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 Liver function tests Liver function tests, also known as hepatic function panels, are one of the most commonly performed screening blood tests. Such tests are also used to detect, evaluate, and monitor acute and chronic liver diseases. Liver Function Tests (LFTs) and drug levels, if available. Management consists of discontinuing the drug, supportive therapy, and monitoring for complications. Acetaminophen Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. 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 Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. 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 Malnutrition Malnutrition is a clinical state caused by an imbalance or deficiency of calories and/or micronutrients and macronutrients. The 2 main manifestations of acute severe malnutrition are marasmus (total caloric insufficiency) and kwashiorkor (protein malnutrition with characteristic edema). Malnutrition in children in resource-limited countries
    • Pre-existing liver disease
    • Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics (alterations in enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of 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 Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. Acetaminophen 
    • Tetracycline
    • Amanita phalloides mushroom

Idiosyncratic reactions: 

  • Not dose dependent (unpredictable)
  • Variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables 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 Antiretroviral therapy Antiretroviral therapy (ART) targets the replication cycle of the human immunodeficiency virus (HIV) and is classified based on the viral enzyme or mechanism that is inhibited. The goal of therapy is to suppress viral replication to reach the outcome of undetected viral load. Anti-HIV Drugs

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 Cell injury The cell undergoes a variety of changes in response to injury, which may or may not lead to cell death. Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Cell Injury and Death:

  • Drug disrupts calcium homeostasis: actin fibrils disassemble → cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: 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 T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells and cytokines attack the adducts as targets 
  • Drug activation of apoptotic pathways: 
    • Stimulation of death receptors ( tumor necrosis factor Tumor necrosis factor Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF) ( TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF)) receptor or Fas) 
    • Results in programmed cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death 
  • Mitochondrial disruption: 
    • ↓ Adenosine triphosphate (ATP) levels; ↑ lactate, and reactive oxygen species; lipid peroxidation → cell injury Cell injury The cell undergoes a variety of changes in response to injury, which may or may not lead to cell death. Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Cell Injury and Death
    • 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 Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface 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 Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice, nausea/vomiting.
  • May have pruritus (in cholestasis)
  • In severe cases: mental status changes occur due to hepatic encephalopathy Hepatic Encephalopathy Hepatic encephalopathy is a reversible condition in which elevated ammonia levels cause impaired brain function in patients with advanced liver disease. Hepatic encephalopathy can be precipitated by conditions that affect the normal absorption, metabolism, or clearance of ammonia, including dehydration, renal failure, infections, and gastrointestinal bleeding. Hepatic Encephalopathy.

Signs

Acute liver failure:

  • Rapid onset (< 3-month duration)
  • Hepatomegaly and RUQ tenderness
  • Disorientation/confusion, jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice
  • Abnormalities of liver function tests Liver function tests Liver function tests, also known as hepatic function panels, are one of the most commonly performed screening blood tests. Such tests are also used to detect, evaluate, and monitor acute and chronic liver diseases. 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 Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. 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 Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. 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 Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. 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 injury Blood 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 Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. 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 Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation with hepatocellular injury
  • Chronic cholestasis:
    • Chronic portal inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. 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 Budd-Chiari syndrome Budd-Chiari syndrome is a condition resulting from the interruption of the normal outflow of blood from the liver. The primary type arises from a venous process (affecting the hepatic veins or inferior vena cava) such as thrombosis, but can also be from a lesion compressing or invading the veins (secondary type). The patient typically presents with hepatomegaly, ascites, and abdominal discomfort. Budd-Chiari Syndrome (drug-induced thrombosis)
  • Others: phospholipidosis, peliosis hepatis
Table: Histologic patterns of liver injury
Pattern of injury Examples
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 Budd-Chiari syndrome Budd-Chiari syndrome is a condition resulting from the interruption of the normal outflow of blood from the liver. The primary type arises from a venous process (affecting the hepatic veins or inferior vena cava) such as thrombosis, but can also be from a lesion compressing or invading the veins (secondary type). The patient typically presents with hepatomegaly, ascites, and abdominal discomfort. 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 Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia
    • Monitor level of consciousness
    • Prevent gastrointestinal bleeding Gastrointestinal bleeding Gastrointestinal bleeding (GIB) is a symptom of multiple diseases within the gastrointestinal (GI) tract. Gastrointestinal bleeding is designated as upper or lower based on the etiology's location to the ligament of Treitz. Depending on the location of the bleeding, the patient may present with hematemesis (vomiting blood), melena (black, tarry stool), or hematochezia (fresh blood in stools). 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 Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver transplantation for fulminant liver failure

Acetaminophen-induced Hepatotoxicity

Acetaminophen Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. Acetaminophen

  • Most common cause of ALF 
  • ALT/AST > 1,000 U/L followed by jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. 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 Anticonvulsant Anticonvulsant drugs are pharmacological agents used to achieve seizure control and/or prevent seizure episodes. Anticonvulsants encompass various drugs with different mechanisms of action including ion-channel (Na+ and Ca+2) blocking and GABA reuptake inhibition. First-Generation Anticonvulsant Drugs 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 Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. 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 Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain and hepatomegaly occur.
  • Stage III (72–96 hours): 
    • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. 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 Electrocardiogram An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG) ( ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal 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.

Image by Lecturio.

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 Antidote An antidote is a substance that counteracts poisoning or toxicity. Substances that can cause poisoning include heavy metals (from occupation, treatments, or diet), alcohols, environmental toxins, and medications. Overview of Antidotes (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 Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. 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 Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview causing an acute inflammatory reaction in the liver. Presents with jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. 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 Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins in the serum. Treatment is based on etiology. For certain hepatitis types, prevention is achieved by vaccination Vaccination Vaccination is the administration of a substance to induce the immune system to develop protection against a disease. Unlike passive immunization, which involves the administration of pre-performed antibodies, active immunization constitutes the administration of a vaccine to stimulate the body to produce its own antibodies. Vaccination
  • Autoimmune hepatitis Autoimmune hepatitis Autoimmune hepatitis (AIH) is a rare form of chronic liver disease in which the immune system attacks the liver causing inflammation. It predominantly affects women. Clinical presentation ranges from asymptomatic cases to patients that present with symptoms of acute liver failure (jaundice, right upper quadrant pain). Autoimmune Hepatitis: an ALF that presents with fatigue, jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. 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 Immunosuppressants Immunosuppressants are a class of drugs widely used in the management of autoimmune conditions and organ transplant rejection. The general effect is dampening of the immune response. Immunosuppressants such as steroids. 
  • Alcoholic liver disease Alcoholic Liver Disease Alcoholic liver disease is a spectrum of disorders ranging from fatty liver to cirrhosis secondary to chronic alcohol abuse. Excessive and prolonged consumption of alcohol results in impairment of the lipolysis pathway, causing inflammatory changes within the hepatocytes. Patients typically present during the hepatitis stage with jaundice, fever, and abdominal pain. Alcoholic Liver Disease: liver failure associated with chronic alcohol abuse. Alcoholic liver disease Alcoholic Liver Disease Alcoholic liver disease is a spectrum of disorders ranging from fatty liver to cirrhosis secondary to chronic alcohol abuse. Excessive and prolonged consumption of alcohol results in impairment of the lipolysis pathway, causing inflammatory changes within the hepatocytes. Patients typically present during the hepatitis stage with jaundice, fever, and abdominal pain. 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 Burns A burn is a type of injury to the skin and deeper tissues caused by exposure to heat, electricity, chemicals, friction, or radiation. Burns are classified according to their depth as superficial (1st-degree), partial-thickness (2nd-degree), full-thickness (3rd-degree), and 4th-degree burns. Burns, M., Friedman, S., & Larson, A. (2020). Acetaminophen Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. 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 Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. 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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