Liver Damage (Hepatotoxicity)

Hepatotoxicity implies chemical-driven liver damage. The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents when taken in overdoses and sometimes even when introduced within therapeutic ranges may injure the organ. Other chemical agents such as those 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More than 900 drugs have been implicated in causing liver injury and it is the most common reason for a drug to be withdrawn from the market. Chemicals often cause subclinical injury to liver which manifests only as abnormal liver enzyme tests. Drug induced liver injury is responsible for 5% of all hospital admissions and 50% of all acute liver failures.

Alternative names

• Toxic liver disease
• Toxin induced liver disease
• Drug induced liver disease
• Drug induced liver damage
• Hepatogenous poisoning

 Subordinate terms

• Toxic hepatitis
• Toxin induced 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

Mechanism of liver damage

Drugs continue to be taken off the market due to late discovery of hepatotoxicity. Due to its unique metabolism and close relationship with the gastrointestinal tract, the liver is susceptible to injury from drugs and other substances. 75% of blood coming to the liver arrives directly from gastrointestinal organs and then spleen via portal veins which bring drugs and xenobiotics in concentrated form. Several mechanisms are responsible for either inducing hepatic injury or worsening the damage process. Many chemicals damage mitochondria, an intracellular organelle that produce energy. Its dysfunction releases excessive amount of oxidants which in turn injures hepatic cells. Activation of some enzymes in the cytochrome P-450 system such as CYP2E1 also lead to oxidative stress. Injury to hepatocyte and bile duct cells lead to accumulation of bile acid inside liver. This promotes further liver damage. Non-parenchymal cells such as Kupffer cells, fat storing stellate cells and leukocytes (i.e. neutrophil and monocyte) also have role in the mechanism.

Factors influencing drug induced hepatotoxicity:

• Age
• Ethnicity and race
• Gender
• Nutritional status
• underlying liver disease
• Renal function
• Pregnancy
• Duration and dosage of drug
• Enzyme induction
• Drug- drug interaction

Adverse drug reactions

Adverse drug reactions are classified as type A (intrinsic or pharmacological) or type B (idiosyncratic). Type A drug reaction accounts for 80% of all toxicities.

Drugs or toxins that have a pharmacological (type A) 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 the case of acetaminophen overdose, this type of injury occurs shortly after some threshold for toxicity is reached.

Idiosyncratic (type B) injury occurs without warning; when agents cause non-predictable hepatotoxicity in susceptible individuals which is not related to dose and has variable latency period. 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; Troglitazone (Rezulin) and trovafloxacin (Trovan) are two prime examples of idiosyncratic hepatotoxins.

Patterns of injury

Chemicals produce a wide variety of clinical and pathological hepatic injury. Biochemical markers (i.e. alanine transferase, alkaline phosphatase and bilirubin) are often used to indicate liver damage. Liver injury is defined as rise in either (a) ALT level more than three times of upper limit of normal (ULN), (b) ALP level more than twice ULN, or (c) total bilirubin level more than twice ULN when associated with increased ALT or ALP. Liver damage is further characterized into hepatocellular (predominantly initial Alanine transferase elevation) and cholestatic (initial alkaline phosphatase rise) types. However they are not mutually exclusive and mixed type of injuries are often encountered.

Specific histo-pathological patterns of liver injury from drug induced damage are discussed below.

Zonal Necrosis

This is the most common type of drug induced liver cell necrosis where the injury 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 include:

• Paracetamol, carbon tetrachloride

Hepatitis

In this pattern hepatocellular necrosis is associated with infiltration of inflammatory cells. There can be three types of drug induced hepatitis. (A) viral hepatitis type picture is the commonest, where histological features are similar to acute viral hepatitis. (B) in the focal or non specific hepatitis scattered foci of cell necrosis may accompany lymphocytic infiltrate. (C) 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

Liver injury leads to impairment of bile flow and clinical picture is predominated by itching and jaundice. Histology may show inflammation (cholestatic hepatitis) or it can be bland without any 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 steatosis where phospholipid accumulation leads to a pattern similar to the diseases with inherited phospholipid metabolism defects (e.g. Tay-Sachs disease)

Causes:

• Microvesicular: 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

Neoplasms have been described with prolonged exposure to some medications or toxins. Hepatocellular carcinoma, angiosarcoma and liver adenomas are the ones usually reported.

Causes:

• Vinyl chloride
• combined oral contraceptive pill
• anabolic steroid
• arsenic
• thorotrast

Clinical assessment

This remains a challenge in clinical practice due to lack of reliable markers. Many other conditions lead to similar clinical as well as pathological picture. To diagnose hepatotoxicity, a causal relationship between the use of the toxin or drug and subsequent liver damage has to be established, but might be difficult, especially when idiosyncratic reaction is suspected. Simultaneous use of multiple drugs may add to the complexity. As in acetaminophen toxicity, well established dose dependent pharmacological hepatotoxicity is easier to spot. Several clinical scales such as CIOMS/RUCAM scale and Maria and Victorino criteria have been proposed to establish causal relationship between offending drug and liver damage. CIOMS/RUCAM scale involves a scoring system which categorizes the suspicion into "definite or highly probable" (score > 8), “probable” (score 6-8), “possible” (score 3-5), “unlikely” (score 1-2) and “excluded” (score ≤ 0). In clinical practice physicians put more emphasis on the presence or absence of similarity between the biochemical profile of the patient and known biochemical profile of the suspected toxicity ( e.g. cholestatic damage in amoxycillin-clauvonic acid ).

Treatment and prognosis

In most cases, liver function will return to normal if the offending drug is stopped early. Additionally, the patient may require supportive treatment. In acetaminophen toxicity, however, the initial insult can be fatal. Fulminant hepatic failure from drug-induced hepatotoxicity may require liver transplantation. In the past, glucocorticoides in allergic features and ursodeoxycholic acid in cholestatic pictures had been used, but there is no good evidence to support their effectiveness.

An elevation in serum bilirubin level of more that 2 times ULN with associated transaminase rise is an ominous sign. This indicates severe hepatotoxicity and is likely to lead to mortality in 10% to 15% of patients, especially if the offending drug is not stopped (Hy's Law). This is because it requires significant damage to the liver to impair bilirubin excretion, hence minor impairment (in the absence of biliary obstruction or Gilbert syndrome) would not lead to jaundice. Other poor predictors of outcome are old age, female sex, high AST.