一个遗传性血色病家系的临床特点及其遗传基础初探

目的 探讨一个遗传性血色病家系的临床特点及初步查找该家系的遗传基础. 方法对该家系成员进行问诊、体检、实验室检查、多器官MRI检查、肝穿刺活组织检查(铁染色),绘制家系图谱.采集血样,对常见的遗传性血色病致病基因进行测序分析. 结果该家系成员中有7人存在铁过载,临床诊断为遗传性血色病.家系患者代代相传,无性别差异,外显率约46%.常见的SLC40A1和HFE基因突变位点在该家系成员中未发现. 结论该遗传性血色病家系患者以皮肤色素沉着、肝脾等脏器铁沉积最具特征,为常染色体显性遗传,但其遗传基础尚不明确.     

原发性血色病临床病理诊断研究进展

原发性血色病(hereditary haemochromatosis,HH)是一种常染色体隐性遗传病,由于基因突变导致小肠铁吸收增加,进而使铁在组织内沉积,导致组织损伤,肝脏是受影响的主要器官。最常见的类型是HFE相关原发性血色病,非HFE相关原发性血色病较少见。HH最初的临床表现是非特异性的,临床诊断时多是晚期,常见的临床并发症包括肝硬化、糖尿病、皮肤色素沉着和肝细胞癌等。当HH患者肝功能异常或血清铁蛋白高于1000μg/L时应进行肝组织活检,这有助于鉴定铁沉积的程度和纤维化分期。本文对HH的临床表现和病理诊断进行综述,包括铁沉积引起的组织学改变、肝铁浓度测量和治疗后病理改变。     

遗传性血色病五例临床分析

目的探讨遗传性血色病的临床特点,评价铁生化指标、MRI、肝穿病理学检查在遗传性血色病诊断中的作用。方法5例患者,4男1女。先证者因不明原因肝硬化伴皮肤黏膜色素沉着来院确诊。通过对先证者的家系调查,进行临床、铁生化指标、胸腹部MRI、病理组织学和特殊染色的观察,确诊4例早期患者。结果该家系5例患者中3例出现皮肤黏膜色素沉着,1例肝硬化,未见糖尿病;5例患者血清铁均正常,其中3例血清铁蛋白异常;2例肝穿病理检查,其中1例肝铁过多沉积;而MRI显示每例患者至少有1个内脏器官的铁沉积,以肝脏铁沉积最为显著。结论遗传性血色病患者在我国较少见,临床特点不明显,诊断困难,尤其是遗传性血色病早期患者。家系调查结合MRI检测对遗传性血色病的早期诊断显得更为重要。     

原发性及继发性血色病对心脏结构及功能影响的对比研究

目的 比较原发性血色病与继发性血色病对心脏结构及功能的影响.方法 回顾分析2008年1月至2018年12月在首都医科大学附属北京友谊医院诊断为铁过载的住院患者,收集患者临床表现及实验室指标、心电图及超声心动图心脏结构参数并进行对比分析.结果 原发性血色病20例,平均年龄45岁,男性14例;继发性血色病20例,平均年龄4...     

3个携带HJV E3D变异的遗传性血色病家系临床表型分析

目的了解3个携带HJV E3D变异的遗传性血色病家系基因变异及临床表型特点。方法 3个遗传性血色病家系中的先证者均完成了病史采集、铁指标、肝功能、腹部核磁检查、肝活检,排除铁过载的继发性原因,临床考虑为遗传性血色病。先证者及其一级亲属分别检测目前已知的遗传性血色病相关的5个基因(HFE、HAMP、HJV、TFR2和SLC40A1)。结果 3个携带HJV E3D变异的遗传性血色病先证者均具有明确的铁过载表现,家系1和家系2中各有1个成员具有铁过载。2例携带HJV E3D变异的先证者还同时携带其他类型血色病基因变异。结论 HJV基因E3D变异可能为我国遗传性血色病的热点变异,可能需要同时伴随其他位点变异才会出现表型,且男性、年龄增加更容易出现血色病表型。     

遗传性血色病分子机制的研究进展

遗传性血色病是由于基因变异引起铁代谢异常,进而造成多器官铁沉积.目前认为铁代谢转运主要由hepcidin-转铁蛋白(FPN)轴控制,血色病蛋白编码基因(HFE)、FPN受体2(TfR2)、血幼素(HJV)、HAMP(hepcidin的编码基因)基因突变都可以影响hepcidin水平.FPN突变也可引起铁超负荷,但机制有所不同.各调节蛋白的基因突变可引起不同的疾病表型.     

血色病临床病理尸检2例报告

血色病(hemochmnmtosis)指心脏、肝脏、胰腺和其他器官大量铁沉积,导致器官功能损害和结构破坏的疾病,按病因分为原发性和继发性两大类.原发者为一种铁代谢缺陷的遗传性疾病,继发者多见于严重的慢性贫血.在我国血色病十分罕见.我们在实际工作中遇到2例,现报告如下.     

原发性血色病合并慢性胰腺炎一例并文献复习

血色病分原发性和继发性两种,原发性血色病临床非常罕见,现结合文献,共同复习一下本病的临床特点、诊断和治疗。患者男,30岁,1个月前体检时发现总胆红素69．5μmol／L,间接胆红素60．6μmol／L。MRI提示:慢性胰腺炎,胰管结石,脾脏轻度肿大,肝铁色素沉积?体检:巩膜、全身皮肤黏膜轻度黄染,心肺腹部无异常,四肢关节未见异     

美国肝病学会2011年血色病诊疗指南要点

铁过度沉积综合征按照病因可分为遗传性血色病（HH,即狭义的血色病,HFE或非-HFE基因缺陷）、继发性铁过度沉积（最常见的病因为无效红细胞造血、胃肠外铁超负荷和慢性肝病等）和混合性,其中HH是白种人常见的遗传病,     

非HFE相关遗传性血色病

遗传性血色病(HH)多为常染色体隐性遗传病,其特征是肠道铁吸收过多导致肝、胰、心及其它脏器铁过量沉积,引发肝硬化、内分泌疾病、心力衰竭、心律失常、关节病和皮肤色素沉着等临床表现.Ⅰ型HH最常见,由6号染色体HFE基因突变所致.非HFE相关HH是指无HFE致病性突变的几种表型相近但遗传学形式独特的HH,由于受累基因在铁代谢作用中的不同,较典型HH临床发病可能更早,表型表现度更严重.     

A family study of a patient with idiopathic hemochromatosis

A family study of a patient with idiopathic hemochromatosis using noninvasive techniques is presented. All 6 of the patient's asymptomatic children had an increase in transferrin saturation and/or an increase in the absorption of Co⁵⁷. The Co⁵⁷ absorption test was the most sensitive index of family involvement since one of the children had an increase in absorption at a time when transferring saturation was normal. The family data strongly support the hereditary nature of the disorder, with the mode of inheritance not clearly established from the available data.     

The Effect of Transferrin Polymorphisms on Iron Metabolism

ABSTRACT: The effect of five different transferrin variants (TFv1, TFv2, TFv3, TFv4, and TFv5) on the hemoglobin level, mean corpuscular volume (MCV), ferritin level, percent transferrin saturation (%TS), and the unsaturated iron binding capacity (UIBC) was investigated in subjects with defined HFE haplotypes, 919 persons undergoing health screening and 113 patients with clinical hemochromatosis. The most common variant is TFv4; the population distribution of this variant was also studied. None of the variants were found to have an effect on any of the parameters of iron metabolism that were investigated. Moreover, the frequency of these variants in patients with clinically significant hemochromatosis was no different from that in the general population. We conclude that these polymorphisms in transferrin do not play a role in the expression of hemochromatosis, nor do they produce any other significant changes in iron metabolism.     

Non-HLA-linked hemochromatosis in a Chinese woman

Summary A 55-year-old Chinese woman is described with severe iron overload similar in degree and distribution to that seen in hereditary hemochromatosis in the Causasian population. Autopsy findings confirmed severe iron overload in the liver, pancreases, skin, heart, and endocrine organs. Hepatic iron concentration was 482 mol/g with a hepatic iron index of 8.8. There was no history of thalassemia, transfusions, or alcohol abuse. Pedigree analysis revealed two HLA identical brothers that had no clinical or biochemical evidence of iron overload. This case is an unsual example of severe iron overload in a non-Causasian kindred and may represent a non-HLA-linked form of iron overload.     

Identification of heterozygous p.Y150C and p.V274M mutations in the HJV gene in a Japanese patient with a mild phenotype of juvenile hemochromatosis: A case report

Juvenile hemochromatosis (JH) is known as a progressive iron‐storage disease, and causes severe organ impairments, including cardiomyopathy and liver cirrhosis. However, JH is a rare genetic disorder, and information for genetic mutations and phenotypes is limited. Here, we report a case of JH with heterozygous p.Y150C and p.V274M mutations in the HJV gene. A 39‐year‐old Japanese man was referred to Kurume University Hospital, Kurume, Japan, for fatigue and liver injury, which first appeared at the age of 25 years. There was no history of alcohol abuse and medication, and viral hepatitis, autoimmune liver diseases, and Wilson's disease were absent. However, transferrin saturation, serum ferritin, and fasting serum hepcidin levels were 98.4%, 6421 ng/mL, and 7.4 ng/mL, respectively. Furthermore, a marked reduction in signal intensity of the liver in T1/T2‐weighted magnetic resonance images was seen and the R2* maps showed hepatic iron overload. Family history of hemochromatosis and severe organ impairment, such as cardiac dysfunction and diabetes mellitus, were negative. In addition, the HFE and HAMP genes did not show any mutation. However, we identified novel heterozygous p.Y150C and p.V274M mutations in the HJV gene in the patient. The p.Y150C and p.V274M mutations were seen in his mother and father, respectively. After phlebotomy, fatigue disappeared and serum transaminase levels were normalized. Furthermore, R2* maps showed a reduction of hepatic iron concentration. We first demonstrated heterozygous p.Y150C and p.V274M mutations in the HJV gene of patients with a mild JH phenotype. Thus, genetic testing should be considered even in patients with a mild phenotype of hemochromatosis.     

A Case of Hemochromatosis in which Laparoscopy was Useful for Differentiation from a Hepatocellular Tumor

Abstract: The case of a 54-year-old man with hemochromatosis who developed cirrhosis of the liver and hepatocellular tumor is discussed. Before laparoscopy, the possibility of hepatocellular carcinoma was not ruled out by imaging tests only. Laparoscopy revealed a tumor, 60 mm in diameter, protruding from the lower portion of the left lobe of the liver. The tumor was biopsied during laparoscopy, and tentatively identified as a regeneration nodule. Laparoscopy is useful for the definite diagnosis of hepatocellular tumors.     

Monocyte transferrin-iron uptake in hereditary hemochromatosis

Transferrin-iron uptake by peripheral blood monocytes was studied in vitro to test the hypothesis that the relative paucity of mononuclear phagocyte iron loading in hereditary hemochromatosis results from a defect in uptake of iron from transferrin. Monocytes from nine control subjects and 17 patients with hemochromatosis were cultured in the presence of ⁵⁹Fe-labelled human transferrin. There was no difference in ⁵⁹Fe uptake between monocytes from control subjects and monocytes from patients with hemochromatosis who had been treated by phlebotomy and who had normal body iron stores. However, ⁵⁹Fe uptake by monocytes from iron-loaded patients with hemochromatosis was significantly reduced compared with either control subjects or treated hemochromatosis patients. It is likely that this was a secondary effect of iron loading since iron uptake by monocytes from treated hemochromatosis patients was normal. Assuming that monocytes in culture reflect mononuclear phagocyte iron metabolism in vivo, this study suggests that the relative paucity of mononuclear phagocyte iron loading in hemochromatosis is not related to an abnormality in transferrin-iron uptake by these cells.     

Hemochromatosis as a secondary condition to systemic lupus erythematosus: A case report

Systemic lupus erythematosus (SLE) is an autoimmune disorder that affects multiple organs and systems, including joints, the cardiovascular system, lungs, skin, kidneys, the nervous system, and blood. The clinical presentations of SLE are diverse and vary widely. In this report, we present a case of a patient whose SLE was complicated by hemochromatosis to enhance clinicians' comprehension of this infrequent or rare complication of SLE. We aim to provide insights into the diagnosis and treatment processes of this condition.     

Does hemochromatosis predispose to celiac disease? A study of 29,096 celiac disease patients

Abstract

Background and aim. Case reports suggest an association between hereditary hemochromatosis (HH) and celiac disease (CD), but estimates of association are lacking. We estimated the association between HH and CD in a population-based study. Material and methods. Case–control study. We identified 29,096 individuals with biopsy-verified CD (equal to villous atrophy, Marsh stage III) through biopsy reports from all 28 pathology departments in Sweden. We then investigated the risk of a clinical diagnosis of HH in CD and in 144,522 controls matched for age, sex, county and calendar year. Conditional logistic regression was used to calculate odds ratios (ORs) for CD in patients with HH. Results. HH was seen in 30 patients with CD and in 60 matched controls. HH was hence associated with an increased risk of CD (OR = 2.30; 95% CI = 1.53–3.45). Restricting HH to individuals with at least two records of HH, the OR for CD was 2.54 (95% CI = 1.57–4.11), with a similar risk estimate when we only looked at HH diagnosed before CD (and matched date in controls) (OR = 2.64; 95% CI = 1.24–5.60). Conclusion. HH seems to be associated with an increased risk of CD.     

Decreased liver hepcidin expression in the Hfe knockout mouse

Hepcidin is a circulating antimicrobial peptide which has been proposed to regulate the uptake of dietary iron and its storage in reticuloendothelial macrophages. Transgenic mice lacking hepcidin expression demonstrate abnormalities of iron homeostasis similar to Hfe knockout mice and to patients with HFE-associated hereditary hemochromatosis (HH). To identify any association between liver hepcidin expression and the iron homeostasis abnormalities observed in HH, we compared liver hepcidin mRNA content in wild type and Hfe knockout mice. Because the iron homeostasis abnormalities in the Hfe knockout mice are greatest early in life, we analyzed mice at different ages. At four weeks of age, Hfe knockout mice had significantly decreased liver hepcidin mRNA expression compared to wild type mice. The decreased hepcidin expression was associated with hepatic iron deposition, elevated transferrin saturations, and decreased splenic iron concentrations. At 10 weeks of age, despite marked hepatic iron loading, Hfe knockout mice demonstrated liver hepcidin mRNA expression similar to that observed in wild type mice. Placing 8 week-old wild type and Hfe knockout mice on a 2% carbonyl iron diet for 2 weeks led to a similar degree of hepatic iron loading in each group. However, while the wild type mice demonstrated a mean five-fold increase in liver hepcidin mRNA, no change was observed in the Hfe knockout mice. The lack of an increase in liver hepcidin expression in these iron-loaded Hfe knockout mice was associated with sparing of iron deposition into the spleen. These data indicate that the normal relationship between body iron stores and liver hepcidin mRNA levels is altered in Hfe knockout mice, such that liver hepcidin expression is relatively decreased. We speculate that decreased hepcidin expression relative to body iron stores contributes to the iron homeostasis abnormalities characteristic of HH.     

Hepatic iron in hemochromatosis

Ninety-two families with familial hemochromatosis were reviewed and analyzed in regard to hepatic iron and the value of the hepatic iron index (hepatic iron/age). Hepatic iron was measured in 29 hemochromatosis homozygotes, in 10 hemochromatosis heterozygotes, and in 30 control patients with other liver diseases. Hepatic iron content increased with age in homozygotes. Hepatic iron index differentiated homozygotes from heterozygotes (P<0.05) and heterozygotes from controls (P<0.05). The hepatic iron index is a useful measurement in the diagnosis and management of patients with familial hemochromatosis.The author acknowledges grant support from the Ministry of Health of Ontario and the Medical Research Council of Canada.