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).
• The most important clinical characteristics are:

– Asymptomatic—incidentally discovered
– Arthralgias/arthritis
– Chronic liver disease
– Alcohol is a key factor in determining clinical expression.

• Biochemical abnormalities include elevated transferrin saturation and ferritin.
• Liver biopsy indicated in the presence of hepatomegaly, raised liver enzymes, very high ferritin levels.
• Imaging studies. MRI is the preferred modality for quantification of hepatic iron.
• Ultrasonography important in staging of liver disease.
• Treatment: phlebotomy—monitor haemoglobin and haematocrit.
• Avoid alcohol and high doses of ascorbic and citric acids.

Hereditary haemochromatosis (HH) is inherited as an autosomal recessive disorder. Most adult patients are homozygous for the C282Y mutation of the HFE gene (C282Y: C282Y). A small but significant percentage of HH patients have the mutation C282Y:H63D termed the compound heterozygote state (see Chapter 37).

Prevalence

HH is the most common genetic disease in white persons of Northern European descent—approximately 1:250.

Molecular pathogenesis

Haemochromatosis arises from an imbalance between iron (Fe) absorption and excretion. It is generally accepted that pathologic Fe in HH arises from inappropriately increased absorption of dietary Fe.

The molecular pathophysiology of HH is unknown. There is increasing evidence that hepcidin (an ‘iron hormone’) might serve as a signalling molecule because it is produced by the liver and released into the blood in response to iron loading or acute infections. Hepcidin is thus emerging as an important regulator of Fe metabolism. Low hepcidin expression and secretion is a unifying feature of all primary overload syndromes.

Clinical presentation

The most common presenting symptoms are:

• Asymptomatic – incidental diagnosis because of discovery of elevated serum Fe markers (↑ serum transferrin Fe saturation, ↑ ferritin) and/or raised aminotransferase levels
• Joint pains (arthritis or arthralgias)
• Chronic liver disease (often associated with diabetes mellitus). The liver disease may progress from fibrosis to cirrhosis and hepatocellular carcinoma.
• Heavy alcohol intake can accelerate liver damage in homozygous HH.

Investigations

• Biochemical abnormalities: elevated transferrin saturation and ferritin. Note: ferritin is an acute phase reactant and, when used alone, is often raised in other disease states such as hepatitis, fatty liver, inflammatory conditions and malignancy. Other parameters that should be assessed include: serum Fe, transferrin, full blood count, liver function tests, coagulation studies.
• Genetic testing: predisposition to HH is indicated if there is homozygosity for C282Y or compound heterozygosity for C282Y and H63D. Several less common mutations in the HFE gene may occur (Table 42.1).
• Imaging studies: Magnetic resonance imaging (MRI) is the preferred modality. Quantification of Fe storage can be assessed. Computed tomography (CT) scan sensitivity for quantification of hepatic Fe is lower than MRI. Ultrasonography has a poor sensitivity for iron but is important in the staging of liver disease and portal hypertension, and for surveillance of malignant tumours.
• Liver biopsy: indicated for patients with hepatomegaly and raised liver enzymes. Extreme elevation of ferritin (>1000 mg/L) has been associated with cirrhosis. Fe stains, Fe quantification and histopathology should be assessed.
• Other causes of Fe overload due to increased Fe absorption: chronic liver diseases (hepatitis B and C; alcoholic liver disease, non-alcoholic fatty liver disease, porphyria cutanea tarda), dietary Fe overload, miscellaneous causes (African iron overload, neonatal Fe overload, atransferrinaemia) (Table 42.1).

TABLE 42.1 Causes of iron overload

Inherited Acquired
Hereditary haemochromatosis

• Type I HFE-related:

– C282Y homozygotes
– C282Y:H63D compound heterozygotes

• Rare alternative HFE mutations
• Types 2, 3, 4, non-HFE mutations

Chronic liver diseases
• End-stage cirrhosis
• Hepatitis B and C
• Alcoholic liver disease
• Non-alcoholic steatohepatitis
• Porphyria cutanea tarda
Dietary iron overload
Haematological disorders

• Iron-loading anaemias:

– Thalassaemia major
– Sideroblastic anaemia
– Chronic haemolytic anaemia
– Parenteral iron overload

Inherited/acquired?

• African iron overload
• Neonatal haemochromatosis

Treatment

Phlebotomy at weekly intervals with regular monitoring of haemoglobin and haematocrit values. The target ferritin level should be 25–50 mg/L. Once Fe stores have been mobilised, phlebotomy 3 or 4 times per year may be adequate.

High doses of ascorbic and citric acid and dietary supplements containing Fe should be avoided.

Alcohol should be avoided.

All first-degree relatives of homozygous HH patients should be screened as the expressivity of HFE gene mutation is higher in family members of patients with HH.

HEPATIC PORPHYRIAS

KEY POINTS

• Inherited metabolic disorders due to deficiencies of specific enzymes in haem biosynthesis.
• The hepatic porphyrias are: acute intermittent porphyria, variegate porphyria, hereditary coproporphyria; porphyria cutanea tarda; ALA dehydratase porphyria.
• The hepatic porphyrias are autosomal dominant except for ALA dehydratase deficiency which is autosomal recessive.
• Clinical features include abdominal pain, neurological symptoms and cutaneous lesions.
• Precipitating factors: environmental agents (alcohol, smoking, dietary restriction and infection), pharmacological agents (anticonvulsants, antimicrobials, diuretics, cardiovascular drugs and substance abuse).
• Management: identify and avoid precipitating factors, treat pain with opiates (not oxycodone), correct fluids and electrolytes, glucose, intravenous haem for severe attacks. Protoporphyria requires liver transplantation.

Hepatic porphyrias are inherited metabolic disorders due to deficiencies of specific enzymes in haem biosynthesis.

The hepatic porphyrias are: acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, porphyria cutanea tarda, ALA dehydratase porphyria (Table 42.2).

TABLE 42.2 Hepatic porphyrias

image

Hepatoerythropoietic porphyria and erythropoietic protoporphyria involve the liver and bone marrow.

Clinical features

Acute porphyrias

• Characterised by potentially life-threatening neurologic symptoms.
• Females more frequently affected, often in the fourth decade of life. Symptoms rarely occur before puberty.
• Attacks usually last for several days, often require hospitalisation and are followed by complete recovery. Abdominal pain is the most common symptom, often accompanied by nausea, constipation and symptoms of sympathetic overactivity and neuropsychiatric disturbances.
• Attacks are often precipitated by environmental agents (alcohol, smoking, infection, stress, low-energy diets) or pharmacologic compounds (anticonvulsants, barbiturates, various antimicrobial agents, cardiovascular drugs, diuretics, substance abuse).

Photocutaneous porphyrias

• Characterised by variety of severe skin lesions.
• Porphyrin accumulation leads to photosensitisation and skin damage following exposure to sunlight.
• Presents with subepidermal bullae, pigmentation and hypertrichosis.
• Sporadic porphyria cutanea tarda (PCT): associated with chronic alcoholic liver disease, hepatitis C infection and Fe overload.
• High rates of hepatocellular carcinoma occur in PCT patients with chronic liver disease.

Treatment

Acute attacks

• Avoid drugs and other precipitating factors. Treat pain with opiates (not oxycodone).
• Aggressive management of fluid and electrolyte disturbances (glucose inhibits ALA synthetase activity).
• Intravenous haematin in severe attacks (haematin is a stable form of haem that inhibits ALA synthetase and subsequent ALA and porphobilinogen accumulation).
• Haematin can have a dramatic effect on neurologic symptoms.
• Liver transplantation is indicated for patients with protoporphyria.

Photocutaneous porphyrias

• Avoid ultraviolet exposure.
• Sunscreens and protective clothing.
• In PCT phlebotomy and chloroquine may be useful.

CYSTIC FIBROSIS (CF)

KEY POINTS

• Autosomal recessive disease of epithelial cell ion transport.
• The gene encodes for the cystic fibrosis transmembrane regulator (CFTR).
• Focal biliary cirrhosis is the pathognomonic lesion. Biliary tree abnormalities include gallstones, micro-gallbladder and mucocele. Sclerosing cholangitis and cholangiocarcinoma occur in higher frequency in cystic fibrosis patients.
• Liver biochemical tests may not correlate with severity of the disease.
• Treatment: ursodeoxycholic acid may hep to improve clinical status.

Cystic fibrosis (CF) is an autosomal recessive disease of epithelial cell ion transport. The gene involved is on the long arm of chromosome 7 and encodes for the cystic fibrosis transmembrane regulator (CFTR). In this discussion, the hepatic complications of CF will be reviewed.

Hepatobiliary characteristics

Focal biliary cirrhosis, a patchy distribution of cirrhotic transformation with inspissation of the small bile ducts, which occurs predominately in the portal tracts, is the pathognomonic lesion in CF-associated liver disease. Biliary tree abnormalities include gallstones, micro-gallbladder and mucocele.

Sclerosing cholangitis, and cholangiocarcinoma occur with higher frequency in patients with CF.

• Biochemistry: liver biochemical tests may remain relatively normal and do not correlate with the severity of the liver disease.
• Liver biopsy: sampling error may occur because of the focal distribution of the lesions.
• Imaging: ultrasonography may detect the presence of abnormalities.
• Gene testing: useful, although cirrhosis and portal hypertension affect only a very small proportion of the total CF population.

Treatment

Ursodeoxycholic acid has been shown to improve the biochemical indices of liver injury and may help to improve overall clinical status. Portal hypertension can be treated with portosystemic shunts.

GAUCHER’S DISEASE

KEY POINTS

• Gaucher’s disease is an autosomal recessive condition resulting in a deficiency of glucocerebrosidase.
• This leads to an accumulation of sphingolipids in the reticuloendothelial system including the liver and spleen.
• There are 3 forms:

– Type 1—hepatosplenomegaly
– Type 2—hepatosplenomegaly plus neuropathic features and is often fatal by age 2 years
– Type 3—hepatosplenomegaly and a later onset of neuropathic features.

POLYCYSTIC LIVER DISEASE

KEY POINTS

• Dominant inheritance.
• Characterised by presence of four or more liver cysts of biliary epithelial origin in individuals over 40 years of age.
• Often associated with autosomal dominant polycystic kidney disease.
• Diagnosis: imaging studies of the abdomen; ultrasonography, CT scan and MRI.
• Clinical: often asymptomatic. Symptoms may develop due to mass effect of the cyst or complications (intracystic haemorrhage, infection or cyst rupture).
• Treatment: fenestration of the cyst.

Polycystic liver disease (PCLD) is a dominantly inherited condition characterised by the presence of four or more liver cysts of biliary epithelial origin in individuals older than 40 years. PCLD can exist as a specific clinical entity separate from autosomal dominant polycystic kidney disease (ADPKD) and is termed autosomal dominant polycystic liver disease (ADPLD). However, it is common for PCLD to be associated with polycystic kidney disease with patients presenting initially with kidney cysts first followed by hepatic cysts. The prevalence of hepatic cysts in ADPKD is age-related, ranging from 0% at 20 years to 80% at 60 years. The mutant gene (PRKCSH) is usually located on chromosome 19 and encodes for a protein called hepatocystin.

Diagnosis

Diagnosis is made by imaging studies of the abdomen: ultrasonography, CT and MRI.

Clinical

Often asymptomatic. Symptoms develop during fourth or fifth decade due to mass effect of the cyst or complications such as intracystic haemorrhage, or infection and cyst rupture.

Treatment

Therapy of cysts is surgical with fenestration of the cysts the usual procedure.

GILBERT’S SYNDROME

Gilbert’s syndrome is a common cause of unconjugated hyperbilirubinaemia that affects 3% to 8% of the population and is inherited in an autosomal recessive pattern. Average age at presentation is 18 years and it is rarely recognised before puberty. Splenomegaly and a mild haemolytic anaemia may be present.

Pathogenesis

There is a defect in the hepatic uptake of bilirubin by the hepatocyte and a partial defect in conjugation of bilirubin. There is a reduction in the enzyme bilirubin UDP-glucuronosyltransferase 1 (B-UGT), the enzyme responsible for formation of conjugated bilirubin in the hepatocyte. This is from a mutation in the gene encoding B-UGT (in the promoter region upstream to exon-1) that reduces production. Gilbert’s syndrome arises in those homozygous for the variant promoter.

image

FIGURE 42.1 A background of liver disease in a family.

α1-ATD = alpha1-antitrypsin deficiency; α1-ATZ = the defective α1-antitrypsin molecule; AIP = acute intermittent porphyria; ALA = 5 aminolevulinic acid; B-UGT = bilirubin UDP-glucuronosyltransferase 1; CNS = central nervous system; Cu = copper; Fe = iron; HCC = hepatocellular carcinoma; HP = hepatic porphyrias; IV = intravenous; K-F = Kayser-Fleischer; MRI = magnetic resonance imaging; PCT = porphyria cutanea tarda; RES = reticuloendothelial system.

image

Clinical characteristics

Most patients are asymptomatic and jaundice develops with intercurrent illness, fasting, stress, fatigue, ethanol, nicotinic acid intake and premenstrually.

Diagnosis

Rise in bilirubin with fasting is a good diagnostic test. Total bilirubin levels are usually less than 3 mg/mL and may rise to 5–6 mg/mL during illness or stress.

Gilbert’s syndrome is a benign condition and no therapy is required.

FURTHER READING

Ferenci P. Wilson’s disease. Clin Gastroenterol Hepatol. 2005;3:726-733.

Lazaridis KN, Petersen GM. Genomics, genetic epidemiology and genomic medicine. Clin Gastroentrol Hepatol. 2005;3:320-328.

Stoller JK, Aboussouan LS. α1-antitrypsin deficiency. Lancet. 2005;365:2225-2236.

Zoller H, Cox T. Haemochromatosis: genetic testing and clinical practice. Clin Gastroenterol Hepatol. 2005;3:945-958.

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