Abstract
Numerous clinical entities have now been identified to cause pathologic iron accumulation in the liver. Some are well described and have a verified hereditary basis; in others the genetic basis is still speculative, while in several cases nongenetic iron-loading factors are apparent. The non- HFE hemochromatosis syndromes identifies a subgroup of hereditary iron loading disorders that share with classic HFE-hemochromatosis, the autosomal recessive trait, the pathogenic basis (i.e., lack of hepcidin synthesis or activity), and key clinical features. Yet, they are caused by pathogenic mutations in other genes, such as transferrin receptor 2 ( TFR2), hepcidin ( HAMP), hemojuvelin ( HJV) , and ferroportin ( FPN), and, unlike HFE-hemochromatosis, are not restricted to Caucasians. Ferroportin disease, the most common non- HFE hereditary iron-loading disorder, is caused by a loss of iron export function of FPN resulting in early and preferential iron accumulation in Kupffer cells and macrophages with high ferritin levels and low-to-normal transferrin saturation. This autosomal dominant disorder has milder expressivity than hemochromatosis. Other much rarer genetic disorders are associated with hepatic iron load, but the clinical picture is usually dominated by symptoms and signs due to failure of other organs (e.g., anemia in atransferrinemia or neurologic defects in aceruloplasminemia). Finally, in the context of various necro-inflammatory or disease processes (i.e., chronic viral or metabolic liver diseases), regional or local iron accumulation may occur that aggravates the clinical course of the underlying disease or limits efficacy of therapy.
Highlights
Numerous clinical entities have been identified to cause pathologic iron accumulation in the liver
Other iron genes whose mutations were associated with hereditary iron overload syndromes with some, or many, or apparently even all of the phenotypic features of classic HC, were reported: transferrin receptor 2 (TFR2),[6] hepcidin (HAMP),[7] hemojuvelin (HJV),[8] and ferroportin (FPN) (Table 1).[9,10]
The term non-HFE hereditary hemochromatosis embraces all forms of HC nonlinked to the common HFE p.Cys282Tyr polymorphism, and far associated with pathogenic mutations of TFR2, HJV, HAMP, and in rare cases, the FPN gene
Summary
TFR2, transferrin receptor-2; HAMP, hepcidin; HJV, hemojuvelin; FPN, ferroportin; NASH, nonalcoholic steatohepatitis. Reflect systemic iron overload, others, in the context of a necro-inflammatory, or in as yet unknown disease processes, results in regional or local iron accumulation (e.g., chronic liver diseases) (Table 1). An increasingly recognized class of iron disorders is due to disrupted intracellular (e.g., Friedreich ataxia) or body iron traffic (e.g., anemia of chronic diseases) leading to iron misdistribution despite a normal total body iron content (Table 1). We will discuss causes and consequences of most common hereditary or acquired disorders associated with hepatic iron overload beyond HFE-hemochromatosis
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