Drug-induced Liver Injury
rates of INH metabolism exist; slow metabolizers are likely to develop high transaminase levels in response to INH administration. Co-administration of drugs that increase cytochrome p450 activity has an additional effect: rifampin, for example, enhances the toxicity of INH.71,72
Most patients
recover in several weeks after discontinuing the drug, while continuing the medication may result in severe hepatotoxicity (potentially leading to acute liver failure).21,70,73
Mechanistically, rifampin competes with bilirubin for the bile salt export pump, and results in hyperbilirubinemia and cholestatic liver disease.77
of patients); however, it may occur in patients with pre-existing liver disease.72,74–76
In addition, drug-induced hypersensitivity may also be responsible for a minority of cases.
Pirazinamide is generally not toxic per se, but when administered in combination with other drugs (INH, rifampin, ethambutol or quinolones) the risk of hepatic adverse reaction is significantly increased.78–82 Therefore, rifampin is no longer combined with pirazinamide for treating latent tuberculosis infections.70
Other Antibiotics
Beta-lactams, such as penicillins and cephalosporins, are commonly associated with DILI. The presence of beta-lactamase inhibitors (clavulanic acid) significantly increases the frequency of adverse reactions leading to cholestasis or a mixed pattern of liver injury. DILI induced by clavulanic acid compounds typically is manifested by reversible jaundice, but severe cases requiring liver transplant or resulting in fatal outcomes have been reported.30,83–85
cholestatic forms of DILI.86–89
Penicillinase-resistant penicillins are also associated with Macrolides are generally associated with
reversible cholestatic liver injury. The risk of erythromycin inducing DILI is estimated at 3.6/100,000 cases.90
Patients present with abdominal pain,
anorexia, nausea, and vomiting two–four weeks following the initial administration or after two–three days if re-challenged, suggesting a hypersensitivity mechanism. Liver abnormalities generally subside within two–five weeks after stopping the drug.91 for up to six months.
In rare cases, cholestasis persists
Sulfonamide-induced liver injury occurs within the first month of administering the medication. Most forms of liver injury are cholestatic, but inflammation and necrosis may also occur. The patients usually recover within several weeks after stopping the antibiotic, although chronic cholestasis or enhanced severity has been reported.92–95 Macrodantin is well recognized to induce both acute and chronic liver disease, and may be indistinguishable from autoimmune hepatitis.96,97
Antifungals
Ketoconazole and other azoles are associated with an increased risk .of hepatotoxicity. Liver injury generally presents as increased transaminase levels that are usually reversible.98
Although the hepatitis pattern is the
most common, cholestatic and mixed forms have been observed.99,100 Patients on antifungal therapy require careful monitoring, and administration should be abruptly stopped if the liver enzymes become elevated. Failure to do so can result in severe liver damage, and death.100,101 Oral terbinafine rarely induces DILI (1/45,000 to 1/54,000); however, severe cases have been reported, thus monitoring liver enzymes at baseline and after four–six weeks of treatment may assess for the potential hepatotoxicity of the drug.102,103
US GASTROENTEROLOGY & HEPATOLOGY REVIEW Kava root Cascara Sagrada-
Rhamnus Prusiana Germander -
Teucrium Chamaedrys Jin Bu Huan Ephedra Sinica HIV Antiretroviral Therapy
Up to 18% of patients treated with highly active antiretroviral therapy (HAART) develop DILI. The risk is increased by alcohol consumption, older age, and female gender. In addition, HBV and HCV co-infection enhances both the frequency and the severity of liver injury.104–109
Successful
treatment of the HCV infection results in reduced hepatic toxicity of antiretroviral drugs.110,111
Drug combinations employed in HAART
complicate the attempts to clearly identify the hepatotoxic potential of each individual medication. Clinical manifestations range from asymptomatic patients to acute liver failure and death. Although all antiretrovirals may induce hepatototoxicity, non-nucleoside analog reverse transcriptase inhibitors are the most likely culprits. Hypersensitivity and idiosyncratic mechanisms are implicated in the liver toxicity caused by these agents. Nevirapine is associated with a high incidence of liver toxicity,112
and low body mass index (BMI).113–119
and the risk is associated with HLA–DRB*0101 Clinically, hepatotoxicity due to
nevirapine occurs either early or after several months of therapy and it has a mixed pattern of liver injury.120
A risk factor for abacavir-induced DILI
is HLA-B*5701 positivity, thus patients should be screened for this phenotype prior to abacavir treatment.121,122
Liver toxicity occurs through
Protease inhibitors induce DILI in 6–11% of patients, but the incidence is significantly increased in HBV or HCV co-infections and alcohol consumption.126,127
mitochondrial damage resulting in lactic acidosis and hepatic steatosis.123–125
Among this class of drugs, ritonavir is the most
frequently associated with hepatotoxicity. Interestingly, simultaneously employing two protease inhibitors does not augment liver toxicity.128,129 Although many protease inhibitors increase unconjugated bilirubin levels, liver injury is not reported with this abnormality.130
Oral Hypoglycemics
The first drug of the thiazolidinedione class, troglitazone, was withdrawn due to its potential to cause severe hepatotoxicity.131,132
77 Sedative,
Lycopodium Serratum analgesic Ma Huang -
Rifampin alone seldom induces DILI (in up to 2.7%
Table 3: Hepatotoxicity Associated with Herbal Medications
Herbal supplement Use Chaparral-Larrea Tridentata
Multiple
Comfrey–Symphytum Anti- Officinale
Greater Celandine - Chelidonium Majus
Type of Liver Injury Cholestasis,
zone 3 necrosis, chronic hepatitis
inflammatory
Biliary diskinesia Anxiety,
depression, sleeping aid Laxative
Multiple
Veno-occlusive disease, 168 cholestasis in some cases
Irritable bowel Cholestasis, autoimmune 169, 170 syndrome
reaction
Necrosis, cholestasis, 171 fulminant hepatic failure
Cholestatic hepatitis Cholestatic hepatitis,
chronic hepatitis, cirrhosis
Acute and chronic hepatitis Weight reduction Acute hepatitis 180–182 177–179 172 173–176 Refs. 166, 167
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