Rechallenge with crystalline niacin after drug-induced
Yaakov Henkin, Karen C. Johnson, Jere P. Segrest
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.
Report Cases
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.
Comment
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.
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hepatitis from sustained-release niacin
JAMA, The Journal of the American Medical Association
July 11, 1990
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