Maternal and perinatal outcomes in pregnant women with sickle cell disease: an update

ABSTRACT Introduction: The aim of this study was to describe maternal and perinatal outcomes in pregnant women with sickle cell disease (SCD) followed at Santa Casa de Sao Paulo over a 10-year period (between 2010 and 2019). Method: Fifty-five records of pregnancies were analyzed among 35 women with SCD. Results: Among 29 newborns, 19 (65.5%) were full-term and 10 pre-term; 24 (82.7%) caesareans and 5 (17.2%) natural births were observed. The mean gestational age at birth and mother's age were 36.6 weeks (30-40) and 26.7 years (17-39), respectively. No maternal death was observed. The main maternal obstetric and non-obstetric complications were: preeclampsia and gestational diabetes, and vaso-occlusive crisis, urinary tract infection and acute chest syndrome, respectively. Twenty-six (47.0%) fetal deaths were observed, 24 being intrauterine fetal (14 early abortions, 10 late abortions and 2 stillbirths). Regarding the red blood cell transfusion history, 40 (72.7%) out of 55 pregnancies received transfusion. Pregnant women who received 6 or more transfusions throughout pregnancy had a significantly lower number of abortions, i.e., no cases of early abortion and only 1 case of late abortion, versus 14 and 9 cases in pregnancies with 0-5 transfusions, respectively. Despite advances in the management of SCD, pregnant women with SCD (particularly those with HbSS) are at a high risk for maternal and fetal complications, even though they are followed in reference centers. Conclusion: The lower risk of intrauterine fetal death for those women who received more transfusions throughout pregnancy observed in the current study leads us once more to raise the need for prospective, multicenter, randomized trials to determine whether the potential benefits balance the risks of prophylactic transfusions.

Economic burden of sickle cell disease in Brazil.

BACKGROUND: Sickle cell disease (SCD) may cause several impacts to patients and the whole society. About 4% of the population has the sickle cell trait in Brazil, and 60,000 to 100,000 have SCD. However, despite recognizing the significant burden of disease, little is known about SCD costs. OBJECTIVE: To estimate SCD societal costs based on disease burden modelling, under Brazilian societal perspective. METHODS: A disease burden model was built considering the societal perspective and a one-year time horizon, including direct medical and indirect costs (morbidity and mortality). The sum of life lost and disability years was considered to estimate disability-adjusted life years (DALYs). Data from a public database (DATASUS) and the prevalence obtained from literature or medical experts were used to define complications prevalence and duration. Costs were defined using data from the Brazilian public healthcare system table of procedures and medications (SIGTAP) and the human capital method. RESULTS: Annual SCD cost was 413,639,180 USD. Indirect cost accounted for the majority of burden (70.1% of the total; 290,158,365 USD vs 123,480,816 USD). Standard of care and chronic complications were the main source of direct costs among adults, while acute conditions were the main source among children. Vaso-occlusive crisis represented the complication with the highest total cost per year in both populations, 11,400,410 USD among adults and 11,510,960 USD among children. CONCLUSIONS: SCD management may impose an important economic burden on Brazilian society that may reach more than 400 million USD per year.

HFE hemochromatosis: an overview about therapeutic recommendations

Abstract Hemochromatosis is currently characterized by the iron overload caused by hepcidin deficiency. Large advances in the knowledge on the hemochromatosis pathophysiology have occurred due to a better understanding of the protein of the iron metabolism, the genetic basis of hemochromatosis and of other iron overload diseases or conditions which can lead to this phenotype. In the present review, the main aims are to show updates on hemochromatosis and to report a practical set of therapeutic recommendations for the human factors engineering protein (HFE) hemochromatosis for the p.Cys282Tyr (C282Y/C282Y) homozygous genotype, elaborated by the Haemochromatosis International Taskforce.

Maternal and perinatal outcomes in pregnant women with sickle cell disease: an update.

INTRODUCTION: The aim of this study was to describe maternal and perinatal outcomes in pregnant women with sickle cell disease (SCD) followed at Santa Casa de Sao Paulo over a 10-year period (between 2010 and 2019). METHOD: Fifty-five records of pregnancies were analyzed among 35 women with SCD. RESULTS: Among 29 newborns, 19 (65.5%) were full-term and 10 pre-term; 24 (82.7%) caesareans and 5 (17.2%) natural births were observed. The mean gestational age at birth and mother`s age were 36.6 weeks (30-40) and 26.7 years (17-39), respectively. No maternal death was observed. The main maternal obstetric and non-obstetric complications were: pre-eclampsia and gestational diabetes, and vaso-occlusive crisis, urinary tract infection and acute chest syndrome, respectively. Twenty-six (47.0%) fetal deaths were observed, 24 being intrauterine fetal (14 early abortions, 10 late abortions and 2 stillbirths). Regarding the red blood cell transfusion history, 40 (72.7%) out of 55 pregnancies received transfusion. Pregnant women who received 6 or more transfusions throughout pregnancy had a significantly lower number of abortions, i.e., no cases of early abortion and only 1 case of late abortion, versus 14 and 9 cases in pregnancies with 0-5 transfusions, respectively. Despite advances in the management of SCD, pregnant women with SCD (particularly those with HbSS) are at a high risk for maternal and fetal complications, even though they are followed in reference centers. CONCLUSION: The lower risk of intrauterine fetal death for those women who received more transfusions throughout pregnancy observed in the current study leads us once more to raise the need for prospective, multicenter, randomized trials to determine whether the potential benefits balance the risks of prophylactic transfusions.

HFE hemochromatosis: an overview about therapeutic recommendations.

Hemochromatosis is currently characterized by the iron overload caused by hepcidin deficiency. Large advances in the knowledge on the hemochromatosis pathophysiology have occurred due to a better understanding of the protein of the iron metabolism, the genetic basis of hemochromatosis and of other iron overload diseases or conditions which can lead to this phenotype. In the present review, the main aims are to show updates on hemochromatosis and to report a practical set of therapeutic recommendations for the human factors engineering protein (HFE) hemochromatosis for the p.Cys282Tyr (C282Y/C282Y) homozygous genotype, elaborated by the Haemochromatosis International Taskforce.

Consensus statement for diagnosis and treatment of paroxysmal nocturnal haemoglobinuria

Paroxysmal nocturnal hemoglobinuria is a chronic, multi-systemic, progressive and lifethreatening disease characterized by intravascular hemolysis, thrombotic events, serious infections and bone marrow failure. Paroxysmal nocturnal hemoglobinuria results from the expansion of a clone of hematopoietic cells that due to an inactivating mutation of the X-linked gene PIG-A are deficient in glycosylphosphatidylinositol-linked proteins. Early diagnosis, using flow cytometry performed on peripheral blood, the gold standard test to confirm the diagnosis of paroxysmal nocturnal hemoglobinuria, is essential for improved patient management and prognosis. The traditional therapy for paroxysmal nocturnal hemoglobinuria includes blood transfusion, anti-thrombosis prophylaxis or allogeneic bone marrow transplantation. The treatment that has recently become available is the complement blockade by the anti-C5 monoclonal antibody eculizumab. In this consensus, we are aiming to review the diagnosis and treatment of the paroxysmal nocturnal hemoglobinuria patients, as well as the early recognition of its systemic complications. These procedures express the opinions of experts and have been based on the best available evidence and international guidelines, with the purpose of increasing benefits and reducing harm to patients.

Consensus statement for diagnosis and treatment of paroxysmal nocturnal haemoglobinuria.

Paroxysmal nocturnal hemoglobinuria is a chronic, multi-systemic, progressive and life-threatening disease characterized by intravascular hemolysis, thrombotic events, serious infections and bone marrow failure. Paroxysmal nocturnal hemoglobinuria results from the expansion of a clone of hematopoietic cells that due to an inactivating mutation of the X-linked gene PIG-A are deficient in glycosylphosphatidylinositol-linked proteins. Early diagnosis, using flow cytometry performed on peripheral blood, the gold standard test to confirm the diagnosis of paroxysmal nocturnal hemoglobinuria, is essential for improved patient management and prognosis. The traditional therapy for paroxysmal nocturnal hemoglobinuria includes blood transfusion, anti-thrombosis prophylaxis or allogeneic bone marrow transplantation. The treatment that has recently become available is the complement blockade by the anti-C5 monoclonal antibody eculizumab. In this consensus, we are aiming to review the diagnosis and treatment of the paroxysmal nocturnal hemoglobinuria patients, as well as the early recognition of its systemic complications. These procedures express the opinions of experts and have been based on the best available evidence and international guidelines, with the purpose of increasing benefits and reducing harm to patients.

Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: A SUSTAIN study analysis.

The cell adhesion molecule P-selectin plays a key role in the pathogenesis of a vaso-occlusive crisis (VOC) in patients with sickle cell disease (SCD). In the double-blind, placebo-controlled phase 2 SUSTAIN study, crizanlizumab (humanized, anti-P-selectin monoclonal antibody) 5 mg/kg significantly lowered the rate of VOC in patients with SCD by 45% vs placebo. In SUSTAIN, patients with SCD were randomized to crizanlizumab 2.5 mg/kg, crizanlizumab 5 mg/kg, or placebo intravenously 14 times over 52 weeks. The primary endpoint was the annual rate of VOC with crizanlizumab vs placebo. This post hoc descriptive analysis evaluated the proportion of patients who did not experience a VOC during the study in the following subgroups: VOCs in the year prior to study entry (2-4/5-10), SCD genotype (HbSS/non-HbSS), and concomitant hydroxyurea use (yes/no). More patients were VOC event-free in the crizanlizumab 5 mg/kg arm than in the placebo arm, including those with more frequent prior VOCs (ie, 5-10; 28.0% vs 4.2%), the HbSS genotype (31.9% vs 17.0%) and/or using concomitant hydroxyurea (33.3% vs 17.5%). Further analyses of secondary endpoints demonstrated that crizanlizumab treatment significantly increased time-to-first VOC vs placebo in these subgroups. The rates of treatment-emergent adverse events were similar between treatment arms across all subgroups. This post hoc analysis of SUSTAIN shows that in patients with a high number of prior VOCs, on concomitant hydroxyurea and/or with the HbSS genotype, crizanlizumab treatment increases the likelihood of patients being VOC event-free and delays time-to-first VOC.

Hereditary hemochromatosis: mutations in genes involved in iron homeostasis in Brazilian patients.

BACKGROUND: p.C282Y mutation and rare variants in the HFE gene have been associated with hereditary hemochromatosis (HH). HH is also caused by mutations in other genes, such as the hemojuvelin (HJV), hepcidin (HAMP), transferrin receptor 2 (TFR2) and ferroportin (SLC40A1). The low rate homozygous p.C282Y mutation in Brazil is suggestive that mutations in non-HFE genes may be linked to HH phenotype. AIM: To screen exon-by-exon DNA sequences of HFE, HJV, HAMP, TFR2 and SLC40A1 genes to characterize the molecular basis of HH in a sample of the Brazilian population. MATERIALS AND METHODS: Fifty-one patients with primary iron overload (transferrin saturation ≥50% in females and ≥60% in males) were selected. Subsequent bidirectional DNA sequencing of HFE, HJV, HAMP, TFR2 and SLC40A1 exons was performed. RESULTS: Thirty-seven (72.5%) out of the 51 patients presented at least one HFE mutation. The most frequent genotype associated with HH was the homozygous p.C282Y mutation (n=11, 21.6%). In addition, heterozygous HFE p.S65C mutation was found in combination with p.H63D in two patients and homozygous HFE p.H63D was found in two patients as well. Sequencing in the HJV and HAMP genes revealed HJV p.E302K, HJV p.A310G, HJV p.G320V and HAMP p.R59G alterations. Molecular and clinical diagnosis of juvenile hemochromatosis (homozygous form for the HJV p.G320V) was described for the first time in Brazil. Three TFR2 polymorphisms (p.A75V, p.A617A and p.R752H) and six SLC40A1 polymorphisms (rs13008848, rs11568351, rs11568345, rs11568344, rs2304704, rs11568346) and the novel mutation SLC40A1 p.G204S were also found. CONCLUSIONS: The HFE p.C282Y in homozygosity or in heterozygosity with p.H63D was the most frequent mutation associated with HH in this sample. The HJV p.E302K and HAMP p.R59G variants, and the novel SLC40A1 p.G204S mutation may also be linked to primary iron overload but their role in the pathophysiology of HH remain to be elucidated.

Hemojuvelin and hepcidin genes sequencing in Brazilian patients with primary iron overload.

BACKGROUND: most hereditary hemochromatosis (HH) patients are homozygous for the p.C282Y mutation in the HFE gene. Some studies reported that HH phenotypic expression could be modulated by genetic factors such as HJV and HAMP gene mutations. AIMS: the aims of this study were to identify HJV and HAMP mutations and to analyze their impact on HH phenotype in non-p.C282Y homozygous individuals. METHODS: Twenty-four Brazilian patients with primary iron overload and non-p.C282Y homozygous genotype (transferrin saturation >50% in women and >60% in men and absence of secondary causes) were selected. Subsequent bidirectional sequencing of the HJV and HAMP exons was performed. RESULTS: sequencing revealed a substitution in heterozygosis, c.929C > G, which corresponds to p.A310G polymorphism in HJV exon 4 (rs7540883). In the same gene, in another individual, an IVS1-36C > G intronic variant was detected in heterozygosis. In the HAMP gene, an IVS3 + 42G > A intronic variant was identified. There were six (25.0%) patients carrying a heterozygous genotype for the HFE p.C282Y and nine (37.5%) patients carrying a heterozygous genotype for the HFE p.H63D. CONCLUSION: HJV p.A310G polymorphism and two intronic variants were found, but none of these alterations were associated with digenic inheritance with the HFE gene. Our data indicate that HJV and HAMP functional mutations are not frequent in these patients.

HFE gene mutations in patients with primary iron overload: is there a significant improvement in molecular diagnosis yield with HFE sequencing?

Rare HFE variants have been shown to be associated with hereditary hemochromatosis (HH), an iron overload disease. The low frequency of the HFE p.C282Y mutation in HH-affected Brazilian patients may suggest that other HFE-related mutations may also be implicated in the pathogenesis of HH in this population. The main aim was to screen for new HFE mutations in Brazilian individuals with primary iron overload and to investigate their relationship with HH. Fifty Brazilian patients with primary iron overload (transferrin saturation>50% in females and 60% in males) were selected. Subsequent bidirectional sequencing for each HFE exon was performed. The effect of HFE mutations on protein structure were analyzed by molecular dynamics simulation and free binding energy calculations. p.C282Y in homozygosis or in heterozygosis with p.H63D were the most frequent genotypic combinations associated with HH in our sample population (present in 17 individuals, 34%). Thirty-six (72.0%) out of the 50 individuals presented at least one HFE mutation. The most frequent genotype associated with HH was the homozygous p.C282Y mutation (n=11, 22.0%). One novel mutation (p.V256I) was indentified in heterozygosis with the p.H63D mutation. In silico modeling analysis of protein behavior indicated that the p.V256I mutation does not reduce the binding affinity between HFE and ß2-microglobulin (ß2M) in the same way the p.C282Y mutation does compared with the native HFE protein. In conclusion, screening of HFE through direct sequencing, as compared to p.C282Y/p.H63D genotyping, was not able to increase the molecular diagnosis yield of HH. The novel p.V256I mutation could not be implicated in the molecular basis of the HH phenotype, although its role cannot be completely excluded in HH-phenotype development. Our molecular modeling analysis can help in the analysis of novel, previously undescribed, HFE mutations.

Tratamento da anemia ferropriva com ferro por via oral: [revisão] / Treatment of iron deficiency anemia with oral iron: [review]

A anemia ferropriva permanece como uma das deficiências nutricionais mais frequentes e importantes no mundo. O tratamento com ferro deve ser iniciado preferencialmente por via oral e a investigação apropriada de sua causa é obrigatória. Os autores discutem os compostos com ferro atualmente disponíveis, o perfil de eficácia, segurança e tolerabilidade desses medicamentos, e o plano terapêutico mais adequado possível para o sucesso no tratamento dessa doença tão comum e importante.

Iron deficiency anemia remains one of the commonest and most important nutritional deficiencies in the world today. The treatment of iron deficiency should preferably be initiated with oral iron; an appropriate investigation of the cause of iron deficiency anemia is mandatory. The authors discuss the currently available iron preparations as well as their efficacy, safety and tolerability and the optimal therapeutic plan to successfully treat this common and important disease.

Tratamento da anemia ferropriva com ferro por via parenteral: [revisão] / Iron deficiency anemia treatment with parenteral iron: [review]

Embora o ferro por via oral seja considerado a primeira opção de tratamento da deficiência de ferro, em algumas situações específicas, a administração de ferro por via parenteral é uma opção terapêutica que deve ser considerada. Diferentemente do ferro dextran de alto peso molecular utilizado na década de 80 e lembrado como um composto associado ao alto risco de reação anafilática e morte, o desenvolvimento e comercialização de novos compostos com ferro para uso parenteral, sobretudo por via endovenosa - como o ferro sacarato, ferro gluconato e, mais recentemente, a carboximaltose férrica - , tem se tornado cada vez mais uma alternativa terapêutica segura e efetiva, e tem possibilitado ampliar o leque de indicações desta modalidade de tratamento além da nefrologia, como obstetrícia e ginecologia, cirurgia, pediatria, gastroenterologia, hematologia e hemoterapia. Os autores revisam as principais indicações do tratamento com ferro por via parenteral, analisam as principais drogas disponíveis para a correção da anemia ferropriva por via endovenosa e propõem uma estratégia de investigação diagnóstica, tratamento e seguimento laboratorial dos pacientes com indicação desta opção terapêutica.

Although oral iron is generally considered the first choice in the treatment of iron deficiency, in some specific situations, parenteral iron administration is a therapeutic option that should be considered. Different to the high-molecular-weight iron dextran utilized in the eighties and remembered as a compound associated with a high risk of anaphylaxis and death, the development and marketing of newer preparations for parenteral, in particular endovenous, administration, such as iron sucrose, ferric gluconate and more recently ferric carboxymaltose, are becoming a more effective and safe therapeutic alternative, that have extended the range of indications beyond nephrology to obstetrics and gynecology, surgery, pediatrics, gastroenterology, hematology and hemotherapy. The authors review the main indications of parenteral iron treatment, analyse the drugs available for the correction of iron deficiency anemia by intravenous iron administration and propose a new strategy of diagnostic investigation, treatment and laboratory follow up of the patient with indication for this therapeutic option.

Consenso brasileiro em transplante de células-tronco hematopoéticas: comitê de hemoglobinopatias / Brazilian consensus meeting on stem cell transplantation: hemoglobinopathies comittee

Os distúrbios hereditários das hemoglobinas são as doenças genéticas mais frequentes do homem e mais difundidas no mundo, abrangendo sobretudo continentes como África, Américas, Europa e extensas regiões da Ásia. Estima-se que haja 270 milhões de portadores de hemoglobinopatias no mundo, dos quais 80 milhões são portadores de talassemia. Aproximadamente 60 mil crianças nascem anualmente no mundo com talassemia e 250 mil com anemia falciforme, dando uma frequência de 2,4 crianças afetadas para cada 1.000 nascimentos. No Brasil, a doença falciforme é a doença hereditária monogênica mais comum, estimando-se que haja entre 20 a 30 mil pacientes portadores desta doença. O transplante de células-tronco hematopoéticas alogênico (TCTH alo) é atualmente a única modalidade terapêutica capaz de curar pacientes com hemoglobinopatias. Neste artigo discutiremos os dados disponíveis na literatura e sugerimos os critérios para a indicação do TCTH nas hemoglobinopatias.

Hemoglobinopathies are the most prevalent genetic diseases in man. Most cases are described in Europe, Africa and in the Americas. About 270 million hemoglobinopathy carriers are alive today with 80 million being carriers of thalassemia. We estimate that, throughout the world, about 60,000 children are born annually with thalassemia and 250,000 with sickle cell disease with an estimated frequency of 2.4 children in every 1000 births. Sickle cell disease is the most common monogenic hereditary disease in Brazil with a total of from 20,000 to 30,000 patients. Allogeneic stem cell transplantation is the only curative approach. Here we describe published data and propose criteria to indicate stem cell transplantation in thalassemia and sickle cell disease patients.

The XmnI polymorphic site 5' to the gene G(γ) in a Brazilian patient with sickle cell anaemia - fetal haemoglobin concentration, haematology and clinical features.

We report a 20-year-old female with sickle cell anaemia and with an HbF concentration of 15.8%. The patient was not using hydroxyurea and was not receiving regular blood transfusions. The patient never had chronic manifestations of sickle cell anaemia, only pain crises of a mild intensity. After laboratory tests, we found that she was homozygous for HbS with the Bantu/atypical haplotype, and was heterozygous for the XmnI site. The influence of the XmnI site on the expression of HbF can explain the amelioration in clinical features in this haplotype association in a case of sickle cell anaemia.

Anemia ferropênica no adulto: causas, diagnóstico e tratamento: [revisão] / Iron deficiency anaemia in the adult: causes, diagnosis and treatment: [review]

A deficiência de ferro, especificamente a anemia ferropênica, permanece como uma das deficiências nutricionais mais frequentes e importantes no mundo. Este artigo revisa as principais causas de anemia ferropênica, os atuais métodos de investigação diagnóstica e as estratégias de prevenção. O tratamento com ferro deve ser iniciado sempre por via oral, e a investigação apropriada de sua causa é obrigatória; quando houver falha nesse tratamento por causa de grande perda de sangue, má absorção do ferro ou intolerância a ele, o tratamento por via parenteral deve ser considerado. Os autores discutem os compostos com ferro atualmente disponíveis, o perfil de eficácia, segurança e tolerabilidade desses medicamentos, e o plano terapêutico ideal para o sucesso no tratamento dessa doença tão comum e importante.

Iron deficiency, and especifically iron deficiency anaemia, remains one of the commonest and most important nutritional deficiencies in the world today. This article reviews the main causes of iron deficiency anaemia, the current diagnostic methods and prevention strategies of iron deficiency. The treatment of iron deficiency should always be initiated with oral iron and an investigation of the cause of iron deficiency anaemia is mandatory. When oral iron therapy fails due to high blood losses, iron malabsorption or intolerance to oral iron, parenteral iron administration should be considered. The authors discuss available iron preparations, their efficacy, safety and tolerability, and the optimal therapeutic approach to successfully treat this common and important disease.

Management of transfusional iron overload in Latin America: current outlook and expert panel recommendations.

The results of a meeting of physicians convening in Latin America to develop expert opinions on the diagnosis, monitoring and treatment of iron overload are as follows. An accurate diagnosis can be obtained by neonatal screening for haemoglobinopathies, especially sickle cell disease and the thalassaemias. Disease-specific registries are needed to demonstrate the extent of the problem to health authorities. Disparities in the quantity and quality of blood products must be addressed, and uniform transfusion guidelines are necessary. Serum ferritin level is a feasible marker for iron overload in the region, while magnetic resonance imaging assessment can improve the diagnosis and monitoring of cardiac and liver iron content. Medical specialists, including radiologists, pathologists and others, and health authorities, can help to implement these methods and provide adequate resources. The recently available oral deferasirox can be used to conveniently administer iron chelation to transfusional iron-overloaded patients.

Alterações moleculares associadas à hemocromatose hereditária / Molecular changes associated with hereditary hemochromatosis

A hemocromatose hereditária (HH) é a mais comum doença autossômica em caucasianos e caracteriza-se pelo aumento da absorção intestinal de ferro, o qual resulta em acúmulo progressivo de ferro no organismo. A classificação da HH é realizada de acordo com a alteração genética encontrada, sendo os casos divididos em tipos 1, 2A, 2B, 3 e 4, quando a sobrecarga de ferro for associada aos genes HFE, HJV, HAMP, TFR2 e SLC40A1, respectivamente. Não existem estudos brasileiros que avaliaram a presença de mutações em genes relacionados à fisiopatologia da HH (genes HJV, HAMP, TFR2 e SLC40A1), além da pesquisa das três mutações no gene HFE (C282Y, H63D e S65C). Porém, está descrito, nos estudos realizados no Brasil, que alguns pacientes com sobrecarga de ferro primária não são portadores da HH tipo 1 (associada ao gene HFE). Portanto, é de suma importância a identificação das características genéticas dessa população, uma vez que outras mutações nos genes HJV, HAMP, TFR2 e SLC40A1 podem estar associadas à fisiopatologia da doença, podendo haver interações entre os genes alterados, de forma que possa auxiliar no entendimento da fisiopatologia da HH em pacientes brasileiros.

Hereditary Hemochromatosis (HH) is the most common autosomal disease in Caucasians. It is characterized by an increase in intestinal absorption of iron, which results in a progressive accumulation of iron in the body. The classification of HH is carried out according to the genetic alteration found; thus cases of HH are divided into Types 1, 2A, 2B, 3 and 4, when the iron overload is associated to the HFE, HJV, HAMP, TFR2 and SLC40A1 genes, respectively. There is research on the three HFE gene mutations (C282Y, H63D and S65C) in the Brazilian population however there are no Brazilian studies that evaluate the presence of mutations in other genes related to the pathophysiology of HH (HJV, HAMP, TFR2 and SLC40A1 genes). Nevertheless, studies conducted in Brazil have described that some patients with primary iron overload are not carriers of the Type 1 HH (associated with the HFE gene). Hence, it is very important to identify the genetic characteristics of this population, as mutations of the HJV, HAMP, TFR2 and SLC40A1 genes may be associated with the pathophysiology of the disease, and there may be interactions between mutations. These findings will help in understanding the pathophysiology of patients with HH in Brazil.