SERUM IRON is elevated (>30/-Lmol Iitre=’}, with a reduction in the TIBC and complete or almost complete transferrin saturation (>60%). SERUM FERRITIN is elevated (usually >500 /-Lglitre-lor 240 nmollitre -I).
LIVER BIOCHEMISTRY is often normal, even with established cirrhosis.
Heterozygotes may have normal biochemical tests or modest increases in serum iron transferrin saturation (>50%) or serum ferritin (usually >400 /-Lglitre:”).
This can define the extent of tissue damage, assess tissue iron, and the hepatic iron concentration can be measured (> 180 /-Lmolg-I dry weight of liver indicates haernochromatosis). Mild degrees of parenchymal iron deposition in patients with alcoholic cirrhosis can often cause confusion with true homozygous IHC. It is highly likely that many of this former group are heterozygotes for the haemochromatosis gene.
Magnetic resonance imaging
This shows a decreased T2 relaxation time but is not, as yet, accurate enough for diagnosis.
Causes of secondary iron overload such as multiple transfusions must be excluded.
TREATMENT AND MANAGEMENT
Venesection prolongs life and may reverse tissue damage;
the risk of malignancy still remains if cirrhosis is present. All patients should have excess iron removed as rapidly as possible. This is achieved using venesection of 500 rnl performed twice weekly for up to 2 years, i.e. 160 units x 250 mg of iron per unit, which equals 40 g removed. During venesection, serum iron and ferritin and the mean corpuscular volume (MCV) should be monitored. These fall only when available iron is depleted. Three or four venesections per year are required to prevent reaccumulation of iron. Serum ferritin should remain within the normal range. Liver biopsy is useful to ensure removal of iron and to assess progress of hepatic disease.
Manifestations of the disease usually improve or disappear, except for diabetes, testicular atrophy and chondrocalcinosis. The requirements for insulin often diminish in diabetic patients. Testosterone replacement is often helpful.
In rare-patients who cannot tolerate venesection (because of severe cardiac disease or anaemia), chelation therapy with desferrioxamine either intermittently or continuously by infusion has been successful in removing iron.
Screening of relatives
In all cases of IHC all first-degree family members must be screened to detect early and asymptomatic disease. Serum ferritin is an excellent test with only occasional false-positives in hepatocellular necrosis and rare falsenegatives in some family studies.
Wilson’s disease (hepatolenticular degeneration)
This is a very rare inborn error of copper metabolism that results in copper deposition in various organs to produce cirrhosis and degeneration of the basal ganglia of the brain. It is potentially treatable and all young patients with cirrhosis must be screened for this condition.
COPPER METABOLISM. Dietary copper is absorbed from the stomach and upper small intestine. It is transported to the liver loosely bound to albumin. Here it is incorporated into caeruloplasmin, a glycoprotein synthesized in the liver, and secreted into the blood. Copper is normally excreted in the bile.
It is inherited as an autosomal recessive gene located on chromosome 13. It occurs worldwide, particularly in coutries where consanguinity is common. The basic problem is a failure to excrete copper but, although there is a low serum caeruloplasmin, the precise defect remains unknown.
The histology is not diagnostic and varies from that of CAH to macro nodular cirrhosis. Stains for copper show a periportal distribution but this can be unreliable. The basal ganglia are damaged and show cavitation, the kidneys show tubular degeneration, and erosions are seen in bones.
Children usually present with hepatic problems, whereas young adults have more neurological problems, such as tremor, dysarthria, involuntary movements and eventually dementia.
Signs are of chronic liver disease with neurological signs of basal ganglia involvement. A specific sign is the Kayser-Fleischer ring, which is due to copper depositionin Descemet’s membrane in the cornea. It appears as a greenish brown pigment at the corneoscleral junction just within the cornea. Identification of this ring frequently requires slit-lamp examination. It may be absent in young children.
The serum copper and caeruloplasmin are usually reduced but can be normal. The urinary copper is usually increased (100-1000 p,g in 24 hours; normal levels <40 p,g in 24 hours). The diagnosis depends on the measurement of the amount of copper in the liver, although high levels of copper are also found in the liver in chronic cholestasis. Measurement of 64Cu incorporation into the liver may be helpful. Haemolysis and anaemia may be present.
Long-term penicillamine, approximately 1 g daily, is effective in chelating copper and leads to clinical and biochemical improvement. Serious side-effects of the drug occur in 10% and include skin rashes, leucopenia and renal damage. Urine copper levels should be monitored. All siblings and children of patients should be screened. Homozygotes may have the above physical signs, Kayser- Fleischer rings and a low serum caeruloplasmin. Symptomless homozygous relatives should be treated.
Early diagnosis and effective treatment have improved the outlook. Neurological damage is, however, permanent. Death is from liver failure, bleeding varices or intercurrent infection.
A deficiency of ai-antitrypsin (alA T) is sometimes associated with liver disease and pulmonary emphysema (particularly in smokers). alA T is a glycoprotein and part of a family of protease inhibitors (Pi) that control various inflammatory cascades, e.g. complement (Cl inhibitor), coagulation (antithrombin). It is synthesized in the liver and comprises 90% of the serum ai-globulin seen on electrophoresis. The gene is located on chromosome 14. The genetic variants of alAT are characterized by their electrophoretic mobilities as medium (M), slow (S) or very slow (Z). The normal genotype is PiMM, the homozygote for Z is PiZZ and the heterozygotes are PiMZ and PiSZ. Sand Z variants are due to a single amino acid replacement of glutamic acid at positions 264 and 342 of the polypeptide, respectively, and this results in decreased synthesis and secretion of the normal protease inhibitor. S thus forms about 60% of that produced normally by M, whilst the Z variant forms only 15%. alA T is inherited as an autosomal dominant and 1 : 10 of northern Europeans carry a deficiency gene.
The majority of patients with clinical disease have the PiZZ phenotype. Approximately 10-15% of these patients will develop cirrhosis usually over the age of 50 years and75% will have respiratory problems. Approximately 5% of patients die of their liver disease.
THE SERUM alAT IS LOW.
LIVER BIOPSY. Periodic acid-Schiff (PAS)-positive, diastase-resistant globules are seen in periportal hepatocytes. These can be shown to be alA Tusing immunodiagnostic techniques.
PHENOTYPES. PiM is associated with serum levels of alA T of 2-4 g litre “. Homozygotes for the protease inhibitor Z (i.e. PiZZ) have low alA T levels and are seriously affected with liver disease. Heterozygotes (e.g. PiSZ, PiMZ) exist and may develop signs of deficiency.
There is no treatment apart from dealing with the complications of liver disease. Patients with hepatic decompensation should be considered for liver transplantation. Patients should be advised to stop smoking.