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Niacin (nicotinic acid), a drug used to regulate blood lipid (fat) levels, is associated with side effects that are harmful to the liver. The drug is available in several forms, including a crystalline form and sustained-release (SR) capsules. The case studies of three patients who developed hepatitis while taking SR niacin are presented.

One, a 62-year-old man, had been treated with crystalline niacin for high levels of low-density lipoprotein cholesterol (one form in which cholesterol is stored). He received the drug in this form for five months, then changed to SR niacin. After five days, the patient became nauseated, and fainted after drinking a glass of champagne. Tests for liver function were abnormal, and niacin was withheld. The patient recovered and resumed taking crystalline niacin.

The second patient, a 50-year-old woman with familial hypercholesterolemia (high blood cholesterol), took SR niacin and developed impaired liver function. However, she was able to take the crystalline form.

Crystalline niacin was prescribed for the third patient, a 47-year-old man, because of elevated cholesterol, but, based on his pharmacist's advice, he changed to the SR form. This led to abnormal liver functions tests and symptoms which disappeared when the crystalline form was re-instituted.

In summary, it is likely that niacin will be prescribed more frequently in the future, since the National Cholesterol Education Program calls for aggressive treatment of high cholesterol levels.

The cause of niacin-induced hepatitis is not known. However, the ease of access to SR preparations, which do not require a prescription, is cause for concern. (Consumer Summary produced by Reliance Medical Information, Inc.) Rechallenge With Crystalline Niacin After Drug-Induced Hepatitis From Sustained-Release Niacin (nicotinic acid) is available in several forms, including crystalline preparations and various types of sustained-release preparations.

Evidence exists that sustained-release niacin, with respect to both dosage and severity, is more hepatotoxic than crystalline niacin. Three patients who developed hepatitis during treatment with sustained-release niacin were rechallenged with equivalent or higher doses of crystalline niacin, with no evidence of recurring hepatocellular damage.

Although the mechanism for niacin-induced hepatitis is unknown, these cases support previous observations that crystalline niacin may be less hepatotoxic than sustained-release preparations in certain patients. NIACIN (nicotinic acid) is an effective hypolipidemic agent available in several forms, including crystalline preparations ("regular" niacin) and various forms of sustained-release (or slow-release SR) capsules and caplets.

Hepatotoxic effects are an uncommon but well-documented complication of niacin therapy. Cholestatic and hepatocellular reactions have been described clinically, with liver biopsy findings of parenchymal necrosis and centrilobular cholestasis in most patients. Although the mechanism by which niacin or one of its metabolites induces hepatic injury is unknown, evidence exists to suggest a dose-related, direct toxic effect rather than an idiosyncratic drug reaction.

Although all forms of niacin have shown efficacy in modifying serum lipid levels, differences exist in their side effect profiles. Sustained-release niacins produce less cutaneous flushing, but a greater frequency and severity of hepatic and gastrointestinal side effects have been observed. Although most cases of hepatotoxic reactions are mild and reversible, fulminant hepatic failure has been reported, occurring within days of switching a patient from crystalline to SR niacin.

We describe the experience of three patients who developed hepatitis while receiving SR niacin therapy. These patients were rechallenged with equivalent (or higher) doses of crystalline niacin, and they maintained normal liver function test results after 6 to 10 months of therapy.

CASE 1.--A 62-year-old man with a medical history of a cardiac arrest and subsequent coronary artery bypass graft was referred to the Atherosclerosis Detection and Prevention Clinic for evaluation of his condition. His lipoprotein profile showed an elevated level of low-density lipoprotein cholesterol with a mildly decreased level of high-density lipoprotein cholesterol. A low-fat diet was started and a gradually increasing dose of crystalline niacin was given to the patient. On reevaluation at 4 months, the patient was tolerating well a niacin dose of 3000 mg/d, with normal results of liver function tests and an improved lipoprotein profile. He was advised to increase his daily niacin dose gradually to 4000 mg during the following month.

Four weeks later, the patient purchased an SR niacin capsule preparation (Major Pharmaceuticals, Chicago Ill) at a health food store and substituted it for his prescribed crystalline niacin. After ingesting SR niacin for 5 days (1000 mg four times daily) he began to experience nausea. Two days later, after drinking a glass of champagne on an empty stomach, the patient experienced a brief syncopal episode and was taken to the hospital.

On admission to the hospital, the patient was noted to be alert and oriented, with a blood pressure of 110/68 mm Hg and a pulse rate of 73 beats per minute. The results of physical examination were normal, except for orthostatic hypotension. Admission laboratory tests were remarkable for the following values: aspartate aminotransferase, 323 U/L; alanine aminotransferase, 210 U/L; albumin, 33 g/L; total bilirubin, 7 micromol/L; alkaline phosphatase, 66 U/L; lactate dehydrogenase, 360 U/L; and prothrombin time, 24s. The patient denied recent exposure to hepatotoxins; no serologic evidence of present or past viral hepatitis infection was noted. Myocardial infarction was ruled out. Niacin was withheld and the patient was treated with parenteral vitamin K. Maximal liver aminotransferase level elevations occurred 2 days after hospitalization and gradually declined to normal during the following 4 weeks.

At the patient's reevaluation 1 month later, crystalline niacin was readministered and the dosage was gradually raised back to 4000 mg/d. After more than 6 months at this dosage, there were minimal side effects, a greatly improved lipoprotein profile, and normal results of liver function tests.

CASE 2.--A 50-year-old woman with a medical history of hypertension, mitral valve prolapse, and coronary heart disease had a coronary artery bypass graft at the age of 45 years. familial hypercholesterolemia was diagnosed based on the lipoprotein profile, the presence of Achilles tendinous xanthomas, and a strong family history of hyperlipidemia and premature coronary heart disease. The patient was a heavy smoker and drank a glass of wine daily. Her medications included verapamil and hydrochlorothiazide. Treatment with SR niacin (Nicobid; USV Pharmaceutical Corp, Tarrytown, NY) was started at a dose of 1500 mg/d but was discontinued twice (after 5 months of therapy and again 4 months after readministration) because of elevations of the aspartate aminotransferase level to 111 and 177 U/L, respectively. Because of its effectiveness is modifying the patient's lipoprotein profile, SR niacin was readministered both times after normalization of the serum aminotransferase levels.

Six months after reinitiation of SR niacin therapy (several weeks after increasing her daily dose to 1000 ng twice daily), the patient came to the hospital with atypical chest pain. On admission to the hospital she was found to be icteric, with a blood pressure of 120/92 mm Hg and a pulse of 88 beats per minute. Results of physical examination were otherwise normal, except for a cardiac murmur consistent with mitral regurgitation and bruits over the carotid, femoral, and rental arteries. Laboratory tests were remarkable for the following values: alanine aminotransferase, 241 U/L; aspartate aminotransferase, 227 U/L; alkaline phosphatase, 2325 U/L; y-glutamyltransferase, 870 U/L; direct bilirubin, 80 micromol/L; indirect bilirubin, 41 micromol/L; lactase dehydrogenase, 278 U/L; partial thromboplastin time, 38 s; and prothrombin time, 24 s. No evidence of acute myocardial infarction was noted; results of serologic tests for viral hepatitis were negative. Niacin therapy was discontinued; the liver function test results gradually improved and normalized within 6 weeks.

Subsequently the patient was referred for evaluation at the Atherosclerosis Detection and Prevention Clinic. Treatment with 80 mg/d of lovastatin (Mevacor) caused a 16% reduction in the level of serum low-density lipoprotein cholesterol. As this response was considered to be insufficient, crystalline niacin was cautiously added (250 mg/d). The daily dose was gradually increased by 250 mg each week and finally maintained at 2500 mg. The patient tolerated this combination of lovastatin and crystalline niacin for more than 10 months with minimal side effects, normal results of liver function tests, and a much improved lipoprotein profile (Tabel).

CASE 3.--One year after a myocardial infarction and subsequent coronary angioplasty, a 47-year-old man was referred to the Atherosclerosis Detection and Prevention Clinic for evaluation. His medications included dipyridamole, diltiazem hydrochloride, and low-dose aspirin. Results of thyroid and liver function tests were normal. Lipoprotein analysis revealed mild elevations in levels of low-density lipoprotein cholesterol, intermediate-density lipoprotein cholesterol, and very-low-density lipoprotein cholesterol, with moderately reduced levels of high-density lipoprotein cholesterol. In light of the patient's premature coronary heart disease and syslipidemia, crystalline niacin was prescribed. He was instructed to begin with 250 mg/d and to increase the daily dose by 250 mg every week, up to a dose of 2000 mg/d. During the first 2 weeks he experienced pronounced flushing, and on his pharmacist's advice the patient switched to SR niacin (Slo-Niacin caplets, Upsher-Smith Laboratory Inc. Minneapolis, Minn), which he took according to the previously prescribed schedule.

On reevaluation 2 months later, just after increasing the daily niacin dose to 500 mg four times daily, the patient's liver function tests revealed the following levels: alanine aminotransferase, 160 U/L; aspartate aminotransferase, 155 U/L; alkaline phosphatase, 85 U/L; and total bilirubin, 9 micromol/L. Treatment with SR niacin was promptly discontinued, and treatment with crystalline niacin was reinstated at a daily dose of 1000 mg, which was gradually increased to 4000 mg/d with careful monitoring of liver function. After 6 months, the patient was tolerating crystalline niacin well and had normal results of liver function tests.

The National Cholesterol Education Program guidelines and recent studies suggesting regression of atherosclerotic plaques after aggressive hypolipidemic therapy have aroused an increased interest in the diagnosis and treatment of hyperlipidemia. Because niacin is inexpensive, and particularly because it is most effective in raising high-density lipoprotein cholesterol levels, its use can be expected to increase.

The mechanism of niacin-induced hepatitis is unknown. It has been speculated that SR niacin affects the liver enzyme systems for longer periods than does crystalline niacin, resulting in shorter recovery periods and thus more severe toxic effects. Another possibility is that different gastrointestinal tract absorption sites influence the metabolism and action of the preparations.

In our patients, the diagnosis of niacin-induced hepatitis was made on clinical grounds, as no evidence of viral hepatitis or exposure to other hepatotoxic agents was noted. Furthermore, all clinical and biochemical abnormalities resolved on withdrawal of the drug. Patient 2 exhibited serum aminotransferase abnormalities on three occasions during SR niacin treatment that resolved each time the drug was withdrawn. Patient 1, on the other hand, experienced a syncopal episode that could have resulted in ischemic hepatitis. However, most cases of ischemic hepatitis are characterized by a rapid rise and fall of serum aminotransferase levels, marked elevations in the serum level of lactate dehydrogenase, mild hyperbilirubinemia, and normal prothrombin time and serum albumin level. In contrast, our patient exhibited a rather gradual decline in serum aminotransferase levels, markedly abnormal prothrombin time and serum albumin level, only mildly elevated serum lactate dehydrogenase level, and no hyperbilirubinemia.

The time course for the development of niacin-induced hepatitis is unpredictable; although hepatitis may develop many months after beginning niacin therapy, much shorter intervals have also been documented with SR preparations, as illustrated by our patients 1 and 3.

Our data support previous observations that SR niacin preparations may be more hepatotoxic in certain patients. Concern must be expressed over the accessibility of such preparations without a prescription and the potential for individuals to ingest large doses in an unmonitored manner.