This document discusses hepatotoxicity (liver toxicity or damage). It begins by describing the liver's important roles and how an imbalance between protective and aggressive forces can lead to hepatotoxicity from environmental and chemical agents. Common mechanisms of hepatotoxicity include inflammation, immunomodulation, and oxidative stress. Several drugs are described as potential causes of hepatotoxicity, including acetaminophen, carbontetrachloride, ethanol, and some antitubercular drugs. Signs and symptoms of hepatotoxicity and treatments such as supportive care or liver transplant are also summarized. A case study describes hepatotoxicity resulting from antitubercular therapy.

1. Fatma SaeedAltalaqani
Higher diploma in toxicology
Supervised by
Dr. Ammar alihussein
Baghdad university college of pharmacy

2. General consideration
The liver is a crucial organ for maintenance of
gastrointestinal homeostasis and body function in
general. In addition to its role in the digestive process,
it also serves as a source of nutrients and detoxifier of
unwanted substances. Hence, its optimal functioning
is crucial for health and disease. An imbalance
between aggressive and protective forces results in
damage to the liver and complex mechanism are
involved in such hepatotoxicity induced by a variety of
environmental and chemical agents .

3. So , It is important to understand the mechanisms
of hepatotoxicity for devising pharmacological
strategies for their prevention. Inflammation,
immunomodulation and oxidative stress are amongst
the common biological mechanisms contributing to
compromised liver function

4. Introduction
 Liver is also the main organ for metabolism and elimination of
drugs . At the same time liver is prone to many diseases like allergy
to food and involves immune system as well. Hepatitis is caused
due to viruses, poisons, autoimmunity and can also result from
non-alcoholic fatty liver disease connected with obesity and
steatosis. Hepatic encephalopathy is caused by accumulation of
toxins in the bloodstream that are normally removed by the liver.
 Liver damage can also be caused by drugs, particularly anti-
tubercular drugs, general anesthetics, paracetamol and some anti-
cancer drugs.

5. Alcoholic liver diseases with
cirrhosis (formation of fibrous tissue
in liver) caused by excessive alcohol
consumption is a common
occurrence. Liver can sometimes be
damaged by some chemicals called
hepatotoxins, such as galactosamine
and chloroform . Moreover, steroids,
vaccines and antiviral drugs which
are used as therapy for liver diseases,
may produce adverse effects
especially after chronic

7. Structural organization
 two concepts exist or organization o the liver into operational units, namely, the lobule and the
acinus.
 Classically, the liver is divided into hexagonal lobules oriented around terminal hepatic venules
(also known as central veins). At the corners o the lobule are the portal triads (or portal tracts),
containing a branch o the portal vein, a hepatic arteriole, and a bile duct .
 Blood entering the portal tract via the portal vein and hepatic artery is mixed in the penetrating
vessels, enters the sinusoids, and percolates along the cords of parenchymal cells (hepatocytes).
 The lobule is divided into three regions known as centrilobular, midzonal, and periportal .
 The acinus is the preferred concept for a functional hepatic unit.
 The acinus has three zones: zone 1 is closest to the entry of blood, zone 3 abuts the terminal
hepatic vein, and zone 2 is intermediate. Despite the utility of the acinar concept, lobular
terminology is still used

9.  Acinar zonation is of considerable functional consequence regarding
gradients of components both in blood and in hepatocytes . Blood entering
the acinus consists of oxygen-depleted blood from the portal vein (60%–70%
of hepatic blood flow) plus oxygenated blood from the hepatic artery (30%–
40%). Enroute to the terminal hepatic venule, oxygen rapidly leaves the
blood to meet the high metabolic demands of the parenchymal cells .
 Approximate oxygen concentrations in zone 1 are 9% to 13%, compared
with only 4% to 5% in zone 3 , Therefore, hepatocytes in zone 3 are exposed
to substantially lower concentrations of oxygen than hepatocytes in zone 1.
In comparison to other tissues, zone 3 is hypoxic .

10. Hepatotoxicity
Liver is the Primary site for the metabolic process to
occur.
Most of the drugs undergo metabolism mainly in the
liver.
Hepatotoxicity implies liver injury caused due to
chemicals.
Liver injury may follow the inhalation, ingestion, or
parenteral administration of a number of
pharmacologic and chemical agents.
 Chemical agents include industrial toxins such as
carbon tetrachloride, trichloroethylene, yellow
phosphorous.

12. Mechanism 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
then spleen via portal veins which bring drugs and xenobiotics in concentrated
form.
 Several mechanisms are responsible for either inducing hepatic injury or worsening
the damage process.
 Many chemicals damage mitochondria, an intracellular organelle that produce
energy.
 Its dysfunction releases excessive amount of oxidants which in turn injures hepatic
cells.
 Injury to hepatocyte and bile duct cells lead to accumulation of bile acid inside liver.
This promotes further liver damage.

13. Hepatotoxicity is of two types:
direct toxic type
Direct toxic type: dose
dependent and results in
morphological
abnormalities.
Idiosyncratic type
Idiosyncratic type: not
dose dependent, and may
appear shortly after
exposure of drugs. Results
in hypersensitivity
reactions: rash arthralgia,
eosinophilia etc.

14. Signs and symptoms:-
Yellowing of the skin and whites
of the eyes (jaundice)
Fatigue
Loss of appetite
Nausea and vomiting
Weight loss
Dark or tea-colored urine

15. How drug induce hepatotoxicity ?
 Drugs can cause liver disease in several ways. Some drugs are directly
injurious to the liver; others are transformed by the liver into chemicals that
can cause injury to the liver directly or indirectly. (There are three types of
liver toxicity; dose-dependent toxicity, idiosyncratic toxicity, and drug
allergy.

16. How you treating hepatotoxicity
 • Supportive care. People with severe symptoms are likely to receive supportive therapy in the
hospital, including intravenous fluids and medication to relieve nausea and vomiting. Your
doctor will also monitor for liver damage.
 • Medication to reverse liver damage caused by acetaminophen. If your liver damage was
caused by an overdose of acetaminophen, you'll receive a chemical called acetylcysteine
right away. The sooner this medication is administered, the greater the chance of limiting
liver damage. It's most effective if administered within 16 hours of the acetaminophen
overdose.
 • Emergency care. For people who overdose on a toxic medication, emergency care is
essential. People who overdose on certain medications other than acetaminophen may
benefit from treatments to remove the offending medication from the body or reduce its
toxic effect.
 • Liver transplant. When liver function is severely impaired, a liver transplant may be the
only option for some people. A liver transplant is an operation to remove your diseased liver
and replace it with a healthy liver from a donor.
Most livers used in liver transplants come from deceased donors. In some cases, livers can come
from living donors who donate a portion of their livers.

17. AGENTSWHICHCAUSE OF LIVERDAMAGE
Toxins - Drugs, Chemicals, Fe,Cu, alpha-1-AT.
Ischaemia - venous or arterial thrombosis, hypertension.
Infection - viral,protozoal, bacterial.
Immunological - autoimmune, response to infection.
Cholesterol or triglycerides can accumulate (such as in
steatosis; steat=fat + osis=accumulation).
Obstruction of bile flow (such as in cholestasis:chole=bile +
stasis=standing).
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18. Drugs causing Liver damage
Acetaminophen:-
(Paracetamol, also known by the brand name
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.
 MANGEMANT
IpecacSyrup
ActivatedCharcoal
N-AcetylCysteine(loadingdoseis150mg/kgin200mlof5%dextrose
infusedover15-60minutes).
Mehtioninecanalsobegiven.
 Acetaminophen (3D
structure) overdose is the
most common cause of
drug induced liver disease

19. CARBONTETRACHLORIDE:
Carbontetrachloridewaswidelyusedasa
cleaningsolvent,fireextinguisheragent,and
anthelmintics.
Becauseofitslivertoxicityandknown
carcinogenicityinanimals,itsrolehas
becomelimited;itisnowusedmainlyasan
intermediateinchemicalmanufacturing.
MECHANISMOFTOXICITY
Carbontetrachlorideisapotenthepaticandrenal
toxin.Themechanismisthoughttobearesultofa
toxicfree-radicalintermediateofmetabolism.
(CCl4)undergoeshepaticreductivemetabolismto
CCl3andCCl3OOfreeradicalstoxicintermediates
whichmayinitiatehepatocellulardamage..
Chronicuseofmetabolicenzymeinducerssuchas
phenobarbitalandethanolincreasethetoxicityof
carbontetrachloride.Carbontetrachlorideisa
knownanimalandsuspectedhumancarcinogen.

20. MANGEMANT
Removethesubjectfromexposurearea.
Maintainnormobaricorhyperbaricoxygen.
Incaseofingestionadministeractivatedchahrcoal.
Ipecacinducedvomitingmaybeusefulforinitialtreatment.
N-acetylcysteinemayminimizehepaticandrenaltoxicityby
providingascavengerforthetoxicintermediate.

21. ETHANOL
Commercial beer,wine,andliquorscontainvariousamountsofethanol.Ethanolisalsofoundina
varietyofperfumes,mouthwashes,manyfoodflavorings(eg,vanilla,almond,andlemonextracts),
pharmaceutical preparations(eg,elixirs),andmanyotherproducts.
Ethanolisfrequentlyingestedrecreationallyandisthemostcommonco-ingestantwithotherdrugsin
suicideattempts.Ethanolmayalsoserveasanantidoteintheemergency treatmentofmethanoland
ethyleneglycolpoisonings.

22. MECHANISMOFTOXICITY
Ethanolisalsooxidizedinliverbyanethanolinducible
cytochromeP-450enzymethatconvertedthecontentsto
toxicradicals.Inductionalsoresultsinenergywastageand
increasedproductionofacetaldehydethatresultsininjury
tocellsandmitochondriawithastrikingimpairmentof
oxygenutilization.
Acetaldehydealsocausesglutathionedepletionandlipid
peroxidation,andstimulateshepaticcollagensynthesis,
therebypromotingfibrosisandcelldamage.
MANAGEMENT
Protecttheairwayandprovidesupportive
treatment.
Don’tinducevomitingoractivatedcharcoal
Giveglucose&thiaminetotreatalcoholic
ketoacidosis
Correcthypothermiawithgradualrewarming
Nospecificantidoteavailable
Performhemodylasisforefficientethanol
removal.

23. Nonsteroidalanti-inflammatorydrugs-Aspirin, phenylbutazone, ibuprofen,
sulindac, phenylbutazone, piroxicam, diclofenac and indomethacin.
Glucocorticoids- Glucocorticoids are so named due to their effect on
carbohydrate mechanism. they promote glycogen storage in liver.
The classical effect of prolonged use both in adult and paediatric
population is steatosis.
Isoniazid-Isoniazide (INH) is one of the most commonly used drug
for tuberculosis; it is associated with mild elevation of liver enzymes
in up to 20% of patients and severe hepatotoxicity in 1-2% of

24.  Natural products- Amanita mushroom,
particularly the destroying angels,
aflatoxins.
 Industrial toxin- Arsenic, Carbon
tetraChloride, Vinyl Chloride.
 Herbal and alternative remedies- Ackee
fruit, Camphor, Pyrrolizidine alkaloids,
Horse chestnut leaf, Valerian, Comfrey
(often used in herbal tea).

25. Forms of liver toxicity:-
 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.
 Hepatitis- Disease of the liver causing inflammation.
 Cholestasis- Cholestasis is a condition where bile cannot flow from the liver to the
duodenum.
 Steatosis- Steatosis is a condition characterised by the build up of fat within the liver,
sometimes triggering inflammation of the liver
 Granuloma- A granuloma is one of a number of forms of localized nodular
inflammation found in tissues.
 Vascular lesions- They result from injury to the vascular endothelium.
 Neoplasm- Neoplasm or tumor, tissue composed of cells that grow in an abnormal
way.

27. Complications:-
 Except for gallstone disease and some
viral infections such as Hepatitis A and
infectious mononucleosis, most liver
diseases are managed and not cured.
 Liver disease can progress to cirrhosis
and liver failure. Associated
complications may include increased
risk of bleeding and infection,
malnutrition and weight loss, and
decreased cognitive function.
 Some liver diseases are associated with
an increased risk for developing liver
cancer

28. CELLULAR TARGETS OF LIVER DAMAGE
HEPATOCYTES - Paracetamol
toxicity;Viral Hepatitis
BILE DUCTS - Primary Biliary
Cirrhosis, Sclerosing Cholangitis.
ENDOTHELIAL CELLS - Drugs.

29. Treatment:-
 No specific treatment exists for most kinds of
toxic hepatitis
 For most other cases of drug-induced toxic
hepatitis, stopping the medication is the only
treatment.
 Other treatments include:
 Supportive therapy. People with severe
symptoms are likely to receive supportive
therapy in the hospital, including intravenous
fluids and medication to relieve nausea and
vomiting.
 Liver transplant. When liver function is
severely impaired, a liver transplant may be
the only option for some people
19

30. Case study
 A 53 year old male patient who was a known case of Tuberculosis Meningoencephalitis recently
started up on ATT and steroids for the past 15 days, suddenly came to the hospital with chief
complaints of altered sensorium for 1 day, history of grade IV breathlessness, history of decreased
responsiveness to surroundings, history of abdominal distension for the past 2 days.
 his therapy was initiated with CAT I ATT (Isoniazid 300mg, Rifampicin 450mg and Ethambutol
800mg). After few days of continuous therapy with ATT he had symptoms of malaise, epigastric
pain with pale skin. Without recognizing the symptoms he carried on further with his ATT therapy

31. Discussion
 Almost all the CAT I ATT drugs are metabolized by the liver and when the therapy lasts for a
long time there are increased chances of hepatotoxicity and liver injuries. The physicians
and pharmacists could help the patients out by making them understand the adverse effect
and side effects of each of the drugs so that immediate withdrawal of the drug could be
done by the patient itself and letting it know to the physician. This would prevent the further
worsening of the condition, remaining as the exacerbating condition in most of the cases.

32. References
KentR,andOlsonM.PoisoningandOverdose.7thEdition2017
 SinghR,KumarS,RanaAC,SharmaN.Differentmodelsofhepatotoxicityandrelatedliverdiseases:Areview.
IRJP.2012;3(7):86-95.
 RobbinsBASICPATHOLOGY.
 PrinciplesofToxicologybyStephenM.Robert
https://www.researchgate.net/profile/S_Vedha_Jeyamani2/publication/336810769_Drug_Induced_hepatotoxicity_i
n_Anti-tubercular_therapy_A_case_study/links/5dbfe660299bf1a47b11d6dc/Drug-Induced-hepatotoxicity-in-Anti-
tubercular-therapy-A-case-study.pdf?origin=publication_detail 2019
https://www.medicinenet.com/drug_induced_liver_disease/article.htm#cholestasis
https://www.mayoclinic.org/diseases-conditions/toxic-hepatitis/diagnosis-treatment/drc-20352208