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Hepatotoxicity associated with sustained-release niacin
Hepatotoxicity
Associated With Sustained-Release Niacin
THOMASA. DALTON,M.D., ROBERTS. BERRY,M.D., Birmingham,
Niacin (nicotinic acid) is a widely used agent in the treatment of hyperlipidemias characterized by elevated low-density lipoprotein and very-low- density lipoprotein. The tendency of the conventional crystalline niacin to cause flushing has limited its use in many patients. Sustained-release (SR) niacin preparations are increasingly utilized due to a lower incidence of flushing and convenient dosing frequency. Although gastrointestinal and hepatotoxic side effects are common to both formulations, they are more frequent and occasionally more severe with the SR preparations. We describe a patient who developed an acute illness characterized by hypothermia, hypotension, metabolic acidosis, and severe hepatic dysfunction 2 days after substitution of an SR preparation for a previously well-tolerated crystalline niacin,
From the Department of Medicine, University of Alabama School of Medicine, Birmingham, Alabama. Requests for reprints should be addressed to Thomas A. Dalton, M.D., Division of Gastroenterology, Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232. Manuscript submitted January 4. 1991, and accepted in revised form April 22, 1991.
102
July 1992 The American Journal of Medlclne
Volume 93
Alabama
iacin (nicotinic acid) is a widely used agent in N the treatment of hyperlipidemia. It is effective in the treatment of all lipoprotein disorders characterized by elevated low-density lipoprotein and very-low-density lipoprotein and is often chosen as a hypolipidemic agent because of its ability to also increase the high-density lipoprotein cholesterol level [l]. The side-effect profile of nicotinic acid is well described and includes flushing (most common), heartburn, nausea, bloating, diarrhea, hepatic dysfunction, hyperglycemia, and hyperuricemia [2]. The hepatotoxic effects are usually transient with evidence of both cholestasis and hepatocellular injury, and histopathologic findings are consistent with centrilobular cholestasis and parenchyma1 necrosis [3]. Although the mechanism of hepatic injury remains unknown, current evidence implicates a dose-related toxicity and not a hypersensitivity reaction [4]. Sustained-release (SR) preparations of nicotinic acid are available. These compounds produce less flushing than the conventional crystalline preparations, but controversy has arisen over their use. Gastrointestinal and hepatic side effects are more frequent and occasionally more severe with the SR preparations [5,6]. Niacin is readily available in pharmacies and health food stores without prescription and remains one of the least expensive lipid-lowering drugs. The patient can switch to SR preparations in order to decrease dosing frequencies and flushing. This is frequently done without medical supervision. Two articles have recently reported eight cases of hepatitis in patients during treatment with SR niacin [7,8]. All patients recovered, and three demonstrated no evidence of hepatic injury after rechallenge with crystalline niacin. We describe a patient who became acutely ill with evidence of severe hepatic dysfunction only 2 days after substituting an SR preparation for her previously well-tolerated crystalline niacin.
CASE REPORT A 67-year-old woman presented with a medical history remarkable for hypothyroidism secondary to thyroidectomy for which she was receiving Lthyroxine, hypertension, which was being treated with nifedipine, coronary artery disease requiring
NIACIN HEPATOTOXICITV / DALTON AND BERRY
bypassgrafting, and hyperlipidemia, which shehad beentreating for approximately 2 years with crystalline niacin. Two days prior to admission,at the suggestionof a local pharmacist,an SR formulation of equal dose (capsule, Rugby Labs Inc., West Hempstead,NY) wassubstituted. The patient was well until the day of admission when she complained of malaise and fatigue, and felt cool and diaphoretic. Her condition rapidly deteriorated, and, on presentation to the emergencyroom, she was agitated and unable to follow verbal commands. She was responsiveto painful stimuli only. The rectal temperature was 34.3OC,respirations were 24 breaths/minute, pulse rate was 72 beats/ minute, and blood pressurewas88/50 mm Hg. The neckwassupple,without thyromegaly or mass.The chestwas clear. Cardiac examination revealednormal Si and S2without murmur or gallop. The abdomen wassoft and nondistended,bowelsoundswere hypoactive, and there was no organomegaly.Extremities werewithout cyanosisor edema.On neurologic examination, sherespondedto painful stimuli and moved all extremities spontaneously.Her deeptendon reflexeswere normal throughout, and the plantar responseswere flexor. Laboratory studies revealedan increasedaniongap metabolic acidosis(sodium, 145mEq/L; potassium, 3.6 mEq/L; chloride, 108 mEq/L; bicarbonate, 13 mmol/L, blood urea nitrogen, 18 mg/dL, creatinine, 1.3mg/dL; and glucose,81 mg/dL). The calculated anion gap was 24 mEq/L. Arterial blood gasvalues on supplemental oxygen (2 L/min) were as follows: pH, 7.21; partial carbon dioxide pressure, 35 mm Hg; and oxygenpartial pressure,160 mm Hg. Liver function studies yielded the following results: serum glutamic oxaloacetic transaminase,363 IU/L; serum glutamic pyruvic transaminase, 105 III/L; r-glutamyl transferase,130 IU/L; alkaline phosphate, 252 IU/L; lactate dehydrogenase,446IU/L; total bilirubin, 0.5mg/dL; albumin, 3.3 g/dL; and a prothrombin time of 15.8seconds (control of 12.0 seconds). The white blood cell (WBC) count was 9,300/mm3,with 77% polymorphonuclearneutrophils and 22%lymphocytes.The hemoglobin measured 10.9g/dL, and the platelet count was147,000/mm3.Urinalysis showeda specific gravity of 1.015,pH of 5.0,one red blood cell per high-power field, one WBC per high-power field, and nine hyaline casts per low-power field. The chest radiograph demonstrated no acute disease, and the electrocardiogramshowedevidenceof prior inferior myocardial infarction without acute changes. A central venouscatheter was placed for parenteral hydration. Blood and urine cultures were ob-
tained and remained sterile. The patient received early empiric therapy with parenteral glucocorticoida, levothyroxine, broad-spectrum antibiotics, and thiamine. Computed tomographic scansof the head were normal. Serum and urine drug screens, salicylate level, and disseminatedintravascular coagulation studies were unremarkable. Pretreatment serum free thyroxine, thyroid-stimulating hormone,and cortisol levelswerewithin the normal range,and hepatitis B serologicresults were negative. There was no evidenceof myocardial infarction by electrocardiography or blood chemistry values. The patient’s condition rapidly stabilized, and her agitation resolved.Upon further questioning, the patient describedan episodeof flushing in the early morning on the day of admission similar to that which shehad previouslyexperiencedwith her crystalline niacin pills. She noted switching to the SR preparation (2 g/d) only 2 days prior to admission. Although hypothermia and significant metabolic acidosis have not typically been described with previously reported casesof niacin-associated hepatitis, the overall clinical presentationwasmost consistent with that diagnosis.Vitamin K was administered subcutaneouslyto correct a prothrombin time that had increasedto 17.1seconds(control 12.0seconds)on the secondhospital day; otherwise, treatment was supportive.There was rapid resolution of all symptoms,and at discharge(third hospital day), the liver function studieswere nearly normal (serum glutamic oxaloacetictransaminase,70 IU/L; y-glutamyl transferase, 92 IU/L; alkaline phosphatase,169 IU/L; and prothrombin time of 14.3 seconds). Approximately 1 month after discharge,the patient wasrechallengedwith a lower doseof crystalline niacin and experienced flushing and mild lightheadedness.Shewasreluctant to continue this therapy and subsequently switched to lovastatin without complication. COMMENTS Hepatotoxicity is an infrequent but well-described adverseeffect of nicotinic acid, usually occurring at a dosethat exceeds3 g/d. Liver biopsy is consistentwith both parenchymalnecrosisand centrilobular cholestasis,and this is reflected in the biochemicalprofile of thesepatients [3,4].Although most hepatic illness is mild and self-limiting, there havebeenreports of severehepatic dysfunction associated with this drug [3,9,10].There is growing evidencethat the SR formulations may be associated with much greaterhepatoxicity, including fulminant hepatic failure, than that typically associ-
July 1992 The American Journal of Medicine
Volume 93
103
NIACIN
HEPATOTOXICITY
/ DALTON
AND BERRY
ated with the crystalline preparations [4,6,7,11]. Two reports [7,8] have previously described eight cases of SR niacin-induced hepatitis, all of which responded to discontinuation of the drug. Rechallenge with crystalline niacin was tolerated, and normal liver function was maintained. The mechanism(s) by which SR niacin induces liver injury in those previously tolerating crystalline preparations remains unclear. Christensen et al [5] suggest that prolonged exposure of the liver enzyme system to the SR formulations would allow for increased toxicity with less time for recovery. In our case, the diagnosis of drug-induced hepatitis was made on clinical grounds. There was no evidence of viral or other toxin exposure. The unusual features of this patient’s presentation were the increased anion-gap metabolic acidosis and marked hypothermia; these have not been described previously with SR niacin. We postulate that the prolonged flushing (peripheral vasodilatation) noted by the patient resulted in significant transcutaneous heat loss and perhaps hypotension. Gibson and Dudley [12] described a series of 17 patients with ischemic hepatitis in whom the principal pathogenic mechanism was thought to be an acute decrease in hepatic blood flow. In that series, 16 of 17 patients had underlying heart disease, and, in nearly every instance, a cause for an acute decline in cardiac output was identified (26% had documented hypotension). Although the authors were careful to distinguish between ischemic and drug-induced liver injury, we believe that our patient clearly demonstrated components of both disorders. We attribute the metabolic acidosis to the accumulation of lactate, which is commonly seen in the setting of hepatocellular injury, vascular collapse, and hypothermia. Although we did not measure lactate directly, the presence of a gap acidosis of abrupt onset in the absence of ketoacidosis, salicylism, or the ingestion of toxic alcohols (methanol, ethylene glycol) is most compatible with lactic acidosis. Nicotinic acid is a useful drug in the treatment of hyperlipidemia. Side effects are described, but the drug is usually well tolerated at adequate doses. Patients, physicians, and pharmacists must be aware of potential complications and the observed differences in the crystalline and SR preparations. Henkin and co-workers [13] have reported that most pharmacists are not aware of the association of
104
July
1992
The Americen
Journal
of Medlclne
Volume
93
SR niacin and hepatitis and that 90% of surveyed pharmacists would recommend SR niacin to their customers, citing crystalline niacin-induced flushing as the primary consideration. This group has also observed differences in the frequency and severity of hepatotoxicity among the various SR niacin formulations. Because of the prolonged exposure of the liver to nicotinic acid that occurs with the SR preparations, it may be important to reduce the dose by 50% from the dose of crystalline nicotinic acid until tolerance is assessed. We share in the growing concern of the easy accessibility of SR niacin. We suggest that the “non-prescription” status of SR niacin preparations be reconsidered and urge supervision with periodic monitoring of liver function by the attending physician. This is especially important when a change in drug dose or preparation is under consideration.
ACKNOWLEDGMENT We wish to thank Theresa Varnedoe and Cheri Vice for their help in the preparation of this manuscript.
REFERENCES 1. Blum CB, Levy RI. Current 261: 3582-7.
therapy
of hypercholesterolemia.
JAMA 1989;
2. Nicotinic acid and its derivatives. In: Dukes MNG, editor. Meyler’s side effects of drugs. Amsterdam: Elsevier, 1988: 923. 3. Patterson DJ, Dew EQ, Gyorkey F. Graham DY. Niacin hepatitis. South Med J
1983; 76: 239-41. 4. Clements GL, Holmes AW. Nicotinic acid-induced fulminant hepatic failure. J Clin Gastroenterol 1987; 9: 582-4. 5. Christensen NA, Anchor RWP. Berge KG, Mason HL. Nicotinic acid treatment of hypercholesterolemia: comparison of plain and sustained-action preparations and two cases of jaundice. JAMA 1961; 177: 76-W. 6. Knopp RH, Ginsberg J, Albers JJ, eta/. Contrasting effects of unmodified and time-release forms of niacin on lipoproteins in hyperlipidemic subjects: clues to mechanism ‘of action of niacin. Metabolism 1985; 34: 642-50. 7. Henkin Y, Johnson KC, Segrest JP. Rechallenge with crystalline niacin after drug-induced hepatitis from sustained-release niacin. JAMA 1990; 264: 241-3. 6. Etchason JA, Miller TD, Squires RW, et a/. Niacin-induced hepatitis: a potential side effect with lowdose time-release niacin. Mayo Clin Proc 1991; 66: 23-8. 9. Pardue WO. Severe liver dysfunction during nicotinic acid therapy. JAMA
1961; 175: 137-8. 10. Winter SL. Boyer JL. Hepatic toxicity from large doses of vitamin 83 (nicotinamide). N Engl J Med 1973; 289: 1180-2. 11. Mullin GE, Greenson JK, Mitchell MC. Fulminant hepatic failure after ingestion of sustained-release nicotinic acid. Ann Intern Med 1989; 111: 253-5. 12. Gibson prognosis. 13. Henkin vations on
PR. Dudley FJ. lschemic hepatitis: clinical features, diagnosis and Aust N 2 J Med 1984; 14: 822-5. Y. Oberman A, Hurst DC, Segrest JP. Niacin revisited: clinical obseran important but underutilized drug. Am J Med 1991; 91: 239-46.
Associated With Sustained-Release Niacin
THOMASA. DALTON,M.D., ROBERTS. BERRY,M.D., Birmingham,
Niacin (nicotinic acid) is a widely used agent in the treatment of hyperlipidemias characterized by elevated low-density lipoprotein and very-low- density lipoprotein. The tendency of the conventional crystalline niacin to cause flushing has limited its use in many patients. Sustained-release (SR) niacin preparations are increasingly utilized due to a lower incidence of flushing and convenient dosing frequency. Although gastrointestinal and hepatotoxic side effects are common to both formulations, they are more frequent and occasionally more severe with the SR preparations. We describe a patient who developed an acute illness characterized by hypothermia, hypotension, metabolic acidosis, and severe hepatic dysfunction 2 days after substitution of an SR preparation for a previously well-tolerated crystalline niacin,
From the Department of Medicine, University of Alabama School of Medicine, Birmingham, Alabama. Requests for reprints should be addressed to Thomas A. Dalton, M.D., Division of Gastroenterology, Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232. Manuscript submitted January 4. 1991, and accepted in revised form April 22, 1991.
102
July 1992 The American Journal of Medlclne
Volume 93
Alabama
iacin (nicotinic acid) is a widely used agent in N the treatment of hyperlipidemia. It is effective in the treatment of all lipoprotein disorders characterized by elevated low-density lipoprotein and very-low-density lipoprotein and is often chosen as a hypolipidemic agent because of its ability to also increase the high-density lipoprotein cholesterol level [l]. The side-effect profile of nicotinic acid is well described and includes flushing (most common), heartburn, nausea, bloating, diarrhea, hepatic dysfunction, hyperglycemia, and hyperuricemia [2]. The hepatotoxic effects are usually transient with evidence of both cholestasis and hepatocellular injury, and histopathologic findings are consistent with centrilobular cholestasis and parenchyma1 necrosis [3]. Although the mechanism of hepatic injury remains unknown, current evidence implicates a dose-related toxicity and not a hypersensitivity reaction [4]. Sustained-release (SR) preparations of nicotinic acid are available. These compounds produce less flushing than the conventional crystalline preparations, but controversy has arisen over their use. Gastrointestinal and hepatic side effects are more frequent and occasionally more severe with the SR preparations [5,6]. Niacin is readily available in pharmacies and health food stores without prescription and remains one of the least expensive lipid-lowering drugs. The patient can switch to SR preparations in order to decrease dosing frequencies and flushing. This is frequently done without medical supervision. Two articles have recently reported eight cases of hepatitis in patients during treatment with SR niacin [7,8]. All patients recovered, and three demonstrated no evidence of hepatic injury after rechallenge with crystalline niacin. We describe a patient who became acutely ill with evidence of severe hepatic dysfunction only 2 days after substituting an SR preparation for her previously well-tolerated crystalline niacin.
CASE REPORT A 67-year-old woman presented with a medical history remarkable for hypothyroidism secondary to thyroidectomy for which she was receiving Lthyroxine, hypertension, which was being treated with nifedipine, coronary artery disease requiring
NIACIN HEPATOTOXICITV / DALTON AND BERRY
bypassgrafting, and hyperlipidemia, which shehad beentreating for approximately 2 years with crystalline niacin. Two days prior to admission,at the suggestionof a local pharmacist,an SR formulation of equal dose (capsule, Rugby Labs Inc., West Hempstead,NY) wassubstituted. The patient was well until the day of admission when she complained of malaise and fatigue, and felt cool and diaphoretic. Her condition rapidly deteriorated, and, on presentation to the emergencyroom, she was agitated and unable to follow verbal commands. She was responsiveto painful stimuli only. The rectal temperature was 34.3OC,respirations were 24 breaths/minute, pulse rate was 72 beats/ minute, and blood pressurewas88/50 mm Hg. The neckwassupple,without thyromegaly or mass.The chestwas clear. Cardiac examination revealednormal Si and S2without murmur or gallop. The abdomen wassoft and nondistended,bowelsoundswere hypoactive, and there was no organomegaly.Extremities werewithout cyanosisor edema.On neurologic examination, sherespondedto painful stimuli and moved all extremities spontaneously.Her deeptendon reflexeswere normal throughout, and the plantar responseswere flexor. Laboratory studies revealedan increasedaniongap metabolic acidosis(sodium, 145mEq/L; potassium, 3.6 mEq/L; chloride, 108 mEq/L; bicarbonate, 13 mmol/L, blood urea nitrogen, 18 mg/dL, creatinine, 1.3mg/dL; and glucose,81 mg/dL). The calculated anion gap was 24 mEq/L. Arterial blood gasvalues on supplemental oxygen (2 L/min) were as follows: pH, 7.21; partial carbon dioxide pressure, 35 mm Hg; and oxygenpartial pressure,160 mm Hg. Liver function studies yielded the following results: serum glutamic oxaloacetic transaminase,363 IU/L; serum glutamic pyruvic transaminase, 105 III/L; r-glutamyl transferase,130 IU/L; alkaline phosphate, 252 IU/L; lactate dehydrogenase,446IU/L; total bilirubin, 0.5mg/dL; albumin, 3.3 g/dL; and a prothrombin time of 15.8seconds (control of 12.0 seconds). The white blood cell (WBC) count was 9,300/mm3,with 77% polymorphonuclearneutrophils and 22%lymphocytes.The hemoglobin measured 10.9g/dL, and the platelet count was147,000/mm3.Urinalysis showeda specific gravity of 1.015,pH of 5.0,one red blood cell per high-power field, one WBC per high-power field, and nine hyaline casts per low-power field. The chest radiograph demonstrated no acute disease, and the electrocardiogramshowedevidenceof prior inferior myocardial infarction without acute changes. A central venouscatheter was placed for parenteral hydration. Blood and urine cultures were ob-
tained and remained sterile. The patient received early empiric therapy with parenteral glucocorticoida, levothyroxine, broad-spectrum antibiotics, and thiamine. Computed tomographic scansof the head were normal. Serum and urine drug screens, salicylate level, and disseminatedintravascular coagulation studies were unremarkable. Pretreatment serum free thyroxine, thyroid-stimulating hormone,and cortisol levelswerewithin the normal range,and hepatitis B serologicresults were negative. There was no evidenceof myocardial infarction by electrocardiography or blood chemistry values. The patient’s condition rapidly stabilized, and her agitation resolved.Upon further questioning, the patient describedan episodeof flushing in the early morning on the day of admission similar to that which shehad previouslyexperiencedwith her crystalline niacin pills. She noted switching to the SR preparation (2 g/d) only 2 days prior to admission. Although hypothermia and significant metabolic acidosis have not typically been described with previously reported casesof niacin-associated hepatitis, the overall clinical presentationwasmost consistent with that diagnosis.Vitamin K was administered subcutaneouslyto correct a prothrombin time that had increasedto 17.1seconds(control 12.0seconds)on the secondhospital day; otherwise, treatment was supportive.There was rapid resolution of all symptoms,and at discharge(third hospital day), the liver function studieswere nearly normal (serum glutamic oxaloacetictransaminase,70 IU/L; y-glutamyl transferase, 92 IU/L; alkaline phosphatase,169 IU/L; and prothrombin time of 14.3 seconds). Approximately 1 month after discharge,the patient wasrechallengedwith a lower doseof crystalline niacin and experienced flushing and mild lightheadedness.Shewasreluctant to continue this therapy and subsequently switched to lovastatin without complication. COMMENTS Hepatotoxicity is an infrequent but well-described adverseeffect of nicotinic acid, usually occurring at a dosethat exceeds3 g/d. Liver biopsy is consistentwith both parenchymalnecrosisand centrilobular cholestasis,and this is reflected in the biochemicalprofile of thesepatients [3,4].Although most hepatic illness is mild and self-limiting, there havebeenreports of severehepatic dysfunction associated with this drug [3,9,10].There is growing evidencethat the SR formulations may be associated with much greaterhepatoxicity, including fulminant hepatic failure, than that typically associ-
July 1992 The American Journal of Medicine
Volume 93
103
NIACIN
HEPATOTOXICITY
/ DALTON
AND BERRY
ated with the crystalline preparations [4,6,7,11]. Two reports [7,8] have previously described eight cases of SR niacin-induced hepatitis, all of which responded to discontinuation of the drug. Rechallenge with crystalline niacin was tolerated, and normal liver function was maintained. The mechanism(s) by which SR niacin induces liver injury in those previously tolerating crystalline preparations remains unclear. Christensen et al [5] suggest that prolonged exposure of the liver enzyme system to the SR formulations would allow for increased toxicity with less time for recovery. In our case, the diagnosis of drug-induced hepatitis was made on clinical grounds. There was no evidence of viral or other toxin exposure. The unusual features of this patient’s presentation were the increased anion-gap metabolic acidosis and marked hypothermia; these have not been described previously with SR niacin. We postulate that the prolonged flushing (peripheral vasodilatation) noted by the patient resulted in significant transcutaneous heat loss and perhaps hypotension. Gibson and Dudley [12] described a series of 17 patients with ischemic hepatitis in whom the principal pathogenic mechanism was thought to be an acute decrease in hepatic blood flow. In that series, 16 of 17 patients had underlying heart disease, and, in nearly every instance, a cause for an acute decline in cardiac output was identified (26% had documented hypotension). Although the authors were careful to distinguish between ischemic and drug-induced liver injury, we believe that our patient clearly demonstrated components of both disorders. We attribute the metabolic acidosis to the accumulation of lactate, which is commonly seen in the setting of hepatocellular injury, vascular collapse, and hypothermia. Although we did not measure lactate directly, the presence of a gap acidosis of abrupt onset in the absence of ketoacidosis, salicylism, or the ingestion of toxic alcohols (methanol, ethylene glycol) is most compatible with lactic acidosis. Nicotinic acid is a useful drug in the treatment of hyperlipidemia. Side effects are described, but the drug is usually well tolerated at adequate doses. Patients, physicians, and pharmacists must be aware of potential complications and the observed differences in the crystalline and SR preparations. Henkin and co-workers [13] have reported that most pharmacists are not aware of the association of
104
July
1992
The Americen
Journal
of Medlclne
Volume
93
SR niacin and hepatitis and that 90% of surveyed pharmacists would recommend SR niacin to their customers, citing crystalline niacin-induced flushing as the primary consideration. This group has also observed differences in the frequency and severity of hepatotoxicity among the various SR niacin formulations. Because of the prolonged exposure of the liver to nicotinic acid that occurs with the SR preparations, it may be important to reduce the dose by 50% from the dose of crystalline nicotinic acid until tolerance is assessed. We share in the growing concern of the easy accessibility of SR niacin. We suggest that the “non-prescription” status of SR niacin preparations be reconsidered and urge supervision with periodic monitoring of liver function by the attending physician. This is especially important when a change in drug dose or preparation is under consideration.
ACKNOWLEDGMENT We wish to thank Theresa Varnedoe and Cheri Vice for their help in the preparation of this manuscript.
REFERENCES 1. Blum CB, Levy RI. Current 261: 3582-7.
therapy
of hypercholesterolemia.
JAMA 1989;
2. Nicotinic acid and its derivatives. In: Dukes MNG, editor. Meyler’s side effects of drugs. Amsterdam: Elsevier, 1988: 923. 3. Patterson DJ, Dew EQ, Gyorkey F. Graham DY. Niacin hepatitis. South Med J
1983; 76: 239-41. 4. Clements GL, Holmes AW. Nicotinic acid-induced fulminant hepatic failure. J Clin Gastroenterol 1987; 9: 582-4. 5. Christensen NA, Anchor RWP. Berge KG, Mason HL. Nicotinic acid treatment of hypercholesterolemia: comparison of plain and sustained-action preparations and two cases of jaundice. JAMA 1961; 177: 76-W. 6. Knopp RH, Ginsberg J, Albers JJ, eta/. Contrasting effects of unmodified and time-release forms of niacin on lipoproteins in hyperlipidemic subjects: clues to mechanism ‘of action of niacin. Metabolism 1985; 34: 642-50. 7. Henkin Y, Johnson KC, Segrest JP. Rechallenge with crystalline niacin after drug-induced hepatitis from sustained-release niacin. JAMA 1990; 264: 241-3. 6. Etchason JA, Miller TD, Squires RW, et a/. Niacin-induced hepatitis: a potential side effect with lowdose time-release niacin. Mayo Clin Proc 1991; 66: 23-8. 9. Pardue WO. Severe liver dysfunction during nicotinic acid therapy. JAMA
1961; 175: 137-8. 10. Winter SL. Boyer JL. Hepatic toxicity from large doses of vitamin 83 (nicotinamide). N Engl J Med 1973; 289: 1180-2. 11. Mullin GE, Greenson JK, Mitchell MC. Fulminant hepatic failure after ingestion of sustained-release nicotinic acid. Ann Intern Med 1989; 111: 253-5. 12. Gibson prognosis. 13. Henkin vations on
PR. Dudley FJ. lschemic hepatitis: clinical features, diagnosis and Aust N 2 J Med 1984; 14: 822-5. Y. Oberman A, Hurst DC, Segrest JP. Niacin revisited: clinical obseran important but underutilized drug. Am J Med 1991; 91: 239-46.