Hepatotoxicity

{{Short description|Liver damage caused by a drug or chemical}} {{Infobox medical condition (new) | name = | synonyms = see below list | image = Drug-induced hepatitis low mag.jpg | alt = | caption = Drug-induced hepatitis with granulomata. Other causes were excluded with extensive investigations. Liver biopsy. H&E stain. | pronounce = | field = Gastroenterology, Toxicology | symptoms = | complications = Cirrhosis, liver failure | onset = | duration = | types = | causes = | risks = | diagnosis = | differential = | prevention = | treatment = | medication = | prognosis = | frequency = | deaths = }} {| class="infobox" style="font-size: 88%; text-align: center; width: 22em; line-height: 1.5em" ! Synonyms |- | Drug-induced liver injury (DILI) Toxin-induced hepatitis Drug-induced hepatitis Drug-induced hepatic necrosis Drug-induced hepatic fibrosis Drug-induced hepatic granuloma Toxic liver disease with hepatitis Toxic liver disease with cholestasis Toxic hepatitis Toxic liver disease Toxin-induced liver disease Drug-induced liver disease Drug-induced liver damage Hepatogenous poisoning |}

'''Hepatotoxicity''' refers to chemical-driven liver damage. '''Drug-induced liver injury''' (DILI) is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdrawn from the market after approval.

The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents when taken in overdoses (e.g. paracetamol, sometimes called acetaminophen), and sometimes even when introduced within therapeutic ranges (e.g. halothane), may injure the organ. Other chemical agents, such as those used in laboratories and industries, natural chemicals (e.g., alpha-amanitin), and herbal remedies (two prominent examples being kava, though the causal mechanism is unknown, and comfrey, through pyrrolizidine alkaloid content) can also induce hepatotoxicity. Chemicals that cause liver injury are called hepatotoxins.

More than 900 drugs have been implicated in causing liver injury<ref name="isbn0-8385-1551-7">{{cite book |vauthors = Friedman SE, Grendell JH, McQuaid KR |title=Current diagnosis & treatment in gastroenterology |publisher=Lang Medical Books/McGraw-Hill |location=New York |year=2003 |pages=[https://archive.org/details/isbn_9780838515518/page/664 664–679] |isbn=978-0-8385-1551-8 |url=https://archive.org/details/isbn_9780838515518/page/664 }}</ref> (see LiverTox, external link, below) and it is the most common reason for a drug to be withdrawn from the market. Hepatotoxicity and drug-induced liver injury also account for a substantial number of compound failures, highlighting the need for toxicity prediction models (e.g. DTI),<ref name="pmid30997019">{{cite journal | vauthors = Dixit VA | title = A simple model to solve a complex drug toxicity problem | journal = Toxicol Res | volume = 8 | issue = 2 | pages = 157–171 | date = March 2019 | pmid = 30997019 | pmc = 6417485 | doi = 10.1039/c8tx00261d }}</ref> and drug screening assays, such as stem cell-derived hepatocyte-like cells, that are capable of detecting toxicity early in the drug development process.<ref name="stem2012">{{cite journal |vauthors=Greenhough S, Hay DC |title=Stem Cell-Based Toxicity Screening: Recent Advances in Hepatocyte Generation |journal=Pharm Med |volume=26 |issue=2 |pages=85–89 |year=2012 |doi=10.1007/BF03256896|s2cid=15893493 }}</ref> Chemicals often cause subclinical injury to the liver, which manifests only as abnormal liver enzyme tests.

Drug-induced liver injury is responsible for 5% of all hospital admissions and 50% of all acute liver failures.<ref name="isbn1-56053-618-7">{{cite book |vauthors = McNally PF |title=GI/Liver Secrets: with STUDENT CONSULT Access |publisher=C.V. Mosby |location=Saint Louis |year= 2006|isbn=978-1-56053-618-5 }}</ref><ref name="pmid12484709">{{cite journal | vauthors = Ostapowicz G, Fontana RJ, Schiødt FV, Larson A, Davern TJ, Han SH, McCashland TM, Shakil AO, Hay JE, Hynan L, Crippin JS, Blei AT, Samuel G, Reisch J, Lee WM |display-authors = 6| title = Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States | journal = Ann Intern Med | volume = 137 | issue = 12 | pages = 947–54 | date = December 2002 | pmid = 12484709 | doi = 10.7326/0003-4819-137-12-200212170-00007 |s2cid=11390513 }}</ref>

== Causes == Adverse drug reactions are classified as type A (intrinsic or pharmacological) or type B (idiosyncratic).<ref>{{cite book |vauthors = Davies D |title=Textbook of adverse drug reactions |publisher=Oxford University Press |location=Oxford [Oxfordshire] |year=1985 |pages=[https://archive.org/details/textbookofadvers0003unse/page/18 18–45] |isbn=978-0-19-261479-7 |oclc=12558288 |url=https://archive.org/details/textbookofadvers0003unse/page/18 }}</ref> Type A drug reaction accounts for 80% of all toxicities.<ref name="pmid9554902">{{cite journal | vauthors = Pirmohamed M, Breckenridge AM, Kitteringham NR, Park BK | title = Adverse drug reactions | journal = BMJ | volume = 316 | issue = 7140 | pages = 1295–8 | date = April 1998 | pmid = 9554902 | pmc = 1113033 | doi = 10.1136/bmj.316.7140.1295 }}</ref>

Drugs or toxins that have a pharmacological (type A) hepatotoxicity are those that have ''predictable'' dose-response curves (higher concentrations cause more liver damage) and well characterized mechanisms of toxicity, such as directly damaging liver tissue or blocking a metabolic process. As in the case of paracetamol overdose, this type of injury occurs shortly after some threshold for toxicity is reached. Carbon tetrachloride is commonly used to induce acute type A liver injury in animal models.

Idiosyncratic (type B) injury occurs without warning, when agents cause ''non-predictable'' hepatotoxicity in susceptible individuals, which is not related to dose and has a variable latency period.<ref name="pmid352664">{{cite journal |vauthors = Zimmerman HJ |title=Drug-induced liver disease |journal=Drugs |volume=16 |issue=1 |pages=25–45 |year=1978 |pmid=352664|doi=10.2165/00003495-197816010-00002|s2cid=45207777 }}</ref> This type of injury does not have a clear dose-response nor temporal relationship, and most often does not have predictive models. Idiosyncratic hepatotoxicity has led to the withdrawal of several drugs from market even after rigorous clinical testing as part of the FDA approval process; Troglitazone (Rezulin)<ref name="pmid30997019"/><ref name="pmid21657230">{{cite journal | vauthors = Dixit VA, Bharatam PV | title = Toxic metabolite formation from Troglitazone (TGZ): new insights from a DFT study | journal = Chem Res Toxicol | volume = 24 | issue = 7 | pages = 1113–22 | date = July 2011 | pmid = 21657230 | doi = 10.1021/tx200110h }}</ref> and trovafloxacin (Trovan) are two prime examples of idiosyncratic hepatotoxins pulled from market.

The herb kava has caused a number of cases of idiosyncratic liver injury, ranging everywhere from asymptomatic to fatal.

Oral use of the antifungal ketoconazole has been associated with hepatic toxicity, including some fatalities;<ref>{{cite web|title=Ketoconazole Tablets|url=https://www.drugs.com/pro/ketoconazole-tablets.html}}</ref> however, such effects appear to be limited to doses taken over a period longer than 7 days.<ref name="pmid26829173">{{cite journal | vauthors = Banankhah PS, Garnick KA, Greenblatt DJ | title = Ketoconazole-Associated Liver Injury in Drug-Drug Interaction Studies in Healthy Volunteers | journal = J Clin Pharmacol | volume = 56 | issue = 10 | pages = 1196–202 | date = October 2016 | pmid = 26829173 | doi = 10.1002/jcph.711 | s2cid = 206060985 }}</ref>

===Paracetamol=== {{Main|Paracetamol poisoning}} thumb|Paracetomol (3D structure) overdose is the most common cause of drug-induced liver disease Paracetamol also known as acetaminophen, and by the brand names of Tylenol and Panadol, is usually well-tolerated in prescribed dose, but overdose is the most common cause of drug-induced liver disease and acute liver failure worldwide.<ref name="isbn0-443-06633-7"/> Damage to the liver is not due to the drug itself but to a toxic metabolite (''N''-acetyl-''p''-benzoquinone imine (NAPQI)) produced by cytochrome P-450 enzymes in the liver.<ref name="pmid15345657">{{cite journal | vauthors = Wallace JL | title = Acetaminophen hepatotoxicity: NO to the rescue | journal = Br J Pharmacol | volume = 143 | issue = 1 | pages = 1–2 | date = September 2004 | pmid = 15345657 | pmc = 1575258 | doi = 10.1038/sj.bjp.0705781 }}</ref> In normal circumstances, this metabolite is detoxified by conjugating with glutathione in phase 2 reaction. In an overdose, a large amount of NAPQI is generated, which overwhelms the detoxification process and leads to liver cell damage. Nitric oxide also plays a role in inducing toxicity.<ref name="pmid14625346">{{cite journal | vauthors = James LP, Mayeux PR, Hinson JA | title = Acetaminophen-induced hepatotoxicity | journal = Drug Metab Dispos | volume = 31 | issue = 12 | pages = 1499–506 | date = December 2003 | pmid = 14625346 | doi = 10.1124/dmd.31.12.1499 | s2cid = 1556558 }}</ref> The risk of liver injury is influenced by several factors including the dose ingested, concurrent alcohol or other drug intake, interval between ingestion and antidote, etc. The dose toxic to the liver is quite variable from person to person and is often thought to be lower in chronic alcoholics.<ref name="pmid12006215">{{cite journal |vauthors=Riordan SM, Williams R |title=Alcohol exposure and paracetamol-induced hepatotoxicity |journal=Addict Biol |volume=7 |issue=2 |pages=191–206 |year=2002 |pmid=12006215 |doi=10.1080/13556210220120424 |s2cid=370682 }}</ref><ref name="pmid10759684">{{cite journal | vauthors = Prescott LF | title = Paracetamol, alcohol and the liver | journal = Br J Clin Pharmacol | volume = 49 | issue = 4 | pages = 291–301 | date = April 2000 | pmid = 10759684 | pmc = 2014937 | doi = 10.1046/j.1365-2125.2000.00167.x }}</ref> Measurement of blood level is important in assessing prognosis, higher levels predicting a worse prognosis. Administration of Acetylcysteine, a precursor of glutathione, can limit the severity of the liver damage by capturing the toxic NAPQI. Those that develop acute liver failure can still recover spontaneously, but may require transplantation if poor prognostic signs such as encephalopathy or coagulopathy is present (see King's College Criteria).<ref name="pmid2490426">{{cite journal | vauthors = O'Grady JG, Alexander GJ, Hayllar KM, Williams R | title = Early indicators of prognosis in fulminant hepatic failure | journal=Gastroenterology | volume = 97 | issue = 2 | pages = 439–45 | date = August 1989 | pmid = 2490426 | doi = 10.1016/0016-5085(89)90081-4 }}</ref>

=== Nonsteroidal anti-inflammatory drugs === Although individual analgesics rarely induce liver damage due to their widespread use, NSAIDs have emerged as a major group of drugs exhibiting hepatotoxicity. Both dose-dependent and idiosyncratic reactions have been documented.<ref>{{cite journal |vauthors=Manov I, Motanis H, Frumin I, Iancu TC |title=Hepatotoxicity of anti-inflammatory and analgesic drugs: ultrastructural aspects |journal=Acta Pharmacol. Sin. |volume=27 |issue=3 |pages=259–72 |year=2006 |pmid=16490160|doi=10.1111/j.1745-7254.2006.00278.x|s2cid=26874901 |doi-access=free }}</ref> Aspirin and phenylbutazone are associated with intrinsic hepatotoxicity; idiosyncratic reaction has been associated with ibuprofen, sulindac, phenylbutazone, piroxicam, diclofenac and indomethacin.

=== Glucocorticoids === Glucocorticoids are so named due to their effect on the carbohydrate mechanism. They promote glycogen storage in the liver. An enlarged liver is a rare side-effect of long-term steroid use in children.<ref name="pmid3944744">{{cite journal |vauthors=Iancu TC, Shiloh H, Dembo L |title=Hepatomegaly following short-term high-dose steroid therapy |journal=J. Pediatr. Gastroenterol. Nutr. |volume=5 |issue=1 |pages=41–6 |year=1986 |pmid=3944744 |doi=10.1097/00005176-198601000-00008|s2cid=35749798 |doi-access=free }}</ref> The classical effect of prolonged use both in adult and paediatric population is steatosis.<ref> {{cite book| vauthors = Alpers DH, Sabesin SM|veditors = Schiff L, Schiff ER| title =Diseases of the liver | publisher =JB Lippincott | year =1982 | location =Philadelphia | pages =813–45 }}</ref>

=== Isoniazid === Isoniazide (INH) is one of the most commonly used drugs for tuberculosis; it is associated with mild elevation of liver enzymes in up to 20% of patients and severe hepatotoxicity in 1-2% of patients.<ref name="pmid10215642">{{cite journal |vauthors=Sarich TC, Adams SP, Petricca G, Wright JM |title=Inhibition of isoniazid-induced hepatotoxicity in rabbits by pretreatment with an amidase inhibitor |journal=J. Pharmacol. Exp. Ther. |volume=289 |issue=2 |pages=695–702 |year=1999 |doi=10.1016/S0022-3565(24)38190-X |pmid=10215642 }}</ref>

=== Other hydrazine derivative drugs === There are also cases where other hydrazine derivative drugs, such as the MAOI antidepressant iproniazid, are associated with liver damage.<ref name="pmid4026902">{{cite journal | vauthors = Schläppi B | title = The lack of hepatotoxicity in the rat with the new and reversible MAO-A inhibitor moclobemide in contrast to iproniazid | journal = Arzneimittelforschung | volume = 35 | issue = 5 | pages = 800–3 | date = 1985 | pmid = 4026902 }}</ref><ref name="pmid14238042">{{cite journal | vauthors = Cook GC, Sherlock S | title = Jaundice And Its Relation To Therapeutic Agents | journal = Lancet | volume = 1 | issue = 7378 | pages = 175–9 | date = January 1965 | pmid = 14238042 | doi = 10.1016/s0140-6736(65)90969-4 }}</ref> Phenelzine has been associated with abnormal liver tests.<ref name="pmid14411298">{{cite journal | vauthors = Kothari UC | title = Toxic and other side effects of nardil phenelzine sulphate W-1544A | journal = Am J Psychiatry | volume = 116 | issue = 8| pages = 746–7 | date = February 1960 | pmid = 14411298 | doi = 10.1176/ajp.116.8.746 }}</ref> Toxic effects can develop from antibiotics, such as amoxicillin/clavulanic acid.<ref>{{cite journal |last1=Das |first1=J.A. |last2=Azad |first2=S. |last3=Kapp |first3=M.E. |last4=Liu |first4=W. |last5=Nguyen |first5=V. |url=https://link.springer.com/article/10.1007/s42399-025-01814-6|title=Utility of Tissue Biopsy in Amoxicillin-Clavulanate-Induced Concomitant Hepatic Failure and Renal Failure |journal=SN Comprehensive Clinical Medicine |date=4 March 2025 |volume=7 |issue=54 |doi=10.1007/s42399-025-01814-6 |access-date=4 March 2025 |publisher=Springer Nature|url-access=subscription }}</ref><ref name = Davisnorflox>{{cite web| url = http://davisplus.fadavis.com/3976/meddeck/pdf/norfloxacin.pdf| access-date = March 24, 2017| publisher = Davis| title = Amoxicillin| date = 2017| archive-date = October 27, 2017| archive-url = https://web.archive.org/web/20171027125502/https://davisplus.fadavis.com/3976/meddeck/pdf/norfloxacin.pdf| url-status = dead}}</ref>

=== Natural products === [[File:Akee.jpg|thumb|Ackee fruit]] Examples include alpha-Amanitin containing mushrooms, kava, and aflatoxin producing molds. Pyrrolizidine alkaloids, which occur in some plants, can be toxic.<ref name=FDA>{{cite web|publisher=United States Food and Drug Administration|url=https://www.fda.gov/Food/FoodSafety/FoodborneIllness/FoodborneIllnessFoodbornePathogensNaturalToxins/BadBugBook/ucm071047.htm|archive-url=https://web.archive.org/web/20090611062245/http://www.fda.gov/Food/FoodSafety/FoodborneIllness/FoodborneIllnessFoodbornePathogensNaturalToxins/BadBugBook/ucm071047.htm|url-status=dead|archive-date=June 11, 2009|work=Bad Bug Book|title=Foodborne Pathogenic Microorganisms and Natural Toxins Handbook: Pyrrolizidine Alkaloids |access-date=2009-07-11 }}</ref><ref name="pmid13642195">{{cite journal | vauthors = Schoental R | title = Liver lesions in young rats suckled by mothers treated with the pyrrolizidine (Senecio) alkaloids, lasiocarpine and retrorsine | journal = J Pathol Bacteriol | volume = 77 | issue = 2 | pages = 485–95 | date = April 1959 | pmid = 13642195 | doi = 10.1002/path.1700770220 }}</ref> Green tea extract is a growing cause of liver failure due to its inclusion in more products.<ref>{{cite book | url=https://livertox.nih.gov/GreenTea.htm | archive-url=https://web.archive.org/web/20130218110719/http://www.livertox.nih.gov/GreenTea.htm | url-status=dead | archive-date=February 18, 2013 | title=GreenTea| year=2012| publisher=National Institute of Diabetes and Digestive and Kidney Diseases| pmid=31643176}}</ref><ref>{{cite web | url=https://www.consumerreports.org/health/liver-damage-from-supplements-is-on-the-rise/ | title=Liver Damage from Supplements is on the Rise| date=19 May 2017}}</ref><ref name="pmid24935270">{{cite journal | vauthors = Chalasani NP, Hayashi PH, Bonkovsky HL, Navarro VJ, Lee WM, Fontana RJ | title = ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury | journal = Am J Gastroenterol | volume = 109 | issue = 7 | pages = 950–66; quiz 967 | date = July 2014 | pmid = 24935270 | doi = 10.1038/ajg.2014.131|s2cid = 2417493 | doi-access = free }}</ref>

===Alternative remedies=== Examples include: Ackee fruit, Bajiaolian, Camphor, Copaltra, Cycasin, Garcinia,<ref name="pmid23922466">{{cite journal | vauthors = Kim YJ, Choi MS, Park YB, Kim SR, Lee MK, Jung UJ | title = Garcinia Cambogia attenuates diet-induced adiposity but exacerbates hepatic collagen accumulation and inflammation | journal = World J Gastroenterol | volume = 19 | issue = 29 | pages = 4689–701 | date = August 2013 | pmid = 23922466 | pmc = 3732841 | doi = 10.3748/wjg.v19.i29.4689 | doi-access = free }}</ref> Kava leaves, pyrrolizidine alkaloids, Horse chestnut leaves, Valerian, Comfrey.<ref name="pmid20696856">{{cite journal | vauthors = Zhou P, Gross S, Liu JH, Yu BY, Feng LL, Nolta J, Sharma V, Piwnica-Worms D, Qiu SX | title = Flavokawain B, the hepatotoxic constituent from kava root, induces GSH-sensitive oxidative stress through modulation of IKK/NF-kappaB and MAPK signaling pathways | journal = FASEB J | volume = 24 | issue = 12 | pages = 4722–32 | date = December 2010 | pmid = 20696856 | pmc = 2992378 | doi = 10.1096/fj.10-163311 | doi-access = free }}</ref><ref name="pmid15264453">{{cite journal | vauthors = Pak E, Esrason KT, Wu VH | title = Hepatotoxicity of herbal remedies: an emerging dilemma | journal = Prog Transplant | volume = 14 | issue = 2 | pages = 91–6 | date = June 2004 | pmid = 15264453 | doi = 10.1177/152692480401400203 | s2cid = 208042609 }}</ref> Chinese herbal remedies: Jin Bu Huan, Ephedra, Shou Wu Pian, Bai Xian Pi.<ref name="pmid11984156">{{cite journal | vauthors = McRae CA, Agarwal K, Mutimer D, Bassendine MF | title = Hepatitis associated with Chinese herbs | journal = Eur J Gastroenterol Hepatol | volume = 14 | issue = 5 | pages = 559–62 | date = May 2002 | pmid = 11984156 | doi = 10.1097/00042737-200205000-00015 }}</ref><ref name="pmid20686286">{{cite journal | vauthors = Furukawa M, Kasajima S, Nakamura Y, Shouzushima M, Nagatani N, Takinishi A, Taguchi A, Fujita M, Niimi A, Misaka R, Nagahara H |display-authors = 6| title = Toxic hepatitis induced by show-wu-pian, a Chinese herbal preparation | journal = Intern Med | volume = 49 | issue = 15 | pages = 1537–40 | date = 2010 | pmid = 20686286 | doi = 10.2169/internalmedicine.49.3509 | doi-access = free }}</ref>

=== Industrial toxin === Examples include arsenic, carbon tetrachloride, and vinyl chloride.<ref>{{cite journal |vauthors = Kumar EP, Kumar A, Parasuraman S, Rajan VR, Emerson SF |title=Hepatoprotective activity of Clearliv a polyherbal formulation in Wistar rats |journal=Archives of Medicine and Health Sciences |volume=1 |issue=2 |year=2013 |pages=120–5 |doi=10.4103/2321-4848.123023|s2cid=98429527 |doi-access=free }}</ref>

== Mechanism == {| style="background:#E0FFFF;float:right;padding:0.3em; float:right; font-size: 80%; margin-left:5px; border:1px solid #A3B1BF" !bgcolor="#B0C4DE"|Factors influencing drug-induced hepatotoxicity<ref name="isbn0-443-06633-7">{{cite book |vauthors = Keeffe EB, Friedman LM |title=Handbook of liver diseases |url=https://archive.org/details/handbookliverdis00mdla_151 |url-access=limited |publisher=Churchill Livingstone |location=Edinburgh |year=2004 |pages=[https://archive.org/details/handbookliverdis00mdla_151/page/n110 104]–123 |isbn=978-0-443-06633-7 }}</ref> |- | * Age * Ethnicity and race * Gender * Nutritional status * Underlying liver disease * Renal function * Pregnancy * Duration and dosage of drug * Enzyme induction * Drug-to-drug interaction |} Drugs continue to be taken off the market due to late discovery of hepatotoxicity. Due to its unique metabolism and close relationship with the gastrointestinal tract, the liver is susceptible to injury from drugs and other substances. 75% of blood coming to the liver arrives directly from gastrointestinal organs and the spleen via portal veins that bring drugs and xenobiotics in near-undiluted form. Several mechanisms are responsible for either inducing hepatic injury or worsening the damage process.

Many chemicals damage mitochondria, an intracellular organelle that produces energy. Its dysfunction releases excessive amount of oxidants that, in turn, injure hepatic cells. Activation of some enzymes in the cytochrome P-450 system such as CYP2E1 also lead to oxidative stress.<ref name="pmid11812920">{{cite journal |vauthors=Jaeschke H, Gores GJ, Cederbaum AI, Hinson JA, Pessayre D, Lemasters JJ |title=Mechanisms of hepatotoxicity |journal=Toxicol. Sci. |volume=65 |issue=2 |pages=166–76 |year=2002 |pmid=11812920|doi=10.1093/toxsci/65.2.166|doi-access= }}</ref> Injury to hepatocyte and bile duct cells lead to accumulation of bile acid inside the liver. This promotes further liver damage.<ref name="pmid9606808">{{cite journal |vauthors=Patel T, Roberts LR, Jones BA, Gores GJ |title=Dysregulation of apoptosis as a mechanism of liver disease: an overview |journal=Semin. Liver Dis. |volume=18 |issue=2 |pages=105–14 |year=1998 |pmid=9606808 |doi=10.1055/s-2007-1007147|s2cid=28395693 }}</ref> Non-parenchymal cells such as Kupffer cells, collagen-producing stellate cells, and leukocytes (i.e. neutrophil and monocyte) also have a role in the mechanism.

=== Drug metabolism in liver === thumb|Drug metabolism in liver: transferases are: glutathione, sulfate, acetate, glucoronic acid. P-450 is cytochrome P-450. Different pathways are shown for Drugs A, B and C. The human body subjects most, but not all, compounds to various chemical processes (i.e. metabolism) to make them suitable for elimination. This involves chemical transformations to (a) reduce fat solubility and (b) to change biological activity. Although almost all tissues in the body have some ability to metabolize chemicals, smooth endoplasmic reticulum in the liver is the principal "metabolic clearing house" for both endogenous chemicals (e.g., cholesterol, steroid hormones, fatty acids, proteins) and exogenous substances (e.g., drugs, alcohol).<ref>{{cite book |vauthors= Blumenthal D, Brunton L, Parker K, Lazo JS, Buxton I |title=Goodman and Gilman's Pharmacological Basis of Therapeutics Digital Edition |publisher=McGraw-Hill Professional |year= 2006|isbn=978-0-07-146804-6 }}</ref> The central role played by liver in the clearance and transformation of chemicals makes it susceptible to drug-induced injury.

Drug metabolism is usually divided into two phases: ''phase 1'' and ''phase 2''. Phase 1 reaction is generally speaking to prepare a drug for phase 2. However, many compounds can be metabolized by phase 2 directly or be excreted without any phase 2 reactions occurring. Phase 1 reaction involves oxidation, reduction, hydrolysis, hydration and many other rare chemical reactions. These processes tend to increase water solubility of the drug and can generate metabolites that are more chemically active and/or potentially toxic. Most of phase 2 reactions take place in cytosol and involve conjugation with endogenous compounds via transferase enzymes. Phase 1 are typically more suitable for elimination.

A group of enzymes located in the endoplasmic reticulum, known as cytochrome P-450, is the most important family of metabolizing enzymes in the liver. Cytochrome P-450 is not a single enzyme, but rather consists of a closely related family of 50 isoforms; six of them metabolize 90% of drugs.<ref name="isbn0-7487-6011-3">{{cite book |author1=Skett, Paul |author2=Gibson, G. Gordon |title=Introduction to drug metabolism |publisher=Nelson Thornes Publishers |location=Cheltenham, UK |year=2001 |isbn=978-0-7487-6011-4 }}</ref><ref name="pmid17708140">{{cite journal |vauthors=Lynch T, Price A |title=The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects |journal=American Family Physician |volume=76 |issue=3 |pages=391–6 |year=2007 |pmid=17708140 }}</ref> There is a tremendous diversity of individual P-450 gene products, and this heterogeneity allows the liver to perform oxidation on a vast array of chemicals (including most drugs) in phase 1. Three important characteristics of the P-450 system have roles in drug-induced toxicity:

:'''1. Genetic diversity:''' Each of the P-450 proteins is unique and accounts (to some extent) for the variation in drug metabolism between individuals. Genetic variations (polymorphism) in P-450 metabolism should be considered when patients exhibit unusual sensitivity or resistance to drug effects at normal doses. Such polymorphism is also responsible for variable drug response among patients of differing ethnic backgrounds.

:'''2. Change in enzyme activity:'''

{| style="padding:0.3em; float:right; margin-left:5px; font-size: 80%; border:1px solid #A3B1BF;background:#F0FFFF;"|+ ''Cytochrome P-450 enzyme induction and inhibition<ref name="pmid17708140"/><ref name="isbn1-58562-111-0">{{cite book |vauthors = Oesterheld JR, Cozza KL, Armstrong S |title=Concise Guide to Drug Interaction Principles for Medical Practice: Cytochrome P450s, Ugts, P-Glycoproteins |url=https://archive.org/details/conciseguidetodr0000cozz |url-access=registration |publisher=American Psychiatric Association |location=Washington, DC |year= 2003|pages=167–396 |isbn=978-1-58562-111-8 }}</ref><ref>{{cite web |url=http://medicine.iupui.edu/flockhart/table.htm |title=P450 Table |access-date=2007-09-29 |archive-date=2007-10-10 |archive-url=https://web.archive.org/web/20071010053126/http://medicine.iupui.edu/flockhart/table.htm |url-status=dead }}</ref>'' !bgcolor="#D3D3D3"|Potent inducers !! bgcolor="#D3D3D3"|Potent inhibitors !! bgcolor="#D3D3D3"|Substrates |- | Rifampicin, Carbamazepine, Phenobarbital, Phenytoin, St John's wort, || Amiodarone, Cimetidine, Ciprofloxacin, Fluconazole, Fluoxetine, Erythromycin, Isoniazid, Diltiazem ||Caffeine, Clozapine, Omeprazole, Losartan, Theophylline |} Many substances can influence the P-450 enzyme mechanism. Drugs interact with the enzyme family in several ways.<ref name="pmid9469685">{{cite journal | vauthors = Michalets EL | title = Update: clinically significant cytochrome P-450 drug interactions | journal = Pharmacotherapy | volume = 18 | issue = 1 | pages = 84–112 | date = 1998 | doi = 10.1002/j.1875-9114.1998.tb03830.x | pmid = 9469685 | s2cid=18552904 | doi-access = free }}</ref> Drugs that modify cytochrome P-450 enzyme are referred to as either inhibitors or inducers. Enzyme inhibitors block the metabolic activity of one or several P-450 enzymes. This effect usually occurs immediately. On the other hand, inducers increase P-450 activity by increasing enzyme production, or, in the case of CYP2E1, preventing degradation in the proteasome. There is usually a delay before enzyme activity increases.<ref name="pmid17708140"/>

:'''3. Competitive inhibition:''' Some drugs may share the same P-450 specificity and thus competitively block their biotransformation. This may lead to accumulation of drugs metabolized by the enzyme. This type of drug interaction may also reduce the rate of generation of toxic metabolites.

===Patterns of injury===

{| style="padding:0.3em; float:right; font-size: 80%; margin-left:5px; border:1px solid #A3B1BF;background:#E0FFFF;" |+ ''Patterns of drug-induced liver disease'' !bgcolor="#B0C4DE"|Type of injury: !! bgcolor="#B0C4DE"|Hepatocellular !! bgcolor="#B0C4DE"|Cholestatic!!bgcolor="#B0C4DE"|Mixed |- !ALT | ≥ Twofold rise|| Normal||≥ Twofold rise |- !ALP |Normal ||≥ Twofold rise||≥ Twofold rise |- !ALT: ALP ratio |High, ≥5|| Low, ≤2||2–5 |- !Examples<ref name="pmid16710915">{{cite journal |vauthors=Mumoli N, Cei M, Cosimi A |title=Drug-related hepatotoxicity |journal=N. Engl. J. Med. |volume=354 |issue=20 |pages=2191–3; author reply 2191–3 |year=2006 |pmid=16710915 |doi=10.1056/NEJMc060733}}</ref> |Acetaminophen Allopurinol Amiodarone HAART NSAID||Anabolic steroid Chlorpromazine Clopidogrel Erythromycin Hormonal contraception||Amitriptyline, Enalapril Carbamazepine Sulfonamide Phenytoin |} Chemicals produce a wide variety of clinical and pathological hepatic injury. Biochemical markers (e.g. alanine transferase, alkaline phosphatase and bilirubin) are often used to indicate liver damage. Liver injury is defined as a rise in either (a) ALT level more than three times of upper limit of normal (ULN), (b) ALP level more than twice ULN, or (c) total bilirubin level more than twice ULN when associated with increased ALT or ALP.<ref name="pmid16710915"/><ref name="pmid2254635">{{cite journal | vauthors = Bénichou C | title = Criteria of drug-induced liver disorders. Report of an international consensus meeting | journal = J Hepatol | volume = 11 | issue = 2 | pages = 272–6 | date = September 1990 | pmid = 2254635 | doi = 10.1016/0168-8278(90)90124-a }}</ref> Liver damage is further characterized into hepatocellular (predominantly initial Alanine transferase elevation) and cholestatic (initial alkaline phosphatase rise) types. However they are not mutually exclusive and mixed types of injuries are often encountered.

Specific histo-pathological patterns of liver injury from drug-induced damage are discussed below.

====Zonal necrosis====

This is the most common type of drug-induced liver cell necrosis where the injury is largely confined to a particular zone of the liver lobule. It may manifest as a very high level of ALT and severe disturbance of liver function leading to acute liver failure. :Causes include: :Paracetamol, carbon tetrachloride

====Hepatitis====

In this pattern, hepatocellular necrosis is associated with infiltration of inflammatory cells. There can be three types of drug-induced hepatitis. (A) viral hepatitis is the most common, where histological features are similar to acute viral hepatitis. (B) in focal or non-specific hepatitis, scattered foci of cell necrosis may accompany lymphocytic infiltration. (C) chronic hepatitis is very similar to autoimmune hepatitis clinically, serologically, and histologically. :Causes: :(a) Viral hepatitis: Halothane, isoniazid, phenytoin :(b) Focal hepatitis: Aspirin :(c) Chronic hepatitis: Methyldopa, diclofenac

====Cholestasis==== Liver injury leads to impairment of bile flow and cases are predominated by itching and jaundice. Histology may show inflammation (cholestatic hepatitis) or it can be bland (without any parenchymal inflammation). On rare occasions, it can produce features similar to primary biliary cirrhosis due to progressive destruction of small bile ducts (vanishing duct syndrome). :Causes: :(a) Bland: Oral contraceptive pills, anabolic steroid, androgens :(b) Inflammatory: Allopurinol, co-amoxiclav, carbamazepine :(c) Ductal: Chlorpromazine, flucloxacillin

====Steatosis==== Hepatotoxicity may manifest as triglyceride accumulation, which leads to either small-droplet (microvesicular) or large-droplet (macrovesicular) fatty liver. There is a separate type of steatosis by which phospholipid accumulation leads to a pattern similar to the diseases with inherited phospholipid metabolism defects (e.g., Tay–Sachs disease) :Causes: :(a) Microvesicular: Aspirin (Reye's syndrome), ketoprofen, tetracycline (especially if expired) :(b) Macrovesicular: Acetaminophen, methotrexate :(c) Phospholipidosis: Amiodarone, total parenteral nutrition :(d) Antiviral: nucleoside analogues :(e) Corticosteroid :(f) Hormonal: Tamoxifen

====Granuloma==== Drug-induced hepatic granulomas are usually associated with granulomas in other tissues and patients typically have features of systemic vasculitis and hypersensitivity. More than 50 drugs have been implicated. : Causes: :Allopurinol, phenytoin, isoniazid, quinine, penicillin, quinidine

====Vascular lesions==== These result from injury to the vascular endothelium. :Causes: :Venoocclusive disease: Chemotherapeutic agents, bush tea :Peliosis hepatis: Anabolic steroids :Hepatic vein thrombosis: Oral contraceptives

====Neoplasm==== Neoplasms have been described with prolonged exposure to some medications or toxins. Hepatocellular carcinoma, angiosarcoma, and liver adenomas are the ones usually reported. :Causes: :Vinyl chloride, combined oral contraceptive pill, anabolic steroid, arsenic, thorotrast

== Diagnosis == thumb|Algorithm for suspected drug-induced hepatic toxicity This remains a challenge in clinical practice due to a lack of reliable markers.<ref name="pmid17230599">{{cite journal |vauthors=Andrade RJ, Robles M, Fernández-Castañer A, López-Ortega S, López-Vega MC, Lucena MI |title=Assessment of drug-induced hepatotoxicity in clinical practice: a challenge for gastroenterologists |journal=World J. Gastroenterol. |volume=13 |issue=3 |pages=329–40 |year=2007 |pmid=17230599 |doi=10.3748/wjg.v13.i3.329|pmc=4065885 |doi-access=free }}</ref> Many other conditions lead to similar clinical as well as pathological pictures. To diagnose hepatotoxicity, a causal relationship between the use of the toxin or drug and subsequent liver damage has to be established, but might be difficult, especially when idiosyncratic reaction is suspected.<ref>{{cite journal |vauthors=Arundel C, Lewis JH |title=Drug-induced liver disease in 2006 |journal=Curr. Opin. Gastroenterol. |volume=23 |issue=3 |pages=244–54 |year=2007 |pmid=17414839 |doi=10.1097/MOG.0b013e3280b17dfb|s2cid=5842491 }}</ref> Simultaneous use of multiple drugs may add to the complexity. As in acetaminophen toxicity, well established, dose-dependent, pharmacological hepatotoxicity is easier to spot. Several clinical scales such as CIOMS/RUCAM scale and Maria and Victorino criteria have been proposed to establish causal relationship between offending drug and liver damage. CIOMS/RUCAM scale involves a scoring system that categorizes the suspicion into "definite or highly probable" (score > 8), "probable" (score 6–8), "possible" (score 3–5), "unlikely" (score 1–2) and "excluded" (score ≤ 0). In clinical practice, physicians put more emphasis on the presence or absence of similarity between the biochemical profile of the patient and known biochemical profile of the suspected toxicity (e.g., cholestatic damage in amoxycillin-clauvonic acid ).<ref name="pmid17230599"/>

== Treatment == In most cases, liver function will return to normal if the offending drug is stopped early. Additionally, the patient may require supportive treatment. In acetaminophen toxicity, however, the initial insult can be fatal. Fulminant hepatic failure from drug-induced hepatotoxicity may require liver transplantation. In the past, glucocorticoids in allergic features and ursodeoxycholic acid in cholestatic cases had been used, but there is no good evidence to support their effectiveness.{{citation needed|date=March 2022}}

==Prognosis==

An elevation in serum bilirubin level of more than 2 times ULN with associated transaminase rise indicates severe hepatotoxicity and is likely to lead to mortality in 10% to 15% of patients, especially if the offending drug is not stopped (Hy's Law).<ref name="pmid14768020">{{cite journal | vauthors = Reuben A | title = Hy's law | journal = Hepatology | volume = 39 | issue = 2 | pages = 574–8 | date = February 2004 | pmid = 14768020 | doi = 10.1002/hep.20081 | s2cid=5916660 |doi-access=free}}</ref><ref name="pmid16618822">{{cite journal |vauthors=Arora N, Goldhaber SZ |title=Anticoagulants and transaminase elevation |journal=Circulation |volume=113 |issue=15 |pages=e698–702 |year=2006 |pmid=16618822 |doi=10.1161/CIRCULATIONAHA.105.603100|s2cid=32207352 |doi-access=free }}</ref> This is because it requires significant damage to the liver to impair bilirubin excretion, hence minor impairment (in the absence of biliary obstruction or Gilbert syndrome) would not lead to jaundice. Other poor predictors of outcome are old age, female sex, high AST.<ref>{{cite journal |vauthors=Andrade RJ, Lucena MI, Kaplowitz N, etal |title=Outcome of acute idiosyncratic drug-induced liver injury: Long-term follow-up in a hepatotoxicity registry |journal=Hepatology |volume=44 |issue=6 |pages=1581–8 |year=2006 |pmid=17133470 |doi=10.1002/hep.21424|s2cid=9067701 |doi-access=free }}</ref><ref>{{cite journal |vauthors=Björnsson E, Olsson R |title=Outcome and prognostic markers in severe drug-induced liver disease |journal=Hepatology |volume=42 |issue=2 |pages=481–9 |year=2005 |pmid=16025496 |doi=10.1002/hep.20800|s2cid=2742529 |doi-access=free }}</ref>

== Drugs withdrawn == The following therapeutic drugs were withdrawn from the market primarily because of hepatotoxicity: Troglitazone, bromfenac, trovafloxacin, ebrotidine, nimesulide, nefazodone, ximelagatran and pemoline.<ref name="pmid17230599"/><ref name="pmid10687025">{{cite journal | vauthors = Shah RR | title = Drug-induced hepatotoxicity: pharmacokinetic perspectives and strategies for risk reduction | journal = Adverse Drug React Toxicol Rev | volume = 18 | issue = 4 | pages = 181–233 | date = November 1999 | pmid = 10687025 }}</ref><ref>{{EMedicine|article|169814|Drug-Induced Hepatotoxicity}}</ref>

==See also== * Hepatoprotection * Reye's syndrome

==References== {{Reflist}}

== External links == {{Medical resources | DiseasesDB = | ICD10 = {{ICD10|K71.0}} | ICD9 =  | ICDO = | OMIM = | MedlinePlus = | MeSH = | GeneReviewsNBK = | GeneReviewsName = }} * [https://web.archive.org/web/20120407000658/http://livertox.nih.gov/ LiverTox] at the United States National Library of Medicine

Category:Toxicology Category:Diseases of liver Category:Hepatology