Liver Toxicity: Mechanism and Drug-Induced Injury

Mechanism of Liver Toxicity

• The liver serves as the body's chemical engineering and control center.
• It regulates the metabolism of internal compounds.
• The liver processes compounds from external sources, including drugs.
• It is an adaptable organ, capable of regrowing even if two-thirds are resected.
• Liver cells regenerate rapidly when killed or removed.
• Enzyme and transporter function in the liver can be altered.

Physiologic functions

• Formation and secretion of bile
• Nutrient and Vitamin Metabolism (AA, Lipid, Glucose)
• Synthesis of Plasma proteins
• Detoxification & Inactivation of various substances (toxins, drugs)
• Immune System function

Introduction to Drug-Induced Liver Injury (DILI)

• DILI is a significant cause of liver dysfunction leading to a spectrum of symptoms.
• Symptoms can range from mild, non-specific issues like asymptomatic transaminitis to severe conditions such as acute hepatitis, chronic hepatitis, cholestasis, and liver failure.
• DILI can be triggered by prescription drugs, herbal remedies, and dietary supplements.

Liver-Related Conditions

• Transaminitis means elevated levels of certain liver enzymes, called transaminases.
• Acute hepatitis is inflammation or hepatocellular injury lasting less than six months, characterized by normalization of liver function tests.
• Chronic hepatitis is inflammation of the liver lasting at least six months, stemming from hepatitis B and C viruses or certain drugs.
• Cholestasis is a marked reduction in bile secretion and flow that can be caused by functional impairment of hepatocytes or obstruction of the excretory pathway of bile.

More Liver-Related Conditions

• Hepatocellular carcinoma (HCC), or liver cancer, occurs when a tumor grows on the liver
• Fibrosis indicates liver scarring, and cirrhosis is the most severe form, increasing the risk of complications.
• A granuloma is a small cluster of white blood cells and other tissue that can appear in various parts of the body.
• Granulomas aren't cancerous and form in reaction to infections, inflammation, irritants, or foreign objects.
• Fatty liver disease (steatosis) is the build-up of excess fat in the liver cells.

Epidemiology of DILI

• DILI is the most common cause of acute liver failure (ALF) in the USA and Europe.
• DILI accounts for 20% to 40% of all instances of fulminant hepatic failure.
• The incidence of DILI is underestimated as many cases are missed or underreported, making the true incidence difficult to determine.
• It is hard to confidently ascribe hepatic injury to a drug due to the absence of universally accepted assessment guidelines.
• Fulminant hepatic failure (FHF) is defined by the appearance of severe liver injury with hepatic encephalopathy in a previously healthy person

Etiology of DILI

• Drugs known to cause drug-induced liver injury include:
• Nonsteroidal anti-inflammatory drugs (NSAIDs)
• Anti-infective drugs (anti-tubercular drugs)
• Anti-cancer drugs
• Hormonal drugs
• Immunosuppressive agents
• Sedatives
• Neuropsychiatric drugs.

Risk Factors for DILI

• Increased risk of drug-induced liver injury:
• Old age
• Female gender
• Chronic alcoholism
• Pregnancy
• Children are at an increased risk of liver toxicity caused by valproate and are more prone to Reye syndrome with aspirin.
• With increasing age, the risk of toxicity increases with drugs like amoxicillin-clavulanate.

Reye's Syndrome

• Reye's syndrome is a rare condition that happens in children after a viral infection or illness, especially if they took aspirin to treat their symptoms.
• It is characterized by progressive encephalopathy with hepatic dysfunction.
• Reye's syndrome targets the brain, blood, and liver, and can be life-threatening if not treated early.

Pathophysiology of Liver Damage

• Liver damage can manifest as hepatocellular, cholestatic, or mixed types and involves foreign chemicals called xenobiotics.
• Xenobiotics include plant constituents, drugs, pesticides, cosmetics, flavorings, fragrances, food additives, and industrial chemicals and environmental pollutants.
• Cholestatic damage commonly occurs from the drug itself or its metabolites.
• The liver inhibits hepatobiliary transporter systems essential for bile formation and secretion of cholephilic substances and xenobiotics.
• "Cholephil" refers to endogenous and exogenous substances that are removed from circulation by the liver and concentrated in the bile.
• Hepatocellular damage occurs through direct hepatotoxicity, innate immune responses and adaptive immune responses

Dose-Dependent and Independent DILI

• DILI can be dose-dependent or dose-independent
• Acetaminophen typically causes drug-induced liver injury in a dose-dependent manner.
• Most other drugs cause a dose-independent pattern of hepatotoxicity.

Classification of DILI

• Intrinsic
• Idiosyncratic
• Allergic
• Non-allergic

Drug-Induced Liver Injury Classification

• Intrinsic: Paracetamol, Amiodarone, Valproic acid, Statins, Arti-metabolites
• Hepatic: Isoniazid, Nitrofurantoin, Lamotrigine, Interferon-B, Anti-TNF agerts, Proton-pump inhibitors
• Idiosyncratic: Mixed Fluoroquinolone, Macrolides, Phenytoin, Carbamazepine, Sufasalazine
• Cholestatic: Amoxicillin/Clavulanate, Trimethoprim, Azathioprine
• Steatohepatitis: Amiodarone, Tamoxifen, Methotrexate
• Anabolic steroids
• Vascular: Azathioprine

Intrinsic DILI Characteristics

• Intrinsic DILI is typically dose-dependent.
• It occurs in a predictable manner.
• The onset of hepatotoxicity is observed within hours to days of exposure.
• Drugs causing intrinsic DILI are often lipophilic, enabling free access across the hepatocyte's lipid bilayer.
• These drugs undergo biomodification into reactive metabolites that cause oxidative stress.
• It activates cellular signalling pathways to induce mitochondrial dysfunction and disturbances of bile acid homeostasis.

Idiosyncratic DILI

• Idiosyncratic DILI typically follows an unpredictable course with variable latency of onset of weeks to months.
• It is a rare occurrence observed in one in more than 10,000 patients but accounts for 10–15% of ALF in the USA.
• Idiosyncratic DILI lacks a clear dose dependence.
• A minimum dose of 50-100 mg/day of the offending drug is required.

Patterns and Classification of Idiosyncratic DILI

• The pattern of liver injury in idiosyncratic DILI can be divided into hepatocellular, cholestatic, or mixed types, according to the liver enzyme derangement profile.
• Idiosyncratic DILI can be further classified into immune-mediated (allergic) and non-immune-mediated reactions.

Immune-Mediated vs Non-Immune-Mediated Idiosyncratic DILI

• Immune-mediated idiosyncratic DILI usually presents within 1-6 weeks of drug administration.
• It is characterized by fever, rash, eosinophilia, presence of autoantibodies
• Non-immune-mediated idiosyncratic DILI does not manifest the aforementioned features and has a delayed onset of clinical presentation.

Common Drugs Implicated in DILI

• The most common drug implicated in DILI is acetaminophen.
• Antibiotics are the class of drugs most commonly causing liver toxicity.
• Amoxicillin-clavulanate stands out as the most common drug in this class.
• Herbal supplements cause a variety of symptoms, but their usage remains under-reported.

Amoxicillin-Clavulanate

• Amoxicillin-clavulanate is one of the most frequently used antimicrobials.
• It is a combination of two different drugs: amoxicillin and clavulanic acid.
• It includes penicillins and beta-lactamase inhibitors.

Spectrum and Coverage of Amoxicillin

• Amoxicillin is a penicillin derivative active against both gram-positive and gram-negative bacteria.
• It is used against Enterococcus species, Listeria monocytogenes, Streptococcus species, Haemophilus influenzae, Corynebacterium diphtherias, Escherichia coli, Klebsiella pneumoniae, Salmonella spp., and Shigella spp.
• The spectrum is increased to include all beta-lactamase-producing strains (of the previously mentioned organisms).
• It broadens the coverage to include other species like methicillin-sensitive Staphylococcus aureus (MSSA), Neisseria species, and Proteus species.
• Methicillin, withdrawn from the market in the United States because of the high incidence of interstitial nephritis associated with its use

Acetaminophen Toxicity

• Acetaminophen is also known as N-acetyl-para-aminophenol, and paracetamol (APAP).
• It is an antipyretic (to prevent or reduce fever) and analgesic (to relieve pain).
• Acetaminophen is used in many products in combination with other preparations, especially with opioids and diphenhydramine.
• It appears to inhibit cyclooxygenase (COX) in the brain selectively resulting in its ability to treat fever and pain and inhibits prostaglandin synthesis in the CNS.
• Acetaminophen directly acts on the hypothalamus producing an antipyretic effect.
• Diphenhydramine is an antihistamine used to relieve symptoms of allergy, hay fever, and the common cold.

Cyclooxygenase Isoenzymes, COX-1 & COX-2

• Catalyze the formation of prostaglandins.
• Prostaglandins affect virtually all known physiological and pathological processes.
• Inhibition of prostaglandin synthesis is a central mechanism to which gastrointestinal injury occurs.
• This is a result of inhibition of the COX which converts unsaturated fatty acids such as arachidonic acid released by cell injury to prostaglandins.