Drug-Induced Liver Injury (Clinical)

Overview

Epidemiology^[1,7,8,12]

• Drug-induced liver injury 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. The injury mechanisms can have the following effects: hepatitis, cholestasis, vascular lesions, or overlapping changes. Drug-Induced Liver Injury (DILI) incidence Incidence The 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
• 10% of all cases of acute hepatitis Acute Hepatitis Autoimmune Hepatitis 
• Most common cause of acute liver failure Liver failure Severe 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^[4,5,8,10]

• Over 1,000 medications and herbal products have been implicated in DILI.
• 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 DILI 
  • ALT ALT An enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate. Liver Function Tests/ AST AST Enzymes 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 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 Encephalopathy Hyper-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/ 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
• Prescription medications:
  • Antibiotics and antiepileptics account for > 60% of DILI (e.g., amoxicillin Amoxicillin A broad-spectrum semisynthetic antibiotic similar to ampicillin except that its resistance to gastric acid permits higher serum levels with oral administration. Penicillins–clavulanate, valproic acid Valproic acid A 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)
  • Anticancer therapeutics (e.g., tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids kinase inhibitors or immune-checkpoint inhibitors)
• Herbal medications and dietary supplements
• Illegal drugs:
  • Cocaine Cocaine An alkaloid ester extracted from the leaves of plants including coca. It is a local anesthetic and vasoconstrictor and is clinically used for that purpose, particularly in the eye, ear, nose, and throat. It also has powerful central nervous system effects similar to the amphetamines and is a drug of abuse. Cocaine, like amphetamines, acts by multiple mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is thought to involve inhibition of dopamine uptake. Local Anesthetics
  • MDMA MDMA An n-substituted amphetamine analog. It is a widely abused drug classified as a hallucinogen and causes marked, long-lasting changes in brain serotonergic systems. It is commonly referred to as mdma or ecstasy. Stimulants (“ ecstasy Ecstasy An n-substituted amphetamine analog. It is a widely abused drug classified as a hallucinogen and causes marked, long-lasting changes in brain serotonergic systems. It is commonly referred to as mdma or ecstasy. Stimulants”)
• 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 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: Anatomy 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

Metabolism of drugs^[2]

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: Anatomy metabolism of drugs changes their biologic activity and makes them water-soluble for excretion in the urine and bile Bile An 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.

Phase I reaction:

• Mediated by cytochrome P450 Cytochrome P450 A superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed function oxygenases). In animals, these p450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (biotransformation). They are classified, according to their sequence similarities rather than functions, into cyp gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the cyp1, cyp2, and cyp3 gene families are responsible for most drug metabolism. Drug-Induced Liver Injury
• Drug undergoes oxidation or hydroxylation.
• Not all drugs go through phase I.
• Drug-related hepatotoxicity Hepatotoxicity Acetaminophen can occur due to phase I metabolites (e.g., the metabolite of 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, N-acetyl-P-benzoquinone-imine N-Acetyl-P-Benzoquinone-Imine Acetaminophen Overdose ( NAPQI NAPQI Drug-Induced Liver Injury), 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 Bile An 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.

Pathophysiology

Mechanisms of drug toxicity Toxicity Dosage Calculation^[1,2,10]

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 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: Anatomy
• Examples:
  • Carbon tetrachloride Carbon tetrachloride A solvent for oils, fats, lacquers, varnishes, rubber waxes, and resins, and a starting material in the manufacturing of organic compounds. Poisoning by inhalation, ingestion or skin absorption is possible and may be fatal. Drug-Induced Liver Injury 
  • 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 Tetracycline A naphthacene antibiotic that inhibits amino Acyl tRNA binding during protein synthesis. Drug-Induced Liver Injury
  • Aspirin Aspirin The prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. Nonsteroidal Antiinflammatory Drugs (NSAIDs)
  • Amiodarone Amiodarone An 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
  • Methotrexate Methotrexate An 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
  • Amanita phalloides Amanita Phalloides Toxicology of Plants 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-mediated (related to host factors/ genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics)
• Examples:
  • Isoniazid Isoniazid Antibacterial agent used primarily as a tuberculostatic. It remains the treatment of choice for tuberculosis. Antimycobacterial Drugs
  • Phenytoin Phenytoin An 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
  • Amoxicillin Amoxicillin A broad-spectrum semisynthetic antibiotic similar to ampicillin except that its resistance to gastric acid permits higher serum levels with oral administration. Penicillins–clavulanate
  • Macrolides Macrolides Macrolides and ketolides are antibiotics that inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit and blocking transpeptidation. These antibiotics have a broad spectrum of antimicrobial activity but are best known for their coverage of atypical microorganisms. Macrolides and Ketolides
  • Fluoroquinolones Fluoroquinolones Fluoroquinolones are a group of broad-spectrum, bactericidal antibiotics inhibiting bacterial DNA replication. Fluoroquinolones cover gram-negative, anaerobic, and atypical organisms, as well as some gram-positive and multidrug-resistant (MDR) organisms. Fluoroquinolones
  • Valproic acid Valproic acid A 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
  • Statins Statins Statins are competitive inhibitors of HMG-CoA reductase in the liver. HMG-CoA reductase is the rate-limiting step in cholesterol synthesis. Inhibition results in lowered intrahepatocytic cholesterol formation, resulting in up-regulation of LDL receptors and, ultimately, lowering levels of serum LDL and triglycerides. Statins
  • 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 drugs

Pathophysiology of DILI^[1,3,7]

Drugs can cause toxic effects by several mechanisms, resulting in mixed hepatocellular and cholestatic damage.

Potential mechanisms of how drugs cause 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: Anatomy 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 Calcium A 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. Electrolytes homeostasis Homeostasis The processes whereby the internal environment of an organism tends to remain balanced and stable. Cell Injury and Death: actin Actin Filamentous 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 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 Cytochrome P450 A superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed function oxygenases). In animals, these p450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (biotransformation). They are classified, according to their sequence similarities rather than functions, into cyp gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the cyp1, cyp2, and cyp3 gene families are responsible for most drug metabolism. Drug-Induced Liver Injury enzyme binds with the drug, producing non-functioning adducts.
  • Adducts reach the cell surface → cytolytic T cells T cells Lymphocytes 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 cytokines Cytokines Non-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 activates apoptotic pathways:
  • Stimulation of death receptors Receptors Receptors 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 ( tumor Tumor Inflammation necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage factor ( 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 Receptor Receptors 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 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 Adenosine A 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 species Reactive oxygen species Molecules 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. Nonalcoholic Fatty Liver Disease; lipid peroxidation Lipid peroxidation Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor. Drug-Induced Liver Injury → 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 Fatty acid metabolism Fatty 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 ( steatosis Steatosis Nonalcoholic Fatty Liver Disease)

Potential mechanisms of how drugs affect the biliary excretion pathway:

• Damaged actin Actin Filamentous 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 affect transport proteins Transport proteins Proteins and Peptides at the canalicular membrane, preventing bile Bile An 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 flow Flow Blood 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.
• Villous processes are lost and canalicular pumps are impaired → ↓ bile Bile An 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  
• Bile Bile An 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 bile Bile An 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 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: Histology → cholestasis
  • Protracted cholestasis leads to “ vanishing bile duct syndrome Vanishing Bile Duct Syndrome Jaundice.”

Clinical Presentation

Symptoms^[1,2,4,7]

• Can be asymptomatic
• Hepatitis-like or cholestatic features:
  • Right upper quadrant Right upper quadrant Anterior Abdominal Wall: Anatomy (RUQ) pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways
  • 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 Nausea An 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/ vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia
  • Malaise Malaise Tick-borne Encephalitis Virus, low-grade fever Low-Grade Fever Erythema Infectiosum
  • Acholic stools or dark urine
  • Pruritus Pruritus An intense itching sensation that produces the urge to rub or scratch the skin to obtain relief. Atopic Dermatitis (Eczema) (with cholestasis)
  • Mental status changes (hepatic encephalopathy Encephalopathy Hyper-IgM Syndrome) in severe cases
• Immunoallergenic features:
  • 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
  • Rash Rash Rocky Mountain Spotted Fever
  • Arthralgia Arthralgia Pain in the joint. Rheumatic Fever
  • Lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy

Signs^[2,10,11]

Acute liver failure Liver failure Severe 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
• Disorientation Disorientation St. Louis Encephalitis Virus/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 (high risk for severe outcome)
• Hypersensitivity reaction to drugs:
  • 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, rash Rash Rocky Mountain Spotted Fever
  • Eosinophilia Eosinophilia Abnormal increase of eosinophils in the blood, tissues or organs. Autosomal Dominant Hyperimmunoglobulin E Syndrome
  • Other organ toxicity Toxicity Dosage Calculation in some cases:
    • Bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis ( anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia)
    • Acute kidney injury Acute Kidney Injury Acute kidney injury refers to sudden and often reversible loss of renal function, which develops over days or weeks. Azotemia refers to elevated levels of nitrogen-containing substances in the blood that accompany AKI, which include BUN and creatinine. Acute Kidney Injury
    • Vasculitis Vasculitis Inflammation of any one of the blood vessels, including the arteries; veins; and rest of the vasculature system in the body. Systemic Lupus Erythematosus
• 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:
  • Alanine Alanine A 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 Acids aminotransferase ( ALT ALT An enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate. Liver Function Tests)
  • Aspartate Aspartate One 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 Acids aminotransferase ( AST AST Enzymes of the transferase class that catalyze the conversion of l-aspartate and 2-ketoglutarate to oxaloacetate and l-glutamate. Liver Function Tests)
  • Alkaline phosphatase Alkaline Phosphatase An enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate. Osteosarcoma ( ALP ALP An enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate. Osteosarcoma)
  • Bilirubin Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism
• Coagulation abnormality ( prothrombin Prothrombin A 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 ratio International normalized ratio System 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 (WBC) count

Chronic 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: Anatomy injury:

• Duration > 3 months
• Elevated 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 
• Resembles chronic 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: Anatomy disease, such as 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 Spider Arthropods 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
  • Ascites Ascites Ascites 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
  • Palmar erythema Palmar Erythema Cirrhosis

Diagnosis

Diagnosing DILI can be difficult because it is a diagnosis of exclusion and the clinical picture can mimic other conditions. A thorough medical history (including medication) and thoughtful workup are necessary.

Clinical^{[1,4,7–9,12]}

• Clinical history:
  • Specific drug intake prior to the onset of 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: Anatomy injury (or overdose)
  • No other explanation for elevated 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
  • Cessation of the offending drug leads to improvement of 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: Anatomy injury.
  • Repeated use causes 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: Anatomy abnormalities (rechallenge is not recommended).
• Research Research Critical and exhaustive investigation or experimentation, having for its aim the discovery of new facts and their correct interpretation, the revision of accepted conclusions, theories, or laws in the light of newly discovered facts, or the practical application of such new or revised conclusions, theories, or laws. Conflict of Interest on the suspected drug:
  • Hepatotoxic potential and “likelihood score”
  • Typical type of 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: Anatomy injury (e.g., hepatocellular)
  • Multiple databases exist to assist, such as that from the National Institutes of Health.
• Physical examination findings of 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: Anatomy disease

Laboratory tests

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:^{[1,4,7,8,10,12]}

• Can signal 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: Anatomy injury and define the type of damage
• Lab values can be used to calculate R value:
  • Calculator
  • R value = ( ALT ALT An enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate. Liver Function Tests/upper limit Limit A value (e.g., pressure or time) that should not be exceeded and which is specified by the operator to protect the lung Invasive Mechanical Ventilation of normal)/( ALP ALP An enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate. Osteosarcoma/upper limit Limit A value (e.g., pressure or time) that should not be exceeded and which is specified by the operator to protect the lung Invasive Mechanical Ventilation of normal)
• Hepatocellular injury/hepatitis:
  • R ≥ 5 → aminotransferase ( AST AST Enzymes of the transferase class that catalyze the conversion of l-aspartate and 2-ketoglutarate to oxaloacetate and l-glutamate. Liver Function Tests, ALT ALT An enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate. Liver Function Tests) elevation disproportionate to ALP ALP An enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate. Osteosarcoma elevation
  • May have ↑ bilirubin Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism and PT/INR
  • May have↓ albumin Albumin Serum 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:
  • R ≤ 2 → ALP ALP An enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate. Osteosarcoma elevation disproportionate to aminotransferase elevation
  • May have ↑ bilirubin Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism and PT/INR
  • May have ↓ albumin Albumin Serum 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
  • R = 3‒4

Consider testing to exclude other suspected causes when clinically appropriate:^{[1,4,7,10,12]}

• Viral hepatitis (e.g., A, B, C, E): standard serologies and HCV RNA HCV RNA Hepatitis C Virus testing
• Other causes: EBV EBV Epstein-barr virus (EBV) is a linear, double-stranded DNA virus belonging to the herpesviridae family. This highly prevalent virus is mostly transmitted through contact with oropharyngeal secretions from an infected individual. The virus can infect epithelial cells and B lymphocytes, where it can undergo lytic replication or latency. Epstein-Barr Virus and CMV
• 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 or primary biliary cholangitis Primary Biliary Cholangitis Primary biliary cholangitis (PBC) is a chronic disease resulting in autoimmune destruction of the intrahepatic bile ducts. The typical presentation is that of a middle-aged woman with pruritus, fatigue, and right upper quadrant abdominal pain. Elevated liver enzymes and antimitochondrial antibodies (AMAs) establish the diagnosis. Primary Biliary Cholangitis: serum antinuclear 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: Types and Functions (ANAs), antimitochondrial antibodies Antimitochondrial Antibodies Primary Biliary Cholangitis (AMAs), and IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis levels
• Wilson disease Wilson disease Wilson disease (hepatolenticular degeneration) is an autosomal recessive disorder caused by various mutations in the ATP7B gene, which regulates copper transport within hepatocytes. Dysfunction of this transport mechanism leads to abnormal copper accumulations in the liver, brain, eyes, and other organs, with consequent major and variably expressed hepatic, neurologic, and psychiatric disturbances. Wilson Disease: serum ceruloplasmin Ceruloplasmin A multi-copper blood ferroxidase involved in iron and copper homeostasis and inflammation. Wilson Disease and urine copper Copper A heavy metal trace element with the atomic symbol cu, atomic number 29, and atomic weight 63. 55. Trace Elements levels
• Alpha-1-antitrypsin deficiency: alpha-1-antitrypsin
• Hemochromatosis Hemochromatosis A disorder of iron metabolism characterized by a triad of hemosiderosis; liver cirrhosis; and diabetes mellitus. It is caused by massive iron deposits in parenchymal cells that may develop after a prolonged increase of iron absorption. Hereditary Hemochromatosis: ferritin Ferritin Iron-containing proteins that are widely distributed in animals, plants, and microorganisms. Their major function is to store iron in a nontoxic bioavailable form. Each ferritin molecule consists of ferric iron in a hollow protein shell (apoferritins) made of 24 subunits of various sequences depending on the species and tissue types. Hereditary Hemochromatosis and transferrin Transferrin An iron-binding beta1-globulin that is synthesized in the liver and secreted into the blood. It plays a central role in the transport of iron throughout the circulation. Heme Metabolism saturation
• Alcoholic Alcoholic Persons who have a history of physical or psychological dependence on ethanol. Mallory-Weiss Syndrome (Mallory-Weiss Tear) hepatitis: alcohol level

Drug levels:^[2]

• Obtained if history is suggestive and the test is available
• May correlate with the degree of hepatotoxicity Hepatotoxicity Acetaminophen ( 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)

Imaging^[1,4,10]

• Abdominal imaging should be done for all patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with suspected cholestatic DILI to exclude:
  • Biliary tract Biliary tract Bile is secreted by hepatocytes into thin channels called canaliculi. These canaliculi lead into slightly larger interlobular bile ductules, which are part of the portal triads at the “corners” of hepatic lobules. The bile leaves the liver via the right and left hepatic ducts, which join together to form the common hepatic duct. Gallbladder and Biliary Tract: Anatomy pathology 
  • Infiltrative processes
  • Malignancy Malignancy Hemothorax
  • Vascular disease (e.g., ischemia Ischemia A hypoperfusion of the blood through an organ or tissue caused by a pathologic constriction or obstruction of its blood vessels, or an absence of blood circulation. Ischemic Cell Damage, 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)
• Options:
  • Ultrasonography (including endoscopic US)
  • CT
  • MRI (including magnetic resonance cholangiopancreatography Magnetic resonance cholangiopancreatography Non-invasive diagnostic technique for visualizing the pancreatic ducts and bile ducts without the use of injected contrast media or x-ray. Mri scans provide excellent sensitivity for duct dilatation, biliary stricture, and intraductal abnormalities. Primary Sclerosing Cholangitis ( MRCP MRCP Non-invasive diagnostic technique for visualizing the pancreatic ducts and bile ducts without the use of injected contrast media or x-ray. Mri scans provide excellent sensitivity for duct dilatation, biliary stricture, and intraductal abnormalities. Primary Sclerosing Cholangitis))

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: Anatomy biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma^{[1‒4,8,10,12]}

• Not required for diagnosis but performed if the diagnosis or severity is uncertain
• Can help rule out other causes of 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: 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 necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage, apoptosis Apoptosis A 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 hepatocytes Hepatocytes The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. Liver: Anatomy.
  • Massive necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage is seen with extensive injury/ALF.
• Chronic hepatocellular injury:
  • Resembles changes in chronic 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: Anatomy disease
  • Periportal and pericellular fibrosis Fibrosis Any 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: bile Bile An 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 Cholestatic Hepatitis Drug-Induced Liver Injury: 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 Bile An 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 duct syndrome”)
• Steatosis Steatosis Nonalcoholic Fatty Liver Disease and steatohepatitis Steatohepatitis Drug-Induced Liver Injury:
  • Due to mitochondrial disruption: ↑ triglycerides Triglycerides Fatty Acids and Lipids
  • Acute DILI (microvesicular); chronic DILI (macrovesicular)
• Granulomas Granulomas A relatively small nodular inflammatory lesion containing grouped mononuclear phagocytes, caused by infectious and noninfectious agents. Sarcoidosis:
  • Non-necrotizing granulomas Granulomas A 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 venules Venules The minute vessels that collect blood from the capillary plexuses and join together to form veins. Veins: Histology and sinusoids Sinusoids Liver: Anatomy)
  • 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 Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus)
• Others: phospholipidosis, peliosis hepatis Peliosis hepatis A 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 (small, dilated, blood-filled cavities in the hepatic parenchyma)

Causality Causality Causality is a relationship between 2 events in which 1 event causes the other. Simply because relationships are observed between 2 variables (i.e., associations or correlations) does not imply that one variable actually caused the outcome. Demonstrating causality between an exposure and an outcome is the main objective of most published medical research. Causality, Validity, and Reliability assessment^[4,6,12]

The Roussel Uclaf Causality Causality Causality is a relationship between 2 events in which 1 event causes the other. Simply because relationships are observed between 2 variables (i.e., associations or correlations) does not imply that one variable actually caused the outcome. Demonstrating causality between an exposure and an outcome is the main objective of most published medical research. Causality, Validity, and Reliability Assessment Method (RUCAM) can be used as an objective evaluation of the likelihood for drug toxicity Toxicity Dosage Calculation:

• Worksheet
• Based on clinical, serologic, and radiologic factors:
  • R value pattern
  • Time to onset
  • Course
  • Risk factors (e.g., pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care)
  • Concomitant drugs
  • Nondrug causes of 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: Anatomy injury
  • Drug hepatotoxicity Hepatotoxicity Acetaminophen information
  • Response to rechallenge (not recommended, but information may already be available)
• Scoring:
  • ≤ 0: excluded
  • 1–2: unlikely
  • 3–5: possible
  • 6–8: probable
  • > 8: highly probable

Emerging tests^[1,7,10]

• Genetic risk assessment Risk assessment The qualitative or quantitative estimation of the likelihood of adverse effects that may result from exposure to specified health hazards or from the absence of beneficial influences. Preoperative Care (HLA typing) has a high negative predictive value Negative predictive value The NPV is the percentage of people with a negative test result who are actually disease free, among all people with a negative result regardless of whether or not they have the disease. Epidemiological Values of Diagnostic Tests for DILI.
• Biomarkers that may give insight Insight Psychiatric Assessment into the mechanism of injury:
  • Cytokeratin Cytokeratin Squamous Cell Carcinoma (SCC) 18 (CK 18) → indicates necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage
  • Caspase-cleaved CK 18 → marker of apoptosis Apoptosis A 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
  • Macrophage colony-stimulating factor Macrophage colony-stimulating factor A mononuclear phagocyte colony-stimulating factor (M-CSF) synthesized by mesenchymal cells. The compound stimulates the survival, proliferation, and differentiation of hematopoietic cells of the monocyte-macrophage series. M-CSF is a disulfide-bonded glycoprotein dimer with a mw of 70 kda. It binds to a specific high affinity receptor. White Myeloid Cells: Histology receptor Receptor Receptors 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 1 (MCSFR1) → indicates immune activation 
• Monocyte-derived hepatocytes Hepatocytes The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. Liver: Anatomy → shows promise in identifying the DILI-causing agent from among a panel of co-prescribed drugs

Management

Management may vary depending on practice location. The following information is based on US, UK, and European literature and guidelines.

General recommendations:^{[1,2,4,7,8,10]}

• Main treatment: cessation of the offending drug
• Management is generally supportive.
• Need for hospitalization Hospitalization The confinement of a patient in a hospital. Delirium depends on the severity (e.g., mild 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: Anatomy function test elevation versus ALF)
• Serial laboratory tests until 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 return to normal
• Symptomatic therapy for pruritus Pruritus An intense itching sensation that produces the urge to rub or scratch the skin to obtain relief. Atopic Dermatitis (Eczema):
  • Bile Bile An 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
  • Antihistamines Antihistamines Antihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation. Antihistamines (e.g., diphenhydramine Diphenhydramine A histamine h1 antagonist used as an antiemetic, antitussive, for dermatoses and pruritus, for hypersensitivity reactions, as a hypnotic, an antiparkinson, and as an ingredient in common cold preparations. It has some undesired antimuscarinic and sedative effects. Antihistamines, hydroxyzine Hydroxyzine A histamine h1 receptor antagonist that is effective in the treatment of chronic urticaria, dermatitis, and histamine-mediated pruritus. Unlike its major metabolite cetirizine, it does cause drowsiness. It is also effective as an antiemetic, for relief of anxiety and tension, and as a sedative. Antihistamines)
• Glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids:
  • Only for hypersensitivity reactions
  • Not otherwise beneficial
  • May be used if DILI cannot be distinguished from 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
• Ursodeoxycholic acid Ursodeoxycholic acid An epimer of chenodeoxycholic acid. It is a mammalian bile acid found first in the bear and is apparently either a precursor or a product of chenodeoxycholate. Its administration changes the composition of bile and may dissolve gallstones. It is used as a cholagogue and choleretic. Primary Biliary Cholangitis and NAC NAC Acetaminophen Overdose:
  • Used by some clinicians
  • Efficacy not yet established
• 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 Pump ACES and RUSH: Resuscitation Ultrasound Protocols inhibitor ALF
  • Infection
  • Multi-organ failure
• Hepatology specialist consultation if there is concern for ALF:
  • 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
  • Encephalopathy Encephalopathy Hyper-IgM Syndrome
  • Coagulopathy
• Liver transplantation Liver transplantation The transference of a part of or an entire liver from one human or animal to another. Hepatocellular Carcinoma (HCC) and Liver Metastases may be required for fulminant liver failure Liver failure Severe 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

Specific therapy^[1,2,8,10]

There are limited specific treatments for DILI, which may include:

• 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 toxicity Toxicity Dosage Calculation (intentional or unintentional overdose) → NAC NAC Acetaminophen Overdose
• Valproic acid Valproic acid A 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 → L-carnitine L-carnitine A constituent of striated muscle and liver. It is an amino acid derivative and an essential cofactor for fatty acid metabolism. Drug-Induced Liver Injury:
  • Potentially counteracts impairment of mitochondrial beta-oxidation
  • Dose:^[10] 
    • 100 mg/kg IV over 30 minutes (maximum, 6 g)
    • Followed by 15 mg/kg every 4 hours
• Leflunomide Leflunomide An isoxazole derivative that inhibits dihydroorotate dehydrogenase, the fourth enzyme in the pyrimidine biosynthetic pathway. It is used an immunosuppressive agent in the treatment of rheumatoid arthritis. Disease-Modifying Antirheumatic Drugs (DMARDs) or terbinafine Terbinafine In addition to the 3 other major classes of antifungal agents (azoles, polyenes, and echinocandins), several other clinically important antifungal agents are used, including flucytosine, griseofulvin, and terbinafine. Terbinafine acts within the stratum corneum of the skin and are used to treat dermatophyte infections of the skin, hair, and nails. Flucytosine, Griseofulvin, and Terbinafine → cholestyramine Cholestyramine A strongly basic anion exchange resin whose main constituent is polystyrene trimethylbenzylammonium cl(-) anion. Lipid Control Drugs:
  • Accelerates clearance of the medication
  • Dose: 4 g every 6 hours for 2 weeks^[10]

Prognosis Prognosis A 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^[1,4,12]

• Typically resolves in days to weeks with discontinuation of the offending medication
• Based on the type of 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: Anatomy injury:
  • Cholestatic DILI has a higher risk of leading to chronic 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: Anatomy injury
  • Hepatocellular DILI more likely (though still rare) to result in:
    • Liver transplantation Liver transplantation The transference of a part of or an entire liver from one human or animal to another. Hepatocellular Carcinoma (HCC) and Liver Metastases
    • Death
• Factors associated with a worse prognosis Prognosis A 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:
  • Acute liver failure Liver failure Severe 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, particularly if related to:
    • Antiepileptics in children
    • Acetaminophen overdose Acetaminophen Overdose Acetaminophen (APAP) is an over-the-counter nonopioid analgesic and antipyretic medication. Acetaminophen is the most commonly used analgesic worldwide. Acetaminophen overdose is also one of the most common causes of medication poisoning and death. Acetaminophen Overdose requiring hemodialysis Hemodialysis Procedures which temporarily or permanently remedy insufficient cleansing of body fluids by the kidneys. Crush Syndrome
  • Elevated serum creatinine
  • Preexisting 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: Anatomy disease
• Prognostic scores:
  • MELD (Model for End-Stage 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: Anatomy Disease) score (ages 12 and older): calculator
  • Charlson comorbility index (CCI): calculator 
  • 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 (with serum bilirubin Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism > 2x ULN) plus transaminases Transaminases A 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. Autoimmune Hepatitis > 3x ULN
    • Associated with 10%–50% mortality Mortality All deaths reported in a given population. Measures of Health Status

Differential Diagnosis

• Non-alcoholic fatty 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: Anatomy disease: 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: Anatomy disease with findings of steatohepatitis Steatohepatitis Drug-Induced Liver Injury on imaging, presenting with similar laboratory results (elevation in ALT ALT An enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate. Liver Function Tests/ AST AST Enzymes 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 index Body mass index An 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 ( BMI BMI An 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 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: Anatomy 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 causing an acute inflammatory reaction in the 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: Anatomy. 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 ALT An enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate. Liver Function Tests/ AST AST Enzymes 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. Can be further differentiated 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: Types and Functions in the serum. Treatment is based on etiology. Prevention of hepatitis A Hepatitis A Hepatitis A is caused by the hepatitis A virus (HAV), a nonenveloped virus of the Picornaviridae family with single-stranded RNA. HAV causes an acute, highly contagious hepatitis with unspecific prodromal symptoms such as fever and malaise followed by jaundice and elevated liver transaminases. Hepatitis A Virus and B 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 is recommended.  
• 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: ALF that presents with fatigue Fatigue The 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, 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 by history. Positive lab testing for anti-smooth muscle antibody Anti-Smooth Muscle Antibody Autoimmune Hepatitis is a strong indicator Indicator Methods 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 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. 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 Steroids A 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. 
• Alcoholic Alcoholic Persons who have a history of physical or psychological dependence on ethanol. Mallory-Weiss Syndrome (Mallory-Weiss Tear) 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: Anatomy disease: liver failure Liver failure Severe 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 abuse. Alcoholic Alcoholic Persons who have a history of physical or psychological dependence on ethanol. Mallory-Weiss Syndrome (Mallory-Weiss Tear) 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: Anatomy disease presents with the same laboratory results (elevation in ALT ALT An enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate. Liver Function Tests/ AST AST Enzymes 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 Steatohepatitis Drug-Induced Liver Injury is noted. Characteristic history (alcohol abuse) and chronic nature of the disease typically distinguish alcoholic Alcoholic Persons who have a history of physical or psychological dependence on ethanol. Mallory-Weiss Syndrome (Mallory-Weiss Tear) fatty 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: Anatomy disease from drug-induced hepatitis. Treatment is alcohol cessation.