DRUG INDUCED HEPATOTOXICITY

DRUG INDUCED HEPATOTOXICITY
Ackerman Zvi M.D. Hadassah-Hebrew University Medical Center

LIVER Inputs and Outputs Heart Intestines Hepatic Artery Portal Vein
First pass ??? Hepatic recycle ??? Heart Intestines Hepatic Artery Portal Vein Bile Duct Hepatic Vein LIVER

PREDICTIVE PARAMETERS OF DRUG-INDUCED LIVER INJURY
There are relatively few ways by which acute and chronic liver diseases become clinically manifest.. Signs and symptoms of drug-induced liver disease are generally nonspecific and reflect more the extent of the liver injury than the cause. Slight elevations of aminotransferase or alkaline phosphatase levels do not of themselves cause symptoms and may be present as only as an abnormality of one or more biochemical test detected during a random predetermined evaluation schedule. Most instances of drug-induced aminotransferase elevations are transient and nonprogressive.

Spectrum of DILI Symptomatic disease 0.01 - 1.0%
ALF (Death, Txp) % Symptomatic disease % Mild liver injury (ALT < 3X ULN) %

Tip of the Iceberg Death or Tx Acute Liver Failure
Serious DILI – Threatening Detectable DILI – but Not Serious Patient Adaptation to New Agent Exposure Patients/People Tolerate Exposure Without Effects

SPECTRUM OF HEPATOTOXICITY INDUCED BY DRUGS-1
minimal, nonspecific alterations in biochemical tests of no clinical consequence to acute hepatitis chronic hepatitis acute liver failure prolonged cholestatic disease cirrhosis hepatic tumors.

Drug-Induced Liver Injury (DILI)
“adaptors”

minimal, nonspecific alterations in biochemical tests of no clinical consequence to acute hepatitis chronic hepatitis acute liver failure prolonged cholestatic disease cirrhosis hepatic tumors.

death jaundice enceph Days on drug Slide from Paul Watkins

Sulphasalazine Hepatotoxicity

CAH from Methyldopa

Furthermore, some drugs have been shown to cause : fatty liver (simulating alcohol-induced liver disease) granulomas (simulating sarcoidosis) acquired phospholipidosis predispose to development of the Budd-Chiari syndrome or veno-occlusive disease.

Amiodarone induce NASH

Post BMT veno- occlusive disease

Normal Liver

Mechanism of liver injury-1
Disruption of itra-cellular calcium homeostasis leads to disassembly of actin fibrils at the surface of the hepatocyte, resulting in blebbing of cell membrane, rupture, and cell lysis

In cholestatic diseases, disruption of actin filament may occur next to the canaliculus, the specialized portion of the cell responsible for bile excretion. Loss of villous process and the interruption of transport pumps such as multidrug-resistance-associated protein 3(MRP3) prevent the excretion of bilirubin and other organic compounds

Mechanism of liver injury-2a
Drugs that affect transport proteins at the canalicular membrane can interrupt bile flow. Certain drugs, for example, bind to or disable the bile salt export protein. This process causes cholestasis; however, little cell injury occurs. Genetic defects in transporters, as in the multidrug-resistance–associated protein 3, in combination with hormones may promote cholestasis during pregnancy or during treatment with estrogen-containing medications.

Cholestasis from estrogens

Mechanism of liver injury-2b
In mixed forms of hepatic injury, the combined failure of canalicular pumps and other intracellular processes allows toxic bile acids to accumulate, causing secondary injury to hepatocytes . If cells of the bile ducts are injured, a likely outcome is protracted or permanent cholestasis, a disorder that has been termed the "vanishing bile duct syndrome."

Drugs are relatively small molecules and, therefore, are unlikely to evoke an immune response. However, biotransformation involving high-energy reactions can result in the formation of adducts — that is, drugs covalently bound to enzymes.

Mechanism of liver injury-3b
Adducts that are large enough to serve as immune targets may migrate to the surface of the hepatocyte, where they can induce the formation of antibodies (antibody-mediated cytotoxicity) or induce direct cytolytic T-cell responses . The secondary cytokine response thus evoked may cause inflammation and additional neutrophil-mediated hepatotoxicity

Mechanism of liver injury-3 con

Mechanism of liver injury-3c
For a growing number of drugs, there is evidence that genetic polymorphism in metabolic pathways are important in determining which individuals are likely to have an adverse reaction. Immunologic reactions of the immuno-allergic type appear to play less important (or at best augmenting) roles in the production of most drug-induced injuries. Haptens formed by a drug product and a cellular constituent may provoke formation of antibodies to the neo-antigen and add to injury. Reactions to several drugs, including halothane, diphenylhydantoin, and sulindac, occur in settings suggesting

Programmed cell death (apoptosis) can occur in concert with immune-mediated injury, destroying hepatocytes by way of the tumor necrosis factor (TNF) and the Fas pathways, with cell shrinkage and fragmentation of nuclear chromatin Proapoptotic receptor enzymes, if activated by drugs, will compete with protective so-called survival pathways within the cell, and this dynamic interaction may shift the balance either in favor of or against further cell damage.

Certain drugs inhibit mitochondrial function by a dual effect on both -oxidation (affecting energy production by inhibition of the synthesis of nicotinamide adenine dinucleotide and flavin adenine dinucleotide, resulting in decreased ATP production) and the respiratory-chain enzymes. Free fatty acids cannot be metabolized, and the lack of aerobic respiration results in the accumulation of lactate and reactive oxygen species.

Mechanism of liver injury-5 b
. The presence of reactive oxygen species may further disrupt mitochondrial DNA. The presence of reactive oxygen species may further disrupt mitochondrial DNA. This pattern of injury is characteristic of a variety of agents, including nucleoside reverse-transcriptase inhibitors, which bind directly to mitochondrial DNA, as well as valproic acid, tetracycline, and aspirin.

Other cells within the liver may be the target of drug injury or serve as modulators of an incipient reaction. For example, Kupffer's cells activate cytokines that may amplify injury, and fat-storage cells (stellate cells) or macrophages may augment injury, produce fibrosis, or form granulomas. Chemotherapeutic agents can injure sinusoidal endothelial cells, a process that can lead to veno-occlusive disease. Therapeutic hormone administration may induce hepatocyte dedifferentiation, resulting in benign adenomas and, rarely, carcinomas. Clearly, multiple cellular pathways to liver injury are possible.

Sinusoidal Damage

Methotrexate induced fibrosis

Vitamin A Toxicity

When to suspect DILI-1 There are few clinical or laboratory manifestations which specifically suggest that a liver injury is the result of a therapeutic drug. The most important clue is often the temporal relationship between initiation of a drug (or drugs) and the appearance of the injury, and of equal importance is the resolution of an abnormality following withdrawal (deceleration). In many (likely most) instances, a slight elevation of a serum aminotransferase is of no clinical importance and may well resolve through poorly understood adaptive mechanisms that develop with continued drug use.

Most people exposed to a new drug show no injury; “tolerators” Some people show transient injury, but adapt; “adaptors” A few fail to adapt and show serious toxicity ! “susceptibles”

“tolerators”

When to suspect DILI-2 The combination of elevated aminotransferase (at least >3 × ULN) and clinically evident jaundice (>3 mg/dL) identifies patients at heightened risk of developing severe injury.

Definition of DILI for inclusion Criteria
· Serum ALT or AST >5 x ULN or A P’ase >2 x ULN confirmed on at least 2 consecutive blood draws. · If baseline (BL) ALT, AST or A P’ase are known and elevated, then ALT or AST >5 x BL or A P’ase >2 x BL on at least 2 consecutive blood draws. or Any elevation of serum ALT, A P’ase, or AST, associated with (a) increased serum total bilirubin [ ≥ 2.5 mg/dL], in absence of prior diagnosis of liver disease, Gilbert’s syndrome, or evidence of hemolysis.

Acute DILI Hepatocellular: R > 5 and ALT > 2x ULN or baseline
Cholestatic: R < 2 and Alk > ULN Mixed: 2< R < 5 R= (ALT/ULN)/ (Alk / ULN) (J Hepatol 1990; 11: 272)

Hy Zimmerman

“Hy’s Law” ...for drug-induced hepatotoxicity
If both hepatocellular injury and jaundice occur, look out for at least 10% mortality! i.e., when both transaminase and bilirubin elevations occur together. Robert Temple, FDA, 1999

Prognosis in Acute Liver Failure
Etiology an important outcome determinant Good prognosis: Acetaminophen Hepatitis A Shock Bad prognosis: Drugs Indeterminate Hepatitis B Wilson Disease

… not DILI

A significant number of drugs has been proven, or at least suggested, to cause hepatotoxicity.
It must be recognized that a drug is a chemical or biologic agent that has been found to cause a favorable effect on a symptom or disease process, has been tested for safety (relative), has been given a name, and then if approved, is widely available. Usually, the propensity to cause liver injury is identified during preapproval evaluations, especially those in large pivotal Phase 3 trials.

Attribution of liver injury to a specific drug in a patient may be difficult, and the difficulties are compounded if the patient has underlying acute or chronic liver disease such as chronic hepatitis C, chronic hepatitis B, nonalcoholic fatty liver disease, or alcohol-induced liver disease.

Much attention has been given to the identification of factors that identify individuals who are at increased risk of developing an adverse hepatic reaction from a drug. There are concerns not only about the drug itself, but also about the effects of drug-drug and drug-disease interactions. In general, it appears that patients with acute or chronic liver diseases are not more likely to develop a hepatotoxic reaction of the idiosyncratic type.

However, especially in patients who have advanced liver disease, any adverse hepatic reaction that occurs is more likely to lead to clinical evidence of liver injury, in part related to decreased liver mass and decreased abilities to respond to the injury and appropriately regenerate hepatocytes.

Drug Signature Most drugs have a “signature” of hepatotoxicity regarding time of onset, frequency, and type of hepatotoxicity that may be encountered.

When to suspect DILI-3 There may be few clinical signs suggesting liver injury, even in a patient who has biochemical and histologic evidence of considerable damage. Early symptoms associated with drug-induced liver injury are usually nonspecific and include loss of appetite, lassitude, and occasionally a dull discomfort in the right upper quadrant of the abdomen. With a few drugs, there is the presence of fever, rash, or eosinophilia: the hallmarks of immuno-allergic reactions. These reactions may (or may not) be important in the pathogenesis of the liver injury.

When to suspect DILI-4 Rechallenge with a suspected drug to establish a diagnosis is seldom necessary and, if the initial reaction was clinically apparent, may not be safe. Even histologic evaluation of the liver only allows recognition of what type and how much injury is present, rather than clearly indicating that the liver injury is from a specific drug.

“susceptibles”

FACTORS THAT AFFECT SUSCEPTIBILITY TO DILI-1
Age, sex, and the concomitant use of other medications are important factors to consider in assessing an individual patient's susceptibility to drug-induced liver disease, as is weight and a history of previous reactions to drugs. . For some drugs, there is a well-established increase in the risk of adverse reactions with age, especially for individuals who are older than 50 years

Older patients (>50 years) are quite likely to have some evidence of hepatic toxicity from isoniazid (up to 2%). Few reactions have been reported in patients who are younger than 20 years. There are a few agents, among them valproic acid and erythromycin estolate, which predominantly cause adverse hepatic reactions in children

Valproic acid-induced hepatotoxicity is also more prevalent in patients who have inherited mitochondrial disorders. Duration of therapy before a reaction occurs is an important part of the “signature.” Phenytoin rarely causes significant hepatic toxicity after 6 weeks of therapy. Liver injury from nitrofurantoin-induced hepatotoxicity may appear after many months of therapy.

For many drugs, females are at an increased risk of developing an adverse hepatic reaction, far exceeding that found in males.

Acute hepatitis: Differential Dx
Ultrasound/ CT + + Viral (A, B, C, CMV, EBV HEV, HSV) Autoimmune (SPEP, ANA, SmAb) NAFLD Mass (AFP, MRI) Biliary (ERCP) Ischemia (History, 2D-Echo) Observe/ biopsy Metabolic (Iron, TIBC, ferritin, ceruloplasmin, SPEP) Drug

Liver Lobule

Liver Function Example Consequence
Glucose metabolism, protein metabolism, storage of nutrients Glucose storage as glycogen Hypoglycemia, altered protein synthesis, decreased vitamin A, Cu, Fe Filtration Removal of polypeptides, lipoproteins coming from GI track Endotoxemia Protein synthesis Albumen Transport proteins Blood clotting factors Hypoalbumenia, ascites, decreased blood clotting Removal of bile pigments Bile acids Jaundice Lipid metabolism Cholesterol Increased levels Xenobiotic removal and metabolism Drugs, toxins, metals Protection, intoxication

Commonly Used Tests “transaminases”: ALT AST alkaline phosphatase
injury “transaminases”: ALT AST hepatocellular cholestatic enzymes alkaline phosphatase gamma-glutamyl transferase function excretory synthetic bilirubin (total, “direct”) albumin prothrombin (INR) substances

DILI Diagnosis Temporal relationship Biochemical injury pattern
Not dose related ? Clinical risk factors Biochemical injury pattern “Signature” vs protean Prior reports/ cases Exclude other likely causes Improvement with discontinuation

Drug Induced Liver Injury
Two types of hepatotoxicity are of interest: Dose-related-or exposure related. Idiosyncratic-rare, unpredictable.

Factors in Idiosyncrasy
genetic, bestowed at onception gender cytochromes, enzymes, transport systems acquired in life since conception age, activities, travels infections, immunities, diseases diet, obesity, dietary supplements other drugs, chemical exposures

Especially Susceptible Patients
adverse effect, often not dose-related may not be duration-related may not depend on prior disease unexpected, unpredictable (up to now) risk factors not well known toxicity often uncommon or rare who are they? how can they be identified?

Intrinsic vs Idiosyncratic Toxicity
predictable dose-related similar in animals high incidence short interval types directly destructive indirect, metabolic cholestatic “idiosyncratic” unpredictable not dose-related not seen in animals low incidence, rare variably longer interval types hypersensitivity metabolic

It may be DILI if it’s nothing else
Diagnosis of exclusion; no test FOR DILI Must gather data to rule out other causes Need to educate “docs” to do it better Develop model for quantitative likelihood estimate Prospective large safety studies needed: for true incidence for risk factors and to design risk management plans for ‘omic’ analyses (gen-, prote-, metabon-) specimens for elucidation of mechanisms

Acetaminophen-induced hepatic injury 1
Acetaminophen-induced hepatic injury is the most common form of drug-induced liver disease and more particularly of acute liver failure in the United States, accounting for nearly 50% of all cases. Acetaminophen is likely the most widely used drug in the western world and is found in a remarkable number of prescribed and over-the-counter single and combination products, including cold remedies and medications for pain. with names that in no way indicate acetaminophen is a component.

Acetaminophen-2 In healthy individuals, there is apparently a considerable therapeutic range between harmless and harmful doses of acetaminophen. In therapeutic doses (<3 g/day), the drug is usually quite safe and well tolerated. Ingestion of excessive amounts of acetaminophen (>10-15 g), often in suicidal attempts, predictably leads to liver injury and occasionally death. The issues lie in assessing the risk of patients receiving acetaminophen of 3 to 10 g/day, and whether there are settings in which liver injury is more likely to occur when the patient has not taken a large amount of the drug with a suicidal intent (so-called “therapeutic misadventures”).

Acetaminophen Normal Glutathione P450 5% 95% NAPQI Sulfate Glucuronide
(N-acetyl-p-benzoquinoneimine) Sulfate Glucuronide Glutathione Glutathione Conjugate

Acetaminophen Overdose P450 5% 95% NAPQI Sulfate Saturated Glucuronide
(N-acetyl-p-benzoquinoneimine) Sulfate Saturated Glucuronide Covalent Binding to Macromolecules Glutathione Glutathione Conjugate Cell Death (Zone 3)

Acetaminophen- 3 Hepatic injury from acetaminophen is caused by the effects of a highly reactive metabolic product, N-acetyl-benzoquinone-imide (NAPQI). Acetaminophen is predominantly metabolized by conjugation reactions to form sulfate and glucuronide metabolites, which are excreted in the urine. A lesser amount of the drug is metabolized by cytochrome P450 2E1 to form NAPQI, which is rapidly bound to intracellular glutathione and excreted in the urine as mercapturic acid.

Acetaminophen- 4 When excessive amounts of acetaminophen are ingested, the ability to conjugate is overwhelmed and metabolism by cytochrome P450 2E1 becomes of much greater importance. In these situations, the capacity of glutathione to serve as an effective hepatoprotectant may be overwhelmed, and the hepatocyte becomes relatively defenseless against attack by the reactive intermediates

Oxygenation Zones Zone 1 – 9% to 13% Zone 2 – < zone 1
Zone 3 has most of the biotransformation enzymes especially CYP2E1

Acetaminophen- 5 Two important factors determine the likelihood of production of hepatic injury by acetaminophen: the amount of NAPQI produced by P450 2E1 and the availability of glutathione as a hepatoprotectant. The intracellular concentration of NAPQI and dose of acetaminophen ingested are clearly associated. However, there is more to the story than simply dosage. Factors that affect the production of cytochrome P450 2E1 and of glutathione are of importance

Acetaminophen- 6 With chronic ingestion of alcohol, doses of acetaminophen near or even with the suggested therapeutic range may lead to liver injury, promoted by an alcohol-induced decrease in intracellular glutathione and an increase (actual or relative to GSH) of cytochrome P450 2E1. The end result is overproduction of NAPQ1 relative to the dispositional pathway of GSH leading to a heightened likelihood of liver

Acetaminophen- 7 There continues to be controversy regarding the risk of acetaminophen use in patients who drink alcohol. Many discussions have occurred at the U.S. Food and Drug Administration regarding labeling and the need for increased awareness of risks by the public. There is general agreement that an overdose of acetaminophen is more likely to cause liver injury in a patient who is a chronic alcoholic. The debate is the definition of overdose and the amount of alcohol ingestion needed to predispose the patient to injury

Acetaminophen Toxic dose 4 stages in untreated patients
150mg/kg in children less than 12 Estimated at 7.5 g for adolescents and adults 4 stages in untreated patients Stage I (0 - 24h) - nausea, vomitting, diaphoresis Stage II ( h) - clinical improvement, RUQ pain Stage III ( h) - peak liver function abnormalities, GI symptoms may reappear Stage IV (4d to 2wks) - hepatic problems resolve, <1% will develop fulminant hepatic necrosis requiring a liver transplant

Acetaminophen Measure a plasma acetaminophen level at >4h after ingestion Antidote is N-acetylcysteine - most effective within 8 hours of ingestion Give antidote if at risk for hepatotoxicity Activated charcoal should be considered

Amoxicillin/Clavulanic Acid Hepatotoxicity
Thank you, In the next 15 minutes it is my charge to discuss future therapies of hepatitis C. It is not possible in this short time to provide a comprehensive overview of all current and future developments, and for these reasons I will confine my comments to compounds that are or will soon be in clinical development in chronic hepatitis C, and as such, if they are effective, may be clinically available in the next 3-5 years.

Case Presentation 68 yo female Referred for transplant evaluation
Jaundice and failure to thrive 3 month illness Laparotomy x 2, cholecystectomy and multiple pancreatic head biopsies Biopsy profound cholestasis and bile duct injury Small nasal scar, solar keratosis surgery Dermatologists records No malignant Infected Augmentin for 14 days

Therapeutics: Prescribing Information
Amoxicillin Semisynthetic antibiotic C16H19N3O5S.3H20 MW = clavulanate potassium (salt) Potent β- lactamase inhibitor C8H8KNO5 MW = Addition of clavulanate prevents degradation of amoxicillin by β- lactamases

Mechanism of Action unclear Idiosyncratic/immunologic
Not dose dependent Prevalence not uniformly assoc with re-exposure Eosinophilia HLA association Not seen with amoxicillin alone Presumed due to clavulante Cholestasis described with Timentim® Ticarcillin + clavulante Rarely observed with sulbactam, tazobactam; i.e. other β lactamases

“Indicated for the treatment of infections caused by susceptible strains of the following designated organisms”: H. influenzae; M. catarrhalis; E. coli; S. aureus; Klebsiella spp, Enterobacter spp Lower respiratory tract infections (COPD) Otitis media Simusitis Skin and skin structure infections Urinary tract infections

Augmentin® First introduced 1981 Generics introduced Hepatotoxocity first reported 1988 Year 2000 18.9 M new prescriptions Fourth most commonly prescribed drug

US Frequency Hepatotoxicity
Assuming incidence between 1: 100,000 and 1:10,000 ≈ 20 million new prescriptions annually Number of expected cases HTX ≈ 200-2,000 per year ≈ 122-1,220 adult cases ≈ pediatric cases ??

Frequent Concomitant Medications
Pyrexia associated with bacterial Unclear, not well documented infections Acetominophen probably common 8/21 (38%) cases exposed to other HTX drugs Acetominophen NSAID’s Trimethoprim Flucloxacillin Valproate Carbamazepine imipramine 43% another potential or suspected agent

Clinical Presentation
Signs and Symptoms are nonspecific Nausea Vomiting Fatigue Malaise Abdominal pain fevers Itch Jaundice rash Allergic phenomena: Eosinophilia 23-30% patients

Timing Interval start Rx to jaundice 4-63 days (89 days) Cessation Rx to onset jaundice 1-48 days 80% developed jaundice after cessation Rx Larrey D et al. Gut 1992;33:368-71 Hautekeete ML et al. Gasroenterology 1999:117;

Laboratory tests Bilirubin x ULN ALT X ULN AST x ULN AP x ULN γGT x ULN

Pattern of Laboratory tests Cholestatic 66-76% Mixed 14-23% Hepatocellular 10-11%

Clinical Presentation Liver Biopsy
Architecture normal Mixed, LM portal infiltrate Intralobular Bile ducts Nuclear irregularity Vacuolization LM infiltrate Proliferation Cholestasis lobules Variable degrees necrosis Mild cellular infiltrate Rarely granulomas; focal destructive cholangiopathy

Outcome of Hepatotoxicity
Fatalities rare but reported Chronicity uncommon Jaundice can be prolonged up to 19 weeks 1 case 2 years Cases associated with PBC Interstitial nephritis Sialadenitis ? Underlying liver disease Pre-exisiting DILI

HLA Class II Association
DRB1*1501-DRB5*0101-DQB1*0602 35 cases, 300 donors 57% vs 11.7% (p < ) haplotype more frequently assoc. with cholestatic/mixed 22 cases, 134 controls 70% vs. 20% (p < ; RR 6.43) More frequently homozygotes No clinical correlates ? Formation neo-antigen and their recognition as foreign

Minimal Criteria for Causality Amoxicillin/clavulanic acid
Start and stop date Age, sex, demographics Drug exposure within 8 weeks Serologic tests Additional but not necessary Prior exposure Eosinophils biopsy Dosage Imaging to exclude obstruction Concomitant medications

“Definite” Case Amoxicillin/clavulanic acid
Male Age > yo Cholestatic pattern Repeat exposure Eosinophilia Imaging negative Onset after cessation of drug Recovery within 6-8 weeks All serologies negative

Isoniazid Hepatotoxicity -1
Isoniazid has been the mainstay therapeutic agent for the treatment of tuberculosis for more than 50 years. Combination therapies anchored by INH are generally used to prevent the development of resistance to a single therapeutic agent. In the 1960s, INH was used as a single agent in patients who were found to be at risk for developing tuberculosis because of the findings of a positive tuberculin skin test. INH given alone often leads to elevations of aminotransferase and occasionally to overt liver disease.

When INH was used as a sole agent, instances of hepatotoxicity appeared suggesting that when given in combination therapies ,the combination of drugs may have been associated with a reduced production of intermediate metabolites of INH.

Elevations of aminotransferase levels from INH usually appear within several weeks following initiation of treatment and are found in 10% to 20% of patients. Usually, these elevations are modest and not associated with signs or symptoms suggestive of liver disease. In many (likely most) patients, continued use of INH is well tolerated and often the aminotransferase levels return to or near normal. If INH is discontinued when the elevations are noted, the aminotransferase levels generally return to normal within 1 to 4 weeks.

However, a few patients receiving INH develop significant clinical hepatitis, and drug-induced hepatic failure may occur (0.1%-2.0%) Patients older than 50 years are at an increased risk of developing clinically evident hepatitis from INH. Children rarely manifest any clinically evident liver disease from INH. Women are more likely to be severely affected than men.

Presently, patient-monitoring schedules with discontinuation of treatment in those in whom there are significant or rising levels of aminotransferases are recommended and appear to be effective.

The liver injury from INH appears to be mediated by toxic metabolic products, including hydrazine and monoacetyl derivatives formed during metabolism. There are generally no signs or symptoms suggestive of hypersensitivity. INH is metabolized by N-acetyltransferase and CYP 2E1 to form reactive intermediates.

In the first phase, isoniazid is metabolized by N-acetyltransferase (NAT2) to acetylisoniazid, which is then hydrolyzed to acetylhydrazine. Acetylhydrazine is further metabolized by CYP 2E1 to produce hepatotoxic derivatives.

In a study from Taiwan of 318 patients who had tuberculosis and were receiving INH, the genotypes of CYP 2E1 and NAT2 were determined by a restriction fragment length polymorphism method. Forty-nine (5.4%) of the patients showed some evidence of hepatotoxicity. The risk of hepatotoxicity based on CYP 2E1 activity and the acetylator status (rapid or slow) was analyzed.

The wild-type allele for CYP 2E1 is c1. The risk of hepatotoxicity was 3.94 for CYP 2E1 c1/c1 with rapid acetylation status to 7.43 for CYP 2E1 c1/c1 with slow acetylation. Even after adjustment for acetylation status, CYP 2E1 c1/c1 was an independent risk factor for hepatotoxicity (P = 0.017). Volunteers who were CYP 2E1 c1/c1 had higher CYP2E1 activity than those with c1/c2 or c2/c2, suggesting accelerated production of hepatotoxins

Possible induction of CYP 2E1 by alcohol may explain the increases in INH hepatotoxicity seen in regular to heavy users of alcohol. Based on these studies, determination of the CYP 2E1 phenotype before institution of isoniazid therapy may prove clinically useful.

Troglitazone Hepatotoxicity-1
Troglitazone, a thiazolidinedione agent that is a PPAR-[gamma] agonist used in the treatment of diabetes, was withdrawn from the market after early extensive use when several instances of acute liver failure leading to death or the need for liver transplantation were identified A debate has ensued as to whether there was a signal in the prerelease clinical trials, which indicated likely major hepatotoxicity. In the trials, 2510 patients received the drug- Two developed jaundice and 1.9% had aminotransferase elevations of >3 times ULN as compared with 0.6% in patients who received placebo

Troglitazone Hepatotoxicity-2
The hepatic injury in patients who developed liver injury was predominantly hepatocellular. The mechanism for troglitazone-induced liver injury has not been established. Other PPAR-[gamma] agonists (rosiglitazone and pioglitazone) have been associated with hepatotoxicity in rare instances.

Statins Hepatotoxicity-1
Few drugs have been as widely prescribed as the statins. There have been lingering concerns regarding statin-induced hepatotoxicity from the time of introduction in 1987 of lovastatin, the first member of the class. Millions of patients have now received these drugs. Asymptomatic increases in aminotransferase levels develop frequently. Elevations to >3 times upper limit of normal occur in 1% to 3%.

In one study, 127 of 6,605 patients treated with lovastatin had ALT elevations of 1.5 to 3 times the upper limit of normal The elevations in ALT generally return to or toward normal despite continued therapy. There have been remarkably few well-documented instances of statin-induced severe liver injury.

There is evidence that suggests the increases in aminotransferases may represent a pharmacologic effect associated with lipid lowering. An intracellular accumulation of precursors following HMG-CoA reductase inhibitors may lead to enlargement of hepatocyte and to ALT increases. Exactly how lowering cholesterol or favorably affecting the lipid profile is associated with aminotransferase elevations remains unknown.

There is no evidence that patients who have elevated baseline ALT levels associated with diabetes, steatohepatitis, or chronic hepatitis C are at increased risk. Therefore, present evidence supports the concept that statins are hepatically safe agents despite the rather frequent elevations of ALT. Again, this supports the concept that mild to moderate elevations of ALT do not equate to liver injury. There is scant support for following a regular biochemical monitoring schedule in patients receiving statins.

Minocycline Hepatotoxicity-1
Minocycline, a semisynthetic derivative of tetracycline that has been widely used in the treatment of acne, has been reported to cause acute hepatitis, a chronic hepatitis with autoimmune features, and a systemic lupus erythematosus syndrome. Several deaths from liver disease have occurred.

Positive rechallenges with recurrence of liver disease have been observed. The autoimmune hepatitis syndrome, which is more frequently observed in females who have received the drug for months to more than a year and is characterized by the presence of fever, arthralgias, hyperglobulinemia, antinuclear antibodies, and a liver biopsy indistinguishable from classic type autoimmune hepatitis

It is important for the clinician to recognize the role of minocycline and withdraw the drug, which usually leads to rapid improvement. If the patient is considered to have Type 1 autoimmune hepatitis and is treated with corticosteroids while minocycline is continued, there is a risk of partially masking the drug-induced injury. This masking was the case with methyldopa-induced chronic hepatitis and oxyphenistatin-induced chronic hepatitis. The mechanism of minocycline-induced liver injury is unknown.

HERBAL HEPATOTOXICITY-1
There has been increasing recognition that herbal products of many types can cause hepatotoxicity. Patients who have underlying liver disease often use a variety of herbals as alternative medicines. Milk thistle (silymarin) has been widely embraced by patients with hepatitis C, despite lack of extensive controlled studies supporting benefit. Fortunately, there is equally scant evidence of any hepatotoxicity from the compound.

Acute hepatitis and acute liver failure have been reported with a number of compounds including kava. There are special difficulties in associating an herbal product with hepatic injury. These include problems in obtaining an accurate history of ingestion and often an unwillingness of the patient to fully disclose what has been ingested. Traditional and alternative treatment regimens abound throughout the world. These products may vary from lot to lot and are not manufactured to approved standards

Extracts of kava-kava, a plant in the pepper family, has been used as a beverage for centuries by South Pacific islanders for reducing anxiety and as a remedy for sleeplessness and menopausal symptoms. More recently, standardized extracts of kava-kava containing concentrated extract have been produced in Europe and subsequently introduced into the United States. Instances of acute hepatic failure and death have been attributed to kava-kava. The commercially available standardized extracts that have caused liver injury contain 30% to 70% lactones

VITAMIN A (Retinol )-HEPATOTOXICITY-1
Excessive ingestion of vitamin A is an established cause of liver disease leading to cirrhosis with ascites and portal hypertension. Chronic ingestion of large amounts of vitamin A often used as part of the megavitamin generalized health protection programs can lead to chronic intoxication and liver injury.

Vitamin A Toxicity

VITAMIN A HEPATOTOXICITY-2
Hypervitaminosis A most often results from self-medication. The usual recommended dose of vitamin A for adults is 5,000 IU per day. Hepatic injury has been seen in patients who received 15,000 to greater than 40,000 units a day for a period of years. Even higher doses may produce signs of intoxication within several months..

The liver is a principal storage site for retinol and, more specifically, the stellate cells bear the brunt of the attack. Many patients with liver injury from ingesting excessive vitamin A go unrecognized, and only an astute clinician is likely to make the association between chronic ingestion of vitamin A and otherwise unexplained advanced hepatic disease with cirrhosis, ascites, and portal hypertension

The clinical picture most often is one of insidious onset of cirrhosis. Elevations of aminotransferases are found in over 70% of patients with vitamin A-induced liver injury, along with slightly elevated levels of alkaline phosphatase and occasional minimal to modest elevations of serum bilirubin. In patients with advanced vitamin A intoxication, hypoalbuminemia and hypoprothrombinemia are present.

Vitamin A is stored in stellate cells. A syndrome of hepatoportal sclerosis with portal and perisinusoidal fibrosis as well as sclerosis of terminal venules and atrophy of zone 3 of the hepatic lobule are characteristic findings. Portal hypertension results from the compromising of sinusoids by the enlarged stellate cells as well as by fibrous tissue deposited in the sinusoids and the sclerosis of the terminal venules. Occasionally microvesicular steatosis is found.

Vitamin A-induced hepatic injury apparently results from the intrinsic toxicity of vitamin A, and the extent of the injury depends on the dose and duration of exposure. The increased levels of vitamin A in stellate cells lead to multiplication of the cells and conversion to myofibroblasts. Alcoholic patients appear to be unusually susceptible to vitamin A intoxication. Alcohol potentiates the toxicity of vitamin A in experimental situations. The treatment is withdrawal, and the diagnosis depends on careful history taking and awareness

Acetaminophen (APAP) Budget suicide: cheap, accessible, popular
80% OD’s > 15 g Toxic dose >150mg/kg (~6g) S. levels useful 4-15 h out Nomogram: know it, use it

APAP Dose-dependent production of toxic metabolite (NAPQI)
produced by P450 conjugated by glutathione

(highly reactive intermediate)
HN C CH3 O Cytochromes P450 lead to unstable compounds! N C CH3 O O C HN CH3 GSH SG glutathione-S-transferase OH Cytochrome p450 2E1 Mercapturic Acid (nontoxic) (phase I) O OH NAPQI (highly reactive intermediate) Glucuronidation Sulfation Hepatocyte Damage (phase II) Covalent binding to cell proteins, including enzyme itself ADDUCTS Derangement of apoptosis? CAR? Nontoxic Metabolites

NAPQI directly cytotoxic Hepatic Renal
APAP NAPQI directly cytotoxic Hepatic Renal

“Will tylenol taken with EtOH prevent hangover?”
EtOH Use Increased p450 = more NAPQI EtOH metabolism depletes glutathione stores = more NAPQI

APAP Labs gone wild Transaminitis Hyperbilirubinemia
Coagulopathy (INR) ATN + / - myocardial necrosis

APAP NAC – glutathione substitute Charcoal if < 4 h Antiemetics prn
load 140 mg/kg PO 17 doses over 72 h Can give by NGT / IV Charcoal if < 4 h Antiemetics prn

APAP NAC Best within 8-10 h Still useful > 24 h
Give first, ask questions later!

Drug-Induced Liver Disease
Predictable Dose-related Unpredictable Not dose-related Immune-mediated Idiosyncratic

Bile Composed of bile salts, glutathione, phospholipids, cholesterol, bilirubin, organic anions, proteins, metals, ions, xenobiotics Bile formation essential for: lipid uptake from small intestines Protection of small intestines from oxidative injury Excretion of endogenous and xenobiotic compounds

Bile Excretion Metals ATP-dependent exporters
Uptake (facilitated diffusion vs. receptor) Excretion (lysosomes, transporters) Copper, manganese, cadmium, selenium, gold, silver, arsenic ATP-dependent exporters MDR (multiple-drug resistance) cMOAT (canalicular multiple organic ion transporter)

Drugs, hormones, xenobiotics
Bile Formation Drugs, hormones, xenobiotics Metals Bile Salts Bilirubin MDR Bile Canaliculi cMOAT Organic cations, drugs, phospholipids Conjugates of glutathione, glucuronide, sulfate

Bile Excretion Canaliculi Channels Bile Ducts Common Bile Duct
Small Intestine Enterohepatic Cycling

Zones of Oxygenation of The Liver

Fatty Degeneration Increased lipid content of the hepatocytes (liver parenchymal cells) steatosis Etiology (cause) can be nutrition and it can be due to a toxic substance Over supply of fatty acids (FA) Alteration of triglyceride cycle Increase FA synthesis Decrease aproprotein synthesis

Characterization and Classification
Clinical Pathology Appropriate Hepatobiliary Injury Classification Morphologic Pathology Mechanistic Pathology

Fatty Degeneration (cont)
Toxic substances Liver may be enlarged Ethionine – metabolic inhibitor Valproic acid

Hepatocellular Necrosis
Necrosis and apoptosis Necrosis Nucleus is often marginated Cell swells Leakage of cytoplasm Pyknosis of the nucleus Karyorrhexis

Liver Necrosis Leakage of cytoplasm
Enzymes in the hepatocyte are leaked into systemic circulation, for example Aspartate aminotransferase Alanine aminotransferase Sorbitol dehydrogenase Forms of lactic acid dehydrogenase

Hepatocellular Necrosis
Histopathology is evident for days after the hepatocytes have died. Described by the area of the hepatic cords or the lobule (acinus) that has undergone necrosis Toxic substances can produce necrosis in certain areas Eg, CCl4 is zone 3 or centrilobular

Canalicular Cholestasis
Decrease in volume of bile or impaired secretion of bile Patient is jaundice May be bile plugs in the bile ducts Have elevated bilirubin, icterus index, ect Toxic substances Chlorpromazine Cyclosporin Estrogens

Canalicular Cholestasis
Decrease in the volume bile formed or impaired secretion of solutes into bile Compounds found in bile will be elevated in blood (eg bilirubin  jaundice)

Cholestasis 1 5 2 6 3 4 Chlorpromazine: 1, 4 Estrogen: 1, 2
Manganese: 6 1 5 2 6 3 4

Bile Duct Damage Cholangiodestructive cholestasis
Increased serum activity of gamma glutamyltransferase (GGT) and other enzymes Damage to epithelium of bile ducts Increased cells - hyperplasia Aflatoxins Pyrrolizidine alkaloids

Bile Duct Damage (Cont)
Damage to epithelium of bile ducts (cont) Necrosis of bile duct cells Sporidesmin A mycotoxin Methylene dianiline Human exposure in contaminated flour Mistaken for a drug of abuse

Sinusoidal Damage Fenestration of endothelium for high permeability
Fills with blood Occurs with veno-occlusive disease See with fibrosis of the liver Pyrrolizidine alkaloids Cyclophosphamide After GSH is used up

Sinusoidal Damage

Cirrhosis Progressive liver injury Accumulation of fibrous tissue
Collagen fibers Around central vein Space of Disse Result of repetitive damage of liver cells Humans EtOH abuse Chronic aflatoxicosis

Liver Neoplasms Primary neoplasm Secondary neoplasm Aflatoxins
Neoplasm from cells in the liver Secondary neoplasm Neoplasm outside the liver Invasion Metastasis Aflatoxins Hepatocellular carcinomas

Uptake of Toxic Substances
First Pass Effect Term used to describe the rapid uptake of some chemicals by the liver Microcystin Blue-green algae Plalloidin Amanita phalloides Block uptake with cyclosporin A

Bioactivation EtOH EtOH rapidly metabolized by alcohol dehydrogenase to acetaldehyde Acetaldehyde metabolized slowly by aldehyde dehydrogenase to acetate Balance of Phase 1 and Phase II biotransformation reactions

Major Cell Types Hepatocytes (parenchymal) Endothelial Cells
large -  75% of lobule Endothelial Cells line sinusoids – small - form fenestrate (pores) -  25% of lobule Ito (stellate) Cells store fat – store & metabolism, vitamin A - synthesize collagen Kupffer Cells few – phagocytic - immune - can release active molecules and secrete cytokines, present antigens

DILI Diagnosis DILI is a diagnosis of exclusion based on circumstantial evidence due to lack of objective confirmatory lab test, rechallenge, or “GOLD” standard Requires a high index of suspicion DILI diagnosis is usually retrospective Exclude other causes Dechallenge requires follow-up

Drugs, hormones, xenobiotics
Bile Formation Drugs, hormones, xenobiotics Metals Bile Salts Bilirubin MDR Bile Canaliculi cMOAT Organic cations, drugs, phospholipids Conjugates of glutathione, glucuronide, sulfate

Blood Supply to The Liver
The venous blood from the majority of the gastrointestinal tract and peritoneum flows to the liver in the hepatic portal vein. Hepatic artery is small and supplies arterial blood to the liver Blood from the liver empties into the vena cava below the heart

Issues: Idiosyncratic Drug Toxicity
Occurs despite careful preclinical testing in animals … and despite careful and costly clinical trials Some problem (perhaps wrong) assumptions: Assuming drug variability is the key to safety Obsolete concepts of “safe and effective” – for all? Assuming one dose/regimen suits all patients Focus on efficacy, little on safety (especially if rare)

Cholestasis 1 5 2 6 3 4 Chlorpromazine: 1, 4 Estrogen: 1, 2
Manganese: 6 1 5 2 6 3 4

Cholestasis Chlorpromazine: Estrogen 1 5 2 6 3 4

Types of Liver Injury Hepatocellular death Fatty degeneration
Canalicular cholestasis Bile duct damage Sinusoidal damage Damage to cytoskeleton Cirrhosis Neoplasm

DRUG INDUCED HEPATOTOXICITY

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