Review Article: The Iron Overload Syndromes

A. Siddique; K. V. Kowdley


Aliment Pharmacol Ther. 2012;35(8):876-893. 

In This Article

Secondary Iron Overload

Haematological Disorders

Erythroid disorders associated with ineffective erythropoiesis may manifest a haemochromatosis phenotype. Four main groups of haematological disorders may cause iron overload: (i) The thalassaemia syndromes (thalassaemia major and intermedia) (ii) Sideroblastic anaemias, both acquired and congenital (iii) congenital dyserythropoietic anaemias which include pyruvate kinase deficiency, chronic pernicious anaemia, hereditary spherocytosis and sickle cell anaemia (iv) acquired myelodysplastic syndrome. The thalassaemia syndromes represent the most common causes of ineffective erythropoiesis and secondary iron overload.[79] Individuals with haematological disorders, especially those with thalassaemia and myelodysplastic syndrome, eventually become transfusion dependant. One unit of packed red blood cells (RBCs) contains 200–250 mg of elemental iron. Therefore, significant iron overload may develop over time secondary to multiple transfusions.

Apart from transfusional iron overload, various other mechanisms may also be involved in the pathogenesis of iron overload in these patients, including downregulation of hepcidin. Hepatocyte cell lines exposed to hypoxia demonstrate a down-regulation of hepcidin production.[80,81] Furthermore, the soluble form of HJV (sHJV) by competing with membrane form of HJV (mHJV) may suppress BMP signalling resulting in downregulation of hepcidin.[82,83] Therefore, any stimulus resulting in increased sHJV, including iron deficiency and hypoxia, may lead to decreased hepcidin expression. Tissue hypoxia also increases erythropoietin (EPO) expression, which directly down-regulates hepcidin expression in vitro.[84] Finally, two molecules (GDF15 and TWSG1) have been identified that may serve as 'signals' for iron regulation. Serum from patients with beta thalassaemia and other congenital anaemias were found to contain high levels of GDF15 which, by virtue of its inhibitory effect of hepcidin, may contribute to iron overload in these individuals.[85,86,87] TWSG1 acts by inhibiting the BMP-dependent activation of Smad-mediated signal transduction resulting in iron overload.[88] Unlike primary haemochromatosis, these conditions are commonly associated with anaemia and iron accumulation is predominantly in liver macrophage cells.[89] Because of the associated anaemia, these patients do not tolerate phlebotomy and chelation therapy is required to prevent long-term sequelae.

African Iron Overload

African Iron Overload is prevalent in a number of Sub-Saharan African countries and has been attributed to consumption of large quantities of traditionally fermented home brewed beer rich in iron. The iron content in this beer may be as high as 46–82 mg/L, in comparison with standard commercial beer that has an iron content of only 0.5 mg/L.[90] Although patients with African Iron Overload may have a history of heavy alcohol consumption, overt histological features of alcoholic liver disease are usually not evident. In fact, the pathophysiology is probably more complex and it has been suggested that African Iron Overload may have a genetic component. A Q248H mutation of ferroportin gene SLC4OA1 has been frequently reported in families with African iron overload.[91] African Americans in the US have a lower prevalence of primary iron overload compared with Caucasians. However, the Q248H mutation has also been reported in African Americans; iron overload among African-Americans is associated with a pattern of hepatic iron deposition similar to African Iron Overload, with iron deposition in both hepatocytes and macrophages.[92]

Chronic Liver Disease

Chronic viral hepatitis, most commonly Hepatitis C virus infection (HCV), may be associated with iron overload.[93,94] The pathophysiology of iron overload in HCV is likely a combination of release of iron from necrotic hepatocytes, a direct effect of HCV on iron homeostasis, presence of HFE mutations and/or dysregulation of hepcidin.[95] In a transgenic mice model of HCV, reactive oxygen species associated with the virus caused inhibition of C/EBPa resulting in downregulation of hepcidin and hepatic iron accumulation.[96,97] Furthermore, release of proinflammatory cytokines by liver macrophages may activate hepatic stellate cells causing up-regulation of alpha smooth muscle actin and procollagen α-1 resulting in increased fibrogenesis.[98]

Alcoholic liver disease is associated with iron deposition initially in the hepatocytes, but with advanced disease, iron accumulates in both hepatocytes and macrophages.[99] Iron and alcohol act synergistically in causing liver injury. Alcohol consumption is associated with elevated serum iron and abstinence of just 2–6 weeks significantly reduces these elevated serum iron indices.[100] The mechanism by which alcohol induces hepatic iron overload is likely similar to HCV. Alcohol and its metabolites generate reactive oxygen species and lipid peroxidation products, which cause cellular damage in hepatocytes.[101] Thioredoxin, an indicator of oxidative stress, is significantly higher in patients with ALD compared with healthy subjects.[102] Similar to HCV, hepcidin expression may be depressed due to inhibition of C/EBPa leading to iron accumulation and subsequent activation of macrophages.

Non-alcoholic fatty liver disease (NAFLD) is now considered the most common cause of chronic liver disease with a spectrum of disease ranging from benign fatty liver to non-alcoholic steatohepatitis (NASH); the latter may predispose to cirrhosis and hepatocellular carcinoma.[103] Mild to moderate elevation of iron indices and hepatic iron concentration are frequently observed in patients with NASH.[104] Oxidative stress, iron overload and insulin resistance act synergistically resulting in liver injury. The pathogenesis of NASH has been proposed to be caused by a 'multiple-hit hypothesis'. The first 'hit' results in accumulation of hepatic fatty acids leading to steatosis. A second 'hit' then leads to progression of simple steatosis to steatohepatitis.[105] Hepatic iron may enhance oxidative stress and may be the second hit contributing to the pathogenesis of NASH, at least in some patients.[106,107] The pathogenesis of increased hepatic iron in NAFLD and NASH is likely multifactorial. The role of HFE mutations in the pathogenesis of NASH remains controversial. Some studies have shown an increased prevalence of HFE mutation in patients with NASH although data from groups with a low prevalence of HFE mutations have not shown the same association.[108,109] Recent studies have shown that FPN and HJV are both down regulated by increased expression of TNF-alpha, which may occur in NASH.[110] The role of hepcidin in NASH remains uncertain. Although hepcidin expression by adipose tissue may be increased, increased insulin levels may have the opposite effects.[111] Further studies are needed to elucidate whether hepcidin expression is increased or decreased in NAFLD and NASH.

Porphyria Cutanea Tarda (PCT) is an iron-dependent condition characterised by vesiculo-bullous eruption on the hands and face. Mild to moderate iron overload maybe present in 60–70% of patients with PCT.[112] Several studies have shown a high prevalence of C282Y and H63D mutation in patients with PCT, and these mutations maybe present in up to 70% of individuals with PCT.[113]


Aceruloplasminaemia is an autosomal recessive condition due to a mutation in the ceruloplasmin gene.[114] Ceruloplasmin (CP) is a multicopper ferroxidase synthesised in the hepatocytes.[115] CP is required for mobilisation of iron and oxidation of Fe2+ to Fe3+ which is essential for release to transferrin. Deficiency of ceruloplasmin results in iron deposition in liver, pancreas, basal ganglia and other organs. The classic triad of aceruloplasminaemia is comprised of retinal degeneration, neurological symptoms and diabetes mellitus.[116] Patients with aceruloplasminaemia have normal hepatic copper content, but markedly elevated hepatic iron concentration and SF concentrations equivalent to those observed in persons with haemochromatosis.[117]