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ASSISTANT PROFESSOR VMMC & SAFDARJUNG HOSPITAL, DELHI EULAR CERTIFICATION COURSE IN RHEUMATIC DISEASES EULAR CERTIFICATION COURSE IN MUSCULOSKELETAL ULTRASOUND EDITORIAL BOARD AUSTIN JOURNAL OF TROPICAL MEDICINE AND HYGIENE & PUBLIC HEALTH OPEN ACCESS JOURNAL

INTERNAL MEDICINE Clinical features Mechanism of DILI Role of liver biopsy Types of drug reactions Genetic risk factors

"Any liver injury caused by medication or herbal supplements that has led to biochemical abnormalities or liver dysfunction with the exclusion of other causes." It may be of 2 types - Dose dependent - eg. aspirin, acetaminophen

Greater than 1000 medications have been implicated in DILI, most commonly antibiotics & acetaminophen Most cases of acute liver failure are due to DILI Most of the cases of DILI are attributed to a single prescription drug However, up to 18% have been the result of multiple agents Dietary supplements have been linked to DILI in 7-9% of cases

Patel et al BMC Clinical Pharmacology Uppal et al Natl Med J India Ramesh et al Pharmacoepidemiology and drug safety S K Acharya et al. Journal of gastroenterology and hepatology. MECHANISM OF DILI Hepatic metabolism Drugs with > 50% hepatic metabolism conveyed a significant risk of ALT increases, liver failure & mortality related to DILI Veno occlusive disease Idiosyncratic reactions MECHANISM OF DILI - NEWER INSIGHTS Related to mitochondrial Emerging role of superoxide dismutase & glutathione peroxidase Effect of polymerase Ɣ on cellular proliferation and non apoptotic cell death DRUG INDUCED CHOLESTASIS Acute drug induced cholestasis is defined as an elevation of ALP at least 2 times the upper limit of normal (ULN) or an ALT/ALP ratio of < 2, with both ALT and ALP greater than the ULN.
Cholestatic liver injury is defined by isolated elevation of alkaline phosphatase, which is released by damaged cholangiocytes, thus suggesting injury to the bile ducts CHOLESTATIC DILI(ALP >2 ULN or ALP/ALT <2 with both ALP and ALT >1 ULN ) 1. Antibiotics: amoxicillin-clavulanic acid, erythromycin, trimethoprim-
sulfamethoxazole 2. Anti-inflammatory medications: sulindac
3. Cardiac medications: clopidogrel, ACE inhibitors
4. Neurologic/psychiatric medications: carbamazepine, chlorpromazine,
tricyclic antidepressants 5. Other: azathioprine, anabolic steroids, oral contraceptives
DRUG INDUCED HEPATOCELLULAR INJURY Hepatocellular injury is defined as ALT elevation of at least 5 times ULN in combination with a bilirubin elevation of at least 2 times ULN Such a presentation occurs more commonly Drug induced hepatocellular injury has been correlated with worse outcome HEPATOCELLULAR DILI (ALT > 5 X ULN and Bilirubin > 2 X ULN) 1. Antibiotics: ciprofloxacin, nitrofurantoin, tetracycline, trimethoprim-sulfamethoxazole
2. Antidepressants: bupropion fluoxetine, paroxetine
3. Anti-inflammatory medications: acetaminophen, bromfenac, diclofenac, ibuprofen, naproxen
4. Cardiac medications: amiodarone, lisinopril, statins
5. Neurologic/psychiatric medications: methyldopa, nefazodone, risperidone, sertraline, trazodone,
6. Other: acarbose, amatoxin, allopurinol, cimetidine, ketoconazole, halothane, isoniazid,
omeprazole, protease inhibitors, pyrazinamide, quinidine, rifampin, troglitazone DRUG INDUCED MIXED INJURY Elements of both hepatocellular and cholestatic injury Increases in ALT, ALP, bilirubin MIXED DILI(ALT >5 ULN or Bilirubin >2 ULN and ALP >2 ULN or ALP/ALT <2 with both ALP and ALT >1 ULN) 1. Antibiotics: clindamycin, sulfonamides
2. Cardiac medications: ACE inhibitors, statins
3. Neurologic/psychiatric medications: phenytoin, amitriptyline
4. Other: azathioprine, protease inhibitors reverse transcriptase inhibitors
VENO OCCLUSIVE DISEASE LEADING TO PORTAL HYPERTENSION 1. Antineoplastic agents: busulfan, cyclophosphamide
2. Environmental exposures: arsenic, vinyl chloride, thorium dioxide
3. Other: Vitamin A
➢Manifestations include ascites, varices, and hepatic encephalopathy PATTERN OF LIVER BIOCHEMISTRY The pattern of liver injury is defined by R value, [where R = Hepatocellular pattern: R > or = 5, Mixed pattern: R >2 and <5, Cholestatic pattern: R < or = 2 RISK FACTORS FOR DILI Age - old and young Alcohol consumption (acetaminophen, INH, nicotinamide & methotrexate) Genetic polymorphisms (i.e. HLA-B*5701) RISK FACTORS FOR DILI Gender - Male in younger patients, females in older patients History of chronic liver disease (if aspirin, methotrexate, INH, antiretroviral Dose and duration of treatment Coincidental metabolic disorders and exposure to other drugs/environmental PROPOSED MECHANISM/GENETIC RISK FACTOR AMOXYCILLIN CLAVULANATE HLA Class II SNP rs 9274407 ANTITUBERCULOSIS DRUGS NAT 2 POLYMORPHISM CYP2E1 POLYMORPHISM DRUG TRANSPORTER GENES (ABCB1, SLCO1B1, UGTA1 POLYMORPHISM PREGNANE X RECEPTOR (PXR) PXR POLYMORPHISM (rs 3814055;C-25385 T) Bcl-2 DOWNREGULATION CYP2E1 POLYMORPHISM NAT 2 POLYMORPHISM Nutritional status Fasting predisposes to acetaminophen hepatotoxicity Malnutrition also increases the risk and severity of hepatotoxicity from drugs used to treat tuberculosis Overnutrition (obesity) increases the risk of halothane hepatitis Increased risk of NASH and hepatic fibrosis among those taking methotrexate, estrogens, tamoxifen, corticosteroids Instances of cross reactivity to similar agents are reported with haloalkane anesthetics (eg halothane, enflurane, isoflurane) INH and pyrazinamide Sulfonamides and some COX 2 inhibitors Some NSAIDs and macrolide antibiotics Any history of previous adverse drug reaction increases the risk of DILI to other agents Previous reaction to the same drug is the single most important factor predisposing to unusual severity of drug induced hepatitis (eg acute liver failure, chronic liver disease) Other medical disorders Renal failure - methotrexate induced hepatic fibrosis, tetracycline induced fatty Renal/solid organ transplantation - hepatic vascular injury with azathioprine Use of cancer chemotherapeutic agents in BMT/radiotherapy - VOD/SOS RA & SLE - salicylate hepatotoxicity & sulfasalazine induced hepatitis HIV/AIDS & SLE - drug reactions to sulfonamides Halothane, oral corticosteroids cholestasis, valproic acid and phenytoin reactions are those for which more than one case has occurred in the same family There are strong associations between human leukocyte antigens (HLA) and cholestatic drug reactions to amoxicillin clavulanate and tiotropinin Phenytoin is an example of reactive metabolite syndrome (RMS) CLINICAL FEATURES Drugs have become the great mimickers of "natural" liver diseases
nonspecific abnormalities of liver nodular regenerative hyperplasia chronic hepatitis resembling autoimmune hepatitis acute liver failure hepatic sinusoidal/venous outflow obstruction syndromes benign/malignant liver tumors Thorough & complete history including information from pharmacy records Diagnosis is always presumptive as it is based on logistic approach "Causality assessment" - a. determine whether link between drug ingestion & liver injury (ADR, liver histology) is plausible b. exclude other disorders The correct diagnosis is facilitated by identifying specific risk factors for hepatotoxicity eg prolonged fasting, chronic excessive alcohol intake by a person regularly taking acetaminophen the presence of extrahepatic features of drug hypersensitivity clinicopathologic syndrome associated with a particular drug However, the absence of the "drug signature" should not be used to exonerate a given drug as the cause of liver injury Certain criteria used as tools to assist in clinical diagnosis of DILI DIAGNOSTIC CRITERIA FOR DILI Hy's Law: AST and/or ALT > 3 X ULN without initial ALP > 2 X ULN and no other causes of liver disease Roussel Uclaf Causality Assessment Method (RUCAM): Risk factors, temporal relationship, exclusion of other causes, concomitant therapy, extrahepatic manifestations, prior reports of hepatotoxicity, rechallenge results DDW - J: Temporal relationship, eosinophilia, positive lymphocyte stimulation Clinical diagnostic scale (M & V scale): Temporal relationship, exclusion of other causes, prior reports of hepatotoxicity, rechallenge results LIMITATIONS OF DIAGNOSTIC TOOLS Hy's law is not as sensitive as other parameters as it does not consider the temporal relationships RUCAM - can specifically associate liver injury to a particular medication, it is complicated to administer, and rechallenging patients is rare. Thus modification to this scale has been proposed. A summed score of -10 to 14 Best modification is Digestive disease week - Japan (DDW-J) scale - higher sensitivity and lower specificity than the original scale M&V scale - less predictive Drug induced liver disease is a diagnosis of exclusion: consider the following Hepatitis viruses Other infectious agents - Epstein Barr virus, cytomegalovirus, human immunodeficiency virus, herpes simplex virus, coxiella burnetti Autoimmune hepatitis: antinuclear antibodies, smooth muscle antibodies, liver/kidney microsomal antibodies, immunoglobulin G levels Acute biliary obstruction, exclude cholangitis Metabolic disorders: Wilson disease, alpha 1 antitrypsin deficiency, risk factors for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis Drug induced liver disease is a diagnosis of exclusion: consider the following Vascular disorders of liver Bacterial infection Hepatic metastases Systemic malignancy or lymphoma ROLE OF LIVER BIOPSY Excluding other hepatobiliary disorders Most strongly indicated when the cause of liver disease remains in doubt there may be ambiguous evidence of autoimmunity or the pattern of reaction may be very unusual or the pattern of reaction may not be previously reported for the drug in question persistence of abnormal liver biochemistries in case of continued use and contemplated rechallenge HISTOLOGICAL CHANGES INDICATING DILI Zonal lesions, including necrosis and/or steatosis Microvesicular steatosis (often results from mitochondrial injury) Necrotic lesions of disproportionate severity of the clinical picture Mixed hepatitis and cholestasis Destructive bile duct lesions HISTOLOGICAL CHANGES INDICATING DILI Prominent neutrophils and (in later stages) eosinophils (>25%) Vascularity of hepatic tumors - sinusoidal dilatation, peliosis Florid steatohepatitis - resembles alcohol related steatohepatitis more than typical "primary" nonalcoholic steatohepatitis Appropriate use of drugs (nonpharmacologic approaches, optimal choice of agents, avoiding polypharmacy where possible, avoiding excessive dosage) Restricted availability and blister packaging of OTC medications Physician and public education about possible drug side effects and about how to recognize and what to do about them Monitoring for adverse drug reactions LFT monitoring - agents for which LFT monitoring is strongly endorsed eg methotrexate, INH, etretinate and other synthetic retinoids, ketoconazole, anti cancer drugs and prolonged therapy with minocycline Drug should be stopped if ALT > 5 X ULN but any abnormality of serum bilirubin/albumin/prothrombin time & the presence of any symptoms are clear indication to stop therapy Most important - early recognition & discontinuation of putative agent At each visit patients should be warned to report any untoward new symptoms With possible ADR, physicians should immediately check LFT to document Most ADR will resolve spontaneously, rapidly & completely Drugs with prolonged half life are associated with protracted hepatic ADR eg Amiodarone, etretinate, ketoconazole & hypervitaminosis A Aspiration of stomach contents to remove unabsorbed drug - acetaminophen, metals & and toxic mushrooms Use of charcoal/resins/osmotic cathartics unlikely to be effective Chelating resins, hemodialysis, forced diuresis - not effective for most Largely supportive, except when acetaminophen/Amanita mushroom poisoning is suspected for which antitoxins are available Testing of drug levels may be indicated in dose dependant hepatotoxicity Hospitalization in case of severe reactions - repeated vomiting, deepening jaundice & development of laboratory/clinical features of liver failure Early transfer to a liver transplant unit before the worsening (bleeding, HRS, hepatic encephalopathy) of the patients ROLE OF CORTICOSTEROIDS DILI associated with vasculitis (eg allopurinol, sulfonamides) Some cases of drug induced chronic hepatitis When D/D between AIH & drug induced chronic hepatitis remains in doubt "Steroid whitewash" - short course of corticosteroids to hasten recovery in persons with prolonged drug induced cholestasis A pragmatic approach is to observe the course for 3-6 weeks after stopping the drug (unless there is evidence of further deterioration), reserving corticosteroids for cases in which there is failure to show clinical or biochemical improvement UDCA used with success in patients presenting with cholestatic liver injury attributed to amoxycillin-clavulanate, flucloxacillin, flutamide, cyclosporin Dose of ursodeoxycholic acid (15 mg/kg body weight) During prolonged cholestatic reactions fat soluble vitamin deficiency should Treat pruritus: consider emollients, diphenhydramine, bile acid resins, selective norepinephrine reuptake inhibitors MANAGEMENT- ACETAMINOPHEN POISONING Administer N Acetylcysteine if elevated AST or ALT or detectable serum acetaminophen levels, consider IV administration if presentation is > 10 hours after ingestion or if vomiting precludes oral administration Continual observation and psychiatry consult if intentional overdose MANAGEMENT - MUSHROOM POISONING Administer silibinin Administer high dose Penicillin G Consider administering N acetylcysteine or cimetidine As of now, ALT remains the gold standard to predict DILI However, ALT is not the ideal biomarker as it merely reflects injury after it has A truly predictive biomarker identifies at risk patients prior to the initiation of potentially hepatotoxic drug therapy (eg. HLA B*5701 & abacavir) Research in proteomics, metabolomics, transcriptomics & pharmacogenomics may find clues in accurate prediction of DILI Genetic predispositions recently identified for flucloxacillin and lumiracoxib Greater than 1000 medications have been implicated in DILI Greater than 1 in 100 hospitalized patients are diagnosed with DILI DILI is responsible for greater than 50% of cases of fulminant hepatic failure Drug induced hepatocellular injury carries a worse prognosis than cholestatic Management includes withdrawing the offending drug, administering proven antidotes when appropriate, symptomatic treatment, and monitoring of biochemical tests Early recognition of DILI and subsequent referral and transfer to a transplant center can be life saving. In most cases, biochemical resolution of DILI occurs within 60 days Hepatotoxicity remains an important cause of drugs withdrawn from market Proteomics, metabolomics, transcriptomics and pharmacogenomics may help in the accurate prediction of DILI in future

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