Hereditary haemochromatosis type 1 (HFE-related haemochromatosis) 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 mechanism to regulate excess iron, simply losing a limited amount through various means like sweating or menstruating.
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 haemochromatosis: type 1, 2 (2A, 2B), 3, 4 and 5, all caused by mutated genes. Hereditary haemochromatosis type 1 is the most frequent, and uniquely related to the HFE gene. It is most common among those of Northern European ancestry, in particular those of Celtic descent.
The disease follows an autosomal recessive pattern of inheritance, meaning that an individual must inherit two copies of the mutated gene involved in each cell to develop the condition. In most cases, when a person has this autosomal recessive condition, their parents have acted as hereditary carriers, possessing one copy of the mutated gene but not manifesting any signs or symptoms associated with the disease. The unaffected carrier parents play an integral role in transmitting one copy of the mutated gene to their child, who ultimately develops the disease. However, carriers may experience iron overload themselves at a later stage if certain factors come into play. Still, in most cases, they remain asymptomatic throughout their lives unless other genetic or environmental factors contribute to excessive iron accumulation within their bodies.
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.Hemochromatosis-Diagnosis National Digestive Diseases Information Clearinghouse, National Institutes of Health, U.S. Department of Health and Human Services
Presently, the classic triad of cirrhosis, bronze skin, and diabetes is less common because of earlier diagnosis.
The more common clinical manifestations include:Hemochromatosis National Digestive Diseases Information Clearinghouse, National Institutes of Health, U.S. Department of Health and Human Services 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 a transmembrane protein involved in the induction of hepcidin expression upon high iron load. 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 combination 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 10-33% of C282Y homozygotes with less than 10% going on to experience severe iron overload and organ damage, and biochemical expression is present in 38-50%.nih.gov Although this condition has autosomal recessive inheritance, there has been at least one individual with heterozygous C282Y experienced iron overload symptoms reported. Researchers have suspected a digenic condition (with mutations of other gene locus, such as HAMP, HJV, TFR2), or environmental factors.
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.
Each patient with the susceptible genotype accumulates iron at different rates depending on iron intake, the exact nature of the genetic variant, and the presence of other insults to the liver, such as alcohol and viral disease. As such, the degree to which the liver and other organs are affected is highly variable and is dependent on these factors and co-morbidities, as well as age at which they are studied for manifestations of disease. Penetrance differs between populations.
Disease-causing genetic variants of the HFE gene account for 90% of the cases of non-transfusion iron overload.
This gene is closely linked to the HLA-A3 locus.
Pathophysiology
Since the regulation of iron metabolism is still poorly understood, a clear model of how haemochromatosis operates is still not available. A working model describes the defect in the HFE gene, where a mutation puts the intestinal absorption of iron into overdrive. Normally, HFE facilitates the binding of transferrin, which is iron's carrier protein in the blood. Transferrin levels are typically elevated at times of iron depletion (low ferritin stimulates the release of transferrin from the liver). When transferrin is high, HFE works to increase the intestinal release of iron into the blood. When HFE is mutated, the intestines perpetually interpret a strong transferrin signal as if the body were deficient in iron. This false signal leads to maximal iron absorption from ingested foods and iron overload in the tissues. However, HFE is only part of the story, since many patients with mutated HFE do not manifest clinical iron overload, and some patients with iron overload have a normal HFE genotype. A possible explanation is the fact that HFE normally plays a role in the production of hepcidin in the liver, a function that is impaired in HFE mutations.