1. Drug induced liver injury (DILI) can occur through intrinsic, idiosyncratic, metabolic, or immune-mediated mechanisms. Paracetamol is an example of an intrinsic hepatotoxin while amiodarone and diclofenac are known to cause idiosyncratic DILI. 2. DILI presentations include acute or chronic hepatocellular injury, cholestatic injury, and mixed patterns of injury. Common culprit drugs are amoxicillin-clavulanate, atorvastatin, and methotrexate. 3. Antitubercular drugs like isoniazid and rifampin can cause DILI, with is

1. Wilson’s disease
Drug induced liver disease

2. Copper metabolism
1 to 3 mg ingested per day
50% is absorbed from GI
Stomach and duodenum
Biliary excretion is the route of elimination
90% is tightly bound to ceruloplasmin
10% loosely bound to albumin
Very little is free copper in the plasma

3. Defective protein is ATP7B
Copper transporter enzyme
P type ATPase
Necessary for copper excretion in to the bile
Also for incorporation into apo-ceruloplasmin to form
ceruloplasmin

4. Hepatic copper accumulation
Hepatic copper content is very high
Low plasma levels of ceruloplasmin
Low total copper in plasma
Free plasma copper is increased
Urinary copper excretion is high
Copper deposition in eye, brain, kidneys

5. Aceruloplasminemia
Conversion of ferrous iron to feriric iron
Necessary for binding with transferrin, the iron
transport protein
Failure to transport iron from tissues to deliver to red
cell precursors
Iron overload particularly in the brain
High ferritin levels and low serum iron levels
Adults with neurological features analogous to Wilson’s
disease

6. Menke’s disease
Copper transporter in the intestinal epithelium ATP7A
Defective copper absorption
Copper deficiency

7. Wilson disease
Prevalence: 1 to 3 per lakh population
Gene frequency of 1 in 100 (90 – 150)
Hepato lenticular degeneration
Liver disease
Neurological and Psychiatric manifestations
Other features
Hemolysis
Renal tubular disease

8. Age of presentation 5 to 45
Liver disease: Childhood and early adolescence
Neurological: Later adolescence

9. Liver disease
Acute hepatitis
May be recurrent
May progress to fulminant hepatic failure
Chronic hepatitis
Cirrhosis
HCC

10. When to consider Wilson’s disease
Patient under the age of 40 presenting with
Recurrent acute hepatitis or
Chronic liver disease of unknown cause,
Especially when accompanied by haemolysis

11. Neurological disease
Usually present during adolescence or early adulthood, but
presentations up to age 51 have been reported.
A variety of EP features
Dystonia
Involuntary movements (Tremor, Choreoathetosis)
Rigidity (Parkinsonism)
Ataxia, Titubation
Dysarthria
Seizure

12. Dementia, if present, is mild.
Sensation is spared.
Muscle weakness does not occur
Fixed stare with a smiling expression and drooling is
classical

13. Psychiatric manifestations
Psychiatric manifestations are very common and may
be quite disabling.
Mood and personality disorders, behavioral changes,
and psychosis are reported.

14. Early Clues
Clumsiness
Worsening of handwriting
Mood, behavioural and personality changes

15. Diagnosis
KF ring in 99% with neurologic or psychiatric
presentation
But in only about 30 to 50% of those with hepatic
presentation and presymptomatic state
Low ceruloplasmin levels
High free plasma copper levels
High urinary copper excretion
Very high hepatic copper content

16. Ceruloplasmin level is normal in about 10% of patients
with Wilson’s disease
Levels may be low in 20% of carriers also

17. Treatment
Chelators
D penicillamine
Trientine
Tetra thio molybdate
Zinc

18. Treatment
Liver disease without decompensation
Zinc
Liver disease with decompensation
Chelator with zinc / Transplantation
Neurological disease
Avoid chelators
Tetra-thio-molybdate, Zinc

19. Drug Induced Liver Injury (DILI)
1.Mechanism of hepatotoxicity:
Predictable
Idiosyncratic
2.Clinical presentation:
Hepatocellular injury
Cholestatic injury
Mixed injury

20. 3.Histologic findings, such as:
Acute and chronic hepatocellular injury
Acute and chronic cholestasis
Steatosis and steatohepatitis
Granulomas
Signs of hepatic venous outflow obstruction
Sinusoidal obstruction syndrome
Peliosis hepatis

21. Assessing causality
The key elements for attributing liver injury to a drug
Drug exposure preceded the onset of liver injury (although
the latent period is highly variable)
Underlying liver disease is excluded
Stopping the drug leads to improvement in the liver injury
Rapid and severe recurrence may occur if there is repeated
exposure to the drug (however, rechallenge is not advised)

22. Clinically significant DILI
ALT: more than 3 × ULN
ALP: more than 2 × ULN
Total bilirubin: more than 2 × ULN and is associated
with any elevation of the ALT or alkaline
phosphatase.

24. Intrinsic hepatotoxins
Idiosyncratic reactions
Metabolic
Imunoallergic
,

25. Intrinsic hepatotoxins
Predictable
Dose dependent
Interval is brief – hours to a few days
The drug itself or its toxic metabolite
Paracetamol

26. Idiosyncratic reactions
Only in 1% to 0.01% of patients
(1 in 100 to one in 10,000)
Not identified by clinical trials which involve about
3000 patients
Post marketing surveillance is necessary
Species specific and not identified by animal studies

27. Metabolic injury
Metabolic DILI is probably due to genetically
determined aberrant metabolism of the drug in
susceptible patients.
The duration of exposure before the development of
toxicity varies from weeks to months, and reactions
can develop several weeks after drug
discontinuation.
The disease recurs within many days to weeks after
rechallenge.
Features of hypersensitivity are absent.

28. Metabolic injury- mechanism
Genetically determined aberrant metabolism of the
drug
Local accumulation of toxic metabolites
Covalent binding of the metabolite to cellular proteins,
lipids, and DNA
Oxidative stress to the hepatocyte
Organelle dysfunction, cell injury and necrosis

29. Immunoallergic DILI
Immunoallergic DILI is the least well understood form
of DILI, and the role of the immune system remains
controversial.
Immunoallergic DILI may be accompanied by clinical
and histologic evidence of classic hypersensitivity.
There is generally a delay in the onset of symptoms and
the duration of exposure is generally about one to
eight weeks

30. Rash, fever, joint pain and inflammation,
lymphadenopathy, eosinophilic leukocytosis and, in
severe cases, the Stevens-Johnson syndrome may
occur. However, these symptoms may be mild or
absent.
In some cases, the presentation may be similar to
infectious mononucleosis (with atypical
lymphocytes)

31. There is a prompt recurrence of symptoms in response
to drug rechallenge of one or two doses.
This type of injury is believed to be a metabolite-
initiated, immune-mediated attack on the liver

32. amiodarone, diclofenac, disulfiram, isoniazid,
ketoconazole, troglitazone, and valproate

33. Immuno allergic injury - mechanism
Haptenization: modification of "self" proteins due to
covalent binding of the active metabolite
Drug-protein products (adducts) then behave as
neoantigens
Neoantigens elicit an immune response

34. Acute hepatocellular injury
90% of DILI is acute hepatocellular injury
Necrosis of isolated liver cells (spotty necrosis)
Confluent necrosis of a group of liver cells
Zonal or non zonal; If extensive leads AHF
Zonal necrosis
Paracetamol , CCl4, Yellow phosphorus
Non-zonal necrosis
Phenytoin, Methyldopa, Isoniazid, and Diclofenac

35. Chronic hepatocellular injury
Acute HC injury can progress to chronic injury in 5 to 10% of
cases
Chronic hepatocellular injury can histologically resemble
other causes of chronic liver disease, such as
autoimmune hepatitis, viral hepatitis, or alcoholic liver
disease
amoxicillin-clavulanic acid, atorvastatin, methotrexate,
hypervitaminosis a, vinyl chloride, heroin, herbal
products, and dietary supplements

36. Drugs that can present clinically, serologically, and
histologically like autoimmune hepatitis (AIH):
infliximab and other TNF alpha blocking
agents, methyldopa, minocycline, and nitrofurantoin

37. Acute Cholestatic Injury
Pure cholestasis without inflammation
OC pill
Anabolic steroids
Cholestatic hepatitis
Amoxicillin clavulanate
Erythromycin
ACE inhibitors

38. Chronic cholestatic Injury
Amoxicillin-clavulanate,
Flucloxacillin,
ACE inhibitors

39. Prognosis - acute liver injury
Acute liver injury
Majority of patients recover once the drug is stopped
Recovery may be delayed with cholestatic injury; jaundice
may take weeks or months to recover
5 to 10%progress to chronic liver disease
More likely with cholestatic and mixed pattern

40. Prognosis – chronic liver injury
Chronic liver injury
Generally stooping the drug leads to recovery
Gradual progression to cirrhosis can be seen without
any manifestation of clinical illness (as
with amiodarone, methotrexate, or methyldopa)

41. ATT induced hapatotoxicity
How to diagnose
TA elevation > 5 times
TA elevation > 3 times with symptoms
INH
Rifampicin
Pyrazinamide

42. INH hepato-toxicity
Mostly within 2 to 3 months of initiation
Can occur upto 14 months after initiation
Overall risk is 0.1 to 0.6% as per various studies
Prodromal symptoms resemble viral hepatits
Symptoms for days / weeks prior to appearance of
jaundice

43. INH hepato-toxicity
Age
20 to 34 years — 0.3 percent
35 to 49 years — 1.2 percent
50 to 64 years — 2.3 percent
Over age 65 years — 4.6 percent
Alcohol use
Chronic viral hepatitis
Female gender
Pregnancy, post partum period
Other medications