Therapeutic Approaches in Management of Drug-induced Hepatotoxicity
Drugs are an important reason of hepatotoxicity. In general more than 900 drugs, toxins and herbs have been reported to cause hepatotoxicity and drugs account for 20-40% of all instances of fulminant hepatic failure. Specific therapy against drug-induced hepatotoxicity is limited to the use of N-acetylcysteine in the early phases of paracetamol toxicity. L-carnitine is potentially valuable in cases of valproate toxicity. In general, corticosteroids have no definitive role in treatment. They may prevent the systemic features associated with hypersensitivity or allergic reactions. Cholestyramine can be used for alleviation of pruritus. Ursodeoxycholic acid may be used. Lastly, consulting a hepatologist is always useful for other agents, supportive measures and the increasing use of liver-assist devices as well as emergency liver transplantation are available when drug injury evolves into irreversible liver failure. It is expected that a better understanding of hepatotoxicity mechanisms will lead to the development of more specific and effective forms of therapy in the near future.
Received: March 19, 2010;
Accepted: May 28, 2010;
Published: July 14, 2010
Drugs are an important reason of hepatotoxicity. In general more than 900 drugs,
toxins and herbs have been reported to cause hepatotoxicity and drugs account
for 20-40% of all instances of fulminant hepatic failure (Nilesh
et al., 2009) (Table 1). Acute hepatitis, with
or without cholestasis, is the usual histological pattern of DILI (drug-induced
liver disease) and drugs such as acetaminophen are the leading causes of acute
liver failure. Most cases of DILI resolve on discontinuation of the drug, but
recovery can take months or rarely the disease can progress despite drug withdrawal.
Drugs such as methotrexate may lead to chronic hepatitis and cirrhosis, while
others such as minocycline, nitrofurantoin and methyldopa are implicated in
Drug-induced steatohepatitis is not a common pattern, but is well described
with drugs such as amiodarone and irinotecan. In the presence of risk factors
such as obesity and diabetes, some drugs such as tamoxifen, oestrogens and nifedipine
can cause or exacerbate steatohepatitis. Other observed patterns include granulomatous
hepatitis, vascular injury (e.g., sinusoidal obstruction syndrome), cell lipidosis
and neoplasms (e.g., adenomas) (Ramachandran and Kakar,
DILD is a potential complication of any prescribed medication, because of the
central role of the liver in drug metabolism and elimination (Javed
et al., 2009). Drug-induced hepatotoxic reactions are of several
types and origin and the time to onset varies from being very short to exhibiting
a long latency. Clinically, the most relevant reactions include liver necrosis,
hepatitis, cholestasis, vascular changes and steatosis. It can be emphasized
that species differences in drug metabolism, target molecule and pathobiology
must be taken into account in the interpretation of findings and in assessing
the relevance of such findings to humans. For example, steatosis has significant
implications to clinicians, i.e., Non-Alcoholic Steato Hepatitis (NASH), yet
it is generally a less important finding non-clinically, particularly if observed
A drug can induce liver toxicity via several mechanisms. For example, it can
be directly acting or indirectly through reactive metabolites. The drug or its
metabolites may precipitate liver toxicity after specific receptor binding,
or reactive metabolites can react with hepatic macromolecules leading to direct
cytotoxicity. On the other hand, liver toxicity can be mediated via an immunological
cascade. Increases in the levels of the liver enzymes alanine aminotransferase
(ALT) and aspartate aminotransferase (AST) in serum, in combination with increased
bilirubin levels, are actually considered to be the most relevant indication
of liver toxicity (CHMP, 2008).
Clinical pattern of hepatotoxicity: Generaly, hepatotoxicity caused
by drugs is known to be either Type A dose dependent (intrinsic toxicity) or
Type B idiosyncratic (Rawlins and Thompson, 1977; Park
et al., 1998). Perhaps with the main exception of single high dose
of acetaminophen-associated hepatotoxicity, most drug-induced hepatotoxicity
cases, evaluated in clinical practice, are considered as idiosyncratic (Gunawan
and Kaplowitz, 2004). Normally, predictable reactions can be detected at
the preclinical and clinical stage of drug development. In general, these reactions
are dose related (intentional or accidental). Predictable reactions have a short
latency period, usually several hours to a few days (e.g., acetaminophen or
chemotherapy drugs) (Walgren et al., 2005).
The mechanism behind hepatotoxicity is poorly understood. It can be accompanied
with (1) immunoallergic features such as eosinophilia, rash, antibody titer
and fever having variable, usually short latency period (1-6 weeks) or (2) proceed
without immunoallergic manifestations and delayed latency period (up to 1 year)
(Larrey, 2002; Egger et al.,
2005). However, the absence of the common features of hypersensitivity does
not exclude an immune mediated toxicity. These features are only present in
23% of the patients with drug induced hepatotoxicity (Andrade
et al., 2005a). Many independent co-stimulatory factors may determine
idiosyncratic drug induced hepatotoxicity such as environment, age, sex, infections
and pharmacogenetic variation in drug metabolising polymorphisms between individuals
Important and specific agents with their effects on the liver.
Most drugs have a signature effect, which is a specific pattern of liver injury,
although some drugs such as rifampin can cause all kinds of liver injury, including
hepatocellular injury, cholestasis, or even isolated hyper bilirubinemia. However,
knowledge of the most commonly implicated agents and a high index of suspicion
are very essential in diagnosis (Nilesh et al., 2009).
Paracetamol: Acetaminophen [N-acetyl-p-aminophenol (APAP)], either singly
or as a component of a drug cocktail, is a frequently used over-the-counter
and prescription medication worldwide for analgesic and antipyretic effects
and it has a reasonable safety profile when consumed in therapeutic doses. In
contrast, supratherapeutic doses (intentionally or inadvertently ingested) were
recognized to cause severe liver toxicity and even fatal hepatic failure as
early as the 1960s. APAP can also induce renal failure and eventually death
in severe cases (Nelson, 1990).
The therapeutic serum concentration of APAP ranges from 10 to 20 μg mL-1.
However, the diagnosis of APAP-induced hepatotoxicity should be entertained
in a patient with a history of chronic, excessive APAP ingestion and elevated
liver enzymes, regardless of measured serum levels. Toxicity is unlikely to
occur with a single dose of less than 150 mg kg-1 in children or
less than 7.5 g in adults. Conversely, it is likely to occur when amounts greater
than 250 mg kg-1 in children or more than 12 g in adults are ingested
over a 24 h period (Tan et al., 2009).
Amoxicillin: Amoxicillin precipitates a moderate rise in SGOT levels,
SGPT levels, or both, but the significance of this finding is unknown. Hepatic
dysfunction, including jaundice, hepatic cholestasis and acute cytolytic hepatitis,
have been reported (Nilesh et al., 2009).
Amiodarone: Amiodarone causes abnormal liver function test results in
15-50% of patients. The spectrum of liver injury is wide, ranging from isolated
asymptomatic transaminase elevations to a fulminant disorder. Hepatic dysfunction
usually develops more than 1 year after starting therapy, but it can occur in
1 month. It is usually predictable, dose dependent and has a direct hepatotoxic
effect. Some patients with elevated aminotransferase levels have detectable
hepatomegaly and clinically important hepatic disease develops in less than
5% of patients. In rare cases, amiodarone toxicity manifests as alcoholic liver
disease. Hepatic granulomas are rare. Importantly, amiodarone has a very long
half-life and therefore may be present in the liver for several months after
withdrawal of therapy. Amiodarone is iodinated and this result in increased
density on CT scans, which does not correlate with hepatic injury (Chang
et al., 1999; Morelli et al., 1991).
Aspirin: Aspirin is rapidly converted to salicylic acid after absorption.
The major metabolites of aspirin are salicyluric and salicylphenolic glucuronide.
Aspirin overdose leads to systemic toxicity, but liver failure is rare. The
exact mechanism of the cellular injury is not clear, although several possible
modes of action have been postulated. These include lipid peroxidation, mitochondrial
damage, hydroxyl radical scavenging and toxicity to hepatocyte membranes (Zimmerman,
Chlorpromazine: Chlorpromazine liver toxicity resembles that of infectious
hepatitis with laboratory features of obstructive jaundice rather than those
of parenchymal damage. The overall incidence of jaundice is low irrespective
of dose or indication of the drug. Most cases occur 2-4 weeks after therapy.
Any surgical intervention should be withheld until extra hepatic obstruction
is confirmed. It is usually promptly reversible upon withdrawal of the medication;
however chronic jaundice has been reported. Chlorpromazine should be administered
with caution to persons with liver dysfunction (Bass, 2003).
Ciprofloxacin: Cholestatic jaundice has been reported with repeated administration of quinolones. Approximately 1.9% of patients taking ciprofloxacin show elevated SGPT levels, 1.7% has elevated SGOT levels, 0.8% has increased alkaline phosphatase levels and 0.3% has elevated bilirubin levels. Jaundice is transient and enzyme levels return to the reference range (Bass, 2003).
Diclofenac: Elderly females are more susceptible to diclofenac-induced
liver injury. Elevations of one or more liver test results may occur. These
laboratory abnormalities may progress, may remain unchanged, or may be transient
with regular therapy. Borderline or greater elevations of transaminase levels
occur in approximately 15% of patients treated with diclofenac. Of the hepatic
enzymes, ALT is recommended for monitoring liver injury. Meaningful (>3 times
the upper limit of the reference range) elevations of ALT or AST occur in approximately
2% of patients during the first 2 months of treatment. In patients receiving
long-term therapy, transaminase levels should be measured periodically within
4-8 weeks of initiating treatment (Batt and Ferrari, 1995).
Erythromycin: Erythromycin may cause hepatic disorder, including increased liver enzyme levels and hepatocellular and/or cholestatic hepatitis with or without jaundice. A cholestatic reaction is the most common adverse effect and usually begins within 2-3 weeks of therapy. The liver mainly excretes erythromycin; exercise caution when this drug is administered to patients with impaired liver function. The use of erythromycin in patients concurrently taking drugs metabolized by the P-450 system may be associated with elevations in the serum levels of other drugs (Bass, 2003).
Ethambutol: There are fewer reports of hepatic dysfunction with ethambutol
in the treatment of tuberculosis. Abnormal liver function tests have been reported
in some patients taking ethambutol; however, these patients were also taking
other anti tubercular drugs known to cause liver dysfunction (Tahaoglu
et al., 2001).
Fluconazole: The spectrum of hepatic reactions ranges from mild transient elevations in transaminase levels to hepatitis, cholestasis and fulminant hepatic failure. In fluconazole-associated liver toxicity, hepatotoxicity is not obviously related to the total daily dose, duration of therapy, or sex or age of the patient. Fatal reactions occur in patients with serious underlying medical manifestations. Fluconazole-associated hepatotoxicity is usually, but not always, reversible upon discontinuation of therapy (Bass, 2003).
Isoniazid: Around 10-20% of patients during the first 4-6 months of
therapy have a mild hepatic dysfunction shown by mild and transient increase
in serum AST, ALT and bilirubin concentration. But in some patients the hepatic
damage can be progressive and cause fatal hepatitis. Acetyl hydrazine, a metabolite
of Isoniazid is responsible for liver damage. Isoniazid should be stopped if
the AST increases to over 5 times the normal value. A prospective cohort study
of 11,141 patients receiving Isoniazid preventive therapy reported a rate of
hepatitis lower than that previously reported. Of these, 11 patients (0.10%
of those starting and 0.15% of those completing therapy) developed clinical
hepatitis (Nolan et al., 1999).
Methyldopa: Methyldopa is an antihypertensive that is contraindicated
in patients with active hepatic dysfunction. Periodic determination of hepatic
function should be performed during the first 6-12 weeks of therapy. Occasionally,
fever may occur within 3 weeks of methyldopa therapy, which may be associated
with abnormalities in liver function test results or eosinophilia, necessitating
discontinuation. In some patients, findings are consistent with those of cholestasis
and hepatocellular injury. Rarely, fatal hepatic necrosis has been reported
after use of methyldopa, which may represent a hypersensitivity reaction (Lee
and Denton, 1989).
Oral contraceptives: Oral contraceptives can lead to intra hepatic cholestasis
with pruritus and jaundice in a small number of patients. Patients with recurrent
idiopathic jaundice of pregnancy, severe pruritus of pregnancy, or a family
history of these disorders are more susceptible to hepatic injury. Oral contraceptives
are contraindicated in patients with a history of recurrent jaundice of pregnancy.
Benign neoplasm, rarely malignant neoplasm of the liver and hepatic vein occlusion
has also been associated with oral contraceptive treatment (Edmondson
et al., 1976).
Pyrazinamide: The well known adverse effect of this drug is hepatotoxicity.
Hepatotoxicity is dose related and may occur any time during therapy. In the
Centre for Diseases Control (CDC) update, 48 cases of hepatotoxicity were reported
in association with a 2 month regimen of Rifampin-pyrazinamide for the treatment
of latent tuberculosis. Thirty-seven patients recovered and 11 died of liver
failure. Of the 48 reported cases, 33 (69%) occurred in the second month of
therapy (CDC Update, 2003).
Rifampicin: Transient abnormalities in liver function are common in
the initial stages of therapy. But in some cases it may cause severe hepatotoxicity,
more so in those with pre-existing liver disease, forcing the physician to change
treatment and opt for liver friendly treatment. Rifampicin causes transient
elevations in hepatic enzymes usually within the first 8 weeks of therapy in
10 to 15% of patients, with less than 1% of the patients demonstrating overt
rifampicin-induced hepatotoxicity. The occurrence of mortality associated with
hepatotoxicity has been reported to be 16 in 500,000 patients receiving rifampicin.
A higher incidence of hepatotoxicity has been reported in patients receiving
Rifampicin with other anti tubercular agents and is estimated to be fewer than
4% (Kucers et al., 1987).
Statins/HMG-Co A reductase inhibitors (package inserts): The use of
statins is associated with biochemical abnormalities of liver function. Moderate
elevations of serum transaminase levels have been reported following initiation
of therapy and are often transient. Elevations are not accompanied by any symptoms
and do not require interruption of treatment. Persistent increases in serum
trans- aminase levels occur in approximately 1% of patients and these patients
should be monitored until liver function returns to normal after drug withdrawal.
Active liver disease or unexplained transaminase elevations are contraindications
to use of these drugs. Exercise caution in patients with a recent history of
liver disease or in persons who drink alcohol regularly and in large quantities.
Statins are among the most widely prescribed medications in the western world
(Chalasani, 2005; Chalasani et
Valproic acid and divalproex sodium: Microvesicular steatosis is found
with alcohol, aspirin, valproic acid, amiodarone, piroxicam, stavudine, didanosine,
nevirapine and high doses of tetracycline. Prolonged treatment with methotrexate,
isonizde, ticrynafen, perhexiline, enalapril and valproic acid may lead to cirrhosis.
Valproic acid typically causes microsteatosis.
This drug should not be given to patients with hepatic disease; exercise caution
in patients with a prior history of hepatic disease. Those at particular risk
include children younger than 2 years, those with congenital metabolic disorders
or organic brain disease and those with seizure disorders treated with multiple
anticonvulsants (Beyeler et al., 1997).
Herbs: The increasing use of alternative medicines also has led to many
reports of toxicity. The spectrum of liver disease is wide with these medicines
(Bateman et al., 1998; Gordon
et al., 1995).
||Jaundice with high transaminase levels may occur after 2 months of use,
but it disappears after stopping the drug
||Chaparral is used for a variety of conditions, including weight loss,
cancer and skin conditions. It may cause jaundice and fulminant hepatic
||Chinese herbs (Jin bu huan [Lycopodium serratum], Inchin-ko-to [TJ-135],
Ma-huang [Ephedra equisetina]) have been associated with hepatotoxicity
Risk factors and Hepatotoxicity
Gender: It is well known that women are more vulnerable than men to the
toxic effects of drugs in the liver, however gender differences have not always
become apparent when large case series were analyzed (Andrade
et al., 2005a). Regarding the clinic pathological expression of hepatotoxicity,
the variety of chronic auto immune hepatitis that is induced by drugs is seen
almost exclusively in women. Hepatotoxicity with certain medications such as
nitrofurantoin, chlorpromazine, tetracycline, halothane and diclofenac has been
reported more frequently in women (Andrade et al., 2005b). Female sex
along with hepatocellular liver damage and increased total bilirubin levels
on admission is suggested to be a risk factor for development of fulminant liver
failure (Andrade et al., 2005a).
Age: Analysis of a cohort of patients with hepatic dysfunction, considered
all drugs collectively suggested older age to be a risk factor to develop hepatotoxicity
(Andrade et al., 2005a). A large Spanish cohort
study reported the age-related pattern of liver damage resulting from Amoxicillin-Clavulanate
(AC) treatment. According to this study older age is related to cholestatic/
mixed type of damage while younger age is associated with cytolitic damage (Lucena
et al., 2006). Hepatocellular damage in the whole population was
directly correlated with age and had the worst outcome (Andrade
et al., 2005a).
Alcohol: Alcohol is capable of modulating the hepatotoxic potential of other drugs through CYP induction, inhibition, or substrate competition. Alcohol seems to have a dual effect on CYP2E1. During chronic regular intake, ethanol enhances acetaminophen hepatotoxicity by inducting CYP2E1, as well as susceptibility to liver damage from isoniazid, methotrexate, halothane and cocaine and perhaps to other drugs that are substrates for this microsomal isoform. During acute intake, however, substrate competition with acetaminophen occurs, actually decreasing the speed of metabolism of this drug to its toxic intermediate. However, this latter effect is partially counteracted by the ability of alcohol to slow the degradation of the CYP2E1 fraction, thus enhancing again the formation of the harmful metabolite once alcohol intake is interrupted. Alcohol also contributes to paracetamol hepatotoxicity by the direct inhibition of glutathione synthesis and through the malnutrition that frequently accompanies chronic alcoholism (Andrade et al., 2005b).
Smoking: Cigarette smoking was reported to be a risk factor for the
development of hepatic dysfunction (Sun et al., 2006;
Benowitz et al., 2003). Cigarette smoke contains
thousands of structurally diverse chemicals that possess cytotoxic, genotoxic
and tumorigenic activity. A toxic air pollutant formed by smoking such as acrolein
was reported to induce hepatotoxicity through direct mitochondrial damage (Sun
et al., 2006). Moreover, smoking may induce CYP isoform (CYP2E1)
and could contribute to acetaminophen hepatotoxicity and alcohol-induced liver
disease (Benowitz et al., 2003).
Early diagnosis of drug-induced liver reactions is essential to minimizing toxicity. Monitoring hepatic enzyme levels is appropriate and necessary with a number of agents, especially with those that lead to overt toxicity. For drugs that produce hepatotoxicity unpredictably, biochemical monitoring is less useful. ALT (Alanin Transferase) values are more specific than AST (Aspartate Transferase) values. ALT values that are within the reference range at baseline and rise 2- to 3-fold should lead to enhanced vigilance in terms of more frequent monitoring. ALT values 4-5 times higher than the reference range should lead to prompt discontinuation of the drug.
No specific treatment is indicated for drug-induced liver disease. Treatment
is generally supportive and based on symptomatology. Other than different synthetic
compounds several hundred plants have been examined for use in a wide variety
of liver disorders. About 170 phytoconstituents isolated from 110 plants belonging
to 55 families were stated to possess liver protective activity about 600 commercial
herbal formulations with claimed hepatic protective activity are being marketed
worldwide (Trease and Evans, 2002).
The first step of management of hepatotoxicity is to discontinue the suspected drug. Specific therapy against drug-induced hepatotoxicity is limited to the use of N-acetylcysteine in the early phases of paracetamol toxicity. L-carnitine is potentially valuable in cases of valproate toxicity. In general, corticosteroids have no definitive role in treatment. They may suppress the systemic features associated with hypersensitivity or allergic reactions. Management of protracted drug-induced cholestasis is similar to that for primary biliary cirrhosis. Cholestyramine may be used for alleviation of pruritus. Ursodeoxycholic acid may be used. Lastly, consulting a hepatologist is always helpful (Bass, 2003).
Management of paracetamol-induced hepatotoxicity
N-Acetylcysteine: The antidote for APAP hepatotoxicity is NAC (N-Acetylcysteine).
It is recommended in all patients in whom the quantities of APAP ingested, serum
drug levels, or rising aminotransferases indicate a risk of hepatotoxicity.
Its use is also suggested in patients with acute liver failure when APAP ingestion
is possible or even when knowledge of circumstances surrounding admission is
inadequate (Polson and Lee, 2005).
When administered early (within 8 h of APAP ingestion), NAC limits the accumulation
of NAPQI (N-acetyl-para-benzoquinoneimine/N-acetylbenzoquinoneimine) by directly
binding to it, increasing glutathione stores and increasing sulfate conjugation
(Lin and Levy, 1981). No deaths have been reported in
larger studies in which NAC was administered within 10 h of APAP ingestion,
regardless of serum levels (Smilkstein et al., 1991).
Oral charcoal: Oral activated charcoal is also useful if given within
4 h of APAP ingestion. It may be used beyond the initial 4 h in the presence
of delayed gastric emptying or APAP absorption (e,g., with co-ingestants that
reduce gut motility). It has been noted to adsorb APAP, resulting in reduced
absorption of the drug. In patients with known or suspected APAP overdose who
present within 4 h of ingestion, administration of activated charcoal is recommended
as first-line therapy, even before NAC (Polson and Lee,
2005; Green et al., 2001). A study comparing
the use of gastric lavage, syrup of ipecac and oral activated charcoal among
20 patients found that activated charcoal produced a greater lowering of mean
serum APAP levels than other interventions (Underhill et
al., 1990). It has the best risk-benefit ratio in comparison with other
decontaminants (Brok et al., 2006). Oral activated
charcoal is administered as a single oral dose of 1 g kg-1. There
is no benefit to the use of divided doses.
Cimetidine: The use of cimetidine to treat APAP toxicity was based on
the observation that it is also metabolized by the cytochrome P450 2E1 pathway,
which would theoretically lead to competitive inhibition of the enzyme and reduce
APAP metabolism to NAPQI. In an early study, however, Slattery
et al. (1989) reported that the administration of 300 mg of cimetidine
every 6 h to 13 subjects after 8 h of APAP ingestion did not alter APAP metabolism
or APAP elimination or reduce alanine transferase or aspartate transferase levels.
It was suggested that this lack of effect reflected the late administration
of cimetidine after APAP ingestion (Burkhart et al.,
Dialysis: The role of extracorporeal elimination in APAP intoxication
is controversial and the data are scanty. Hemodialysis has been used in severe
APAP hepatotoxicity as the drug is dialyzable. However, results have not shown
that hemodialysis prevents or reduces the risk of hepatotoxicity (McBride
and Rumack, 1992).
Prevention and treatment of acute hepatotoxicity caused by unpredictable
(idiosyncratic) hepatotoxins: Because no specific antidotal treatments exist
for the forms of toxicity that are caused by drug allergy or metabolic idiosyncrasy,
prevention is paramount. Severe immunologically mediated or allergic hepatitis
is generally considered an indication for steroid therapy, but only anecdotal
reports support its use and there is scarce evidence of its benefits (Deleve
and Kaplowitz, 2000). Management of acute non-immunologic hepatic injury
consists of supportive and symptomatic treatment, the nature of which depends
on the form of injury.
Treatment of idiosyncratic acute hepatocellular injury: Drug-induced
hepatocellular jaundice has a potential case fatality rate of 10% or more. Accordingly,
it warrants careful observation for evidence of impending hepatic failure. In
the patient whose jaundice is not severe, whose prothrombin time is normal or
negligibly prolonged and who has no clinical evidence of impending encephalopathy
or coagulopathy, medical management can be simply supportive and the individual
can be followed on an outpatient basis. Unless there is evidence of impending
hepatic failure, a standard diet is appropriate, with no need to modify the
protein or other components. Persistent anorexia may be managed by multiple
small feedings and by providing fruits, vegetables and dairy foods rather than
meat. Carbonated drinks, fruit juice and hard candy are usually well tolerated
even when nausea is marked. There is no need to restrict physical activity,
although patients should be advised to stay within limits of fatigability. The
patient with measurable prolongation of prothrombin time and elevated bilirubin
levels should be hospitalized (or observed very closely as an outpatient), particularly
if there is persistent nausea and anorexia after the drug has been withdrawn
Treatment of acute cholestatic injury: Acute drug-induced cholestatic
jaundice is rarely fatal. Over 99% of patients with cholestatic jaundice caused
by erythromycin, chlorpromazine, amoxicillin-clavulanate, or anabolic steroids
have survived the episode. There is no firm evidence that any therapeutic measures
affect the rate of disappearance of drug-induced cholestasis. However, several
anecdotal observations suggest that treatment with ursodeoxycholic acid increases
the rate of return to normal status (Mork et al.,
1997; OBrien et al., 1996; Katsinelos et
al., 2000) and in our view the effort is warranted. The most important
aspects of treatment of cholestatic jaundice relate to the treatment of pruritus.
Cholestyramine, which can offer relief, presumably traps elements involved in
the itching. Other potentially useful agents include hydroxyzine, rifampin (Rifadin)
and narcotic antagonists. There is no evidence that glucocorticoids provide
symptomatic or other benefit in drug-induced cholestasis. Perhaps most important
is an awareness that certain drug-induced cholestatic reactions can be mistaken
for syndromes of anatomic biliary obstruction calling for surgical intervention,
as has been seen with erythromycin and amoxicillin-clavulanate (Lewis
and Zimmerman, 1999).
Management of chronic drug-induced hepatic disease: Treatment of the various syndromes of chronic hepatic disease that may be drug-induced mainly involves recognition of symptoms and withdrawal of the responsible agent. The lesion and syndrome of chronic hepatitis may be caused by a number of agents and by different mechanisms.
Chronic autoimmune hepatitis: Drug-induced chronic autoimmune hepatitis
may resemble, to a striking degree, the form of chronic necroinflammatory disease
dubbed autoimmune in origin. This type of injury has been reported
following use of several agents, including nitrofurantoin, minocycline, methyldopa,
diclofenac and pemoline, among others (Lewis and Zimmerman,
1998). Indeed, in any form of non viral chronic hepatitis, especially with
autoimmune features, a drug should be suspected as the cause. Following withdrawal,
improvement should become noticeable within 1 to 4 weeks. In some instances
where injury fails to abate despite withdrawal of the drug, glucocorticoid therapy
may be included.
Chronic cholestasis: Drug-induced chronic cholestasis is usually a sequel
to acute cholestatic injury with loss of portal area bile ducts Vanishing Bile
Duct Syndrome, (VBDS). Currently, there is no accepted therapy for the cholestatic
process in patients with VBDS; however, ursodiol has been used successfully
in a few reported patients who had received amoxicillin-clavulanate, chlorpromazine,
prochlorperazine (improving pruritus and liver function tests) androgens, anabolic
steroids and tetracycline (Mork et al., 1997;
OBrien et al., 1996; Katsinelos
et al., 2000; Singh et al., 1996).
Long-term treatment with ursodiol, 300 to 600 mg, has been required in some
patients with VBDS to control the manifestations of cholestasis (OBrien
et al., 1996). This syndrome usually resolves spontaneously, although
it may take several months to years and only a minority of these patients develop
secondary biliary cirrhosis (Desmet et al., 1998).
Fatty liver, fibrosis and cirrhosis: Drug-induced macrovesicular fatty
liver is a lesion that, per se, offers little threat. The steatosis may, as
with methotrexate (MTX), be the forerunner of a more severe form of liver disease,
namely cirrhosis. Serious hepatic disease, however, appears to occur only in
patients who are alcoholics or obese diabetics. Aminotransferase testing is
considered to be adequate for monitoring of patients with rheumatoid arthritis
(Kremer et al., 1996; Lewis,
1997), juvenile rheumatoid arthritis (Hashkes et
al., 1999) taking MTX.
Referral to liver transplantation centre/surgical care: No specific antidote is available for the vast majority of hepatotoxic agents. Emergency liver transplantation has increasing utility in the setting of drug-induced fulminant hepatotoxicity. Considering early liver transplantation is important. The Model for End-Stage Liver Disease score can be used to evaluate short-term survival in an adult with end-stage liver disease. This can help stratify candidates for liver transplantation. The parameters used are serum creatinine, total bilirubin, international normalized ratio and the cause of the cirrhosis (Bass, 2003).
A large prospective database creation on drug-induced hepatotoxicity in collaboration
with multidisciplinary and multicentric networks focused on the identification
of bona fide cases following the same structural report form has been the very
first step to provide insights into epidemiology and pathogenesis of drug-induced
hepatotoxicity. This has allowed creating a pharmacoepidemiological culture
in the attending physicians that become more alert in the detection of drug-induced
hepatotoxicity and understanding of complex mechanism of drug-induced hepatotoxicity.
Drug-induced hepatotoxicity in paediatric patients is an orphan field and there
is obvious need to develop strategies to accomplish implementation of a specific
network in paediatric patients (Hoofnagle, 2004; Pineiro-Carrero
and Pineiro , 2004; Squires et al., 2006).
It is hoped that a better understanding of hepatotoxicity mechanisms will provide
the development of more specific and effective forms of hepatic therapy in the
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