Drug induced liver disease

Refers to any injury to the liver by a prescribed medication, OTC medications, dietary supplements that manifests disease ranging from asymptomatic liver function elevations to acute liver failure.

The true incidence of drug-induced liver injury (DILI) is difficult to discern.

Felt to be the most common cause of acute liver failure in the US.

Drug-Induced Liver Injury accounts for approximately 52% of cases of fulminant hepatic failure in the United States.

Incidence between 1 in 10,000 and 1 in 100,000 patients.

Incidence estimated to be 14-19 cases per hundred thousand persons, with jaundice accompaning 30% of cases.

Responsible for 3-5% of hospitals admissions for jaundice.

It is the most frequent cause of acute liver failure in most western countries, accounting for more than half of cases.

Drug induced liver injury is classified as direct or idiosyncratic, but indirect injury is now considered a third type.

Direct liver toxicity is caused by drugs there intrinsically toxic to the liver.

Direct hepatotoxicity injury is common, predictable, dose dependent.

The latency period In direct hepatotoxicity is typically short short, usually within 1-5 days after a high therapeutic or supra therapeutic dose, as with intentional or accidental overdose.

Direct the drug induced liver injury is associated with serum enzyme elevations without jaundice, with elevations of alanine aminotransferase or alkaline phosphatase levels but without hyperbilirubinemia and with minimal or no symptoms.
With direct hepatotoxicity liver function elevations resolve when the drug is stopped or the doses lowered but can also resolve spontaneously-adaptation.
Acute hepatic necrosis is the most common clinical finding in direct hepatotoxicity.
Hepatic necrosis from drug toxicity occurs abruptly, soon after the initiation of the medication, and often after exposure to a single high dose or a dose increase.
In severe cases of acute hepatic necrosis, signs of hepatic failure such as coagulopathy, hyperammonemia, or coma arise within days.
Histologic findings with acute hepatic necrosis show central lobular or panlobular necrosis.
Acute hepatic necrosis can be fatal, but if not so, recovery is rapid.
High doses of acetaminophen, aspirin, niacin, amiodarone, and many anti-neoplastic agents can cause acute hepatic necrosis.
Poisonous mushrooms can cause acute hepatic necrosis.
With direct hepatotoxicity serum alanine aminotransferase levels rise to high levels, whereas alkaline phosphatase levels are only minimally elevated.
If adaptation does not occur enzyme elevation worsens and jaundice symptoms may arise.

Adaptation may result from changes in drug-metabolizing enzyme activity, up regulation of hepato-protective pathways, or down regulation of hypersensitivity reactions to the drug.

Idiosyncratic hepatotoxicity is caused by agents that have a little intrinsic toxicity and causes injury only in rare cases, after one in 2000 to 1 in 100,000 patient exposures.

Idiosyncratic toxicity injury unpredictable, and not reproducible.

With idiosyncratic liver toxicity the injury is unpredictable, it is not dose-dependent.
Idiosyncratic liver injury may be hepatocellular, cholestatic, or both on the basis of the R ratio calculated by dividing the alanine aminotransferase level by the alkaline phosphatase level, with both values expressed as multiples of the upper limit of normal range.
Idiosyncratic drug induced hepatitis can be associated with rash, fever, and eosinophilia, signs of drug hypersensitivity.
Prominent causes of idiosyncratic drug induced Hepatitis with immunoallergic features include: allopurinol,carbamazine, phenytoin, sulfonamides, and macrolide antibiotics.

Immuno allergic hepatitis is more common among black individuals.

Hepatocellular injury is defined as R value of more than five, cholestatic injury is a value of less than two, and a mixed injury as a value of 2-5.

Cholestatic Hepatitis is characterized by pruritus and jaundice accompanied by moderate-marked elevations in alkaline phosphatase levels.
Drug induced cholestatic liver injury is usually self-limiting but can be protracted.
Rarely  cases can evolve into vanishing bile duct syndrome, with prolonged jaundice, liver failure, a need for transplantation, or death.
Common causes of drug induced cholestatic hepatitis are: amoxicillin-clavulanate, cephalosporins, terbinafine, azothioprine , and temozolomide.
Mixed drug induced causes of hepatitis usually have benign outcomes and are associated with the fluoroquinolones and macrolide anabiotics, phenytoin, and sulfonamides.

There are no specific diagnostic markers for drug induced liver injury, and special tests including liver biopsy, imaging and serological tests are helpful in ruling out other causes of liver injury.

The mean alanine aminotransferase level of 1200 units per liter and an international normalized ratio of 1.6.

The leading offending agents are antibiotics, herbal and dietary supplements.

There are more than 1200 agents including prescription drugs, over-the-counter medications, herbal products, electrician supplements, metals, and toxins that have a potential cause liver injury.

In most cases no effective treatment exists except stopping the agent and providing supportive care.

The majority of patients with DILI will experience complete recovery.


Jaundice may take months to resolve after cholestatic DILI. 

Leading cause of acute liver failure for those sent for liver transplantation and acetaminophen is the primary drug implicated in such cases.

N-acetylcysteine utilized after acetaminophen overdose.

In acute liver failure due to nonacetaminophen drug-induced liver injury, N-acetylcysteine administration may improve transplant-free survival.I

Intravenous carnitine used for valproate induced mitochondrial injury.

Drug related hepatotoxicity most common reason for FDA regulatory actions.

Because of its rarity, hepatotoxicity may not be noted during clinical trials but after approval, use by large number of patients may expose rare toxic effects.

Liver injury defined as increase of more than twice the upper limit of normal range in the levels of serum alanine aminotransferase or conjugated bilirubin, or a combined increase in the levels of aspartate aminotransferase, alkaline phosphatase and total bilirubin, provided that one of these tests was more than 2 times the upper limit of normal.

DILI more likely to occur in females, the elderly, patients with pre-existing chronic liver disease, obesity, and HIV.

it is necessary to differentiate DILI from predictable to unpredictable causation.

Acetaminophen is the most common drug causing predictable DILI.

Acetaminophen injury has a short latency, and is dose-related.

Unpredictable DILI, is idiosyncratic, has a longer and more variable latency period and is a less common phenomenon.

Idiosyncratic DILI responses include those related to amoxicillin/clavulanate, nonsteroidal anti-inflammatory drugs and INH.

Annual incidence is about 19.1 cases per 100,000 persons.

The main cause of DILI are amoxicillin/clavulanate, isoniacid and and nonsteroidal anti-inflammatory drugs as the top 3 agents.

Old age is a risk factor for DILI from INH.

DILI related to younger age in patients with valproate and aspirin toxicity.

Cholestasis hepatic drug-induced injury is more likely seeing an old individuals.

Most common drug causing liver injury is amoxicillin/clavulanate.

Antibiotics are the most common class of drugs responsible for acute liver failure.

Antibiotics associated with acute liver failure primarily: isoniazid, sulfa drugs and nitrofurantoin.

The DILI Network evaluation of 300 cases revealed a mean age of 48 years, 60% female, the largest category of drugs were antimicrobial agents and CNS agents, and 2% of patients required liver transplantation.

Approximately 11% of patients with acute liver failure have idiosyncratic DILI.

TILI can also be categorized as hepatic, with hepatocellular changes, cholestatic or mixed on the basis of liver biochemical parameters.

R ratio: the ratio of the alanine aminotransferase (ALT) to the alkaline phosphatase relative to their respective upper limits of normal.

The R ratio for hepatic DILI is more than five, for cholestasis DILI is less than two and for mixed DILI is between two and five.

Cholestatic injury has a better prognosis than hepatocellular DILI, but it is more likely to persist and lead to chronic injury (31% vs 13%).

Immune-related DILI is associated with fever, rash, eosinophilia, and autoantibodies.

Immune-related DILI is associated with early onset and rapid reinjury with reintroduction of the drug.

Drug induced autoimmune induced hepatitis is treated with corticosteroids.

Drug induced autoimmune hepatitis associated with elevated levels of aminotransferase, elevated levels of gammaglobulin and ANA or anti-smooth muscle antibodies.

Drug induced autoimmune hepatitis agents include minocycline, nitrofuantoin, floroquinolones and anti-TNF inhibitors.

Difficult to distinguish drug-induced autoimmune hepatitis from idiopathic autoimmune hepatitis.

Examples of immune-mediated DILI include ACE inhibitors, allopurinol, diclofenac, phenytoin, amoxicillin/clavulanate, and tricyclic antidepressants.

Nonimmune-mediated DILI has a later onset of action, as much as a year, lacks systemic features of immune DILI and is not associated with rapid reinjury when rechallenge with the drug.

Veno-occlusive disease is due to acute injury and loss of intrasinoisal endothelial cells that result in obstruction of sinusoidal bloodflow and liver injuries: drugs as usual cause-the most common myeloablative agents used in preparation for hemetppoetic cell transplantion.

Biopsy generally is not required to diagnose most cases of DILI and many of the histologic features are seen with drugs and other disease states and are not specific.

Transplant free, 3 week survival with idiosyncratic drug induced acute liver failure is poor, at about 27% (Reuben A et al).

Drug induced autoimmune hepatitis response to steroids, and generally does not recur after improvement.

Females have a higher risk of idiosyncratic DILI.

Females have a higher risk of DILI from nitrofuantoin, erythromycin, minocycline, and INH.

Chronic alcohol increases risk of DILI from supratherapeutic doses of acetaminophen, and increases risk of fibrosis/cirrhosis from methotrexate.

Hepatitis E can simulate drug-induced liver injury and 3-13% of cases.

Drug induced liver injury with elevations in aminotransferase levels in patients that develop jaundice is associated with mortality rate of approximately 10%.

N-Acetylcysteine is considered in patients with drug induced acute liver failure, because it improves transplant-free mortality.

Nodular regenerative hyperplasia manifests as non-cirrhotic portal hypertension with esophageal varices or ascites.
Nodular regeneration can be caused by chemotherapeutic agents, and antiviral agents, causing hepatoc microvasculature injury.
Lactic acidosis with microvesicular steatosis and a pair of dysfunction typically occurs with no specific symptoms of a domino discomfort, fatigue, and weakness, with subsequent confusion, stupor and coma a company liver injury.
Jaundice occurs late, enzyme elevations are variable.
The time of hepatotoxicity onset can be days with aspirin and weeks with other agents or even months.
Liver biopsy shows microvesicular steatosis with minimal inflammation and necrosis.
Liver injury is related to mitochondrial toxicity and failure of aerobic metabolism. Therapy focuses on withdrawal of the responsible agent, the administration of glucose infusions and correction of acidosis.
Acute hepatitis is the most common manifestation of idiosyncratic liver injury.
The latency period for acute hepatocellular hepatitis ranges from 5-90 days.
The symptoms of acute idiosyncratic hepatotoxicity resemble those of acute viral hepatitis with elevations of alanine aminotransferase by 5 to 50 times, where is alkaline phosphatase levels are only modestly increased.
Liver biopsy in idiosyncratic hepatotoxicity looks like viral hepatitis.
Death rate from icteric hepatocellular injury due to medications is 10% or higher.
Drug-induced idiosyncratic acute hepatocellular injury causes 11-15% of cases of acute liver failure in the US.
Drug-induced idiosyncratic acute hepatocellular injury drugs or isoniazid, nitrofurantoin, and diclofenac.
Chronic hepatitis is uncommon from drug-induced liver disease.
Chronic hepatitis with chronic hepatocellular pattern of disease can arise after months of exposure to the same agents noted above for acute disease.
Chronic hepatitis induced by drugs is frequently associated with with autoantibodies. 
Common causes of drug-induced, autoimmune-like chronic liver injury or nitrofurantoin, minocycline, hydralazine, methyldopa, statins, amoxicillin-clavulanate, and fenofibrate.
While  these medications might be the most common cause of idiosyncratic drug induced liver injury the process in patients taking these drugs is rare.
The incidence of idiosyncratic liver injury from drugs ranges from 1 case per 1000 to one case per 50,000 exposure.
Of the top 10 drugs, nine associated with drug induced liver injury are anti-microbial agents, largely antibiotics.
Among the top 25 commonly implicated drugs, only three were introduced after 2000: rosubastatin, duloxetine, and telithromycin
Most antineoplastic agents and kinases cause transient elevations in serum liver enzyme levels but rarely cause serious liver injury.
The management of chronic drug induced hepatitis is with glucocorticoids.
Chronic drug induced hepatitis usually resolves without intervention by discontinuing drug exposure.
A distinctive phenotype of drug induced liver injury characterized by marked and prolonged jaundice with pruritus, is bland cholestasis.
Bland cholestasis is typically caused by estrogens or oral contraceptives in women.
In men bland cholestasis is typically caused by anabolic steroids usually used by bodybuilders to improve athletic performance.
Blend cholestasis arises within 30-60 days and elevations of liver enzymes are minimal or modest along with prolonged  jaundice.
Liver biopsy shows bland cholestasis with scant inflammation and hepatocellular necrosis.
Cholestasis of the bland type can be prolonged, but the injury is almost always self limited and deaths are rare.
Indirect drug induced liver injury results from medication’s actions rather from its hepato-toxic effects with an injury that represents induction or exacerbation of a liver disease: fatty liver disease and indirect effect of drugs that cause weekend, or drugs that alter triglyceride disposition, indirect effects of anti-cancer agents that can reactivate hepatitis B, antiviral agents  that cause immune reconstitution exacerbation of hepatitis C, immune mediated liver injury due to immunomodulating agents, tumotr necrosis factor antagonists and checkpoint Inhibitors.
Indirect drug liver injury is much more frequent than idiosyncratic forms and it’s a common reaction to a whole classes of medications.
Herbal and dietary supplements have increase the number of cases of liver injury in recent years.

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