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DILD pdf - Drug induced liver disease

Drug induced liver disease
Course

Environmental and nutritional disease

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Academic year: 2020/2021
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Rajiv Gandhi University of Health Sciences

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DRUG INDUCED LIVER DISORDERS

  • Drug-induced liver diseases are diseases of the liver that are caused by physician- prescribed medications, over-the-counter medications, vitamins, hormones, herbs, illicit ("recreational") drugs, and environmental toxins.
  • Drug-induced liver disease is a rare but potentially fatal, often debilitating and largely unpredictable outcome of drug treatment.
  • Drug-induced liver disease accounts for as much as 20% of acute liver failure in pediatric populations and a similar percentage of adults with acute liver failure.
  • In approximately 75% of these cases, liver transplantation is ultimately required for patient survival.

ETIOLOGY

➢ NSAID- Acetaminophen, Nimesulide, Diclofenac ➢ Anti- TB- Isoniazid, Rifampicin ➢ Antiepileptics – Phenytoin, Carbamazepine, Valproate ➢ Antibiotics – Amoxicillin, Trimethoprim+Sulfamethoxazole, Fluoroquinolones, Macrolides, Nitrofurantoin ➢ Hypolipidemic Drugs- Statins, Niacin, Fibrates ➢ Anaesthetic Agents- Halothane, Chloroform, Nitrous Oxide ➢ Anti-Rheumatic Drugs- Sulphasalazine, Gold Salt, Methotrexate ➢ Anti- Retriviral Drugs- Protease Inhibitor (Ritonavir, Indinavir), NRTI (Lamivudin, Tenofovir, Zidovudine), NNRTI (Nevirapine, Efavirenz)

CLINICAL PRESENTATIONS

➢ Idiosyncratic reactions, ➢ Allergic hepatitis, ➢ Toxic hepatitis, ➢ Chronic active toxic hepatitis, ➢ Toxic cirrhosis, ➢ Liver vascular disorders.

  • The mechanisms of drug-induced liver disease are diverse, representing many phases of biotransformation, and are susceptible to genetic polymorphism.
  • A fulminant or severe drug-induced reaction within the liver usually involves the immune system and is marked by large-scale cell necrosis.

PATTERN OF DRUG INDUCED LIVER DISEASE

1. HEPATOCELLULAR INJURY

➢ Hepatocellular injury is characterized by significant elevations in the serum aminotransferases, which usually precede elevations in total bilirubin levels and alkaline phosphatase levels. ➢ Most injuries occur within 1 year of initiating the offending agent. Hepatocellular injury can lead to fulminant hepatitis with a corresponding 20% survival rate with supportive care. ➢ For those patients who present with the combination of hepatocellular injury and jaundice, there is a 10% mortality rate.

NON-ALCOHOLIC STEATOHEPATITIS
  • Nonalcoholic steatohepatitis (NASH), also known as steatohepatitis and steatonecrosis, results from the accumulation of fatty acids in the hepatocyte.
  • In the preacute stages, this is known as nonalcoholic fatty liver disease (NAFLD).
  • Drugs or their metabolites that cause NAFLD do so by affecting fatty-acid esterification and oxidation rates within the mitochondria of the hepatocyte.
  • Hepatic vesicles become engorged with fatty acids, eventually disrupting hepatocyte homeostasis.
  • In patients with diabetes, various dyslipidemias and even hypertension, the de novo production of free fatty acids from excess circulating carbohydrates, accelerates this process of accumulation.
  • The liver biopsy is marked by a massive infiltration by polymorphonuclear leukocytes, degeneration of the hepatocytes, and the presence of Mallory bodies.

ALCOHOL INDUCED HEPATOTOXICITY

  • Alcohol is the drug that most commonly produces steatonecrotic changes in the liver.
  • When alcohol is converted into acetaldehyde, the synthesis of fatty acids is increased.
  • The hepatocyte can become completely engorged with microvesicular fat, resulting in alcoholic fatty liver.
  • Metabolically this type of de novo free fatty acid synthesis depletes NADPH in favor of NADP+ and reduces the hepatocytes’ ability to respond to stress, bypassing normal apoptosis and increasing the rate of necrocytolysis.
  • In NAFLD, the same end point is often achieved through oxidation of lipid peroxidases.
  • If the offending agent is withdrawn before significant numbers of hepatocytes become necrotic, the process is completely reversible without long-term sequelae.
  • If not, then ever-increasing rates of necrocytolysis will induce an innate immune response and result in hepatitis.

TETRACYCLINE produces NAFLD and NASH. The lesions are characterized by large vesicles of fat found diffused throughout the liver. The development of this reaction is related to the high concentrations achieved when tetracycline is given IV and in doses greater than 1 g/day. The mortality of tetracycline steatohepatitis is high (70% to 80%), and those who do survive often develop cirrhosis.

SODIUM VALPROATE also can produce steatonecrosis through the process of bioactivation. Cytochrome P450 (CYP450) converts valproate to delta-4-valproic acid, a potent inducer of microvesicular fat accumulation.

Symptoms of steatohepatitis

✓ Abdominal fullness or pain ✓ Nausea, vomiting, ✓ Steatorrhea, ✓ Abdominal pain, ✓ Pruritus, and ✓ Fatigue.

PHOSPHOLIPIDOSIS

  • Phospholipidosis is the accumulation of phospholipids instead of fatty acids.
  • The phospholipids usually engorge the lysosomal bodies of the hepatocyte.

AMIODARONE INDUCED HEPATOTOXICITY

  • Patients treated with amiodarone who develop overt hepatic disease tend to have received higher doses of the drug.
METHOTREXATE INDUCED HEPATOTOXICITY
  • Methotrexate causes periportal fibrosis in most patients who experience hepatotoxicity.
  • The lesion results from the action of a bioactivated metabolite produced by CYP450.
  • This process occurs most commonly in patients treated for psoriasis and arthritis.
  • Vitamin A is normally stored in liver cells, and causes significant hypertrophy and fibrosis when taken for long periods in high doses.
  • Hepatomegaly is a common finding, along with ascites and portal hypertension.
  • In patients with vitamin A toxicity, gingivitis and dry skin are also very common.
  • This is accelerated by ethanol, which competes with retinol for aldehyde dehydrogenase.

3. CHOLESTATIC INJURY

  • A second pattern of hepatic damage is an injury that primarily involves the bile canalicular system and is known as cholestatic injury.
  • Cholestatic disease is more often seen in patients over the age of 60 (compared with under age 60) and is slightly more common in males.
  • In cholestatic disease, disturbance of the subcellular actin filaments around the canaliculi prevents the movement of bile through the canalicular system.
  • In addition, mutations in hepatic transporter genes can result in slower function prior to toxin exposure.
  • The inability of the liver to remove bile causes intrahepatic accumulation of toxic bile acids and excretion products.
  • Drug-induced cholestasis can occur as an acute disorder (e., cholestasis with or without hepatitis and cholestasis with bile duct injury) or as a chronic disorder (e., vanishing bile duct syndrome, sclerosing cholangitis, and cholelithiasis).
  • Most common form of drug-induced cholestasis is cholestasis with hepatitis.
  • Most patients with this acute disorder present with nausea, malaise, jaundice, and pruritus.
  • Elevations in serum alkaline phosphatase levels are more prominent and usually precede the elevations of other liver enzymes in serum.
  • A liver biopsy is not usually required, but is sometimes pursued when other causes of cholestatic disease are suspected.
  • Although the antipsychotic drug chlorpromazine appears to be the prototype drug for this disorder, other medications are associated with other forms of cholestatic injury, such as erythromycin estolate, amoxicillin–clavulanic acid, and carbamazepine.
  • 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.
  • This reaction occurs rarely with dicloxacillin, sulfonamides, sulfonylureas, erythromycin estolate and ethylsuccinate, captopril, lisinopril, and other phenothiazines.

4. MIXED HEPATOCELLULAR AND CHOLESTATIC INJURY

  • In some patients, an injury may begin as hepatocellular (or cholestatic) and simply spread so rapidly that by the time the patient presents for diagnosis and treatment, all areas of the liver are affected.
  • In other patients, the underlying mechanism of damage is such that cells are injured regardless of their anatomical location or primary metabolic role.
5. LIVER VASCULAR DISORDERS
  • Focal lesions in hepatic venules, sinusoids, and portal veins occur with various drugs.
  • The most commonly associated drugs are the cytotoxic agents used to treat cancer, the pyrrolizidine alkaloids, and the sex hormones.
  • A centralized necrosis often follows and can result in cirrhosis.
  • Azathioprine and herbal teas that contain comfrey (a source of pyrrolizidine alkaloids) are associated with the development of venoocclusive disease.
  • The exact incidence is rare and may be dose related.

Peliosis hepatitis is a rare type of hepatic vascular lesion that can be seen as both an acute and a chronic disease. The liver develops large, blood-filled lacunae (space or cavity) within the parenchyma. Rupture of the lacunae can lead to severe peritoneal hemorrhage. Peliosis hepatitis is associated with exposure of the liver to androgens, estrogens, tamoxifen, azathioprine, and danazol. Androgens with a methyl alkylation at the 17-carbon position of the testosterone structure are the most frequently reported agents that cause peliosis hepatitis, usually after at least 6 months of therapy.

MECHANISMS OF DRUG-INDUCED LIVER DISEASE

STIMULATION OF AUTOIMMUNITY

Autoimmune injuries involve antibody-mediated cytotoxicity or direct cellular toxicity.

Enzyme–drug adducts migrate to the cell surface and form neoantigens.

 The liver plays host to all of the cells that make up the innate immune response system in the body along with kupffer cells, which are a type of macrophage.  These cells sit in anticipation around the hepatocytes, in the space of disse and elsewhere waiting for antigens (or neoantigens) to present themselves.  The neoantigens serve as targets for cytolytic attack by killer t-cells, and others.

  • Halothane, sulfamethoxazole, carbamazepine, and nevirapine are associated with autoimmune injuries.

Dantrolene, Isoniazid, Phenytoin, Nitrofurantoin, And Trazodone are associated with a type of autoimmune-mediated disease in the liver called chronic active hepatitis. It is a progressive disease with a high mortality rate and is more common in females than males. Antinuclear antibodies appear in most patients. These drugs appear to form antiorganelle antibodies. The exact identification of a causative agent is sometimes difficult as diagnosis requires multiple episodes occurring long after exposure to the offending drug.

IDIOSYNCRATIC REACTIONS

  • Idiosyncratic drug-related hepatotoxicity is rare and usually occurs in a small proportion of individuals.

  • These adverse reactions are often categorized into allergic and nonallergic reactions.

  • The allergic reactions are characterized by fever, rash, and eosinophilia.

  • In acute disease, prolonged interruption of β -oxidation leads to microvesicular steatosis, whereas, in chronic disease, macrovesicular disease is present.

  • Severe damage to the mitochondria eventually leads to hepatic failure and death.

  • Aspirin, valproic acid, and tetracycline cause mitochondrial injury by inhibiting β -oxidation and amiodarone via disruption of oxidative phosphorylation.

  • Inborn errors in mitochondrial metabolism can predispose a patient to these types of disruptions in function.

LIVER NEOPLASTIC DISEASE

  • Both carcinoma- and sarcoma-like lesions have been identified.
  • Hepatic tumors associated with drug therapy are usually benign and remit when drug

therapy is discontinued.

  • Androgens, estrogens, and other hormonal-related agents are the most frequently

associated causes of neoplastic disease.

ASSESSMENTOF DRUG-INDUCED LIVER DISEASE

  • Patient’s history

  • Questions addressing the patient’s drug use along with a thorough review of

systems are essential. Cocaine has been directly linked to liver disease.

  • Blood concentrations of the compound could be used to confirm the suspicion of toxicity.

AUTOANTIBODIES SPECIFIC TO DRUG-INDUCED HEPATOTOXICITY

Autoantibody

Example

Anti-mitochondrial (anti-M6)

autoantibody

Iproniazid

Anti-liver kidney microsomal 2 antibody

(anti-LKM2)

Tienilic acid

Anti CYP 1A2 Dihydralazine

Anti CYP 2E1 Halothane

Anti-liver microsomal autoantibody Carbamazepine

Anti-microsomal epoxide hydrolase Germander

  • It is also important to determine nondrug hepatic disease risk from occupational or

environmental exposure. Arsenic, for example, is known to induce both acute and chronic hepatic reactions.

MEASUREMENT OF LIVER FUNCTION

A good compound for a liver function test would theoretically be

(a) nontoxic and lacking any pharmacologic effect;

oral administration and found that hepatoxicity occurred less often in patients who received IV therapy within 12 hours of ingestion. Patients presenting within 24 hours of acetaminophen ingestion, the oral protocol is superior to the 21-hour intravenous protocol in persevering hepatocytes. Regardless, NAC therapy should be started if there is an elevation in AST, a detectable acetaminophen level, or if the level is above the treatment line on the Rumack- Matthew nomogram. International Normalized Ratio (INR) did not undertreat patients but did lead to overtreatment, whereas treating until ALT peaked did not undertreat and rarely overtreated patients. At the point, AST should be less than 100 IU/L and acetaminophen level should be less than 10 mcg/mL.

Amanita mushroom ingestion can lead to liver injury via the amatoxin, which inhibits RNA polymerase II and leads to hepatocyte necrosis. The gastrointestinal phase is characterized by nausea, vomiting, and abdominal pain. This is followed by symptomatic improvement but an elevation in AST and ALT followed by the development of jaundice. Since the hepatic phase is preceded by a gastrointestinal phase where dehydration and metabolic derangements may have developed, it is important to treat any dehydration and electrolyte abnormalities. While it has no proven efficacy for long-term survival, repeated activated charcoal administration is often recommended, which will prevent reabsorption of the amatoxin. While amatoxin may cause metabolic acidosis on its own, activated charcoal , which contains propylene glycol, can also cause a high anion gap metabolic acidosis. While clinicians should be aware of this potential complication, it should not preclude treatment with activated charcoal. Silibinin is universally accepted as a treatment modality for amatoxin poisoning because it inhibits the transfer of amanitin into hepatocytes. It should be administered within 48 hours of mushroom ingestion. The current recommended dose is 20 to 50 mg/kg/day IV, which should be continued for 48–96 hours. High dose penicillin G is also known to displace amatoxin and promote its excretion. The recommended dose is 1,000,000 IU/kg for first day and 500,000 IU/kg for next two days via continuous IV administration.

Patients who present with fever, rash, and eosinophilia should be considered for a diagnosis of drug-induced autoimmune hepatitis. If the DILI is severe, corticosteroid therapy should be considered as studies have demonstrated normalization of biochemical tests within six months.

Patients who present with a cholestatic picture may complain of intense pruritus. Treatment options for these patients include emollients, hydroxyzine, diphenhydramine, bile acid resins, and rifampicin.

POTENTIAL ROLE FOR LIVER ASSIST DEVICES

Extracorporeal systems have progressed through advances in genetically produced cell lines, stem cell-derived functional hepatocytes, immortalized human hepatocytes as well as improved techniques and methods for preserving the hepatocytes.

LIVER TRANSPLANT

The criteria include a prothrombin time (PT) over 100 seconds or at least three of the following: PT over 50 seconds, bilirubin> 300 micromol/Liter, age below 10 or over 40, an interval between jaundice and encephalopathy greater than seven days, or drug toxicity.

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DILD pdf - Drug induced liver disease

Course: Environmental and nutritional disease

15 Documents
Students shared 15 documents in this course

University: Rajiv Gandhi University of Health Sciences

Was this document helpful?
DRUG INDUCED LIVER DISORDERS
• Drug-induced liver diseases are diseases of the liver that are caused by physician-
prescribed medications, over-the-counter medications, vitamins, hormones, herbs, illicit
("recreational") drugs, and environmental toxins.
• Drug-induced liver disease is a rare but potentially fatal, often debilitating and largely
unpredictable outcome of drug treatment.
• Drug-induced liver disease accounts for as much as 20% of acute liver failure in pediatric
populations and a similar percentage of adults with acute liver failure.
• In approximately 75% of these cases, liver transplantation is ultimately required for patient
survival.
ETIOLOGY
➢ NSAID- Acetaminophen, Nimesulide, Diclofenac
➢ Anti- TB- Isoniazid, Rifampicin
➢ Antiepileptics – Phenytoin, Carbamazepine, Valproate
➢ Antibiotics – Amoxicillin, Trimethoprim+Sulfamethoxazole, Fluoroquinolones,
Macrolides, Nitrofurantoin
➢ Hypolipidemic Drugs- Statins, Niacin, Fibrates
➢ Anaesthetic Agents- Halothane, Chloroform, Nitrous Oxide
➢ Anti-Rheumatic Drugs- Sulphasalazine, Gold Salt, Methotrexate
➢ Anti- Retriviral Drugs- Protease Inhibitor (Ritonavir, Indinavir), NRTI
(Lamivudin, Tenofovir, Zidovudine), NNRTI (Nevirapine, Efavirenz)
CLINICAL PRESENTATIONS
➢ Idiosyncratic reactions,
➢ Allergic hepatitis,
➢ Toxic hepatitis,
➢ Chronic active toxic hepatitis,
➢ Toxic cirrhosis,
➢ Liver vascular disorders.
• The mechanisms of drug-induced liver disease are diverse, representing many phases
of biotransformation, and are susceptible to genetic polymorphism.
• A fulminant or severe drug-induced reaction within the liver usually involves the
immune system and is marked by large-scale cell necrosis.

Students also viewed

Related documents