Drug Induced Liver Disease

Drug Induced Liver Disease (DILD) and Drug Induced Liver Injury (DILI) are often used synonymously. Drug toxicity is a common cause of liver injury. It accounts for approximately one-half of the cases of acute liver failure and mimics all forms of acute and chronic liver disease. During many analyses an estimated 1000 drugs have been implicated in causing liver disease.(1)

Jaundice is one of the delayed clinical signs of liver injury. Zimmerman observed that hepatocellular injury sufficient to impair bilirubin excretion was ominous and if accompanied by jaundice had a poor prognosis, with a 10 to 50 percent mortality from acute liver failure (in pre transplantation days). DILD is the most frequent single cause of safety-related drug marketing withdrawals for the past 50 years (2)

Aetiopathology

Hepatic arterioles, hepatic venuoles and bile duct form a triad that traverses the liver forming a vast network around which the hepatocytes are placed. DILI takes the form of hepatocellular disease, cholestasis with or without jaundice, or a mixed hepatocellular-cholestatic presentation. (3)

Table below lists out various forms of injury and the drugs responsible for the same (3)

Type of hepatic Injury	Causative agents
Acute hepatic necrosis	High doses of acetaminophen, aspirin, niacin, and intravenous amiodarone
Acute hepatitis	Isoniazid, ketoconazole and flutamide
Pure or bland cholestasis	Estrogenic and anabolic steroids
Cholestatic and mixed hepatitis	Phenytoin, sulfonamides, macrolide antibiotics and enalapril
Serum enzyme elevations without jaundice	Can occur in < 1 to 50 - 70% patients with almost any drug
Acute fatty liver with lactic acidosis	Fialuridine, zidovudine, didanosine and stavudine, and tetracycline IV
Nonalcoholic fatty liver	Methotrexate and tamoxifen
Chronic hepatitis (injury persisting for >6 months).	Often a slow resolution of a severe acute injury; OR medication possibly triggered a chronic liver disease
Sinusoidal obstruction syndrome	Busulfan (used for myeloablation)
Nodular regenerative hyperplasia	Azathioprine, thioguanine and oxaliplatin
Liver tumors and cancer	Hepatic adenomas (estrogen ) hepatic angiosarcoma (radiologic contrast agent thorotrast;) hepatocellular ca (androgens )
Immunoallergic hepatitis	sulfonamides, sulindac, phenytoin and ciprofloxacin.
Autoimmune hepatitis	Methyldopa, nitrofurantoin, minocycline
Acute liver failure	Diclofenac, isoniazid, troglitazone
Cirrhosis	Amiodarone, valproate and methotrexate.
Vanishing bile duct syndrome	The small intra- and interlobular bile ducts are injured and gradually lost, causing cholestasis and "ductopenia - amoxy-clav, NSAIDs, sulfonamides, anticonvulsants

Clinical features

DILI could be expected if one is using a known hepatotoxic drug like paracetamol. It will be dose related and present within a short time (hours to days) after exposure to drug. The hepatitis will be fulminant with possible necrosis.

Often hepatic adverse reactions are unexpected, occurring with almost any drug even at low doses and could be a delayed reaction (weeks or months post ingestion).There is an element of idiosyncracy in these reactions

It could be Immune mediated idiosyncrasy (Hypersensitivity), presenting as rash fever arthralgia eosinophilia (Phenytoin, Sulfonamides, Valproate have been implicated) or metabolic idiosyncrasy due to production of toxic metabolites directly affecting liver parenchyma. (INH, Ketoconazole, and Diclofenac have been named for such toxicity)

To diagnose DILI one will look for history of ingestion of a known hepatotoxic drug, the dose administered, duration of exposure and latency between exposure and presentation(temporal relationship). Clinical and laboratory signs of hepatitis with jaundice will help clinch the diagnosis provided other causes of liver disease like viral hepatitis B or C, alcoholic liver disease, non alcoholic fatty liver disease or metabolic disorders like haemochromatosis can be ruled out.

Further evidence is the positive dechallenge test; an improvement after discontinuing the drug. In case of hepatocellular injury there is a 50% reduction in hepatic –associated enzymes after 2 weeks of stopping therapy. These would return to normal by 4 weeks. In cholestatic injury the recovery period may be prolonged, upto a few months

Some examples of DILI

Minocycline: The current prescribing information for minocycline, under the head adverse reactions, states, hyperbilirubinemia, hepatic cholestasis, increases in liver enzymes, fatal hepatic failure, and jaundice. Hepatitis, including autoimmune hepatitis and liver failure have been reported.

Under the head precautions it states, should be used with caution in patients with hepatic dysfunction and in conjunction with other hepatotoxic drugs.

This prescribing information sheet is a result of a series of changes over a decade after launch when the product went on a journey from elevated liver enzymes to hepatitis to hyperbilirubinemia to cholestasis and jaundice to liver failure and death in certain cases. Since it was an effective antibiotic, the risk benefit was in its favor, but gave rise to changes in prescribing information. (4)

Amoxycillin: Fontana RJ (5), reported one case each of acute liver failure with Amoxycillin and Amoxycillin with Clavulanic acid in 2005. Literature states that estimated risk of hepatotoxicity increases from 3/100,000 prescriptions to 17 / 100,000 presumably due to the clavulanate component. A thorough search revealed six published articles describing 14 fatalities in patients receiving amoxicillin/clavulanate and none due to amoxicillin alone. Amoxicillin is from the penicillin class of drugs considered safe even during pregnancy. So the risk benefit is in favour of these drugs and they will escape with an addition to prescribing information. (5)

Metronidazole: In 2014, a 54 yr old male, after being treated for C difficile infection, presented 3 months later with clinical signs of hepatitis and increased enzymes. After ruling out other causes a clinical diagnosis of metronidazole related DILI was made. It was labeled as delayed immune-allergic hepatocellular liver injury masquerading as autoimmune hepatitis. Interesting to note that such effects have been noted after this useful drug has been on the market for more than 40 years.This will again find mention in the prescribing information since it is a very useful drug (6)

Zafirlucast: Since the drug was first marketed in1996, more than 100 cases of significant liver dysfunction have been reported worldwide, including 14 of liver failure. Astra Zeneca, warned health care professionals about this rare but potentially serious adverse event. Zafirlukast should not be prescribed to patients with hepatic dysfunction. Again a case of favourable risk benefit for this antiasthma drug. (7)

Why is prediction of DILI so difficult?

Incidence of DILI is rare, about 1 in 10,000 or more. So a normal phase III study with a few thousand cases cannot detect possibility of hepatic toxicity. Drugs that have shown severe DILI in humans have not shown clear hepatotoxicity in animals. Thus there is poor concordance between preclinical and clinical findings of liver toxicity.

Elevation of hepatic enzymes cannot be considered a marker of this possibility because many drugs like tacrine, statins, aspirin or heparin cause AST/ALT elevation > 3 ULN(upper limit of normal) without conferring risk on DILI .

A negative rechallenge also does not necessarily exclude culpability; this organ in most people can adapt to new drugs, and develop tolerance for them as in case of isoniazid. (2, 8)

Prediction of DILI potential of a drug

Often indications of possible liver injury are seen during clinical studies in stray cases in the form of raised liver enzymes or raised bilirubin. But it is difficult to come to a conclusion based on such isolated cases. After retrospectively analyzing many instances Hy came up with an algorithm that is as under.

Cases that indicate future DILI, or HY’s law cases have the following components

1. A higher incidence of 3-fold or greater elevations above the ULN of ALT or AST than the (nonhepatotoxic) control drug or placebo
   
2. Among trial subjects showing such AT elevations, one or more also show elevation of serum TBL(total bilirubin level) to >2xULN, without initial findings of cholestasis (elevated serum ALP)
   
3. No other reason can be found to explain the combination of increased AT and TBL, such as viral hepatitis A, B, or C; preexisting or acute liver disease; or another drug capable of causing the observed injury
   

Finding one Hy’s Law case in the clinical trial database is worrisome; finding two is considered highly predictive that the drug has the potential to cause severe DILI when given to a larger population.

Dilevalol showed 2 cases in 1000 exposures and post marketing studies revealed fatal liver injury Tasosartan showed only one case, hence a larger premarketing database was asked for. Drug was later abandoned (2)

Other Prediction methods – Microarray

The US Food and Drug Administration has supported a programme called MicroArray Quality Control Phase-II (MAQC-II). The purpose of the project is to identify genomic biomarkers for liver injury. Gene expression data was acquired from the blood of rats chemically stressed to identify gene and pathway-based indicators of liver necrosis. These represent biological mechanisms related to a severe immune response, induction of apoptosis, targeting of the mitochondria, and angiogenesis , the main pathways of liver necrosis. Using this system to assay peripheral blood for the identification of novel biomarkers of DILI may be a useful diagnostic test in the near future. (9)

Other Prediction methods – Cytochrome P450

Genotype panels are available to identify cyochrome P450 gene variations so as to detect fast, slow, rapid and ultrarapid metabolisers of various drugs. This helps adjust dosing and prevent side effects (10).

Other Prediction methods – Mechanism Based Integrated Systems

In EU, under the Innovative Medicines Initiative, many universities and pharma companies have collaborated to start the Mechanism-Based Integrated Systems for the Prediction of Drug-Induced Liver Injury (MIP DILI). Together, they will develop new tests that will help researchers detect potential liver toxicity issues much earlier in development.

The team will do an in depth study of the science behind DILI. They will focus on current and new laboratory systems including cultures of human cells in both one dimensional and three dimensional configuration. Induced pluripotent stem cells derived from individuals susceptible to DILI will be used in the modelling.(11)

Other Prediction methods – Translational Research

Translational research involves utilization of clinical data to address challenges in drug discovery. The rationale is that the side effects observed in clinical trial and PMS can be translated into a screening system for use in drug discovery

The group identified 13 types of liver injuries that give high prediction accuracy in isolating drugs responsible for liver injury. They then created an in silico model for each of these side effects purely based on the chemical structure. A DILI prediction system was then created combining all these models. The system showed >91% accuracy in predicting DILI (8).

 

Clinical Significance of DILI prediction

The most important outcome of research on DILI prediction will be the ability to incorporate checks and balances during clinical trials and product life cycle. During the early trials provision can be made for

• Frequent evaluation of hepatic parameters
• Interim analysis in case of double blind studies
• Composite evaluation of all data applying Hy’s law During the post marketing phase
• Additional phase IV studies could be planned
• Additional in vitro studies with advanced technologies could be conducted Followed by
• Maintanence of transparent and updated prescribing information
• Timely information to physicians and health authorities

References

1. Kalpowitz N. Drug Induced Liver Injury , CID.(2004)38:S44
   
2. FDA guidance for industry on DILI: premarketing Clinical Evaluation(2009)
   
3. http://livertox.nih.gov/drugliverinjury.html, download feb 2014
   
4. http://www.drugs.com/pro/minocycline.html downloaded Feb 2014
   
5. Fontana RJ, Digestive Diseases and Sciences,(2005) 50,1785
   
6. Kancheria D,Gastrointestinal Medicine (2013) Article ID 568193, download feb 2014
   
7. Eric Wooltorton. Asthma drug zafirlukast (Accolate): serious hepatic Events, CMAJ (2004) 170 :1668
   
8. Zhichao L, PLoS Computational Biology, (2011)7: e1002310
   
9. Huang J, The Pharmacogenomics Journal, (2010)10:267
   
10. www.iversongenetics.com downloaded jan2014
    
11. http://www.mip-dili.eu/#2 downloaded feb 2014

Dr. Vishwas Sovani (April 2014)