Cholestatic jaundice associated with lovastatin (Mevacor) therapy Matthew J. McQueen, MB, ChB, PhD, FRCPC
A recent significant advance in the treatment of dyslipidemia is the use of lovastatin (Mevacor), an inhibitor of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase, the rate-limiting enzyme in the cholesterol synthesis pathway.' This drug has been available in the United States since September 1987 and in Canada since July 1988. The efficacy and long-term adverse effects have been described.2 Therapy has been stopped in 2% of patients because of adverse events, most frequently asymptomatic hepatocellular rather than cholestatic increases in the transaminase levels more than three times the upper limit of normal. Monitoring of liver function is recommended by the manufacturer. Drug-induced jaundice has not yet been reported from clinical trials involving over 10 000 patients.
Case report A healthy, nonsmoking 40-year-old man presented to the Lipid Research Clinic, Hamilton General Hospital, Hamilton, Ont., in August 1984 with a 5-year history of hyperlipidemia unresponsive to dietary changes. On average his alcoholic intake was less than one drink per week. Hypertension had recently been diagnosed, and an oxalate renal stone had been removed when he was 28 years old. His father had died of myocardial infarction; his paternal grandfather and six uncles had had either myocardial infarction or cerebrovascular accident. There were no ocular, cutaneous or tendinous signs of hyperlipidemia, and his blood pressure was 150/90 mm Hg. He was taking allopurinol, 100 mg/d, and hydrochlorothiazide-amiloride, one tablet per day. The laboratory test results are presented in Table 1. Until the end of 1985 the patient followed the American Heart Association dietary guidelines.3 In early 1986 his weight and cholesterol level increased, but, since he did not want to take medication, good dietary control was continued, with further emphasis on exercise. By mid-July 1987 there was no improve-
ment in the lipid levels, so therapy with cholestyramine, 12 g/d, was started, without adverse effects. In September 1988 the cholestyramine therapy was stopped at the patient's request because of inconvenience, and lovastatin, 20 mg/d, was given along with a detailed explanation of possible side effects based on about 2 to 3 years of personal experience, although one group of investigators had over 6 years' experience with small numbers of patients.4 After 7 weeks there were no adverse effects, and the results of the liver (Table 2) and lipid (Table 1) biochemistry tests were normal. Three weeks later he received a short course of amoxicillin therapy for a sore throat. Eleven weeks after the start of the lovastatin therapy the patient noticed increasing fatigue, a progressive decrease in appetite, severe itching, darkening of his urine and light-coloured, floating stools. He saw his family physician in early January 1989, only after friends and family had commented that he did not look well and his dentist had told him that he looked jaundiced. His skin and sclera were jaundiced, and his liver was enlarged. The lovastatin therapy was stopped. The results of tests for hepatitis A and B, autoimmune hepatitis, hemochromatosis and Wilson's disease were negative. Ultrasonography revealed that there were no calculi, that the gallbladder and the common bile duct had thickened walls and that there was some dilation of the hepatic ducts. At the Lahey Clinic, Burlington, Mass., endoscopic retrograde cholangiopancreatography showed clean and normal bile ducts with no evidence of stone, stricture or tumour. After the lovastatin therapy was stopped the patient felt increasingly well. Cholestyramine, 12 g/d, was started in mid-February. His appetite slowly returned, and the jaundice receded. At follow-up in March 1989 he felt much better and was not jaundiced, and his urine and bowel motions were normal; his liver was still enlarged and smooth but not tender. He was told that the condition might require
Dr. McQueen is professor ofpathology, McMaster University, and director of clinical chemistry, Hamilton General Hospital, Hamilton, Ont. He also works in the Lipid Research Clinic, Hamilton General Hospital.
Reprint requests to: Dr. Matthew J. McQueen, Lipid Research Clinic, Hamilton General Hospital, 237 Barton St. E, Hamilton, Ont. L8L 2X2 CAN MED ASSOC J 1990; 142 (8)
841
aoie I: Lipid levels and weight over 5 years of the patient who subsequently hao :atndice associated with lovastatin therapy
cholestr7t
i: nholesterol level. mmol/l
Hign-density
iriglycerides r:Iml
L-ow-density
4-; !hv^ry ..rtei
aVe r
'evei
r)O'irote!r
23- 1984.
-epf
'I 984 1 98s4
2.(
.J. 4:)39
-ne 8. 1985 :;c . 8 1985 -eb.18.1986 \4ov 20, 1986 £D 30 1987 'ilv 1987 LIg 26 1987
.
.88
--
'.66 4(
'3c.
ept 631988 )4 1988i e.12 19891: \err ce va c[u'syar . *.' enot reYcelvin,i ViSt> . -. receiviriu t
.½ t,
abie 2 riesults o* i'ver biocnemlstr V, -I..,
Lactate Gamr-a*giu AlkalineJ Aspartatae!,-:, sFei's^ 3rninotransrease ;.rTransetase nhosphata>.s eyarorger,s.
;.v
ieve-i
'eve
.
.
24 1988
ar;lt 245 19898 A.
'..
,19893 a 30. 98j [a> 6 '989
I
4!t
A recent significant advance in the treatment of dyslipidemia is the use of lovastatin (Mevacor), an inhibitor of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase, the rate-limiting enzyme in the cholesterol synthesis pathway.' This drug has been available in the United States since September 1987 and in Canada since July 1988. The efficacy and long-term adverse effects have been described.2 Therapy has been stopped in 2% of patients because of adverse events, most frequently asymptomatic hepatocellular rather than cholestatic increases in the transaminase levels more than three times the upper limit of normal. Monitoring of liver function is recommended by the manufacturer. Drug-induced jaundice has not yet been reported from clinical trials involving over 10 000 patients.
Case report A healthy, nonsmoking 40-year-old man presented to the Lipid Research Clinic, Hamilton General Hospital, Hamilton, Ont., in August 1984 with a 5-year history of hyperlipidemia unresponsive to dietary changes. On average his alcoholic intake was less than one drink per week. Hypertension had recently been diagnosed, and an oxalate renal stone had been removed when he was 28 years old. His father had died of myocardial infarction; his paternal grandfather and six uncles had had either myocardial infarction or cerebrovascular accident. There were no ocular, cutaneous or tendinous signs of hyperlipidemia, and his blood pressure was 150/90 mm Hg. He was taking allopurinol, 100 mg/d, and hydrochlorothiazide-amiloride, one tablet per day. The laboratory test results are presented in Table 1. Until the end of 1985 the patient followed the American Heart Association dietary guidelines.3 In early 1986 his weight and cholesterol level increased, but, since he did not want to take medication, good dietary control was continued, with further emphasis on exercise. By mid-July 1987 there was no improve-
ment in the lipid levels, so therapy with cholestyramine, 12 g/d, was started, without adverse effects. In September 1988 the cholestyramine therapy was stopped at the patient's request because of inconvenience, and lovastatin, 20 mg/d, was given along with a detailed explanation of possible side effects based on about 2 to 3 years of personal experience, although one group of investigators had over 6 years' experience with small numbers of patients.4 After 7 weeks there were no adverse effects, and the results of the liver (Table 2) and lipid (Table 1) biochemistry tests were normal. Three weeks later he received a short course of amoxicillin therapy for a sore throat. Eleven weeks after the start of the lovastatin therapy the patient noticed increasing fatigue, a progressive decrease in appetite, severe itching, darkening of his urine and light-coloured, floating stools. He saw his family physician in early January 1989, only after friends and family had commented that he did not look well and his dentist had told him that he looked jaundiced. His skin and sclera were jaundiced, and his liver was enlarged. The lovastatin therapy was stopped. The results of tests for hepatitis A and B, autoimmune hepatitis, hemochromatosis and Wilson's disease were negative. Ultrasonography revealed that there were no calculi, that the gallbladder and the common bile duct had thickened walls and that there was some dilation of the hepatic ducts. At the Lahey Clinic, Burlington, Mass., endoscopic retrograde cholangiopancreatography showed clean and normal bile ducts with no evidence of stone, stricture or tumour. After the lovastatin therapy was stopped the patient felt increasingly well. Cholestyramine, 12 g/d, was started in mid-February. His appetite slowly returned, and the jaundice receded. At follow-up in March 1989 he felt much better and was not jaundiced, and his urine and bowel motions were normal; his liver was still enlarged and smooth but not tender. He was told that the condition might require
Dr. McQueen is professor ofpathology, McMaster University, and director of clinical chemistry, Hamilton General Hospital, Hamilton, Ont. He also works in the Lipid Research Clinic, Hamilton General Hospital.
Reprint requests to: Dr. Matthew J. McQueen, Lipid Research Clinic, Hamilton General Hospital, 237 Barton St. E, Hamilton, Ont. L8L 2X2 CAN MED ASSOC J 1990; 142 (8)
841
aoie I: Lipid levels and weight over 5 years of the patient who subsequently hao :atndice associated with lovastatin therapy
cholestr7t
i: nholesterol level. mmol/l
Hign-density
iriglycerides r:Iml
L-ow-density
4-; !hv^ry ..rtei
aVe r
'evei
r)O'irote!r
23- 1984.
-epf
'I 984 1 98s4
2.(
.J. 4:)39
-ne 8. 1985 :;c . 8 1985 -eb.18.1986 \4ov 20, 1986 £D 30 1987 'ilv 1987 LIg 26 1987
.
.88
--
'.66 4(
'3c.
ept 631988 )4 1988i e.12 19891: \err ce va c[u'syar . *.' enot reYcelvin,i ViSt> . -. receiviriu t
.½ t,
abie 2 riesults o* i'ver biocnemlstr V, -I..,
Lactate Gamr-a*giu AlkalineJ Aspartatae!,-:, sFei's^ 3rninotransrease ;.rTransetase nhosphata>.s eyarorger,s.
;.v
ieve-i
'eve
.
.
24 1988
ar;lt 245 19898 A.
'..
,19893 a 30. 98j [a> 6 '989
I
4!t
