European Journal of Clinical Nutrition (2014) 68, 1362–1364 © 2014 Macmillan Publishers Limited All rights reserved 0954-3007/14 www.nature.com/ejcn
CLINICAL CASE REPORT
Carotenoderma in a young woman of normal body mass index with hypothalamic amenorrhoea: a 2-year follow-up case report M Nyekiova, S Ghaderi and TS Han Hypothalamic amenorrhoea has been shown to be associated with hypercarotenaemia, but no causal link has been established. Many people are unaware of the health implications of carotenoderma. We report on a 36-year-old woman with normal body mass index and with a history of secondary amenorrhoea for 2 years and carotenoderma for 5 years. She had a history of practising a fixed-menu diet of predominantly leafy greens, exercised intensively and had a stressful job. Blood tests confirmed the presence of hypercarotenaemia and hypogonadotrophic hypogonadism. Carotenoderma subsided after 6 months of lifestyle modification, but she remained amenorrhoeic up to 12 months later. Since then, her condition had relapsed up to the time of 2 years of follow-up. We conclude that hypercarotenaemia/carotenoderma and hypothalamic amenorrhoea are manifestations of a constrained lifestyle rather than causally linked. The presence of carotenoderma should alert public individuals and clinicians, especially in primary care, alike for signs of potential health complications including reproductive dysfunction even without weight problems. European Journal of Clinical Nutrition (2014) 68, 1362–1364; doi:10.1038/ejcn.2014.128; published online 2 July 2014
INTRODUCTION Carotenoderma, an orange skin pigmentation, has been observed frequently in patients with anorexia nervosa,1 likely because of a combination of increased dietary intake of carotene-rich vegetables or nutritional supplements, reduced hepatic conversion of β-carotene to vitamin A and/or hyperlipidaemia. Anorexia nervosa is also commonly associated with hypothalamic amenorrhoea. The observation of nine out of ten patients with secondary amenorrhoea who had hypercarotenaemia led Kemmann et al.2 to speculate that high levels of β-carotene may relate to hypothalamic hypogonadotrophic anovulation, but their causal links remain unestablished. In some conditions such as hypothyroidism, patients may develop hypogonadotrophic anovulation and carotenoderma/hypercarotenaemia3 (due to reduced conversion of β-carotene to vitamin A). Here we report on a young woman with normal body mass index who presented with progressive carotenoderma and secondary amenorrhoea with a 2-year followup to assess her progress after lifestyle modification.
CASE REPORT A 36-year-old Caucasian former air stewardess presented with secondary amenorrhoea for over 2 years, which was preceded by a 5-year history of ‘orange’ skin, becoming progressively more visible on her face, hands and feet over 18 months prior to the consultation. The patient was unaware neither of the underlying cause of her skin pigmentation nor its health implications. She had spontaneous onset of pubescence and menarche at the age of 16 years. She was exceptionally ‘health conscious’, practising for the past 5 years a fixed-menu diet of boiled chicken breast, steamed broccoli, sugar-snap peas, asparagus and multivitamin supplements while avoiding red/orange colour vegetables and red
meats, and exercising 60–80 min in the gymnasium five to six times a week. Dietary assessment (Supplementary material) showed that the patient’s estimated total calorie intake of 1950 kcal/day was slightly lower than the recommended total energy requirement of 2103 kcal/day.4 Her basal metabolic rate was 1396 kcal/day according to Schofield equation5 for her age (36 years) and weight (67.9 kg). The proportions of energy derived from fat (23.2%) and carbohydrate (19.2%) were well below, while energy derived from protein (57.7%) was well above, the dietary reference values for nutrition.4 Physical examination showed the presence of carotenoderma over the patient’s nasolabial folds, palms and soles (Figures 1a–c). There was no evidence of scleral icterus. She had a normal body mass index (23 kg/m2), waist circumference (78 cm) and percent body fat (25% of body weight) calculated from skinfold thicknesses.6 Biochemistry tests revealed low levels of gonadotrophins and oestradiol consistent with a diagnosis of hypogonadotrophic hypogonadism. She had raised levels of β-carotene (10.30 μmol/l), which were 6.5-fold greater than the upper limit of reference (0.19–1.58 μmol/l), and raised levels of cryptoxanthine and zeaxanthine/lutein, which are found mainly in leafy greens.7 Her ferritin levels were low (10 μg/l; reference range: 15–300 μg/l). The remaining pituitary and metabolic profiles were normal. Her bone mineral density assessed by dual X-ray absorptiometry and pituitary assessed by magnetic resonance imaging were both normal. Our patient was offered dietetic counselling but preferred to perform lifestyle modification by herself. After 6 months of lifestyle modification by halving the exercise frequency and duration, changing to a more relaxing job and altering to a more varied diet with a reduction in intake of green vegetables, the patient’s carotenoderma had subsided but secondary
Department of Diabetes and Endocrinology, Ashford and St Peter’s NHS Foundation Trust, Chertsey, UK. Correspondence: Dr TS Han, Department of Diabetes and Endocrinology, Ashford and St Peter’s NHS Foundation Trust, St Peter’s NHS Foundation Trust, Guildford Road, Chertsey, UK. E-mail: [email protected] Received 9 April 2014; revised 23 May 2014; accepted 23 May 2014; published online 2 July 2014
Carotenoderma in a young woman M Nyekiova et al
1363
Figure 2. Leuteinising hormone pulse frequency in a 30-year-old male with secondary hypogonadism induced by excessive exercise: venous sampling was carried out to assess leuteinising hormone levels every 10 min for 6 h, showing that leuteinising hormone pulse began only after 310 min from the beginning of sampling (TS Han, unpublished)—normal frequency is about one pulse every 2 h.14
Figure 1. Pictures showing carotenoderma visible on nasolabial folds (a), palms (b) and soles (c) of a 36-year-old Caucasian woman.
amenorrhoea continued to persist up to 12 months. Since then her condition had relapsed back to her previous dietary habits and exercise regimen up to the time of 2 years of follow-up. DISCUSSION In healthy individuals, the lipid-soluble provitamin β-carotene undergoes irreversible oxidative cleavage to vitamin A by the cytosolic enzyme β-carotene 15,15'-dioxygenase. This enzyme is a 66-kDa sulfhydryl protein that is found predominantly in the duodenal mucosa and liver.8 Vitamin A has a range of vital © 2014 Macmillan Publishers Limited
systemic functions, but too much of its precursor β-carotene leads to carotenoderma, which tends to occur more frequently in infancy primarily due to increased bioavailability of carotene in their pureed/mashed vegetables and their slower metabolism of carotene than adults. There are a number of non-dietary (secondary) causes of hypercarotenaemia/carotenoderma including metabolic abnormalities, which were not present in our patient, such as hypothyroidism and diabetes mellitus (decreased conversion of carotene to vitamin A), hyperlipidaemia (increased binding sites for carotenoids from raised circulating lipoproteins), renal disease (reduced clearance), liver disease (reduced liver storage and conversion of carotene)9 and rarely enzyme defect in the metabolism of carotene.10 Our patient appeared to endure a triad of eating disorder, excessive exercise and work-related stress resulting in hypercarotenaemia/carotenoderma and hypothalamic amenorrhoea. Our patient’s slightly low total calorie consumption may reflect underestimation of her intake rather than a restricted calorie diet as her weight remained relatively stable. She had a particularly high-protein, low-fat and low-carbohydrate diet. Our patient had a number of behavioural features suggestive of a compulsive disorder. Excessive exercise induces hypogonadism by suppressing gonadotrophin-releasing hormone pulsatile release, resulting in attenuation of leuteinising hormone pulses,11 as demonstrated in a young male of similar age to our patient who acquired secondary hypogonadism from excessive exercise (Figure 2). Our patient was not aware that her ‘orange skin’ discoloration was caused by high consumption of predominantly green vegetables. This is perhaps not surprising since only about 3% of the general public are aware that fruit and vegetables are the sources of β-carotene.12 Carotenoderma is rarely seen in healthy adults but occurs in about 21–24% of females with eating disorder1,13 and is frequently observed to be associated with hypothalamic amenorrhoea,2 but no causal link has been established. The observation that the continuation of amenorrhoea in our patient for another 12 months after carotenoderma had subsided indicates that raised levels of β-carotene were unlikely to be causally related to hypothalamic amenorrhoea and may simply reflect a constrained lifestyle that led both to carotenoderma and to hypothalamic–pituitary–gonadal dysfunction. Recovery from exercise-induced amenorrhoea in athletes European Journal of Clinical Nutrition (2014) 1362 – 1364
Carotenoderma in a young woman M Nyekiova et al
1364 has been observed to take up to 6 months after relaxation of strenuous exercise.14 Our patient still found it hard to maintain a less strict diet and exercise regimen and her condition had relapsed. CONCLUSION We report a case of a young woman with normal body mass index and fat distribution who presented with secondary amenorrhoea and associated carotenoderma, both of which are likely to be a consequence of constrained lifestyle. The presence of carotenoderma should alert public individuals and clinicians, especially in primary care, alike for signs of potential health complications including reproductive dysfunction even when there is no apparent sign of weight problems. CONSENT Written informed consent was obtained from the patient for publication of this case report and any accompanying images. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS We thank Professor MEJ Lean, Rank Professor of Human Nutrition, Glasgow Royal Infirmary, University of Glasgow, Scotland, for his insightful comments.
AUTHOR CONTRIBUTIONS All authors were involved in study design, drafting the manuscript and revising it critically, and read and approved the final manuscript.
REFERENCES 1 Strumìa R, Varotti E, Manzato E, Gualandi M. Skin signs in anorexia nervosa. Dermatology 2001; 203: 314–317. 2 Kemmann E, Pasquale SA, Skaf R. Amenorrhea associated with carotenemia. J Am Med Assoc 1983; 249: 926–929. 3 Wiersinga WM, DeGroot LJ. Adult hypothyroidism. Thyroid Disease Manager 2010. Available at: www.thyroidmanager.org/chapter/adult-hypothyroidism/# toc-9-2definition-and-epidemiology-of-hypothyroidism (accessed 16 May 2014). 4 Scientific Advisory Committee on Nutrition. Dietary Reference Values for Nutrition. TSO: London, 2011. 5 Schofield WN. Predicting basal metabolic rate, new standards and review of previous work. Hum Nutr Clin Nutr 1985; 39 (Suppl 1): 5–41. 6 Lean ME, Han TS, Deurenberg P. Predicting body composition by densitometry from simple anthropometric measurements. Am J Clin Nutr 1996; 63: 4–14. 7 Maiani G, Castón MJ, Catasta G, Toti E, Cambrodón IG, Bysted A et al. Carotenoids: actual knowledge on food sources, intakes, stability and bioavailability and their protective role in humans. Molec Nutr Food Res 2009; 53(Suppl 2): S194–S218. 8 Lakshman MR. Alpha and omega of carotenoid cleavage. J Nutr 2004; 134: 241 S–245 S. 9 Haught JM, Patel S, English JC III. Xanthoderma: a clinical review. J Am Acad Dermatol 2007; 57: 1051–1058. 10 Svensson A, Vahlquist A. Metabolic carotenemia and carotenoderma in a child. Acta Dermato-Venereol 1995; 75: 70–71. 11 Han TS, Bouloux PMG. Kallmann syndrome and other causes of hypothalamic hypogonadism and related development disorders. In Fink G, Pfaff DW, Levine JE (eds) Handbook of Neuroendocrinology. 1st edn, Chapter 27, Academic Press, Elsevier: London, Waltham, San Diego, 2012, pp 597–618. 12 Braun M, Venter I. Awareness and knowledge of phytonutrient food sources and health benefits for functional food application among health food store customers in the Cape Town city bowl. J Family Ecol Consumer Sci 2008; 36: 30–39. 13 Glorio R, Allevato M, De Pablo A, Abbruzzese M, Carmona L, Savarin M et al. Prevalence of cutaneous manifestations in 200 patients with eating disorders. Int J Dermatol 2000; 39: 348–353. 14 Warren MP. Health issues for women athletes: exercise-induced amenorrhea. J Clin Endocrinol Metab 1999; 84: 1892–1896.
Supplementary Information accompanies this paper on European Journal of Clinical Nutrition website (http://www.nature.com/ejcn)
European Journal of Clinical Nutrition (2014) 1362 – 1364
© 2014 Macmillan Publishers Limited
CLINICAL CASE REPORT
Carotenoderma in a young woman of normal body mass index with hypothalamic amenorrhoea: a 2-year follow-up case report M Nyekiova, S Ghaderi and TS Han Hypothalamic amenorrhoea has been shown to be associated with hypercarotenaemia, but no causal link has been established. Many people are unaware of the health implications of carotenoderma. We report on a 36-year-old woman with normal body mass index and with a history of secondary amenorrhoea for 2 years and carotenoderma for 5 years. She had a history of practising a fixed-menu diet of predominantly leafy greens, exercised intensively and had a stressful job. Blood tests confirmed the presence of hypercarotenaemia and hypogonadotrophic hypogonadism. Carotenoderma subsided after 6 months of lifestyle modification, but she remained amenorrhoeic up to 12 months later. Since then, her condition had relapsed up to the time of 2 years of follow-up. We conclude that hypercarotenaemia/carotenoderma and hypothalamic amenorrhoea are manifestations of a constrained lifestyle rather than causally linked. The presence of carotenoderma should alert public individuals and clinicians, especially in primary care, alike for signs of potential health complications including reproductive dysfunction even without weight problems. European Journal of Clinical Nutrition (2014) 68, 1362–1364; doi:10.1038/ejcn.2014.128; published online 2 July 2014
INTRODUCTION Carotenoderma, an orange skin pigmentation, has been observed frequently in patients with anorexia nervosa,1 likely because of a combination of increased dietary intake of carotene-rich vegetables or nutritional supplements, reduced hepatic conversion of β-carotene to vitamin A and/or hyperlipidaemia. Anorexia nervosa is also commonly associated with hypothalamic amenorrhoea. The observation of nine out of ten patients with secondary amenorrhoea who had hypercarotenaemia led Kemmann et al.2 to speculate that high levels of β-carotene may relate to hypothalamic hypogonadotrophic anovulation, but their causal links remain unestablished. In some conditions such as hypothyroidism, patients may develop hypogonadotrophic anovulation and carotenoderma/hypercarotenaemia3 (due to reduced conversion of β-carotene to vitamin A). Here we report on a young woman with normal body mass index who presented with progressive carotenoderma and secondary amenorrhoea with a 2-year followup to assess her progress after lifestyle modification.
CASE REPORT A 36-year-old Caucasian former air stewardess presented with secondary amenorrhoea for over 2 years, which was preceded by a 5-year history of ‘orange’ skin, becoming progressively more visible on her face, hands and feet over 18 months prior to the consultation. The patient was unaware neither of the underlying cause of her skin pigmentation nor its health implications. She had spontaneous onset of pubescence and menarche at the age of 16 years. She was exceptionally ‘health conscious’, practising for the past 5 years a fixed-menu diet of boiled chicken breast, steamed broccoli, sugar-snap peas, asparagus and multivitamin supplements while avoiding red/orange colour vegetables and red
meats, and exercising 60–80 min in the gymnasium five to six times a week. Dietary assessment (Supplementary material) showed that the patient’s estimated total calorie intake of 1950 kcal/day was slightly lower than the recommended total energy requirement of 2103 kcal/day.4 Her basal metabolic rate was 1396 kcal/day according to Schofield equation5 for her age (36 years) and weight (67.9 kg). The proportions of energy derived from fat (23.2%) and carbohydrate (19.2%) were well below, while energy derived from protein (57.7%) was well above, the dietary reference values for nutrition.4 Physical examination showed the presence of carotenoderma over the patient’s nasolabial folds, palms and soles (Figures 1a–c). There was no evidence of scleral icterus. She had a normal body mass index (23 kg/m2), waist circumference (78 cm) and percent body fat (25% of body weight) calculated from skinfold thicknesses.6 Biochemistry tests revealed low levels of gonadotrophins and oestradiol consistent with a diagnosis of hypogonadotrophic hypogonadism. She had raised levels of β-carotene (10.30 μmol/l), which were 6.5-fold greater than the upper limit of reference (0.19–1.58 μmol/l), and raised levels of cryptoxanthine and zeaxanthine/lutein, which are found mainly in leafy greens.7 Her ferritin levels were low (10 μg/l; reference range: 15–300 μg/l). The remaining pituitary and metabolic profiles were normal. Her bone mineral density assessed by dual X-ray absorptiometry and pituitary assessed by magnetic resonance imaging were both normal. Our patient was offered dietetic counselling but preferred to perform lifestyle modification by herself. After 6 months of lifestyle modification by halving the exercise frequency and duration, changing to a more relaxing job and altering to a more varied diet with a reduction in intake of green vegetables, the patient’s carotenoderma had subsided but secondary
Department of Diabetes and Endocrinology, Ashford and St Peter’s NHS Foundation Trust, Chertsey, UK. Correspondence: Dr TS Han, Department of Diabetes and Endocrinology, Ashford and St Peter’s NHS Foundation Trust, St Peter’s NHS Foundation Trust, Guildford Road, Chertsey, UK. E-mail: [email protected] Received 9 April 2014; revised 23 May 2014; accepted 23 May 2014; published online 2 July 2014
Carotenoderma in a young woman M Nyekiova et al
1363
Figure 2. Leuteinising hormone pulse frequency in a 30-year-old male with secondary hypogonadism induced by excessive exercise: venous sampling was carried out to assess leuteinising hormone levels every 10 min for 6 h, showing that leuteinising hormone pulse began only after 310 min from the beginning of sampling (TS Han, unpublished)—normal frequency is about one pulse every 2 h.14
Figure 1. Pictures showing carotenoderma visible on nasolabial folds (a), palms (b) and soles (c) of a 36-year-old Caucasian woman.
amenorrhoea continued to persist up to 12 months. Since then her condition had relapsed back to her previous dietary habits and exercise regimen up to the time of 2 years of follow-up. DISCUSSION In healthy individuals, the lipid-soluble provitamin β-carotene undergoes irreversible oxidative cleavage to vitamin A by the cytosolic enzyme β-carotene 15,15'-dioxygenase. This enzyme is a 66-kDa sulfhydryl protein that is found predominantly in the duodenal mucosa and liver.8 Vitamin A has a range of vital © 2014 Macmillan Publishers Limited
systemic functions, but too much of its precursor β-carotene leads to carotenoderma, which tends to occur more frequently in infancy primarily due to increased bioavailability of carotene in their pureed/mashed vegetables and their slower metabolism of carotene than adults. There are a number of non-dietary (secondary) causes of hypercarotenaemia/carotenoderma including metabolic abnormalities, which were not present in our patient, such as hypothyroidism and diabetes mellitus (decreased conversion of carotene to vitamin A), hyperlipidaemia (increased binding sites for carotenoids from raised circulating lipoproteins), renal disease (reduced clearance), liver disease (reduced liver storage and conversion of carotene)9 and rarely enzyme defect in the metabolism of carotene.10 Our patient appeared to endure a triad of eating disorder, excessive exercise and work-related stress resulting in hypercarotenaemia/carotenoderma and hypothalamic amenorrhoea. Our patient’s slightly low total calorie consumption may reflect underestimation of her intake rather than a restricted calorie diet as her weight remained relatively stable. She had a particularly high-protein, low-fat and low-carbohydrate diet. Our patient had a number of behavioural features suggestive of a compulsive disorder. Excessive exercise induces hypogonadism by suppressing gonadotrophin-releasing hormone pulsatile release, resulting in attenuation of leuteinising hormone pulses,11 as demonstrated in a young male of similar age to our patient who acquired secondary hypogonadism from excessive exercise (Figure 2). Our patient was not aware that her ‘orange skin’ discoloration was caused by high consumption of predominantly green vegetables. This is perhaps not surprising since only about 3% of the general public are aware that fruit and vegetables are the sources of β-carotene.12 Carotenoderma is rarely seen in healthy adults but occurs in about 21–24% of females with eating disorder1,13 and is frequently observed to be associated with hypothalamic amenorrhoea,2 but no causal link has been established. The observation that the continuation of amenorrhoea in our patient for another 12 months after carotenoderma had subsided indicates that raised levels of β-carotene were unlikely to be causally related to hypothalamic amenorrhoea and may simply reflect a constrained lifestyle that led both to carotenoderma and to hypothalamic–pituitary–gonadal dysfunction. Recovery from exercise-induced amenorrhoea in athletes European Journal of Clinical Nutrition (2014) 1362 – 1364
Carotenoderma in a young woman M Nyekiova et al
1364 has been observed to take up to 6 months after relaxation of strenuous exercise.14 Our patient still found it hard to maintain a less strict diet and exercise regimen and her condition had relapsed. CONCLUSION We report a case of a young woman with normal body mass index and fat distribution who presented with secondary amenorrhoea and associated carotenoderma, both of which are likely to be a consequence of constrained lifestyle. The presence of carotenoderma should alert public individuals and clinicians, especially in primary care, alike for signs of potential health complications including reproductive dysfunction even when there is no apparent sign of weight problems. CONSENT Written informed consent was obtained from the patient for publication of this case report and any accompanying images. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS We thank Professor MEJ Lean, Rank Professor of Human Nutrition, Glasgow Royal Infirmary, University of Glasgow, Scotland, for his insightful comments.
AUTHOR CONTRIBUTIONS All authors were involved in study design, drafting the manuscript and revising it critically, and read and approved the final manuscript.
REFERENCES 1 Strumìa R, Varotti E, Manzato E, Gualandi M. Skin signs in anorexia nervosa. Dermatology 2001; 203: 314–317. 2 Kemmann E, Pasquale SA, Skaf R. Amenorrhea associated with carotenemia. J Am Med Assoc 1983; 249: 926–929. 3 Wiersinga WM, DeGroot LJ. Adult hypothyroidism. Thyroid Disease Manager 2010. Available at: www.thyroidmanager.org/chapter/adult-hypothyroidism/# toc-9-2definition-and-epidemiology-of-hypothyroidism (accessed 16 May 2014). 4 Scientific Advisory Committee on Nutrition. Dietary Reference Values for Nutrition. TSO: London, 2011. 5 Schofield WN. Predicting basal metabolic rate, new standards and review of previous work. Hum Nutr Clin Nutr 1985; 39 (Suppl 1): 5–41. 6 Lean ME, Han TS, Deurenberg P. Predicting body composition by densitometry from simple anthropometric measurements. Am J Clin Nutr 1996; 63: 4–14. 7 Maiani G, Castón MJ, Catasta G, Toti E, Cambrodón IG, Bysted A et al. Carotenoids: actual knowledge on food sources, intakes, stability and bioavailability and their protective role in humans. Molec Nutr Food Res 2009; 53(Suppl 2): S194–S218. 8 Lakshman MR. Alpha and omega of carotenoid cleavage. J Nutr 2004; 134: 241 S–245 S. 9 Haught JM, Patel S, English JC III. Xanthoderma: a clinical review. J Am Acad Dermatol 2007; 57: 1051–1058. 10 Svensson A, Vahlquist A. Metabolic carotenemia and carotenoderma in a child. Acta Dermato-Venereol 1995; 75: 70–71. 11 Han TS, Bouloux PMG. Kallmann syndrome and other causes of hypothalamic hypogonadism and related development disorders. In Fink G, Pfaff DW, Levine JE (eds) Handbook of Neuroendocrinology. 1st edn, Chapter 27, Academic Press, Elsevier: London, Waltham, San Diego, 2012, pp 597–618. 12 Braun M, Venter I. Awareness and knowledge of phytonutrient food sources and health benefits for functional food application among health food store customers in the Cape Town city bowl. J Family Ecol Consumer Sci 2008; 36: 30–39. 13 Glorio R, Allevato M, De Pablo A, Abbruzzese M, Carmona L, Savarin M et al. Prevalence of cutaneous manifestations in 200 patients with eating disorders. Int J Dermatol 2000; 39: 348–353. 14 Warren MP. Health issues for women athletes: exercise-induced amenorrhea. J Clin Endocrinol Metab 1999; 84: 1892–1896.
Supplementary Information accompanies this paper on European Journal of Clinical Nutrition website (http://www.nature.com/ejcn)
European Journal of Clinical Nutrition (2014) 1362 – 1364
© 2014 Macmillan Publishers Limited
