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1. Introduction
1
2. Forms of liver injury
3. Causes of hepatotoxicty4. Example of drugs
5. Drug reaction
6. Drug metabolism in the liver
7. Mechanism of liver toxicity
8. Example:Acetaminophen9. Signs and symtoms10. Factors influencing hepatotoxicity11. Diagnosis
12. Treatment
13. Drug withdrawn from market
14. Conclusion

Introduction:
Hepatotoxicity is the medical term that is used to describe the effect of harmful or poisonous or toxic substances on the liver . Hepatotoxicity or liver damage causes the critical organ liver to under function or to function irregularly. When specific medicinal agents taken in overdose, certain chemical agents that are used in laboratories and Industries, natural chemicals as well as herbal remidies can cause hepatotoxicity and these type of chemicals are known as hepatotoxins(– UNM Comprehensive Cancer Center, 2018).

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Figure: Heptatoxicity(Medindia,2018).

Liver : An Introduction
Liver is the largest organ in the body which serves many vital functions and maintains body’s internal environment. The principal function of the liver are carbohydrate, protein and fat metabolism, detoxification, secretion of bile and storage of vitamins as well as liver is involved with most of the biochemical pathways to growth, energy provision and reproduction(Anon, 2018).

The major cells of liver :-
Hepatocytes (Parenchymal cell)
Endothelial cells
(Line sinusoids)
Stellate cells
Kupffer cells
(Anon, 2018).

Figure : Liver(HUMAN ANATOMY ORGAN, 2018).

If the liver is damaged, it may not be able to perform body’s function properly most importantly it may not be able to excrete bile by which liver disposes the waste products(– UNM Comprehensive Cancer Center, 2018).

Inflamed or damaged liver cells produce increased amount of liver enzyme into blood stream. These elevated liver enzymes are-
Alanine transaminaseAspartate transaminaseAspartate transaminaseAlkaline PhosphataseGamma-glutamyl transpeptidase(Mayo Clinic, 2018).

Forms of Liver injury:
1) Hepatic fibrosis and cirrhosis:
When excessive amount of fibrous tissue accumulate in the liver, then it is known as hepatic fibrosis (scaring). Drug causing submassive hepatocellular injury may be followed by fibrosis nodular regeneration and cirrhosis. Some agents cause an increase in collagen deposition. As a result blood flow through liver becomes obstructed which can lead to hypertension, internal hemorrhage.
Chemicals that cause hepatic fibrosis – Carbon tetra chloride, ethanol, trinitrotoluene.

Figure: Stages of liver damage (Columbiaasia.com, 2018).

Zonal Necrosis: It is the most common type of drug induced liver necrosis where the injury is largely confined to a particular zone of the liver lobule.

2) Hepatitis:
It is characterized by the inflammation of the liver chemicals anabolic steroid, danazol.

3) Steatosis:
it occurs by the accumulation of lipids in the liver due to some chemicals.Microvesicular steatosis is associated with alcohol, aspirin, amiodarone, valproic acid, didanosine, nevirapine and high doses of tetracycline. Macrovesicular steatosis is observed with alcohol, methotrexate, corticosteroids, nifedipine, parenteral nutrition and perhexilline maleate.

These chemicals can –
Inhibit lipoprotein synthesis.

Decrease conjugation of triglyceride with lipoproteins.

Interfere with very low density lipoprotein transfer.

Increase synthesis of fatty acid.

Impairs oxidation of lipid by mytochondria.

The excess fat accumulation in the liver is a risk factor for cirrhosis and liver cancer.

Cholestasis:
It occurs when bile can not flow from liver to the duodenum which means it refers to decreased bile flow and increased serum levels- bile salts and bilirubin. Chemicals include-chlorpromazine, ethanol, cyclosporin A, ampicillin, estrogen etc.

Neoplasm:
Tissue composed of cells which grow in an abnormal way is known as neoplasm or tumor. Various chemicals can induce liver tumors such as alcohol, tobacco, aflatoxins, thorium oxide.

Vascular lesions:
They result from injury to vascular endothelium. Drugs can cause injury to sinusoids, hepatic veins and arteries. Azathiprine, alcohol, floxuridine, excess vitamin A and dacarbazine may lead to vascular lesions.

Granulomatous hepatitis:
Granuloma is one of a number of forms of localized nodular inflammation which is found in tissue. Drugs include-sulfonamide, phenytoin, sulfonylurea, quinidine and hydralazine. Allopurinol can cause granulomas with a fibrin ring, gold salt may cause lipogranulomas with black pigment and carbamazepine is the most common cause of granulomatous hepatitis (Emedicine.medscape.com, 2018).

Causes of hepatotoxicity:
There are many causes for toxic liver damage.

They are-
Medications:
The most common cause of toxic liver disease is due to many over the counter (OTC) and prescription medications.

OTC pain relievers:
Acetaminophen
Non-steroidal anti-inflammatory drugs (NSAIDs)
If someone takes too much Aspirin, Ibuprofen or takes it with alcohol then it can cause hepatotoxicity.

Figure : Drug induced hepatotoxicity (Medindia, 2018).

Prescription drugs:
Antiobiotics such as amoxicillin-clavulanate or erythromycin.

Arthritis drugs like azathioprine or methotrexateAntifungal drugs
Niacin
StatinsAllopurinol for gout
Antiviral drugs for HIV infection
Chemotherapy: Chemotherapy or cancer treatment is another possible cause. These drugs creat toxicity to liver and can cause stress on the Liver.

Herbal supplements: Some common herbs can cause toxic liver disease such as Camphor, Comfrey, Cascara, Chaparral, Black cohosh, Pyrrolizidine alkaloids, Valerian etc.

Chemicals and Solvents: Chemicals that are used in industry can cause liver toxicity. Such as vinyl chloride that is used to make plastics, dry cleaning solution like Carbon tetrachloride, weed killer paraquat and polychlorinated biphenyls.

Uptake of toxic substances:
First pass effect:Rapid uptake of some chemicals by liver
Repeated accumulation
Bioactivation:Induction of cytochrome P450 isoenzymes can cause oxidant stress and cell injury.

Reactive intermediates:
Activation of sinusoidal cell, kupffer cell and stellate cell.

Immune/Inflammatory cell can migrate to injury site(Cold et al., 2018).

Drug induced hepatotoxicity :Example of drugs :1. Antibiotics:
Amoxicillin/ Clavulanate.

FluoroquinolonesTrimethoprim/sulfamethoxazoleMacrolidesMinocyclineNitrofurantoin.

Antiepileptics:
PhenytoinCarbamazepineLamotrigineValproateAntitubercular:
RefampicinIsoniazidNSAIDs:
Acetaminophen, Aspirin
Diclofenac, Ibuprofen, PhenylbutazoneHypolipidemic drugs:
StatinsNiacin
Anaesthetic agents:
Halothane
Chloroform
Isoflurane, Enflurane and Desflurane.

Antirheumatic drugs:
SulphasalazineAzathioprinMethotrexateAntiretroviral drugs:
Ritonavir, IndinavirTenofovir, Zidovudine, LamivudinNevirapine, Efavirenz(Emedicine.medscape.com, 2018).

Drug reaction:
Intrinsic drug reaction:
Intrinsic hepatotoxins are considered to be dose related and cause reproducible injuries in animals. The effect of these hepatotoxins is predictable. The drug itself or its reactive metabolite can cause the liver injury in overdose situations in normal recipients but they can also induce similar liver damage at lower doses in people who have genetic or acquired abnormalities in drug metabolism. By covalent binding to cellular macromolecules such as hydrogen peroxide, hydroxyl radicals or lipid peroxides- these hepatotoxins cause direct damage to liver. As a result, they interrupt cell membranes or inactivate critical cellular enzyme systems. Example- Carbon tetrachloride. Acetaminophen, Chloroform.

Figure: Graphical presentation of intrinsic and idiosyncratic drug reactions (Roth and Ganey, 2018).

Idiosyncratic drug reactions:
Idiosyncratic hepatotoxins are dose independent and hepatic injury can not be reproduced in animal models. They occur in very small proportion of exposed people and the effect of these hepatotoxins are unpredictable as well as unrelated to the drug’s therapeutic action or overdose toxicity.

Idiosyncratic drug reactions are divided into :1) hypersensitivity-related idiosyncrasies
2) Toxic metabolite dependent idiosyncrasies.

In hypersensitivity reactions, the response is characterized by fever, rash and eosinophillia and is an immune-mediated response which have a typical short latency period of 1-4 weeks. The drug metabolites covalently bird to the liver proteins and forms neoantigens which is recognized as foreign by the immune system and causes liver injury.

Toxic metabolic idiosyncratic reaction occurs through excessive generation of a regular toxic metabolite or altered metabolism to unusual hepatotoxic metabolites.

Example-Phenytoin, Isoniazid, Halothane, ticrynafen and
valproic acid(Sciencedirect.com, 2018).

PREPARED BY: MALIHA MEHNAZ ENAMUL
ID: 2016-1-70-050
References:
Emedicine.medscape.com. (2018). Drug-Induced Hepatotoxicity: Overview, Metabolism of Drugs, Clinical and Pathological Manifestations of Drug-Induced Liver Disease. online Available at: https://emedicine.medscape.com/article/169814-overview#a3 Accessed 5 Nov. 2018.

HUMAN ANATOMY ORGAN. (2018). Liver Circulatory System – HUMAN ANATOMY ORGAN. online Available at: https://anatomyorgans.com/liver-circulatory-system/ Accessed 5 Nov. 2018.

Medindia. (2018). Hepatotoxicity Due to Drugs – Causes, Symptoms, Diagnosis ; Treatment. online Available at: https://www.medindia.net/patientinfo/hepatotoxicity-due-to-drugs.htm Accessed 5 Nov. 2018.

Columbiaasia.com. (2018). Fatty Liver | Columbia Asia Hospital – Malaysia. online Available at: https://www.columbiaasia.com/malaysia/health-articles/fatty-liver Accessed 5 Nov. 2018.

Roth, R. and Ganey, P. (2018). Intrinsic versus Idiosyncratic Drug-Induced Hepatotoxicity–Two Villains or One?. online Available at: http://jpet.aspetjournals.org/content/332/3/692?fbclid=IwAR3FkiPwFttJk0qs0v8eb4bgp1dGa-9LWpHkyOwu1Ne0KpPAjB6goZFTJc0 Accessed 5 Nov. 2018.

Anon, (2018). ebook Available at: http://www.japsonline.com/admin/php/uploads/490_pdf.pdf?fbclid=IwAR0z54kTmdMRYmt8EV7MDi9Ee6G6VdYK7p9j4_QjtHNV5OmxvSKDjbmpb3E Accessed 5 Nov. 2018.

– UNM Comprehensive Cancer Center. (2018). Liver Damage (Hepatotoxicity). online Available at: http://cancer.unm.edu/cancer/cancer-info/cancer-treatment/side-effects-of-cancer-treatment/less-common-side-effects/organ-problems/liver-damage-hepatotoxicity/?fbclid=IwAR3ajujtx_0TCrzQ9gl45n_2Eho9iQwExrc4tGT3Af2p_KASkzGC3nPvcjs Accessed 5 Nov. 2018.

Anon, (2018). online Available at: https://www.ncbi.nlm.nih.gov/m/pubmed/11729749/?fbclid=IwAR0mCw5dB5st4MsxMEsR3oWhaFsv7LykdBD34VMSezDyWOUY3IDvhPcWOdA Accessed 5 Nov. 2018.

Cold, F., Health, E., Disease, H., Disease, L., Management, P., Conditions, S., Problems, S., Disorders, S., Checker, S., Interviews, E., Boards, M., Answers, Q., Guide, I., Doctor, F., Medications, M., Identifier, P., Interactions, C., Drugs, C., Pregnant, T., Management, D., Obesity, W., Recipes, F., Exercise, F., Beauty, H., Balance, H., Relationships, S., Care, O., Health, W., Health, M., Well, A., Teens, H., Kids, F., Pregnant, G., Trimester, F., Trimester, S., Trimester, T., Baby, N., Health, C., Vaccines, C., Kids, R., Cats, H., Dogs, H., Bell, P., Spread, P., Don’t Fall for Venus Flytrap Health Claims, E., Supplements, R., Marijuana, A., Boards, M., Blogs, E. and Center, N. (2018). Toxic for Your Liver: Drugs, Chemicals, and Herbs. online WebMD. Available at: https://www.webmd.com/hepatitis/toxic-liver-disease?fbclid=IwAR2juP-oV7NrJJ1vkk700twG8Zukg4BceKMdpFGXqNVY_9PbM1207iDi6_E#1 Accessed 5 Nov. 2018.

Sciencedirect.com. (2018). Hepatotoxicity – an overview | ScienceDirect Topics. online Available at: https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/hepatotoxicity?fbclid=IwAR0z54kTmdMRYmt8EV7MDi9Ee6G6VdYK7p9j4_QjtHNV5OmxvSKDjbmpb3E Accessed 5 Nov. 2018.

Mayo Clinic. (2018). Elevated liver enzymes. online Available at: https://www.mayoclinic.org/symptoms/elevated-liver-enzymes/basics/definition/sym-20050830 Accessed 5 Nov. 2018.

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