pharmacology

• DILI


  Drug Induced Liver Injury

  
• More than 1000 medications and herbal compounds are known to cause hepatotoxicity and can be found on a searchable database maintained by the National Institute of Diabetes and Digestive, and Kidney Diseases (NIDDK) called LiverTox

  
• Liver


  • Plays a vital functions in the maintenance, performance and regulating homeostasis of the body
  • Regulates the metabolism of internal compounds
  • Processes compounds from external sources (drugs)
  • Adaptable
  • Can regrow even if 2/3 resected
  • Regenerates rapidly if cells killed/removed
  • Enzyme and transporter function can be altered

  
• DILI


  Drug-induced hepatotoxicity or drug-induced liver injury

  
• DILI can be classified based on

  • Clinical presentation (hepatocellular, cholestatic, or mixed)
  • Mechanism of hepatotoxicity
  • Histological appearance from a liver biopsy

  
• DILI


  • Most cases are asymptomatic
  • The most common sign is jaundice
  • In hepatocellular injury, aminotransferases are elevated
  • In cholestatic injury, alkaline phosphatase (ALP) is elevated

  
• Treatment of DILI


  1. Removal of the offending agent

  2. Prognosis for recovery is usually favorable after discontinuation of the drug
• NSAIDs


  • The most important cause of drug induced toxic injury to several organ systems, including well known injury to GIT and kidneys
  • Nearly all NSAIDs have been implicated in causing liver injury and tend to be hepatocellular in nature
  • The mechanism is thought to be immunological idiosyncrasy

  
• NSAIDs used in large numbers as analgesics and antipyretics


  • Acetaminophen
  • Diclofenac
  • Ibuprofen
  • Sulindac
  • Celecoxib
  • Rofecoxib
  • Nimesulide

  
• Mechanism of Acetaminophen induced hepatotoxicity


  1. In overdose, Acetaminophen produces centrilobular hepatic necrosis

  2. The covalent binding of N-acetyl-P-benzoquinoneimine, an oxidative product of paracetamol to sulphydryl groups of protein, result in lipid peroxidative degradation of glutathione level and thereby, produces cell necrosis in the liver

  
• Diclofenac


  Associated with a predominantly hepatocellular pattern of liver injury

  
• Sulindac


  Has been the drug most consistently associated with hepatotoxicity, competitively inhibits canalicular bile salt transport, and such inhibition may contribute to cholestatic liver injury

  
• Anti-tubercular drugs


  • The first line anti-tubercular drugs namely, Rifampicin, Isoniazid and Pyrazinamide are potentially hepatotoxic drugs
  • When given in combination, their toxic effect is enhanced

  
• Rifampicin


  • Patients on concurrent Rifampicin therapy have an increased incidence of hepatitis
  • Rifampicin-induced cytochrome P450 enzyme-induction, causing an increased production of the toxic metabolites
  • Rifampicin also increases the metabolism of INH to isonicotinic acid and hydrazine, both of which are hepatotoxic
  • Rifampicin also interacts with antiretroviral drugs and affects the plasma levels of these drugs as well as risk of hepatotoxicity

  
• Isoniazid


  • Isoniazid hepatotoxicity is a common complication of antituberculosis therapy that ranges in severity from asymptomatic elevation of serum transaminases to hepatic failure
  • This appears to represent an idiosyncratic response
  • INH is metabolized to mono-acetyl hydrazine, which is further metabolized to a toxic product by cytochrome P450 leading to hepatotoxicity

  
• Anti-retroviral drugs


  • Several antiretrovirals have been reported to cause fatal acute hepatitis
  • They most often cause asymptomatic elevations of transaminases
  • Liver toxicity is more frequent among subjects with chronic hepatitis C and/or B on HAART (Highly active antiretroviral therapy usually combination of two or three drugs)

  
• Protease inhibitors


  • Ritonavir
  • Indinavir
  • Saquinavir
• Nucleoside analogues reverse transcriptase inhibitors (NRTI)


  • Didanosine
  • Stavudine
• Non-nucleoside analogues reverse transcriptase inhibitors


  • Nevirapine
  • Efavirenz
• Mechanism of toxicity of Antiretrovirals


  • Direct toxicity: Direct cell stress (idiosyncratic polymorphisms)
  • Hypersensitivity reactions: Immune mediated drug reactions involve the generation of neoantigens formed by the reaction of liver proteins with reactive drug metabolites
  • Direct Mitochondrial toxicity

  
• Anti-hyperlipidemic drugs


  • The pattern of liver injury is typically hepatocellular or mixed in nature
  • The proposed mechanisms of hepatotoxicity are varied depending on the drug or drug class, and include effects on the Cytochrome P450 system, Impairment of bile acid transport proteins, Immune-mediated inflammatory response to the medication or its metabolites, and Oxidative stress due to intracellular damage

  
• Niacin


  • The antihyperlipidemic drug with the highest potential for hepatic injury is the sustained-release formulation
  • The typical pattern of injury involves an elevation in aminotransferase levels although a mixed pattern of hepatocellular and cholestatic injury can be seen

  
• Statins


  Very rarely cause clinically significant liver injury, although asymptomatic elevation in amino transferases is common

  
• Anaesthetic agents


  • Cause hepatocellular damage through direct toxicity and immune mediated hypersensitivity
  • Interfere with bilirubin metabolism and cause cholestasis

  
• Anaesthetic agents


  • Isoflurane
  • Enflurane
  • Desflurane
• Mechanism of hepatotoxicity of anaesthetic agents


  Hepatotoxicity results from an immune response directed against hepatic proteins altered by trifluoroacetyl or trifluoroacetyl-like metabolites of the anesthetics
• Sulfasalazine hepatotoxicity


  The majority of cases occur within the first month of starting sulfasalazine therapy, and these can present either as a hepatocellular or cholestatic pattern of liver injury
• Azathioprine hepatotoxicity


  Hepatotoxic effects associated with azathioprine use include acute DILI as well as vascular syndromes including nodular regenerative hyperplasia (NRH)

  
• Methotrexate hepatotoxicity


  • Mechanism: MTX inhibits dihydrofolate reductase leading to impaired pyrimidine and purine synthesis
  • Methotrexate therapy in patients with RA has been shown to raise plasma homocysteine levels which generate oxidative stress and activate proinflammatory cytokines
  • The combination of these insults contribute to the activation of hepatic stellate cells, which leads to liver fibrosis

  
• TNF inhibitors induced hepatotoxicity


  Hepatic sinusoids are involved in the clearance of immune complexes that in turn could activate Kupffer cells to release reactive oxygen species or lead to local hepatocyte damage
• Carbamazepine


  Its metabolite can lead to cholestatic and hepatocellular injury, even granuloma formation in the liver
• Valproic acid


  Valproic acid forms an ester conjugate with carnitine that may lead to secondary carnitine deficiency

  
• Phenytoin hepatotoxicity


  A serious idiosyncratic reaction

  
• Antibiotics associated with liver toxicity

  • Amoxicillin-clavulanate
  • Erythromycin estolate
  • Sulfamethoxazole-trimethoprim
  • Ciprofloxacin

  
• Antibiotic-induced DILI


  • The severity varies widely, with the hepatitis-like (hepatocellular) damage tending to be more severe that than cholestatic/mixed type
  • Appears, in most instances, to be idiosyncratic
• Steroids


  Methyltestosterone and contraceptive steroids have been associated with cholestatic damage

  
• Treatment / Management of DILI

  1. Removal of the offending agent

  2. N-acetyl-cysteine (NAC) for intrinsic DILI secondary to acetaminophen toxicity

  3. L-carnitine for valproic acid overdose

  4. Glucocorticoid therapy when the histological appearance of DILI resembles that of autoimmune hepatitis

  5. Symptomatic therapies such as bile acid sequestrants for cholestatic DILI or antihistamines for pruritis