Hemochromatosis Type 1
Disease Details
Family Health Simplified
- Description
- Hemochromatosis type 1 is a genetic disorder causing the body to absorb too much iron from the diet, leading to excess iron deposits in various organs and potential organ damage.
- Type
- Hemochromatosis type 1 is an autosomal recessive genetic disorder.
- 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 lossLess 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 virusIn 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. - Prognosis
- Persons with symptomatic haemochromatosis have somewhat reduced life expectancy compared to the general population, mainly due to excess mortality from cirrhosis and liver cancer. Patients who were treated with phlebotomy lived longer than those who were not. Patients without liver disease or diabetes had similar survival rate to the general population.
- Onset
- Hemochromatosis type 1, also known as hereditary hemochromatosis, typically has an adult onset. Symptoms usually appear in men between the ages of 40 and 60 and in women after menopause, due to the loss of iron through menstruation before menopause.
- Prevalence
- Hemochromatosis type 1, also known as hereditary hemochromatosis, is particularly common among individuals of Northern European descent. The prevalence varies geographically, but in populations of Northern European ancestry, it is estimated to affect approximately 1 in 200 to 1 in 250 individuals.
- Epidemiology
- Haemochromatosis is one of the most common heritable genetic conditions in people of Northern Europe, with a prevalence of 1:200. The disease has a variable penetration, and about one in 10 people of this demographic carry a mutation in one of the genes regulating iron metabolism. In the U.S., the frequency of the C282Y and H63D mutations is 5.4% and 13.5%, respectively. Whereas, the worldwide frequency of the C282Y and H63D mutations is about 1.9% and 8.1%, respectively, so mutation in H63D allele are more than C282Y allele. The prevalence of mutations in iron-metabolism genes varies in different populations. A study of 3,011 unrelated white Australians found that 14% were heterozygous carriers of an HFE mutation, 0.5% were homozygous for an HFE mutation, and only 0.25% of the study population had clinically relevant iron overload. Most patients who are homozygous for HFE mutations do not manifest clinically relevant haemochromatosis (see Genetics above). Other populations have a lower prevalence of both the genetic mutation and the clinical disease. It is the most frequent genetic disease in the U.S. with a prevalence of 1:300 in the non-Hispanic white population, It is 2-3 times more common in males.Genetics studies suggest the original haemochromatosis mutation arose in a single person, possibly of Celtic ethnicity, who lived 60–70 generations ago. At that time, when dietary iron may have been scarcer than today, the presence of the mutant allele may have provided an evolutionary advantage by maintaining higher iron levels in the blood.The distribution of the C282Y variant was noted in various countries. Non-HFE associated hemochromatosis, as Haemochromatosis type 2, Haemochromatosis type 3, Haemochromatosis type 4 and Haemochromatosis type 5, were discovered in Mediterranean countries. On the other side, Northern European ancestry is closely linked to hereditary hemochromatosis disease (HFE). In one study, over 93% of Irish patients with HFE C282Y mutation were homozygotic. The G320V mutation in the HJV gene, which produces hemojuvelin protein, is widely distributed in central Europe and Greece.
- Intractability
- Hemochromatosis type 1, also known as hereditary hemochromatosis, is not considered intractable. It is a genetic condition that leads to excessive iron absorption and accumulation in various organs. Early diagnosis and management, typically through regular phlebotomy (blood removal) to reduce iron levels, can prevent complications and maintain a normal quality of life. If left untreated, however, it can lead to severe conditions such as liver cirrhosis, heart disease, and diabetes.
- Disease Severity
- Hemochromatosis type 1 is generally a severe disorder if left untreated. It can lead to significant organ damage, particularly in the liver, heart, and pancreas, due to excessive iron accumulation. Early diagnosis and management are crucial to prevent serious complications such as liver cirrhosis, heart disease, diabetes, and arthritis. Regular phlebotomy or chelation therapy can help manage iron levels and mitigate severe outcomes.
- Healthcare Professionals
- Disease Ontology ID - DOID:0111029
- 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 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.People with abnormal iron regulatory genes do not reduce their absorption of iron in response to increased iron levels in the body. Thus, the iron stores of the body increase. As they increase, the iron which is initially stored as ferritin is deposited in organs as haemosiderin and this is toxic to tissue, probably at least partially by inducing oxidative stress. Iron is a pro-oxidant. Thus, haemochromatosis shares common symptomology (e.g., cirrhosis and dyskinetic symptoms) with other "pro-oxidant" diseases such as Wilson's disease, chronic manganese poisoning, and hyperuricaemic syndrome in Dalmatian dogs. The latter also experience "bronzing".
- Carrier Status
- Hemochromatosis type 1 (HFE hemochromatosis) is an autosomal recessive disorder. A carrier of hemochromatosis type 1 has one mutated copy of the HFE gene and typically does not show symptoms of the disease. Carriers can pass the mutated gene to their offspring. If both parents are carriers, there is a 25% chance their child will inherit two mutated genes (one from each parent) and develop the disease. If only one parent is a carrier, their child cannot develop the disease but has a 50% chance of being a carrier.
- Mechanism
-
Hemochromatosis type 1 (also known as hereditary hemochromatosis) is a genetic disorder characterized by excessive absorption of dietary iron, leading to iron overload in various organs. Here are the relevant details:
### Mechanism
Hereditary hemochromatosis type 1 primarily results from mutations in the HFE gene, which plays a crucial role in the regulation of iron absorption. The two most common mutations associated with this disease are C282Y and H63D. The C282Y mutation is especially prevalent and is considered the primary genetic cause.
### Molecular Mechanisms
- **HFE Gene and Protein Function:** The HFE gene encodes the HFE protein, which normally interacts with the transferrin receptor on the surface of cells, particularly in the small intestine. This interaction helps regulate iron uptake by modulating the receptor's affinity for transferrin-bound iron.
- **Iron Sensing and Hepcidin Regulation:** The HFE protein is also involved in the regulation of hepcidin, a liver-produced hormone that is the main regulator of systemic iron homeostasis. Hepcidin controls iron absorption by binding to ferroportin, the iron exporter on enterocytes (intestinal cells), causing its internalization and degradation.
- **Disruption in HFE Function:** When mutations such as C282Y occur, the HFE protein's interaction with the transferrin receptor is impaired, affecting the iron sensing mechanism. This leads to decreased production of hepcidin.
- **Iron Absorption and Overload:** Low levels of hepcidin result in increased ferroportin activity, thereby enhancing iron absorption from the diet. The excess iron is deposited in various organs, including the liver, heart, pancreas, joints, and skin, leading to the symptoms and complications associated with hemochromatosis.
Overall, the molecular defect in HFE disrupts the normal feedback regulation of iron metabolism, resulting in pathogenic iron overload. - Treatment
- The primary treatment for Hemochromatosis Type 1 is phlebotomy, which involves the regular removal of blood to reduce iron levels. Initially, this may be done weekly until iron levels normalize, followed by maintenance sessions every few months. In some cases, iron chelation therapy may be used if phlebotomy is not possible. It is also advised to avoid iron supplements, vitamin C supplements (which increase iron absorption), and alcohol. Regular monitoring of iron levels and organ function is crucial to manage the condition effectively.
- Compassionate Use Treatment
-
For Hemochromatosis Type 1:
**Compassionate Use Treatment:**
Compassionate use treatments are medical interventions that are made available to patients with serious or life-threatening diseases when no comparable or satisfactory alternative therapy options are available. For Hemochromatosis Type 1, compassionate use treatments might include experimental drugs or interventions that are still in the clinical trial phase but could provide benefits to the patient.
**Off-label or Experimental Treatments:**
While not specifically approved for Hemochromatosis Type 1, off-label or experimental treatments may include:
1. **Deferoxamine (Desferal):** Though primarily used for secondary iron overload conditions, it can sometimes be used off-label for managing iron levels in severe Hemochromatosis cases.
2. **Deferasirox (Exjade) and Deferiprone (Ferriprox):** These are oral iron chelators commonly used for patients with secondary iron overload but could be considered experimentally for primary Hemochromatosis management.
3. **Gene Therapy:** Experimental approaches are being investigated that aim to correct the genetic mutations responsible for the disease.
4. **Liver Transplant:** In cases of severe liver damage due to iron overload, liver transplants may be explored, albeit this is a more radical treatment approach.
Note that the standard treatment for Hemochromatosis Type 1 remains phlebotomy, which involves regularly removing blood to reduce iron levels in the body. - Lifestyle Recommendations
-
Lifestyle recommendations for hemochromatosis type 1 include:
1. **Dietary Changes**:
- **Limit Iron Intake**: Avoid iron-rich foods like red meat, liver, and iron-fortified products.
- **Avoid Vitamin C Supplements**: Vitamin C increases iron absorption.
- **Moderate Alcohol Consumption**: Alcohol can increase iron absorption and damage the liver.
- **Reduce Sugar Intake**: High sugar levels can increase iron absorption.
2. **Regular Phlebotomy**: Follow your doctor's schedule for regular blood removal to reduce iron levels.
3. **Avoid Raw Seafood**: Risk of infection is higher in people with hemochromatosis.
4. **Stay Hydrated**: Adequate fluid intake is important for overall health.
5. **Exercise Regularly**: Engage in regular physical activity to maintain overall health but be cautious to avoid excessive strain if joint pain or fatigue is present.
6. **Monitor and Manage Symptoms**: Regular check-ups with healthcare providers to monitor iron levels and other potential complications.
7. **Communicate with Healthcare Providers**: Inform all healthcare providers about your condition for better-coordinated care.
Implementing these lifestyle changes can help manage symptoms and prevent complications associated with hemochromatosis type 1. - Medication
- For hemochromatosis type 1, medication options typically include **chelation therapy** using agents like deferoxamine, deferasirox, or deferiprone. These medications help bind excess iron and facilitate its removal from the body. Regular phlebotomy (blood removal) is the primary treatment, and medications are usually considered when phlebotomy is not effective or possible.
- Repurposable Drugs
-
For **hemochromatosis type 1 (HFE-related hereditary hemochromatosis)**, some repurposable drugs that have been investigated include:
1. **Deferoxamine** - An iron chelator traditionally used for conditions such as thalassemia to reduce iron overload.
2. **Deferasirox** - Another iron chelator, which helps in removing excess iron from the body.
3. **Deferiprone** - A further chelating agent considered for managing iron overload.
These drugs operate by binding to excess iron in the body and facilitating its excretion, thus potentially mitigating the iron accumulation associated with hemochromatosis type 1. Regular monitoring and additional treatments such as phlebotomy are typically part of the comprehensive management strategy for patients with this condition. - Metabolites
- In hemochromatosis type 1, the key metabolites affected are iron and related compounds. Hemochromatosis type 1 leads to excessive absorption and accumulation of dietary iron in various organs. This excess iron can deposit in the liver, heart, pancreas, joints, and skin, causing tissue damage and dysfunction. Elevated serum ferritin and transferrin saturation are commonly used biomarkers for diagnosing and monitoring the condition.
- Nutraceuticals
- For hemochromatosis type 1, no specific nutraceuticals are recommended as primary treatment. The standard management involves phlebotomy to reduce iron levels and dietary modifications to limit iron intake. Please consult a healthcare professional for personalized guidance.
- Peptides
-
Hemochromatosis type 1, also known as hereditary hemochromatosis, is a genetic disorder characterized by excessive iron accumulation in the body. Peptides specifically related to this disease are not typically a primary focus, as the condition is primarily linked to genetic mutations.
Nanotechnology (nan) in the context of hemochromatosis is an emerging area of research, potentially involving the development of nanoscale diagnostic tools or targeted therapies for better management of iron levels in affected individuals.