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Potential Liver Damage Associated with Over-the-Counter Vitamin Supplements
RESEARCH Practical Solutions
Potential Liver Damage Associated with Over-the-Counter Vitamin Supplements ANKUR SHETH, MD, MPH; RITU KHURANA, MD; VIKAS KHURANA, MD, FACP, FACG
ABSTRACT The growing popularity and availability of over-thecounter (OTC) health products, including vitamins, raises serious concern about vitamin toxicity. We report a case of cirrhosis in a patient with habitual daily ingestion of an OTC dietary supplement that contained 13,000 g vitamin A and was associated with marked clinical improvement after discontinuation. This case highlights the potential for liver damage that may be associated with long-term intake of OTC vitamin supplements, and indicates the need for medical supervision of such products. J Am Diet Assoc. 2008;108:1536-1537.
T
he growing popularity and availability of over-thecounter (OTC) health products is of concern due to potential health hazards from their unsupervised use. Vitamins are one of the most commonly used OTC agents for self-medicating. In the United States, about 25% of adults ingest vitamin A– containing supplements, and 5% take supplements of vitamin A alone (1). An intake of one or two capsules of vitamin A preparations containing 7,500 g vitamin A is not uncommon (2). However, this dosage vastly exceeds the dietary reference intakes for adult men (900 g/day) and women (700 g/ day) and the tolerable upper intake levels (3,000 g/day) for adults (3), and raises serious concerns about vitamin A toxicity. We report a case of cirrhosis in a patient with habitual daily ingestion of OTC dietary supplements containing 13,000 g vitamin A.
A. Sheth is clinical fellow, Department of Gastroenterology, and R. Khurana is clinical fellow, Department of Rheumatology, Louisiana State University Health Sciences Center, Shreveport, LA. V. Khurana is staff physician, Department of Gastroenterology and Hepatology, Overton Brooks VA Medical Center, Shreveport, LA, and assistant professor of Medicine, Louisiana State University Health Sciences Center, Shreveport, LA. Address correspondence to: Vikas Khurana, MD, FACP, FACG, Overton Brooks VA Medical Center, 510 E Stoner Ave, 111G, Shreveport, LA 71101. E-mail: [email protected] Manuscript accepted: March 10, 2008. Copyright © 2008 by the American Dietetic Association. 0002-8223/08/10809-0016$34.00/0 doi: 10.1016/j.jada.2008.06.443
1536
Journal of the AMERICAN DIETETIC ASSOCIATION
CASE REPORT A 59-year-old man with a past medical history significant for diabetes mellitus, dyslipidemia, and obstructive sleep apnea was referred from his primary care physician for worsening ascites of 6-months duration. He had been abstinent from alcohol for 15 years and had been taking a variety of unsupervised OTC multivitamin tablets that contained an aggregate of 13,000 g vitamin A for 2 years. On examination, he was a well-developed, poorly nourished man with wasted extremities. His weight was 84.1 kg with a 9.0 kg weight gain noted in the previous 6 months, resulting in a current body mass index of 25.0. Abdominal examination was significant for marked distension with shifting dullness suggestive of ascites. No other stigmata of liver disease were noted on physical exam. Laboratory workup revealed a total bilirubin 0.5 mg/dL, alkaline phosphatase 154 IU/L, alanine amino transferase 40 IU/L, aspartate amino transferase 45 IU/L, total protein 7 g/dL, albumin 2.7 g/dL, international normalized ratio 1.1, serum ascitic albumin gradient 1.5, and vitamin A level 21 g/L (normal range 30 to 95 g/L). Serum levels of ceruloplasmin, ferritin, transferrin, and ␣-1 antitrypsin were normal. Hepatitis and autoimmune serology were negative. Initial abdominal computerized tomogram revealed a liver of normal size and texture with marked ascites. The echocardiogram showed an ejection fraction of 55% with normal right ventricular systolic pressure. Cardiac ascites was ruled out by the normal echocardiogram. Viral and autoimmune causes of liver dysfunction were ruled out by negative viral and autoimmune serology. Normal serum levels of ceruloplasmin, ferritin, transferrin, and ␣-1 antitrypsin ruled out other causes of cirrhosis such as Wilson’s disease, hemochromatosis, and ␣-1 antitrypsin deficiency. Liver biopsy showed chronic hepatitis (grade II, stage II), hypertrophied stellate cells, and perisinusoidal fibrosis suggestive of vitamin A toxicity. Vitamin supplements were subsequently discontinued and at 2-year follow-up the patient had minimal ascites and improved liver functions without use of diuretics or other medical interventions. At the time of follow-up, ultrasonogram revealed a mildly shrunken liver and upper endoscopy revealed grade I esophageal varices. DISCUSSION Retinol is the main compound with vitamin A function and is found in food sources such as liver, kidney, and milk. The provitamin beta carotene is widely distributed in plants and when consumed is cleaved to form retinol in intestinal mucosa. Vitamin A is principally stored as retinyl esters in hepatic stellate cells. It is mobilized from
© 2008 by the American Dietetic Association
these liver stores into plasma as retinol bound to retinol binding protein (3). Vitamin A hepatotoxicity is rare, and ranges from elevated liver enzymes to cirrhosis. Toxicity may be observed in the absence of extra hepatic signs of vitamin A intoxication or an increase in serum vitamin A concentration (4). In this patient, serum vitamin A levels were observed to be low, likely due to the low serum concentrations of retinol binding protein as a result of malnutrition and/or hepatic dysfunction. Vitamin A hepatotoxicity has been reported at doses as low as 7,500 g/day (5). Vulnerable groups, such as pregnant women and children, can develop hepatotoxicity with intakes of only 3,333 g/day (6) and 500 g/kg/day (1), respectively. Hyperplasia and hypertrophy of perisinusoidal stellate cells and perisinusoidal fibrosis on liver biopsy are consistent with hepatic storage of excess vitamin A. Although not applicable to this case, concomitant alcohol use can further potentiate the intrinsic hepatotoxicity of vitamin A (2,7,8). This patient’s clinical course illustrates the potential for hepatotoxicity that may be associated with long-term intake of vitamin A. Marked improvement in the patient’s clinical and laboratory values upon discontinuation of vitamin A supplements without other medical interventions and the presence of hypertrophied stellate cells and perisinusoidal fibrosis on liver biopsy are highly suggestive of hepatotoxicity from chronic vitamin A ingestion. CONCLUSIONS This case exemplifies the potential harmful effects of OTC vitamin A supplements and highlights the need for medical supervision of such products. Clinicians should
be aware that vitamin A hepatotoxicity may be observed in the absence of extra hepatic signs of vitamin A intoxication or increases in serum vitamin A concentration. As a consequence of the increasing use of OTC vitamin A supplements, clinicians need to provide information regarding the relative safety and toxicity of such products. Furthermore, a history of vitamin A supplement use should be routinely elicited in the evaluation of liver dysfunction. A short abstract of this case report was presented as a poster at the American College of Gastroenterology 70th Annual Scientific Meeting, October 28-November 2, 2005, Honolulu, HI. References 1. Hathcock JN, Hattan DG, Jenkins MY, McDonald JT, Sundaresan PR, Wilkening VL. Evaluation of vitamin A toxicity. Am J Clin Nutr. 1990;52:183-202. 2. Leo MA, Lieber CS. Alcohol, vitamin A, and beta-carotene: Adverse interactions, including hepatotoxicity and carcinogenicity. Am J Clin Nutr. 1999;69:1071-1085. 3. Goodman DS. Vitamin A and retinoids in health and disease. N Engl J Med. 1984;310:1023-1031. 4. Verneau A, Rosenbaum J, Zafrani ES, Roudot-Thoraval F, Leclercq M, Dhumeaux D. Hepatic fibrosis and portal hypertension in chronic vitamin A poisoning. Gastroenterol Clin Biol. 1984;8:121-125. 5. Kowalski TE, Falestiny M, Furth E, Malet PF. Vitamin A hepatotoxicity: A cautionary note regarding 25,000 IU supplements. Am J Med. 1994;97:523-528. 6. Rothman KJ, Moore LL, Singer MR, Nguyen US, Mannino S, Milunsky A. Teratogenicity of high vitamin A intake. N Engl J Med. 1995;333: 1369-1373. 7. Lieber CS. Relationships between nutrition, alcohol use, and liver disease. Alcohol Res Health. 2003;27:220-231. 8. Leevy CM, Moroianu SA. Nutritional aspects of alcoholic liver disease. Clin Liver Dis. 2005;9:67-81.
September 2008 ● Journal of the AMERICAN DIETETIC ASSOCIATION
1537
Potential Liver Damage Associated with Over-the-Counter Vitamin Supplements ANKUR SHETH, MD, MPH; RITU KHURANA, MD; VIKAS KHURANA, MD, FACP, FACG
ABSTRACT The growing popularity and availability of over-thecounter (OTC) health products, including vitamins, raises serious concern about vitamin toxicity. We report a case of cirrhosis in a patient with habitual daily ingestion of an OTC dietary supplement that contained 13,000 g vitamin A and was associated with marked clinical improvement after discontinuation. This case highlights the potential for liver damage that may be associated with long-term intake of OTC vitamin supplements, and indicates the need for medical supervision of such products. J Am Diet Assoc. 2008;108:1536-1537.
T
he growing popularity and availability of over-thecounter (OTC) health products is of concern due to potential health hazards from their unsupervised use. Vitamins are one of the most commonly used OTC agents for self-medicating. In the United States, about 25% of adults ingest vitamin A– containing supplements, and 5% take supplements of vitamin A alone (1). An intake of one or two capsules of vitamin A preparations containing 7,500 g vitamin A is not uncommon (2). However, this dosage vastly exceeds the dietary reference intakes for adult men (900 g/day) and women (700 g/ day) and the tolerable upper intake levels (3,000 g/day) for adults (3), and raises serious concerns about vitamin A toxicity. We report a case of cirrhosis in a patient with habitual daily ingestion of OTC dietary supplements containing 13,000 g vitamin A.
A. Sheth is clinical fellow, Department of Gastroenterology, and R. Khurana is clinical fellow, Department of Rheumatology, Louisiana State University Health Sciences Center, Shreveport, LA. V. Khurana is staff physician, Department of Gastroenterology and Hepatology, Overton Brooks VA Medical Center, Shreveport, LA, and assistant professor of Medicine, Louisiana State University Health Sciences Center, Shreveport, LA. Address correspondence to: Vikas Khurana, MD, FACP, FACG, Overton Brooks VA Medical Center, 510 E Stoner Ave, 111G, Shreveport, LA 71101. E-mail: [email protected] Manuscript accepted: March 10, 2008. Copyright © 2008 by the American Dietetic Association. 0002-8223/08/10809-0016$34.00/0 doi: 10.1016/j.jada.2008.06.443
1536
Journal of the AMERICAN DIETETIC ASSOCIATION
CASE REPORT A 59-year-old man with a past medical history significant for diabetes mellitus, dyslipidemia, and obstructive sleep apnea was referred from his primary care physician for worsening ascites of 6-months duration. He had been abstinent from alcohol for 15 years and had been taking a variety of unsupervised OTC multivitamin tablets that contained an aggregate of 13,000 g vitamin A for 2 years. On examination, he was a well-developed, poorly nourished man with wasted extremities. His weight was 84.1 kg with a 9.0 kg weight gain noted in the previous 6 months, resulting in a current body mass index of 25.0. Abdominal examination was significant for marked distension with shifting dullness suggestive of ascites. No other stigmata of liver disease were noted on physical exam. Laboratory workup revealed a total bilirubin 0.5 mg/dL, alkaline phosphatase 154 IU/L, alanine amino transferase 40 IU/L, aspartate amino transferase 45 IU/L, total protein 7 g/dL, albumin 2.7 g/dL, international normalized ratio 1.1, serum ascitic albumin gradient 1.5, and vitamin A level 21 g/L (normal range 30 to 95 g/L). Serum levels of ceruloplasmin, ferritin, transferrin, and ␣-1 antitrypsin were normal. Hepatitis and autoimmune serology were negative. Initial abdominal computerized tomogram revealed a liver of normal size and texture with marked ascites. The echocardiogram showed an ejection fraction of 55% with normal right ventricular systolic pressure. Cardiac ascites was ruled out by the normal echocardiogram. Viral and autoimmune causes of liver dysfunction were ruled out by negative viral and autoimmune serology. Normal serum levels of ceruloplasmin, ferritin, transferrin, and ␣-1 antitrypsin ruled out other causes of cirrhosis such as Wilson’s disease, hemochromatosis, and ␣-1 antitrypsin deficiency. Liver biopsy showed chronic hepatitis (grade II, stage II), hypertrophied stellate cells, and perisinusoidal fibrosis suggestive of vitamin A toxicity. Vitamin supplements were subsequently discontinued and at 2-year follow-up the patient had minimal ascites and improved liver functions without use of diuretics or other medical interventions. At the time of follow-up, ultrasonogram revealed a mildly shrunken liver and upper endoscopy revealed grade I esophageal varices. DISCUSSION Retinol is the main compound with vitamin A function and is found in food sources such as liver, kidney, and milk. The provitamin beta carotene is widely distributed in plants and when consumed is cleaved to form retinol in intestinal mucosa. Vitamin A is principally stored as retinyl esters in hepatic stellate cells. It is mobilized from
© 2008 by the American Dietetic Association
these liver stores into plasma as retinol bound to retinol binding protein (3). Vitamin A hepatotoxicity is rare, and ranges from elevated liver enzymes to cirrhosis. Toxicity may be observed in the absence of extra hepatic signs of vitamin A intoxication or an increase in serum vitamin A concentration (4). In this patient, serum vitamin A levels were observed to be low, likely due to the low serum concentrations of retinol binding protein as a result of malnutrition and/or hepatic dysfunction. Vitamin A hepatotoxicity has been reported at doses as low as 7,500 g/day (5). Vulnerable groups, such as pregnant women and children, can develop hepatotoxicity with intakes of only 3,333 g/day (6) and 500 g/kg/day (1), respectively. Hyperplasia and hypertrophy of perisinusoidal stellate cells and perisinusoidal fibrosis on liver biopsy are consistent with hepatic storage of excess vitamin A. Although not applicable to this case, concomitant alcohol use can further potentiate the intrinsic hepatotoxicity of vitamin A (2,7,8). This patient’s clinical course illustrates the potential for hepatotoxicity that may be associated with long-term intake of vitamin A. Marked improvement in the patient’s clinical and laboratory values upon discontinuation of vitamin A supplements without other medical interventions and the presence of hypertrophied stellate cells and perisinusoidal fibrosis on liver biopsy are highly suggestive of hepatotoxicity from chronic vitamin A ingestion. CONCLUSIONS This case exemplifies the potential harmful effects of OTC vitamin A supplements and highlights the need for medical supervision of such products. Clinicians should
be aware that vitamin A hepatotoxicity may be observed in the absence of extra hepatic signs of vitamin A intoxication or increases in serum vitamin A concentration. As a consequence of the increasing use of OTC vitamin A supplements, clinicians need to provide information regarding the relative safety and toxicity of such products. Furthermore, a history of vitamin A supplement use should be routinely elicited in the evaluation of liver dysfunction. A short abstract of this case report was presented as a poster at the American College of Gastroenterology 70th Annual Scientific Meeting, October 28-November 2, 2005, Honolulu, HI. References 1. Hathcock JN, Hattan DG, Jenkins MY, McDonald JT, Sundaresan PR, Wilkening VL. Evaluation of vitamin A toxicity. Am J Clin Nutr. 1990;52:183-202. 2. Leo MA, Lieber CS. Alcohol, vitamin A, and beta-carotene: Adverse interactions, including hepatotoxicity and carcinogenicity. Am J Clin Nutr. 1999;69:1071-1085. 3. Goodman DS. Vitamin A and retinoids in health and disease. N Engl J Med. 1984;310:1023-1031. 4. Verneau A, Rosenbaum J, Zafrani ES, Roudot-Thoraval F, Leclercq M, Dhumeaux D. Hepatic fibrosis and portal hypertension in chronic vitamin A poisoning. Gastroenterol Clin Biol. 1984;8:121-125. 5. Kowalski TE, Falestiny M, Furth E, Malet PF. Vitamin A hepatotoxicity: A cautionary note regarding 25,000 IU supplements. Am J Med. 1994;97:523-528. 6. Rothman KJ, Moore LL, Singer MR, Nguyen US, Mannino S, Milunsky A. Teratogenicity of high vitamin A intake. N Engl J Med. 1995;333: 1369-1373. 7. Lieber CS. Relationships between nutrition, alcohol use, and liver disease. Alcohol Res Health. 2003;27:220-231. 8. Leevy CM, Moroianu SA. Nutritional aspects of alcoholic liver disease. Clin Liver Dis. 2005;9:67-81.
September 2008 ● Journal of the AMERICAN DIETETIC ASSOCIATION
1537