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.
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
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
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
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
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