HEPATOTOXICITY

Alternative names
Toxic liver disease Drug induced liver disease Drug induced liver damage Hepatogenous poisoning
'Subordinate terms'
Toxic hepatitis Drug induced hepatitis Drug-induced hepatic necrosis Drug induced hepatic fibrosis Drug induced hepatic granuloma Toxic liver disease with hepatitis Toxic liver disease with cholestasis

'Hepatotoxicity' (from ''hepatic toxicity'') implies chemical-driven liver damage. Liver plays central role in transformation and clearance of most chemicals and is susceptible to the toxicity from drugs, xenobiotics, and oxidative stress. Certain medicinal agents when taken in overdoses and sometime even when introduced within therapeutic ranges may injure the organ. Other chemicals such as agents used in laboratories and industries, natural chemicals (e.g. microcystins) and herbal remedies can also induce hepatotoxicity. Chemicals that cause liver injury are called hepatotoxins.
More than 900 drugs have been implicated in causing liver injury^[1] and it is the most common reason for a drug to be withdrawn from the market. Drug induced liver injury is responsible for 5% of all hospital admissions and 50% of all acute liver failures^[2].

Contents

Drug metabolism in liver

Mechanism of liver damage

Patterns of injury

Specific drug or toxin

Acetaminophen

Nonsteroidal anti-inflammatory drugs

Isoniazid

Natural products

Industrial toxin

Herbal and alternative remedies

Reference

Drug metabolism in liver

Many common drugs are metabolised by the liver in significant amounts. This, together with its role as first filter of blood loaded with substances absorbed from the gut, makes hepatotoxicity one of the main concerns of pharmaceutical companies in their research for new drugs. All lead optimisation cascades must deal in some way with the issue of hepatic toxicity. Enterohepatic circulation is an especially thorny issue in drug discovery.

Mechanism of liver damage

Factors influencing drug induced hepatotoxicity[3]
★ Age ★ Ethnicity and race ★ Gender ★ Nutritional status ★ underlying liver disease ★ Renal function ★ Pregnancy ★ Duration and dosage of drug ★ Enzyme induction ★ Drug- drug interaction

Drugs or toxins that have a 'intrinsic' hepatotoxicity are those that have ''predictable'' dose-response curves (higher concentrations cause more liver damage) and well characterized mechanisms of toxicity such as directly damaging liver tissue or blocking a metabolic process. As in case of Acetamenophan overdose this type of injury occur shortly after some threshold for toxicity is reached .
'Idiosyncratic' injury occurs without warning, when agents cause ''non-predictable'' hepatotoxicity in susceptible individuals which is not related to dose and has variable latency period^[4]. This type of injury does not have a clear dose-response or temporal relationship, and most often do not have predictive models. Idiosyncratic hepatotoxicity has led to the withdrawal of several drugs from market even after rigorous clinical testing as part of the FDA approval process - Rezulin®(troglitazone), Ranitidine (Zantac®), and trovafloxacin (Trovan®) are three prime examples of idiosyncratic hepatotoxins. The development of ximelagatran (Exanta®) was discontinued for concerns of liver damage.

Patterns of injury

Chemicals produce a wide variety of clinical and pathological hepatic injury. Some of them can produce more than one pattern. Hepatocellular (predominantly initial Alanine transferase elevation) and cholestatic (initial alkaline phosphatase rise) patterns are the most common types of hepatic damage. However they are not mutually exclusive and mixed type of injuries are often encountered. Their biochemical findings are tabled.

''Patterns of drug-induced liver disease''

Type of injury	Hepatocellular	Cholestatic	Mixed
ALT	≥ Twofold rise	Normal	≥ Twofold rise
Alk Phos	Normal	≥ Twofold rise	≥ Twofold rise
ALT: Alk Phos ratio	High, ≥5	Low, ≤2	2-5
Examples[5]	Acetamenophan Allopurinol Amiodarone HAART NSAID	Anabolic steroid Chlorpromazine Clopidogrel Erythromycin Contraceptive pill	Amitryptyline, Enalapril Carbamazepine Sulphonamide Phenytoin

'Zonal Necrosis'
In this type of injury liver cell necrosis is largely confined to a particular zone of the liver lobule. It may manifest as very high level of ALT and severe disturbance of liver function leading to acute liver failure.
:Causes:
:Acetaminophen, carbon tetrachloride
'Hepatitis'
In this pattern hepatocellular necrosis is associated with infiltration of inflammatory cells. There can be three types of drug induced hepatitis. Viral hepatitis type picture is the commonest whre histological features are similar to acute viral hepatitis. In focal or nonspecific hepatitis scatterred foci of cell necrosis may accompany lymphocytic infiltrate. Chronic hepatitis type is very similar to autoimmune hepatitis clinically, serologically as well as histologically.
:Causes:
:Viral hepatitis like: Halothane, Isoniazid, Phenytoin
:focal hepatitis: Aspirin
:Chronic hepatitis: Methyldopa, Diclofenac
'Cholestasis'
Itching and jaundice often predominate clinical picture. Histology may show inflammation (Cholestatic hepatitis) or it can be bland with no parenchymal inflammation. In rare occasions it can produce features similar to primary biliary cirrhosis due to progressive destruction of small bile ducts (Vanishing duct syndrome).
:Causes:
:Bland:Oral contraceptive pills, anabolic steroid, Androgens
:Inflammatory:Allopurinol, Co-amoxiclav, Carbamazepine
:Ductal: Chlorpromazine, flucloxacillin
'Steatosis'
Hepatotoxicity may manifest as triglyceride accumulation which leads to either small droplet (microvesicular) or large droplet(macrovesicular) fatty liver. There is a separate type of phospholipid accumulation whose pattern is similar to diseases with inherited phospholipid metabolism defects (e.g. Tay-Sachs disease)
:Causes:
:Microvesicuilar: Aspirin (Reye's syndrome), Ketoprofen, Tetracycline
:Macrovesicular: Acetamenophen, methotrexate
:Phospholipidosis: Amiodarone, Total parenteral nutrition
'Granuloma'
Drug induced hepatic granulomas are usually associated with granulomas in other tissues and patients typically have features of systemic vasculitis and hypersensitivity. More than 50 drugs have been implicated.
: Causes:
:Allopurinol, Phenytoin, Isoniazid, Quinine, Penicillin, Quinidine

'Vascular lesions'
They result from injury to the vascular endothelium.
:Causes:
:Venoocclusive disease: Chemotherapeutic agents, bush tea
:Peliosis hepatis: anabolic steroid
:Hepatic vein thrombosis: Oral contraceptives
'Neoplasm'
Occassionally described with prolonged exposure to some medications or toxins. Hepatocellular carcinoma, angiosarcoma and liver adenomas are usually reported.
:Causes: Vinyl chloride, Oral contraceptive pill,Anabolic steroid, Arsenic, Thorotrast

Specific drug or toxin

Acetaminophen

Acetaminophen (paracetamol, also known by the brand name Tylenol®) is usually well tolerated in prescribed dose but overdose is the most common cause of drug induced liver disease and acute liver failure worldwide. The risk of liver injury is influenced by several factors including the dose ingested, concurrent alcohol or other concurrent drug intake, interval between ingestion and antidote. The dose toxic to liver is quite variable. Acetylcysteine can limit the severity of the liver damage by capturing the toxic acetaminophen metabolite.

Nonsteroidal anti-inflammatory drugs

Isoniazid

Natural products

Amanita mushroom (Amanita muscaria) toxic to liver

★ amanita mushroom

★ aflatoxins

Industrial toxin

★ Arsenic

★ Carbon tetraChloride

★ Vinyl Chloride

Herbal and alternative remedies

★ Ackee fruit

★ Bajiaolian

★ Camphor

★ Chinese herbal remedies:
:Jin Bu Huan
:Ma-huan
:Sho-wu-pian

★ Copaltra

★ Cycasin

★ Kava

★ Pyrrolizidine alkaloids

★ Horse chestnut leaf

★ Valerian

Reference

1. Current diagnosis & treatment in gastroenterology, Friedman, Scott E.; Grendell, James H.; McQuaid, Kenneth R., , , Lang Medical Books/McGraw-Hill, 2003,
2. GI/Liver Secrets: with STUDENT CONSULT Access, McNally, Peter F., , , C.V. Mosby, ,
3. Handbook of liver diseases, Keeffe, Emmet B; Friedman, Lawrence M., , , Churchill Livingstone, 2004,
4. Drug-induced liver disease., Zimmerman HJ, , , Drugs, 1978
5. Drug-related hepatotoxicity, Mumoli N, Cei M, Cosimi A, , , N. Engl. J. Med., 2006