Drug-induced 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 (DILI) is the most common cause of acute 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 failure (ALF). Hepatotoxic drugs can cause injury to the hepatocytes Hepatocytes The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. Liver: Anatomy directly in a predictable dose-dependent way or through idiosyncratic reactions (which may be mediated by immune or non-immune processes). The injury mechanisms can have the following effects: hepatitis, cholestasis, vascular lesions, or overlapping changes. The presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor can be acute or chronic, with severe toxicity Toxicity Dosage Calculation manifesting as fulminant 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 failure. The diagnosis of DILI requires a thorough history and laboratory tests including 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 tests (LFTs) and drug levels, if available. Management consists of discontinuing the drug, supportive therapy, and monitoring for complications. Acetaminophen Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. Acetaminophen, one of the most common causes of DILI, has a specific treatment, N-acetylcysteine N-Acetylcysteine Acetaminophen Overdose ( NAC NAC Acetaminophen Overdose).
Last updated: 8 Jan, 2021
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 handles metabolism of drugs/toxins, thus making 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 susceptible to injury. The drugs themselves undergo processes to be inactivated and become water soluble (for proper renal or biliary excretion).
Phase I reaction:
Phase II reaction:
Phase III reaction:
Intrinsic/direct hepatotoxins:
Idiosyncratic reactions:
Potential mechanism overlaps of drugs may occur as mixed hepatocellular and cholestatic changes occur.
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:
Potential mechanisms of how drugs affect Affect The feeling-tone accompaniment of an idea or mental representation. It is the most direct psychic derivative of instinct and the psychic representative of the various bodily changes by means of which instincts manifest themselves. Psychiatric Assessment the biliary excretion pathway:
Acute 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 failure:
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:
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 is defined as lasting > 3 months, thereby resembling 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 or cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis:
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 tests:
Drug levels:
Type of injury | Blood test |
---|---|
Hepatitis |
|
Cholestasis |
|
Mixed |
|
Histologic patterns of injury:
Pattern of injury | Examples |
---|---|
Acute hepatitis Acute Hepatitis Autoimmune Hepatitis |
|
Chronic hepatitis/ fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans |
|
Cholestatic hepatitis (mixed) |
|
Cholestasis |
|
Steatosis Steatosis Nonalcoholic Fatty Liver Disease or steatohepatitis |
|
Granulomas Granulomas A relatively small nodular inflammatory lesion containing grouped mononuclear phagocytes, caused by infectious and noninfectious agents. Sarcoidosis |
|
Vascular lesions |
|
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 specimen showing lobular hepatitis secondary to ibuprofen Ibuprofen A nonsteroidal anti-inflammatory agent with analgesic properties used in the treatment of rheumatism and arthritis. Nonsteroidal Antiinflammatory Drugs (NSAIDs)
Image: “A rare coexistence: drug-induced hepatitis and meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis in association with Ibuprofen Ibuprofen A nonsteroidal anti-inflammatory agent with analgesic properties used in the treatment of rheumatism and arthritis. Nonsteroidal Antiinflammatory Drugs (NSAIDs)” by Nayudu SK SK Seborrheic keratosis (sk) is the most common benign epithelial cutaneous neoplasm. The condition consists of immature keratinocytes. Seborrheic keratosis is the most common benign skin tumor in middle-aged and elderly adults and presents as a sharply demarcated, exophytic, skin lesion that may be tan or black and has a “stuck-on” appearance. Seborrheic Keratosis, Kavuturu S, Niazi M, Daniel M, Dev A, Kumbum K. License: CC BY 2.0.
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 of a patient with human
immunodeficiency
Immunodeficiency
Chédiak-Higashi Syndrome
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 (
HIV
HIV
Anti-HIV Drugs) infection taking
stavudine
Stavudine
A dideoxynucleoside analog that inhibits reverse transcriptase and has in vitro activity against HIV.
Anti-HIV Drugs:
Laboratory tests showed elevated
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; image showed
acidophil bodies
Acidophil Bodies
Cellular Accumulations and foamy degeneration of
hepatocytes
Hepatocytes
The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules.
Liver: Anatomy (
steatosis
Steatosis
Nonalcoholic Fatty Liver 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
biopsy
Biopsy
Removal and pathologic examination of specimens from the living body.
Ewing Sarcoma of a patient with elevated
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
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 after treatment of
Helicobacter
Helicobacter
Helicobacter pylori is a gram-negative bacterium that causes gastric infection. It is the most well known and clinically significant species of Helicobacter. Transmission is believed to occur by ingestion of contaminated food or water; therefore, a higher prevalence of infection is seen in areas with poor sanitation.
Helicobacter pylori infection (using
clarithromycin
Clarithromycin
A semisynthetic macrolide antibiotic derived from erythromycin that is active against a variety of microorganisms. It can inhibit protein synthesis in bacteria by reversibly binding to the 50s ribosomal subunits. This inhibits the translocation of aminoacyl transfer-RNA and prevents peptide chain elongation.
Macrolides and Ketolides and
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):
Image shows 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.
Image of
albendazole
Albendazole
A benzimidazole broad-spectrum anthelmintic structurally related to mebendazole that is effective against many diseases.
Anthelmintic Drugs-induced granulomatous hepatitis:
hepatic parenchyma with epithelioid
macrophages
Macrophages
The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells.
Innate Immunity: Phagocytes and Antigen Presentation that have formed
granulomas
Granulomas
A relatively small nodular inflammatory lesion containing grouped mononuclear phagocytes, caused by infectious and noninfectious agents.
Sarcoidosis without
necrosis
Necrosis
The death of cells in an organ or tissue due to disease, injury or failure of the blood supply.
Ischemic Cell Damage, interspersed with
lymphocytes
Lymphocytes
Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage.
Lymphocytes: Histology
Limited specific treatments for DILI:
Pathogenesis:
Clinical presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor:
Diagnosis:
Initial management:
Management 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
toxicity
Toxicity
Dosage Calculation:
1. Obtain history, identify agents involved, and determine severity and possible drug
toxicity
Toxicity
Dosage Calculation.
If
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 ingestion (potentially toxic dose > 7.5 g) has been < 4 hours, activated
charcoal
Charcoal
An 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 is given to prevent
absorption
Absorption
Absorption 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 of residual drug.
Patient should be alert to protect the
airway
Airway
ABCDE Assessment and avoid aspiration.
2. Serum
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 level is obtained (recommended at 4 hours after ingestion; 2nd drug level is obtained later if extended
release
Release
Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane.
Virology preparation was ingested).
3. N-acetyl-
cysteine
Cysteine
A thiol-containing non-essential amino acid that is oxidized to form cystine.
Synthesis of Nonessential Amino Acids is administered in the following cases:
Levels above the treatment line in the nomogram
Unclear time of ingestion and serum
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 level is > 10 µg/mL
Evidence of
hepatotoxicity
Hepatotoxicity
Acetaminophen
Suspected single dose of > 7.5 g or 150 mg/kg and result 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 level will not be available for at least 8 hours.
Management:
Rumack-Matthew nomogram
Rumack-Matthew nomogram
Guides the use of the antidote n-acetylcysteine (NAC) based on sapap and hours since ingestion in relation to probability of hepatotoxicity.
Acetaminophen Overdose (
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 nomogram):
The nomogram is used after a single acute
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 ingestion, and predicts potential
hepatotoxicity
Hepatotoxicity
Acetaminophen 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
Presentation
The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck.
Normal and Abnormal Labor.
The upper (red) line is the Rumack-Matthew line; values above this line develop
toxicity
Toxicity
Dosage Calculation (noted in 60%).
The lower (blue) line is the treatment line (the U.S. Food and Drug Administration required the treatment line to be 25% below the original line).
The
NAC
NAC
Acetaminophen Overdose treatment is given when the
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 level is at the treatment line 4 hours post ingestion (which is below the
toxicity
Toxicity
Dosage Calculation
threshold
Threshold
Minimum voltage necessary to generate an action potential (an all-or-none response)
Skeletal Muscle Contraction).