Wilson disease and haemochromatosis

Overview

Wilson disease (copper) and hereditary haemochromatosis (iron) are inherited causes of chronic hepatitis and cirrhosis that are treatable. Both must be screened for in young patients with unexplained liver disease, because early treatment prevents permanent organ damage. Both also need family screening.

Wilson disease (hepatolenticular degeneration)

Normal copper handling

Dietary copper is carried to the liver. There it is either built into caeruloplasmin (a copper-carrying protein released into blood) or excreted in bile.

Aetiology and pathophysiology

• Autosomal recessive; mutation in ATP7B, a copper-transporting ATPase, on chromosome 13. Kumar quotes a frequency of 1 in 30,000 to 1 in 100,000; commoner where consanguinity is common (relevant in Pakistan).
• The defect causes failure of biliary copper excretion and failure to load copper onto caeruloplasmin, so caeruloplasmin is low.
• Copper builds up in the liver, then spills into blood and deposits in the brain (basal ganglia, especially the lentiform nucleus), cornea, kidneys and red cells.

Clinical features

Investigations

• Serum caeruloplasmin: low in over 80% (can be normal, e.g. in acute inflammation or pregnancy, as it is an acute-phase protein).
• Serum copper: usually low total copper (because caeruloplasmin-bound copper is low), though the unbound fraction is high.
• 24-hour urinary copper: raised, typically 100–1000 µg/24 h (normal under 40 µg). A very useful test when caeruloplasmin is borderline.
• Slit-lamp for Kayser-Fleischer rings.
• Liver biopsy with measured hepatic copper: over 250 µg/g dry weight supports the diagnosis (high levels also occur in long cholestasis).
• Genetic testing of ATP7B (helps family screening).
• MRI brain: changes in the basal ganglia.
• Liver tests vary; in acute liver failure from Wilson disease the ALP is often disproportionately low with high bilirubin and haemolysis.

Treatment

• Lifelong chelation:
  • Penicillamine (Kumar: 1–1.5 g daily): chelates copper and increases its urinary loss. Serious side effects in about 10%: rash, leucopenia and other cytopenias, proteinuria/nephrotic syndrome, lupus-like illness; can cause zinc deficiency with altered taste. Neurological symptoms may worsen at first.
  • Trientine (1.2–1.8 g/day): alternative chelator with fewer side effects.
  • Zinc acetate (150 mg/day): blocks copper absorption in the gut; used for maintenance and in asymptomatic siblings.
• Low-copper diet: avoid chocolate, nuts, shellfish and liver.
• Liver transplant for acute liver failure or decompensated cirrhosis; it corrects the defect.
• Screen all siblings and children.

Hereditary haemochromatosis (HH)

Aetiology and types

• Most people with clinical HH (about 85–90%) carry two copies of C282Y.
• Common in people of northern European descent (about 1 in 400 homozygous). It is uncommon in South Asians; in Pakistan, secondary iron overload (from repeated transfusion in thalassaemia) is far more common.
• Expression is variable: many homozygotes never develop disease.

Mechanism

• Hepcidin, made by the liver, normally switches off iron release by degrading the exporter ferroportin in gut cells and macrophages.
• In HH, hepcidin is inappropriately low, so the gut keeps absorbing iron even when stores are full.
• Iron collects slowly in parenchymal cells: liver, pancreas, heart, pituitary, joints and skin. Total body iron may reach 20–40 g (normal about 3–4 g).

Clinical features

• Men usually present in the fifth decade; women later because menstruation and pregnancy remove iron.
• Early: tiredness, arthralgia, raised liver enzymes.
• Classic triad ("bronze diabetes"): skin pigmentation, hepatomegaly/cirrhosis, diabetes. Only seen with gross overload.
• Hypogonadism from pituitary iron (low LH, FSH and testosterone): loss of libido, testicular atrophy. The commonest endocrine feature.
• Heart: dilated cardiomyopathy, arrhythmias (common cause of death in younger patients).
• Joints: arthropathy of the 2nd and 3rd metacarpophalangeal joints; chondrocalcinosis (calcium pyrophosphate).
• Liver cancer: in those with cirrhosis, HCC develops in a large proportion (Kumar quotes about 30%).

Investigations

• Transferrin saturation (serum iron ÷ TIBC × 100): over 45%; the best and cheapest first test.
• Serum ferritin: raised (often over 500 µg/L in homozygotes); reflects stores but also rises with inflammation, alcohol and fatty liver.
• HFE genotyping if iron studies are abnormal.
• MRI (T2-weighted) estimates liver and heart iron. In HH the pancreas is loaded; in transfusion overload iron sits mainly in macrophages and the pancreas is relatively spared.
• Liver biopsy: not needed for diagnosis, but stages fibrosis and measures hepatic iron (Perls stain shows blue iron in hepatocytes). Consider it when ferritin is very high or liver enzymes are raised.

Treatment

• Venesection: 500 mL removed weekly or twice weekly (each unit removes about 250 mg of iron) until ferritin falls to the low-normal range and the MCV and haemoglobin start to fall; this may take up to 2 years. Then 3–4 venesections a year for life.
• Venesection improves survival and reverses tiredness, pigmentation, heart and liver changes (if caught before cirrhosis).
• Not reversed: diabetes (insulin needs may fall), testicular atrophy and arthropathy/chondrocalcinosis.
• Desferrioxamine chelation if venesection is not possible (severe anaemia or heart disease).
• Avoid vitamin C supplements (increase iron absorption), iron tablets and alcohol.
• Testosterone replacement for hypogonadism.
• HCC surveillance (6-monthly ultrasound) if cirrhosis is present.
• Screen first-degree relatives with transferrin saturation, ferritin and HFE testing.

Secondary iron overload (haemosiderosis)

Repeated transfusion (thalassaemia major, sickle cell, aplastic anaemia) and ineffective erythropoiesis load iron first into macrophages, then organs. Treat with chelators (desferrioxamine, deferasirox, deferiprone), not venesection. This is the common iron overload in Pakistani practice.

Comparison at a glance

Quick revision

• Wilson: AR, ATP7B (chromosome 13), failure of biliary copper excretion.
• Liver disease in children, neuropsychiatric disease in young adults; KF rings in Descemet membrane.
• Low caeruloplasmin, urinary copper over 100 µg/24 h, liver copper over 250 µg/g.
• Penicillamine or trientine for life; zinc for maintenance; transplant for liver failure.
• HH: HFE C282Y (chromosome 6), low hepcidin, iron in parenchymal cells.
• Transferrin saturation over 45% is the best screening test; ferritin shows stores.
• Bronze skin, cirrhosis, diabetes, hypogonadism, cardiomyopathy, MCP arthropathy.
• Venesection; diabetes, testicular atrophy and chondrocalcinosis do not reverse.
• Screen relatives in both diseases.

Written by The House Job from standard references (Kumar and Clark's Clinical Medicine).

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