American Journal of Medicine Volume 88
73
he essentiality of zinc for humans was established more than 25 years ago [1,2]. It is involved in reacT tions of over 150 metalloenzymes that participate in a
the entire body except the head and neck (Figure 1). Healing necrolytic erosions were present over bony prominences such as the patellae. Laboratory values wide variety of metabolic processes and plays an im- a r e listed in Table I. Notably decreased were levels of portant role in the metabolism of proteins and nucleic serum albumin and plasma zinc, copper, iron, ~-caroacids [2,3]. Zinc deficiency can occur in the presence of tene, ascorbate, retinol-binding protein (RBP), and poor intake, malabsorption, chronic renal failure, cir- testosterone. Not listed in Table I are a mildly elevatrhosis of the liver, and sickle cell disease, and its der- ed bilirubin level and elevated lactate dehydrogenase matologic manifestations include poor wound healing, and aspartate aminotransferase activities. Barium hyperkeratosis, hyperpigmentation, progressive bul- contrast studies and computed tomography showed lous-erythematous dermatitis, and alopecia. To aid in partial obstruction of the distal ileum because of a recognizing dermatitis due to zinc deficiency in clini- possible mass. Examination of biopsied skin specical medicine, we describe a patient with Crohn's dis- mens from the neck and abdomen revealed changes ease in whom dermatitis secondary to zinc deficiency consistent with malnutrition, such as zinc deficiency. resolved rapidly with zinc supplementation. These included an irregular psoriasiform epidermal hyperplasia with mild acanthosis, confluent parakeraCASE REPORT tosis, dilated superficial blood vessels, and neutrophil A 58-year-old white man was admitted to the Bir- infiltration of the acanthotic epidermis and parakeramingham Veterans Administration Medical Center on totic areas. Periodic acid-Schiff stain was negative for October 27, 1988, with diarrhea, anorexia, weight loss, fungi. and a rash. In 1984, he first began to experience watery Diagnosed with kwashiorkor and presumed zinc dediarrhea, two to 15 times per day, and anorexia, nau- ficiency, the patient was treated with nasogastric sucsea, and vomiting. Radiologic studies revealed dilata- tion and total parenteral nutrition including dextrose, tion and thickening of the small bowel wall. Small amino acids (Aminosyn®, Abbott Laboratories, North bowel biopsy revealed nonspecific duodenal inflam- Chicago, Illinois), lipid emulsion (Liposyn II ®, Abbott mation. In 1986, he was given a presumptive diagnosis Laboratories, North Chicago, Illinois), maintenance of Crohn's disease and was treated with corticoste- doses of 12 vitamins (MVI-12 ®, Armour Pharmaceutiroids and nutritionally complete liquid supplements, cal Co., Tarrytown, New York), and zinc, copper, manwith resultant weight gain and improvement in diar- ganese, and chromium (MTE-4 ® Concentrate, Lyrhea. However, he apparently discontinued the ste- phoMed Inc., Melrose Park, Illinois). In addition, he roids, and inpatient treatment was required in 1987 received supplemental intravenous zinc, bringing his because of weight loss, steatorrhea (23 g stool fat/day), total zinc intake to 16 mg/day. No topical therapy was and edema. Once again, his symptoms improved sub- applied. Within three to four days, the rash had ceased stantially. to progress, and after two weeks it had substantially The patient did not return for further care until the resolved (Figure 2). The patient's serum albumin levpresent admission. During the interim, he had discon- el increased only slightly, but the plasma and erythrotinued all of his medications and nutritional supple- cyte zinc, RBP, and testosterone concentrations inments. He gave a history of continued diarrhea, steat- creased markedly (Table I). Because of unremitting small bowel obstruction, on orrhea, anorexia, and weight loss of 18 kg during the four months before the current admission. Progressive December 14, the patient underwent exploratory lapaedema, malaise, easy bruising, and a new scaling pru- rotomy, with resection of 18 cm of narrowed terminal ritic erythematous rash had developed over the previ- ileum. The mucosal surface of the resected segment ous four to five weeks. At the time of hospitalization, was diffusely nodular. Histologic findings included sehe had clinical and radiologic evidence of intestinal vere chronic inflammation of the mucosa with lymobstruction, and a presumptive diagnosis of Crohn's phocytic and eosinophilic infiltration and blunting of the villi, all of which are consistent with Crohn's disdisease was made. The patient weighed 65 kg, with anasarca. He had a ease. generalized reticulated blanchable erythema with focal overlying hyperpigmented retained scale involving C O M M E N T S The low plasma and erythrocyte levels of zinc, which increased to normal after zinc therapy, together with the prompt response of the skin lesions and the serum From the Departments of Nutrition Sciences (DCH, TT) and Medicine (DCH, RDM), Universityof Alabamaat Birmingham, Birmingham, Alabama. RBP level, strongly suggests that this patient's skin This work was supported by Public Health Service Grant POl-CA28103, lesions were caused by zinc deficiency. Although apawarded by the National Cancer Institute, Department of Health and Human Services. Requestsfor reprints should be addressed to Douglas C. proximately 80% of plasma zinc is bound to albumin, Heimburger, M.D., F.A.C.P., Department of Nutrition Sciences, University the greater increase in plasma zinc than in serum albuof Alabamaat Birmingham, Birmingham, Alabama35294. Manuscriptsubmin after treatment excludes the possibility that the mitted April 7, 1989, and accepted in revisedform August 7, 1989. low zinc level was only caused by hypoalbuminemia. January 1990 The American Journal of Medicine Volume88
71
DERMATITIS IN ZINC DEFICIENCY / HEIMBURGER ET AL
Figure 1. Skin of the patient's abdomer and knee (inset) on November 3, 1988 before zinc treatment.
TABLE I Laboratory Values Test Serumalbumin(g/L) Serumcalcium(mmol/L) Serumalkalinephosphatase(U/L) Wholebloodhemoglobin(g/L) Plasmazinc (#mol/L) Erythrocytezinc (pmol/L) Plasmacopper(#mol/L) Serumceruloplasmin(mg/L) Plasmairon (pmol/L) Plasmaretinol (#mol/L) Plasmaretinol-bindingprotein (rag/L) Plasma/~-carotene(#mol/L) Plasmavitamin B12 (pmol/L) Plasmafolate (nmol/L) Erythrocytefolate (nmol/L) Plasmaascorbate(pmol/L) Plasmatestosterone(nmol/L)
Normal Range
November3, 1988
November18, 1988
40-60 2.20-2.58 30-120 136-172 1].5-18.5 >100 11.0-22.0 200-350 14-32 0.35-1.75 30-60 1.47-4.34 150-750 4-22 550-2,200 30-] 10 14.0-28.0
15 1.78 179 131 3.7 106 6.9 150 6.4 0.52 15 0.47 900~ 6.8 698 22 1.0
19 1.82 90 105 13.5 211 11.8 210 15.8 2.27 52 0.35 ---127 5.5
* A vitamin B12injection was administeredseveraldays prior to measurementof the level.
Figure 2. Skin of the patient's abdomen on November 18, 1988, after 14 days of zinc treatment.
72
January 1990 The American Journal of Medicine Volume 88
DERMATITIS IN ZINC DEFICIENCY / HEIMBURGER ET AL
The dermatologic findings are not pathognomonic for zinc deficiency and could have been caused in part by kwashiorkor or by deficiencies of essential fatty acids, biotin, or vitamin A. However, the resolution of these lesions was more rapid than would be expected in kwashiorkor. The development of the skin lesions before the use of parenteral nutrition makes deficiency of essential fatty acids or biotin less likely, since virtually all reports of these deficiencies are in patients treated with parenteral nutrition devoid of the respective nutrient. The initially low plasma retinol level can be explained in large part by the low level of RBP, and the increase in plasma retinol was commensurate with the increase in RBP during the initial two weeks of treatment. Serum levels of RBP are closely associated with zinc status, being low in zinc deficiency and responding promptly to zinc supplementation [5]. The fact that the increase in RBP was proportionally greater than that in albumin may be a combined effect of zinc supplementation and of the more rapid synthesis rate of RBP [6]. The serum level of testosterone increased markedly after zinc supplementation. This is consistent with observations in zinc-deficient patients with sickle cell disease [7]. However, the level remained below the normal range, possibly because the time interval was too short to observe a full response of testosterone production to zinc therapy. Normally, alkaline phosphatase levels are low in zinc deficiency and increase after supplementation [7,8]. However, with the initial elevation of other liver tests, the increased activity of serum alkaline phosphatase may have been due to liver dysfunction. Zinc deficiency is reported to be present in 35% to 45% of patients with stable Crohn's disease [9]. The mechanisms involved in the development of zinc deficiency in these patients may be a combination of long-
term intestinal malabsorption, excessive intestinal loss of endogenous zinc due to diarrhea, and low dietary intake [9]. The patient reported herein had prolonged uncontrolled Crohn's disease and poor dietary intake for a few months before the current admission. Despite the presence of zinc deficiency in a relatively high proportion of patients with Crohn's disease, most clinicians and medical students may not be adequately trained to identify its dermatologic manifestations. Prompt recognition and more aggressive and routine supplementation of zinc may improve the symptoms in these patients.
ACKNOWLEDGMENT We gratefully acknowledgeLarry Boots, Ph.D., for measuringtestosterone levels, and Jo-David Fine, M.D., for reviewing the manuscript.
REFERENCES 1. PrasadAS, MialeA Jr, FaridZ, StandsteadHH, Schubert AR: Zinc metabolism in patients with the syndrome of iron deficiencyanemia, hepatosplenomegaly,dwarfism and hypogonadism. J Lab Clin Med 1963; 61: 537-549. 2. Halsted JA, Smith JC Jr, Irwin MI: A conspectus of research on zinc requirements of man. J Nutr 1974; 104: 345-378. 3. Hambidge KM, Casey CD, Krebs NF: Zinc. In: Mertz W, ed. Trace elements in human and animal nutrition, ed 5, vol 2. Orlando, Florida: AcademicPress, 1986; 1-137. 4. Fine JD, Wise TG, Falchuck KH: Zinc in cutaneous disease and dermatologic therapeutics. In: Moschella SL, ed. Dermatology update--reviews for physicians. New York: Elsevier, 1982; 299-312. 5. McClainCJ: Zinc metabolism in malabsorptionsyndromes. J Am Coil Nutr 1985; 4: 49-64. 6. Latimer JS, McClain CJ, Sharp HL: Clinical zinc deficiency during zinc-supplemented parenteral nutrition. J Pediatr 1980; 97: 434-437. 7. PrasadAS, AbbasiAA, RabbaniP, DuMouchelleE: Effect of zinc supplementation on serum testosterone level in adult male sickle cell anemia subjects. Am J Hematol 1981; 10: 119-127. 8. ArakawaT, TamuraT, IgarashiY, SuzukiH, SandsteadHH: Zinc deficiency in two infants during total parenteral alimentation for diarrhea. Am J Clin Nutr 1976; 29: 197-204. 9. Hendricks KM, Walker WA: Zinc deficiency in inflammatory bowel disease. Nutr Rev 1988; 46: 401-408.
January 1990 The American Journal of Medicine Volume 88
73
