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Algorithms and recommendations for diagnosis and management of hyperferritinemia

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Management and Recommendations

Magagement, treatment and recommendations in patients with hyperferritinemia depends on their causes

Hyperferritinemia can be associated with:

• Aceruloplasminemia
• Alcoholic hepatitis
• Benign hyperferritinemia (HHB)
• Chronic inflammation
• Chronic kidney disease
• Hemolytic anaemias
• Hemosiderosis
• Hereditary hemochromatosis
• Hereditary hyperferritinemia cataracts syndrome (HHCS)
• Iron poisoning
• Iron-loading anaemias
• Metabolic syndrome
• Multiple red blod cell transfusions
• Neoplasia
• Porphyria cutanea tarda
• Viral hepatitis

Management and recommendations in Hereditary Hemochromatosis

• HH type 1. Hereditary Hemochromatosis patients with type 1 are those with a genotype homozygous for the C282Y mutation of the HFE gene and evidence of iron overload. Currently it is not considered that the variations H63D and S65C or other heterozygous compound genotypes with the C282Y mutation are causative of hereditary hemochromatosis type 1 by themselves. In people with other genotypes different from the C282Y homozygous genotype, genetic or non-genetic causes should be considered including a complete mutational study of all HH genes, presence of alcoholism, metabolic syndrome, liver disease, porphyria cutanea tarda.
• HH type 2. Hereditary Hemochromatosis patients type 2 patients are those with functional mutations in genes HAMP (Hepcidin protein) or HFE2 (hemojuvelin protein) and with evidence of iron overload.
• HH type 3. Hereditary Hemochromatosis patients type 3 are those patients with functional mutations in the TFR2 gene (transferrin receptor 2 protein) and with evidence of iron overload.
• HH type 4 or ferroportin disease. Patients with Hereditary Hemochromatosis type 4 are those patients with functional mutations in the SLC40A1 gene (protein Ferroportin). Usually only patients with hereditary hemochromatosis type 4b have evidence of iron overload, since the 4a form normally do not appear with tissue damage or clinical complications.

• Hereditary Hemochromatosis patients with evidence of iron overload should be treated with phlebotomy or erythro-apheresis.
• Hereditary Hemochromatosis patients without evidence of iron overload should be followed annually and only be treated when their ferritin levels and/or transferrin saturation exceeding normal levels (ferritin> 200ng/ml in women, > 300 ng / ml in men; IST> 45%). Patients with serum ferritin levels > 1000 µg/L should be treated.
• Phlebotomy consists in weekly or biweekly extraction of 450-500 ml of blood. For patients with Hereditary Hemochromatosis type 4, phlebotomy should be done with lower volumes because these patients tend to develop anaemia after phlebotomies. Good hydration is recommended before and after treatment. Patient should avoid strenuous physical activity during the subsequent 24 hours. The blood obtained by phlebotomies is suitable for human transfusion provided that no other contraindication exists. In case of having the appropriate equipment, HH patients can be treated by erythro-apheresis. Erythro-apheresis can selectively remove a greater amount of red cells and return the remaining blood components to the patient, avoiding the spoliation of platelets and coagulation factors, especially in patients who require such treatment often. It also allows for automatic compensation of the volume extracted with either saline or 5% albumin.
• Patients with hemochromatosis and liver fibrosis or cirrhosis should be also treated with phlebotomies.
• Before starting phlebotomies it should be assessed the possible complications including diabetes mellitus, osteoarthritis, endocrine defects, heart disease, porphyria cutanea tarda and osteoporosis.
• Complications of hemochromatosis such as hepatic cirrhosis, diabetes, and so on will be treated similarly as in individuals without hemochromatosis.
• Patients should be vaccinated against viral Hepatitis A and B.
• In HH patients with ferritin levels > 1000 ug/L, elevated AST, hepatomegaly or older than 40 years a liver biopsy can be done to anatomically study the degree of hepatic damage.
• It is recommended that affected persons with HH known and contact with Hemochromatosis patient associations.
• Genetic testing should be done in siblings and children of HH patients.

Management and recommendations in Hemosiderosis

• Transfusional hemosiderosis can be treated with iron chelators or controlled phlebotomies.
• Some cases of idiopathic pulmonary hemosiderosis have responded favourably to treatment with oral corticosteroids. It should be noted that steroid therapy has significant side effects. Other immunomodulatory therapies have been described in the literature.

Management and recommendations in Porphyria cutanea tarda (PCT)

• Patients diagnosed with PCT should avoid alcohol consumption, iron supplements, excess exposure to sunlight, as well as estrogens and chlorinated cyclic hydrocarbons, all of which can potentially exacerbate the disorder.
• The management of excess iron (due to the commonality of hemochromatosis in PCT patients) can be achieved through phlebotomies.
• Low doses of antimalarials (cloroquine) can be used to remove excess porphyrins from the liver by increasing the excretion rate.
• Due to the strong association between PCT and Hepatitis C, the treatment of Hepatitis C (if present) is vital to the effective treatment of PCT.

Management and recommendations in Hereditary Hyperferritinemia Cataracts Syndrome (HHCS)

• In HHCS apart from the cataracts there are no other clinical manifestations associated with this syndrome and the prognosis is good.
• There must be a proper and correct diagnosis for HHCS. Phlebotomies must be avoided because they are not well tolerated and produces patient's anaemia.
• Cataract can be chirurgical operated.

Management and recommendations in Benign Hyperferritinemia

• In Benign Hyperferretinemia there are no clinical associated symptoms and the prognosis is good. This condition does not require of any specific treatment.
• There must be a proper and correct diagnosis for BH. Phlebotomies must be avoided because they are not well tolerated and produces patient's anaemia.

Management and recommendations in Aceruloplasminemia

• There is no established treatment for neurological symptoms.
• Liver iron overload can be reduced by phlebotomy therapy, although the volume of blood removed at each session and the timing of repeat phlebotomies must be carefully controlled.
• In patients with very low haemoglobin levels or those intolerant to phlebotomies iron chelation therapy (such as deferoxamine, deferiprone or deferasirox chelation) should be done.

Management and recommendations in Metabolic Syndrome

• Controlling variables related to the metabolic syndrome that can be controlled (overweight, hypertension, dyslipidemia, hyperglycemia, level of exercise, changes in lifestyle) significantly improve ferritin levels.

Management and recommendations in Alcoholic Hepatitis

• Stop drinking alcohol will reverse liver damage or, in more advanced cases, prevent the disease from becoming worse.
• Follow a special diet to reverse nutritional deficiencies that often occur in people with alcoholic hepatitis.
• Doctor may prescribe medications to reduce liver inflammation. Corticosteroids drugs may be recommended if you have severe alcoholic hepatitis. These drugs have shown some short-term benefit in increasing survival. Steroids have significant side effects and are not recommended if you have failing kidneys, gastrointestinal bleeding or an infection. About 40 percent of people do not respond to corticosteroids.
• Avoid the exposure to hepatitis virus. Alcohol enhances the detrimental effects of hepatitis viruses and contributes to the development of liver cirrhosis.

Management and recommendations in Viral Hepatitis

• A detailed history and physical examination is essential and patients should be queried about alcohol consumption.
• Avoid alcohol consumption and medications toxic to the liver.
• Your doctor may recommend a high-calorie diet if you are losing weight.
• No specific treatment exists for hepatitis A because your body will clear the hepatitis A virus on its own. In most cases of hepatitis A, the liver heals completely in a month or two with no lasting damage.
• The hepatitis B infection (HBV) does not usually require treatment because most adults clear the infection spontaneously. Some patients may require medication with antiviral drugs and/or immune system modulators (interferon alpha). Response to treatment differs between the genotypes.
• Treatment for HCV consists of a combination of interferon alpha and the antiviral drug ribavirin. Responses to treatment vary by genotype.
• Treatment and recommendations may vary depending on the presence of additional concurrent medical diseases and other concomitant viral infections. Please consult the EASL clinical practice guidelines for more details.

Management and recommendations in Inflammation

• There are multiple causes of acute or chronic inflammation. Possible causes of a chronic inflammation may be persistent infections, diseases mediated by the immune system (allergic reactions, Crohn's disease, autoimmune diseases like rheumatoid arthritis, multiple sclerosis, lupus erythematosus, Still's disease) or prolonged exposure to exogenous toxic agents (for example exposure to silica causes silicosis) or endogenous (e.g. LDL lipid accumulation in blood vessels causes atherosclerosis). Moreover, chronic inflammation is important in the development of cancer and degenerative diseases such as Alzheimer's.
• Many diseases involve inflammation and each requires a concrete and specific treatment.
• Because of the dual functionality of ferritin as iron storage protein or acute phase response protein is important in people with hyperferritinemia to rule out inflammation, which may be causing the increase in ferritin levels. This requires measuring inflammatory markers such as C-reactive protein (CRP).

Management and recommendations in Iron Poisoning

• Appropriate life support measures should be administered, including hydration, transfusions, correction of acidosis, cardiovascular stabilization.
• Prevent the absorption of iron by:
  • Ipecac syrup, is used to remove the tablets from the stomach. Evaluate its effectiveness in poisoning of less than two hours if the patient has no vomited spontaneously and has preserved his/her consciousness.
  • Gastric lavage is not recommended in children because of the size of the tablets.
  • Complete intestinal lavage may be useful when the tablets are bonded or cause obstruction. It is contraindicated in patients with inadequate intestinal motility (megacolon, suspected intestinal perforation).
• Iron chelation treatment with dexferroxamine is used in moderate to severe iron poisoning. Chelation therapy with parenteral dexferroxamina can eliminate 9 micrograms of iron per 100 milligrams of dexferroxamina administered.
• If after decontamination tablets residues remain in the intestine, it may be necessary an endoscopic or a gastrostomy.
• Iron-containing medicines should not be considered safe. These medications should be kept out of reach of children.

Management and recommendations in Chronic Kidney Disease

• The presence of chronic kidney disease confers a markedly increased risk of cardiovascular disease, and people with CKD often have other risk factors for heart disease, such as hyperlipidemia. The most common cause of death in people with CKD is therefore cardiovascular disease rather than renal failure. Aggressive treatment of hyperlipidemia is warranted.
• Control of blood pressure and treatment of the original disease, whenever feasible, are the broad principles of management.

Management and recommendations in Neoplasia

• Treatments of cancers that undergo with hyperferretinemia are specific of each type and subtype. For specific treatment please consult cancer treatment guidelines.

Management and recommendations in Multiple Red Blood Cell Transfusions

• Multiple red blood cells transfusions are needed to treat some hereditary anaemias such as thalassemia, congenital sideroblastic anaemia and congenital dyserythropoietic anaemias and some acquired diseases such as myelodysplastic syndrome. However, it is important to count the number of transfusions given to a patient for establishing an iron chelation therapy to prevent iron overload in this person.

Management and recommendations in Hemolytic Anaemias

• Haemolityc anaemias are a large and heterogeneous pathology group, including acquired (such as the autoimmune or microangiopathic anaemia) and hereditary forms (such as membranopathies, haemoglobinopathies or enzymopathies, and others). The haemolysis can sometimes be resolved by the bone marrow itself and in this case there will be no anaemia (for instance in hereditary spherocytosis, homozygous haemoglobin C...), in the rest of cases the anaemia will be from mild to severe.
• In all these pathologies it can exist a variable grade of iron overload due to: red blood cells intravascular destruction, ineffective erythropoiesis with increased absorption of iron that may occur in some of these anaemias, or due to transfusion support itself mainly in severe anaemia.
• Haemolytic anaemia with evidence of iron overload should be treated. However, in this group of disorders where anaemia is presented in a variable grade it is not indicated a treatment with phlebotomy and therefore, the proper iron chelators should be used according to the aetiology and the cause of the iron overload.
  • Deferiprone is an oral iron chelator that is only indicated in thalassemia major or intermedia. Although there are some reported cases where deferiprone was used in other types of diseases such as sickle cell disease.
  • Deferasitox is another oral iron chelator. This chelator is currently only used in iron overload due to transfusions. It is expected that soon the use of this chelator will be authorized in some iron overload diseases with ineffective erythropoiesis and without transfusion requirements.
  • Desferoxamine (parenteral administration) is used in haemolytic anaemias with iron overload that have not transfused or only transfused few times. This chelator is normally subcutaneously infused using an administration pump but it can be administered also intramuscularly in cases with low iron overload.
• Without evidence of iron overload, one should monitor the patient during the follow up visits and treat him/her only when the ferritin and transferrin saturation levels exceed normal values. Special care should be given to patients with serum ferritin levels > 1000 µg/L.
• Besides the treatment of the iron overload, the routine treatments for each specific pathology should be carried out (corticosteroids in autoimmune haemolytic anaemias, blood transfusions...).
• The management and treatment of haemolytic anaemias should be monitored by an expert physician with experience in treating them.

Management and recommendations in Iron-loading Anaemias

• Severe anaemias are treated with red cell transfusions. Transfusion should be carefully monitored because they contribute to iron overload. In some cases continuous oral iron supplementation or intravenous iron may raises haemoglobin values improving quality of life.
• Iron overload is treated with chelation therapy.
• Bone marrow transplantation has been successfully done in some patients (β-thalasemia major, SLC25A38 CSA, and others). The suitability of this treatment should be carefully evaluated by specialists in the field.
• Erythropoietin (EPO) treatment allowed transfusion independency or reduction in some cases.
• In some cases spleen removal (splenectomy) may improve the anaemia and thereby patient’s clinical situation. However, since the spleen has relevant functions for the immunity, the decision whether this operation is of benefit should be made by the specialist in the field.
• X-linked sideroblastic anaemia may respond to treatment with vitamin B6 (pyridoxine) and folic acid. In unresponsive cases with severe anaemia supportive measures such as red cell transfusions are needed. Other sideroblastic anaemias (ie., SLC25A38-related CSA, GLRX5-related CSA) do not respond to treatment with vitamin B6 (pyridoxine) and patients often need regular blood transfusions for normal development.
• In atransferrinemia, periodic infusions of normal plasma (which contains transferrin) or purified apotransferrin may allow the correction of anaemia and a normal development, without iron overload. Treatment with chelating agents, controlled phlebotomies or both can be required to diminish tissue iron overload.
• CDA I patients may need treatment with Interferon alpha to normalize the blood counts. This type of treatment has to be controlled by a specialist with experience with treatment of chronic anaemias.