遗传代谢性肝病的诊治

肝脏是大多数代谢途径的关键场所,因此在遗传代谢性疾病中肝脏一般最早被累及且损伤最重,某些遗传代谢性疾病的肝脏损伤甚至会发展为肝硬化甚至肝脏的恶性肿瘤,预后较差。遗传代谢性肝病临床表现复杂,常规诊断和治疗方法局限,是临床医生面临的棘手问题。随着细胞和分子生物学技术的发展,新的诊疗手段,如基因检测、基因治疗、干细胞移植等已逐步开展临床应用,为难治性患者带来希望。就肝豆状核变性、遗传性血色病、糖原累积病、α1-抗胰蛋白酶缺乏症、遗传性高胆红素血症、遗传性胆汁淤积等相对常见的遗传代谢性肝病的诊治进展作一综述。     

遗传代谢性肝病患者临床和基因突变特征分析*

目的 总结过去20年洛阳市各大医院诊治的遗传代谢性肝病(IMLD)患者的临床特征。方法 2000～2021年期间洛阳市各大医院诊治的IMLD患者16例,总结、分析其临床特征。结果 在16例IMLD患者中,男性10例,女性6例,平均年龄为(26±15)岁;其中金属代谢障碍性疾病8例(肝豆状核变性7例、遗传性血色病1例),遗传性高胆红素血症3例(Gilbert综合征2例、Dubin-Johnson 综合征1例),遗传性胆汁淤积症4例【良性复发性肝内胆汁淤积症(BRIC) 2例、Alagille综合征1例、Citrin缺乏症1例】和糖原累积病1例;7例肝豆状核变性患者分别来自4个家族,主要为ATP7B基因突变;遗传性血色病为HFE基因突变,Gilbert综合征为UGT1A1基因突变,Dubin-Johnson综合征为ABCC2基因突变,BRIC为ATP8B1基因突变,Alagille综合征为JAG1基因突变,Citrin缺乏症为SLC25A13基因突变,糖原累积病为G6Pase基因突变。结论 IMLD以肝豆状核变性较常见,大多IMLD的诊断需要依靠临床资料综合和基因检测。     

遗传性铜代谢异常的致病机制及临床诊断

铜是人体重要的微量元素,铜缺乏或过载均会导致一系列的机体功能障碍。主要聚焦肝豆状核变性及其相关铜代谢异常的疾病。肝豆状核变性临床表型多样,而胆汁淤积性肝病、遗传性铜蓝蛋白缺乏症及先天性糖基化异常等疾病又常给肝豆状核变性的临床诊断带来混淆和困惑。结合目前研究的最新进展及肝豆状核变性诊疗方面的经验,从肝病角度探讨遗传性铜代谢异常的致病机制及临床诊断。     

肝穿组织学检查在非病毒性肝病诊断中的价值

目的探讨肝穿组织学检查在非病毒性肝病诊断中的价值。方法总结我院近20年经过肝穿组织学检查诊断的59例非病毒性肝病患者的资料。结果经过肝穿组织学检查以及其他特异性诊断指标最后诊断肝糖原贮积病13例,肝豆状核变性12例,遗传性血色病5例,DubinJohnson综合征3例,肝性血卟啉病1例,自身免疫性肝炎3例,原发性胆汁性肝硬化1例,原发性硬化性胆管炎1例,药物性肝损伤7例,BuddChiari综合征6例,酒精性肝病5例,非酒精性脂肪性肝炎2例。结论肝穿组织学检查在非病毒性肝病诊断中具有重要价值。     

41例青少年非病毒性肝病临床和病理分析

目的探讨青少年非病毒性肝病的病因、临床和病理特点。方法回顾性分析41例非病毒性肝病患儿的临床和病理资料。结果本组患者中有肝豆状核变性20例（48．8％），糖原累积症3例（7．3％），先天性肝纤维化2例（4．8％），非酒精性脂肪肝3例（7．3％），良性复发性肝内胆汁淤积症1例（2．4％），遗传性高胆红素血症3例（7．3％），原发性肝癌4例（9．7％），原因不明者5例（12．1％）。结论在青少年肝病的非病毒性病因中，以肝豆状核变性最常见；肝脏活检检查为非病毒性肝病诊断提供了极大的帮助。     

肝豆状核变性诊疗指南(2022年版)

为帮助肝病相关临床医师在肝豆状核变性诊断和治疗中做出合理决策, 中华医学会肝病学分会遗传代谢性肝病协作组于2021年组织国内相关领域专家, 以肝豆状核变性的临床和基础研究进展为依据, 共同编写了该《肝豆状核变性诊疗指南(2022年版)》。     

肝豆状核变性诊疗指南(2022年版)

为帮助肝病相关临床医师在肝豆状核变性诊断和治疗中做出合理决策,中华医学会肝病学分会遗传代谢性肝病协作组于2021年组织国内相关领域专家,以肝豆状核变性的临床和基础研究进展为依据,共同编写了该《肝豆状核变性诊疗指南(2022年版)》。     

儿童肝豆状核变性97例分析

目的 总结儿童肝豆状核变性的临床表现以及肝脏组织病理学特点.方法 对97例确诊为肝豆状核变性儿童的就诊原因、临床表现、实验室及肝脏活组织病理学检查结果进行回顾性分析.结果 患者以肝功能异常或肝病表现就诊为主(74%).97例(100%)患者均有肝脏损害,44例(45%)神经系统异常,95例行K-F环检查患者中63例呈阳性;94例行血铜蓝蛋白检测患者中,91例降低,3例正常;37例患者行24 h尿铜检测,其中＞100 μg者25例.17例行病理检查的患者肝组织均有不同程度的炎症及纤维化,其中8例有脂肪变性,3例有糖原累积样改变.结论 儿童肝豆状核变性以肝病表现为主,角膜K-F环、血清铜蓝蛋白、24 h尿铜检查在早期诊断中均存在一定困难,肝脏病理检查对诊断有一定参考价值.     

《肝豆状核变性诊疗指南（2022年版）》解读

为帮助肝病相关临床医师在肝豆状核变性诊断和治疗中做出合理决策,中华医学会肝病学分会遗传代谢性肝病协作组发表了《肝豆状核变性诊疗指南（2022年版）》。该文介绍了该版指南在流行病学、发病机制、临床特点、实验室检查、诊断、治疗和监测等方面的十大亮点,其突出的特点是注重实用性和可操作性。     

电镜观察肝超微结构早期诊断肝豆状核变性

肝豆状核变性(Wilson 病)是一种常染色体隐性遗传性铜代谢障碍性疾病。临床对早期病例的诊断并不容易。我院近10年以以来共对20例不同肝病患者的肝穿活检组织用电子显微镜观察了肝超微结构改变,发现4例早期肝豆状核变性     

Clinical presentation of metabolic liver disease

Some clinical clues should alert paediatricians to the possibility of metabolic liver diseases. They can be classified into three categories: (i) Manifestations due to hepatocellular necrosis, acute or subacute, which can reveal galactosaemia, hereditary fructose intolerance, tyrosinaemia type I, Wilson disease and alpha 1-antitrypsin deficiency. Symptoms and signs suggestive of Reye syndrome should lead to a study of fatty acid oxidation and urea cycle enzymes. All these manifestations may necessitate a rapid diagnosis and treatment when liver dysfunction is severe. (ii) Cholestatic jaundice can reveal alpha 1-antitrypsin deficiency, Byler's disease, cystic fibrosis, Niemann-Pick disease and some disorders of peroxisome biogenesis. (iii) Hepatomegaly can reveal disorders with liver damage but also storage diseases such as glycogen storage diseases, cholesteryl ester storage disease and, when associated with splenomegaly, lysosomal storage diseases. Appropriate investigations for recognizing all these entities are proposed.     

Metabolic liver disease in the young adult

This chapter describes the gene mutations, phenotypes, diagnosis and therapy of the common metabolic liver diseases in young adulthood: haemochromatosis, Wilson disease, alpha(1)-anti-trypsin deficiency and cystic fibrosis. The remarkable variability of the phenotypical expression of the mutated genotypes makes screening recommendations and the establishment of prognosis for these liver disorders in young adults problematical. The diagnosis and therapy of the young adult with metabolic liver disease is discussed, with an emphasis on maintaining quality-of-life and balancing the importance of early intervention with the stigmatization of the diagnosis of potentially life-threatening liver disease. There is a critical need for the development of biochemical markers that would predict the risk of expression of clinical phenotypes and prognosis.     

Other genetic liver diseases in children

Wilson disease is rare but proteiform, and should be suspected in any child with liver disease and older than 3 years of age. The treatment is very efficient, and must be taken life-long. Fifteen percent of patients with alpha-1-antitrypsin deficiency develop a neonatal jaundice, and 3% a cirrhosis in childhood. There is no specific treatment except liver transplantation. Five percent of cystic fibrosis patients develop a cirrhosis, with a very slow progression. Milder abnormalities are frequent, as well as biliary stones. Liver disease in ciliopathies may be a congenital hepatic fibrosis, with risks of portal hypertension and cholangitis, or a more variable biliary disease. Gilbert disease is frequent and benign. Crigler-Najjar syndrome is rare, severe, and may be an indication for liver or liver-cell transplantation.     

Hepatocellular carcinoma complicating liver cirrhosis in type IIIa glycogen storage disease

Type III glycogen storage disease (GSD III) is an autosomal recessive disorder characterized by the accumulation of abnormal glycogen in the liver and, in most patients, in the muscle. Although liver fibrosis is a well-known consequence of GSD III, until now only eight cases of liver cirrhosis and two cases of hepatocellular carcinoma have been described in patients affected by this disease. In this case report, the authors describe the clinical history of a patient affected by GSD III who developed severe liver disease during her adult life, progressing from fibrosis to cirrhosis and finally to hepatocellular carcinoma. Until now, the hepatic involvement in GSD III has been considered by most authors as mild and almost always self-limiting. This report, together with the previously published cases, clearly indicates that severe and progressive liver disease may complicate this metabolic disorder. These observations advise a careful hepatologic follow-up of patients affected by GSD III.     

Molecular genetics of chronic liver diseases

The molecular genetics of five common single gene and one polygenic chronic liver disease is discussed. In two of the single gene disorders, alpha 1-antitrypsin deficiency and cystic fibrosis, the gene responsible is now known and the repertoire of different mutations underlying the disease is being defined. In the other three single gene defects (haemochromatosis, polycystic liver disease and Wilson's disease) the chromosomal location of the disease allele is known. It is anticipated that recombinant DNA techniques will enable the genes responsible for these diseases to be cloned in the near future, thus allowing the biochemical abnormalities to be defined through reverse genetics. In many chronic liver diseases the relative contribution of genetic and environmental factors remains unclear. Evidence suggests there is a definite genetic component in predisposition to alcoholic cirrhosis; the role of putative candidate genes is discussed. It is hoped that the definition of a genetic locus linked to alcoholic cirrhosis will ultimately teach us more about the basic pathogenesis of this disease.     

The haemochromatosis gene: A co-factor for chronic liver diseases?

There is increasing evidence that hepatotoxins, such as alcohol and the hepatitis viruses, act as co-factors in causing hepatic fibrosis and cirrhosis. For example, alcohol aggravates the hepatic damage produced by iron in hereditary haemochromatosis. We present evidence that the reverse is also true, that is, that iron loading of mild to moderate degree due to heterozygosity or homozygosity for the haemochromatosis genetic mutations acts as a significant hepatotoxin aggravating hepatic damage from other causes of liver disease. These include non-alcoholic steatohepatitis, chronic hepatitis C, porphyria cutanea tarda and possibly primary liver cell cancer. However, any additional hepatotoxic effect is due to the hepatic iron concentration and not the mutations in the haemochromatosis genes.     

Congenital cystic diseases of the intra and extrahepatic bile ducts

Congenital cystic lesions of bile ducts may affect intra or extrahepatic bile ducts. Intrahepatic lesions include five entities: congenital hepatic fibrosis, Caroli's syndrome, von Meyenburg complexes, simple cyst of the liver and polycystic liver disease. Congenital hepatic fibrosis and von Meyenburg complexes are secondary to ductal plate malformation affecting the smallest intrahepatic bile ducts. Cystic dilatations are of small size and only detected at histological examination of the liver. They have few clinical consequences. In congenital hepatic fibrosis, the main manifestations result from portal hypertension. Caroli's syndrome is secondary to ductal plate malformation affecting the largest intrahepatic bile ducts. Cystic dilatations are macroscopic and responsible for cholangitis and may lead to biliary stones and carcinoma which develop within cystic dilatations. Caroli's syndrome may be or not associated with congenital hepatic fibrosis. In case of associated congenital hepatic fibrosis, portal hypertension is present. Simple cyst of the liver and polycystic liver disease are characterized by cystic dilatations which, by contrast to the preceding entities, do not communicate with the rest of biliary tree. As a result, they have only few clinical consequences. In congenital hepatic fibrosis and polycystic liver disease, renal abnormalities are frequently observed. They correspond to renal malformations associated with biliary malformations. In congenital hepatic fibrosis, renal lesions are characterized by ectatic collecting tubules which are present in two thirds of the cases and transmitted as an autosomal recessive trait. In polycystic liver disease, renal lesions are characterized by polycystic disease which is present in half of the cases and transmitted as an autosomal dominant trait. Congenital cystic lesions of extrahepatic bile ducts consist of choledochal cyst, which is secondary to malformation of the pancreato-biliary ductal junction. The major risk of choledochal cyst is the development of intracystic cancer, the prevention of which is total surgical resection of the cyst.     

Glycogen storage diseases： New perspectives

Glycogen storage diseases (GSD) are inherited metabolic disorders of glycogen metabolism. Different hormones, including insulin, glucagon, and cortisol regulate the relationship of glycolysis, gluconeogenesis and glycogen synthesis. The overall GSD incidence is estimated 1 case per 20 000-43 000 live births. There are over 12 types and they are classified based on the enzyme deficiency and the affected tissue. Disorders of glycogen degradation may affect primarily the liver, the muscle, or both. TypeⅠa involves the liver, kidney and intestine (andⅠb also leukocytes), and the clinical manifestations are hepatomegaly, failure to thrive, hypoglycemia, hyperlactatemia, hyperuricemia and hyperlipidemia. Type Ⅲa involves both the liver and muscle, and Ⅲb solely the liver. The liver symptoms generally improve with age. Type Ⅳ usually presents in the first year of life, with hepatomegaly and growth retardation. The disease in general is progressive to cirrhosis. Type Ⅵ and Ⅸ are a heterogeneous group of diseases caused by a deficiency of the liver phosphorylase and phosphorylase kinase system. There is no hyperuricemia or hyperlactatemia. Type Ⅺ is characterized by hepatic glycogenosis and renal Fanconi syndrome. Type Ⅱ is a prototype of inborn lysosomal storage diseases and involves many organs but primarily the muscle. Types Ⅴ and Ⅶ involve only the muscle.     

Role of early case detection by screening relatives of patients with HFE-associated hereditary haemochromatosis

Hereditary haemochromatosis is a primary inherited disorder of iron metabolism leading to progressive iron loading of parenchymal cells of the liver and other organs with diverse clinical manifestations, including cirrhosis, diabetes and skin pigmentation. This chapter will focus on HFE-associated hereditary haemochromatosis, which accounts for approximately 90% of cases in Caucasian populations. Penetrance is incomplete, with variable clinical expression. The majority of cases demonstrate biochemical expression, but a much lower proportion develop advanced disease. Clinical disease--especially hepatic fibrosis--is related to the level of body iron stores, which is reflected primarily in the liver. The available evidence indicates that adequate screening and diagnostic strategies ensure that early case detection and treatment occur prior to the development of irreversible end-organ damage. The most cost-effective methods of early case detection are family (cascade) screening and evaluation of potential cases by primary care physicians with a high index of clinical suspicion.