Drug-induced liver injury (DILI) is the most common cause of acute liver failure (ALF). Hepatotoxic drugs can cause dose-dependent, direct liver injury or idiosyncratic reactions mediated by immune or metabolic processes.This injury can result in hepatitis, cholestasis, steatosis, 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, liver function tests, and drug levels, if available. Management consists of discontinuing the drug, supportive therapy, and monitoring for complications. Acetaminophen is the most common cause of DILI and is treated with a specific therapy, N-acetylcysteine (NAC).
Drug-induced liverLiverThe 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: Anatomy injury (DILI) incidenceIncidenceThe number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time.Measures of Disease Frequency: 10–15 per 10,000 to 100,000 persons exposed to prescription medications
Most common cause of acute liver failureLiver failureSevere inability of the liver to perform its normal metabolic functions, as evidenced by severe jaundice and abnormal serum levels of ammonia; bilirubin; alkaline phosphatase; aspartate aminotransferase; lactate dehydrogenases; and albumin/globulin ratio.Autoimmune Hepatitis (ALF) in the United States
Most common reason for withdrawing a drug from the market
Etiology
Prescription medications:
AcetaminophenAcetaminophenAcetaminophen 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 use disorder
MalnutritionMalnutritionMalnutrition 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 liverLiverThe 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: Anatomy disease
GeneticsGeneticsGenetics is the study of genes and their functions and behaviors.Basic Terms of Genetics (alterations in enzymesEnzymesEnzymes 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 isoniazidIsoniazidAntibacterial agent used primarily as a tuberculostatic. It remains the treatment of choice for tuberculosis.Antimycobacterial Drugs increases with age)
Metabolism of drugs
The liverLiverThe 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: Anatomy handles metabolism of drugs/toxins, thus making the liverLiverThe 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: Anatomy 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 hepatotoxicityHepatotoxicityAcetaminophen can occur due to phase I metabolites (e.g., the metabolite of acetaminophenAcetaminophenAcetaminophen 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, N-acetyl-P-benzoquinone-imineN-Acetyl-P-Benzoquinone-ImineAcetaminophen Overdose (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 bileBileAn emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum.Gallbladder and Biliary Tract: Anatomy.
Effect of the drug/hepatotoxin is reproducible and predictable.
Produce toxic hepatitis (e.g., poisons) or are converted to a toxic metabolite in the liverLiverThe 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: Anatomy (e.g., acetaminophenAcetaminophenAcetaminophen 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)
Examples:
Carbon tetrachloride
AcetaminophenAcetaminophenAcetaminophen 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
VariableVariableVariables 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-mediated (related to host factors/geneticsGeneticsGenetics is the study of genes and their functions and behaviors.Basic Terms of Genetics)
Examples:
IsoniazidIsoniazidAntibacterial agent used primarily as a tuberculostatic. It remains the treatment of choice for tuberculosis.Antimycobacterial Drugs
PhenytoinPhenytoinAn anticonvulsant that is used to treat a wide variety of seizures. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs.First-Generation Anticonvulsant Drugs
AmoxicillinAmoxicillinA broad-spectrum semisynthetic antibiotic similar to ampicillin except that its resistance to gastric acid permits higher serum levels with oral administration.Penicillins–clavulanate
Valproic acidValproic acidA fatty acid with anticonvulsant and anti-manic properties that is used in the treatment of epilepsy and bipolar disorder. The mechanisms of its therapeutic actions are not well understood. It may act by increasing gamma-aminobutyric acid levels in the brain or by altering the properties of voltage-gated sodium channels.First-Generation Anticonvulsant Drugs
Antiretroviral therapyAntiretroviral therapyAntiretroviral 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 liverLiverThe 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: Anatomycell injuryCell injuryThe 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 calciumCalciumA basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes.ElectrolyteshomeostasisHomeostasisThe processes whereby the internal environment of an organism tends to remain balanced and stable.Cell Injury and Death: actinActinFilamentous proteins that are the main constituent of the thin filaments of muscle fibers. The filaments (known also as filamentous or f-actin) can be dissociated into their globular subunits; each subunit is composed of a single polypeptide 375 amino acids long. This is known as globular or g-actin. In conjunction with myosins, actin is responsible for the contraction and relaxation of muscle.Skeletal Muscle Contraction fibrils disassemble → cell membraneCell MembraneA 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 cellsT cellsLymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen.T cells: Types and Functions and cytokinesCytokinesNon-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner.Adaptive Immune Response attack the adducts as targets
Drug activation of apoptotic pathways:
Stimulation of death receptorsReceptorsReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors (tumorTumorInflammationnecrosisNecrosisThe death of cells in an organ or tissue due to disease, injury or failure of the blood supply.Ischemic Cell Damage factor (TNFTNFTumor 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)) receptorReceptorReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors or Fas)
Results in programmed cell deathCell deathInjurious 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:
↓ AdenosineAdenosineA nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter.Class 5 Antiarrhythmic Drugs triphosphate (ATP) levels; ↑ lactate, and reactive oxygen speciesReactive oxygen speciesMolecules or ions formed by the incomplete one-electron reduction of oxygen. These reactive oxygen intermediates include singlet oxygen; superoxides; peroxides; hydroxyl radical; and hypochlorous acid. They contribute to the microbicidal activity of phagocytes, regulation of signal transduction and gene expression, and the oxidative damage to nucleic acids; proteins; and lipids.Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD); lipid peroxidation → cell injuryCell injuryThe 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 metabolismFatty acid metabolismFatty acid metabolism includes the processes of either breaking down fatty acids to generate energy (catabolic) or creating fatty acids for storage or use (anabolic). Besides being a source of energy, fatty acids can also be utilized for cellular membranes or signaling molecules. Synthesis and beta oxidation are almost the reverse of each other, and special reactions are required for variations.Fatty Acid Metabolism → triglyceride accumulation (steatosisSteatosisMetabolic Dysfunction-associated Steatotic Liver Disease (MASLD))
Potential mechanisms of how drugs affect the biliary excretion pathway:
Damaged actinActinFilamentous proteins that are the main constituent of the thin filaments of muscle fibers. The filaments (known also as filamentous or f-actin) can be dissociated into their globular subunits; each subunit is composed of a single polypeptide 375 amino acids long. This is known as globular or g-actin. In conjunction with myosins, actin is responsible for the contraction and relaxation of muscle.Skeletal Muscle Contraction filaments next to the canaliculus:
Transport proteinsTransport proteinsProteins and Peptides at the canalicular membrane are affected, preventing bileBileAn emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum.Gallbladder and Biliary Tract: AnatomyflowFlowBlood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls.Vascular Resistance, Flow, and Mean Arterial Pressure.
Loss of villous processes and impaired canalicular pumps → ↓ bileBileAn emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum.Gallbladder and Biliary Tract: Anatomy excretion
BileBileAn emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum.Gallbladder and Biliary Tract: Anatomy duct damage:
Toxic metabolites (excreted in bileBileAn emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum.Gallbladder and Biliary Tract: Anatomy) damage bile-duct epitheliumEpitheliumThe 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: Histology → cholestasis
Possible pathophysiology of drug-induced liver injury:
1. A reactive metabolite may be formed by hepatocytes, which can covalently bond to proteins to form neoantigens.
2. A release of neoantigens and damage-associated molecular pattern (DAMP) molecules from damaged hepatocytes, which can lead to activation of antigen-presenting cells (APCs) and recruitment of innate immune cells.
3. APC activation leads to the expression of signal 1 and signal 2
4. T helper (Th) cells and cytotoxic T (Tc) cells are activated, leading to an adaptive immune response.
5. 5a: The dominant adaptive immune response in idiosyncratic drug-induced liver injury (IDILI) is usually a cell-mediated immune response.
5b: However, if the binding of the drug or drug-modified peptide is not very strong, the adaptive immune response will end in immune tolerance, preventing or limiting liver injury.
Image by Lecturio.
Clinical Presentation
Symptoms
Can be asymptomatic
When symptomatic, may present with right upper quadrantRight upper quadrantAnterior Abdominal Wall: Anatomy (RUQ) painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways, jaundiceJaundiceJaundice 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, nauseaNauseaAn unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses.Antiemetics/vomitingVomitingThe forcible expulsion of the contents of the stomach through the mouth.Hypokalemia.
May have pruritusPruritusAn intense itching sensation that produces the urge to rub or scratch the skin to obtain relief.Atopic Dermatitis (Eczema) (in cholestasis)
Acute liver failureLiver failureSevere inability of the liver to perform its normal metabolic functions, as evidenced by severe jaundice and abnormal serum levels of ammonia; bilirubin; alkaline phosphatase; aspartate aminotransferase; lactate dehydrogenases; and albumin/globulin ratio.Autoimmune Hepatitis:
Rapid onset (< 3-month duration)
Hepatomegaly and RUQ tenderness
DisorientationDisorientationSt. Louis Encephalitis Virus/confusion, jaundiceJaundiceJaundice 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 testsLiver function testsLiver 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):
AlanineAlanineA non-essential amino acid that occurs in high levels in its free state in plasma. It is produced from pyruvate by transamination. It is involved in sugar and acid metabolism, increases immunity, and provides energy for muscle tissue, brain, and the central nervous system.Synthesis of Nonessential Amino AcidstransaminaseTransaminaseA subclass of enzymes of the transferase class that catalyze the transfer of an amino group from a donor (generally an amino acid) to an acceptor (generally a 2-keto acid). Most of these enzymes are pyridoxyl phosphate proteins.Catabolism of Amino Acids/aminotransferase (ALTALTAn enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate.Liver Function Tests)
AspartateAspartateOne of the non-essential amino acids commonly occurring in the l-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a neurotransmitter.Synthesis of Nonessential Amino AcidstransaminaseTransaminaseA subclass of enzymes of the transferase class that catalyze the transfer of an amino group from a donor (generally an amino acid) to an acceptor (generally a 2-keto acid). Most of these enzymes are pyridoxyl phosphate proteins.Catabolism of Amino Acids/aminotransferase (ASTASTEnzymes of the transferase class that catalyze the conversion of l-aspartate and 2-ketoglutarate to oxaloacetate and l-glutamate.Liver Function Tests)
Alkaline phosphataseAlkaline PhosphataseAn enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate.Osteosarcoma (ALPALPAn enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate.Osteosarcoma)
Coagulation abnormality (prothrombinProthrombinA plasma protein that is the inactive precursor of thrombin. It is converted to thrombin by a prothrombin activator complex consisting of factor Xa, factor V, phospholipid, and calcium ions.Hemostasis/international normalized ratioInternational normalized ratioSystem established by the world health organization and the international committee on thrombosis and hemostasis for monitoring and reporting blood coagulation tests. Under this system, results are standardized using the international sensitivity index for the particular test reagent/instrument combination used.Hemostasis or PT/INR > 1.5)
May have ↑ white blood cell count (WBC)
Chronic liverLiverThe 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: Anatomy injury:
Chronic liverLiverThe 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: Anatomy injury is defined as lasting > 3 months, thereby resembling chronic liverLiverThe 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: Anatomy disease or cirrhosisCirrhosisCirrhosis 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:
SpiderSpiderArthropods of the class arachnida, order araneae. Except for mites and ticks, spiders constitute the largest order of arachnids, with approximately 37, 000 species having been described. The majority of spiders are harmless, although some species can be regarded as moderately harmful since their bites can lead to quite severe local symptoms.Spider Bites angiomas
AscitesAscitesAscites is the pathologic accumulation of fluid within the peritoneal cavity that occurs due to an osmotic and/or hydrostatic pressure imbalance secondary to portal hypertension (cirrhosis, heart failure) or non-portal hypertension (hypoalbuminemia, malignancy, infection).Ascites
Specific drug intake prior to the onset of liverLiverThe 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: Anatomy injury
Any underlying liverLiverThe 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: Anatomy disease ruled out
Cessation of the offending drug leads to improvement of liverLiverThe 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: Anatomy injury.
Repeated use causes liverLiverThe 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: Anatomy abnormalities (rechallenge is not recommended and should not be tried).
Physical examination findings are suggestive of liverLiverThe 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: Anatomy disease.
Laboratory tests
Liver function testsLiver function testsLiver 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:
Hepatocellular injury/hepatitis:
ASTASTEnzymes of the transferase class that catalyze the conversion of l-aspartate and 2-ketoglutarate to oxaloacetate and l-glutamate.Liver Function Tests/ALTALTAn enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate.Liver Function Tests elevation disproportionate to ALPALPAn enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate.Osteosarcoma elevation
May have elevated bilirubinBilirubinA bile pigment that is a degradation product of heme.Heme Metabolism
May have abnormal PT/INR, albuminAlbuminSerum albumin from humans. It is an essential carrier of both endogenous substances, such as fatty acids and bilirubin, and of xenobiotics in the blood.Liver Function Tests
Cholestatic injury:
ALPALPAn enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate.Osteosarcoma elevation disproportionate to ALTALTAn enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate.Liver Function Tests/ASTASTEnzymes of the transferase class that catalyze the conversion of l-aspartate and 2-ketoglutarate to oxaloacetate and l-glutamate.Liver Function Tests elevation
May have elevated bilirubinBilirubinA bile pigment that is a degradation product of heme.Heme Metabolism
May have abnormal PT/INR, albuminAlbuminSerum albumin from humans. It is an essential carrier of both endogenous substances, such as fatty acids and bilirubin, and of xenobiotics in the blood.Liver Function Tests
Mixed injury: combination of the above findings, but ALTALTAn enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate.Liver Function Tests/ASTASTEnzymes of the transferase class that catalyze the conversion of l-aspartate and 2-ketoglutarate to oxaloacetate and l-glutamate.Liver Function Tests:ALPALPAn enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate.Osteosarcoma ratio < 5
Hy’s law:
Presence of jaundiceJaundiceJaundice 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 bilirubinBilirubinA bile pigment that is a degradation product of heme.Heme Metabolism > 2x normal) with ↑ serum ALTALTAn enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate.Liver Function Tests/ASTASTEnzymes of the transferase class that catalyze the conversion of l-aspartate and 2-ketoglutarate to oxaloacetate and l-glutamate.Liver Function Tests (> 3x normal)
Indicative of worse prognosisPrognosisA prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations.Non-Hodgkin Lymphomas (mortalityMortalityAll deaths reported in a given population.Measures of Health Status > 10%)
Drug levels:
Obtained if history is suggestive and test is available
May correlate with degree of hepatotoxicityHepatotoxicityAcetaminophen (acetaminophenAcetaminophenAcetaminophen 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)
Type of injury
Blood test
Hepatitis
ALTALTAn enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate.Liver Function Tests ≥ 3 x ULN
ALTALTAn enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate.Liver Function Tests/ALPALPAn enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate.Osteosarcoma ratio > 5
Cholestasis
ALPALPAn enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate.Osteosarcoma ≥ 2 x ULN
Mixed
ALTALTAn enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate.Liver Function Tests ≥ 3 x ULN and ALPALPAn enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate.Osteosarcoma ≥ 2 x ULN
ALTALTAn enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate.Liver Function Tests/ALPALPAn enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate.Osteosarcoma ratio > 2, but < 5
ALT: alanine transaminase
ALP: alkaline phosphatase
ULN: upper limit of normal
LiverLiverThe 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: AnatomybiopsyBiopsyRemoval and pathologic examination of specimens from the living body.Ewing Sarcoma
Not required for diagnosis but performed if the diagnosis or severity is uncertain
Can help rule out other causes of liverLiverThe 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: Anatomy 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 necrosisNecrosisThe death of cells in an organ or tissue due to disease, injury or failure of the blood supply.Ischemic Cell Damage, apoptosisApoptosisA regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth.Ischemic Cell Damage, degeneration
Affected areas can be spotty, with isolated hepatocytesHepatocytesThe main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules.Liver: Anatomy.
If injury is extensive, massive necrosisNecrosisThe death of cells in an organ or tissue due to disease, injury or failure of the blood supply.Ischemic Cell Damage is noted (seen in ALF).
Chronic hepatocellular injury:
Resembles changes in chronic liverLiverThe 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: Anatomy disease
Periportal and pericellular fibrosisFibrosisAny pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury.Bronchiolitis Obliterans
Acute cholestatic injury:
Pure cholestasis: bileBileAn emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum.Gallbladder and Biliary Tract: Anatomy plugging/accumulation with minimal hepatocellular injury
Cholestatic hepatitis: cholestasis, portal inflammationInflammationInflammation 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 inflammationInflammationInflammation 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
BileBileAn emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum.Gallbladder and Biliary Tract: Anatomy duct degeneration or loss (vanishing bile duct syndromeVanishing Bile Duct SyndromeJaundice)
Acute DILI (microvesicular); chronic DILI (macrovesicular)
GranulomasGranulomasA relatively small nodular inflammatory lesion containing grouped mononuclear phagocytes, caused by infectious and noninfectious agents.Sarcoidosis:
Non-necrotizing granulomasGranulomasA relatively small nodular inflammatory lesion containing grouped mononuclear phagocytes, caused by infectious and noninfectious agents.Sarcoidosis
Often in the periportal and portal areas
Vascular lesions:
Sinusoidal obstruction syndrome (occlusion of terminal hepatic venulesVenulesThe minute vessels that collect blood from the capillary plexuses and join together to form veins.Veins: Histology and sinusoidsSinusoidsLiver: Anatomy)
Budd-Chiari syndromeBudd-Chiari syndromeBudd-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 thrombosisThrombosisFormation and development of a thrombus or blood clot in the blood vessel.Epidemic Typhus)
Others: phospholipidosis, peliosis hepatisPeliosis hepatisA vascular disease of the liver characterized by the occurrence of multiple blood-filled cysts or cavities. The cysts are lined with endothelial cells; the cavities lined with hepatic parenchymal cells (hepatocytes). Peliosis hepatis has been associated with use of anabolic steroids (anabolic agents) and certain drugs.Bartonella
Table: Histologic patterns of liverLiverThe 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: Anatomy injury
IbuprofenIbuprofenA nonsteroidal anti-inflammatory agent with analgesic properties used in the treatment of rheumatism and arthritis.Nonsteroidal Antiinflammatory Drugs (NSAIDs), methyldopa, phenytoinPhenytoinAn anticonvulsant that is used to treat a wide variety of seizures. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs.First-Generation Anticonvulsant Drugs
Massive necrosisNecrosisThe death of cells in an organ or tissue due to disease, injury or failure of the blood supply.Ischemic Cell Damage: acetaminophenAcetaminophenAcetaminophen 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, halothaneHalothaneA nonflammable, halogenated, hydrocarbon anesthetic that provides relatively rapid induction with little or no excitement. Analgesia may not be adequate. Nitrous oxide is often given concomitantly. Because halothane may not produce sufficient muscle relaxation, supplemental neuromuscular blocking agents may be required.Inhaled Anesthetics
Chronic hepatitis/fibrosisFibrosisAny pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury.Bronchiolitis Obliterans
IsoniazidIsoniazidAntibacterial agent used primarily as a tuberculostatic. It remains the treatment of choice for tuberculosis.Antimycobacterial Drugs, methotrexateMethotrexateAn antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of tetrahydrofolate dehydrogenase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA.Antimetabolite Chemotherapy, atorvastatinAtorvastatinA pyrrole and heptanoic acid derivative, hydroxymethylglutaryl-CoA reductase inhibitor (statin), and anticholesteremic agent that is used to reduce serum levels of ldl-cholesterol; apolipoprotein b; and triglycerides. It is used to increase serum levels of hdl-cholesterol in the treatment of hyperlipidemias, and for the prevention of cardiovascular diseases in patients with multiple risk factors.Statins
Cholestatic hepatitis (mixed)
ClindamycinClindamycinAn antibacterial agent that is a semisynthetic analog of lincomycin.Lincosamides, phenytoinPhenytoinAn anticonvulsant that is used to treat a wide variety of seizures. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs.First-Generation Anticonvulsant Drugs, azathioprineAzathioprineAn immunosuppressive agent used in combination with cyclophosphamide and hydroxychloroquine in the treatment of rheumatoid arthritis. According to the fourth annual report on carcinogens, this substance has been listed as a known carcinogen.Immunosuppressants, nitrofurantoin
Cholestasis
Oral contraceptives, anabolic steroidsSteroidsA group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus.Benign Liver Tumors, antiretroviral therapyAntiretroviral therapyAntiretroviral 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, antibiotics, thiabendazole, tricyclic
antidepressants
Valproic acidValproic acidA fatty acid with anticonvulsant and anti-manic properties that is used in the treatment of epilepsy and bipolar disorder. The mechanisms of its therapeutic actions are not well understood. It may act by increasing gamma-aminobutyric acid levels in the brain or by altering the properties of voltage-gated sodium channels.First-Generation Anticonvulsant Drugs, amiodaroneAmiodaroneAn antianginal and class III antiarrhythmic drug. It increases the duration of ventricular and atrial muscle action by inhibiting potassium channels and voltage-gated sodium channels. There is a resulting decrease in heart rate and in vascular resistance.Pulmonary Fibrosis, antiretroviral therapyAntiretroviral therapyAntiretroviral 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, tamoxifenTamoxifenOne of the selective estrogen receptor modulators with tissue-specific activities. Tamoxifen acts as an anti-estrogen (inhibiting agent) in the mammary tissue, but as an estrogen (stimulating agent) in cholesterol metabolism, bone density, and cell proliferation in the endometrium.Antiestrogens
GranulomasGranulomasA relatively small nodular inflammatory lesion containing grouped mononuclear phagocytes, caused by infectious and noninfectious agents.Sarcoidosis
SulfonamidesSulfonamidesA group of compounds that contain the structure so2nh2.Sulfonamides and Trimethoprim, amiodaroneAmiodaroneAn antianginal and class III antiarrhythmic drug. It increases the duration of ventricular and atrial muscle action by inhibiting potassium channels and voltage-gated sodium channels. There is a resulting decrease in heart rate and in vascular resistance.Pulmonary Fibrosis, allopurinolAllopurinolA xanthine oxidase inhibitor that decreases uric acid production. It also acts as an antimetabolite on some simpler organisms.Gout Drugs, isoniazidIsoniazidAntibacterial agent used primarily as a tuberculostatic. It remains the treatment of choice for tuberculosis.Antimycobacterial Drugs, phenytoinPhenytoinAn anticonvulsant that is used to treat a wide variety of seizures. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs.First-Generation Anticonvulsant Drugs
Vascular lesions
Budd-Chiari syndromeBudd-Chiari syndromeBudd-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 steroidsSteroidsA group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus.Benign Liver Tumors
Sinusoidal obstruction syndrome: high-dose chemotherapyChemotherapyOsteosarcoma (oxaliplatinOxaliplatinAn organoplatinum complex in which the platinum atom is complexed with 1, 2-diaminocyclohexane, and with an oxalate ligand which is displaced to yield active oxaliplatin derivatives. These derivatives form inter- and intra-strand DNA crosslinks that inhibit DNA replication and transcription. Oxaliplatin is an antineoplastic agent that is often administered with fluorouracil and folinic acid in the treatment of metastatic colorectal neoplasms.Alkylating Agents and Platinum), oral contraceptives
Liver biopsy specimen showing lobular hepatitis secondary to ibuprofen
Image: “A rare coexistence: drug-induced hepatitis and meningitis in association with Ibuprofen” by Nayudu SK, Kavuturu S, Niazi M, Daniel M, Dev A, Kumbum K. License: CC BY 2.0.
Liver biopsy of a patient with human immunodeficiency virus (HIV) infection taking stavudine Laboratory tests showed elevated transaminases; image showed acidophil bodies, foamy degeneration of hepatocytes (steatosis).
Image: “Dideoxynucleoside HIV reverse transcriptase inhibitors and drug-related hepatotoxicity” by Lapadula G, Izzo I, Costarelli S, Cologni G, Bercich L, Casari S, Gambarotti M, Torti C. License: CC BY 2.0
Liver biopsy of a patient with elevated liver enzymes after treatment of Helicobacter pylori infection (using clarithromycin and amoxicillin): Image shows portal inflammation.
Image: “Sudden elevation of liver enzymes in a 64-year-old patient” by Wiedmann M, Müller C, Lobeck H, Wölke K. License: CC BY 2.0.
Image of albendazole-induced granulomatous hepatitis: hepatic parenchyma with epithelioid macrophages that have formed granulomas without necrosis, interspersed with lymphocytes
Image: “Albendazole-induced granulomatous hepatitis” by Marin Zuluaga JI, Marin Castro AE, Perez Cadavid JC, Restrepo Gutierrez JC. License: CC BY 2.0.
Management
General recommendations
Main treatment: cessation of the offending drug
Serial laboratories until the LFTs return to normal
Monitor for complications:
HypoglycemiaHypoglycemiaHypoglycemia 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 bleedingGastrointestinal bleedingGastrointestinal 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 pumpPumpACES and RUSH: Resuscitation Ultrasound Protocols inhibitor
L-carnitine for cases of valproic acidValproic acidA fatty acid with anticonvulsant and anti-manic properties that is used in the treatment of epilepsy and bipolar disorder. The mechanisms of its therapeutic actions are not well understood. It may act by increasing gamma-aminobutyric acid levels in the brain or by altering the properties of voltage-gated sodium channels.First-Generation Anticonvulsant Drugs overdose (associated with hyperammonemiaHyperammonemiaElevated level of ammonia in the blood. It is a sign of defective catabolism of amino acids or ammonia to urea.Cirrhosis, lethargyLethargyA general state of sluggishness, listless, or uninterested, with being tired, and having difficulty concentrating and doing simple tasks. It may be related to depression or drug addiction.Hyponatremia, and hepatic dysfunction)
Symptomatic therapy: bileBileAn emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum.Gallbladder and Biliary Tract: Anatomy acid sequestrant to relieve the pruritusPruritusAn intense itching sensation that produces the urge to rub or scratch the skin to obtain relief.Atopic Dermatitis (Eczema)
Liver transplantationLiver transplantationThe transference of a part of or an entire liver from one human or animal to another.Hepatocellular Carcinoma (HCC) and Liver Metastases for fulminant liver failureLiver failureSevere inability of the liver to perform its normal metabolic functions, as evidenced by severe jaundice and abnormal serum levels of ammonia; bilirubin; alkaline phosphatase; aspartate aminotransferase; lactate dehydrogenases; and albumin/globulin ratio.Autoimmune Hepatitis
Acetaminophen-induced Hepatotoxicity
AcetaminophenAcetaminophenAcetaminophen 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
ALTALTAn enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate.Liver Function Tests/ASTASTEnzymes of the transferase class that catalyze the conversion of l-aspartate and 2-ketoglutarate to oxaloacetate and l-glutamate.Liver Function Tests > 1,000 U/L followed by jaundiceJaundiceJaundice 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 encephalopathyEncephalopathyHyper-IgM Syndrome
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/anticonvulsantAnticonvulsantAnticonvulsant 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 acetaminophenAcetaminophenAcetaminophen 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 doses produce small amounts.
NAPQI is normally detoxified by glutathione → non-toxic cysteineCysteineA thiol-containing non-essential amino acid that is oxidized to form cystine.Synthesis of Nonessential Amino Acids and mercaptate compounds → renal excretion
Pathogenesis and clinical presentation
Pathogenesis:
↑ AcetaminophenAcetaminophenAcetaminophen 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 eliminationEliminationThe initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy pathways.
↑ Amounts of NAPQI bindBINDHyperbilirubinemia of the Newborn with hepatic macromolecules → produce NAPQI-protein adducts (irreversible process) → ↑ risk of oxidative stressOxidative stressA disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products.Cell Injury and Death → hepatocellular necrosisNecrosisThe death of cells in an organ or tissue due to disease, injury or failure of the blood supply.Ischemic Cell Damage
Clinical presentation:
Stage I (1st 24 hours):
NauseaNauseaAn unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses.Antiemetics and vomitingVomitingThe forcible expulsion of the contents of the stomach through the mouth.Hypokalemia, malaiseMalaiseTick-borne Encephalitis Virus; may be asymptomatic
Laboratory studies are usually normal.
Stage II (24–72 hours):
Ongoing hepatic necrosisNecrosisThe death of cells in an organ or tissue due to disease, injury or failure of the blood supply.Ischemic Cell Damage results in ↑ ALTALTAn enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate.Liver Function Tests/ASTASTEnzymes of the transferase class that catalyze the conversion of l-aspartate and 2-ketoglutarate to oxaloacetate and l-glutamate.Liver Function Tests by 36 hours
RUQ painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways and hepatomegaly occur.
Stage III (72–96 hours):
LiverLiverThe 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: Anatomy function abnormalities peak.
Severe toxicityToxicityDosage Calculation: ALTALTAn enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate.Liver Function Tests/ASTASTEnzymes of the transferase class that catalyze the conversion of l-aspartate and 2-ketoglutarate to oxaloacetate and l-glutamate.Liver Function Tests > 10,000 IU/L, prolonged PT/INR, lactic acidosisLactic AcidosisOxazolidinones, bilirubinBilirubinA bile pigment that is a degradation product of heme.Heme Metabolism > 4 mg/dL
Possibly complicated with ALF, renal failureRenal failureConditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate.Crush Syndrome, pancreatitisPancreatitisInflammation of the pancreas. Pancreatitis is classified as acute unless there are computed tomographic or endoscopic retrograde cholangiopancreatographic findings of chronic pancreatitis. The two most common forms of acute pancreatitis are alcoholic pancreatitis and gallstone pancreatitis.Acute 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 acetaminophenAcetaminophenAcetaminophen 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 correlate with the severity of hepatic injury.
Complete metabolic panel, coagulation tests
Other tests for complications: complete blood count (CBC), electrocardiogramElectrocardiogramAn 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. Electrocardiogram (ECG) (ECGECGAn 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. Electrocardiogram (ECG))
Gastrointestinal decontamination: activated charcoalCharcoalAn amorphous form of carbon prepared from the incomplete combustion of animal or vegetable matter, e.g., wood. The activated form of charcoal is used in the treatment of poisoning.Antidotes of Common Poisonings to all adults presenting within 4 hours of ingestion (most beneficial if ingestion is < 2 hours prior)
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 nomogramRumack-Matthew nomogramGuides the use of the antidote n-acetylcysteine (NAC) based on sapap and hours since ingestion in relation to probability of hepatotoxicity.Acetaminophen Overdose:
Utilized for single acute acetaminophenAcetaminophenAcetaminophen 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 ingestion
Illustrates hepatotoxic levels of acetaminophenAcetaminophenAcetaminophen 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 4 hours after ingestion (absorptionAbsorptionAbsorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation.Digestion and Absorption has likely occurred)
Guides use of the antidoteAntidoteAn 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. Antidotes of Common Poisonings (NACNACAcetaminophen Overdose) based on acetaminophenAcetaminophenAcetaminophen 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 level and hours since ingestion
Cannot be used for ingestion that occurred > 24 hours prior to presentation, repeated elevated doses, or intravenous overdose.
AntidoteAntidoteAn 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. Antidotes of Common Poisonings
Replenishes glutathione and subsequently decreases NAPQI production
Most effective within 8 hours of ingestion, but would be partially effective up to 36 hours after acetaminophenAcetaminophenAcetaminophen 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 intake
AcetaminophenAcetaminophenAcetaminophen 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
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.
Rumack-Matthew nomogram (acetaminophen toxicity nomogram): Used after a single acute acetaminophen ingestion. It predicts potential hepatotoxicity beginning at 4 hours after ingestion. Levels measured earlier than 4 hours may not be reliable. The nomogram cannot be used for ingestions that occurred > 24 hours prior to presentation.
The upper (red) line is the Rumack-Matthew line; values above this line develop toxicity (noted in 60%). The lower (blue) line is the treatment line (U.S. Food and Drug Administration required treatment line to be 25% below the original line).
NAC treatment is given when the acetaminophen level is at the treatment line 4 hours post ingestion (which is below the toxicity threshold).
Non-alcoholic fatty liverLiverThe 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: Anatomy disease:liverLiverThe 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: Anatomy disease with findings of steatohepatitis, presenting with the similar laboratory results (elevation in ALTALTAn enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate.Liver Function Tests/ASTASTEnzymes of the transferase class that catalyze the conversion of l-aspartate and 2-ketoglutarate to oxaloacetate and l-glutamate.Liver Function Tests) and clinical presentation. Characteristic history (no suspicious drug intake), physical examination (elevated body mass indexBody mass indexAn indicator of body density as determined by the relationship of body weight to body height. Bmi=weight (kg)/height squared (m2). Bmi correlates with body fat (adipose tissue). Their relationship varies with age and gender. For adults, bmi falls into these categories: below 18. 5 (underweight); 18. 5-24. 9 (normal); 25. 0-29. 9 (overweight); 30. 0 and above (obese).Obesity (BMIBMIAn indicator of body density as determined by the relationship of body weight to body height. Bmi=weight (kg)/height squared (m2). Bmi correlates with body fat (adipose tissue). Their relationship varies with age and gender. For adults, bmi falls into these categories: below 18. 5 (underweight); 18. 5-24. 9 (normal); 25. 0-29. 9 (overweight); 30. 0 and above (obese).Obesity)), and chronic nature of the disease help differentiate non-alcoholic fatty liverLiverThe 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: Anatomy disease from drug-induced hepatitis.
Viral hepatitis: infection from a virusVirusViruses 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 causing an acute inflammatory reaction in the liverLiverThe 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: Anatomy. Presents with jaundiceJaundiceJaundice 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, feverFeverFever 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 ALTALTAn enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate.Liver Function Tests/ASTASTEnzymes of the transferase class that catalyze the conversion of l-aspartate and 2-ketoglutarate to oxaloacetate and l-glutamate.Liver Function Tests are usually > 1,000 in cases of viral hepatitis. Further differentiation can be established by detecting viral antigens and antibodiesAntibodiesImmunoglobulins (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: Types and Functions in the serum. Treatment is based on etiology. For certain hepatitis types, prevention is achieved by vaccinationVaccinationVaccination 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 hepatitisAutoimmune hepatitisAutoimmune 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 fatigueFatigueThe state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli.Fibromyalgia, jaundiceJaundiceJaundice 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 antibodyAnti-Smooth Muscle AntibodyAutoimmune Hepatitis is a strong indicatorIndicatorMethods for assessing flow through a system by injection of a known quantity of an indicator, such as a dye, radionuclide, or chilled liquid, into the system and monitoring its concentration over time at a specific point in the system.Body Fluid Compartments of autoimmune hepatitisAutoimmune hepatitisAutoimmune 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. Treatment is with immunosuppressantsImmunosuppressantsImmunosuppressants 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 steroidsSteroidsA group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus.Benign Liver Tumors.
AlcoholicAlcoholicPersons who have a history of physical or psychological dependence on ethanol.Mallory-Weiss Syndrome (Mallory-Weiss Tear)liverLiverThe 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: Anatomy disease: liver failureLiver failureSevere inability of the liver to perform its normal metabolic functions, as evidenced by severe jaundice and abnormal serum levels of ammonia; bilirubin; alkaline phosphatase; aspartate aminotransferase; lactate dehydrogenases; and albumin/globulin ratio.Autoimmune Hepatitis associated with chronic alcohol use disorderAlcohol use disorderAlcohol is one of the most commonly used addictive substances in the world. Alcohol use disorder (AUD) is defined as pathologic consumption of alcohol leading to impaired daily functioning. Acute alcohol intoxication presents with impairment in speech and motor functions and can be managed in most cases with supportive care. Alcohol Use Disorder. AlcoholicAlcoholicPersons who have a history of physical or psychological dependence on ethanol.Mallory-Weiss Syndrome (Mallory-Weiss Tear)liverLiverThe 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: Anatomy disease presents with the same laboratory results (elevation in ALTALTAn enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate.Liver Function Tests/ASTASTEnzymes of the transferase class that catalyze the conversion of l-aspartate and 2-ketoglutarate to oxaloacetate and l-glutamate.Liver Function Tests) and clinical presentation. Steatohepatitis is noted. Characteristic history (alcohol use disorderAlcohol use disorderAlcohol is one of the most commonly used addictive substances in the world. Alcohol use disorder (AUD) is defined as pathologic consumption of alcohol leading to impaired daily functioning. Acute alcohol intoxication presents with impairment in speech and motor functions and can be managed in most cases with supportive care. Alcohol Use Disorder) and chronic nature of the disease typically distinguish alcoholicAlcoholicPersons who have a history of physical or psychological dependence on ethanol.Mallory-Weiss Syndrome (Mallory-Weiss Tear) fatty liverLiverThe 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: Anatomy disease from drug-induced hepatitis. Treatment is alcohol cessation.
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.
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.