Changes in markers of hepatic steatosis and fibrosis in patients with type 2 diabetes during treatment with glucagon-like peptide-1 receptor agonists. A multicenter retrospective longitudinal study

AimsMetabolic dysfunction-associated fatty liver disease (MAFLD) is common in people with type 2 diabetes (T2D) and can progress to advanced fibrosis and cirrhosis. In this retrospective study, we explored the longitudinal changes in markers of hepatic steatosis and fibrosis during T2D treatment with glucagon-like peptide-1 receptor agonists (GLP-1RAs).MethodsWe analysed observational data from six diabetes outpatient clinics. In the whole T2D population, we calculated the hepatic steatosis index (HSI), which we previously validated against liver ultrasonography, and the Fibrosis (Fib)-4 index. We then identified patients who initiated a GLP-1RA from 2010 to 2018 and for whom data were available to evaluate changes in both HSI and Fib-4 scores over 24 months.ResultsFrom 83,116 outpatients with T2D, 41,302 (49.7%) had complete data for calculating HSI and Fib-4. Most of these T2D patients (∼70%) had MAFLD (defined as HSI>36), 9.7% of whom had advanced fibrosis based on Fib-4 thresholds. Patients with low compared to high risk of advanced fibrosis were 5-times more likely to be treated with GLP-1RA. In 535 patients who initiated a GLP-1RA, the prevalence of MAFLD based on HSI declined significantly at 6 and 24 months, but Fib-4 categories did not. HSI improved significantly only in patients receiving human-based but not exendin-based GLP-1RA, while patients concomitantly receiving metformin had less worsening in Fib-4 categories.ConclusionsMAFLD is very common among outpatients with T2D (∼70%) and the estimated prevalence of advanced fibrosis was ∼10%. Treatment with GLP-1RAs significantly improved MAFLD, but not MAFLD-associated advanced fibrosis.     

Epidemiology of liver cirrhosis and associated complications: Current knowledge and future directions

Cirrhosis causes a heavy global burden. In this review, we summarized up-to-date epidemiological features of cirrhosis and its complications. Recent epidemiological studies reported an increase in the prevalence of cirrhosis in 2017 compared to in 1990 in both men and women, with 5.2 million cases of cirrhosis and chronic liver disease occurring in 2017. Cirrhosis caused 1.48 million deaths in 2019, an increase of 8.1% compared to 2017. Disability-adjusted life-years due to cirrhosis ranked 16th among all diseases and 7th in people aged 50-74 years in 2019. The global burden of hepatitis B virus and hepatitis C virus-associated cirrhosis is decreasing, while the burden of cirrhosis due to alcohol and nonalcoholic fatty liver disease (NAFLD) is increasing rapidly. We described the current epidemiology of the major complications of cirrhosis, including ascites, variceal bleeding, hepatic encephalopathy, renal disorders, and infections. We also summarized the epidemiology of hepatocellular carcinoma in patients with cirrhosis. In the future, NAFLD-related cirrhosis will likely become more common due to the prevalence of metabolic diseases such as obesity and diabetes, and the prevalence of alcohol-induced cirrhosis is increasing. This altered epidemiology should be clinically noted, and relevant interventions should be undertaken.     

乙肝肝硬化患者门静脉宽度与门静脉血栓形成的关系

背景门静脉血栓(portal vein thrombosis,PVT)的早期诊断仍是临床上一个难题,急需要发现可早期预测诊断的无创指标.目的探讨门静脉宽度与PVT形成之间的关系.方法收集418例乙肝肝硬化患者.根据是否发生PVT分为PVT组(n=66)和非PVT组(n=352)组.比较两组患者的一般资料差异,使用多因素Logistic回顾分析影响PVT发生的危险因素.通过受试者工作特征(receiver operating characteristic,ROC)曲线评估不同危险因素预测PVT的效能.结果与非PVT组患者相比,PVT组患者的Child-Pugh评分更高、Child-Pugh A级比例更低、血小板水平更高、D-二聚体水平更高、门静脉宽度更宽、门静脉血流更慢,上述差异均存在统计学意义(P<0.05).Logistic回归显示门静脉宽度(OR=3.941,P=0.001)、门静脉血流(OR=0.841,P=0.007)、血小板水平(OR=1.024,P=0.008)和D-二聚体水平(OR=2.383,P=0.000)是肝硬化患者发生PVT的独立危险因素.门静脉宽度诊断PVT的ROC曲线下面积最大为0.874,最佳诊断值为>12.5 mm,此时的预测敏感性和特异性分别为78%和82%.结论门静脉直径增加是肝硬化患者PVT发生的危险因素,对PVT诊断具有一定价值.     

Effet protecteur de l'hémochromatose vis-à-vis des lésions vasculaires séniles ou diabétiques

Résumé I. Les lésions vasculaires non spécifiques et spécifiques du diabète ont été recherchées dans 39 cas prouvés de diabète bronzé, dans 22 cas prouvés d'hémochromatose sans diabète, dans 84 cas de cirrhose banale accompagnée de diabète franc, dans 65 cas de cirrhose banale sans diabète, chez 65 sujets normaux, et dans deux groupes de diabétiques banaux pairés individuellement pour le sexe, l'âge, la durée et la gravité du diabète ainsi que le poids corporel avec chacun des diabét ques porteurs de cirrhose banale ou de cirrhose bronzée. Un tiers des sujets a été autopsié. Le tableau 5 résume l'effet protecteur évident de l'hémochromatose dans cinq territoires artériels (rétine, reins, coronaircs, membres inférieurs, aorte) et dans deux localisations capillaires (glomérules, rétine). Cet effet protecteur est lié à l'hémochromatose et n'est pas dû à une moindre durée du diabète bronzé. La cirrhose banale a un effet protecteur beaucoup moins net (malgré sa forte tendance à l'hypocholestérolémie) vis-à-vis de la sclérose banale et vis-à-vis des effets vasculaires propres du diabète dont le degré de contrôle est cependant moins mauvais que dans l'hémochromatose. Plusieurs facteurs protecteurs liés à l'hémochromatose sontenvisagés sans qu'aucun ne paraisse décisif. II. Les deux tiers au moins des cirrhotiques banaux ont une tolérance glucidique réduite. Dans la cirrhose, les chiffres de glycémie à jeun ou post-prandiale s'échelonnent en une série continue allant de la normale au diabète insulino-dépendant (unimodalité). Comme dans la population générale les limites du diabète des cirrhotiques sont conventionelles: plus de 180 mg% deux heures après repas dans le présent travail. Le diabète ainsi défini n'est insulino-dépendant que chez le cinquième des diabétiques avec cirrhose. Cette proportion n'est pas plus élevée chez les diabétiques sans cirrhose de même âge et de même poids. Les traits cliniques du diabète qui accompagne si souvent la cirrhose banale (hérédité, évolutivité, complications typiques) ne permettent pas de le différencier du diabète commun de même gravité (glycosurie accompagnée d'hyperglycémie à jeun et deux heures après repas > 180 mg%).

---

Protective effects of haemochromatosis against micro- and macroangiopathy associated with diabetes. A comparison with common cirrhosis

Summary 1. Signs of common vascular sclerosis and of specific diabetic angiopathy have been sought in 39 cases of proved haemochromatosis with diabetes, in 22 cases of proved haemochromatosis without diabetes, in 84 cases of common cirrhosis with overt diabetes, in 65 cases of common cirrhosis without diabetes, in 65 control subjects and in two groups of patients with common diabetes, each case being carefully paired with a corresponding diabetic either with common cirrhosis or with haemochromatosis as far as sex, age, duration and severity of diabetes as well as body weight are concerned. One out of three cases has been examined at autopsy. — The striking protective effect of haemochromatosis (table 5) was confirmed in five arterial areas (retinae, kidneys, coronary, lower limbs, aorta), and in two areas where diabetic micro-angiopathy (glomeruli and retinae) is typical. This protection is closely related to haemochromatosis, and is not due to the shorter survival of patients with bronze diabetes. Common cirrhosis, despite marked hypocholesterolaemia and better control of the diabetes has but a slight protective effect. Various explanations are suggested, none of them being fully satisfactory. — 2. At least two out of three cases of patients with common cirrhosis have a reduced glucose tolerance. In cirrhosis the values of fasting and of postprandial blood sugar are widely spaced out in an unimodal pattern varying from complete normality to full insulin-dependency. Just as in the general population, the limits of diabetes are quite arbitrary (> 180 mg% two hours after a meal in the present study). According to this definition, diabetes in our series required insulin in only one out of five cases of diabetes associated with cirrhosis, no less in fact than in diabetes without cirrhosis when age and body weight were taken into account. — Clinical features (heredity, evolution, typical vascular complications) do not indicate that diabetes associated with cirrhosis differs markedly from ordinary diabetes of the same severity (glycosuria plus hyperglycaemia > 180 mg% in the fasting state or two hours after a meal).

---

Schutzeffekt der Hämochromatose gegenüber senilen und diabetischen Gefäßleiden

Zusammemfassung I. Spezifische und unspezifische Gefäßleiden des Diabetes wurden untersucht: bei 39 Fällen von Diabetes mit Hämochromatose, bei 22 Fällen von sicherer Hämochromatose ohne Diabetes, bei 84 Fällen von Zirrhose mit manifestem Diabetes, bei 65 Normalen und in zwei Gruppen von Diabetikern mit Zirrhose oder Hämochromatose, von denen jeder einzelne einer Gruppe mit denen der anderen Gruppe in Bezug auf Alter, Geschlecht, Körpergewicht, Dauer und Schwere des Diabetes vergleichbar war. Ein Drittel der Fälle wurde seziert. Die Tabelle 5 faßt den offensichtlichen Schutzeffekt der Hämochromatose auf 5 arteriellen Gefäßbezirken (Retina, Niere, Coronarien, untere Gliedmaßen, Aorta), und in zwei kapillaren Gefäßlokalisationen (Glomerulus und Retina) zusammen. Dieser Schutzeffekt beruht auf der Hämochromatose und nicht auf einer geringeren Dauer des Diabetes bei Hämochromatose. Die Zirrhose hat einen wesentlich geringeren Schutzeffekt (trotz ihrer starken Tendenz zur Hypocholesterinämie) gegenüber der Gefäßsklerose und gegenüber den spezifisch diabetischen Gefäßveränderungen. Mehrere Schutzfaktoren wurden in Erwägung gezögen, ohne daß einer von ihnen als der entscheidende angesehen werden kann. II. Mindestens zwei Drittel der gewöhnlichen Zirrhotiker haben eine verminderte Glukosetoleranz. Bei der Zirrhose erstrecken sich die Blutzuckerwerte, nüchtern oder postprandial, kontinuierlich zwischen den Normwerten und Werten, wie sie bei Insulinbedürftigkeit angetroffen werden. In dieser Arbeit werden die Grenzen des Diabetes bei Zirrhose entsprechend den Konventionen für die allgemeine Bevölkerung angesetzt: mehr als 180 mg% zwei Std. nach der Mahlzeit. Der so definierte Diabetes ist nur bei jedem fünften Diabetiker mit Zirrhose insulinbedürftig. Dieses Verhältnis ist bei Diabetikern ohne Zirrhose des gleichen Alters und Körpergewichtes nicht größer. Die klinischen Erscheinungen des Diabetes, welcher die Zirrhose so häufig begleitet, (Heredität, Verlauf, typische Komplikationen) erlauben es nicht, ihn von dem allgemeinen Diabetes gleichen Schweregrades (Glykosurie mit Hyperglyzämie nüchtern und zwei Std. nach den Mahlzeiten über 180 mg%) zu unterscheiden.

     

疏肝化瘀颗粒治疗慢性乙型肝炎和肝炎肝硬化的临床研究

目的:研究疏肝化瘀颗粒对慢性乙型肝炎和肝炎肝硬化的治疗作用。方法:用疏肝化瘀颗粒治疗慢性乙型肝炎和肝炎肝硬化病人76例,疗程为3～6个月。观察肝功能、肝纤维化指标、B超声像图及肝脏储备功能的变化,对各组检测结果进行比较。结果:治疗组在降低丙氨酸转氨酶、门冬氨酸转氨酶,提高血清白蛋白及肝脏的储备功能,降低血清肝纤维他指标等方面均明显优于对照组。结论:疏肝化瘀颗粒具有明显改善肝功能和抗肝纤维化的作用,临床应用未发现毒副作用,是临床治疗慢性乙型肝炎和肝炎肝硬化的有效药物。     

酒精性肝硬变患者血清干扰素和可溶性干扰素受体的检测及意义

酒精性肝硬变(AC)常伴有体液免疫和细胞免疫系统功能改变,干扰素(IFN)和可溶性干扰素受体(sIFNR)是免疫细胞的重要调理素。为了进一步弄清IFN和sIFNR与AC之间的关系,我们用ELISA法检测了32例AC患者和10例正常人血清IFN和sIFNR水平。结果发现AC组α-IFN,γ-IFN和sIFNR的血清浓度明显高于正常人(P值分别<0.01,<0.05和<0.05),但其变化与疾病的严重程度无相关性。这些结果提示AC患者存在血清α-IFN、γ-IFN和sIFNR的改变。     

Sudden death due to cirrhotic cardiomyopathy: An autopsy case report

Cirrhosis cardiomyopathy is defined by cardiac dysfunction in cirrhotic patients. It is characterized by the reduced contractile response to stress and/or impaired diastolic relaxation associated with electrophysiological disturbances with unknown cardiac disease.Here we report a case of sudden death in a 44-year-old woman, with no personal and family medical history and in apparently good health before death.The death was occurred when performing agricultural activities. The autopsy revealed an elevated weight of the heart with heterogeneous myocardium. The liver was heavy and had a variegated appearance. The histologic examination showed fibrosis and partially disturbance of the texture of the left ventricular myocardial tissue with storiform patterns and circumscribed hypertrophic cardiomyocytes. The microscopic examination of the liver showed cirrhosis with no specific features of etiology.The death was attributed to arrythmia due to cirrhotic cardiomyopathy.Our case highlighted the importance of pathological examination to con-sider the diagnosis of cirrhotic cardiomyopathy in case of sudden death for patient with known or unknown cirrhosis.     

肝炎肝硬化并发自发性细菌性腹膜炎治疗探讨

目的探讨肝炎肝硬化并发自发性细菌性腹膜炎的治疗。方法147例肝炎肝硬化并发自发性细菌性腹膜炎患者行综合治疗:1积极支持治疗;2舒普深抗感染,每日4克,共3周;3每次放腹水后使用罗氏芬1克,腹腔注射。同期另118例肝炎肝硬化并发自发性细菌性腹膜炎患者,接受积极支持治疗和舒普深抗感染,每日4克,共2周。结果与对照组比,抗感染3周疗程加放腹水组患者腹水消退快,总胆红素下降明显,腹腔感染控制较彻底,一年后自发性细菌性腹膜炎复发率显著降低(P<0.05)。结论肝炎肝硬化并发自发性细菌性腹膜炎的抗感染治疗疗程要长,适时放腹水可提高疗效。     

High frequency of the c.3207C〉A （p.H1069Q） mutation in A TP7B gene of Lithuanian patients with hepatic presentation of Wilson＇s disease

AIM： To investigate the prevalence of the ATP7B gene mutation in patients with hepatic presentation of Wilson＇s disease （WD） in Lithuania. METHODS： Eleven unrelated Lithuanian families, including 13 WD patients were tested. Clinically WD diagnosis was established in accordance to the Leipzig scoring system. Genomic DNA was extracted from whole venous blood using a salt precipitation method. Firstly, the semi-nested polymerase chain reaction （PCR） technique was used to detect the c.3207C〉A （p.H1069Q） mutation. Patients not homozygous for the c.3207C〉A （p.H1069Q） mutation were further analyzed. The 21 exons of the WD gene were amplified in a thermal cycler （Biometra T3 Thermocycler, G0ttingen, Germany）. Direct sequencing of the amplified PCR products was performed by cycle sequencing using fluorescent dye terminators in an automatic sequencer （Applied Biosystems, Darmstadt, Germany）. RESULTS： Total of 13 WD patients （mean age 26.4 years; range 17-40; male/female 3/10） presented with hepatic disorders and 16 their first degree relatives （including 12 siblings） were studied. Some of WD patients, in addition to hepatic symptoms, have had extrahepatic disorders （hemolytic anemia 3; Fanconi syndrome 1; neurophsychiatric and behavioural disorder 2）. Liver biopsy specimens were available in all of 13 WD patients （8 had cirrhosis; 1-chronic hepatitis; 3-acute liver failure, 1-1iver steatosis）. Twelve of 13 （92.3%） WD patients had the c.3207C〉A （p.HI069Q） mutation, 6 of them in both chromosomes, 6 were presented as compound heterozygotes with additional c.3472-82delGGTTTAACCAT, c.3402delC, c.3121C〉T （p.RI041W） or unknown mutations. For one patient with liver cirrhosis and psychiatric disorder （Leipzig score 6）, no mutations were found. Out of 16 first degree WD relatives, 11 （68.7%） were heterozygous for the c.3207C〉A （p.H1069Q） mutation. Two patients with fulminant WD died from acute liver failure and ii are in full remission under peniciilam