2.3 Congenital Storage Diseases

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Presents with increased Fe saturation and ferritin.

Approximately 60% of our body iron (Fe) is located in the hemoglobin of the red blood cells. Most of the Fe in the plasma comes from the release from the macrophages of the reticulo-endothelial system. A smaller part comes from the gastro-intestinal system. The two most important Fe-binding proteins in the serum are transferrin and especially ferritin. Hepcidin is a small protein that is produced by the liver parenchymal cells, in response to a disturbed Fe balance and/or to an inflammatory stimulus. The regulation of hepcidin is partly determined by, among other things, the HFE protein. With a high plasma Fe, hepcidin is stimulated, which suppresses the secretion from the macrophages, and there is a reduced absorption from the intestine.

This condition is caused by a mutation in the HFE gene. This gene codes for the protein that modulates hepcidin, which regulates iron absorption in the intestine. It usually involves a mutation from cysteine ​​to tyrosine in amino acid 282 (C282Y mutation). In addition to this classic form, there are other very rare types.

Patients present with fatigue, arthralgia and increased transaminases. On clinical examination the gray-brown skin color is conspicuous. Associated with liver disease may develop diabetes, myocardial infiltration (rhythm disturbance) and chondrocalcinosis (arthralgia).

The diagnosis is made by a Fe saturation of more than 65% (normal saturation less than 45%) and an increase in ferritin, for example 1000 micrograms/dl (normal level: less than 250 micrograms per dl). The definitive diagnosis is made by looking for the gene mutation.

In making the diagnosis, a family screening must be done by detecting the gene mutation. The treatment consists of phlebotomy (bloodletting) with the aim of serum ferritin < 100mg/l.

This disease is caused by mutations that lead to copper accumulation in the liver (excretory disorder) and the brain. This results in neuropsychiatric symptoms and movement disorders. The diagnosis is made by the presence of a very low serum ceruloplasmin level (plasma copper binding protein), increased copper excretion in the urine (> 100 pg/24 hours) and by the presence of copper accumulation at the edge of the cornea, the so-called Kayser-Fleischer ring.

Patients may also present with acute liver failure (ALF) in which unconjugated bilirubin is markedly elevated. This is due to the release of copper from the tissue, which leads to hemolysis. Familial screening should be performed by detecting the gene mutation. The treatment aims to bind copper and increase urinary excretion. For this purpose, D-penicillamine (750 to 1 g/day) is used with supplements of pyridoxine (vitamin B6) (250 mg/week).

This is a congenital abnormality in the structure of the alpha-antitrypsin produced, such that the aberrant isoenzyme is not excreted from the liver cell. The accumulation in the hepatocytes gives rise to neonatal cholestasis in the newborn. In adulthood it gives rise to cirrhosis, but together with alcohol can cause premature development of cirrhosis.

Plasma deficiency can lead to early emphysema at the age of 18 to 30. The diagnosis is made by the dosage of the alpha-1-antitrypsin protein. However, this is usually increased secondary to cirrhosis. The diagnosis is also made by staining the aberrant enzyme in the hepatocyte on liver biopsy and ultimately detecting the gene mutation. There is currently no specific therapy. A smoking ban should be imposed and prevention of lung infections is important. In case of symptomatic cirrhosis, a liver transplant should be performed.

Porphyrias are a group of metabolic diseases caused by a dysfunction or defect in one of the enzymes of heme biosynthesis. This leads to the accumulation of toxic heme precursors. There are genetic and acquired forms. The most common form is porphyria cutanea tarda. It occurs in 0.5 to 1 in 10,000 cases. The pathogenesis is caused by the accumulation of porphyrins in the liver and is further provoked by various factors, such as alcohol and oral contraception. Typical are sunlight toxicity of the skin and dark red urine if it has been in the urethra for a while. Biochemically there is an increased iron saturation and increased ferritin. The treatment consists mainly of avoiding provoking factors. In case of iron overload, bloodletting must be performed (chelation).

There is a whole list of rare hereditary disorders that affect the liver and are called 'metabolic' diseases. These are diseases in which something goes wrong in the metabolism due to a genetic defect. This can be in the production, combustion or storage of sugars (glycogenesis), in the processing of amino acids (for example tyrosinemia), in the production, storage or processing of fats and in the breakdown of old cells and their membranes (Gaucher disease).

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