CASE REPORT
Jaundice Due to Nicotinic Acid Therapy Norman Einstein, BS, Alfred Baker, MD, Jonas Galper, MD, and Hubert Wolfe, MD
R e c e n t surveys i n d i c a t e w i d e s p r e a d v i t a m i n c o n s u m p t i o n in the U n i t e d S t a t e s ( l ) . T h e p r e s e n t case is a n e x a m p l e of a p a t i e n t w h o w a s t r e a t e d w i t h massive doses of several v i t a m i n p r e p a r a t i o n s a n d p r o b a b l y developed j a u n d i c e d u e to n i c o t i n i c acid c o n s u m p t i o n . S u c h m e d i c a tions, p a r t i c u l a r l y in l a r g e doses, m a y h a v e adverse effects, as t h e p r e s e n t case illustrates.
CASE REPORT A 22-year-old woman was admitted to the New England Medical Center Hospital on April 23, 1973, because of jaundice and pruritus. For two and a half years she had been treated with 3 g nicotinic acid, 3 g vitamin C, 100 mg pyridoxine, 2,400 IU vitamin E, and a muhivitamin tablet daily for a psychological disturbance. In mid-March~ 1973, she began to have malaise, pruritus, dark urine, and light stools. Two weeks later she was seen by a physician who noted marked jaundice. All medications except nicotinic acid were discontinued at that time. On admission, the patient denied use of parenteral drugs or exposure to persons with hepatitis. Physical examination revealed jaundice, excoriations, and a slightly tender liver which was palpable two finger breaths below the right costal margin. The spleen was not palpable, and there were no signs of chronic liver disease. The hematocrit, white blood cell count, and differential were within normal limits. The serum ereatinine was 1.0 rag/100 ml, and the BUN was 10 mg/100 ml. Liver function tests are shown in the table. Hepatitis B antigen was not detectable, and the heterophile and antimitochondrial antibody tests were negative. The administration of nicotinic acid was stopped on admission. Because the patient's symptoms and liver function From the Gastroenterology Service of the Department of Medicine and the-Department of Pathology, Tufts-New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts. Dr. Baker's present address is the Pritzker School of Medicine, Department of Medicine, University of Chicago, 950 East 59th Street, Chicago, Illinois, 60637. Address for reprint requests: Dr. Alfred Baker, University of Chicago, Department of Medicine, 950 East 59th Street, Chicago, Illinois, 60637. 282
tests were still essentially unchanged on April 28 (see Table 1), a percutaneous liver biopsy was performed on the seventh day of hospitalization. The liver biopsy showed acute hepatitis with evidence of submassive necrosis (Figure I). In addition, there was marked cholestasis and bile duct proliferation (Figure 2). On May 4 she felt better, and her liver function tests showed definite improvement. Because of continued itching, however, she was begun on cholestyramine, 4 g 4 times daily. The patient was discharged and seen again on May 31, when she felt well and reported only mild pruritus. Liver function tests then showed mildly elevated values, but have subsequently been within normal limits. The cholestyramine treatment was discontinued, and when last seen on June 27 the patient was totally asymptomatie.
DISCUSSION Mild abnormalities of liver function develop frequently in patients who are on large-dose c h r o n i c n i c o t i n i c acid t h e r a p y for h y p e r c h o l e s t e r o l e m i a . O f t h e 66 p a t i e n t s t r e a t e d by B e r g e et al (2), 25 h a d at least o n e r e c o r d e d abn o r m a l i t y of direct or i n d i r e c t b i l i r u b i n , t r a n s a m i n a s e , a l k a l i n e p h o s p h a t a s e , o r sulfobrom o p h t h a l e i n ( B S P ) r e t e n t i o n . L i v e r biopsies were not d o n e in t h e s e p a t i e n t s , a n d t h e liver f u n c t i o n tests u s u a l l y i m p r o v e d w i t h c o n t i n u e d t r e a t m e n t . P a r s o n s (3) r e p o r t e d 10 p a t i e n t s , f r o m a g r o u p of 36 t r e a t e d w i t h n i c o t i n i c acid, w h o developed i n c r e a s e d B S P r e t e n t i o n . T h r e e w e r e r e p o r t e d in detail a n d u n d e r w e n t liver biopsy, but in two the liver d i s o r d e r m i g h t h a v e been d u e to factors u n r e l a t e d to t h e m e d i c a t i o n . M o r e severe liver disease h a s been r e p o r t e d in a few p a t i e n t s on c h r o n i c n i c o t i n i c acid t h e r apy. In o n e (4), the p a t i e n t d e v e l o p e d severe p r u r i t u s after a y e a r ' s t r e a t m e n t w i t h 3 g nicotinic acid daily. T r e a t m e n t w i t h t h e d r u g w a s discontinued and pruritus disappeared. When nicotinic acid was r e a d m i n i s t e r e d , t h e p a t i e n t ' s p r u r i t u s developed a g a i n a n d j a u n d i c e a p Digestive Diseases, Vol. 20, No. 3 (March 1975)
J A U N D I C E DUE TO N I C O T I N I C ACID T H E R A P Y Table 1. Test Results of 22-Year-Old Woman Hospitalized for Pruritus and Jaundice Test Bilirubin (rag/100 ml) Total Direct Alkaline phosphatase (Bodansky units) SGOT (units) SG PT (units) Serum proteins (g/100 ml) Albumin Globulin Prothrombin time (% control)
Normal
April 23
April 28
April 30
May 4
May 31
June 27
Jaundice Due to Nicotinic Acid Therapy Norman Einstein, BS, Alfred Baker, MD, Jonas Galper, MD, and Hubert Wolfe, MD
R e c e n t surveys i n d i c a t e w i d e s p r e a d v i t a m i n c o n s u m p t i o n in the U n i t e d S t a t e s ( l ) . T h e p r e s e n t case is a n e x a m p l e of a p a t i e n t w h o w a s t r e a t e d w i t h massive doses of several v i t a m i n p r e p a r a t i o n s a n d p r o b a b l y developed j a u n d i c e d u e to n i c o t i n i c acid c o n s u m p t i o n . S u c h m e d i c a tions, p a r t i c u l a r l y in l a r g e doses, m a y h a v e adverse effects, as t h e p r e s e n t case illustrates.
CASE REPORT A 22-year-old woman was admitted to the New England Medical Center Hospital on April 23, 1973, because of jaundice and pruritus. For two and a half years she had been treated with 3 g nicotinic acid, 3 g vitamin C, 100 mg pyridoxine, 2,400 IU vitamin E, and a muhivitamin tablet daily for a psychological disturbance. In mid-March~ 1973, she began to have malaise, pruritus, dark urine, and light stools. Two weeks later she was seen by a physician who noted marked jaundice. All medications except nicotinic acid were discontinued at that time. On admission, the patient denied use of parenteral drugs or exposure to persons with hepatitis. Physical examination revealed jaundice, excoriations, and a slightly tender liver which was palpable two finger breaths below the right costal margin. The spleen was not palpable, and there were no signs of chronic liver disease. The hematocrit, white blood cell count, and differential were within normal limits. The serum ereatinine was 1.0 rag/100 ml, and the BUN was 10 mg/100 ml. Liver function tests are shown in the table. Hepatitis B antigen was not detectable, and the heterophile and antimitochondrial antibody tests were negative. The administration of nicotinic acid was stopped on admission. Because the patient's symptoms and liver function From the Gastroenterology Service of the Department of Medicine and the-Department of Pathology, Tufts-New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts. Dr. Baker's present address is the Pritzker School of Medicine, Department of Medicine, University of Chicago, 950 East 59th Street, Chicago, Illinois, 60637. Address for reprint requests: Dr. Alfred Baker, University of Chicago, Department of Medicine, 950 East 59th Street, Chicago, Illinois, 60637. 282
tests were still essentially unchanged on April 28 (see Table 1), a percutaneous liver biopsy was performed on the seventh day of hospitalization. The liver biopsy showed acute hepatitis with evidence of submassive necrosis (Figure I). In addition, there was marked cholestasis and bile duct proliferation (Figure 2). On May 4 she felt better, and her liver function tests showed definite improvement. Because of continued itching, however, she was begun on cholestyramine, 4 g 4 times daily. The patient was discharged and seen again on May 31, when she felt well and reported only mild pruritus. Liver function tests then showed mildly elevated values, but have subsequently been within normal limits. The cholestyramine treatment was discontinued, and when last seen on June 27 the patient was totally asymptomatie.
DISCUSSION Mild abnormalities of liver function develop frequently in patients who are on large-dose c h r o n i c n i c o t i n i c acid t h e r a p y for h y p e r c h o l e s t e r o l e m i a . O f t h e 66 p a t i e n t s t r e a t e d by B e r g e et al (2), 25 h a d at least o n e r e c o r d e d abn o r m a l i t y of direct or i n d i r e c t b i l i r u b i n , t r a n s a m i n a s e , a l k a l i n e p h o s p h a t a s e , o r sulfobrom o p h t h a l e i n ( B S P ) r e t e n t i o n . L i v e r biopsies were not d o n e in t h e s e p a t i e n t s , a n d t h e liver f u n c t i o n tests u s u a l l y i m p r o v e d w i t h c o n t i n u e d t r e a t m e n t . P a r s o n s (3) r e p o r t e d 10 p a t i e n t s , f r o m a g r o u p of 36 t r e a t e d w i t h n i c o t i n i c acid, w h o developed i n c r e a s e d B S P r e t e n t i o n . T h r e e w e r e r e p o r t e d in detail a n d u n d e r w e n t liver biopsy, but in two the liver d i s o r d e r m i g h t h a v e been d u e to factors u n r e l a t e d to t h e m e d i c a t i o n . M o r e severe liver disease h a s been r e p o r t e d in a few p a t i e n t s on c h r o n i c n i c o t i n i c acid t h e r apy. In o n e (4), the p a t i e n t d e v e l o p e d severe p r u r i t u s after a y e a r ' s t r e a t m e n t w i t h 3 g nicotinic acid daily. T r e a t m e n t w i t h t h e d r u g w a s discontinued and pruritus disappeared. When nicotinic acid was r e a d m i n i s t e r e d , t h e p a t i e n t ' s p r u r i t u s developed a g a i n a n d j a u n d i c e a p Digestive Diseases, Vol. 20, No. 3 (March 1975)
J A U N D I C E DUE TO N I C O T I N I C ACID T H E R A P Y Table 1. Test Results of 22-Year-Old Woman Hospitalized for Pruritus and Jaundice Test Bilirubin (rag/100 ml) Total Direct Alkaline phosphatase (Bodansky units) SGOT (units) SG PT (units) Serum proteins (g/100 ml) Albumin Globulin Prothrombin time (% control)
Normal
April 23
April 28
April 30
May 4
May 31
June 27
