Liver plays an important role in the regulation of iron homeostasis. The liver has the ability to sense changes in systemic iron requirements and in turn, can regulate iron concentrations in a vigorous and rapid manner. Various studies in the last decade have been conducted that demonstrated several regulatory mechanisms of liver implicated in the regulation of the production of iron regulatory genes, storage capacity, and iron mobilization. However, dysregulation of any of these functions can result in an imbalance of iron, the leading cause of iron-related disorders. Several researches have revealed that anemia and iron overload are two of the most prevalent disorders affecting over a billion people, worldwide. The central role of the liver in iron homeostasis is established by the identification of several mutations in liver-derived genes. 

Excess liver iron is one of the main mechanisms resulting in increased steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. The excessive iron prompts liver to store more iron in order to protect other tissues from iron-induced cellular damage. This dysregulation of function in the liver leads to increase in free iron, which in turn results in fibrosis and cirrhosis, associated with increase morbidity and mortality. It has been reported that hepatic tissue injury is directly linked to the duration and amount of iron loading. Basal levels of reactive oxygen species (ROS) are normally generated through metabolic function of the mitochondria and other organelles, which are regulated by several antioxidant enzymes, as their low levels are important in maintaining normal cell physiology. ROS in combination with high cellular iron causes rapid increase of hydroxyl radicals leading to cell damage. The superoxide radical (O₂^•−) reduces ferric iron to ferrous iron, which then reacts with hydrogen peroxide (H₂O₂) to produce highly reactive hydroxyl radicals (OH^•). This produced hydroxyl radicals also leads to increase in peroxidation of phospholipids within organelle and cellular membranes, oxidation of amino acid side-chains, DNA strand breaks, and protein fragmentation. Although the underlying mechanisms by which high intracellular iron causes liver fibrosis and cirrhosis are imprecise, iron-induced cellular damage directly increases hepatocyte cell death and activate Kupffer and stellate cells. The increase in iron-induced ROS in Kupffer cells in turn, can stimulate a pro-inflammatory cascade in the liver, which activates NF-κB signaling resulting in elevated levels of IL-6, TNF-α, and IL-1β in the liver. This inflammation of liver can cause hepatic insulin resistance, a prominent pathway responsible for hyperglycemia in type II diabetes. Besides being responsible for playing a major role in hyperglycemia, liver iron overload increases the risk for hepatocellular carcinoma (HCC). It is a major life threatening complication associated with hereditary hemochromatosis. Several trials have estimated the risk factor to be 100-200 fold higher for HCC in hereditary hemochromatosis patients. Additionally, other iron overload disorders such as thalassemia are also found to be associated with an increased risk for HCC. 

Source: Anderson ER, Shah YM. Iron homeostasis in the liver. Compr Physiol. 2013;3(1):315-330.