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Toxic hepatitis
Toxic hepatitis is liver inflammation caused by medications, toxic chemicals, and pollutants, occurring shortly after exposure and leading to acute liver failure in some cases. Various drugs, toxins, and herbs can induce liver injury, with idiosyncratic reactions being common and associated with genetic factors. Diagnosis often includes patient history, hepatic function tests, and imaging studies to assess the extent of liver damage.
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Overview of toxic hepatitis, liver functions, and introduction to inflammation due to toxins or drugs.
Overview of toxic hepatitis, liver functions, and introduction to inflammation due to toxins or drugs.
Data on incidence and causes of drug-induced liver injury, accounting for 10% of acute hepatitis cases.
Overview of substances causing toxic hepatitis and idiosyncratic drug reactions, including examples.
Discussion on acetaminophen toxicity, Reye’s syndrome, and patterns of chronic toxic hepatitis.
Discussion on acetaminophen toxicity, Reye’s syndrome, and patterns of chronic toxic hepatitis.
Overview of liver vascular disorders and various mechanisms resulting in drug-induced liver disease.
Identification of factors increasing susceptibility to drug toxicity, such as age, sex, and race.
Discussion on medication, herbs, and alcohol as potential causes of liver toxicity.
Different mechanisms through which drugs cause liver injury, categorizing them into intrinsic and idiosyncratic.
Common symptoms and clinical manifestations of toxic hepatitis, including jaundice and abdominal pain.
Details on pathological manifestations of liver injury caused by various drugs.
Approaches to diagnosing toxic hepatitis through patient history and laboratory tests.
Management strategies for toxic hepatitis involving removal of causative agents and supportive care.
Nursing diagnoses and interventions to manage patients with toxic hepatitis effectively.
Key guidelines for the recognition and prevention of hepatotoxicity in clinical practice.
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Toxic hepatitis
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- 3. Liver Physiologic Function (Barret,E.K., Barman, S.M., Boitano, S., Brooks, H.L., 2010, Ganong’sReview of Medical Physiology, 23rd edition, USA: The McGraw-HillsComp.) Formation and secretion of bile Nutrient and vitamin metabolism (amino acid, lipid, glucose) Detoxification & inactivation of various substances (toxin, drug) Synthesis of plasma proteins (albumin, clotting factor) Immune system kupffer cells.
- 4. Introduction • Toxic hepatitisrefers to inflammation of the liver due to medication or exposure to toxic chemicals, drugs, pollutants and nutritional supplements. • In some cases, toxic hepatitis develops within hours or days of exposure to a toxin. • It also known as Drug Induced Liver Injury (DILI)
- 5. Epidemiology • Drug-induced liverinjury has an estimated incidence of 10- 15 per 10,000 to 100,000 persons exposed to prescription medications. • It accounts for approximately 10 percent of all cases of acute hepatitis and it is the most common cause of acute liver failure in the United States
- 6. Epidemiology • More than900 drugs, toxins, and herbs have been reported to cause liver injury, and drugs account for 20-40% of all instances of fulminant hepatic failure. • Approximately 75% of the idiosyncratic drug reactions result in liver transplantation or death.
- 7. Toxic Hepatitis • Toxichepatitis is an inflammatory condition caused by ingestion or inhalation of certain substances Dry cleaning, fluid, Glue, Insecticides – pesticides, Poisonous mushrooms, Rat poison, Tylenol, Aspirin, Thorazine, INH, Valium and Alcohol.
- 8. Patterns of drug-inducedliver disease IDIOSYNCRATIC REACTIONS • A genetic or acquired abnormality in a particular metabolic pathway. • The reactions are typically associated with a drug concentration and often respond to simply lowering the dose of the drug. • Idiosyncratic reactions tend to occur without association to particular blood concentrations or specifically identified metabolic abnormalities. For example, sulfonylureas like glipizide and antibiotics like ciprofloxacin
- 9. Allergic Hepatitis • Thereaction usually develops within 4 weeks of the start of therapy. • It is marked by fever, pruritus, rash, eosinophilia, arthritis, and hemolytic anemia. • The formation of granulomas within the liver is often seen on biopsy. Most antibiotics have been associated with this type of reaction, including the fluoroquinolones, macrolides, and β- lactams, trimethoprim, sulphamethoxazole, penicillin resistant penicillins
- 10. Toxic Hepatitis • Whentaken in overdose, acetaminophen becomes bioactivated to a toxic intermediate known as N-acetyl-p- benzoquinone imine (NAPQI). • Reye’s syndrome is an aggressive form of toxic hepatitis often associated with aspirin use in children. • Valproate toxicity can also present in this pattern In advanced stages of Reye’s syndrome, many patients develop intracranial hypertension that can be life threatening and refractory to therapy.
- 12. Chronic active toxichepatitis • Patients experience periods of symptomatic hepatitis followed by periods of convalescence, only to repeat the experience months later. • It is a progressive disease with a high mortality rate and is more common in females than males. Antinuclear antibodies appear in most patients. • Ex: Dantrolene, isoniazid, phenytoin, nitrofurantoin, and trazodone.
- 13. Toxic cirrhosis • Hepatomegalyis a common finding, along with ascites and portal hypertension. • Methotrexate (psoriasis and arthritis) Vit A toxicity.
- 14. Liver vascular disorders •Focal lesions in hepatic venules, sinusoids, and portal veins. • Azathioprine and herbal teas that contain comfrey (a source of pyrrolizidine alkaloids) • Peliosis hepatitis has been associated with exposure of the liver to androgens, estrogens, tamoxifen, and azathioprine. • Rupture of the lacunae can lead to severe peritoneal hemorrhage.
- 15. Mechanisms of DILIcentrolobular necrosis • Two types : Mild drug reactions : asymptomatic elevations in the serum transaminases. More severe forms: nausea, vomiting, upper abdominal pain, and jaundice. • STEATOHEPATITIS Tetracycline given intravenously and in doses greater than 1.5 g/day. (mortality 70% to 80%) • Sodium valproate: Cytochrome P450 converts valproate to D-4- valproic acid, a potent inducer of microvesicular fat accumulation. • PHOSPHOLIPIDOSIS Usually the phospholipidosis develops in patients treated for more than 1 year. The patient can present with either elevated transaminases or hepatomegaly; jaundice is rare. Ex: Amiodarone
- 16. • GENERALIZED HEPATOCELLULARNECROSIS Isoniazid and ketoconazole. • CHOLESTATIC JAUNDICE • The administration of total parenteral nutrition for periods greater than 1 week induces cholestatic changes and nonspecific enzyme elevations in some patients. • Patients with low serum albumin concentrations may be at greater risk than patients with normal serum albumin concentrations. Rarely with sulfonamides, sulfonylureas, erythromycin estolate and ethylsuccinate, captopril, lisinopril, and other phenothiazines
- 17. Mixed hepatocellular necrosisand cholestatic disease • Flutamide causes a mix of lesions that appear at or about the forty-eighth week of treatment. • Niacin in doses greater than 3 g/day, or in doses greater than 1 g/day of sustained-release formulations, causes the same mixed pattern of damage. • NEOPLASTIC DISEASE Both carcinoma- and sarcoma-like lesions have been identified. Lesions are associated with long-term exposure to the offending agent. Androgens, estrogens, and other hormonal-related agents.
- 18. Risk Factors • Race •Age • Sex • Alcohol ingestion • Liver diseases • Genetics Factors • Co-morbidities • Drug formulations Race-Some drugs appear to have different toxicities based on race. For example, blacks and Hispanics may be more susceptible to isoniazid (INH) toxicity. The rate of metabolism is under the control of P-450 enzymes and can vary from individual to individual. Age: • Apart from accidental exposure, hepatic drug reactions are rare in children. • Elderly persons are at increased risk of hepatic injury because of decreased clearance, drug-to-drug interactions, reduced hepatic blood flow, variation in drug binding, and lower hepatic volume. In addition, poor diet, infections, and multiple hospitalizations are important reasons for drug-induced hepatotoxicity. Sex: Although the reasons are unknown, hepatic drug reactions are more common in females. Alcohol ingestion: Alcoholic persons are susceptible to drug toxicity because alcohol induces liver injury and cirrhotic changes that alter drug metabolism. Alcohol causes depletion of glutathione (hepatoprotective) stores that make the person more susceptible to toxicity by drugs. Liver disease: • Patients with chronic liver disease are not uniformly at increased risk of hepatic injury. • Although the total cytochrome P-450 is reduced, some may be affected more than others. • The modification of doses in persons with liver disease should be based on the knowledge of the specific enzyme involved in the metabolism. • Patients with HIV infection who are co-infected with hepatitis B or C virus are at increased risk for hepatotoxic effects when treated with antiretroviral therapy. Genetic factors: • A unique gene encodes each P-450 protein. • Genetic differences in the P-450 enzymes can result in abnormal reactions to drugs, including idiosyncratic reactions. • Debrisoquine is an antiarrhythmic drug that undergoes poor metabolism because of abnormal expression of P-450-II-D6. This can be identified by polymerase chain reaction amplification of mutant genes. This has led to the possibility of future detection of persons who can have abnormal reactions to a drug. Other comorbidities: Persons with AIDS, persons who are malnourished, and persons who are fasting may be susceptible to drug reactions because of low glutathione stores. Drug formulation: Long-acting drugs may cause more injury than shorter- acting drugs.
- 19. Host factors thatmay enhance susceptibility to drugs • Female - Halothane, nitrofurantoin, sulindac • Male - Amoxicillin-clavulanic acid (Augmentin) • Old age - Acetaminophen, halothane, INH, amoxicillin- clavulanic acid • Young age - Salicylates, valproic acid • Fasting or malnutrition - Acetaminophen
- 20. Contd…. • Large bodymass index/obesity - Halothane • Diabetes mellitus - Methotrexate, niacin • Renal failure - Tetracycline, allopurinol • AIDS - Dapsone, trimethoprim-sulfamethoxazole • Hepatitis C - Ibuprofen, ritonavir, flutamide • Pre-existing liver disease - Niacin, tetracycline, methotrexate
- 21. Etiology • Medications • Herbaland Nutritional Supplements • Alcohol Medications-Many medications have the potential to cause liver toxicity and carry a warning on their label to this effect. In most cases when problems occur, they are mild and only apparent from blood tests, and can be resolved by reducing the dose of medication or discontinuing use. Herbs & Nutritional Support • It is important to note that these substances are not subject to the same regulations, testing or approval processes as conventional drugs. • Studies have shown that some herbs and nutritional supplements are adulterated with steroids or antibiotics. • Herbs that may be toxic to the liver include comfrey, chaparral, germander, kava, valerian, mistletoe and traditional Chinese herbs. • People with liver disease should not use herbs or nutritional supplements without the approval of their doctor. Alcohol • Alcohol abuse is well known to cause liver damage, but the extent of injury varies widely among people who drink to excess. • In individuals who are prone to alcohol- related liver injury - possibly due to genetics - heavy drinking can result in acute liver failure • Other people may develop progressive liver disease from regular, heavy use of alcohol.
- 22. Drug Induced LiverInjury Liver injury may be produced by a large variety of chemical substances The type and degree of injury produced is extremely varied, and may mimic the entire spectrum of hepatobiliary disorders. The central role played by the liver in the clearance and biotransformation of chemical susceptibility to drug-induced injury. Drugs can initiate progressive chronic liver disease and are the single leading cause of acute liver failure Friedman, S.L., McQuaid K.R., 2003, Current Diagnosis and Treatment in Gastroenterology, USA: The McGraw-Hills,Comp.
- 23. Mechanisms of liverinjury William, M.Lee, Review Article : Medical Progress Drug-Induced Hepatotoxicity. N Engl J Med 2003;349:474-85) Disruption of the hepatocyte: Covalent binding of the drug to intracellular proteins can cause a decrease in ATP levels, leading to actin disruption. Disassembly of actin fibrils at the surface of the hepatocyte causes blebs and rupture of the membrane. Disruption of the transport proteins: Drugs that affect transport proteins at the canalicular membrane can interrupt bile flow. Loss of villous processes and interruption of transport pumps such as multidrug resistance–associated protein 3 prevent the excretion of bilirubin, causing cholestasis. CytolyticT-cell activation:Covalent binding of a drug to the P-450 enzyme acts as an immunogen, activatingT cells and cytokines and stimulating a multifaceted immune response. Apoptosis of hepatocytes: Activation of the apoptotic pathways by the tumor necrosis factor-alpha receptor of Fas may trigger the cascade of intercellular caspases, which results in programmed cell death. Mitochondrial disruption:Certain drugs inhibit mitochondrial function by a dual effect on both beta- oxidation energy production by inhibiting the synthesis of nicotinamide adenine dinucleotide and flavin adenine dinucleotide, resulting in decreased ATP production. Bile duct injury:Toxic metabolites excreted in bile may cause injury to the bile duct epithelium.
- 24. Drug Toxicity Mechanism Intrinsicor predictable drug reactions • Drugs that fall into this category cause reproducible injuries, and the injury is dose related. • The injury can be due to the drug itself or to a metabolite. • Acetaminophen is a classic example of a known intrinsic or predictable hepatotoxin at supertherapeutic doses. Another classic example is carbon tetrachloride.
- 25. Drug Toxicity Mechanism •Idiosyncratic drug reactions: classified as hypersensitivity or immune-allergic and those that are metabolic-idiosyncratic. • Hypersensitivity • Phenytoin is a classic, if not common, cause of hypersensitivity reactions. • The response is characterized by fever, rash, and eosinophilia and is an immune-related response with a typical short latency period of 1-4 weeks.
- 26. Contd… Metabolic-idiosyncratic • This typeof reaction occurs through an indirect metabolite of the offending drug. • It occurs in a minority of patients taking the drug, and no clinical manifestations of hypersensitivity are noted. INH toxicity is considered to fall into this class.
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- 29. ANICTERIC HEPATITIS ASTRIXIS BLEEDING TENDENCIES, ANEMIA HEPATOMEGALY,SPIDER ANGIOMAS, PALMER ERYTHEMA SPLENOMEGALY, GLOMERULONEPHRIS
- 30. Other symptoms • Headache •Dark Urine • White or Clay coloured stool
- 31. Clinical Manifestations • Rangingfrom asymptomatic elevation of liver enzymes to fulminant hepatic failure. • The injury may suggest a hepatocellular injury, with elevation of aminotransferase levels as the predominant symptom, or a cholestatic injury, with elevated alkaline phosphatase levels (with or without hyperbilirubinemia) being the main feature. • Asymptomatic elevations in aminotransferase-This tolerance is also observed in 25-50% of the patients taking drugs such as methyldopa or phenytoin, and it is especially well described with INH, sulfonamides, salicylates, sulfonylureas and quinidine.
- 32. Pathological Manifestations Acute hepatocellularinjury • Acute viral hepatitis–like picture - INH, halothane, diclofenac, troglitazone • Mononucleosis like picture - Phenytoin, sulfonamides, dapsone • Chronic hepatocellular injury - Pemoline, methyldopa • Massive necrosis - Acetaminophen, halothane, diclofenac
- 33. Pathological Manifestations Steatosis • Macrovesicularsteatosis - Alcohol, methotrexate, corticosteroids, minocycline, nifedipine, TPN • Microvesicular steatosis - Alcohol, valproic acid, tetracycline, piroxicam • Steatohepatitis - Amiodarone, nifedipine, synthetic estrogens, didanosine • Pseudoalcoholic injury - Amiodarone
- 34. Contd.. • Acute cholestasis- Amoxicillin-clavulanic acid, erythromycin, sulindac • Chronic cholestasis - Chlorpromazine, sulfamethoxazole- trimethoprim, tetracycline, ibuprofen • Granulomatous hepatitis - Carbamazepine, allopurinol, hydralazine • Vascular injury - Steroids • Neoplasia - Contraceptives, anabolic steroids Adenoma - Steroids • Angiosarcoma - Vinyl chloride
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- 36. Diagnosis • History • Mustinclude dose, route of administration, duration, previous administration, and use of drugs, including over- the-counter medications and herbs. • The latency period of idiosyncratic drug reactions is highly variable, hence, obtaining a history of every drug ingested in the past 3 months is essential. • Onset-The onset is usually within 5-90 days of starting the drug.
- 37. Dechallenge • A positivedechallenge is a 50% fall in serum transaminase levels within 8 days of stopping the drug. • A positive dechallenge is very helpful in cases of use of multiple medications. • Track record of the drug: Previously documented reactions to a drug aid in diagnosis.
- 38. Rechallenge • Deliberate rechallengein clinical situations is unethical and should not be attempted • Inadvertent rechallenge in the past has provided valuable evidence that the drug was indeed hepatotoxic
- 39. Hepatic Function Tests •Bilirubin (total) - To diagnose jaundice and assess severity • Bilirubin (unconjugated) - To assess for hemolysis • Alkaline phosphatase - To diagnose cholestasis and infiltrative disease • AST/serum glutamic oxaloacetic transaminase (SGOT) - To diagnose hepatocellular disease and assess progression of disease • ALT/serum glutamate pyruvate transaminase (SGPT) - ALT relatively lower than AST in persons with alcoholism • Albumin - To assess severity of liver injury (HIV infection and malnutrition may confound this.)
- 40. Contd.. • Gamma globulin- Large elevations suggestive of autoimmune hepatitis, other typical increase observed in persons with cirrhosis • Prothrombin time after vitamin K - To assess severity of liver disease • Antimitochondrial antibody - To diagnose primary biliary cirrhosis • ASMA - To diagnose primary sclerosing cholangitis
- 41. Imaging Studies Ultrasonography • Ultrasonographyis inexpensive compared with CT scanning and MRI • Less time consuming • Effective to evaluate the gall bladder, bile ducts, and hepatic tumors.
- 42. Contd… CT scan • Canhelp detect focal hepatic lesions 1 cm or larger and some diffuse conditions. • It can also be used to visualize adjacent structures in the abdomen.
- 43. Contd… MRI • MRI providesexcellent contrast resolution. • It can be used to detect cysts, hemangiomas, and primary and secondary tumors. • The portal vein, hepatic veins, and biliary tract can be visualized without contrast injections.
- 44. Procedures Liver biopsy • Histopathologicevaluation remains an important tool in diagnosis. • A liver biopsy is not essential in every case, but a morphologic pattern consistent with the expected pattern provides supportive evidence.
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- 46. Management • The firstand most important step in treating toxic hepatitis is to identify and eliminate the substance that is causing the problem, such as medications, herbs or alcohol. • In the case of alcohol-related liver damage, joining a program such as Alcoholics Anonymous and/or enrolling in a treatment/rehabilitation program is highly recommended.
- 47. Management • Early recognitionof drug-induced liver reactions is essential to minimizing injury. • ALT values are more specific than AST values. • ALT values that are within the reference range at baseline and rise 2- to 3-fold should lead to enhanced vigilance in terms of more frequent monitoring. • ALT values 4-5 times higher than the reference range should lead to prompt discontinuation of the drug.
- 48. Management • No specifictreatment is indicated for drug-induced hepatic disease. • Treatment is largely supportive and based on symptomatology. • The first step is to discontinue the suspected drug. • Specific therapy against drug-induced liver injury is limited to the use of N-acetylcysteine in the early phases of acetaminophen toxicity. • L- carnitine is potentially valuable in cases of valproate toxicity.
- 49. Management • Corticosteroids haveno definitive role in treatment. They may suppress the systemic features associated with hypersensitivity or allergic reactions. • Management of protracted drug-induced cholestasis is similar to that for primary biliary cirrhosis. • Cholestyramine may be used for alleviation of pruritus. • Ursodeoxycholic acid may be used.
- 50. Liver Transplantation • Urgentliver transplantation should be considered for patients with life-threatening liver damage caused by a medication, herb or nutritional supplement. • Patients with end-stage cirrhosis from alcohol may be considered for transplantation. • They are considered candidates for transplantation only if they have been completely abstinent from alcohol and in a treatment program for a minimum of six months.
- 51. Liver Transplantation • Nospecific antidote is available for the vast majority of hepatotoxic agents. • The Model for End-Stage Liver Disease score can be used to evaluate short-term survival in an adult with end- stage liver disease. This can help stratify candidates for liver transplantation. • The parameters used are serum creatinine, total bilirubin, international normalized ratio, and the cause of the cirrhosis. • Another criterion commonly used for liver transplantation is the Kings College criteria
- 52. Kings College Criteria Incases of acetaminophen toxicity are as follows: • pH less than 7.3 (irrespective of grade of encephalopathy) • Prothrombin time (PT) greater than 100 seconds or international normalized ratio greater than 7.7 • Serum creatinine level greater than 3.4 mg/dL in patients with grade III or IV encephalopathy Measurement of lactate levels at 4 and 12 hours also helps in early identification of patients who require liver transplantation.
- 53. Kings College Criteria Inother cases of drug-induced liver failure are as follows: • PT greater than 100 seconds (irrespective of grade of encephalopathy) or • Any 3 of the following criteria: • Age younger than 10 years or older than 40 years • Etiology of non-A/non-B hepatitis, halothane hepatitis, or idiosyncratic drug reactions • Duration of jaundice of more than 7 days before onset of encephalopathy • PT greater than 50 seconds • Serum bilirubin level greater than 17 mg/dL
- 54. Nursing Diagnosis • ImbalancedNutrition: Less Than Body Requirements • Risk for Deficient Fluid Volume • Fatigue • Risk for Impaired Skin Integrity • Deficient Knowledge • Situational Low Self-Esteem • Risk for Infection
- 55. Nursing Interventions • Assessfor the drug history • Ensure removal of causative agent (drug) • Monitor I/O charting • Assess for the edema • Observe the signs of bleeding • Administer vitamin K as indicated. • Infuse FFP as indicated • Adequate rest and promote alleviation of side-effects
- 56. Nursing Interventions • Highcalorie diet with protein and fat as tolerated. • Encourage patients to have atleast 3 meals a day • Encourage and assist the patient with performing bedside exercises and provide him with reading material to stimulate cognitive function daily. • Assess the patient’s energy level before and after each nursing shift. • Follow out the nutritionists plan of care regarding patient caloric intake daily for each meal and snacks. • Administer anti-emetics IV every 8 hours for nausea and vomiting as prescribed.
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- 60. Key Guideline inthe Recognition & Prevention of Hepatotoxicity in Clinical Practice Do not ignore the symptoms Take a careful history Remove the causative agent Monitoring • Symptoms • LFT Victor J. Navarro, M.D., and John R. Senior, M.D., 2006, Drug-Related Hepatotoxicity, The New England Journal of Medicine, vol. 354, pp. 731-739.
- 61. References • Hinkle, J.L. (2014). Brunner & Suddarth's textbook of medical- surgical nursing (Edition 13.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. • Black, J. M., & Hawks, J. H. (2009). Medical-surgical nursing: Clinical management for positive outcomes. St. Louis, Mo: Saunders/Elsevier. • Roberts, D. (Ed.). (2014). Medical–Surgical Nursing Review Questions (3rd ed.). Pitman, NJ: Academy of Medical-Surgical Nurses. • Lewis, S.L., Dirksen, S.R., Heitkemper, M.M., Bucher, L., & Harding, M.M. (2017). Medical-Surgical Nursing: Assessment and Management of Clinical Problems (10th ed.). St. Louis: Elsevier.