Toxic hepatitis can be caused by alcohol, drugs, chemicals or supplements. Acetaminophen is a common cause when taken in high doses, as it is metabolized to a toxic metabolite that depletes glutathione stores. Diagnosis involves a history of exposures, physical exam noting jaundice potentially, and liver function tests showing elevated ALT and bilirubin. Treatment focuses on stopping the toxin and using N-acetylcysteine for acetaminophen toxicity to replenish glutathione within 8-24 hours of overdose. Prevention requires limiting intake, not exceeding medication directions, avoiding alcohol with medications, and following dosage guidelines.

1. TOXIC AND
DRUG INDUCED
HEPATITIS

2. DEFINITION
– Toxic hepatitis is an inflammation of liver in reaction to certain substances to
which you're exposed.
– Toxic hepatitis can be caused by alcohol, chemicals, drugs or nutritional
supplements.
– In some cases, toxic hepatitis develops within hours or days of exposure to a
toxin.

3. ANATOMY OF LIVER
– Right upper quadrant
– Right hypochondriac region
– Hepatocyte
– Kupffer’s cells
– Ductus system-Bile
– Blood circulation
– Lymphatic system

4. FUNCTIONS OF LIVER
– Metabolism
– Synthesis
– Storage
– Detoxification

5. CAUSES
– Alcohol
– Over the counter pain relievers-Acetaminophen, aspirin, ibuprofen and
naproxen
– Prescription medications-Statin drugs used to treat high cholesterol, the
combination drug amoxicillin-clavulanate ,phenytoin, azathioprine, niacin,
ketoconazole, certain antivirals and anabolic steroids
– Herbal medicine and supplements
– Mushroom poisoning
– Industrial chemicals

6. RISK FACTORS
– Taking over the counter pain relievers or certain prescription drugs.Long-acting
drugs may cause more injury than shorter-acting drugs
– Having a liver disease
– Having hepatitis-Chronic infection with a hepatitis virus
– Aging-Body starts to work slowly
– Race-Blacks and Hispanics may be more susceptible to isoniazid (INH) toxicity
– Drinking alcohol-Drinking alcohol while taking medications or certain herbal
supplements increases the risk of toxicity
– Being female-Because women seem to metabolize certain toxins more slowly than
men do, their livers are exposed to higher blood concentrations of harmful
substances for a longer time
– Having certain genetic mutations-Mutations in cytochrome P450 genes

7. TWO TYPES OF
HEPATOTOXICITY
– Direct toxic-Dose dependent
-Carbon Tertrachloride
-Acetaminophen
-Trichloroethylene
– Idiosyncratic-Dose independent/sudden onset to some drugs
-Isoniazid
-Ciprofloxacin
-Valproate
-Phenytoin,
-HMG-CoA reductase inhibitors (statins)

8. DIRECT TOXIC
HEPATOTOXICITY
– Direct toxic hepatitis occurs with predictable regularity in individuals exposed to
the drug and is dose-dependent
– The latent period between exposure and liver injury is usually short (often
several hours), although clinical manifestations may be delayed for 24–48 h
– Liver injury, produced by the direct hepatotoxins, may go unrecognized until
jaundice appears

9. IDIOSYNCRATIC
HEPATOTOXICITY
– In idiosyncratic drug reactions, the occurrence of hepatitis is usually infrequent (1 in
1000–100000) and unpredictable
– The response is not as clearly dose-dependent as injury associated with direct
hepatotoxins,and liver injury may occur at any time during or shortly after exposure
to the drug.
– Recent data suggest that most agents causing idiosyncratic toxicity are given at a
daily dose exceeding 100 mg, suggesting a role for drugs with low potency must be
given in higher doses
– Adding to the difficulty of predicting or identifying idiosyncratic drug hepatotoxicity
is the occurrence of mild, transient, non progressive serum aminotransferase
elevations that resolve with continued drug use. Such “adaptation,” the mechanism
of which is unknown, is well recognized for drugs such as isoniazid, valproate,etc
– Extrahepatic manifestations of hypersensitivity, such as rash, arthralgias, fever,
leukocytosis, and eosinophilia, occur in about one-quarter of patients with
idiosyncratic hepatotoxic drug reactions but are characteristic for certain drugs and
not others.

12. MECHANISM OF
DETOXIFICATION
– Phase I reactions include Oxidation ,Reduction, Hydrolysis with the help of
Cytochrome P450
– Phase II Reactions are usually known as conjugation and involve the
interactions of the polar functional groups of phase I metabolites. Sites on drugs
where conjugation reactions occur include carboxyl (-COOH), hydroxyl (-
OH), amino (NH 2 ), and sulfhydryl (-SH) groups which requires
Glucuronosyltransferase as necessary requirement. This process makes the
products more water soluble for easy excretion

14. DETOXIFICATION OF
ACETAMINOPHEN
– Acetaminophen has a high oral bioavailability (88%), it is well absorbed and
reaches the peak blood concentrations within 90 minutes after ingestion
– Acetaminophen is metabolized predominantly by a phase II reaction to sulfate
and glucuronide metabolites; however, a small proportion of acetaminophen is
metabolized by a phase I reaction to a hepatotoxic metabolite formed from the
parent compound by cytochrome P450(CYP2E1)
– This metabolite, N-acetyl-p-benzoquinone-imine (NAPQI), is detoxified by
binding to glutathione to become harmless, water-soluble mercapturic acid,
which undergoes renal excretion

15. – Acetaminophen consumed in “normal” amounts can be removed by direct
conjugation by sulfotransferase or glucuronidation by glucuronyl transferases to
produce acetaminophen sulfate or acetaminophen glucuronide, which are
excreted
– When present at high levels, the conjugation reactions become limiting and
acetaminophen can be oxidized by several CYP450 to form the reactive N-
acetyl-p-benzoquinone imine
– The quinone imine can be removed by conjugation with GSH(glutathione).
However, when formed in high amounts at high levels of acetaminophen or
when GSH levels are low because of liver disease or alcohol intake, the reactive
quinone imine causes the release of free radicals or metabolic intermediate
that causes peroxidation of membrane lipids into the body and leads to necrosis
of liver

16. – Metabolite may activate components of the innate or adaptive immune system,
stimulate apoptotic pathways, or initiate damage to bile excretory pathways
– 8 g/day, twice the daily recommended maximum dose, over several days can
readily lead to liver failure.
– A single dose of 10–15 g, occasionally less, may produce clinical evidence of
liver injury. Fatal fulminant disease is usually associated with ingestion of ≥25 g.

18. ALCOHOL CONSUMPTION
AND TOXIC HEPATITIS
– Alcohol interactions may decrease the effectiveness of medications or render
them useless. In other cases, alcohol interactions may make drugs harmful or
even toxic to the body
– Alcohol consumption leads to the decrease of glutathione which is mandatory
for the second phase of metabolism
– This leads to the accumulation of N-acetyl-p-benzoquinone imine which causes
the release of toxins further leading to centrilobular necrosis
– Alcohol induces cytochrome P450; consequently, increased levels of the toxic
metabolite NAPQI may be produced in chronic alcoholics after acetaminophen
ingestion

19. – Women are more susceptible to alcoholic liver injury when compared to men.
They develop advanced liver disease with substantially less alcohol intake
– Therefore, in chronic alcoholics, the toxic dose of acetaminophen may be as
low as 2 g, and alcoholic patients should be warned specifically
– Alcohol is also known to strongly inhibit (or block) an enzyme in the liver known
CYP2C9 which helps in the metabolization of warfarin. When this enzyme is
blocked by alcohol use it leads to increased risk of blood clotting inside the
vessels

20. CENTRILOBULAR NECROSIS
Centrilobular Necrosis-
around central vein (acinar
zone 3). Causes-Ischemia,
drugs, venous outflow
impairment

21. SYMPTOMS
– Nausea, vomiting, diarrhea, abdominal pain, and shock are early
manifestations occurring 4–12 h after ingestion.
– Then 24–48 h later, when these features are abating, hepatic injury becomes
apparent. Maximal abnormalities and hepatic failure are evident 3–5 days after
ingestion
– Abdominal pain in the upper right portion of the abdomen
– Yellowing of the skin and whites of the eyes (jaundice)
– Excessive bleeding

22. PHASES OF
ACETOMINOPHEN TOXICITY
Phase 1
– 0.5-24 hours after ingestion
– Patients may be asymptomatic or report anorexia, nausea or vomiting, and malaise
– Physical examination may reveal pallor, diaphoresis, malaise, and fatigue
Phase 2
– 18-72 h after ingestion
– Patients develop right upper quadrant abdominal pain, anorexia, nausea, and
vomiting
– Right upper quadrant tenderness may be present
– Tachycardia and hypotension may indicate volume losses
– Some patients may report decreased urinary output (oliguria)

23. Phase 3: Hepatic phase
– 72-96 h after ingestion
– Patients have continued nausea and vomiting, abdominal pain, and a tender
hepatic edge
– Hepatic necrosis and dysfunction may manifest as jaundice, coagulopathy,
hypoglycemia, and hepatic encephalopathy
– Acute renal failure develops in some critically ill patients
– Death from multiorgan failure may occur
Phase 4: Recovery phase
– 4 d to 3 week after ingestion
– Patients who survive critical illness in phase 3 have complete resolution of
symptoms and complete resolution of organ failure

24. DIAGNOSIS
– Case history
– Physical examination
– Lab tests
– Biopsy

25. CASE HISTORY
– History must include dose, route of administration, duration, previous
administration, and use of any, over-the-counter medications and herbs.
– Knowing whether the patient was exposed to the same drug before may be
helpful. The latency period of idiosyncratic drug reactions is highly variable;
hence, obtaining a history of every drug ingested in the past 3 months is
essential.
– Alcohol consumption should also be mentioned
– The onset is usually within 5-90 days of starting the drug. Excluding other
causes of liver injury is essential.

26. – Tabulate drugs taken
-Prescribed
-Self-administered
– Relate the time drugs taken to onset of illness
-4 days-8 weeks

27. PHYSICAL EXAMINATION
– Inspection-Icterus(Jaundice)
– Auscultation-Hepatic arterial bruit
– Percussion-Normal(acute),Enlarged(chronic)
– Palpation-Smooth,Tender(acute),Irregular(chronic)

29. LAB TESTS
– Liver function tests and blood tests
-Serum creatinine > 300 μmol/L
-Prothrombin time > 100 seconds
-Lactic acidosis in blood
- Elevated total bilirubin level >4 mg/Dl
-Serum concentrations of NAPQI-protein adduct
- Gamma glutamyl transferase >2 than normal
- acetaminophen blood levels >200 μg/mL measured at 4 h or
>100 μg/mL at 8 h after ingestion
-R value, the ratio of alanine aminotransferase (ALT) to alkaline
phosphatase values. An R value of >5.0 is associated with hepatocellular injury

30. - Markedly elevated ALT and AST ≥5 then normal
-AST, ALT higher than alkaline phosphatase level
-Hyperproteinemia
– The normal range of values for AST is about 5 to 40 units per liter of serum
– The normal range of values for ALT is about 7 to 56 units per liter of serum

31. CT SCAN

32. ULRASOUND

33. BIOPSY
– A liver biopsy is not essential in every case, but a morphologic pattern
consistent with the expected pattern provides supportive evidence.
– We can find centrilobular necrosis by histological appearance

34. Central lobular necrosis with inflammatory infiltration of
histiocytes(haematoxylin and eosin)
Normal liver biopsy

35. TREATMENT
– Neither charcoal nor cholestyramine appears to be effective if given >30 min
after acetaminophen ingestion; if they are used, the stomach lavage should be
done before other agents are administered orally.
– N-acetylcysteine are used in the treatment of acetaminophen toxicity
– In patients with high acetaminophen blood levels ,the administration of N-
acetylcysteine reduces the severity of hepatic necrosis
– This agent provides sulfhydryl donor groups to replete glutathione,which is
required to render harmless toxic metabolites
– Therapy should be begun within 8 h of ingestion but may be at least partially
effective when given as late as 24–36 h after overdose

36. – Effect of stopping drugs on normalization of liver. LFTs can be taken after 2
months
– 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

37. COMPLICATIONS
– Over time, untreated hepatitis can cause hardening and scarring (cirrhosis) in the
liver, which slows down blood flow through this large organ
– Toxin produced causes necrosis which leads to irreversible liver failure and
ultimately death
– As there is impaired ALT and AST levels, there is no production of non-essential
amino acids
– Kernicterus is a bilirubin-induced brain dysfunction.Bilirubin is neurotoxic when
its concentration in the blood is too high, a condition known as hyperbilirubinemia.
Hyperbilirubinemia may cause bilirubin to accumulate in the grey matter of
the central nervous system, potentially causing irreversible neurological damage.
Depending on the level of exposure, the effects range from clinically unnoticeable to
severe brain damage and even death.

39. PREVENTION
– Limit medications-Take prescription and nonprescription drugs only when
absolutely necessary
– Take medications only as directed- Follow the directions exactly for any drug you
take. Don't exceed the recommended amount, even if your symptoms don't seem to
improve. Because the effects of over the counter pain relievers sometimes wear off
quickly, it's easy to take too much.
– Don't mix alcohol and drugs-Alcohol and medications are a bad combination. If
you're taking acetaminophen, don't drink alcohol
– The FDA has recommended that the daily dose of acetaminophen be reduced from
4 g to 3 g ,even lower for persons with chronic alcohol use. Within opioid
combination products, the limit for the acetaminophen component has been
lowered to 325 mg per tablet.