drug - induced liver injury ( dili ) is defined as a liver injury due to xenobiotics , herbs , or medications that leads to either liver dysfunction or abnormal liver serology , in the setting of no other identifiable cause . unlike idiosyncratic drug induced liver injury ( idili ) , dili seems to be dose - dependent , predictable , and reproducible .
dili has been associated with more than 1,000 medications and is the most common cause of acute liver failure in the united states , accounting for approximately 50% of fulminant cases.15,6 while retrospective studies have shown acetaminophen to be the most common cause of dili , studies in liver transplant patients have demonstrated antibiotics and immunosuppressive agents , such as tacrolimus and azathioprine , as the top causes.7,8 bjornsson et al . performed a prospective study and found that amoxicillin - clavulanate was the most commonly implicated antibiotic .
the incidence was approximately 19 cases per 100,000.9 in addition to the typical suspects stated above , herbal and dietary supplements have been a rising cause of dili , now accounting for up to 9% of all cases.10 in fact , one study based in china , which spanned eight years , found that nearly half of all cases were secondary to medicinal herbs.11 while dili is most commonly due to only one drug , a prospective study demonstrated that nearly 10% of cases were attributable to more than one medication.9 
  dili has several clinical manifestations ranging from asymptomatic elevations in liver enzymes to fulminant liver failure .
hepatic , or cytochrome p450 , metabolism of a drug has been strongly linked to dili , and one study demonstrated that those medications that rely on more than 50% hepatic metabolism have a greater risk for alanine transferase ( alt ) elevation , liver failure , and mortality.12 other proposed mechanisms for dili include autoimmunity and hypersensitivity.2,13 despite the possible mechanisms , treatment options all follow the same principles .
the most important , and first , step is early diagnosis followed by discontinuation of the offending agent.2 

the most common presenting symptom in most cases of dili is jaundice , although many cases are asymptomatic or have elevated enzymes incidentally detected.11 however , dili can present as cholestatic , hepatocellular , and mixed ; and proper diagnosis will direct the treatment of a particular case .
cholestatic liver injury is defined by predominant elevations of alkaline phosphatase ( alp ) , whereas hepatocellular liver injury is defined as predominant elevations of aspartate transferase ( ast ) and alt , and mixed has elevations in both alp and transaminases.14 it is important to note that alt is liver - specific , whereas elevations in ast may be associated with damage to skeletal or cardiac muscle or in conditions such as myocardial infarction and rhabdomyolysis .
hepatocellular injury remains the most common presentation and is correlated with a worse outcome.15,16 
 table 1 provides specific definitions for both cholestatic and hepatocellular injury , which may aid in the identification of the patient 's clinical diagnosis .
once liver injury has been established , the next step is to determine the underlying cause .
risk factors for dili have been difficult to determine with many studies because of conflicting results in regard to sex and age - related occurrences .
however , a recent study found that older age and female sex was associated with a cholestatic type injury , while younger age and male sex was associated with hepatocellular type injury .
genetic polymorphisms have been consistently found to be a risk factor for dili but are not typically tested for in patients prior to receiving a medication.17,18 finally , liver transplant patients where the reason for transplant was primary sclerosing cholangitis are at greater risk for developing dili.8 chronic liver disease is a risk factor but only for certain medications , including methotrexate , isoniazid , and hiv antiretroviral therapy.2 when diagnosing dili , several established criteria can be used , none of which is considered to be a gold standard .
hy 's law is specific but not sensitive , whereas the roussel uclaf causality assessment method ( rucam ) is more sensitive but more difficult to administer in its truest form as it is complicated and requires rechallenging patients once they have recovered.1921 one modification is the digestive disease week - japan ( ddw - j ) scale , which includes lymphocyte stimulation testing , although this test has not been validated.22 yet another modification is the clinical diagnostic scale ( cds ) or maria and victorino ( m&v ) scale , which is more simple to administer but less predictive in patients who have had a prolonged period of time between drug use and development of symptoms or in those patients who have developed chronic liver injury.23,24 when examining these scales , common features , which make them specific and sensitive tests , include temporal relationship , exclusion of other causes , and prior reports of hepatoxicity of the suspected medication . while specific criteria may be used , at a minimum the above three commonalities should be investigated . for reference ,
wang et al found in china that the majority of cases occurred between 5 and 90 days of the initiation of the drug.11 as an aid for the clinician , table 2 provides medications and their typical liver injury presentation .
once a specific drug has been identified as the cause of dili , it must be discontinued.2 following withdrawal of the suspected agent , therapy is largely supportive with a few notable exceptions for acetaminophen and amanita mushroom poisoning .
all patients ' laboratory values , including ast , alt , alp , bilirubin , and international normalized ratio ( inr ) and mental statuses should be monitored for changes .
it is important to note that measuring only ast and alt is insufficient when monitoring liver function in dili .
damage to hepatocytes causes elevation of ast and alt levels , and once sufficient damage has occurred , there are less hepatocytes and ast and alt levels begin to decrease.14 therefore , bilirubin and inr must also be monitored . with discontinuation of the drug ,
most cases resolve without further sequelae , with one prospective study reporting a median duration from diagnosis to normalization of laboratory values of 64 days.9 
  lee et al .
performed an eight year prospective , double - blind , placebo control trial of n - acetylcysteine ( nac ) for patients with acute liver failure not secondary to acetaminophen overdose .
while overall survival was similar in the populations ( 70% vs. 66% ) , transplant - free survival was significantly better for those who received nac ( 40% vs. 27%).25 at this time , nac therapy can and should be considered for patients who are presenting with acute liver failure . in addition , a small uncontrolled study performed by wree et al . compared steroid pulse therapy with steroid step down therapy , both in combination with ursodeoxycholic acid , in the treatment of drug - induced liver injury , including patients with hepatocellular and/or cholestatic injury .
both therapies demonstrated a decrease in time to normalization of bilirubin , ast , and alt values.26 however , since this was an uncontrolled study , it is uncertain if the observed improvement in their patient population actually reflected the natural history of dili .
treatment for acetaminophen toxicity largely consists of nac therapy . studies have conflicted between whether oral or intravenous ( iv ) therapy should be given .
yarema et al . compared iv to oral administration and found that hepatoxicity occurred less often in patients who received iv therapy within 12 hours of ingestion.27 however , a recent study performed using a simulation system demonstrated that for those patients presenting within 24 hours of acetaminophen ingestion , the oral protocol is superior to the 21-hour intravenous protocol in persevering hepatocytes .
these authors argued that yarema 's study contained two differing treatment groups.28 regardless , nac therapy should be started if there is an elevation in ast , a detectable acetaminophen level , or if the level is above the treatment line on the rumack - matthew nomogram.29 a computer simulation suggested that international normalized ratio ( inr ) did not undertreat patients but did lead to overtreatment , whereas treating until alt peaked did not undertreat and rarely overtreated patients.28 current recommendations are to treat according to the protocol and to recheck ast and the acetaminophen level . at this point , ast should be less than 100 iu / l and acetaminophen level should be less than 10 mcg / ml . if not , therapy should be continued using the normalization of inr as a marker of resolution.30 
  amanita mushroom ingestion can lead to liver injury via the amatoxin , which inhibits rna polymerase ii and leads to hepatocyte necrosis .
this is followed by symptomatic improvement but an elevation in ast and alt followed by the development of jaundice .
since the hepatic phase is preceded by a gastrointestinal phase where dehydration and metabolic derangements may have developed , it is important to treat any dehydration and electrolyte abnormalities.31 while it has no proven efficacy for long - term survival , repeated activated charcoal administration is often recommended , which will prevent reabsorption of the amatoxin . while amatoxin may cause metabolic acidosis on its own , activated charcoal , which contains propylene glycol , can also cause a high anion gap metabolic acidosis . while clinicians should be aware of this potential complication , it should not preclude treatment with activated charcoal.32 silibinin is universally accepted as a treatment modality for amatoxin poisoning because it inhibits the transfer of amanitin into hepatocytes .
it should be administered within 48 hours of mushroom ingestion . the current recommended dose is 20 to 50 mg / kg / day iv , which should be continued for 4896 hours .
the recommended dose is 1,000,000 iu / kg for first day and 500,000 iu / kg for next two days via continuous iv administration .
finally , if started early , the molecular adsorbent recirculating system may be considered as it does improve liver function , although no specific studies have been done with amanita mushroom poisoning.31 
  patients who present with fever , rash , and eosinophilia should be considered for a diagnosis of drug - induced autoimmune hepatitis .
if the dili is severe , corticosteroid therapy should be considered as studies have demonstrated normalization of biochemical tests within six months.33 
  finally , patients who present with a cholestatic picture may complain of intense pruritus .
treatment options for these patients include emollients , hydroxyzine , diphenhydramine , bile acid resins , and rifampicin.34 

extracorporeal systems have progressed through advances in genetically produced cell lines , stem cell - derived functional hepatocytes , immortalized human hepatocytes as well as improved techniques and methods for preserving the hepatocytes .
the system , composed of a hollow - fiber cartridge lined with porcine hepatocytes , was used in a multi - center trial showing survival benefit to those treated.35 advances in bioartificial livers continue with current trials being conducted by vital therapies and hepa wash gmbh ( clinicaltrials.gov ) .
these devices provide the potential for significant benefit to patients with dili , subacute fulminate failure , and fulminate failure ; and we are encouraged for the use of this technology in the future treatment of these patients .
the king 's college criteria have been developed for both paracetamol and non - paracetamol causes in order to determine when a patient should be initially referred for transplantation .
the criteria include a prothrombin time ( pt ) over 100 seconds or at least three of the following : pt over 50 seconds , bilirubin > 300 micromol / liter , age below 10 or over 40 , an interval between jaundice and encephalopathy greater than seven days , or drug toxicity.37 other criteria that may be used include clinchy 's criteria and escudie 's criteria . patients with fulminant liver failure , defined as the presentation of hepatic encephalopathy within eight weeks of the development of symptoms related to liver disease , should be referred for transplant . in the united states , according to united network for organ sharing ( unos ) , a status 1a listing may be obtained if the patient has a life expectancy of seven days or less , does not have a pre - existing liver disease , and is in the intensive care unit requiring either ventilator assistance or dialysis or with an inr greater than two.38 however , it is important to keep in mind the contraindications for transplant , which include significant comorbidities and active malignancy .
each patient should be considered on a case - by - case basis , and the guidelines should be consulted when considering a patient for transplant .
although it has a varied presentation and multiple possible drug causes , treatment for all cases requires discontinuation of the offending agent .
if a patient has ingested acetaminophen or amanita mushrooms , appropriate therapy should be administered .
all patients can now be considered for nac therapy and should be monitored for normalization of biochemical tests .
 drug - induced liver injury ( dili ) has been linked to more than 1,000 medications and remains the most common cause of acute liver failure in the united states . here , we review the most current literature regarding treatment and make recommendations for the management of this relatively common disease . 
 since treatment of dili remains largely elusive , recent studies have attempted to define new management strategies for these difficult patients . early diagnosis and withdrawal of the suspected medication 
 is the mainstay of treatment of dili . for acetaminophen and amanita mushroom poisoning , 
 there are specific therapies in use . 
 finally , there are other possible management modalities for dili , including corticosteroids and ursodeoxycholic acid . 
Introduction
Diagnosis
Specific treatment
Potential role for liver assist devices
Liver transplant referral considerations
Conclusions