RARE DISEASE
Symptomatic form of HFE-related hemochromatosis
Symptomatic form of HFE-related hemochromatosis
Symptomatic form of HFE-related hemochromatosis
Synonyms: Symptomatic form of classic hemochromatosis, Symptomatic form of hemochromatosis type 1
Synonyms: Symptomatic form of classic hemochromatosis, Symptomatic form of hemochromatosis type 1
Synonyms: Symptomatic form of classic hemochromatosis, Symptomatic form of hemochromatosis type 1
Drug discovery
0
drugs
With orphan designations
Overview
The symptomatic form of HFE-related hemochromatosis is a genetic iron overload disorder caused by biallelic pathogenic HFE mutations (typically C282Y), leading to excessive intestinal iron absorption and deposition in vital organs. Clinical manifestations include fatigue, arthropathy, hepatomegaly, cirrhosis, diabetes mellitus, cardiomyopathy, and skin hyperpigmentation. Early diagnosis via elevated transferrin saturation (≥45%) and serum ferritin (≥300 ng/mL in men, ≥200 ng/mL in women) is critical to prevent irreversible organ damage [1][5][6][11].
Burden
Associated with 28% higher healthcare costs vs. controls, driven by complications (cirrhosis, hepatocellular carcinoma, diabetes, cardiomyopathy) [4][9].
Mortality: 50% reduced 5-year survival in untreated cirrhosis; liver disease is the leading cause of death [1][6][9][19].
Morbidity: 75% exhibit liver dysfunction, 45% arthritis, and 15% diabetes at diagnosis [1][5][14].
Therapies
Phlebotomy: First-line therapy (450 mL weekly to monthly) to reduce iron stores (225 mg iron/removal), followed by maintenance (every 2–4 months) [3][8][18].
Iron chelation: Reserved for patients intolerant to phlebotomy [3][8].
Monitoring: Annual serum ferritin and transferrin saturation; avoid alcohol, vitamin C, and iron supplements [5][11][18].
Categories: rare genetic diseases, rare hepatic diseases, rare inborn errors of metabolism, rare transplant-related disorders
Research Papers
41 drug discovery papers about Symptomatic form of HFE-related hemochromatosis, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
41 drug discovery papers about Symptomatic form of HFE-related hemochromatosis, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2024-01-16 | Alcohol Use Unmasking Heterozygous Hereditary Hemochromatosis
Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by excess iron absorption in the body following a mutation in the HFE gene. Though prolonged iron deposition has been shown to cause clinical symptoms such as hyperpigmentation, arthralgias, and liver damage, many individuals remain asymptomatic and exhibit no signs of iron overload. Here, we present a case where a 34-year-old with a history of severe alcohol use disorder presented with high iron, ferritin and transferrin saturation levels indicative of iron overload. Further testing for HFE gene mutations revealed simple heterozygote C282Y status, confirming the diagnosis of hereditary hemochromatosis. Simple heterozygotes, however, typically do not present with any symptoms of iron overload. This patient was counseled on lifestyle modifications which included abstaining from alcohol and reducing iron and vitamin C intake. As a result, his iron panel parameters improved. Thus, our case highlights that excessive alcohol consumption can exacerbate hereditary hemochromatosis and risk for overload even among heterozygotes.
2023-08-24 | HYPERFERRITINAMIA: What the clinician must know
Ferritin is the main intracellular iron storage protein in all organisms.A small proportion of this protein circulates freely in the blood, constituting an indirect marker of iron deposits in the body.Serum ferritin concentrations > 300 μg/L in men and > 200 μg/L in women determine a state of hyperferritinemia, commonly found in routine laboratory tests in asymptomatic individuals.The key to diagnosis is determining its cause and whether it is related to iron overload.Hereditary hemochromatosis (HH) is the most common cause of iron overload, and is often considered the cause of hyperferritinemia, however, between 58% and 70% of cases do not have iron overload.Among the main causes of hyperferritinemia are: alcoholism, inflammatory syndrome, cytolysis and metabolic syndrome.If hyperferritinemia is accompanied by transferrin saturation >50%, a diagnosis of HH must be considered.The etiological diagnosis of hyperferritinemia is made through a careful clinical evaluation, including a detailed history of alcohol consumption, as well as metabolic risk factors (obesity, type 2 diabetes mellitus, dyslipidemia and hypertension).In addition to the clinical history, it is essential to perform ferrokinetic studies (serum ferritin and transferrin saturation).If there is still doubt about the association with iron overload, Nuclear Magnetic Resonance (NMR) must be used, as it is a non-invasive method and allows indirect quantification of the iron content in different organs.If major diagnoses are excluded, it is imperative to investigate rarer causes.It must be remembered that 40% of patients with hyperferritinemia have several causes simultaneously.The treatment for reducing excess iron in patients with hyperferritinemia associated with iron overload is phlebotomy.Other therapeutic modalities such as the use of iron binders and erythrocytapheresis may be considered in patients who cannot tolerate phlebotomy.
2022-07-02 | Diagnosis of Liver Cirrhosis on the Background of Mutations H63D of the HFE Gene and H1069Q of the ATP7B Gene in associated with Hemochromatosis and Wilson's Disease (Clinical Case)
The purpose of the study was to ilustrate the analysis of etiological factors of liver cirrhosis using clinical and anamnestic data and the results of instrumental, laboratory and genetic researches. Materials and methods. The data of anamnesis and objective examination, results of instrumental, laboratory and genetic research methods are evaluated and analyzed. Modern protocols and medical literature were used. Results and discussion. Clinical case of the patient, 52 years old. Complaints of weakness, pain in the left hypochondrium, taste of iron, convulsions of the upper and lower extremities. Laboratory and instrumental methods of research allowed to establish the following indicators in the patient: erythrocytopenia, thrombocytopenia, neutropenia, persistent lymphocytosis, lecopenia, decreased platelet count, increased average erythrocyte volume and average hemoglobin content in one erythromycin distribution, albuminemia, increased beta globulin, decreased albumin to globulin ratio, increased liver enzymes (ALT, AST, bilirubin direct) and GGT, blood iron metabolism (COPD and iron levels), iron saturation and iron ferritin saturation, negative immunological analysis for antinuclear antibodies (ANA), HbS Ag and anti-HCV were not detected. The patient was consulted by a hematologist, lymphoproliferative diseases were excluded. On the basis of data on hepatosplenomegaly, portal hypertension, varicose veins of the esophagus, lymphadenopathy, excluding nonalcoholic fatty liver disease, alcoholic fatty liver disease, viral hepatitis, autoimmune hepatitis, biliary cirrhosis, diagnosed with a diagnosis on the detection of mutations that cause hemochromatosis and Wilson's disease. Molecular genetic studies have shown the following results: the H63D mutation of the HFE gene in the heterozygous state and the H1069Q mutation of the ATP7B gene in the heterozygous state were detected. Mutation testing and phenotype prediction based on genotype opens up prospects not only for personalized therapy, but also for the development of new treatment strategies. The literature provides data about new therapies with different mechanisms of action and discusses studies on Bis-choline tetrathiomolybdate in patients, pre-clinical studies of a novel chelator methanobactin and animal studies exploring cures for WD with gene therapy using adeno-associated vectors that introduce ATP7B into liver cells. Conclusion. The clinical case showed the need to involve specialists in various specialties and a set of research methods to establish the etiology of liver cirrhosis and further etiopathogenetic treatment and the formation of risk groups for primary prevention among relatives
2020-08-05 | What’s Important and New in Hemochromatosis?
Major advances in the understanding of genetic iron overload have led to a clarification of the nosology and terminology of the related diseases. The term hemochromatosis should be reserved to the entities where iron overload is related to hepcidin deficiency or hepcidin resistance. The diagnosis of hemochromatosis is non-invasive, based on clinical examination, blood investigations and, whenever possible, magnetic resonance imaging. Phlebotomies remain the mainstay of the treatment, but new therapeutic approaches should, in the future, constitute a valuable advance, hopefully both as an adjunct to bleeding in the induction phase and as its replacement in the maintenance phase. The goal of the present review is to update the terminology of hemochromatosis in light of major pathophysiological advances, and the main features of its diagnostic and therapeutic approaches.
2019-09-17 | The Efficacy of Iron Chelators for Removing Iron from Specific Brain Regions and the Pituitary—Ironing out the Brain
Iron chelation therapy, either subcutaneous or orally administered, has been used successfully in various clinical conditions. The removal of excess iron from various tissues, e.g., the liver spleen, heart, and the pituitary, in beta thalassemia patients, has become an essential therapy to prolong life. More recently, the use of deferiprone to chelate iron from various brain regions in Parkinson's Disease and Friederich's Ataxia has yielded encouraging results, although the side effects, in <2% of Parkinson's Disease(PD) patients, have limited its long-term use. A new class of hydroxpyridinones has recently been synthesised, which showed no adverse effects in preliminary trials. A vital question remaining is whether inflammation may influence chelation efficacy, with a recent study suggesting that high levels of inflammation may diminish the ability of the chelator to bind the excess iron.
small molecules
2024-01-16 | Alcohol Use Unmasking Heterozygous Hereditary Hemochromatosis
Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by excess iron absorption in the body following a mutation in the HFE gene. Though prolonged iron deposition has been shown to cause clinical symptoms such as hyperpigmentation, arthralgias, and liver damage, many individuals remain asymptomatic and exhibit no signs of iron overload. Here, we present a case where a 34-year-old with a history of severe alcohol use disorder presented with high iron, ferritin and transferrin saturation levels indicative of iron overload. Further testing for HFE gene mutations revealed simple heterozygote C282Y status, confirming the diagnosis of hereditary hemochromatosis. Simple heterozygotes, however, typically do not present with any symptoms of iron overload. This patient was counseled on lifestyle modifications which included abstaining from alcohol and reducing iron and vitamin C intake. As a result, his iron panel parameters improved. Thus, our case highlights that excessive alcohol consumption can exacerbate hereditary hemochromatosis and risk for overload even among heterozygotes.
2023-08-24 | HYPERFERRITINAMIA: What the clinician must know
Ferritin is the main intracellular iron storage protein in all organisms.A small proportion of this protein circulates freely in the blood, constituting an indirect marker of iron deposits in the body.Serum ferritin concentrations > 300 μg/L in men and > 200 μg/L in women determine a state of hyperferritinemia, commonly found in routine laboratory tests in asymptomatic individuals.The key to diagnosis is determining its cause and whether it is related to iron overload.Hereditary hemochromatosis (HH) is the most common cause of iron overload, and is often considered the cause of hyperferritinemia, however, between 58% and 70% of cases do not have iron overload.Among the main causes of hyperferritinemia are: alcoholism, inflammatory syndrome, cytolysis and metabolic syndrome.If hyperferritinemia is accompanied by transferrin saturation >50%, a diagnosis of HH must be considered.The etiological diagnosis of hyperferritinemia is made through a careful clinical evaluation, including a detailed history of alcohol consumption, as well as metabolic risk factors (obesity, type 2 diabetes mellitus, dyslipidemia and hypertension).In addition to the clinical history, it is essential to perform ferrokinetic studies (serum ferritin and transferrin saturation).If there is still doubt about the association with iron overload, Nuclear Magnetic Resonance (NMR) must be used, as it is a non-invasive method and allows indirect quantification of the iron content in different organs.If major diagnoses are excluded, it is imperative to investigate rarer causes.It must be remembered that 40% of patients with hyperferritinemia have several causes simultaneously.The treatment for reducing excess iron in patients with hyperferritinemia associated with iron overload is phlebotomy.Other therapeutic modalities such as the use of iron binders and erythrocytapheresis may be considered in patients who cannot tolerate phlebotomy.
2022-07-02 | Diagnosis of Liver Cirrhosis on the Background of Mutations H63D of the HFE Gene and H1069Q of the ATP7B Gene in associated with Hemochromatosis and Wilson's Disease (Clinical Case)
The purpose of the study was to ilustrate the analysis of etiological factors of liver cirrhosis using clinical and anamnestic data and the results of instrumental, laboratory and genetic researches. Materials and methods. The data of anamnesis and objective examination, results of instrumental, laboratory and genetic research methods are evaluated and analyzed. Modern protocols and medical literature were used. Results and discussion. Clinical case of the patient, 52 years old. Complaints of weakness, pain in the left hypochondrium, taste of iron, convulsions of the upper and lower extremities. Laboratory and instrumental methods of research allowed to establish the following indicators in the patient: erythrocytopenia, thrombocytopenia, neutropenia, persistent lymphocytosis, lecopenia, decreased platelet count, increased average erythrocyte volume and average hemoglobin content in one erythromycin distribution, albuminemia, increased beta globulin, decreased albumin to globulin ratio, increased liver enzymes (ALT, AST, bilirubin direct) and GGT, blood iron metabolism (COPD and iron levels), iron saturation and iron ferritin saturation, negative immunological analysis for antinuclear antibodies (ANA), HbS Ag and anti-HCV were not detected. The patient was consulted by a hematologist, lymphoproliferative diseases were excluded. On the basis of data on hepatosplenomegaly, portal hypertension, varicose veins of the esophagus, lymphadenopathy, excluding nonalcoholic fatty liver disease, alcoholic fatty liver disease, viral hepatitis, autoimmune hepatitis, biliary cirrhosis, diagnosed with a diagnosis on the detection of mutations that cause hemochromatosis and Wilson's disease. Molecular genetic studies have shown the following results: the H63D mutation of the HFE gene in the heterozygous state and the H1069Q mutation of the ATP7B gene in the heterozygous state were detected. Mutation testing and phenotype prediction based on genotype opens up prospects not only for personalized therapy, but also for the development of new treatment strategies. The literature provides data about new therapies with different mechanisms of action and discusses studies on Bis-choline tetrathiomolybdate in patients, pre-clinical studies of a novel chelator methanobactin and animal studies exploring cures for WD with gene therapy using adeno-associated vectors that introduce ATP7B into liver cells. Conclusion. The clinical case showed the need to involve specialists in various specialties and a set of research methods to establish the etiology of liver cirrhosis and further etiopathogenetic treatment and the formation of risk groups for primary prevention among relatives
2020-08-05 | What’s Important and New in Hemochromatosis?
Major advances in the understanding of genetic iron overload have led to a clarification of the nosology and terminology of the related diseases. The term hemochromatosis should be reserved to the entities where iron overload is related to hepcidin deficiency or hepcidin resistance. The diagnosis of hemochromatosis is non-invasive, based on clinical examination, blood investigations and, whenever possible, magnetic resonance imaging. Phlebotomies remain the mainstay of the treatment, but new therapeutic approaches should, in the future, constitute a valuable advance, hopefully both as an adjunct to bleeding in the induction phase and as its replacement in the maintenance phase. The goal of the present review is to update the terminology of hemochromatosis in light of major pathophysiological advances, and the main features of its diagnostic and therapeutic approaches.
2019-09-17 | The Efficacy of Iron Chelators for Removing Iron from Specific Brain Regions and the Pituitary—Ironing out the Brain
Iron chelation therapy, either subcutaneous or orally administered, has been used successfully in various clinical conditions. The removal of excess iron from various tissues, e.g., the liver spleen, heart, and the pituitary, in beta thalassemia patients, has become an essential therapy to prolong life. More recently, the use of deferiprone to chelate iron from various brain regions in Parkinson's Disease and Friederich's Ataxia has yielded encouraging results, although the side effects, in <2% of Parkinson's Disease(PD) patients, have limited its long-term use. A new class of hydroxpyridinones has recently been synthesised, which showed no adverse effects in preliminary trials. A vital question remaining is whether inflammation may influence chelation efficacy, with a recent study suggesting that high levels of inflammation may diminish the ability of the chelator to bind the excess iron.
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