Drug-induced Liver Injury

Drug-induced liver injury (DILI) is the most common cause of acute liver failure (ALF). Hepatotoxic drugs can cause injury to the hepatocytes directly in a predictable dose-dependent way or through idiosyncratic reactions (which may be mediated by immune or non-immune processes). The injury mechanisms can have the following effects: hepatitis, cholestasis, vascular lesions, or overlapping changes. The presentation can be acute or chronic, with severe toxicity manifesting as fulminant liver failure. The diagnosis of DILI requires a thorough history and laboratory tests including liver function tests (LFTs) and drug levels, if available. Management consists of discontinuing the drug, supportive therapy, and monitoring for complications. Acetaminophen, one of the most common causes of DILI, has a specific treatment, N-acetylcysteine (NAC).

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Overview

Epidemiology

  • Drug-induced liver injury (DILI) incidence: 10–15 per 10,000 to 100,000 persons exposed to prescription medications
  • 10% of all cases of acute hepatitis 
  • Most common cause of acute liver failure (ALF) in the United States
  • Most common reason for withdrawing a drug from the market

Etiology

  • Prescription medications:
    • Acetaminophen: most common etiology of DILI in the United States
    • Amoxicillin-clavulanate: most common etiology worldwide
  • Herbal medications and dietary supplements are also associated with DILI.
  • Risk factors:
    • Women > men
    • Adults > children 
    • Alcohol abuse 
    • Malnutrition
    • Pre-existing liver disease
    • Genetics (alterations in enzymes involved in drug metabolism)
    • Concomitant use of other drugs
    • Age (e.g., DILI from isoniazid increases with age)

Metabolism of drugs

The liver handles metabolism of drugs/toxins, thus making the liver susceptible to injury. The drugs themselves undergo processes to be inactivated and become water soluble (for proper renal or biliary excretion).

Phase I reaction:

  • Mediated by cytochrome P450
  • Drug undergoes oxidation or hydroxylation.
  • Not all drugs go through phase I.
  • Drug-related hepatotoxicity can occur due to phase I metabolites (e.g., the metabolite of acetaminophen, N-acetyl-P-benzoquinone-imine (NAPQI), causes DILI).

Phase II reaction:

  • Involves glucuronidation or sulfation or inactivation by glutathione
  • Process further increases drug solubility, forming non-toxic substances that are easily excreted.

Phase III reaction:

  • Product transport across the canalicular membranes
  • Transporters facilitate drug-product excretion into the bile.

Pathophysiology

Mechanisms of drug toxicity

Intrinsic/direct hepatotoxins:

  • Hepatocellular damage that is dose dependent 
  • Short latent periods between exposure and DILI
  • Effect of the drug/hepatotoxin is reproducible and predictable.
  • Produce toxic hepatitis (e.g., poisons) or are converted to a toxic metabolite in the liver (e.g., acetaminophen)
  • Examples:
    • Carbon tetrachloride 
    • Acetaminophen 
    • Tetracycline
    • Amanita phalloides mushroom

Idiosyncratic reactions: 

  • Not dose dependent (unpredictable)
  • Variable latent periods (up to 3 months after starting medication)
  • DILI was not seen in preclinical trials in most cases.
  • Reactions are often not reproducible, and are usually species specific.
  • Mechanisms:
    • Immune mediated (hypersensitivity reactions)
    • Non-immune (related to host factors/genetics)
  • Examples:
    • Isoniazid
    • Phenytoin
    • Amoxicillin-clavulanate
    • Valproic acid
    • Antiretroviral therapy

Pathophysiology of DILI

Potential mechanism overlaps of drugs may occur as mixed hepatocellular and cholestatic changes occur.

Potential mechanisms of how drugs cause liver cell injury:

  • Drug disrupts calcium homeostasis: actin fibrils disassemble → cell membrane blebbing → cell lysis 
  • Immune response activation: 
    • Cytochrome P450 enzyme binds with the drug, producing non-functioning adducts.
    • Adducts reach the cell surface → cytolytic T cells and cytokines attack the adducts as targets 
  • Drug activation of apoptotic pathways: 
    • Stimulation of death receptors (tumor necrosis factor (TNF) receptor or Fas) 
    • Results in programmed cell death 
  • Mitochondrial disruption: 
    • ↓ Adenosine triphosphate (ATP) levels; ↑ lactate, and reactive oxygen species; lipid peroxidation → cell injury
    • Failed free fatty acid metabolism → triglyceride accumulation (steatosis)

Potential mechanisms of how drugs affect the biliary excretion pathway:

  • Damaged actin filaments next to the canaliculus:
    • Transport proteins at the canalicular membrane are affected, preventing bile flow.
    • Loss of villous processes and impaired canalicular pumps → ↓ bile excretion 
  • Bile duct damage: 
    • Toxic metabolites (excreted in bile) damage bile-duct epithelium → cholestasis
    • Protracted cholestasis leads to vanishing bile duct syndrome.

Clinical Presentation

Symptoms

  • Can be asymptomatic
  • When symptomatic, may present with right upper quadrant (RUQ) pain, jaundice, nausea/vomiting.
  • May have pruritus (in cholestasis)
  • In severe cases: mental status changes occur due to hepatic encephalopathy.

Signs

Acute liver failure:

  • Rapid onset (< 3-month duration)
  • Hepatomegaly and RUQ tenderness
  • Disorientation/confusion, jaundice
  • Abnormalities of liver function tests (LFTs):
    • Alanine transaminase/aminotransferase (ALT)
    • Aspartate transaminase/aminotransferase (AST)
    • Alkaline phosphatase (ALP)
    • Bilirubin
  • Coagulation abnormality (prothrombin/international normalized ratio or PT/INR > 1.5)
  • May have ↑ white blood cell count (WBC) 

Chronic liver injury:

Chronic liver injury is defined as lasting > 3 months, thereby resembling chronic liver disease or cirrhosis:

  • Spider angiomas
  • Ascites
  • Palmar erythema
  • LFT abnormalities

Diagnosis

Clinical findings

  • History:
    • Specific drug intake prior to the onset of liver injury
    • Any underlying liver disease ruled out
    • Cessation of the offending drug leads to improvement of liver injury.
    • Repeated use causes liver abnormalities (rechallenge is not recommended and should not be tried).
  • Physical examination findings are suggestive of liver disease.

Laboratory tests

Liver function tests:

  • Hepatocellular injury/hepatitis:
    • AST/ALT elevation disproportionate to ALP elevation
    • May have elevated bilirubin
    • May have abnormal PT/INR, albumin
  • Cholestatic injury:
    • ALP elevation disproportionate to ALT/AST elevation
    • May have elevated bilirubin
    • May have abnormal PT/INR, albumin
  • Mixed injury: combination of the above findings, but ALT/AST:ALP ratio < 5
  • Hy’s law: 
    • Presence of jaundice (serum bilirubin > 2x normal) with ↑ serum ALT/AST (> 3x normal)
    • Indicative of worse prognosis (mortality > 10%)

Drug levels:

  •  Obtained if history is suggestive and test is available
  •  May correlate with degree of hepatotoxicity (acetaminophen)
Type of injuryBlood test
Hepatitis
  • ALT ≥ 3 x ULN
  • ALT/ALP ratio > 5
Cholestasis
  • ALP ≥ 2 x ULN
Mixed
  • ALT ≥ 3 x ULN and ALP ≥ 2 x ULN
  • ALT/ALP ratio > 2, but < 5
ALT: alanine transaminase
ALP: alkaline phosphatase
ULN: upper limit of normal

Liver biopsy

  • Not required for diagnosis but performed if the diagnosis or severity is uncertain
  • Can help rule out other causes of liver injury
  • Histology shows morphologic changes/patterns that can correlate with suspected drug(s).

Histologic patterns of injury:

  • Acute hepatocellular injury/hepatitis (seen in 90% of DILI):
    • Hepatocellular necrosis, apoptosis, degeneration 
    • Affected areas can be spotty, with isolated hepatocytes.
    • If injury is extensive, massive necrosis is noted (seen in ALF). 
  • Chronic hepatocellular injury: 
    • Resembles changes in chronic liver disease
    • Periportal and pericellular fibrosis
  • Acute cholestatic injury:
    • Pure cholestasis: bile plugging/accumulation with minimal hepatocellular injury
    • Cholestatic hepatitis: cholestasis, portal inflammation with hepatocellular injury
  • Chronic cholestasis:
    • Chronic portal inflammation
    • Bile duct degeneration or loss (vanishing bile duct syndrome)
  • Steatosis and steatohepatitis:
    • Due to mitochondrial disruption: ↑ triglycerides
    • Acute DILI (microvesicular); chronic DILI (macrovesicular)
  • Granulomas:
    • Non-necrotizing granulomas
    • Often in the periportal and portal areas
  • Vascular lesions:
    • Sinusoidal obstruction syndrome (occlusion of terminal hepatic venules and sinusoids)
    • Budd-Chiari syndrome (drug-induced thrombosis)
  • Others: phospholipidosis, peliosis hepatis
Table: Histologic patterns of liver injury
Pattern of injuryExamples
Acute hepatitis
  • Ibuprofen, methyldopa, phenytoin
  • Massive necrosis: acetaminophen, halothane
Chronic hepatitis/fibrosis
  • Isoniazid, methotrexate, atorvastatin
Cholestatic hepatitis (mixed)
  • Clindamycin, phenytoin, azathioprine, nitrofurantoin
Cholestasis
  • Oral contraceptives, anabolic steroids, antiretroviral therapy, antibiotics, thiabendazole, tricyclic antidepressants
Steatosis or steatohepatitis
  • Valproic acid, amiodarone, antiretroviral therapy, tamoxifen
Granulomas
  • Sulfonamides, amiodarone, allopurinol, isoniazid, phenytoin
Vascular lesions
  • Budd-Chiari syndrome: oral contraceptives, anabolic steroids
  • Sinusoidal obstruction syndrome: high-dose chemotherapy (oxaliplatin), oral contraceptives

Management

General recommendations

  • Main treatment: cessation of the offending drug
  • Serial laboratories until the LFTs return to normal
  • Monitor for complications: 
    • Hypoglycemia
    • Monitor level of consciousness
    • Prevent gastrointestinal bleeding with a proton pump inhibitor 
    • Infection
    • Multi-organ failure

Specific therapy

Limited specific treatments for DILI:

  • N-acetylcysteine (NAC) for acetaminophen toxicity
  • L-carnitine for cases of valproic acid overdose (associated with hyperammonemia, lethargy, and hepatic dysfunction)
  • Symptomatic therapy: bile acid sequestrant to relieve the pruritus
  • Liver transplantation for fulminant liver failure

Acetaminophen-induced Hepatotoxicity

Acetaminophen

  • Most common cause of ALF 
  • ALT/AST > 1,000 U/L followed by jaundice and encephalopathy
  • Toxic dose (single ingestion):
    • Potentially toxic: > 7.5 g in healthy adults, > 150 mg/kg in children
    • Likely toxic: > 250 mg/kg or 12 g over a 24-hour period 
    • In alcoholics/anticonvulsant users: lower toxic dose
  • Normal metabolism:
    • Metabolized by the hepatic cytochrome P450 system 
    • Metabolite: NAPQI is toxic but appropriate acetaminophen doses produce small amounts.
    • NAPQI is normally detoxified by glutathione → non-toxic cysteine and mercaptate compounds → renal excretion 

Pathogenesis and clinical presentation

Pathogenesis:

  • ↑ Acetaminophen dose → excessive metabolites (NAPQI) deplete glutathione levels and saturate the elimination pathways.
  • ↑ Amounts of NAPQI bind with hepatic macromolecules → produce NAPQI-protein adducts (irreversible process) → ↑ risk of oxidative stress → hepatocellular necrosis 

Clinical presentation:

  • Stage I (1st 24 hours): 
    • Nausea and vomiting, malaise; may be asymptomatic
    • Laboratory studies are usually normal.
  • Stage II (24–72 hours): 
    • Ongoing hepatic necrosis results in ↑ ALT/AST by 36 hours
    • RUQ pain and hepatomegaly occur.
  • Stage III (72–96 hours): 
    • Liver function abnormalities peak.
    • Severe toxicity: ALT/AST > 10,000 IU/L, prolonged PT/INR, lactic acidosis, bilirubin > 4 mg/dL
    • Possibly complicated with ALF, renal failure, pancreatitis
    • Death may occur in multi-organ failure.
  • Stage IV (> 5 days):
    • Resolution or progression to multi-organ failure
    • Symptoms and laboratory values take weeks to return to normal.

Diagnosis and management

Diagnosis:

  • Drug levels of acetaminophen correlate with the severity of hepatic injury.
  • Complete metabolic panel, coagulation tests
  • Other tests for complications: complete blood count (CBC), electrocardiogram (ECG)

Initial management:

  • Secure airway, breathing, and circulation
  • Gastrointestinal decontamination: activated charcoal to all adults presenting within 4 hours of ingestion (most beneficial if ingestion is < 2 hours prior)
Management of drug induced hepatitis

Management of acetaminophen toxicity:
1. Obtain history, identify agents involved, and determine severity and possible drug toxicity.
If acetaminophen ingestion (potentially toxic dose > 7.5 g) has been < 4 hours, activated charcoal is given to prevent absorption of residual drug.
Patient should be alert to protect the airway and avoid aspiration.
2. Serum acetaminophen level is obtained (recommended at 4 hours after ingestion; 2nd drug level is obtained later if extended release preparation was ingested).
3. N-acetyl-cysteine is administered in the following cases:
Levels above the treatment line in the nomogram
Unclear time of ingestion and serum acetaminophen level is > 10 µg/mL
Evidence of hepatotoxicity
Suspected single dose of > 7.5 g or 150 mg/kg and result of acetaminophen level will not be available for at least 8 hours.

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Management:

  • Rumack-Matthew nomogram: 
    • Utilized for single acute acetaminophen ingestion
    • Illustrates hepatotoxic levels of acetaminophen 4 hours after ingestion (absorption has likely occurred)
    • Guides use of the antidote (NAC) based on acetaminophen level and hours since ingestion
    • Cannot be used for ingestion that occurred > 24 hours prior to presentation, repeated elevated doses, or intravenous overdose. 
  • NAC:
    • Antidote
    • Replenishes glutathione and subsequently decreases NAPQI production
    • Most effective within 8 hours of ingestion, but would be partially effective up to 36 hours after acetaminophen intake
  • Indications for NAC: 
    • Acetaminophen levels above the treatment line in the nomogram
    • Unclear time of ingestion and serum drug level of > 10 µg/mL
    • Evidence of hepatotoxicity
    • Suspected single dose of > 7.5 g or 150 mg/kg and result of drug level will not be available for at least 8 hours.

Differential Diagnosis

  • Non-alcoholic fatty liver disease: liver disease with findings of steatohepatitis, presenting with the similar laboratory results (elevation in ALT/AST) and clinical presentation. Characteristic history (no suspicious drug intake), physical examination (elevated body mass index (BMI)), and chronic nature of the disease help differentiate non-alcoholic fatty liver disease from drug-induced hepatitis.
  • Viral hepatitis: infection from a virus causing an acute inflammatory reaction in the liver. Presents with jaundice, fever, and hepatomegaly but ALT/AST are usually > 1,000 in cases of viral hepatitis. Further differentiation can be established by detecting viral antigens and antibodies in the serum. Treatment is based on etiology. For certain hepatitis types, prevention is achieved by vaccination. 
  • Autoimmune hepatitis: an ALF that presents with fatigue, jaundice, hepatomegaly, and RUQ tenderness. Drug-induced hepatitis must be ruled out using the history and a laboratory evaluation. The presence of the anti-smooth muscle antibody is a strong indicator of autoimmune hepatitis. Treatment is with immunosuppressants such as steroids. 
  • Alcoholic liver disease: liver failure associated with chronic alcohol abuse. Alcoholic liver disease presents with the same laboratory results (elevation in ALT/AST) and clinical presentation. Steatohepatitis is noted. Characteristic history (alcohol abuse) and chronic nature of the disease typically distinguish alcoholic fatty liver disease from drug-induced hepatitis. Treatment is alcohol cessation. 

References

  1. Burns, M., Friedman, S., & Larson, A. (2020). Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation and evaluation. UpToDate. Retrieved on Nov 28, 2020, from https://www.uptodate.com/contents/acetaminophen-paracetamol-poisoning-in-adults-pathophysiology-presentation-and-evaluation
  2. Farrell, S. & Defendi, G. (2020). How is the Rumack-Matthew nomogram used in the work-up of acetaminophen toxicity/poisoning and what information does it provide? Medscape. https://www.medscape.com/answers/820200-27243/how-is-the-rumack-matthew-nomogram-used-in-the-workup-of-acetaminophen-toxicitypoisoning-and-what-information-does-it-provide
  3. Heard, K., & Dart, R. (2020). Acetaminophen (paracetamol) poisoning in adults: Treatment. UpToDate. Retrieved Nov 28, 2020, from https://www.uptodate.com/contents/acetaminophen-paracetamol-poisoning-in-adults-treatment
  4. Larson, A. (2020). Drugs and the liver: Metabolism and mechanisms of injury. UpToDate. Retrieved Nov 28, 2020, from https://www.uptodate.com/contents/drugs-and-the-liver-metabolism-and-mechanisms-of-injury
  5. Larson, A. (2019). Drug-induced liver injury. UpToDate. Retrieved Nov 28, 2020, from https://www.uptodate.com/contents/drug-induced-liver-injury?search=drug%20induced%20hepatotoxicity&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1#H29
  6. Lee, W. M., & Dienstag, J.L. (2018). Toxic and drug-induced hepatitis. In Jameson, J.L., et al. (Ed.), Harrison’s Principles of Internal Medicine (20th ed). McGraw-Hill.
  7. Kumar, V., Abbas, A., Aster, J., & Robbins, S. (2020). The liver and bile ducts. In Robbins and Cotran (Eds.), Pathologic Basis of Disease (10th ed., p. 841). Elsevier, Inc.
  8. Mehta, N., & Ozick, L. (2019). Drug-induced hepatotoxicity. Medscape. https://emedicine.medscape.com/article/169814-overview

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