肝源性糖尿病的诊断与治疗

肝源性糖尿病是指继发于肝实质损害的糖尿病,临床表现以高血糖,葡萄糖耐量减低为特征,其发病率与感染的肝炎病毒类型有关.研究表明肝源性糖尿病患者多存在胰岛素抵抗,血清胰岛素样生长因子(IGF-1)降低及生长激素(GH)水平增高.在诊断与治疗方面与2型糖尿病有所不同,要兼顾肝损害和糖尿病两个方面,本文就此方面加以论述.     

La diabetes en la cirrosis hepática

The prevalence of overt diabetes mellitus (DM) in liver cirrhosis is about 30%. However, DM or impaired glucose tolerance can be observed in 90% after an oral glucose tolerance test in patients with normal fasting plasma glucose. Type 2 DM may produce cirrhosis, whereas DM may be a complication of cirrhosis. The latter is known as «hepatogenous diabetes». Overt and subclinical DM is associated with liver complications and death in cirrhotic patients. Treating diabetes is difficult in cirrhotic patients because of the metabolic impairments due to liver disease and because the most appropriate pharmacologic treatment has not been defined. It is also unknown if glycemic control with hypoglycemic agents has any impact on the course of the liver disease.     

Hepatogenous diabetes: Is it time to separate it from type 2 diabetes?

By definition, hepatogenous diabetes is directly caused by loss of liver function, implying that it develops after cirrhosis onset. Therefore, it should be distinguished from type 2 diabetes developing before cirrhosis onset, in which specific causes of liver disease play a major role, in addition to traditional risk factors. Currently, although hepatogenous diabetes shows distinct pathophysiological and clinical features, it is not considered as an autonomous entity. Recent evidence suggests that the failing liver exerts an independent “toxic” effect on pancreatic islets resulting in β‐cell dysfunction. Moreover, patients with hepatogenous diabetes usually present with normal fasting glucose and haemoglobin A_1c levels and abnormal response to an oral glucose tolerance test, which is therefore required for diagnosis. This article discusses the need to separate hepatogenous diabetes from type 2 diabetes occurring in subjects with chronic liver disease and to identify individuals suffering from this condition for prognostic and therapeutic purposes.     

肝硬化伴肝源性糖尿病临床分析

目的分析肝硬化伴肝源性糖尿病的临床特征。方法回顾性分析45例肝硬化伴肝源性糖尿病患者的临床资料。结果 45例患者中,乙型肝炎肝硬化31例（68.9%）;空腹血糖7.3±2.9mmol/L,餐后2h血糖16.2±4.7mmol/L,空腹血糖水平与Child-Pugh分级呈正相关（Spearman等级相关系数rs=0.48,P〈0.01）;通过饮食控制、口服α葡萄糖苷酶抑制剂或皮下注射胰岛素,大部分患者血糖控制在正常水平或接近正常水平;7例死亡病例均死于肝硬化并发症。结论肝硬化伴肝源性糖尿病患者的糖尿病症状多不典型,以餐后高血糖为特征,血糖水平与肝功能的损害程度密切相关,应用胰岛素治疗效果较好,不良预后主要与肝硬化相关。     

Diabetes und Leberzirrhose

Disturbances of glucose metabolism, such as glucose intolerance or hepatogenous diabetes frequently occur in patients with liver cirrhosis and are caused by functional hepatocellular loss and insulin resistance due to chronic liver disease. Until now there have been no recommendations comparable to guidelines on the diagnosis and therapy of hepatogenous diabetes. Regarding basic treatment a sufficient daily energy and protein supply should be guaranteed as the majority of patients with liver cirrhosis are malnourished. The risk of hypoglycemia must be carefully considered under pharmacological treatment of hepatogenous diabetes. Suitable oral antidiabetics are glinides, dipeptidyl peptidase-4 (DPP4) inhibitors and glucagon-like peptide-1 (GLP1) analogues; however, no data from clinical studies are available so far. If a sufficient diabetes adjustment cannot be achieved by oral antidiabetics, prandial insulin therapy using short acting insulin or rapidly acting insulin analogues should be applied. Optimization of diabetic metabolic conditions is not only important to avoid typical late diabetic complications but also cirrhosis-associated complications, e. g. gastrointestinal bleeding, hepatic encephalopathy or the occurrence of hepatocellular carcinoma.     

肝病患者胰高血糖素、糖化血红蛋白检测及胰岛素和C肽释放试验的临床意义

目的:探讨肝病患者糖代谢紊乱与糖尿病之间的鉴别诊断及临床意义。方法:应用放射免疫法研究46例肝病患者和39例糖尿病患者的(?)高血糖素(IRG)、糖化血红蛋白(GHb)及胰岛素(IRI)和C肽释放试验。结果:慢性肝炎肝硬变、肝原性糖尿病、糖尿病有不同程度的高IRG血症,各型糖尿病有不同程度的高GHb血症。胰岛素和C肽释放试验:慢性肝炎肝硬变呈高峰延迟型,肝原性糖尿病呈高反应型,普通糖尿病呈低反应型,它们之间有极显著性差异,结论:高糖化血红蛋白血症与血管并发症的发生有一定关系。高胰高血糖素血症是糖尿病原发的、始动的发病因素。利用胰岛素和C肽释放试验,对慢性肝炎肝硬变的糖代谢紊乱、肝原性糖尿病、胰岛素依赖型糖尿病、非胰岛素依赖型糖尿病可进行鉴别诊断,有助于临床药物的应用。     

肝源性糖尿病临床特征分析

目的 探讨肝源性糖尿病的临床特征及其可能机制,以提高对该病的认识和诊治水平。方法回顾性分析102例肝源性糖尿病患者,并与原发性2型糖尿病进行对比分析。结果102例肝源性糖尿病患者中17％有口干、多饮、多食、多尿等典型糖尿病症状;空腹血糖为（7.8±2．6）mmol／L,餐后2h血糖（12．7±3．0）mmol／L;口服葡萄糖耐量试验（OGTT）显示,肝源性糖尿病患者的空腹血糖水平显著低于原发性2型糖尿病（P〈0．01）,余各时段血糖两组差异无统计学意义;胰岛素＋C肽释放试验显示,两组胰岛素分泌均呈高峰延迟型,但肝源性糖尿病患者各时段胰岛素及C肽分泌水平均高于原发性2型糖尿病（P〈0．05）。经饮食控制、应用胰岛素或口服降糖药治疗后血糖大多能控制在正常或接近正常水平。102例肝源性糖尿病患者中仅5例伴糖尿病并发症,4例死亡病例死因均为慢性肝病并发症。结论肝源性糖尿病临床症状不典型,以餐后高血糖为特征,应用胰岛素治疗效果较好,短期不良预后主要与原发慢性肝病有关。胰岛素抵抗可能是其重要的发病机制。     

Insulin resistance and chronic liver disease

Increased insulin resistance is frequently associated with chronic liver disease and is a pathophysiological feature of hepatogenous diabetes.Distinctive factors including hepatic parenchymal cell damage,portalsystemic shunting and hepatitis C virus are responsible for the development of hepatogenous insulin resistance/diabetes.Although it remains unclear whether insulin secretion from pancreatic beta cells is impaired as it is in type 2 diabetes,retinopathic and cardiovascular risk is low and major causes of death in cirrhotic patients with diabetes are liver failure,hepatocellular carcinoma and gastrointestinal hemorrhage.Hemoglobin A1c is an inaccurate marker for the assessment and management of hepatogenous diabetes.Moreover,exogenous insulin or sulfonylureas may be harmful because these agents may promote hepatocarcinogenesis.Thus,pathogenesis,cause of death,assessment and therapeutic strategy for hepatogenous insulin resistance/diabetes differ from those for lifestyle-related type 2 diabetes.In this article,we review features of insulin resistance in relationship to chronic liver disease.We also discuss the impact of anti-diabetic agents on interferon treatment and hepatocarcinogenesis.     

肝硬化患者口服葡萄糖耐量试验临床意义及研究进展

肝脏和骨骼肌维持糖代谢。随着慢性肝病进展为肝硬化,肝功能恶化会导致糖代谢异常。因此,肝硬化患者常常伴有糖耐量异常和胰岛素抵抗,早期以餐后高血糖和高胰岛素血症为特征。一般而言,即使应用传统的空腹血糖或糖化血红蛋白水平标准,肝硬化伴有糖代谢异常患者往往被低估,因为他们中的多数表现出较低的空腹血糖水平或糖化血红蛋白水平,掩盖了其糖耐量减低的实情。因此,推荐使用口服葡萄糖耐量试验来评估出现空腹血糖正常的餐后高血糖患者。     

Liver pathology in morbidly obese patients with and without diabetes

The contribution of obesity and/or diabetes to liver pathology in the morbidly obese patient is controversial. We studied the liver biopsies of 100 consecutive patients undergoing gastric bypass surgery for morbid obesity. Multiple morphologic parameters were analyzed and graded independently, without knowledge of the clinical history, liver function tests, and oral glucose tolerance results of the patients. Six percent of the entire group demonstrated no fat, 42% mild fat, 20% moderate fat, and 24% severe fatty metamorphosis of the liver. Twenty-three percent of the patients had central vein fibrosis, 23% sinusoidal fibrosis, 19% bridging fibrosis, and 4% cirrhosis. Thirty-six percent of the patients had some degree of steatohepatitis, 66% possessed so-called glycogen nuclei of hepatocytes, 6% had PAS-positive thickening of blood vessels in the portal tracts, and 1% had lipogranulomas. The degree of fatty metamorphosis and fibrosis was analyzed in three separate groups, categorized by the glycemic status of the patient: 46 patients with normal glucose tolerance (NGT), 23 patients with impaired glucose tolerance (IGT), and 31 patients with non-insulin-dependent diabetes mellitus (NIDDM). Increasing severity of fatty metamorphosis from the normoglycemic obese to the diabetic obese patients was found, which was statistically significant by chi 2 analysis. Four of the six patients showing no fatty metamorphosis were normoglycemic. Glycogen nuclei and PAS-positive blood vessels were significantly more prevalent in the diabetic obese than in the normal obese. In conclusion, the distribution of significant liver histopathology in the morbidly obese patient correlates in severity with the degree of impaired glycemic status.     

Contribution of reduced insulin sensitivity and secretion to the pathogenesis of hepatogenous diabetes: effect of liver transplantation

Diabetes mellitus frequently complicates cirrhosis but the pathogenic mechanisms are unknown. To assess the contribution of reduced insulin action and secretion, 24 cirrhotic-diabetic patients waiting for liver transplant because of an unresectable hepatocarcinoma underwent an oral glucose tolerance test (OGTT) to assess the beta-cell function and an insulin clamp combined with [3-(3)H]glucose infusion to measure whole body glucose metabolism before and 2 years after the transplant. Seven cirrhotic nondiabetic patients, 11 patients with chronic uveitis on similar immunosuppressive therapy, and 7 healthy subjects served as control groups. Cirrhotic patients showed a profound insulin resistance, and diabetics in addition also showed increased endogenous glucose production (P <.05) and insulin deficiency during the OGTT (P <.05). Liver transplantation normalized endogenous glucose production and insulin sensitivity but failed to cure diabetes in 8 of the 24 patients because a markedly low insulin response during the OGTT. Age, body mass index, family history of diabetes, immunosuppressive drugs, and pathogenesis of cirrhosis did not predict in whom liver transplant was going to cure diabetes. On the contrary, a reduced secretory response characterized the patients in whom the transplant would not be curative. In summary, insulin resistance was a primary event complicating cirrhosis but additional beta-cell secretory defects were crucial for development of diabetes. Liver transplantation, lessening insulin resistance, cured hepatogenous diabetes in 67% of cirrhotic-diabetic patients; nevertheless 33% were still diabetics because the persistence of a reduced beta-cell function, which makes these patients eventually eligible for combined islet transplantation.     

恩替卡韦治疗乙型肝炎肝硬化合并肝源性糖尿病的临床观察

目的观察恩替卡韦治疗肝源性糖尿病（HD）的临床疗效。方法回顾性分析72例患者的临床资料,按是否应用恩替卡韦抗病毒治疗分为治疗组和对照组各36例。所有患者均给予糖尿病饮食及综合护肝、对症、支持治疗。治疗组给予恩替卡韦0.5 mg,口服,1次/d,观察52周的治疗效果。检测治疗前后患者血清HBV DNA水平,肝功能（ALT、AST、TBil、Alb）,血糖,糖化血红蛋白等指标。两组间计量资料比较应用t检验,计数资料比较采用χ2检验。结果治疗52周后,治疗组有29例患者（80.56%）出现病毒学应答,26例（72.22%）肝功能恢复和糖尿病控制;对照组有7例患者（19.44%）出现病毒学应答,16例患者（44.44%）肝功能恢复和糖尿病控制。两组病毒学应答率及糖尿病控制率差异有统计学意义（χ2=18.00,P〈0.01;χ2=5.774,P〈0.05）;治疗组肝功能、血糖等指标较治疗前明显好转,差异有统计学意义（P〈0.05）,治疗组患者的糖化血红蛋白、空腹血糖均低于对照组,差异有统计学意义（P〈0.01）。结论恩替卡韦治疗HBV DNA阳性的乙型肝炎肝硬化伴HD,不但能有效抑制病毒DNA复制,促进肝功能恢复,也能有效控制HD。     

肝源性糖尿病临床特征及治疗

目的研究探讨肝源性糖尿病临床特征及治疗方法。方法对58例肝源性糖尿病患者的临床表现、肝功能及血糖检测结果进行探讨分析(实验组),并从同期患者中随机抽取58例原发性2型糖尿病患者作为对照组。两组患者均实施了胰岛素、C肽释放及OGTT测定。结果所有肝源性糖尿病患者均出现了不同程度的腹胀、乏力、纳差等典型的肝病特征,但只有4例出现"三多一少"等糖尿病典型症状。肝源性糖尿病患者空腹血糖含量的平均值为(6.9±2.5)mmol/L,饮食后2 h血糖含量的平均值为(12.9±2.7)mmol/L。OGTT结果的比较表明肝源性糖尿病患者在空腹时血糖水平比原发性2型糖尿病低,且两组间差异具有统计学意义(P0.05),但用餐后1、2、3 h两组患者血糖水平无显著性差异。胰岛素释放结果及C肽释放水平的比较表明,肝源性糖尿病患者在任何时间段均比对照组高,且两组间差异具有统计学意义(P0.05)。结论肝源性糖尿病的临床症状表现不典型,主要特征为饮食后高血糖,治疗该病的首选药物为胰岛素。     

The prevalence and clinical characteristics of glucose metabolism disorders in patients with liver cirrhosis. A prospective study

Aims. To define the prevalence and clinical characteristics of glucose metabolism disorders (GMD) in patients with compensated liver cirrhosis (LC).Material and methods. Fasting plasma glucose (FPG) levels were measured to 130 patients with clinically stable LC. Oral glucose tolerance tests (OGTT) and fasting plasma insulin determinations were performed to patients with normal FPG. Insulin resistance (IR) was calculated with HOMA2-IR index. GMD were classified according to FPG and OGTT tests results and to the chronologic relation between diagnosis of diabetes mellitus (DM) and LC as follows: type-2 DM (T2DM), hepatogenous diabetes (HD) and impaired glucose tolerance. Patients from all groups were compared.Results. The prevalence of GMD were as follows: T2DM in 25 patients (19.2%, 95% CI 12.5-25.9), HD in 28 (21.5%, 95% CI 14.5-28.5) and IGT in 36 (38.5%, 95% CI 30.1-46.7). The total of patients with GMD was 79.2% (95% CI 72.3-86.1). In 41% of cases GMD were subclinical and 48.7% of patients had IR. Patients with T2DM had a higher number of variables with significant differences compared with the other groups (more marked compared to the patients without GMD). The only differences between the patients with T2DM and HD were hypercreatininemia: 1.14 ± 0.53 vs. 0.84 ± 0.22 mg/dL (p = 0.005) and family history of DM: 8 (32%) vs. 2 (7%) (p = 0.02).Conclusion. Almost 80% of patients with compensated LC had GMD. Half of them were subclinical. The patients with T2DM had marked clinical differences compared to patients from the other groups, particularly renal impairment.     

Cardiovascular disease in cirrhosis--a point-prevalence study in relation to glucose tolerance

OBJECTIVE: Impaired glucose tolerance or diabetes are frequently observed in cirrhosis. Overt diabetes was reported to affect long term survival of cirrhotic patients by increasing the risk of hepatocellular failure, without increasing the risk of diabetes-associated cardiovascular events. METHODS: We evaluated the prevalence of cardiovascular disease in 122 patients with cirrhosis, subdivided according to their glucose tolerance. The following parameters were considered: arterial pressure, peripheral vascular disease (ankle to brachial pressure ratio), ischemic heart disease, microalbuminuria, retinopathy. The prevalence of abnormal findings was compared with that observed in 60 randomly selected patients with noninsulin-dependent diabetes and in 40 controls. RESULTS: Noninsulin-dependent diabetic patients and patients with cirrhosis and diabetes were comparable for age, metabolic control, and smoking habits; the duration of diabetes was 5 yr longer for noninsulin-dependent diabetes. In cirrhosis, the prevalence of micro- and peripheral macroangiopathy, as well as coronary heart disease, was not different in relation to glucose tolerance, it was comparable to that of controls, and significantly lower than that observed in non-insulin-dependent diabetes. CONCLUSIONS: Cirrhotic patients, even in the presence of overt diabetes, are at low risk of cardiovascular disease. The low prevalence may be related to shorter duration of diabetic disease, also in relation to reduced life expectancy, as well as to liver disease-induced abnormalities protecting the cardiovascular system from atherosclerosis.     

Postprandial hyperinsulinemia is universal in non-diabetic patients with nonalcoholic fatty liver disease

Background and Aims: Despite strong associations between non‐alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D), it is unclear which patients need oral glucose tolerance testing (OGTT). Relationships between hyperglycemia, postprandial hyperinsulinemia and NAFLD severity also need clarification. Methods: Among 111 consecutive NAFLD patients, 35 had established T2D; 70 of the remaining 76 underwent 75G OGTT with fasting, 60 and 120 min insulin. Hepatic fibrotic severity was estimated by NAFLD fibrosis score and evidence of cirrhosis. Results: Twenty‐four (33%) showed abnormal glucose tolerance: seven T2D, 17 impaired glucose tolerance (IGT). NAFLD patients with newly diagnosed T2D or IGT were (mean) 9 years older and more likely female (54% vs 30%). Fasting hyperglycemia (5.6–6.9 mmol/L) had limited sensitivity (46%) but high specificity (89%) for identifying patients with IGT/T2D; positive and negative predictive values were 69% and 76%. Postprandial hyperinsulinemia (120 min) was evident in all non‐diabetic NAFLD cases, and values were higher (151 ± 87 vs 82 ± 53 mU/L, P = 0.001) in those with abnormal OGTT. Patients with established diabetes were more likely to have cirrhosis (40%) than those with IGT (12%) or normal glucose tolerance (4%). Conclusions: All NAFLD patients have postprandial hyperinsulinemia, and OGTT reveals a high frequency of previously unsuspected IGT or T2D. Such testing would identify individuals who may benefit from early intervention to improve insulin sensitivity and prevent diabetes and progression to cirrhosis.     

干扰素诱导蛋白-10在肝源性糖尿病患者体内表达的研究

目的探讨干扰素诱导蛋白-10(interferon-inducibe protein 10,IP-10)在肝源性糖尿病患者肝组织及血清中表达水平,进一步探讨其与肝源性糖尿病的关系。方法用ELISA、Real-time PCR以及免疫组织化学法检测60例肝源性糖尿病患者及60例普通肝病患者血清及肝组织中IP-10的表达水平。结果在肝源性糖尿病患者中,ELISA法检测血清中IP-10的表达水平为(239.542±28.603)pg/ml,明显高于对照组的(205.341±26.952)pg/ml(P0.05);Real-time PCR法检测肝组织中IP-10 m RNA表达水平高于对照组(P0.05)。用免疫组织化学法检测肝组织IP-10表达阳性率,肝源性糖尿病组为30.0%(18/60),高于普通肝病组的11.7%(7/60)(P0.05)。结论 IP-10在肝源性糖尿病患者血清和肝组织中有着高水平表达。     

Hepatogenous diabetes: Is it a neglected condition in chronic liver disease?

Diabetes mellitus(DM) that occurs because of chronic liver disease(CLD) is known as hepatogenous diabetes(HD). Although the association of diabetes and liver cirrhosis was described forty years ago, it was scarcely studied for long time. Patients suffering from this condition have low frequency of risk factors of type 2 DM. Its incidence is higher in CLD of viral, alcoholic and cryptogenic etiology. Its pathophysiology relates to liver damage, pancreatic dysfunction, interactions between hepatitis C virus(HCV) and glucose metabolism mechanisms and genetic susceptibility. It associates with increased rate of liver complications and hepatocellular carcinoma, and decreased 5-year survival rate. It reduces sustained virological response in HCV infected patients. In spite of these evidences, the American Diabetes Association does not recognize HD. In addition, the impact of glucose control on clinical outcomes of patients has not been evaluated. Treatment of diabetes may be difficult due to liver insufficiency and hepatotoxicity of antidiabetic drugs. Notwithstanding, no therapeutic guidelines have been implemented up to date. In this editorial, authors discuss the reasons why they think that HD may be a neglected pathological condition and call attention to the necessity for more clinical research on different fields of this disease.