Iron plays an essential role in many physiological functions, but whenever body iron exceeds its need and storage capabilities are saturated, toxicity due to iron overload may arise. Normal hepatic iron content (HIC) is usually below 35 umol/g of dry weight. HIC above 200-250 umol/g has been associated with liver fibrosis and cirrhosis, as seen in haemochromatosis and thalassemia (1). Even the presence of mild iron excess in the liver represents a risk for toxicity: iron can act as a comorbid factor (along with fat, hepatitis viruses and alcohol) and fuel oxidative stress-driven cell toxicity, or signaling pathways involved in fibrogenesis and carcinogenesis (2). In chronic liver diseases, iron deposits are found either in hepatocytes, Kupffer/sinusoidal cells or in both. Hepatocytic iron usually reflects increased iron influx as a consequence of circulatory iron excess. The cause of increased iron influx is hepcidin deficiency due to either genetic (e.g. C282Y HFE gene mutation) or acquired factors (e.g. alcohol, HCV etc.) (1). Excess iron deposits in Kupffer/sinusoidal cells may affect their immunomodulatory and antiinflammatory activity, cytokine biology, defense against infections, immunosurveillance of tumor growth or response to immunomodulatory drugs (3). Instestinal absorbtion of iron is regulated by hepcidin. Hepcidin is a 25-aminoacid peptide synthesized in the liver. Its binding to ferroportin which is an iron transporter in enterocytes and macrophages, results in internalization and degradation of ferroportin. In this way hepcidin leads to decreased systemic iron bioavailability and parenchymal iron stores but also to increased its macrophagic stores. Hepcidin production is up-regulated by body iron excess and inflammation and down-regulated by anemia and hypoxia. The others hepcidin modulators are: the bone morphogenic protein (BMP), the hemojuvelin ( HJV), HFE gene and transferrin receptor type 2. Mutations in genes encoding these proteins result in hemochromatosis. Many more genes and involved in hepcidin expression and still several questions remains to be answered (4).

The large spectrum of iron-related disease is now divided into 3 main groups (4):

1. Four types of hereditary haemochromatosis,

2. Conditions related to mutations in ferroportin, ceruloplasmin, transferrin or di-metal transporter 1 genes,

3. Acquired iron-overload syndroms.

Genetic iron-overload disorders are divided into haemochromatotic and non-haemochromatotic.

Hemochromatosis is considered to be the most common hereditary metabolic disorder in white adults. It is linked to HFE gene which was identified in 1996. Main mutations of HFE gene namely C282Y and H63D were described and their frequencies analyzed in various population of European descent (5). Most patients with clinical symptoms of haemochromatosis are homozygous for C282Y. This mutation has arised from a single Celt or Viking ancestor. Between 2000-2004 the other genes involved in iron homeostasis were intesively studied, leading to recognition of hepcidin ( HAMP) – the most important iron hormone, hemojuvelin ( HJV), transferin receptor 2 (TfR2) and ferroportin. Recent findings led to a novel hypothesis on potential digenic modes of inheritance or the involvement of modifier genes. Haemochromatotic phenotype is characterized by normal erythropoiesis, increased transferrin saturation (reflecting plasma pool of iron), increased ferritin (reflecting parenchymal pool of iron) with impaired production/regulation/activity of hepcidin (6). Based upon this definition four types of haemochromatosis can now be proposed:

Type 1 or classic, representing more than 90% of all iron-related syndromes, associated with mutations of HFE gene, transmitted as an autosomal recessive trait. Early symptoms are not specific (weakness, fatigue and arthralgia), but advanced disease is a result of iron-overload in several parenchymal organs leading to liver cirrhosis with high risk of HCC development, diabetes mellitus, dark discoloration of the skin, congestive heart failure with arrhythmias, osteoarthritis and hypogonadrotropic hypogonadism.

Type 2 – Juvenile haemochromatosis – is related to mutations on hemojuveline gene ( HJV, type 2A) i.e. G320V or hepcidin ( HAMP, type 2B). There are severe autosomal recessive disorders with early onset, affecting heart and endocrine organs. Patients usually die due to heart failure (7).

Type 3 is related to mutations in Transferrin receptor 2 ( TfR2) (i.e. Y250X, Q317X) and the symptoms of this autosomal recessive disease are similar to typical haemochromatosis (8).

Type 4 of haemochromatosis is associated with mutation of Ferroportin gene (SLC40A1). This condition – called Ferroportin disease type B – is transmitted as a dominant disease (9) and gives late articular and hepatic symptoms.

These conditions are summarized in table 1.

Nonhaemochromatotic iron-overload disorders include:

1. Ferroportin disease type A, an autosomal dominant disease, ill-named as type 4 haemochromatosis, caused by mutation in ferroportin gene (SLC40A1). Biochemical features of disease are different from classic one. Typically high levels of ferritin are observed with normal or slightly elevated transferrin saturation, which reflects mesenchymal iron-overload (9).

2. Hereditary a(hypo)ceruloplasminemia, related to mutations in the ceruloplasmin gene, an autosomal recessive disease with haematological (microcytic anaemia), neurological (retinal degeneration, extrapyramidal syndrome, cerebellar ataxia and dementia) and metabolic (diabetes) symptoms and both low-serum iron and transferrin saturation (10).

3. Hereditary a(hypo)transferrinemia, transmitted as autosomal recessive trait is related to mutations in the transferrin gene, has early onset with severe iron deficiency anaemia and parenchymal iron-overload (11).

4. Mutations in the DMT1 (Divalent Metal Transporter) gene resulting in microcytic anaemia and hepatic iron excess (12).

Acquired iron-overload conditions included a heterogenous spectrum of health problems:

– Chronic excessive iron supply (13).

– Haematological disorders like thalassemia, myelodysplastic syndrome, congenital dyserythropoietic anemia, red cell enzymes deficiencies, sickle cell disease and other haemoglobinopathies that are responsible for hepatic iron excess both by downregulation of hepcidin production and multiple transfusions (14, 15).

– Chronic liver diseases, both by the liver damage and the cause of hepatic iron excess.

This last problem seems to be of particular importance due to a large number of affected patients. Generally a response to necro-inflammatory hepatocytic damage is a phagocytic process resulting redistribution of iron towards the Kupffer cells with slight iron-overload. End-stage liver disease may be associated with significant parenchymal iron excess, related to decreased transferrin and hepcidin synthesis secondary to impaired synthetic function of the liver (16). The pseudo-haemochromatotic cirrhosis pattern appears with increased transferrin saturation and ferritin level although without mutations in HFE gene, heterogenic distribution of iron throughout the liver and absence of iron deposits within fibrous septa at liver biopsy may also be seen.

Hepatitis C is associated with more specific mechanism of iron-overload. It is proposed that interaction between C virus and HFE gene might to some extend explain HCV-associated liver siderosis (3). In alcoholic liver disease (ALD) alcohol has been shown to inhibit hepcidin synthesis and could participate in alcohol-related liver siderosis (17).

A link between serum ferritin, insulin resistance, and non-alcoholic fatty liver disease (NAFLD) development has been suggested. Serum ferritin is postulated to be a potential marker of insulin resistance (18). Hepatic iron overload characterized by hyperferritinemia with normal or slightly increased transferrin saturation was described in non-C282Y homozygotes. Association between hepatic iron-overload with overweight, visceral distribution of fat, arterial hypertension, dyslipidemia, abnormal glucose metabolism was described and subsequently named as insulin-resistance hepatic iron-overload (IR-HIO) or dysmetabolic iron-overload syndrome (DIOS). On the other hand there are some suggestions that in subject with DIOS, hepcidin-resistance state can develop, because in morbid obesity low iron stores caused by hepcidin synthesis by the visceral adipose tissue were reported. Hyperhepcidinuria in patients with DIOS has also been shown (19, 20).