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。     

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。     

探讨Ⅳ型遗传性血色病肝脏hepcidin mRNA表达及意义

目的探讨Ⅳ型遗传性血色病肝脏hepcidin mRNA表达及临床意义。方法对一例遗传性血色病先证者的家系进行遗传学问询,病史采集,体格检查,实验室检查,MRI检查及肝脏组织病理学检查,运用实时荧光定量PCR法检测肝脏hepcidin mRNA表达,并进行遗传性血色病发病相关基因的基因筛查。结果该家系15人有7例经MRI证实存在不同程度实质脏器铁沉积,3例接受肝活检者中的2例肝脏组织普鲁士蓝染色证实铁沉积,实时荧光定量PCR法检测显示肝脏hepcidin mRNA表达上调,外周静脉血基因筛查发现2q32的SLC40A1六号外显子有一处碱基发生点突变,即T173C。结论1.本家系罹患Ⅳ型遗传性血色病,遗传学特征为常染色体显性遗传,SLC40A1六号外显子有一处点突变,但该突变与国际上先前报道的突变位点并不相符,说明该基因突变可能是新的突变类型;2.本家系肝脏hepcidin mRNA表达上调,提示血清hepcidin水平升高,说明可能存在hepcidin抵抗现象,使机体对hepcidin负性调节低反应,从而导致铁代谢紊乱出现铁沉积并出现脏器功能损害。     

遗传性血色病1例报告

目的 探讨遗传性血色病的发病机制、临床表现,评价铁生化指标、肝穿病理学检查在遗传性血色病诊断中的作用.方法 回顾性分析1例遗传性血色病临床资料.结果 本病例男性,41岁,有乏力症状,皮肤有色素沉着;实验室检查示：血清铁蛋白、血糖、肝功异常;MRI示：肝脏体积增大,肝脏实质信号在T1W1/T2W1均匀减低,呈极低信号;予以铁络合剂治疗后诸证缓解,各项化验指标下降.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、MRI检测对遗传性血色病的早期诊断显得更为重要.     

转铁蛋白受体2基因突变相关血色病1例

遗传性血色病是一种铁代谢障碍性疾病,较为罕见。现报道1例转铁蛋白受体（TFR）2基因突变相关血色病患者,临床表现为皮肤色素沉着、糖尿病、肝硬化,血清铁蛋白（8 548.9 ng/ml）、转铁蛋白饱和度（116.77%）明显升高,肝活检示肝硬化,肝内铁沉积（重度Ⅳ级）,对其血液标本进行全外显子捕获和高通量测序,并经San...     

血色病2例及文献复习

血色病在国内甚为少见。主要因十二指肠或空肠粘膜细胞缺陷或铁吸收机制失常,使体内铁质吸收增加,沉积于各脏器,临床相继出现皮肤、肝、胰、心、性腺病变与功能异常。现将我院2例加上国内文     

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.     

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。     

Diagnosis of hemochromatosis with magnetic resonance

Hemochromatosis is a disorder of parenchymal iron overload. The diagnosis is based upon clinical manifestations, laboratory findings and iron concentration in liver. Magnetic resonance imaging (MRI) shows a decrease in liver signal intensity. Its role has not been already defined. Nonetheless, ratio of liver to muscle proton density (LMPD) shows a significant correlation with hepatic iron. One patient with a long-standing cirrhosis with data of hemochromatosis whose coagulation study did not allow to perform a liver biopsy was diagnosed with this method. Hepatic iron concentration was calculated based upon: microgram/g of hepatic iron = (-5.174* LMPD) + 9.932. MRI can be useful in the evaluation of hemochromatosis among patients who refuse or have contraindication to liver biopsy.     

Reversibility of hepatic fibrosis in treated genetic hemochromatosis: a study of 36 cases

The current study was undertaken to assess whether fibrosis could regress under venesection therapy in patients with C282Y homozygous genetic hemochromatosis. The 36 patients studied were recruited from a subfile of our database consisting of 125 C282Y homozygotes with either severe fibrosis or cirrhosis (F3 or F4 fibrosis stage, respectively, according to the METAVIR grading system). The second liver biopsy was performed for management of liver cancer, extrahepatic surgery, or assessment of liver fibrosis. All paired biopsies were reviewed by two pathologists without knowledge of clinical data. Among the 13 patients who had F3 fibrosis on their initial liver biopsy, 3 had F0, 6 had F1, and 2 had F2 on their second liver biopsy. Among the 23 patients with cirrhosis on their initial liver biopsy, 1 had F0, 4 had F1, 3 had F2, and 2 had F3 on their second liver biopsy. When defining regression of fibrosis as a decrease of at least 2 METAVIR units, fibrosis regressed in 9 of 13 (69%) F3 and in 8 of 23 (35%) F4. When the ratio of gammaglobulins (g/L) to (platelets [n/mm(3)] x prothrombin activity [%]) was greater than 7.5, fibrosis never regressed. In conclusion, these data extend the concept of regression of fibrosis to patients with treated genetic hemochromatosis and suggest that some simple biochemical tests would be predictive of further regression of fibrosis as a result of venesection therapy. If confirmed on larger series, this could modify the ultrasound screening policy of hepatocellular carcinoma in genetic hemochromatosis.     

Diagnosis of liver fibrosis using FibroScan and other noninvasive methods in patients with hemochromatosis: a prospective study

BACKGROUND: The role of hepatic iron overload in the development of hepatic fibrosis in patients with hemochromatosis is well-established. Transient elastography (FibroScan) is a new noninvasive, rapid, reproducible bedside method, allowing assessment of liver fibrosis by measuring liver rigidity. OBJECTIVES: The aim of this prospective study was to evaluate liver fibrosis with FibroScan and other noninvasive biochemical methods in patients with hemochromatosis (C282Y homozygosity) compared with control patients. PATIENTS AND METHODS: From January 2004 through October 2006, all consecutive patients with hemochromatosis were evaluated for liver fibrosis using noninvasive methods (FibroScan and biochemical markers). These patients were compared with patients who had chronic cytolysis and no fibrosis on liver biopsy. RESULTS: One hundred and three consecutive patients (57 cases and 46 controls) were fully investigated. Median FibroScan values were similar in both groups, 5.20 kPa versus 4.9 kPa, respectively. No differences were observed between cases and controls for all biochemical markers. A strong correlation was observed between FibroScan and many biochemical markers, although ferritin levels did not correlate with FibroScan values. The prevalence of patients with FibroScan values greater than 7.1 kPa (cut-off level for significant fibrosis) was 22.8% in patients with hemochromatosis and 0% in the controls (P<0.0001). CONCLUSION: FibroScan and biochemical markers could be reliable noninvasive methods for detecting liver fibrosis in patients with hemochromatosis. Such patients have high FibroScan values more often than do control patients. Further longitudinal and prospective studies are necessary to confirm these preliminary data.     

Non-invasive methods for liver fibrosis prediction in hemochromatosis: One step beyond

Advances in recent years in the understanding of, and the genetic diagnosis of hereditary hemochromatosis (HH) have changed the approach to iron overload hereditary diseases. The ability to use a radiologic tool (MRI) that accurately provides liver iron concentration determination, and the presence of non-invasive serologic markers for fibrosis prediction (serum ferritin, platelet count, transaminases, etc), have diminished the need for liver biopsy for diagnosis and prognosis of this disease. Consequently, the role of liver biopsy in iron metabolism disorders is changing. Furthermore, the irruption of transient elastography to assess liver stiffness, and, more recently, the ability to determine liver fibrosis by means of MRI elastography will change this role even more, with a potential drastic decline in hepatic biopsies in years to come. This review will provide a brief summary of the different non-invasive methods available nowadays for diagnosis and prognosis in HH, and point out potential new techniques that could come about in the next years for fibrosis prediction, thus avoiding the need for liver biopsy in a greater number of patients. It is possible that liver biopsy will remain useful for the diagnosis of associated diseases, where other non-invasive means are not possible, or for those rare cases displaying discrepancies between radiological and biochemical markers.     

Computerized measurement of iron in liver biopsies: a comparison with biochemical iron measurement

The measurement of stainable hepatic iron using a microcomputer image analysis system was compared with standard biochemical measurements of liver iron content in 103 liver biopsy specimens--29 of idiopathic hemochromatosis, 51 of alcoholic liver disease and 23 of various nonalcoholic liver diseases. Sections were stained using Perls' method for iron; the mean area staining positively for iron was measured and expressed as a percentage of the area of biopsy measured. Biochemical (biochemical hepatic iron [mumol/gm dry wt]/age) and morphometrical (morphometrical hepatic iron [%]/age x 100) hepatic iron indices were calculated. Patients in the idiopathic hemochromatosis group had significantly higher biochemical hepatic iron concentrations (p less than 0.001) compared with the alcoholic liver disease and nonalcoholic liver disease groups: 284 (range = 119 to 631), 21 (range = 2 to 65) and 15 (range = 3 to 31) mumol/gm dry wt, respectively. The biochemical hepatic iron index was also significantly higher (p less than 0.001) in the hemochromatosis group compared with the alcoholic liver disease and nonalcoholic liver disease groups: 5.8 (range = 2.1 to 13.7), 0.4 (range = 0 to 1.6) and 0.4 (range = 0 to 1.1), respectively. Computerized measurements were significantly higher in the hemochromatosis group (p less than 0.001) compared with the alcoholic liver disease and nonalcoholic liver disease groups: 9.72% (range = 1.50% to 29.26%), 0.13% (range = 0% to 1.20%) and 0.03% (range = 0% to 0.40%), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Magnetic resonance imaging and assessment of liver iron content in genetic hemochromatosis

Computed tomography (CT) scanning is not highly sensitive in the assessment of liver iron content and magnetic resonance imaging (MRI) appears to be more efficient. The aim of this study was to determine the effectiveness of MRI in the evaluation of liver iron content using a standard spin-echo technique. The study included 23 patients with genetic hemochromatosis and 24 non-iron-overloaded patients as controls. A comparison was made of: (a) MRI signal intensity of liver, spleen, paravertebral muscles and subcutaneous adipose tissue using two different spin-echo sequences (SE 500/28; SE 2000/28,56); (b) liver attenuation determined by a single energy CT scan; and (c) a biochemical determination of hepatic iron. There was a significant decrease in liver signal intensity in the genetic hemochromatosis group (256 +/- 201, mean +/- S.D.) compared with the control group (801 +/- 413, p less than 0.001), but there was no correlation with liver iron concentration. However, such a correlation was found and was even more highly significant than in CT when the ratio between the liver and another organ was taken into account. For a lower limit of liver/spleen ratio calculated at 0.46 (mean 2 S.D. in the control group), the specificity (0.96) of MRI was satisfactory, but the sensitivity (0.78) remained insufficient (MRI being unable to detect an iron overload of up to 125 mumol/g). Hopefully, these results might be improved in the near future by using more sensitive sequences such as gradient echo sequences.     

Room-temperature susceptometry predicts biopsy-determined hepatic iron in patients with elevated serum ferritin

Background. There is an ongoing clinical need for novel methods to measure hepatic iron content (HIC) noninvasively. Both magnetic resonance imaging (MRI) and superconducting quantum interference device (SQUID) methods have previously shown promise for estimation of HIC, but these methods can be expensive and are not widely available. Room-temperature susceptometry (RTS) represents an inexpensive alternative and was previously found to be strongly correlated with HIC estimated by SQUID measurements among patients with transfusional iron overload related to thalassemia. Aim. The goal of the current study was to examine the relationship between RTS and biochemical HIC measured in liver biopsy specimens in a more varied patient cohort.Material and methods. Susceptometry was performed in a diverse group of patients with hyperferritinemia due to hereditary hemochromatosis (HHC) (n = 2), secondary iron overload (n = 3), nonalcoholic fatty liver disease (NAFLD) (n = 2), and chronic viral hepatitis (n = 3) within one month of liver biopsy in the absence of iron depletion therapy.Results. The correlation coefficient between HIC estimated by susceptometry and by biochemical iron measurement in liver tissue was 0.71 (p = 0.022). Variance between liver iron measurement and susceptometry measurement was primarily related to reliance on the patient’s body-mass index (BMI) to estimate the magnetic susceptibility of tissue overlying the liver.Conclusions. We believe RTS holds promise for noninvasive measurement of HIC. Improved measurement techniques, including more accurate overlayer correction, may further improve the accuracy of liver susceptometry in patients with liver disease.     

A novel mutation of transferrin receptor 2 in a Taiwanese woman with type 3 hemochromatosis

Hereditary hemochromatosis (HH) is very rare in Asia. Here, we describe a Taiwanese woman presenting with fully developed characteristics of HH including bronze skin, DM, decreased MRI T2 signal intensity over liver and pituitary gland. Biochemistry of iron profile indicated a severe status of iron overload by serum iron: 194 microg/dL, serum ferritin: 6640 microg/L, transferrin saturation: 92.8%. By measuring the hepatic iron index 8.48 (>1.9) of her liver biopsy tissue, the diagnosis of HH was established. Diagnosis of non-HFE HH was carried out since the whole HFE genome was sequenced but failed to localize any genetic alterations. The whole genome of transferrin receptor 2 (TfR2) was sequenced and a novel mutation of 13528 G-->A (Arg 481 His) in exon 11 was detected. Therefore, type 3 hemochromatosis was confirmed. The distinct clinical features, extremely high iron index and impressive iron staining in her liver biopsy tissue may represent an aggravated iron deposition in the liver caused by this novel mutation. Our finding implicates functional importance of histidine in exchange of arginine at amino acid 481 of transferrin receptor 2 in iron homeostasis. This case reminds physicians in Asia to keep in mind that hemochromatosis could be a rare cause of DM.     

Magnetic resonance imaging in idiopathic hemochromatosis

The therapeutic management of patients with idiopathic hemochromatosis (IH) requires an accurate estimate of hepatic iron overload in order to prevent tissue fibrosis and organ failure. Magnetic resonance imaging (MRI) was used to estimate liver iron overload in 5 patients with IH and in 8 normal controls. Signal intensity ratio between liver and subcutaneous fat in T1-, proton- and T2-weighted images was significantly lower in IH when compared with normal controls, and increased gradually during treatment by phlebotomy. Mean serum ferritin at diagnosis was 755 micrograms/l (range: 648-900) in IH and 85 micrograms/l (range: 19-232) in normal controls. A high correlation (r = -0.93) was present between liver signal intensity ratio and serum ferritin; both changed in parallel during removal of iron by phlebotomy. MRI may provide a safe and accurate method of detecting iron overload in the precirrhotic phase of IH, obviating the need for liver biopsy. It may also be used to monitor treatment.