Hemochromatosis: Ferroptosis, ROS, Gut Microbiome, and Clinical Challenges with Alcohol as Confounding Variable

Abstract

Hemochromatosis represents clinically one of the most important genetic storage diseases of the liver caused by iron overload, which is to be differentiated from hepatic iron overload due to excessive iron release from erythrocytes in patients with genetic hemolytic disorders. This disorder is under recent mechanistic discussion regarding ferroptosis, reactive oxygen species (ROS), the gut microbiome, and alcohol abuse as a risk factor, which are all topics of this review article. Triggered by released intracellular free iron from ferritin via the autophagic process of ferritinophagy, ferroptosis is involved in hemochromatosis as a specific form of iron-dependent regulated cell death. This develops in the course of mitochondrial injury associated with additional iron accumulation, followed by excessive production of ROS and lipid peroxidation. A low fecal iron content during therapeutic iron depletion reduces colonic inflammation and oxidative stress. In clinical terms, iron is an essential trace element required for human health. Humans cannot synthesize iron and must take it up from iron-containing foods and beverages. Under physiological conditions, healthy individuals allow for iron homeostasis by restricting the extent of intestinal iron depending on realistic demand, avoiding uptake of iron in excess. For this condition, the human body has no chance to adequately compensate through removal. In patients with hemochromatosis, the molecular finetuning of intestinal iron uptake is set off due to mutations in the high-FE2+ (HFE) genes that lead to a lack of hepcidin or resistance on the part of ferroportin to hepcidin binding. This is the major mechanism for the increased iron stores in the body. Hepcidin is a liver-derived peptide, which impairs the release of iron from enterocytes and macrophages by interacting with ferroportin. As a result, iron accumulates in various organs including the liver, which is severely injured and causes the clinically important hemochromatosis. This diagnosis is difficult to establish due to uncharacteristic features. Among these are asthenia, joint pain, arthritis, chondrocalcinosis, diabetes mellitus, hypopituitarism, hypogonadotropic hypogonadism, and cardiopathy. Diagnosis is initially suspected by increased serum levels of ferritin, a non-specific parameter also elevated in inflammatory diseases that must be excluded to be on the safer diagnostic side. Diagnosis is facilitated if ferritin is combined with elevated fasting transferrin saturation, genetic testing, and family screening. Various diagnostic attempts were published as algorithms. However, none of these were based on evidence or quantitative results derived from scored key features as opposed to other known complex diseases. Among these are autoimmune hepatitis (AIH) or drug-induced liver injury (DILI). For both diseases, the scored diagnostic algorithms are used in line with artificial intelligence (AI) principles to ascertain the diagnosis. The first-line therapy of hemochromatosis involves regular and life-long phlebotomy to remove iron from the blood, which improves the prognosis and may prevent the development of end-stage liver disease such as cirrhosis and hepatocellular carcinoma. Liver transplantation is rarely performed, confined to acute liver failure. In conclusion, ferroptosis, ROS, the gut microbiome, and concomitant alcohol abuse play a major contributing role in the development and clinical course of genetic hemochromatosis, which requires early diagnosis and therapy initiation through phlebotomy as a first-line treatment.

The Impact of the Combined Effect of Inhalation Anesthetics and Iron Dextran on Rats’ Systemic Toxicity

“…Thus, iron-induced liver damage in mice does not fully correspond to damage in humans who consume large amounts of alcohol for a long time due to possible interactions of iron in ethanol-induced liver damage and increased induction of CYP2E1. CYP2E1 may constitute the primary source of superoxide anion production, leading to the formation of hydroxyl radicals via an iron-catalyzed Haber–Weiss reaction, indicating a potential role for iron in CYP2E1-induced free radical production [ 69 , 70 ]. Also, hypersensitivity reactions should be highlighted as idiosyncratic drug-induced hepatitis (IDDIH) resulting from the production of trifluoroacetylated (TFA) liver proteins during the metabolism of volatile anesthetics, mostly halothane, by CYP2E1.…”

Copper, Iron, Cadmium, and Arsenic, All Generated in the Universe: Elucidating Their Environmental Impact Risk on Human Health Including Clinical Liver Injury

“…Ferroptosis, an iron-dependent form of regulated cell death [ 254 , 255 , 256 , 257 ], is closely related to mechanistic sequalae described in conditions of iron overload like hemochromatosis [ 176 , 256 , 257 ], and was discussed in detail more recently [ 257 ]. There is some evidence that ferroptosis is triggered by ferritinophagy, an autophagic process that specifically involves ferritin to release intracellular free iron [ 257 ].…”

“…Ferroptosis, an iron-dependent form of regulated cell death [ 254 , 255 , 256 , 257 ], is closely related to mechanistic sequalae described in conditions of iron overload like hemochromatosis [ 176 , 256 , 257 ], and was discussed in detail more recently [ 257 ]. There is some evidence that ferroptosis is triggered by ferritinophagy, an autophagic process that specifically involves ferritin to release intracellular free iron [ 257 ]. At the morphological level, ferroptosis causes injury to mitochondria, with condensed, ruptured outer membranes, associated with initial iron accumulation, excessive ROS production, and excessive lipid peroxides [ 26 , 257 ].…”

“…There is some evidence that ferroptosis is triggered by ferritinophagy, an autophagic process that specifically involves ferritin to release intracellular free iron [ 257 ]. At the morphological level, ferroptosis causes injury to mitochondria, with condensed, ruptured outer membranes, associated with initial iron accumulation, excessive ROS production, and excessive lipid peroxides [ 26 , 257 ]. Polyunsaturated fatty acids (PUFAs), as structural components of membrane phospholipids, are easily peroxidized, forming lipid peroxides triggered by ROS, generated through the Haber–Weiss reaction.…”

“…The main critical issues related to liver injury caused by iron were discussed and quoted before [ 254 , 255 , 256 , 257 ] with a special focus on ferroptosis [ 257 ], and are summarized ( Figure 5 ).…”