A family history of liver disease

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Chapter 42 A FAMILY HISTORY OF LIVER DISEASE

SUMMARY

• The current status in the understanding of genetic and environmental factors in selected hepatobiliary diseases is discussed.
• These include Wilson’s disease, alpha1-antitrypsin deficiency, hereditary haemochromatosis, the hepatic porphyrias, cystic fibrosis, Gaucher’s disease, polycystic liver disease and Gilbert’s syndrome.
• Discussion embraces the genetics, clinical characteristics, diagnosis and treatment of the above disorders.

INTRODUCTION

Human genomics, the study of structure, function and interactions of all genes in the human genome, promises to improve the diagnosis, treatment and prevention of disease. It is predicted that genomics will influence the practice of medicine in the future. The overall aim is to be able to better predict an individual’s risk of developing common complex disease, so that prevention and treatment can be optimised.

WILSON’S DISEASE

KEY POINTS

• An autosomal recessive genetic disorder characterised by accumulation of copper in liver, brain and cornea, secondary to impaired intrahepatic trafficking and biliary excretion of copper.
• Clinically, Wilson’s disease (WD) involves:

– Liver—cirrhosis, chronic hepatitis or fulminant hepatic failure
– Neurologic—Kayser-Fleischer rings, parkinsonian characteristics and intellectual disturbances
– Miscellaneous: Fanconi’s syndrome, osteoporosis, haemolytic anaemia.

• Diagnosis: caeruloplasmin ↓; free copper ↑; urinary copper excretion ↑; hepatic copper concentration ↑.
• Treatment: D-penicillamine is first-line therapy. Other drugs include trientine and zinc tetrathiomolybdate. Liver transplantation may be appropriate.

Genetics and pathophysiology

Wilson’s disease (WD) is an autosomal recessive disorder characterised by accumulation of copper (Cu) in liver, brain and cornea, secondary to impaired intrahepatic trafficking and biliary excretion of Cu. The WD gene (on chromosome 13) codes for a Cu transporting P-type ATPase (ATP-7B), which can be altered by multiple mutations. An impaired or deficient WD gene product is responsible for the lack of Cu incorporation into caeruloplasmin and the defective biliary excretion of Cu in WD resulting in increased hepatic stores of Cu. Free Cu is released into the serum and deposited into end organs.

Epidemiology

WD is a rare disorder, affecting approximately 3 people per 100,000.

Clinical features

Clinical symptoms are rarely observed before the age of 5 years and most untreated patients become symptomatic by the age of 40 years. The main organ systems involved are the liver, brain, eyes, kidneys and joints.

Hepatic

• Cirrhosis which may be either micronodular or a mixed macro-micronodular histologic pattern.
• Chronic hepatitis characterised by raised serum aminotransferases in the presence of severe hepatocellular necrosis and inflammation.
• Fulminant hepatic failure. Elevated serum aminotransferases with marked elevation of serum bilirubin, low alkaline phosphatase level and Coombs’-negative haemolytic anaemia. Serum caeruloplasmin may be normal but 24-h urinary Cu and free serum Cu are usually raised.

Neurologic

Kayser-Fleischer rings (KF) (on ophthalmic slit-lamp examination) are present in most patients with neurological symptoms and over half of those without. Neurologic symptoms are varied and include parkinsonian characteristics. Intellectual disturbances include mild memory impairment and overt psychosis.

Miscellaneous

Fanconi’s syndrome with proximal tubular acidosis, osteoporosis with spontaneous fractures and Cu-induced haemolytic anaemia.

Diagnosis

• Requires a combination of clinical and biochemistry tests.
• Serum caeruloplasmin. Low serum levels of caeruloplasmin.
• Non-caeruloplasmin serum copper is elevated. Normal free Cu level is under 10 μg/dL. In WD it is greater than 25 μg/dL.
• Urinary Cu excretion (normal 40 μg/24 h). Most WD patients have a urinary Cu excretion greater than 100 μg/24 h.

Liver biopsy: hepatic Cu concentration >250 μg/g dry tissue (normal less than 50 μg/g).

Genetic studies: molecular genetic analysis is of limited value as there are more than 200 mutations. Mutation or haplotype analyses are the only reliable tools for screening the families of an index case.

Treatment

D-penicillamine: first-line drug in Wilson’s disease. In 20% of patients, hypersensitivity reactions (neutropenia, thrombocytopenia, rash and arthritis) can occur.

Trientine: second-line therapy. Less potent Cu chelator. Sideroblastic anaemia a major side effect.

Zinc: used mainly in presymptomatic patients as maintenance therapy and in combination therapy.

Tetrathiomolybdate: mainly used to avoid neurologic deterioration that accompanies chelation treatment in some patients.

Liver transplantation: transplant recipients have an excellent long-term prognosis because the underlying biochemical defect is corrected.

ALPHA1-ANTITRYPSIN DEFICIENCY (A1-ATD)

KEY POINTS

• Autosomal recessive genetic disorder that predisposes to liver disease and chronic obstructive pulmonary disease (COPD).
• Main function of alpha1-antitrypsin is to protect tissues against proteases such as neutrophil elastase.
• Clinically involves liver: chronic hepatitis, cirrhosis and hepatocellular carcinoma.
• Investigations: serum concentration of alpha1-antitrypsin: detection of defective α1-ATZ alleles.
• Treatment: no specific therapy. 4-phenyl butyric acid is promising. Other strategies include liver transplantation and reconstitution of the normal genotype through gene therapy.

Alpha1-antitrypsin deficiency (α1-ATD) is a genetic disorder (autosomal/recessive) that predisposes to chronic liver disease and chronic obstructive pulmonary disease (COPD). It affects 1 in 2,000–5,000 individuals.

α1-ATD is a glycoprotein mainly produced by hepatocytes in the liver. Its main function is to protect tissues against proteases, such as neutrophil elastase.

Pathogenesis and genetics

A mutation in codon 342 of the α1-ATD gene, changing a single amino-acid from lysine to glutamate is the primary cause of α1-ATD. This results in a defective α1-antitrypsin molecule (α1-ATZ) that aggregates in the endoplasmic reticulum of the hepatocyte, leading to a cascade of events causing injury to the liver. There is variation in the severity of the disease because of gene modifiers and environmental factors, which modulate the hepatocyte deposition of α1-ATZ.

Clinical manifestations

Liver disease

Liver disease encompasses chronic hepatitis, cirrhosis and hepatocellular carcinoma. α1-ATD should be considered in any adult who presents with the above diseases of unknown aetiology. α1-ATD is usually diagnosed early in life (4–8 weeks of life) presenting as persistent jaundice with raised liver transaminases and bilirubin.

Investigations: serum concentrations of α1-AT and detection of defective α1-ATZ alleles.

Treatment: no specific therapy is available, though 4-phenyl butyric acid is a promising drug. Other treatment strategies include orthoptic liver transplantation, somatic gene therapy and replacement therapy.

Other diseases

An increased prevalence of pulmonary disease (emphysema, panniculitis, vasculitis) is noted, which require specific treatment.

HEREDITARY HAEMOCHROMATOSIS

KEY POINTS

• Autosomal recessive. Most patients homozygous for C282Y mutation of the HFE gene. A small percentage have the mutation C282Y:H63D.
• Arises from an imbalance between Fe absorption and excretion (inappropriate increased absorption of dietary iron).
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