Approach Considerations
Despite advances in the molecular understanding of hemochromatosis and the impact of C282Y on diagnosis, treatment remains simple, inexpensive, and safe.
The goal of therapy in patients with iron overload disorders is to remove the iron before it can produce irreversible parenchymal damage. [9] This is achieved via chelation therapy or venesection, depending on the underlying cause. [89] Because a normal life span can be expected if iron reduction is initiated before the development of cirrhosis, clinical suspicion and early diagnosis are essential.
The tetrad of cirrhosis, diabetes mellitus, hyperpigmentation of the skin, and cardiac failure may be evident in only a minority of patients. [90] Any patient admitted to the hospital with an isolated case of asthenia or with arthralgia or hypertransaminasemia should be examined by means of transferrin-saturation testing.
Cardiac manifestations of hereditary hemochromatosis could have sudden onset and could be poorly responsive to therapy. The hemochromatic etiology of the cardiomyopathy should be identified to ensure appropriate treatment.
A Cochrane database review of interventions for hereditary hemochromatosis found that phlebotomy remained the treatment of choice in those with hereditary hemochromatosis who required blood letting, but no data from randomized trials provided evidence of benefit from any form of blood letting in these patients. There was also insufficient evidence as to whether erythrocytapheresis is beneficial or harmful compared with phlebotomy. [91] The investigators noted an overall low quality of evidence and a high risk of bias in the trials assessed, and none of the trials evaluated iron-chelating agents or provided mortality data beyond 1 year or long-term follow-up. [91]
Admission to the intensive care unit (ICU) may be warranted for patients who develop hepatic, cardiac, and infectious complications. Indications for inpatient care, preferably in an ICU, include the following:
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Gastroesophageal bleeding
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Hepatic encephalopathy
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Sepsis
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Congestive heart failure
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Arrhythmias
Transfer considerations
In case of end-stage liver disease that is refractory to all methods of medical treatment, transferring the patient to a facility experienced in liver transplantation is preferable.
When the diagnosis of hepatocellular carcinoma is being considered or if the diagnosis is confirmed, transfer the patient to a cancer institution.
Surgical Intervention
Surgical procedures are used to treat two important complications: end-stage liver disease and severe arthropathy.
When end-stage liver disease progresses despite iron-reduction therapy, orthotopic liver transplantation is the only therapeutic option. [10] Another indication for liver transplantation is the development of hepatocellular carcinoma.
Careful patient selection is advised for liver transplantation to treat patients with hepatocellular carcinoma. Particularly, these patients should have a single tumor of 5 cm or smaller in diameter. If multiple tumors are present, the acceptable number is three tumors or less, smaller than 3 cm. The 4-year survival rate can be approximately 90% if these criteria are respected.
Surgical arthroplasty is considered if joint destruction becomes severe despite medical therapy.
Phlebotomy
Once diagnosed, hemochromatosis is treated by phlebotomy to rid the body of excess iron and to maintain normal iron stores. Phlebotomy remains the sole recommended treatment for hereditary hemochromatosis and should be undertaken in a case-specific manner.
The AASLD guidelines state hereditary hemochromatosis patients who have evidence of iron overload are “strongly encouraged” to receive phlebotomy regularly until iron stores are depleted. The regular phlebotomies should continue for life, and the frequency of maintenance therapy should be based on serum ferritin levels. [8]
In the induction phase, weekly phlebotomy is made, with blood removal of 7 mL/kg per phlebotomy (not to exceed 550 mL per phlebotomy). [92] The efficacy of treatment is controlled by ferritin level evaluation in plasma once monthly until the values remain below the upper limits of normal (300 mcg/L in men; 200 mcg/L in women). The hemoglobin level must be checked before each procedure; the reference value is 12-13g/dL (120-130g/L). [92] Subsequently, evaluation of ferritin concentration should be performed bimonthly until its level is reduced below 50 mcg/L.
In the maintenance phase, the phlebotomy should be performed every 2-4 months. The interval between procedures is determined by the level of ferritin, which should be lower than 50 mcg/mL. [92, 84]
In a retrospective analysis of 12 paired patients from the Netherlands with hereditary hemochromatosis homozygous for the C282Y mutation, those who received proton pump inhibitors (PPIs) had a significant reduction in the frequency of median number of phlebotomies (0.50) compared with before the administration of PPIs (3.17), and those who received PPIs for at least 2 years required significantly fewer phlebotomies (1.25) than those in the paired group before they began taking PPIs (3.17). [93] Moreover, there were a significantly lower number of phlebotomies in the paired group after initiation of PPIs compared to that of patients who never received PPIs.
One study showed that phlebotomy therapy can reduce liver fibrosis, and the effects of therapy are dependent on the stage of the disease. [94] Among individuals with biopsy results positive for liver fibrosis, phlebotomy was associated with an improvement of 13-50%, with the greatest improvement among individuals with the least degree of liver fibrosis. Individuals served as their own controls, and improvement was based on qualitative histologic features. When liver cirrhosis is present and in its early stages, therapeutic phlebotomy appears to control or slow the progression of liver disease. In addition, the results of phlebotomy therapy can be predicted by the simple biochemical tests. [94]
Summary
Phlebotomy is generally a safe and efficient method of iron removal. Encourage patients to have weekly therapeutic phlebotomy of 500 mL of whole blood (equivalent to approximately 200-250 mg of iron). [95] Some patients can tolerate twice-weekly phlebotomy, but this regimen is tedious and often inconvenient. Therapeutic phlebotomy should be performed until iron-limited erythropoiesis develops, identified by failure of the hemoglobin level and/or hematocrit to recover before the next phlebotomy. It should be continued until transferrin saturation is less than 50% and serum ferritin levels are less than 50 ng/mL, preferably 20 ng/mL.
Most patients require maintenance phlebotomy in which 1 unit of blood is removed every 2-3 months. Therapeutic phlebotomy may improve or even cure some of the manifestations and complications of the disease, such as fatigue, elevated liver enzymes, hepatomegaly, abdominal pain, arthralgias, and hyperpigmentation. Other complications usually show little or no change after phlebotomy.
Avoid excessive phlebotomy and the risk of hypovolemia and dehydration.
Chelation Therapy
In patients with hemochromatosis and heart disease, anemia, or poor venous access, treatment with iron chelation agents is recommended. The therapeutic perspectives comprise compounds inhibiting intestinal absorption of iron, chelators of iron, hepcidin, or ferroportin supplementation. In disease caused by hepcidin deficiency, protein supplementation with hepcidin is advised.
Deferasirox
Deferasirox (Exjade) is the oral iron chelator that should be taken once daily as an adjunct to phlebotomies or instead of phlebotomy in patients in whom these procedures are poorly tolerated. Deferasirox is very efficacious in liver iron removal. During treatment with deferasirox, kidney function should be controlled. [96]
In an investigational study that evaluated the effects of deferasirox in Hjv-/- mice (knockout animals lacking hemojuvelin [HJV]; ie, an experimental model of hereditary hemochromatosis), a dose of 100 mg/kg markedly reduced the iron level in the liver and heart. (Note that 100 mg/kg of deferasirox is a much larger dose than is used in humans.) However, in the pancreas, deferasirox was less effective, and the splenic iron count was not influenced. [97] Deferasirox was administered once daily 5 times a week.
Dendrimers
The family of dendrimers, iron-selective chelators, have been synthesized. [98] Dendrimers terminated with hydroxypiridinone have high affinity to iron and reduce its absorption in the rat intestine. Therefore, the application of the dendrimers in the treatment of iron overload diseases is considered.
In experiments performed on rats compared the protective effect of two iron chelators, deferoxamine and deferiprone, on iron overload in the heart, deferiprone was found to reduce histopathologic changes in the heart of rats chronically loaded with iron. [99] The two compounds were administered individually or in combination with vitamin C (vitamin C was used as the antioxidative compound aimed at preventing heart oxidative injury). Additional administration of vitamin C improved histopathologic changes and biochemical markers in the heart. [99]
Juvenile hemochromatosis
The first patient affected by juvenile hemochromatosis was successfully treated with chelation therapy. Because of severe congestive heart failure, phlebotomy was contradicted. Simultaneous administration of deferoxamine and deferiprone reduced the myocardial dysfunction and improved the clinical status of that patient.
Anemia
Patients affected with anemia cannot be treated with phlebotomy. Thus, application of iron chelation agents (eg, deferoxamine, deferiprone, deferasirox) is recommended. [100]
Deferoxamine is administered intravenously or subcutaneously at doses ranging from 25 to 40 mg/kg. Intravenous infusion is usually 8-10 hours in duration and is repeated 5 nights per week. Similar effects can be obtained with subcutaneous bolus injections administered twice daily. The main adverse effects are inflammatory reactions at the sites of injection, visual and auditory disturbances, bone growth disturbances, and allergic reactions, including anaphylaxis.
Deferiprone is given orally in 3 divided doses of 75 mg/kg/d. Agranulocytosis, neutropenia, arthralgia, gastrointestinal reactions, and elevation of liver enzyme levels are the main adverse effects. Cardiac iron overload is better reduced by deferiprone than deferoxamine.
Deferasirox is an oral chelation agent, administered at 10-30 mg/kg. Deferasirox adverse effects can include elevation of the creatinine level, skin exanthem, diarrhea, and visual and auditory disturbances.
Dietary Considerations
Dietary factors may influence the phenotypic expression of hemochromatosis. Some modulate absorption of iron and may affect the variability of phenotypic penetrance. However dietary changes intended to minimize or eliminate iron ingestion are usually unnecessary and are often not feasible.
Patients should not consume foods that contain large concentrations of bioavailable iron, such as red meats and organ meats. In addition, they should not use iron supplements, including multivitamins with iron. In addition, vitamin C supplements should be avoided. Substances in foods and drinks, including tannates (in tea), phytates, oxalates, calcium, and phosphates, can bind iron and inhibit its absorption.
Alcohol abuse may accelerate disease progression. Ethanol sometimes increases iron absorption, and certain alcoholic drinks, especially red wine, contain relatively high concentrations of iron. Activity of hydroxyl free radicals is elevated by iron-containing diets combined with alcohol intake, and this is implicated in hepatocarcinogenesis. [101] Ingestion of 30 g or more of ethanol daily potentiates hepatic injury due to iron overload and increases the relative risk for primary liver cancer in persons with cirrhosis. Patients with evidence of hepatic injury should consume little or no ethanol. Other patients should consume ethanol in moderation.
Studies performed on healthy subjects living in the Spanish-Mediterranean coast showed that some genotypes (C282Y heterozygote, H63D heterozygote, and homozygote, as well as H63D/S63C compound heterozygote) together with alcohol and iron intake increased indicators of iron status; however, calcium intake decreased them. [102] These effects were not observed in S63C heterozygotes. [102]
Vitamin C (ascorbic acid) increases intestinal absorption of inorganic iron. No reason exists to discourage patients from eating fresh fruits and vegetables containing vitamin C, but advising them to limit ingestion of vitamin C in supplements to 500 mg/d is prudent. Use mineral supplements for specific deficiencies only.
Seafood from potentially contaminated waters must be cooked thoroughly. Raw or improperly cooked shellfish is sometimes contaminated with Vibrio vulnificus and can cause sepsis in patients with hemochromatosis.
Consultations
Promptly refer patients to a gastroenterologist and a liver transplant center in case of end-stage liver disease, especially if it is refractory to treatment. Most often, a gastroenterologist is required to confirm the diagnosis by liver biopsy and to assist in the management of end-stage liver diseases. A surgeon specializing in liver transplantation may be needed in cases of highly advanced liver disease.
In addition, due to the multiorgan nature of the disease and the injury or damage to many intrinsic systems, care and treatment of patients with hemochromatosis require the collaboration of other physicians in different medical or surgical specialties, such as the following:
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An endocrinologist is helpful in treating patients with diabetes mellitus or other endocrine complications, such as thyroid and gonadal dysfunction
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A cardiologist assists in the management of severe congestive heart failure and other cardiac complications, such as arrhythmias
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An infectious disease specialist can treat patients with sepsis and can also choose the appropriate antibiotic therapy for rare infectious complications
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A rheumatologist or an orthopedist is required for the management of joint complications.
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A geneticist is valuable for family screening in all first-degree relatives of newly diagnosed individuals
Long-Term Monitoring
The patient should have a primary care provider who can coordinate treatment with the other specialists involved. Physicians should be aware of the possibility of hereditary hemochromatosis, and they should perform diagnostic tests when hereditary hemochromatosis is suspected. Moreover, patient education as to the importance of early diagnosis and lifelong treatment is essential for symptom-free life.
Regular monitoring of hematocrit, hemoglobin, and serum ferritin levels is necessary in patients undergoing phlebotomy. Genetic testing for hereditary hemochromatosis should also be performed in family members of patients with hereditary hemochromatosis.
Continuous observation of patients with hereditary hemochromatosis regarding the potential complications of the disease is recommended. Regular follow-up visits should be scheduled with the gastroenterologist. Others, such as a cardiologist, an endocrinologist, or a hematologist, may be needed for serial diagnostic and therapeutic intervention. Quarterly visits with healthcare providers may be necessary depending on the severity of the symptoms or complications.
Hepatocellular carcinoma is one of the most serious complications of hemochromatosis. Most hepatologists recommend periodic screening with serum alpha-fetoprotein (AFP) every 6 months in patients with cirrhosis. The most cost-effective imaging test used to supplement serum AFP screening is ultrasonography; the sensitivity is approximately 80% when serum AFP and ultrasonograms are combined for the screening of hepatocellular carcinoma.
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Hemochromatosis. What is hemochromatosis? Hemochromatosis is a genetic disorder where the body isn’t able to regulate its iron absorption. Iron levels in the body build up over time and damage the liver as well as other organs, through the generation of free radicals. Courtesy of Osmosis.org (https://www.osmosis.org/).
