hereditary haemochromatosis hereditary haemochromatosis hereditary haemochromatosis type 1 (hfe-related hemochromatosis) is a genetic disorder characterized by excessive intestinal absorption of dietary iron, resulting in a pathological increase in total body iron stores. humans, like most animals, have no means to excrete excess iron, with the exception of menstruation which, for the average woman, results in a loss of 3.2 mg of iron. this article is about hereditary haemochromatosis (hhc) associated with the hfe gene. for other causes of haemochromatosis, see iron overload. haemochromatosis type 1other nameshfe hereditary haemochromatosis hfe-related hereditary haemochromatosisiron accumulation demonstrated by prussian blue staining in a patient with homozygous genetic haemochromatosis (microscopy, 10x magnified): parts of normal pink tissue are scarcely present.specialtyendocrinology, hepatology differential diagnosishaemochromatosis type 2, 3, 4, and 5. secondary haemochromatosis. aceruloplasminemia. atransferrinemia excess iron accumulates in tissues and organs, disrupting their normal function. the most susceptible organs include the liver, heart, pancreas, skin, joints, gonads, thyroid and pituitary gland; patients can present with cirrhosis, polyarthropathy, hypogonadism, heart failure, or diabetes. there are five types of hereditary hemochromatosis: type 1, 2 (2a, 2b), 3, 4 and 5, all caused by mutated genes. hereditary hemochromatosis type 1 is the most frequent, and unique related to the hfe gene. it is most common among those of northern european ancestry, in particular those of celtic descent. the disease is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. most often, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but do not express signs or symptoms of the condition. in this situation, the otherwise unaffected parents are referred to as carriers. signs and symptoms haemochromatosis is protean in its manifestations, i.e., often presenting with signs or symptoms suggestive of other diagnoses that affect specific organ systems. many of the signs and symptoms below are uncommon, and most patients with the hereditary form of haemochromatosis do not show any overt signs of disease nor do they have premature morbidity, if they are diagnosed early, but, more often than not, the condition is diagnosed only at autopsy. presently, the classic triad of cirrhosis, bronze skin, and diabetes is less common because of earlier diagnosis. the more common clinical manifestations include: fatigue malaise joint pain (mainly knee and hand) abdominal pain bronze or gray skin color (for this the illness was named "bronze diabetes" when it was first described by armand trousseau in 1865) liver fibrosis or cirrhosis (with an increased risk of hepatocellular carcinoma): liver disease is always preceded by evidence of liver dysfunction, including elevated serum enzymes specific to the liver, clubbing of the fingers, leuconychia, asterixis, hepatomegaly, palmar erythema, and spider naevi. cirrhosis can also present with jaundice (yellowing of the skin) and ascites. diabetes mellitus type 2: hh patients have insulin resistance for liver disease, and poor insulin secretion due to pancreatic damage from iron deposition. erectile dysfunction and hypogonadism, resulting in decreased libido, amenorrhea congestive heart failure, abnormal heart rhythms, or pericarditis arthritis of the hands (especially the second and third metacarpophalangeal joints), but also the knee and shoulder joints weight loss less common findings including: memory loss hair loss splenomegaly adrenal insufficiency deafness dyskinesias, including parkinsonian symptoms dysfunction of certain endocrine organs: parathyroid gland (leading to hypocalcaemia) pituitary gland: secondary hypothyroidism, secondary hypogonadism adrenal gland an increased susceptibility to certain infectious diseases caused by siderophilic microorganisms: vibrio vulnificus infections from eating seafood or wound infection listeria monocytogenes yersinia enterocolica salmonella enterica (serotype typhymurium) klebsiella pneumoniae escherichia coli rhizopus arrhizus mucor species aspergillus fumigatus cytomegalovirus hepatitis b virus hepatitis c virus in the hereditary hemochromatosis (hh or hhc), males are usually diagnosed after their forties and fifties, and women some decades later, during menopause. the severity of clinical disease varies considerably. some evidence suggests that hereditary haemochromatosis patients affected with other liver ailments such as hepatitis or alcoholic liver disease have worse liver disease than those with either condition alone. also, juvenile form of primary haemochromatosis (hemochromatosis type 2) present in childhood with the same consequences of iron overload. end-organ damage iron is stored in the liver, pancreas and heart. long-term effects of haemochromatosis on these organs can be serious, even fatal when untreated. since the liver is a primary storage area for iron and naturally accumulates excess iron over time, it is likely to be damaged by iron overload. toxins may accumulate in the blood and eventually affect mental functioning due to increased risk of hepatic encephalopathy. together, they can increase the risk of liver cancer to one in three persons. if excess iron in the heart interferes with its ability to circulate enough blood, a number of problems can occur, including (potentially fatal) congestive heart failure. the condition may be reversible when haemochromatosis is treated and excess iron stores are reduced. arrhythmia or abnormal heart rhythm can cause heart palpitations, chest pain, and light-headedness, and is occasionally life-threatening. this condition can often be reversed with treatment. the pancreas, which also stores iron, is very important in the body's mechanisms for sugar metabolism. diabetes affects the way the body uses blood sugar (glucose), and diabetes is, in turn, the leading cause of new blindness in adults and may be involved in kidney failure. haemochromatosis may lead to cirrhosis and its complications, including bleeding from dilated veins in the esophagus (esophageal varices) and stomach (gastric varices) and severe fluid retention in the abdomen (ascites). severity of periodontal disease is associated with high transferrin saturation in haemochromatosis patients. genetics the regulation of dietary iron absorption is complex and understanding is incomplete. one of the better-characterized genes responsible for hereditary haemochromatosis is hfe on chromosome 6, which codes for hepcidin, a protein that participates in the regulation of iron absorption. the hfe gene has three often observed genetic variants: rs1799945, c.187c>g, p.his63asp (h63d); rs1800562, c.845g>a, p. cys282tyr (c282y); rs1800730, c.193a>t, p.ser65cys (s65c). the worldwide prevalence rates for h63d, c282y and s65c (minor allele frequencies) are 10%, 3% and 1% respectively. the c282y allele is a transition point mutation from guanine to adenine at nucleotide 845 in hfe, resulting in a missense mutation that replaces the cysteine residue at position 282 with a tyrosine amino acid. heterozygotes for either allele can manifest clinical iron overload, if they have two of any alleles. this makes them compound heterozygous for haemochromatosis and puts them greatly at risk of storing excess iron in the body. homozygosity for the c282y genetic variant is the most common genotype responsible for clinical iron accumulation, though heterozygosity for c282y/h63d variants, so-called compound heterozygotes, results in clinically evident iron overload. considerable debate exists regarding the penetrance—the probability of clinical expression of the trait given the genotype— for clinical disease in homozygotes. most males homozygous for hfe c282y show at least one manifestation of iron-storage disease by middle age. individuals with the relevant genetic variants may never develop iron overload. phenotypic expression is present in 70% of c282y homozygotes with less than 10% going on to experience severe iron overload and organ damage. the h63d variant is just a gene polymorphism, and if there are no other changes, it may not have clinical significance. in a 2014 study, h63d homozygosity was associated with an elevated mean ferritin level, but only 6.7% had documented iron overload at follow-up. as about the people with one copy of the h63d alteration (heterozygous carriers), this genotype is very unlikely to cause a clinical presentation, there is no predictable risk of iron overload. besides that, two 2020 studies revealed that the frequency of homozygous or heterozygous h63d variant is significantly higher in elite endurance athletes comparing to ethnically matched controls, and is associated with high v̇o2max in male athletes.