Drug induced liver injury

Drug-induced liver injury or ‘DILI’, is a rare, unpredictable, and potentially life-threatening acute liver failure caused by adverse drug reaction ¹, ². Drug-induced liver injury (DILI) encompasses the unexpected harms that prescription and non-prescription drugs, herbal and dietary supplements can cause to the liver ³. Drug-induced liver injury (DILI) is a frequent cause of hepatitis (approximately 10% of all cases of acute hepatitis) ⁴ and hospitalization ⁵ and is implicated in 5%-10% of all patients hospitalized for jaundice ⁶, accounting for 95% of adverse drug reactions and 14.6% of drug fatalities in Denmark ⁷. In the United States, approximately 2000 cases of acute liver failure occur annually and drugs account for over 50% of them (39% are due to acetaminophen, 13% are idiosyncratic reactions due to other medications) ⁸.

Drug-induced liver injury (DILI), has been the major reason for denial of approval, withdrawal from the market, or “black box” warnings for many drugs and complementary and alternative medicines (CAMs), by the U.S. Food and Drug Administration (FDA) ⁹, ¹⁰, ¹¹.

More than 1100 drugs, herbal remedies, natural products, vitamins, minerals, dietary supplements, and recreational and illicit compounds have been reported to cause DILI (albeit, some only occasionally) ¹², ¹³, ¹⁴, ¹⁵. DILI prevalences are mostly less than 1 in 100,000 to 1 in 10,000 patients, but are occasionally more frequent ¹⁶. In a population-based study from a rural area in France, the crude global incidence of DILI was 13.9 cases/100,000 population—a rate 16-fold higher than reported to regulatory authorities ¹⁷. Four of 34 (11.8%) patients in that study were hospitalized, and two (5.9%) died ¹⁷. In a 1990s United Kingdom-based survey ⁵, DILI requiring specialist referral affected 2.4 cases/100,000 person-years (similar to the 1980s DILI incidence in Denmark) ⁷, of whom 36/128 (28.2%) were hospitalized, but only one required liver transplantation.

Drug‐induced liver injury (DILI) has been classically divided into two varieties based on the presumed mechanism of action of the chemical compound: intrinsic DILI and idiosyncratic DILI ¹⁸. The intrinsic DILI (or direct, predictable DILI) is dose‐related and occurs shortly after exposure (hours to days) in the majority of individuals exposed to the drug (which is toxic at a dose threshold level) ³. In contrast, the idiosyncratic DILI (unpredictable DILI) is multifactorial and unpredictable drug induced liver injury and does not correlate with the dose and usually occurs in less than 1 of every 1000 to 1 of every 100,000 exposed individuals ¹⁹, ²⁰ and with a longer latency period (from a few days to several months) ²¹, ²². Idiosyncratic DILI is further subdivided into two sub-categories: allergic (immune-mediated) and non-allergic (nonimmune-mediated) as presented in Figure 1 ²¹, ²³, ²⁴. If immune-mediated, the latency is shorter (1–6 weeks) compared with non-immune mediated reactions (1 month to 1 year) ²⁵. However, exceptions do occur with immune reactions appearing after a very long latency with drugs such as nitrofurantoin ²⁶ or even after drug cessation (eg sulfonamides, erythromycin and amoxicillin-clavulanate) ²⁵. Immune-mediated idiosyncratic reactions can be characterized by presence of fever, rash, eosinophilia, autoantibodies (such as antinuclear and anti-smooth muscle antibodies) and Stevens-Johnson syndrome ²⁷. Non-immune mediated reactions lack the aforementioned characteristics and importantly, as described, tend to have a long latency period (1 month to 1 year) ²⁵, ²⁸. The incidence of idiosyncratic DILI is higher in women (59%) when compared to men which may be due to hormonal interactions with immunomodulating drugs or differing pharmacokinetics ²⁹.

Recently, a third type of DILI—indirect DILI—has been described as a liver injury caused by the mechanism of action of the drug (what it does; i.e., rituximab by depletion of B cells reactivates silent hepatitis B virus which is responsible for the damage), in contrast to its idiosyncratic properties (what it is; i.e., the unexpected hepatotoxic reaction of amoxicillin-clavulanate) ³⁰.

Other forms of DILI include steatohepatitis (amiodarone, tamoxifen, methotrexate) ³¹, neoplasms (hepatic adenomas due to androgenic anabolic steroids) ³² and vascular (nodular regenerating hyperplasia due to azathioprine) ³³.

Figure 1. Drug‐induced liver injury (DILI) types

[Source ¹² ]

Table 1. Classification of drug‐induced liver injury (DILI) based on liver enzyme derangement

Phenotype	Case definition	Commonly implicated agents
Idiosyncratic	Hepatocellular: If ALT alone is elevated less than fivefold above ULN or R≥5. Cholestatic: ALP alone is elevated less than twofold above ULN or R≤2. Mixed: R>2 to<5 Chronic DILI: DILI with acute presentation, with evidence of persistent liver injury at >1 year after its onset	Antimicrobials, anticonvulsants, antiarrhythmic, androgens, oestrogens/progesterone, immunomodulatory and antineoplastic
Drug reaction with eosinophilia and systemic symptoms	Drug-related hypersensitivity with eosinophilia and systemic inflammation	Anticonvulsants, NRTIs
Drug-induced autoimmune hepatitis	Acute DILI with serological and/or histological features of AIH	NSAIDs, statins, minocycline and nitrofurantoin
Secondary sclerosing cholangitis	Presenting as acute DILI with histological/radiological features of sclerosing cholangiopathy	Inhalational anaesthetics, atorvastatin, 6-MP
Granulomatous hepatitis	Granulomas on histology with exposure to implicated agent(s)	Anticonvulsants, sulphonamides
Acute fatty liver	Acute development of microvesicular steatohepatitis	Reverse transcriptase inhibitors
Drug-associated fatty liver disease	Consistent with NAFLD and attributable exposure	Methotrexate, corticosteroids, 5-FU
Nodular regenerative hyperplasia	Diffuse nodularity organised around central hepatocytes	Antineoplastic/cytotoxic
Ductopaenia	Chronic cholestasis and ductular loss	Antimicrobials (β-lactams, tetracyclines and sulphonamides)
Liver tumors	Features of hepatocellular adenoma or carcinoma dependent of histological/imaging characteristics	Anabolic androgenic steroids and oral contraceptives

Abbreviations: 5-FU = 5-fluorouracil; 6-MP = 6-mercaptopurine; AIH = autoimmune hepatitis; ALP = alkaline phosphatase; ALT = alanine transferase; DILI = drug-induced liver injury; NAFLD = non-alcoholic fatty liver disease; NRTI = nucleoside reverse transcriptase inhibitor; NSAID = non-steroidal antiinflammatory drug; ULN = upper limit of normal.

[Source ³⁴ ]

Table 2. Drug‐induced liver injury (DILI) severity classifications

Category	Severity	Description
US Drug-Induced Liver Injury Network 35
1	Mild	Elevated ALT and/or ALP but total bilirubin <2.5 mg/dl and INR <1.5
2	Moderate	Elevated ALT and/or ALP and total bilirubin ≥2.5 mg/dl or INR ≥1.5
3	Moderate-severe	Elevated ALT, ALP, total bilirubin and/or INR and hospitalization or ongoing hospitalization prolonged due to DILI
4	Severe	Elevated ALT and/or ALP and total bilirubin ≥2.5 mg/dl and at least 1 of the following criteria: – Hepatic failure (INR >1.5, ascites or encephalopathy) – Other organ failure due to DILI
5	Fatal	Death or liver transplantation due to DILI
International DILI Expert Working Group 36
1	Mild	ALT ≥5 or ALP ≥2 and total bilirubin <2 × upper limit of normal (ULN)
2	Moderate	ALT ≥5 or ALP ≥2 and total bilirubin ≥2 × upper limit of normal (ULN), or symptomatic hepatitis
3	Severe	ALT ≥5 or ALP ≥2 and total bilirubin ≥2 × upper limit of normal (ULN), or symptomatic hepatitis and 1 of the following criteria: – INR ≥1.5 – Ascites and/or encephalopathy, disease duration <26 weeks, and absence of underlying cirrhosis – Other organ failure due to DILI
4	Fatal/transplantation	Death or liver transplantation due to DILI

Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; INR = international normalized ratio

[Source ³⁷ ]

Symptoms of drug induced liver injury (DILI) may vary, ranging from asymptomatic elevations of liver enzymes to severe hepatitis with jaundice, fever, nausea, vomiting, dark urine and itching and only a small fraction of patients develop chronic liver disease (defined as abnormal liver tests for longer than 6 months) ¹². Drug-induced liver injury is responsible for 3 to 5% of hospital admissions for jaundice ³⁸ and is the most frequent cause of acute liver failure in most Western countries, accounting for more than half of cases ³⁹, ⁴⁰. More than 90% of patients with jaundice recover after discontinuation of the drug, and about 10% of patients with severe DILI with jaundice will either die or need liver transplantation ⁴¹. Hy’s Law is based on clinical observations made by the late Hyman Zimmerman that DILI patients with hepatocellular type of liver injury and jaundice have a 10% to 50% higher risk of mortality or need for liver transplantation ⁴². Hy’s Law has since been defined more specifically as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x upper limit of normal (ULN) and total bilirubin > 2 x upper limit of normal (ULN) in the absence of alkaline phosphatase (ALP) elevations and alternative reasons for alanine aminotransferase (ALT) and total bilirubin elevations, and is endorsed by the American Food and Drug Administration as criteria for severe DILI ⁴³.

In fact, up to 10% of patients with drug-induced jaundice fulfilling “Hy’s Law” criteria will go into acute liver failure ⁴². Some of these patients will require a liver transplantation or ultimately died, and others will develop chronic DILI (defined as abnormal liver tests for longer than 6 months). In addition, recently it has been observed that both the extent of drug metabolism and the levels of total bilirubin and alkaline phosphatase (ALP) at DILI onset are associated with the time course for DILI ⁴⁴.

Biochemical signs of drug induced liver injury (DILI) mainly include increased levels of liver enzymes measured in blood, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and total bilirubin ³. Clinically, drug induced liver injury (DILI) is defined when one of the three following thresholds are met ³⁶, ⁴⁵:

1. ALT (alanine aminotransferase) or AST (aspartate aminotransferase) elevation ≥5 times the upper limit of normal (ULN);
2. ALP (alkaline phosphatase) ≥2 × upper limit of normal (ULN);
3. The combination of ALT or AST ≥3 × upper limit of normal (ULN) with simultaneous elevation of total bilirubin exceeding 2 × upper limit of normal (ULN).

Depending on the extent of increase in those enzymes and the “R-value” of ALT/ALP or AST/ALP activity at drug induced liver injury (DILI) presentation, drug induced liver injury (DILI) is roughly classified as hepatocellular when ALT or AST ≥5 × upper limit of normal (ULN) alone or when R-value is ≥5, cholestatic when ALP ≥2 × upper limit of normal (ULN) alone or if R-value is ≤ 2, and mixed if the ratio is 2–5 ³⁶, ⁴⁶. Age is a clear determinant of drug induced liver injury (DILI) phenotype, with older age more frequently showing the cholestatic phenotype across different drug induced liver injury (DILI) cohorts ⁴⁷.

The “R-value” is very useful and beneficial for distinguishing acute liver damage ⁴⁸. This value was formed by the Council for International Organizations of Medical Sciences (CIOMS) of the World Health Organization (WHO) for the differentiation of drug-induced types of acute liver injury ⁴⁹. The R-value is found by proportioning the ratio of the ALT and ALP values, which are measured in the patient, to the upper limit of normal (ULN). If the R-value is ≥5, it can be said that hepatocellular damage occurs. If the R-value is ≤ 2, sepsis, choledocholithiasis and heart failure ocur, and if the R-value is between 2-5, it can be interpreted as mixed type damage ⁵⁰, ⁵¹.

Early recognition of drug‐induced liver injury (DILI) is essential to minimizing injury ⁵². The first step is to discontinue the suspected drug. Specific therapy against acetaminophen-induced liver injury is limited to the use of N-acetyl-cysteine (NAC) in the early phases. In non-acetaminophen-induced acute liver failure, N-acetyl-cysteine (NAC) has been shown to be efficacious at improving overall survival, post-transplant survival, and survival without transplant while decreasing the overall length of hospital stays ⁵³. The other specific therapy that is available is L-carnitine for valproic acid overdose ²⁷.

No specific antidote is available for the vast majority of hepatotoxic agents. In general, corticosteroids have no definitive role in treatment. They may suppress the systemic features associated with hypersensitivity or allergic reactions. Corticosteroid therapy is usually used when the histological appearance of DILI resembles that of autoimmune hepatitis. For this reason, it has a limited role and usually does not change the course of recovery ⁵⁴. Management of protracted drug-induced cholestasis is similar to that for primary biliary cirrhosis. Cholestyramine (a bile acid resin) or antihistamines may be used for alleviation of pruritus ⁵⁵, ⁵⁴. Ursodeoxycholic acid may be used.

Hospital admission is required for patients with signs or symptoms of DILI progression or acute liver failure ⁵⁵. If acute liver failure is suspected, early liver transplant consideration is essential, because there is high mortality with acute liver failure ²⁷. An important additional aspect of management is reporting cases of DILI to regulatory bodies to evaluate if the suspected drug needs to be withdrawn from the market ⁵⁶.

Hy’s law

Hy’s law was developed from the clinical observations of Dr. Hyman Zimmerman is a sensitive and specific predictor of a drug’s potential to cause severe hepatotoxicity ⁵⁷, ⁵⁸, ⁵⁹. Dr. Hyman Zimmerman noted that among patients with DILI, the presence of hepatocellular injury and jaundice conferred a 10% or higher mortality rate from liver failure or the need for liver transplantation ⁵⁷, ⁵⁸, ⁵⁹. Dr. Robert Temple of the U.S. Food and Drug Administration (FDA) later specified formal biochemical criteria for Hy’s Law (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] levels ≥3 times upper limit of normal [ULN] plus a total bilirubin ≥2 times ULN) ⁶⁰, ⁵⁸. Hy’s Law criteria at DILI diagnosis had high specificity and negative predictive value, but low sensitivity and positive predictive value, for incident acute liver failure ⁶¹.

Hy’s law consists of 3 components:

1. A statistically significant higher incidence of 3-fold or greater elevations above upper limit of normal [ULN] of ALT or AST compared to (non-hepatotoxic) control or placebo
2. Individuals showing ALT or AST >3 × upper limit of normal [ULN], combined with elevation of serum total bilirubin >2 × upper limit of normal [ULN], without initial findings of cholestasis, indicated by elevated ALP
3. Absence of any alternative cause likely to explain the combination of increased ALT or AST and total bilirubin, such as viral hepatitis A, B, C, or E, pre-existing or acute liver disease, or another drug capable of causing the observed injury

Now used by the FDA, this ‘10% rule’ has been observed for many drugs and is used to predict the risk of hepatotoxicity of drugs ⁵⁸. If more than one patient meets the criteria for Hy’s law in a clinical trial the implicated drug is unlikely to be marketed as this is likely to lead a hepatotoxicity problem post‐marketing ⁵⁸. The validity of Hy’s law has been confirmed in several studies. Patients with hepatocellular type of jaundice were found to have the worst prognosis in two studies, with a fatality rate of 7‐13% ⁶², ⁴¹, whereas patients with cholestatic type were found to have highest fatality rate in the first report from the Drug Induced Liver Injury Network cohort of 14% ⁶³, which was higher than in the Swedish and the Spanish DILI cohorts with fatality rate of approximately 5‐8% ⁶², ⁴¹. However, jaundice induced by different drugs can have different prognosis. For example, in one study of patients with jaundice due to idiosyncratic DILI the mortality rate varied from 40% (6 of 15) for halothane to 0% for erythromycin (0 of 32) ⁴¹. Recently, researchers from the Spanish hepatotoxicity network have tried to optimize the definition of Hy’s law and to develop a model for predicting acute liver failure in patients with DILI ⁴². These researchers were able to develop a prognostic algorithm that was found be more reliable than Hy’s law, in particular in predicting who will not develop acute liver failure ⁴².

Liver anatomy

Your liver is essential to your life. You cannot live without your liver. Your liver is the largest internal organ in your body. Your liver is about the size of a football and weighs about 3 to 3.5 pounds (1.36–1.59kg). Your liver lies under your right ribs just beneath your right lung. Your liver has two lobes (sections). Your liver is made up mainly of liver cells called hepatocytes. It also has other types of cells, including cells that line its blood vessels and cells that line small tubes in the liver called bile ducts. The bile ducts carry bile from the liver to the gallbladder or directly to the intestines.

Your liver has many important functions:

• It breaks down and stores many of the nutrients absorbed from the intestine that your body needs to function. Some nutrients must be changed (metabolized) in the liver before they can be used for energy or to build and repair body tissues.
• It makes most of the clotting factors that keep you from bleeding too much when you are cut or injured.
• It delivers bile into the intestines to help absorb nutrients (especially fats).
• It breaks down alcohol, drugs, and toxic wastes in the blood, which then pass from the body through urine and stool.

Figure 2. Liver anatomy

Types of Drug-Induced Liver Injury

Drug‐induced liver injury (DILI) has been classically divided into two varieties based on the presumed mechanism of action of the chemical compound: intrinsic DILI and idiosyncratic DILI ¹⁸. The intrinsic DILI (or direct, predictable DILI) is dose‐related and occurs shortly after exposure (hours to days) in the majority of individuals exposed to the drug (which is toxic at a dose threshold level) ³. In contrast, the idiosyncratic DILI (unpredictable DILI) is multifactorial and unpredictable drug induced liver injury and does not correlate with the dose and usually occurs in less than 1 of every 1000 to 1 of every 10,000 exposed individuals ¹⁹ and with a longer latency period (from a few days to several months) ²¹, ²². Idiosyncratic DILI is further subdivided into two sub-categories: allergic (immune-mediated) and non-allergic (nonimmune-mediated) as presented in Figure 1 ²¹, ²³, ²⁴. If immune-mediated, the latency is shorter (1–6 weeks) compared with non-immune mediated reactions (1 month to 1 year) ²⁵. However, exceptions do occur with immune reactions appearing after a very long latency with drugs such as nitrofurantoin ²⁶ or even after drug cessation (eg sulfonamides, erythromycin and amoxicillin-clavulanate) ²⁵. Immune-mediated idiosyncratic reactions can be characterized by presence of fever, rash, eosinophilia, autoantibodies (such as antinuclear and anti-smooth muscle antibodies) and Stevens-Johnson syndrome ²⁷. Non-immune mediated reactions lack the aforementioned characteristics and importantly, as described, tend to have a long latency period (1 month to 1 year) ²⁵, ²⁸.

Recently, a third type of DILI—indirect DILI—has been described as a liver injury caused by the mechanism of action of the drug (what it does; i.e., rituximab by depletion of B cells reactivates silent hepatitis B virus which is responsible for the damage), in contrast to its idiosyncratic properties (what it is; i.e., the unexpected hepatotoxic reaction of amoxicillin-clavulanate) ³⁰.

Other forms of DILI include steatohepatitis (amiodarone, tamoxifen, methotrexate) ³¹, neoplasms (hepatic adenomas due to androgenic anabolic steroids) ³² and vascular (nodular regenerating hyperplasia due to azathioprine) ³³.

Idiosyncratic drug induced liver injury

Idiosyncratic DILI (unpredictable DILI) is multifactorial and unpredictable drug induced liver injury and does not correlate with the dose and usually occurs in less than 1 of every 1000 to 1 of every 100,000 exposed individuals ¹⁹, ²⁰ and with a longer latency period (from a few days to several months) ²¹, ²². Idiosyncratic DILI is further subdivided into two sub-categories: allergic (immune-mediated) and non-allergic (nonimmune-mediated) as presented in Figure 1 ²¹, ²³, ²⁴. If immune-mediated, the latency is shorter (1–6 weeks) compared with non-immune mediated reactions (1 month to 1 year) ²⁵. However, exceptions do occur with immune reactions appearing after a very long latency with drugs such as nitrofurantoin ²⁶ or even after drug cessation (eg sulfonamides, erythromycin and amoxicillin-clavulanate) ²⁵. Immune-mediated idiosyncratic reactions can be characterized by presence of fever, rash, eosinophilia, autoantibodies (such as antinuclear and anti-smooth muscle antibodies) and Stevens-Johnson syndrome ²⁷. Non-immune mediated reactions lack the aforementioned characteristics and importantly, as described, tend to have a long latency period (1 month to 1 year) ²⁵, ²⁸.

Idiosyncratic DILI cases are caused by ²⁰, ⁵⁶:

• Antibiotics (45.4%): amoxicillin-clavulanate (most common), sulfamethoxazole-trimethoprim, ciprofloxacin, isoniazid (INH)
• Nonsteroidal anti-inflammatory drugs (NSAIDs)
• Herbal and dietary supplements (16.1%): green tea extract, anabolic steroids, multi-ingredient nutritional supplements
• Cardiovascular drugs (10%): statins, amiodarone
• Central nervous system (CNS) agents: valproate, phenytoin
• Antineoplastic drugs: tyrosine kinase inhibitors, tumor necrosis factor inhibitors, alpha inhibitors, methotrexate

Idiosyncratic liver injury is categorized as hepatocellular, cholestatic, or both (mixed) on the basis of the “R-value” of ALT/ALP or AST/ALP, calculated by dividing the alanine aminotransferase level by the alkaline phosphatase level from the time of initial presentation, with both values expressed as multiples of the upper limit of the normal range ⁶⁴. Hepatocellular injury is defined as an R value of ALT/ALP or AST/ALP more than 5, cholestatic injury as a value of less than 2, and mixed injury as a value of 2 to 5.

Acute hepatocellular hepatitis is the most common manifestation of idiosyncratic liver injury ²⁰. The latency period generally ranges from 5 to 90 days. The symptoms and course resemble those of acute viral hepatitis, with prominent alanine aminotransferase elevations (increased by a factor of 5 to 50), whereas alkaline phosphatase levels are only modestly increased. Liver histologic studies show changes suggestive of acute viral hepatitis, the major disorder in the differential diagnosis, but eosinophils may be prominent. The rate of death from icteric hepatocellular injury due to medications is high, usually 10% or higher, a feature first stressed by the late Hyman J. Zimmerman, for which reason it is called Hy’s law ⁶⁵. A key feature of Hy’s law is jaundice with hepatocellular rather than cholestatic injury. Drug-induced idiosyncratic acute liver injury is an important cause of acute liver failure, accounting for 11 to 15% of cases in series from the United States and Europe ⁴⁰. Common causes of drug-induced idiosyncratic acute hepatocellular injury are isoniazid, nitrofurantoin, and diclofenac ²⁰, ⁶⁶, ⁶⁷.

Chronic hepatitis is an uncommon form of drug-induced liver injury; the chronicity occurs if the agent is continued and typically resolves slowly once the agent has been stopped. Many agents that cause acute hepatocellular injury can also cause a chronic hepatocellular pattern ⁶⁷. The injury arises after months or years of exposure. Autoantibodies are frequently present, and the differential diagnosis often focuses on ruling out spontaneous autoimmune hepatitis. Common causes of drug-induced, autoimmune-like chronic liver injury are nitrofurantoin, minocycline, hydralazine, methyldopa, statins, and fenofibrate ⁶⁶, ⁶⁷, ⁶⁸. Glucocorticoids, which are frequently used to manage chronic hepatitis (starting dose, 20 to 60 mg of prednisone or its equivalent daily), may alleviate symptoms and speed recovery, but the injury will often resolve without intervention. If prednisone is used, the dose and duration should be kept to a minimum. Monitoring for evidence of relapse should be performed for at least 6 months after the withdrawal of glucocorticoids. Ultimately, spontaneous autoimmune hepatitis is best ruled out by evidence of resolution of the liver injury after withdrawal of the medication and, if glucocorticoids are used, by the absence of relapse when they are discontinued ⁶⁹.

Cholestatic hepatitis is characterized by prominent symptoms of pruritus and jaundice accompanied by moderate-to-marked elevations in alkaline phosphatase levels. Drug-induced cholestatic liver injury is usually self-limited, and although often protracted, it ultimately resolves ⁷⁰. Liver histologic studies show bile duct injury and cholestasis in small bile canaliculi ⁷¹. Exceptions to the usual benign course occur when there is bile duct loss, which is associated with delayed resolution of jaundice and elevated enzyme levels ⁷². Some cases evolve into vanishing bile duct syndrome, with prolonged jaundice, liver failure, need for liver transplantation, or death. Common causes of drug-induced cholestatic hepatitis are amoxicillin–clavulanate, cephalosporins, terbinafine, azathioprine, and temozolomide ⁷³, ⁶⁸.

Drug-induced mixed hepatitis is caused by many agents, some of which also cause hepatocellular or cholestatic hepatitis ²⁰. The mixed forms of drug-induced liver injury tend to have the most benign outcomes, rarely leading to liver failure. Common causes of drug-induced mixed hepatitis include the fluoroquinolone and macrolide antibiotics, phenytoin, and sulfonamides ⁷⁴.

All forms of idiosyncratic drug-induced hepatitis can be accompanied by immunoallergic features, such as rash, fever, and eosinophilia — signs of drug hypersensitivity ²⁰. More extreme examples include drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, toxic epidermal necrolysis, and the Stevens–Johnson syndrome ⁷⁵. Prominent causes of idiosyncratic drug-induced hepatitis with immunoallergic features include allopurinol, carbamazepine, phenytoin, sulfonamides, and macrolide antibiotics ⁷⁵. Immunoallergic hepatitis is more common among black Americans than among non-Hispanic white Americans ⁷⁶.

Bland cholestasis represents a distinctive phenotype of drug-induced liver injury, characterized by marked and prolonged jaundice with pruritus. In women, bland cholestasis is typically caused by estrogens or oral contraceptives ⁷⁷ and in men it is typically caused by anabolic steroids, usually obtained illicitly for bodybuilding or improving athletic performance ⁷⁸. Jaundice and itchy skin arise within 30 to 90 days, and elevations in enzyme levels are minimal or modest, despite marked and prolonged jaundice ⁷⁹. Liver biopsy shows bland cholestasis with scant inflammation and hepatocellular necrosis. The cholestasis can be prolonged, but the injury is almost always self-limited and deaths are rare. The pathogenesis remains unclear.

Drug induced liver injury causes

More than 1100 drugs, herbal compounds, natural products, vitamins, minerals, dietary supplements, and recreational and illicit compounds have been reported to cause DILI (albeit, some only occasionally) ¹², ¹³, ¹⁴, ¹⁵. In addition to specific drug-related properties, there are important host predisposing factors including advancing age, sex, alcohol intake and underlying liver disease. Female sex appears to confer risk for drug‐induced liver injury (DILI) and have a higher risk of progression to acute liver failure ⁴⁵.

Acetaminophen (paracetamol) is one of the most studied drugs that cause intrinsic DILI (predictable DILI), while it is less often seen in aspirin, tetracycline, and vitamin A ²⁷. Acetaminophen (paracetamol) hepatotoxicity is dose-dependent and the hepatic injury occurs due to the activity of the toxic N-acetyl-p-benzoquinone Imine (NAPQI) metabolite, produced by the CYP2E1 pathway of acetaminophen metabolism ⁸⁰. Exposure of Reactive Oxygen Species (ROS) to organelles can lead to apoptosis and necrosis of hepatocytes ⁸⁰. Interestingly, a significant proportion of acetaminophen hepatotoxicity cases occurs unintentionally at doses slightly above the maximum recommended daily dose of 4 g, or even with repeated doses below this safety threshold ⁸¹. Supposedly, a number of factors including fasting, alcoholism, concomitant use of other drugs and coexisting diseases, can decrease the toxic acetaminophen threshold dose by activating the generation of reactive drug metabolites via CYP2E1 and/or by depleting the hepatic glutathione concentration, which is the main detoxification pathway for acetaminophen toxic intermediates.

Bromfenac, cyclophosphamide and methotrexate are also examples of drugs known for induction of dose-related hepatotoxicity (intrinsic DILI) ⁸⁰.

Data from prospective DILI registries suggest that antibiotics remain the most common cause of idiosyncratic DILI (unpredictable DILI) ²⁷. The American DILI Network reported antibiotics to be implicated in 45.4% of cases ²⁰. Other common drug classes reported by the American Drug Induced Liver Injury Network were herbal and dietary supplements (16.1% – a significant increase over the last 10 years), cardiovascular agents (9.8%), central nervous system agents (9.1%), anti-neoplastic agents (5.5%) and analgesics (3.7%)  ²⁰. Amoxicillin-clavulanate antibiotic is the most common individual drug implicated in DILI as confirmed by both European and American studies (Table 4) ²⁷. In some Asian countries, however, herbal and dietary supplements are implicated in more than 70% of all DILI ⁸².

The drugs most commonly implicated in acute liver failure include anti-tuberculosis therapies, herbal and dietary supplements, sulpha-containing drugs, nitrofurantoin, phenytoin, sodium valproate, flutamide and amoxicillin-clavulanate ⁴², ⁴⁰.

Novel causative potentiator of DILI is those related to the classes of novel immunomodulatory therapeutic classes ⁸³, ⁸⁴. These molecules are being increasingly used to treat cancer through restitution of strong humoral, antitumor immune response, thereby improving patient survival. The reduction in tumor tolerance induced by immune checkpoint inhibitors can lead to inflammatory side effects, and an increase in immune related adverse events, including hepatotoxicity. Risk factors include the type of check point inhibitor, higher dose, autoimmune predisposition, pre-existing liver disease and the use of combination agents ⁸³, ⁸⁴. Hepatotoxicity is heterogeneous ranging from mild transaminase derangement to pronounced acute hepatitis and fulminant liver failure.

Table 3. Drugs associated with intrinsic DILI and idiosyncratic DILI

Footnotes: HAART = highly active antiretroviral therapy; *Known examples; withdrawn or unapproved drugs not listed; **Mild ALT elevations without jaundice; §Both intrinsic and idiosyncratic.

[Source ⁴⁵ ]

Table 4. Common drugs implicated in idiosyncratic drug-induced liver injury according to studies from different countries

Iceland 19	American drug-induced liver injury network 20	Spanish registry 42	UK 5
Amoxicillin-clavulanate	Amoxicillin-clavulanate	Amoxicillin-clavulanate	Amoxicillin-clavulanate
Diclofenac	Isoniazid	Isoniazid	Diclofenac
Azathioprine	Nitrofurantoin	Combined anti-tuberculous therapy	Tricyclic antidepressants
Infliximab	Trimethoprim-sulfamethoxazole	Flutamide	Macrolides
Nitrofurantoin	Minocycline	Ibuprofen	Chlorpromazine

[Source ²⁷ ]

Risk factors for drug-induced liver injury

• Race. Some drugs appear to have different toxicities based on race. For example, blacks and Hispanics may be more susceptible to isoniazid (INH) toxicity. The rate of metabolism is under the control of P-450 enzymes and can vary from individual to individual ⁸⁵.
• Age. Apart from accidental exposure, hepatic drug reactions are rare in children. Older patients have an almost threefold increase in the incidence of DILI as shown in a study from Iceland ¹⁹. This was attributed to the increased prescription rate of drugs in older patients ¹⁹. Elderly persons are at increased risk of hepatic injury because of decreased clearance, drug-to-drug interactions, reduced hepatic blood flow, variation in drug binding, and lower hepatic volume. In addition, poor diet, infections, and multiple hospitalizations are important reasons for drug-induced hepatotoxicity ⁸⁶. In general, higher drug dose and longer duration of therapy have also been implicated in poorer outcomes ⁸⁷. In the Spanish Registry, 77% of patients with idiosyncratic DILI received medications with daily doses of ≥50 mg ⁸⁷. Ninety percent of patients with serious DILI needing a liver transplant and reported to the Swedish Adverse Drug Reactions Advisory Committee were consuming ≥50 mg/day of the drug ⁸⁸. A longer duration of drug therapy (135±31 days versus 53±3 days) has been associated with a higher liver-related morbidity and mortality ⁸⁹.
• Female Sex. Although the reasons are unknown, hepatic drug reactions are more common in females ⁸⁶. The American drug-induced liver injury network found a higher prevalence of DILI in women (59% female versus 41% male) ²⁰, although this was not corroborated by the Spanish DILI registry (49% female versus 51% male) ⁴². Potential reasons for increased female susceptibility to DILI include differences in various aspects of drug pharmacokinetics or pharmacodynamics; hormonal effects or interactions with immunomodulating agents or signaling molecules; and differences in the adverse response of the immune system to some drugs, reactive drug metabolites or drug-protein adducts ⁹⁰. It is consistently observed, however, that women tend to be younger and develop hepatocellular DILI whereas men tend to be older and develop cholestatic DILI ⁸⁷, ²⁰.
• Alcohol ingestion. Alcoholic persons are susceptible to drug toxicity because alcohol induces liver injury and cirrhotic changes that alter drug metabolism. Alcohol causes depletion of glutathione (hepatoprotective) stores that make the person more susceptible to toxicity by drugs.
• Liver disease. Preexisting liver disease has not been thought to make patients more susceptible to drug-induced liver injury, but it may be that a diminished liver reserve or the ability to recover could make the consequences of injury worse ⁹¹. Although the total cytochrome P-450 is reduced in chronic liver disease, some may be affected more than others. The modification of doses in persons with liver disease should be based on the knowledge of the specific enzyme involved in the metabolism. Patients with HIV infection who are co-infected with hepatitis B or C virus are at increased risk for hepatotoxic effects when treated with antiretroviral therapy. Similarly, patients with cirrhosis are at increased risk of decompensation by toxic drugs. In the American drug-induced liver injury network, 10% of patients with DILI had pre-existing liver disease, mostly due to hepatitis C and non-alcoholic fatty liver disease (NAFLD) ²⁰. This group was characterized by more severe liver injury and higher overall mortality (16% verus 5.2%) although they had similar liver-related mortality (57% versus 46%) ²⁰. The higher overall mortality in those with pre-existing liver disease may have been due to significantly higher prevalence of comorbidities, specifically diabetes mellitus (38% versus 23%) ²⁰. Additionally, alcohol excess and/or risk factors for NAFLD (non-alcoholic fatty liver disease) increase susceptibility to methotrexate toxicity by three- to fourfold ⁹². Furthermore, some studies have shown that patients with chronic hepatitis B or C could have a threefold increased risk of abnormal liver tests after receiving anti-tuberculosis treatment ⁹³. Nonetheless, the interpretation of liver injury in patients with chronic hepatitis B and C receiving anti-tuberculosis treatment remains complex. It could be due to anti-tuberculosis treatment-induced DILI, viral reactivation and/or immune reconstitution ⁹⁴.
• Genetic factors. Genetic factors also increase susceptibility to DILI. A unique gene encodes each P-450 protein. Genetic differences in the P-450 enzymes can result in abnormal reactions to drugs, including idiosyncratic reactions ⁹⁵. Debrisoquine is an antiarrhythmic drug that undergoes poor metabolism because of abnormal expression of P-450-II-D6. This can be identified by polymerase chain reaction amplification of mutant genes. This has led to the possibility of future detection of persons who can have abnormal reactions to a drug ⁹⁶. Another example is human leukocyte antigen (HLA) B*5701 that confers an eightyfold increased risk to flucloxacillin induced DILI, whereas the absence of this genotype has an 88% negative predictive value for flucloxacillin-related DILI ⁹⁷.
• Drug formulation. Long-acting drugs may cause more injury than shorter-acting drugs.
• Other comorbidities. Persons with AIDS, persons who are malnourished, and persons who are fasting may be susceptible to drug reactions because of low glutathione stores.
• Host factors. Factors that may enhance susceptibility to drugs, possibly inducing liver disease, are as follows:
  • Female – Halothane, nitrofurantoin, sulindac
  • Male – Amoxicillin-clavulanic acid (Augmentin)
  • Old age – Acetaminophen, halothane, isoniazid (INH), amoxicillin-clavulanic acid
  • Young age – Salicylates, valproic acid
  • Fasting or malnutrition – Acetaminophen
  • Large body mass index/obesity – Halothane
  • Diabetes mellitus – Methotrexate, niacin
  • Renal failure – Tetracycline, allopurinol
  • AIDS – Dapsone, trimethoprim-sulfamethoxazole
  • Hepatitis C – Ibuprofen, ritonavir, flutamide
  • Preexisting liver disease – Niacin, tetracycline, methotrexate

Pathophysiology and mechanisms of drug-induced liver injury

The pathogenesis of idiosyncratic DILI remains unknown but is most likely due to a complex interplay between drug (eg dose, duration of therapy, hepatic metabolism, lipophilicity) and host factors (eg age, gender, genetic polymorphisms) ²⁷. The drug may form a reactive metabolite that triggers DILI or may form covalent adducts with tissue proteins, eliciting an immune response and subsequent DILI ⁹⁸. The following are some of the mechanisms that have been described ⁹⁹:

• Disruption of the hepatocyte: Covalent binding of the drug to intracellular proteins can cause a decrease in ATP levels, leading to actin disruption. Disassembly of actin fibrils at the surface of the hepatocyte causes blebs and rupture of the membrane.
• Disruption of the transport proteins: Drugs that affect transport proteins at the canalicular membrane can interrupt bile flow. Loss of villous processes and interruption of transport pumps such as multidrug resistance–associated protein 3 prevent the excretion of bilirubin, causing cholestasis.
• Cytolytic T-cell activation: Covalent binding of a drug to the P-450 enzyme acts as an immunogen, activating T cells and cytokines and stimulating a multifaceted immune response.
• Apoptosis of hepatocytes: Activation of the apoptotic pathways by the tumor necrosis factor-alpha receptor of Fas may trigger the cascade of intercellular caspases, which results in programmed cell death.
• Mitochondrial disruption: Certain drugs inhibit mitochondrial function by a dual effect on both beta-oxidation energy production by inhibiting the synthesis of nicotinamide adenine dinucleotide and flavin adenine dinucleotide, resulting in decreased ATP production.
• Bile duct injury: Toxic metabolites excreted in bile may cause injury to the bile duct epithelium.

Drug toxicity mechanisms

The classic division of drug reactions is into at least two major groups, (1) drugs that directly affect the liver and (2) drugs that mediate an immune response, as follows ⁹⁹:

• Intrinsic or predictable drug reactions: Drugs that fall into this category cause reproducible injuries in animals, and the injury is dose related. The injury can be due to the drug itself or to a metabolite. Acetaminophen is a classic example of a known intrinsic or predictable hepatotoxin at supertherapeutic doses. Another classic example is carbon tetrachloride.
• Idiosyncratic drug reactions: Idiosyncratic drug reactions can be subdivided into those that are classified as hypersensitivity or immunoallergic and those that are metabolic-idiosyncratic. Regarding hypersensitivity reactions, phenytoin is a classic, if not common, cause of hypersensitivity reactions. The response is characterized by fever, rash, and eosinophilia and is an immune-related response with a typical short latency period of 1-4 weeks. A metabolic-idiosyncratic reaction occurs through an indirect metabolite of the offending drug. Unlike intrinsic hepatotoxins, the response rate is variable and can occur within a week or up to one year later. It occurs in a minority of patients taking the drug, and no clinical manifestations of hypersensitivity are noted. Isoniazid (INH) toxicity is considered to fall into this class. Not all drugs fall neatly into one of these categories, and overlapping mechanisms may occur with some drugs (eg, halothane).

Drug induced liver injury signs and symptoms

Symptoms of drug induced liver injury (DILI) may vary, ranging from asymptomatic elevations of liver enzymes to severe hepatitis with jaundice, fever, nausea, vomiting, dark urine and itching and only a small fraction of patients develop chronic liver disease ¹². More than 90% of patients with jaundice recover after discontinuation of the drug, and about 10% of patients with severe DILI with jaundice will either die or need liver transplantation ⁴¹. Hy’s Law states that hepatocellular drug-induced liver injury (DILI) with jaundice indicates a serious reaction, is used widely to determine risk for acute liver failure ⁴². In fact, up to 10% of patients with drug-induced jaundice fulfilling “Hy’s Law” criteria will go into acute liver failure ⁴². Some of these patients will require a liver transplantation or ultimately died, and others will develop chronic DILI. In addition, recently it has been observed that both the extent of drug metabolism and the levels of total bilirubin and alkaline phosphatase (ALP) at DILI onset are associated with the time course for DILI ⁴⁴.

Drug induced liver injury complications

There is a 17% risk of drug induced liver injury (DILI) progresing to chronic liver disease, mostly seen in patients with prolonged cholestatic injury such as vanishing duct syndrome ²⁰, ²⁷. Acute liver failure results more often from hepatocellular injury than cholestatic ¹⁰⁰.

Drug induced liver injury diagnosis

The diagnosis of drug-induced liver injury is particularly challenging, because the presentation is similar to many hepatobiliary disorders and is based largely on exclusion of other causes. Drug-induced liver injury (DILI) is complex, with no unifying criteria and a relatively high index of suspicion is necessary.

The timing of the onset of injury after the implicated agent has been started (latency), resolution after the agent is stopped (“dechallenge”), recurrence on re-exposure (rechallenge), knowledge of the agent’s potential for hepatotoxicity (likelihood), and clinical features (phenotype) are the major diagnostic elements ¹⁰¹. With few exceptions, there are no specific diagnostic markers for drug-induced liver injury, and special tests (liver biopsy, imaging, and testing for serologic markers) are helpful mostly in ruling out other causes of liver injury. The large number of agents that can cause liver injury highlights these challenges. LiverTox website on hepatotoxicity (https://www.ncbi.nlm.nih.gov/books/NBK547852), has descriptions of more than 1200 agents (prescription and over-the-counter medications, herbal products, nutritional supplements, metals, and toxins), along with their potential to cause liver injury. Among the 971 prescription drugs described, 447 (46%) have been implicated in causing liver injury in at least one published case report ¹⁰¹.

Investigations should be appropriate to the severity of the condition in a particular patient. They include:

Blood tests:

• coagulation studies, glucose, and potassium as soon as possible
• full blood count, group and save, bilirubin, albumin, AST, amylase
• hepatitis serology, paracetamol levels, serum copper and caeruloplasmin, plus 24 hour copper where appropriate

Radiology:

• Chest radiograph
• Ultrasound scan of liver and pancreas. Ultrasonography is effective to evaluate the gall bladder, bile ducts, and hepatic tumors.
• CT scanning can help detect focal hepatic lesions 1 cm or larger and some diffuse conditions. It can also be used to visualize adjacent structures in the abdomen.
  MRI provides excellent contrast resolution. It can be used to detect cysts, hemangiomas, and primary and secondary tumors. The portal vein, hepatic veins, and biliary tract can be visualized without contrast injections.

Others:

• blood cultures, even if the patient is afebrile
• arterial blood gases – a CNS induced respiratory alkalosis or metabolic acidosis may occur
• ECG
• A liver biopsy is not essential in every case, but a morphologic pattern consistent with the expected pattern provides supportive evidence and could exclude other causes of liver disease.

Patients with DILI should undergo testing for hepatotropic viruses including hepatitis A to E, particularly in those with acute hepatocellular injury ³⁴. For completeness an autoantibody screen (antinuclear antibody [ANA], anti-smooth muscle antibody [ASMA], M2-anti-mitochondrial antibody [AMA], liver microsomal antibody, immunoglobulins) should be undertaken. DILI assessment should also include coagulation profiles, as elevated prothrombin time ratio values may suggest impending acute liver failure and prompt referral to a liver transplant unit should be considered.

Abdominal ultrasound should be undertaken in all patients suspected of DILI to exclude any biliary, parenchymal or vasculopathy, additional imaging is dependent on the clinical context ³⁴.

Liver biopsy may be reasonable to consider in DILI, as histology may provide information pertaining to severity of liver injury and provide mechanistic insights by identifying specific patterns of injury. Liver biopsy is also warranted in those patients suspected of DILI when serology raises the possibility of autoimmune hepatitis ⁴⁵. Liver biopsy may also be considered in patients whereby suspected DILI progresses, or fails to resolve on withdrawal of the causal agent, since histology may provide prognostic information assisting clinical decision particularly regarding immunosuppression ¹⁰². There are characteristic histological patterns associated with individual check-point inhibitors including presence of ring granulomas and endotheliitis which may aid decision making around immunosuppression ⁴⁵. In select cases of DILI, human leucocyte antigen genotyping can be used, whereby genetic determination may aid diagnosis and management, particularly those with features compatible with autoimmune hepatitis.

DILI should be classified according to the dominant pattern of liver enzyme derangement; hepatocellular, cholestatic and mixed injury.

Biochemical signs of drug induced liver injury (DILI) mainly include increased levels of liver enzymes measured in blood, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and total bilirubin ³. Clinically, drug induced liver injury (DILI) is defined when one of the three following thresholds are met ³⁶, ⁴⁵:

1. ALT (alanine aminotransferase) or AST (aspartate aminotransferase) elevation ≥5 times the upper limit of normal (ULN);
2. ALP (alkaline phosphatase) ≥2 × upper limit of normal (ULN);
3. The combination of ALT or AST ≥3 × upper limit of normal (ULN) with simultaneous elevation of total bilirubin exceeding 2 × upper limit of normal (ULN).

Depending on the extent of increase in those enzymes and the “R-value” of ALT/ALP or AST/ALP activity at drug induced liver injury (DILI) presentation, drug induced liver injury (DILI) is roughly classified as hepatocellular when ALT or AST ≥5 × upper limit of normal (ULN) alone or when R-value is ≥5, cholestatic when ALP ≥2 × upper limit of normal (ULN) alone or if R-value is ≤ 2, and mixed if the ratio is 2–5 ³⁶, ⁴⁶. Age is a clear determinant of drug induced liver injury (DILI) phenotype, with older age more frequently showing the cholestatic phenotype across different drug induced liver injury (DILI) cohorts ⁴⁷.

Given the non-specific nature of traditionally employed liver enzyme measurements there is increasing interest in determining novel serum biomarkers. These markers include glutamate dehydrogenase, keratin 18, glutathione S-transferase, sorbitol dehydrogenase, bile acids, cytochrome P450 and osteopontin ³⁴. These markers may help to improve the specificity of DILI diagnosis, and aid prognostication. Presently, however, none are routinely employed, but represent exciting future avenues of research.

Rechallenging patients who had initial drug-related liver injury can lead to rapid, progressive liver insult often worse than previous with fulminant hepatic failure. A positive rechallenge is defined as an ALT>3 ULN and is the strongest proof of drug causality ¹⁰³. Some essential, irreplaceable medications may be used to rechallenge patients including; antituberculous and chemotherapy agents, however, this should only be considered with meticulous monitoring arrangements under specialist supervision.

Figure 3. Drug-induced liver injury (DILI) diagnostic algorithm

Footnote: Suggested approach to presentation of drug-induced liver injury (DILI).

Abbreviations: ANA, antinuclear antibody; BC, Budd-Chiari syndrome; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HEV, hepatitis E virus; HSV, hepes simplex virus; HCC, hepatocellular carcinoma; LKM, liver microsomal antibody; NRH, nodular regenerative hyperplasia; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis; PVT, portal vein thrombosis; SMA, smooth muscle antibody; USS, ultransound scan; VZV, varicella zoster virus.

[Source ⁴⁵ ]

Drug induced liver injury treatment

The principal treatment for drug-induced hepatotoxicity is the discontinuation of the likely causative agent ²⁹. In the majority of DILI, spontaneous recovery occurs, without any need for treatment or specific supportive measures. This aspect of spontaneous recovery following discontinuation of an offending substance forms an important criterion in the causality assessment of DILI.

N-acetyl-cysteine (NAC) is the treatment for intrinsic DILI (direct, predictable DILI) secondary to acetaminophen toxicity, as this promotes the regeneration of glutathione leading detoxification of the toxic metabolite ¹⁰⁴. In non-acetaminophen-induced acute liver failure, N-acetyl-cysteine (NAC) has been shown to be efficacious at improving overall survival, post-transplant survival, and survival without transplant while decreasing the overall length of hospital stays ⁵³.

The other specific therapy that is available is L-carnitine for valproic acid overdose ²⁷. Corticosteroid therapy is usually used when the histological appearance of DILI resembles that of autoimmune hepatitis. For this reason, it has a limited role and usually does not change the course of recovery ⁵⁴. Symptomatic therapies such as cholestyramine (a bile acid resin) for cholestatic DILI or antihistamines for pruritis can be used with some efficacy ⁵⁵, ⁵⁴. Hospital admission is required for patients with signs or symptoms of DILI progression or acute liver failure ⁵⁵. If acute liver failure is suspected, early liver transplant consideration is essential, because there is high mortality with acute liver failure ²⁷. An important additional aspect of management is reporting cases of DILI to regulatory bodies to evaluate if the suspected drug needs to be withdrawn from the market ⁵⁶.

Emergency liver transplantation has utility in the setting of drug-induced fulminant hepatic injury. The Model for End-Stage Liver Disease score can be used to evaluate short-term survival in an adult with end-stage liver disease. This can help stratify candidates for liver transplantation. The parameters used are serum creatinine, total bilirubin, international normalized ratio, and the cause of the cirrhosis. Another criterion commonly used for liver transplantation is the Kings College criteria.

Kings College criteria for liver transplantation in cases of acetaminophen toxicity are as follows:

• pH less than 7.3 (irrespective of grade of encephalopathy)
• Prothrombin time (PT) greater than 100 seconds or international normalized ratio greater than 7.7
• Serum creatinine level greater than 3.4 mg/dL in patients with grade III or IV encephalopathy
• Measurement of lactate levels at 4 and 12 hours also helps in early identification of patients who require liver transplantation.

Kings College criteria for liver transplantation in other cases of drug-induced liver failure (DILI) are as follows:

• Prothrombin time (PT) greater than 100 seconds (irrespective of grade of encephalopathy) or
• Any three of the following criteria:
  1. Age younger than 10 years or older than 40 years;
  2. Etiology of non-A/non-B hepatitis, halothane hepatitis, or idiosyncratic drug reactions;
  3. Duration of jaundice of more than 7 days before onset of encephalopathy;
  4. Prothrombin time (PT) greater than 50 seconds; (5) serum bilirubin level greater than 17 mg/dL

Drug induced liver injury prognosis

The prognosis of drug‐induced liver injury (DILI) is highly variable depending on the patient’s presentation, several host factors, stage of liver damage and the drug type ¹⁸. Some patients develop acute liver failure and may require liver transplantation, whereas others can develop chronic DILI. In general, most patients (90% of cases) make a full recovery after discontinuation of the offending drug ²⁹. Mortality risk can be predicted through “Hy’s law,” which include the following criteria that are associated with a poorer prognosis: ALT/AST more than 3 times upper limit of normal (ULN), total bilirubin up to 2 times upper limit of normal (ULN) in the absence of obstruction, and no other explanation of the mentioned laboratory values ⁵⁶. Individuals more than 65 years old had a higher incidence of Hy’s law; however, mortality does not differ ²⁰. Hepatocellular injury is more likely than cholestatic injury to have a 10% to 50% higher risk of mortality or to require a liver transplant ²⁷, ⁵⁶. In general, about 10% of patients progress to requiring liver transplantation. Following liver transplantation, survival is 66% ²⁷, ¹². In a prospective study conducted in the United States from 1998-2001, the overall survival rate of patients (including those who received a liver transplant) was 72%. The outcome of acute liver failure is determined by cause, the degree of hepatic encephalopathy present upon admission, and complications such as infections.

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