Wilson’s diseaseDrug induced liver disease

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

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

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

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

Menke’s disease

Copper transporter in the intestinal epithelium ATP7A

Defective copper absorption

Copper deficiency

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

Age of presentation 5 to 45

Liver disease: Childhood and early adolescence

Neurological: Later adolescence

Liver disease

Acute hepatitis

May be recurrent

May progress to fulminant hepatic failure

Chronic hepatitis

Cirrhosis

HCC

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

Neurological disease

Usually present during adolescence or early adulthood, but presentations up to age 51 have been reported.

A variety of EP featuresDystoniaInvoluntary movements (Tremor, Choreoathetosis)Rigidity (Parkinsonism)

Ataxia, TitubationDysarthriaSeizure

Dementia, if present, is mild.

Sensation is spared.

Muscle weakness does not occur

Fixed stare with a smiling expression and drooling is classical

Psychiatric manifestations

Psychiatric manifestations are very common and may be quite disabling.

Mood and personality disorders, behavioral changes, and psychosis are reported.

Early Clues

Clumsiness

Worsening of handwriting

Mood, behavioural and personality changes

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

Ceruloplasmin level is normal in about 10% of patients with Wilson’s disease

Levels may be low in 20% of carriers also

Treatment

Chelators

D penicillamine

Trientine

Tetra thio molybdate

Zinc

Treatment

Liver disease without decompensation

Zinc

Liver disease with decompensation

Chelator with zinc / Transplantation

Neurological disease

Avoid chelators

Tetra-thio-molybdate, Zinc

Drug Induced Liver Injury (DILI)

1.Mechanism of hepatotoxicity:

Predictable

Idiosyncratic

2.Clinical presentation:

Hepatocellular injury

Cholestatic injury

Mixed injury

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

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)

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.

Intrinsic hepatotoxins

Idiosyncratic reactions

Metabolic

Imunoallergic

,

Intrinsic hepatotoxins

Predictable

Dose dependent

Interval is brief – hours to a few days

The drug itself or its toxic metabolite

Paracetamol

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

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.

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

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

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)

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

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

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

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

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

Drugs that can present clinically, serologically, and histologically like autoimmune hepatitis (AIH):

infliximab and other TNF alpha blocking agents, methyldopa, minocycline, and nitrofurantoin

Acute Cholestatic Injury

Pure cholestasis without inflammation

OC pill

Anabolic steroids

Cholestatic hepatitis

Amoxicillin clavulanate

Erythromycin

ACE inhibitors

Chronic cholestatic Injury

Amoxicillin-clavulanate,

Flucloxacillin,

ACE inhibitors

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

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)

ATT induced hapatotoxicity

How to diagnose

TA elevation > 5 times

TA elevation > 3 times with symptoms

INH

Rifampicin

Pyrazinamide

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

INH hepato-toxicity

Age20 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