Hemocromatosis: revisión de la literatura a propósito de un caso clínico / Hemochromatosis: case report and literature review

Hemochromatosis (HC) is a disorder that alters the body's ability to metabolize iron, increasing its absorption, causing iron overload, and consequently an accumulation of the mineral in multiple organs such as the liver, heart, and pancreas. The amount of total iron in the body is 2-4 g in healthy individuals and remains within these limits throughout life thanks to the control of intestinal absorption. In patients with CH, this amount is increased by at least 10 times, which translates into body deposits of 20-40 grams of iron on average. Factors that increase the risk of having HC: having two copies of the mutated HFE gene, family history, ethnicity or ancestry from Northern Europe (less common in blacks, Hispanics, and Asians), and male gender.

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.

Treatment of iron overload syndrome: a general review.

INTRODUCTION: Iron overload is a broad syndrome with a large spectrum of causative etiologies that lead to iron deposition. When iron exceeds defenses, it causes oxidative damage and tissular disfunction. Treatment may prevent organ dysfunction, leading to greater life expectancy. METHODS: Literature from the last five years was reviewed through the use of the PubMed database in search of treatment strategies. DISCUSSION: Different pharmacological and non-pharmacological strategies are available for the treatment of iron overload and must be used according to etiology and patient compliance. Therapeutic phlebotomy is the basis for the treatment of hereditary hemochromatosis. Transfusional overload patients and those who cannot tolerate phlebotomy need iron chelators. CONCLUSION: Advances in the understanding of iron overload have lead to great advances in therapies and new pharmacological targets. Research has lead to better compliance with the use of oral chelators and less toxic drugs.

Treatment of iron overload syndrome: a general review

SUMMARY INTRODUCTION Iron overload is a broad syndrome with a large spectrum of causative etiologies that lead to iron deposition. When iron exceeds defenses, it causes oxidative damage and tissular disfunction. Treatment may prevent organ dysfunction, leading to greater life expectancy. METHODS Literature from the last five years was reviewed through the use of the PubMed database in search of treatment strategies. DISCUSSION Different pharmacological and non-pharmacological strategies are available for the treatment of iron overload and must be used according to etiology and patient compliance. Therapeutic phlebotomy is the basis for the treatment of hereditary hemochromatosis. Transfusional overload patients and those who cannot tolerate phlebotomy need iron chelators. CONCLUSION Advances in the understanding of iron overload have lead to great advances in therapies and new pharmacological targets. Research has lead to better compliance with the use of oral chelators and less toxic drugs.

RESUMO INTRODUÇÃO A síndrome de sobrecarga de ferro engloba um grande espectro de etiologias que levam a um aumento da quantidade de ferro nos tecidos. Esse ferro excede a capacidade de proteção dos tecidos, levando a dano oxidativo e lesão tissular. Tratamento pode prevenir esse dano, levando à melhor sobrevida. METODOLOGIA A literatura dos últimos cinco anos foi revisada por meio de pesquisa na base de dados PubMed buscando identificar estratégias de tratamento. DISCUSSÃO Medidas farmacológicas e não farmacológicas estão disponíveis para o tratamento da síndrome de sobrecarga de ferro e devem ser utilizadas de acordo com a etiologia e a aceitação do paciente. A flebotomia terapêutica é base do tratamento dos pacientes com hemocromatose hereditária. Pacientes com sobrecarga transfusional ou aqueles que não toleram flebotomias devem utilizar quelantes de ferro. CONSIDERAÇÕES FINAIS Avanços no entendimento da síndrome de sobrecarga de ferro têm levado a grandes progressos na terapêutica, com promessas de abordagem de novos alvos farmacológicos. A evolução da pesquisa tem possibilitado melhor aderência com o uso de quelantes orais e com possibilidade de drogas menos tóxicas.

Cirrhosis in Hemochromatosis: Independent Risk Factors in 368 HFE p.C282Y Homozygotes.

INTRODUCTION AND AIM: We sought to identify independent risk factors for cirrhosis in HFE p.C282Y homozygotes in a cross-sectional study. MATERIAL AND METHODS: We evaluated 368 p.C282Y homozygotes who underwent liver biopsy and compared characteristics of those with and without cirrhosis. We performed multivariable logistic regression on cirrhosis with: age; sex; race/ethnicity; diabetes; blood pints/units donated voluntarily; erythrocyte pints/units received; iron supplement use; alcohol intake, g/d; body mass index, kg/m2; swollen/tender 2nd/3rd metacarpophalangeal joints; elevated alanine aminotransferase; elevated aspartate aminotransferase; steatosis/fatty liver; iron removed by phlebotomy, g; and GNPAT p.D519G positivity. RESULTS: Mean age of 368 participants (73.6% men) was 47 ± 13 (standard deviation) y. Cirrhosis was diagnosed in 86 participants (23.4%). Participants with cirrhosis had significantly greater mean age, proportion of men, diabetes prevalence, mean daily alcohol intake, prevalence of swollen/ tender 2nd/3rd metacarpophalangeal joints, mean serum ferritin, elevated alanine aminotransferase, elevated aspartate aminotransferase, and mean iron removed; and significantly fewer mean blood pints/units donated. GNPAT p.D519G positivity was detected in 82 of 188 participants (43.6%). In a multivariable model for cirrhosis, there were four significant positive associations: age (10-y intervals) (odds ratio 2.2 [95% confidence interval 1.5, 3.3]); diabetes (3.3; [1.1, 9.7]); alcohol intake (14 g alcohol drinks/d) (1.5 [1.2, 1.8]); and iron removed, g (1.3 [1.2, 1.4]). There was no statistical evidence of two-way interactions between these variables. CONCLUSION: In conclusion, cirrhosis in HFE p.C282Y homozygotes is significantly associated with age, diabetes, daily alcohol intake, and iron removed by phlebotomy, taking into account the effect of other variables.

The Effects of Gestational Alloimmune Liver Disease on Fetal and Infant Morbidity and Mortality.

OBJECTIVES: To evaluate pregnancy outcomes in pedigrees of neonatal hemochromatosis to determine the spectrum of gestational alloimmune liver disease (GALD) in a large cohort. STUDY DESIGN: We prospectively collected data from women with a prior offspring with proven neonatal hemochromatosis between 1997 and 2015 and analyzed pregnancy outcomes. RESULTS: The pedigrees from 150 women included 350 gestations with outcomes potentially related to GALD. There were 105 live-born infants without liver disease, 157 live-born infants with liver failure, and 88 fetal losses. Fetal loss occurred in 25% of total gestations. Ninety-seven pedigrees contained a single affected offspring, whereas 53 contained multiple affected offspring. Analysis of these 53 pedigrees yielded a per-pregnancy repeat occurrence rate of 95%. Notably, the first poor outcome occurred in the first pregnancy in 60% of pedigrees. Outcomes of the 157 live-born infants with liver failure were poor: 18% survived, 82% died. Of the 134 live-born infants with treatment data, 20 received intravenous immunoglobulin with or without double-volume exchange transfusion of which 9 (45%) survived; 14 infants (10%) received a liver transplant of which 6 (43%) survived. CONCLUSIONS: GALD is a significant cause of both fetal loss and neonatal mortality with a high rate of disease recurrence in untreated pregnancies at risk. Poor outcomes related to GALD commonly occur in the first gestation, necessitating a high index of suspicion to diagnose this disorder at first presentation.

Clinical and Laboratory Associations with Persistent Hyperferritinemia in 373 Black Hemochromatosis and Iron Overload Screening Study Participants.

BACKGROUND: 373 black participants had elevated screening and post-screening serum ferritin (SF) (> 300 µg/L men; > 200 µg/L women). MATERIAL AND METHODS: We retrospectively studied SF and post-screening age; sex; body mass index; transferrin saturation (TS); ALT; AST; GGT; elevated C-reactive protein; ß-thalassemia; neutrophils; lymphocytes; monocytes; platelets; metacarpophalangeal joint hypertrophy; hepatomegaly; splenomegaly; diabetes; HFE H63D positivity; iron/alcohol intakes; and blood/erythrocyte transfusion units. Liver disease was defined as elevated ALT or AST. We computed correlations of SF and TS with: age; body mass index; ALT; AST; GGT; C-reactive protein; blood cell counts; and iron/alcohol. We compared participants with SF > 1,000 and ≤ 1,000 µg/L and performed regressions on SF. RESULTS: There were 237 men (63.5%). Mean age was 55 ± 13 (SD) y. 143 participants had liver disease (62 hepatitis B or C). There were significant correlations of SF: TS, ALT, AST, GGT, and monocytes (positive); and SF and TS with platelets (negative). 22 participants with SF > 1,000 µg/L had significantly higher median TS, ALT, and AST, and prevalences of anemia and transfusion > 10 units; and lower median platelets. Regression on SF revealed significant associations: TS; male sex; age; GGT; transfusion units (positive); and splenomegaly (negative) (p < 0.0001, 0.0016, 0.0281, 0.0025, 0.0001, and 0.0096, respectively). Five men with SF > 1,000 µg/L and elevated TS had presumed primary iron overload (hemochromatosis). Four participants had transfusion iron overload. CONCLUSION: Persistent hyperferritinemia in 373 black adults was associated with male sex, age, TS, GGT, and transfusion. 2.4% had primary iron overload (hemochromatosis) or transfusion iron overload.

GNPAT variant (D519G) is not associated with an elevated serum ferritin or iron removed by phlebotomy in patients referred for C282Y-linked hemochromatosis.

BACKGROUND: Previous studies in high and low expressors has demonstrated that a variant in the GNPAT gene (D519G, Rs11558492, chromosome 1, exon 11) has been associated with severe iron overload in C282Y homozygotes for hemochromatosis. In this study, a GNPAT variant was assessed prospectively in patients referred for HFE testing over a range of serum ferritin levels. MATERIAL AND METHODS: Consecutive patients sent for HFE testing were studied for the GNPAT variant using a TaqMan kit assay (Life Technologies, Burlington, ON). Serum ferritin and iron removed by phlebotomy was compared in C282Y homozygotes with and without the GNPAT variant. The frequency of the GNPAT variant in referred patients was compared to a control population of voluntary blood donors without HFE mutations. RESULTS: There were 533 patients that had GNPAT analysis. The allele frequency for the GNPAT variant in C282Y homozygotes (n = 75) was 0.226 and in wild type control patients (n = 458) was 0.213 (p = .07). Forty-eight percent (of the C282Y homozygotes were heterozygous (n = 28) or homozygous (n = 8) for the GNPAT variant. The mean (log)ferritin and iron removed did not significantly differ between C282Y homozygous with GNPAT homozygotes, GNPAT heterozygotes, and without the GNPAT variant (p = 0.84). CONCLUSIONS: C282Y homozygotes referred for HFE testing commonly have a GNPAT variant. This GNPAT variant does not appear be a co-modifying gene affecting expression of HFE related hemochromatosis in this population. The GNPAT variant does not predict the severity of iron overload.

Hepatitis aloinmune fetal / Fetal alloimmune hepatitis

La hepatitis aloinmune fetal, conocida anteriormente como hemocromatosis neonatal, ha demostrado en los últimos años ser una enfermedad completamente distinta a la hemocromatosis del adulto, tanto en su etiología como en su la fisiopatología. Este conocimiento abre nuevas perspectivas tanto en la prevención de la enfermedad en futuros embarazos, así como en el tratamiento con inmunoglobulina endovenosa en la madre durante el embarazo y eventualmente el tratamiento postnatal, en el que el trasplante de hígado juega un rol primordial.

Fetal alloimmune hepatitis, until few years ago was known as neonatal hemochromatosis, has shown to be a completely different disease from hemochromatosis in the adult, in its etiology and pathophysiology. This knowledge opens up opportunities of counselling in future pregnancies as well as in the treatment with intravenous immunoglobulin to the mother during pregnancy, and eventually the postnatal treatment, in which liver transplantation plays a primary role.

Hemocromatose hereditária / Hereditary hemochromatosis

A hemocromatose é um distúrbio autossômico recessivo ou dominante que ocorre devido ao aumento inapropriado da absorção de ferro pela mucosa gastrointestinal, resultando no armazenamento excessivo desse elemento no fígado, pâncreas, coração, articulações e gônadas. Afeta a populaçãocaucasiana, com prevalência de até um em 200 descendentes da população nórdica ou celta. O diagnóstico se faz por critérios clínicos, bioquímicos (ferritina, saturação da transferrina, etc.), genéticos epor imagem (ressonância magnética, tomografia e ultrassom).

Hemochromatosis is a disorder autosomal recessive or dominant that occurs inappropriate due to the increased absorption of iron by the gastrointestinal mucosa resulting in excessive storage of this element in the liver, pancreas, heart, joints and gonads. It affects the caucasian population with a prevalence reaching up to 1 in 200 people descendants of the population nordic or celtic. The diagnosis is made by clinical criteria, biochemical (ferritin, transferrin saturation of and so on), genetic and by image (magnetic resonance, tomography and ultrasound).

Sobrecarga de hierro y enfermedad hepática: aspectos clínicos y terapéuticos / Iron overload and liver disease: clinical and therapeutic issues

Iron accumulation in parenchymal cells results in toxic damage and cell death which can determine a functional organ failure. The prototypical disease is hereditary hemochromatosis (HH). HH has been associated to mutations affecting any of the proteins that regulate iron metabolism. The most common cause of HH is a mutation in the HFE gene [C282Y]. Mutations in the gene for the hormone hepcidin and any of other eight genes that regulate iron biology, including the transferrin receptor 2 (TfR2), hemojuvelin (HJV) and ferroportin (FPN), also cause iron overload and hemochromatosis. Although information is limited, HFE-associated to HH is uncommon in Chile. Evaluation of iron overload in clinical practice should include consideration of co-factors such as alcohol consumption, the presence of virus infection hepatitis C virus and nonalcoholic steatohepatitis, which independently can contribute to iron accumulation. While genetic testing is useful, analysis of liver histology and imaging evaluation of iron overload by MRI are important tools for clinical evaluation. This article reviews current concepts on the clinical diagnosis and management of hepatic iron overload.

La acumulación de hierro en las células parenquimatosas determina la ocurrencia de daño tóxico y muerte celular, lo que puede producir una insuficiencia funcional. La enfermedad prototípica es la hemocromatosis hereditaria (HH). La HH se ha asociado a mutaciones que afectan a cualquiera de las proteínas que regulan el metabolismo del hierro. La causa más común de HH es una mutación en el gen HFE [C282Y]. Mutaciones en el gen de la hormona hepcidina (HAMP) y cualquiera de los 8 genes que regulan su biología, incluyendo el receptor de transferrina 2 (TfR2), hemojuvelina (HJV) y ferroportina(FPN), también causan sobrecarga de hierro y hemocromatosis. Aunque la información es limitada, la HH asociada a HFE es infrecuente en nuestro medio. La evaluación de la sobrecarga de hierro en la práctica clínica debe contemplar la evaluación de otros factores tales como el consumo de alcohol, la presencia de infección por el virus de la hepatitis por virus C y de esteatohepatitis no alcohólica. Si bien el test genético es de utilidad, los análisis de la histología hepática y la evaluación imagenológica de la sobrecarga de hierro mediante resonancia magnética son útiles para la evaluación clínica de la sobrecarga de hierro. El presente artículo revisa conceptos actuales sobre el manejo clínico de la sobrecarga de hierro hepática.

Hemocromatose hereditária relacionada ao gene HFE / Hereditary hemochromatosis HFE gene related

A Hemocromatose Hereditária (HH) é a desordem hereditária mais comum em caucasianos. Mais de 90% dos casos de HH resultam da simples substituição do aminoácido Cisteína pela Tirosina no gene HFE. Essa mutação causa uma doença recessiva que resulta no acúmulo tissular de ferro. O mecanismo através do qual o HFE influencia a homeostase do ferro nas células e no corpo permanece obscuro. A doença é subdiagnosticada na população em geral devido à inespecificidade de sua apresentação clínica. O prognóstico envolve a detecção precoce da doença e a terapêutica adequada utilizando a flebotomia em fase oportuna. Essa revisão descreve os conceitos atuais a respeito das manifestações clínicas, fisiopatologia, prognóstico e tratamento da Hemocromatose Hereditária relacionada ao gene HFE.

Hereditary hemochromatosis (HH) is the most common inherited disorder in caucasians. Over 90% of the cases of HH result from a single mutation of a Cys to Tyr in the HFE gene. This mutation causes a recessive disease resulting in iron acumulation in selected tissues. The mechanism by which HFE influences iron homeostasis in cells and in the body remains elusive. The disease is underdiagnosed in general population due to inespecific clinical manifestations. Prognosis is related to early diagnostic and correct treatment using pheblotomy. This review describe the current concepts concerning the clinical features, pathophisiology, prognosis and treatment of HFE-related hemochromatosis hereditary.

Hemocromatose hereditária: relato de caso e revisão de literatura / Hereditary hemochromatosis: a case report and literature review

A hemocromatose hereditária (HH) é uma doença autossômica recessiva que acomete principalmente a população caucasiana, geralmente a manifestação ocorre após os 40 anos de idade, é caracterizada pelo aumento de ferro em tecidos e órgãos, levando a disfunções metabólicas importantes, dependendo do tipo de mutação apresentada. Com modificações em sua expressão, o gene HFE pode sintetizar maior ou menor quantidade do transportador DMT-1, responsável pela absorção intestinal do ferro. O quadro clínico da HH é bastante variável, insidioso e dependente do acúmulo de ferro, que ocorre lenta e progressivamente por várias décadas. Então, começam a surgir os sintomas que são em sua maioria inespecíficos e por isso, o diagnóstico de hemocromatose pode ser suspeitado. Objetivo: É relatar um caso de hemocromatose diagnosticado em um paciente do Hospital do Servidor Público Municipal de São Paulo (HSPM) e fazer uma revisão literária da patologia em questão. Metodologia: Revisão de prontuário e pesquisa bibliográfica nas bases de dados MEDLINE, UPTODATE, SciELO. Resultado: Este relato de caso assume importância para alguns aspectos: (1) o alerta para caracterização de sinais bioquímicos de distúrbios do metabolismo do ferro ; (2) não comprovação da mutação C282Y, não diminui o valor diagnóstico; (3) pronta intervenção terapêutica com benefícios comprovados, certamente impedindo que possa haver evolução para fibrose, cirrose e até mesmo CHC, o mais longo prazo (AU)

Hemocromatose hereditária: relato de caso e revisão de literatura

A hemocromatose hereditária (HH) é uma doença autossômica recessiva que acomete principalmente a população caucasiana, geralmente a manifestação ocorre após os 40 anos de idade, é caracterizada pelo aumento de ferro em tecidos e órgãos, levando a disfunções metabólicas importantes, dependendo do tipo de mutação apresentada. Com modificações em sua expressão, o gene HFE pode sintetizar maior ou menor quantidade do transportador DMT-1, responsável pela absorção intestinal do ferro. O quadro clínico da HH é bastante variável, insidioso e dependente do acúmulo de ferro, que ocorre lenta e progressivamente por várias décadas. Então, começam a surgir os sintomas que são em sua maioria inespecíficos e por isso, o diagnóstico de hemocromatose pode ser suspeitado. Objetivo: É relatar um caso de hemocromatose diagnosticado em um paciente do Hospital do Servidor Público Municipal de São Paulo (HSPM) e fazer uma revisão literária da patologia em questão. Metodologia: Revisão de prontuário e pesquisa bibliográfica nas bases de dados MEDLINE, UPTODATE, SciELO. Resultado: Este relato de caso assume importância para alguns aspectos: (1) o alerta para caracterização de sinais bioquímicos de distúrbios do metabolismo do ferro ; (2) não comprovação da mutação C282Y, não diminui o valor diagnóstico; (3) pronta intervenção terapêutica com benefícios comprovados, certamente impedindo que possa haver evolução para fibrose, cirrose e até mesmo CHC, o mais longo prazo

Treatment of neonatal hemochromatosis with exchange transfusion and intravenous immunoglobulin.

OBJECTIVE: To determine if immunomodulatory treatment including intravenous immunoglobulin (IVIG) can favorably affect survival in neontatal hemochromatosis (NH) diagnosed postnatally because it can effectively prevent occurrence of NH when applied during gestations at risk. STUDY DESIGN: We treated 16 newborn infants with liver failure due to NH with high-dose IVIG, in combination with exchange transfusion in 13 (ET/IVIG), and compared the outcome with 131 historical controls treated conventionally. RESULTS: The severity of liver disease as estimated by prothrombin time was similar in the subjects receiving ET/IVIG and the historical controls, and the medical therapy was equivalent with the exception of the ET/IVIG therapy. Twelve subjects (75%) had good outcome, defined as survival without liver transplantation, whereas good outcome was achieved in only 17% (23/131) of historical control patients (P < .001). Four subjects died, 2 without and 2 after liver transplant. Survivors were discharged 6 to 90 days after receiving ET/IVIG therapy, and those followed for more than 1 year are within normal measures for growth, development, and liver function. CONCLUSIONS: Immune therapy with ET/IVIG appears to improve the outcome and reduce the need for liver transplantation in patients with NH.