5.1 Hepatotoxicity

The liver, our body's largest internal organ, plays a crucial role in metabolism and detoxification. It processes nutrients, synthesizes proteins, and filters toxins from our blood. Understanding how the liver works is key to grasping the concept of hepatotoxicity.

Hepatotoxicity occurs when substances damage the liver. This can happen through various mechanisms, including oxidative stress, mitochondrial dysfunction, and immune-mediated reactions. Recognizing the signs and causes of liver damage is essential for preventing and treating hepatotoxicity.

Liver anatomy and physiology

• The liver is the largest internal organ in the human body, weighing approximately 1.5 kg in adults and located in the upper right quadrant of the abdomen
• Comprised of two main lobes (right and left) and further divided into eight segments based on blood supply and biliary drainage
• Performs over 500 vital functions, including metabolism of nutrients and drugs, synthesis of proteins and bile acids, and detoxification of endogenous and exogenous substances
• Receives dual blood supply from the hepatic artery (oxygenated blood) and portal vein (nutrient-rich blood from the intestines) which mix in the hepatic sinusoids before draining into the central vein and eventually the inferior vena cava

Mechanisms of hepatotoxicity

Intrinsic vs idiosyncratic reactions

Top images from around the web for Intrinsic vs idiosyncratic reactions

• 

  Elevated Liver Enzymes: ED-focused Management Pearls & Pitfalls - emdocs View original

  Is this image relevant?

• 

  Elevated Liver Enzymes: ED-focused Management Pearls & Pitfalls - emdocs View original

  Is this image relevant?

• 

  Acetaminophen (infusion) - wikidoc View original

  Is this image relevant?

• 

  Elevated Liver Enzymes: ED-focused Management Pearls & Pitfalls - emdocs View original

  Is this image relevant?

• 

  Elevated Liver Enzymes: ED-focused Management Pearls & Pitfalls - emdocs View original

  Is this image relevant?

1 of 3

Top images from around the web for Intrinsic vs idiosyncratic reactions

• 

  Elevated Liver Enzymes: ED-focused Management Pearls & Pitfalls - emdocs View original

  Is this image relevant?

• 

  Elevated Liver Enzymes: ED-focused Management Pearls & Pitfalls - emdocs View original

  Is this image relevant?

• 

  Acetaminophen (infusion) - wikidoc View original

  Is this image relevant?

• 

  Elevated Liver Enzymes: ED-focused Management Pearls & Pitfalls - emdocs View original

  Is this image relevant?

• 

  Elevated Liver Enzymes: ED-focused Management Pearls & Pitfalls - emdocs View original

  Is this image relevant?

1 of 3

• Intrinsic hepatotoxicity is dose-dependent and predictable, occurring in most individuals exposed to a sufficient dose of the toxicant (acetaminophen)
• Idiosyncratic reactions are rare, unpredictable, and not clearly dose-dependent, often involving individual susceptibility factors such as genetic polymorphisms or immune-mediated responses (isoniazid, diclofenac)

Oxidative stress and lipid peroxidation

• Many hepatotoxicants generate reactive oxygen species (ROS) which can overwhelm the liver's antioxidant defenses and cause oxidative damage to cellular macromolecules
• Lipid peroxidation of polyunsaturated fatty acids in cell membranes leads to formation of reactive aldehydes (malondialdehyde, 4-hydroxynonenal) that can further propagate oxidative injury and trigger inflammatory responses
• Antioxidants such as glutathione and vitamin E play a critical role in protecting against oxidative stress-induced liver damage

Mitochondrial dysfunction

• Mitochondria are key targets of many hepatotoxicants due to their role in energy production, fatty acid oxidation, and cell death pathways
• Toxicants can disrupt mitochondrial function by inhibiting respiratory chain complexes, uncoupling oxidative phosphorylation, or inducing mitochondrial permeability transition pore opening
• Mitochondrial dysfunction can lead to ATP depletion, oxidative stress, and release of pro-apoptotic factors (cytochrome c) into the cytosol

Immune-mediated liver injury

• Certain drugs (diclofenac, halothane) and herbal supplements can trigger immune-mediated liver injury by acting as haptens or priming immune responses
• Activation of innate immune cells (Kupffer cells, natural killer cells) and adaptive immune responses (T-cell mediated cytotoxicity, antibody-dependent cell-mediated cytotoxicity) contribute to liver damage
• Immune checkpoint inhibitors used in cancer immunotherapy (ipilimumab, nivolumab) can also cause immune-related hepatitis

Apoptosis and necrosis

• Apoptosis is a regulated form of cell death characterized by cell shrinkage, chromatin condensation, and formation of apoptotic bodies that are phagocytosed by neighboring cells
• Necrosis is an unregulated form of cell death characterized by cell swelling, organelle dysfunction, and plasma membrane rupture leading to release of cellular contents and inflammation
• Many hepatotoxicants can trigger both apoptosis and necrosis depending on the dose, duration, and cellular context
• Caspase activation and mitochondrial dysfunction are key mediators of apoptotic cell death in the liver

Types of hepatotoxicity

Steatosis and steatohepatitis

• Steatosis refers to excessive accumulation of triglycerides in hepatocytes, often due to impaired fatty acid oxidation or increased de novo lipogenesis
• Drugs such as valproic acid, tamoxifen, and certain antiretrovirals can induce steatosis by disrupting mitochondrial function or activating lipogenic transcription factors (SREBP-1c)
• Steatohepatitis is characterized by steatosis, inflammation, and hepatocellular injury, and can progress to fibrosis and cirrhosis if left untreated
• Alcoholic and non-alcoholic steatohepatitis (ASH and NASH) are common forms of steatohepatitis with similar histological features but different etiologies

Cholestasis and biliary injury

• Cholestasis refers to impaired bile flow leading to accumulation of bile acids and other toxic compounds in the liver and systemic circulation
• Drugs such as chlorpromazine, erythromycin, and anabolic steroids can cause cholestasis by inhibiting bile acid transporters (BSEP) or inducing biliary epithelial cell injury
• Biliary injury can manifest as acute cholestatic hepatitis, vanishing bile duct syndrome, or secondary sclerosing cholangitis
• Accumulation of hydrophobic bile acids during cholestasis can exacerbate hepatocellular injury and trigger inflammatory and fibrogenic responses

Fibrosis and cirrhosis

• Fibrosis is characterized by excessive deposition of extracellular matrix proteins (collagen, fibronectin) in response to chronic liver injury and inflammation
• Activated hepatic stellate cells are the primary source of collagen production in the fibrotic liver and can be activated by various cytokines and growth factors (TGF-β, PDGF)
• Cirrhosis represents an advanced stage of fibrosis characterized by distortion of liver architecture, formation of regenerative nodules, and increased intrahepatic resistance to blood flow
• Drugs such as methotrexate, amiodarone, and methyldopa can cause fibrosis and cirrhosis with long-term use or in susceptible individuals

Hepatocellular carcinoma

• Hepatocellular carcinoma (HCC) is the most common primary liver cancer and often develops in the context of chronic liver disease and cirrhosis
• Risk factors for HCC include viral hepatitis (HBV, HCV), alcohol abuse, aflatoxin exposure, and certain metabolic disorders (hemochromatosis, alpha-1 antitrypsin deficiency)
• Genotoxic compounds such as aflatoxin B1 and vinyl chloride can directly induce DNA damage and mutations in oncogenes or tumor suppressor genes
• Non-genotoxic carcinogens such as hormones (estrogens, androgens) and peroxisome proliferators (fibrates) can promote HCC development by altering gene expression or cell proliferation

Risk factors for hepatotoxicity

Age and gender

• Elderly individuals may be more susceptible to hepatotoxicity due to age-related changes in drug metabolism, comorbidities, and polypharmacy
• Gender differences in hepatotoxicity have been observed for certain drugs (valproic acid, isoniazid) possibly due to hormonal influences on drug metabolism or immune responses
• Pregnancy can alter drug pharmacokinetics and increase susceptibility to certain types of hepatotoxicity (tetracycline-induced fatty liver, herpes simplex virus hepatitis)

Genetic polymorphisms

• Genetic variations in drug-metabolizing enzymes (CYP450s, UGTs), transporters (BSEP, MRP2), and antioxidant enzymes (GSTM1, GSTT1) can influence individual susceptibility to hepatotoxicity
• Polymorphisms in the HLA genes have been associated with increased risk of idiosyncratic drug-induced liver injury (ximelagatran, flucloxacillin)
• Mutations in genes involved in bilirubin metabolism (UGT1A1) or mitochondrial function (POLG) can predispose individuals to certain types of drug-induced liver injury

Nutritional status

• Malnutrition and micronutrient deficiencies (vitamin E, selenium) can impair the liver's ability to handle oxidative stress and increase susceptibility to hepatotoxicity
• Obesity and nonalcoholic fatty liver disease (NAFLD) can sensitize the liver to the toxic effects of certain drugs (acetaminophen, methotrexate) and environmental toxicants
• High-fat and high-carbohydrate diets can modulate drug-metabolizing enzyme activity and alter the bioactivation or detoxification of hepatotoxicants

Alcohol consumption

• Chronic alcohol consumption can induce CYP2E1 activity and increase the bioactivation of certain hepatotoxicants (acetaminophen, carbon tetrachloride)
• Alcohol can also deplete hepatic glutathione stores and impair the liver's ability to handle oxidative stress
• Alcoholic liver disease can sensitize the liver to the toxic effects of other drugs and environmental exposures

Pre-existing liver disease

• Pre-existing liver diseases such as viral hepatitis, cirrhosis, and cholestasis can alter drug pharmacokinetics and increase the risk of hepatotoxicity
• Patients with advanced liver disease may have impaired drug clearance and require dose adjustments to avoid toxicity
• Certain drugs (nonsteroidal anti-inflammatory drugs, rifampin) can exacerbate pre-existing liver conditions or trigger acute-on-chronic liver failure

Diagnosis of hepatotoxicity

Liver function tests

• Serum aminotransferases (ALT, AST) are sensitive markers of hepatocellular injury but lack specificity for etiology
• Alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) are markers of cholestatic injury and biliary dysfunction
• Bilirubin, albumin, and prothrombin time reflect hepatic synthetic function and can be impaired in advanced liver disease
• Hy's law (ALT > 3x ULN, total bilirubin > 2x ULN, and ALP < 2x ULN) is a predictor of severe drug-induced liver injury and mortality

Imaging techniques

• Ultrasound is a non-invasive technique for detecting hepatomegaly, steatosis, and biliary obstruction
• Computed tomography (CT) and magnetic resonance imaging (MRI) can provide detailed information on liver morphology, tumors, and vascular abnormalities
• Magnetic resonance cholangiopancreatography (MRCP) is useful for visualizing the biliary tree and detecting biliary strictures or dilatation
• Transient elastography (FibroScan) is a non-invasive method for assessing liver stiffness and fibrosis

Liver biopsy

• Liver biopsy is the gold standard for diagnosing and staging liver diseases, including drug-induced liver injury
• Histological features can provide clues to the etiology of liver injury (eosinophilic infiltration, granulomas, cholestasis)
• Special stains (trichrome, reticulin) and immunohistochemistry can help assess fibrosis, inflammation, and specific cell types
• Risks of liver biopsy include bleeding, infection, and sampling error, and it should be performed judiciously in selected cases

Common hepatotoxic agents

Acetaminophen overdose

• Acetaminophen is a widely used analgesic and antipyretic that can cause severe hepatotoxicity when taken in excess (>4 g/day)
• At therapeutic doses, acetaminophen is primarily metabolized by glucuronidation and sulfation, with a small fraction undergoing CYP2E1-mediated bioactivation to the reactive metabolite NAPQI
• In overdose situations, glucuronidation and sulfation pathways become saturated, leading to increased formation of NAPQI which depletes hepatic glutathione stores and binds to cellular proteins
• N-acetylcysteine is an effective antidote for acetaminophen toxicity if administered within 8-10 hours of ingestion

Antituberculosis drugs

• Isoniazid, rifampin, and pyrazinamide are first-line drugs for treating tuberculosis that can cause hepatotoxicity individually or in combination
• Isoniazid undergoes acetylation and CYP2E1-mediated bioactivation to reactive metabolites that can cause oxidative stress and immune-mediated liver injury
• Rifampin is a potent inducer of CYP450 enzymes and can increase the bioactivation of other hepatotoxic agents (acetaminophen, herbal supplements)
• Pyrazinamide can cause dose-dependent hepatotoxicity characterized by a mixed hepatocellular-cholestatic pattern of injury

Anticonvulsants

• Phenytoin, carbamazepine, and valproic acid are commonly used anticonvulsants that can cause idiosyncratic liver injury in susceptible individuals
• Phenytoin and carbamazepine can trigger immune-mediated liver injury, possibly due to formation of reactive metabolites that act as haptens or priming of T-cell responses
• Valproic acid can cause microvesicular steatosis and steatohepatitis by inhibiting mitochondrial beta-oxidation and inducing oxidative stress
• Genetic polymorphisms in drug-metabolizing enzymes (CYP2C9, UGT1A6) and antioxidant pathways (GSTM1, GSTT1) have been associated with increased risk of anticonvulsant-induced hepatotoxicity

Herbal and dietary supplements

• Herbal and dietary supplements are a growing cause of hepatotoxicity due to lack of regulation, variable quality, and potential interactions with conventional medications
• Green tea extract, kava, and certain Chinese herbal medicines (Jin Bu Huan, Ma Huang) have been associated with severe hepatotoxicity and acute liver failure
• Pyrrolizidine alkaloids found in comfrey, butterbur, and other plants can cause sinusoidal obstruction syndrome and veno-occlusive disease
• Anabolic steroids and bodybuilding supplements can cause cholestatic liver injury and increase the risk of hepatocellular adenomas and carcinomas

Environmental toxins

• Aflatoxins are mycotoxins produced by Aspergillus fungi that contaminate crops such as corn, peanuts, and cottonseed
• Aflatoxin B1 is a potent hepatocarcinogen that induces DNA damage and mutations in the p53 tumor suppressor gene
• Heavy metals such as arsenic, cadmium, and mercury can accumulate in the liver and cause oxidative stress, mitochondrial dysfunction, and cellular injury
• Organic solvents (carbon tetrachloride, trichloroethylene) and pesticides (organochlorines, organophosphates) can cause acute and chronic liver damage through various mechanisms

Prevention and management strategies

Dose adjustments and drug monitoring

• Dose adjustments based on liver function tests, age, and comorbidities can help prevent hepatotoxicity in susceptible individuals
• Therapeutic drug monitoring can ensure that drug levels remain within the therapeutic range and avoid toxicity
• Pharmacogenetic testing for certain high-risk drugs (abacavir, carbamazepine) can identify patients with genetic susceptibility to hepatotoxicity

Antidotes and supportive care

• N-acetylcysteine is the antidote of choice for acetaminophen overdose and should be administered as soon as possible after ingestion
• Intravenous carnitine supplementation can be used to treat valproic acid-induced hepatotoxicity by restoring mitochondrial function
• Silymarin, a flavonoid extract from milk thistle, has antioxidant and anti-inflammatory properties and may be useful as an adjunctive therapy for various types of hepatotoxicity
• Supportive care measures (fluid resuscitation, electrolyte correction, coagulopathy management) are essential for managing acute liver failure and preventing complications

Liver transplantation

• Liver transplantation is the definitive treatment for end-stage liver disease and acute liver failure refractory to medical management
• Indications for liver transplantation in the context of hepatotoxicity include drug-induced acute liver failure, decompensated cirrhosis, and hepatocellular carcinoma
• Contraindications to liver transplantation include active substance abuse, uncontrolled infections, and extrahepatic malignancies
• Long-term outcomes after liver transplantation for drug-induced liver injury are generally favorable, with 5-year survival rates exceeding 70%

Emerging research and future directions

Novel biomarkers of hepatotoxicity

• MicroRNAs (miR-122, miR-192) are stable, tissue-specific biomarkers that can detect early stages of drug-induced liver injury in serum or plasma
• Glutamate dehydrogenase (GLDH) is a mitochondrial enzyme that is released into circulation during hepatocellular necrosis and may be a more specific marker than ALT
• High-mobility group box 1 (HMGB1) is a nuclear protein that is released by necrotic cells and can activate innate immune responses and inflammation
• Metabolomics and lipidomics approaches can identify novel biomarkers and pathways involved in hepatotoxicity

In vitro and in silico models

• 3D hepatic organoids derived from induced pluripotent stem cells (iPSCs) can model drug-induced liver injury and assess interindividual variability in response
• Organ-on-a-chip devices can simulate the complex interactions between hepatocytes, endothelial cells, and immune cells in a microfl