To date, more than 900 drugs, toxins and herbs have been
reported tocause liver injury. The cautionary tales are
definitely out there — takebromfenac for example.
Bromfenac is an NSAID that was introduced in theUS in
1997 as a short-term analgesic for orthopedic patients.
But somepatients used it for longer than the approved
10-day treatment period, resulting in more than 50 cases
of severe hepatic injury, and withdrawal of the drug a
year later. The story was pretty much the same for troglitazone,
a thiazolidinedione that was approved in the US as an
antidiabetic agent in 1997. More than 90 cases of hepatotoxicity
were reported over three years and the drug was pulled
off the market. Thankfully, neither of these drugs ever
made it to Canada but they could have easily wound up
in the hands of Canadian patients if these adverse effects
weren't detected quite early on.
Rx
WITH CAUTION
Drug-induced liver disease is not usually life-threatening
but the prognosis is poor for the small number of patients
who experience acute liver failure due to their medication.
These patients typically have a 60-80% mortality rate
unless they get a liver transplant. Because of the serious
health risks involved, the prevention of drug-induced
liver disease is one of the main reasons behind drug
regulatory actions, such as restrictions on use and
withdrawal from the market. "The bottom line is
that although drug-induced liver disease should always
be considered in patients with abnormal liver tests,
it is a rare entity, but among those uncommon cases,
some patients can suffer from life threatening liver
disease," said Dr Einar Björnsson of the department
of internal medicine at Sahlgrenska University Hospital
in Gothenburg, Sweden.
To assess the liver toxicity of
new drugs released on the market, physicians are advised
to use Hy's rule — an observation by the late Dr
Hyman Zimmerman, which states that the combination of
drug-induced jaundice and high liver cell damage is
associated with a 10-50% fatality rate. Surprisingly,
this rule-of-thumb has never been scientifically validated.
Dr Björnsson and his colleague
Dr Rolf Olsson aimed to change all that with their study
published in the August 2005 issue of Hepatology,
the journal of the American Association for the Study
of Liver Diseases, which provides evidence to support
Hy's rule. The researchers also identify additional
factors that may predict the outcome of different types
of drug-induced liver diseases. The study looked at
all reports of suspected drug-induced liver disease
received by the Swedish Adverse Drug Reactions Advisory
Committee between 1970 and 2004.
The researchers analyzed 784 cases
in all, each involving levels of bilirubin more than
twice the upper normal limits and levels of aspartate
aminotransferase (AST) — an enzyme that when elevated
signals liver damage — that exceeded three times
the upper normal limits. Of these, 409 cases had hepatocellular
damage, while 206 had cholestatic damage and 169 had
mixed liver damage. Seventy-two patients died of liver
failure or underwent liver transplants.
HIDDEN
SYMPTOMS
Study results show that in accordance with Hy's rule,
hepatocellular jaundice has a high but variable mortality
rate, depending on the drug involved, while AST and
bilirubin levels are the most important predictors of
death or liver transplantation. Despite the support
that the study provides for Hy's rule, Dr Björnsson
warns against exaggerating the immediate applicability
of study findings for patients at risk of drug-induced
liver disease. "We have only studied a selected
population with severe drug-induced liver disease, which
required hospitalization in most cases.... Unfortunately,
many patients with drug-induced liver disease are asymptomatic,
but some patients with liver injury have non-specific
symptoms such as nausea, fatigue and simply not feeling
well shortly after starting a new drug. If these symptoms
are new and do not disappear the patients should be
advised to contact their doctor."
Hepatology August 2005;42(2);481-9
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