Elevated growth hormone levels in patients with non-alcoholic chronic liver disease

High serum concentrations of growth hormone (GH) were found in five patients with chronic liver diseases, including auto-immune chronic active hepatitis (two cases), Budd-Chiari syndrome, primary biliary cirrhosis and hepatitis B virus associated cirrhosis. Mean levels of GH were 27.8 units (normal up to 5). In three patients elevated prolactin levels were also found (mean 37.3 units for two females, normal up to 20), and 36 units in one male (normal up to 9). No other endocrine disorders were found. Although the association of raised GH levels in patients with alcoholic cirrhosis is well known, its occurrence in patients with non-alcoholic chronic liver disease is not fully established. We describe the effect of the disease course, and steroid treatment on GH levels in one patient with auto-immune chronic active hepatitis, and propose possible mechanisms for this elevation.     

Elevated plasma adiponectin concentrations in patients with liver cirrhosis correlate with plasma insulin levels

Abstract: Background: Adiponectin is a hormone secreted by adipocytes and has anti‐diabetic and anti‐atherogenic properties. Hypoadiponectinemia is associated with insulin‐resistant diabetes and liver dysfunction. The aim of this study was to determine plasma adiponectin and insulin levels in patients with liver cirrhosis. Methods: Adiponectin and insulin levels were determined in 38 patients with cirrhosis and 30 healthy controls, and were correlated with various clinical and biochemical parameters. Patients included 21 with Child A, eight Child B, and nine with Child C liver cirrhosis. Results: Log adiponectin and insulin levels were significantly elevated in patients with cirrhosis compared with the control. In liver cirrhosis, the level of adiponectin increased proportionately with the Child's classification score. In control subjects, plasma adiponectin correlated inversely with insulin levels. In contrast, plasma adiponectin correlated positively with insulin levels in patients with liver cirrhosis. Plasma adiponectin levels did not correlate with age, sex, body mass index, total bilirubin, aspartate aminotransferase, and fasting blood sugar levels in both groups, while alanine aminotransferase correlated negatively with adiponectin in control subjects as reported previously. Conclusion: Our results of high plasma adiponectin in patients with liver cirrhosis could reflect an imbalance between its production by adipocytes and metabolism in the liver.     

肝硬化患者血清瘦素水平变化及相关因素分析

目的 探讨瘦素在肝硬化发生、发展中的作用.方法 对44例肝硬化患者(肝硬化组)和17例健康查体者(正常对照组)进行血清瘦素、空腹血糖(FPG)、胰岛素(FINS)水平测定并分析相关因素.结果 肝硬化组血清瘦素水平显著高于对照组(P<0.01),肝功能Child-pugh B、C级者显著多于A级(P<0.05);血清瘦素水平与FINS、FPG、胰岛素敏感指数(ISI)呈显著正相关,FINS是瘦素的显著预测因子.结论 肝硬化患者瘦素水平显著升高;其可能通过胰岛素抵抗诱发肝性糖尿病.     

Elevated neopterin levels are associated with acute-on-chronic liver failure and mortality in patients with liver cirrhosis

BackgroundMacrophage activation plays a central role in hepatic and systemic inflammation and is involved in the pathogenesis of acute-on-chronic liver failure (ACLF).AimsThis study aimed to investigate neopterin levels in patients admitted for acute decompensation (AD) of cirrhosis, evaluating its relationship with ACLF and prognosis.MethodsThis prospective cohort study included 205 adult subjects hospitalized for AD of cirrhosis. Twenty-one healthy subjects and 89 patients with stable cirrhosis were evaluated as controls.ResultsCirculating neopterin was higher in AD as compared to stable cirrhosis and healthy controls (p<0.001). ACLF was independently associated with higher neopterin levels (OR 1.015, 95% CI 1.002–1.028, p = 0.025). In the multivariate Cox regression analysis, neopterin levels (HR = 1.002, IC 95% 1.000–1.004, p = 0.041), Child–Pugh class C, and ACLF were predictors of 30-day survival. Among patients with ACLF, the Kaplan–Meier survival probability was 71.4% in those with neopterin levels < 25 nmol/L and 31.0% if neopterin ≥ 25 nmol/L (p<0.001).ConclusionsHigher circulating neopterin was associated with ACLF in patients hospitalized for AD of cirrhosis. Neopterin levels were also independently predictors of high short-term mortality, especially among patients with ACLF, and could represent a useful biomarker of macrophage activation in clinical practice.     

肝硬化患者胰岛素抵抗与血栓调节蛋白水平的关系

目的探讨肝硬化患者胰岛素抵抗（IR）与血栓调节蛋白（TM）水平的关系。方法选择111例肝硬化患者,其中肝功能Child-Pugh分级A级21例,B级47例,C级43例。检测其血清空腹胰岛素（FINS）、血糖（FPG）和TM,并计算胰岛素敏感性指数（ISI）。结果与Child-Pugh分级A、B级肝硬化患者比较,C级患者的血清FINS、TM明显升高,ISI明显降低（P均〈0.01）。肝硬化患者的Child-Pugh分级与FINS、TM水平呈正相关（r分别为0.523、0.372,P均〈0.01）,与ISI呈负相关（r=-0.536,P〈0.01）;TM水平与FINS呈正相关（r=0.298,P〈0.01）,与ISI呈负相关（r=-0.272,P〈0.01）。结论肝硬化患者存在高胰岛素血症、IR及TM升高,其血清FINS、ISI、TM均与Child-Pugh分级相关;检测以上指标有助于判断患者的肝功能损害程度。     

肝硬化患者生长激素抵抗的可能机制探讨

目的探讨IGF-Ⅰ及其结合蛋白-3(IGFBP-3)与肝硬化患者生长激素抵抗的关系,研究肝硬化患者生长激素抵抗的另一可能机制.方法肝硬化患者65例,按Child-pugh分级法将其分为A(17例),B(20例)和C(28例)三组,对照组30例,应用放射免疫法检测空腹IGF-Ⅰ和IGFBP-3及GH水平.结果肝硬化患者血清IGF-Ⅰ和IGFBP-3水平下降(100.49±38.11 ng/mL对352.55±153.61 ng/mL,P＜0.001;45.02±16.21 nmol/L对114.50±27.09 nmol/L,P＜0.001),而GH水平明显升高(6.02±4.03对0.28±0.40,P＜0.001),IGF-1、IGFBP-3与GH呈负相关(r=-0.728,r=-0.569,P＜0.01).结论肝硬化患者存在生长激素抵抗,IGF-Ⅰ、IGFBP-3可能与肝硬化患者的生长激素抵抗有关.     

Altered control of growth hormone secretion in patients with cirrhosis of the liver.

Ten male patients with cirrhosis of the liver (three with portacaval anastomosis [PCA]) and eight sex- and age-matched controls underwent an arginine infusion test followed by an intravenous glucose tolerance test. Plasma glucose and growth hormone (GH) levels were measured during a period of three hours. In the normal subjects, the peak GH response to arginine occurred 60 minutes after the start of the infusion and was followed by a progressive decline in GH concentration; dextrose injection resulted in a further rapid fall in GH concentration. In cirrhotic patients, both fasting and postarginine GH concentrations were significantly higher than in controls; in addition, the dextrose injection, after causing a transitory drop in plasma GH levels, resulted in a marked increase in plasma GH concentration. In the patients with PCA, the plasma GH increase after arginine and after dextrous was more marked. In these cirrhotic patients, the plasma GH levels correlated directly with the magnitude of the portal hypertension and inversely with the serum albumin concentration, suggesting that the abnormality of GH secretion was a reflection of the derangement in liver function.     

Elevated plasma resistin concentrations in patients with liver cirrhosis

Background: Resistin, an adipose‐derived polypeptide hormone, has been proposed to be a candidate in insulin resistance, although its role in humans remains controversial. Liver cirrhosis (LC) is characterized by an elevated number of circulating proinflammatory cytokines, hyperinsulinemia and insulin resistance. The aim of this study was to determine the plasma resistin levels in patients with LC. Methods: Resistin levels were determined in 79 patients with LC and in 31 healthy controls. Patients included 34 with Child–Pugh grade A, 30 with Child's B and 15 with Child's C LC. Fasting plasma glucose, fasting plasma insulin, adiponectin, the homeostatic model assessment insulin resistance (HOMA‐IR) index, quantitative insulin sensitivity check index (QUICKI) and biochemical parameters were also determined. Results: Plasma resistin levels were 7.61 ± 6.70 ng/mL in the LC patients and 3.38 ± 1.68 ng/mL in the controls, respectively. The plasma resistin levels were significantly elevated in patients with LC in comparison to the controls (P < 0.01). The plasma resistin levels increased in a stepwise fashion in line with a higher grade according to Child–Pugh classification. Fasting plasma insulin, adiponectin and HOMA‐IR index were also significantly elevated in patients with LC in comparison to controls. Inversely, QUICKI significantly decreased in patients with LC. According to Spearman's rank correlation, log resistin showed significantly positive correlation with fasting plasma insulin, log adiponectin, HOMA‐IR index, and a negative correlation with QUICKI (P < 0.01). The plasma resistin levels did not correlate with sex, body mass index and fasting plasma glucose levels. Conclusion: The plasma resistin levels increased in patients with LC, thus showing a positive correlation with fasting plasma insulin, adiponectin, HOMA‐IR index, and a negative correlation with QUICKI. Although a decreased extraction of resistin due to reduced liver function cannot be ruled out, resistin may contribute to insulin resistance in patients with LC. The pathophysiological roles of resistin in LC still require further investigation.     

Mechanism of insulin resistance associated with liver cirrhosis.

Insulin-induced glucose metabolism was investigated in 26 patients with biopsy-proven liver cirrhosis and 10 control subjects. Two glucose clamp protocols together with continuous indirect calorimetry were performed to examine whether reduced rates of glucose oxidation and/or nonoxidative glucose metabolism explain insulin resistance in liver cirrhosis. Using a 4-hour, two-step protocol (0-2 hours, plasma glucose 5.2 mmol/L, plasma insulin 92 mU/L to test the half-maximum response; 2-4 hours, hyperglycemia 10.0 mmol/L, plasma insulin 442 mU/L to test the maximum cellular glucose disposal) liver cirrhosis reduced glucose disposal to 45% and 60% of control values, respectively. Simultaneously, insulin-induced increases in glucose oxidation, plasma lactate levels, and lipogenesis were normal, whereas nonoxidative glucose metabolism was reduced (-82% and -47% of controls, respectively). To determine whether reduced nonoxidative glucose metabolism was caused by reduced glucose disposal, glucose disposal was "matched" to normal values in a subgroup of cirrhotic patients. Nonoxidative glucose metabolism values were normal, but plasma lactate concentrations disproportionally increased (+96%) after "matching" glucose disposal. Insulin resistance was independent of the etiology of the cirrhosis, the biochemical parameters of parenchymal cell damage and liver function, and the clinical and nutritional state of the patients. It is concluded that liver cirrhosis impairs insulin sensitivity and maximum cellular glucose disposal. Reduced glucose disposal is caused by defective glucose storage. Insulin resistance is independent of the etiology of liver cirrhosis and of the clinical and nutritional state of the patient.     

脂肪肝患者血清瘦素水平测定及与胰岛素抵抗关系的探讨

目的了解脂肪肝患者血清瘦素水平变化,探讨其可能的临床意义。方法测定脂肪肝患者肝功、血脂、血糖及胰岛素、血清瘦素水平,测量其身高、体重,计算体重指数、体脂肪含量。瘦素、胰岛素分别采用ELISA、IRA方法测定,胰岛素抵抗用HOMA模式估算。结果脂肪肝组血清瘦素水平高于对照组,与BM I、?t、ALT、CHE相关,与IR无关。结论血清瘦素是脂肪肝患者发病的一个危险因素,与胰岛素抵抗无直接相关性。     

Elevated plasma levels of alpha-melanocyte stimulating hormone (alpha-MSH) are correlated with insulin resistance in obese men

OBJECTIVE: The role of alpha-melanocyte stimulating hormone (MSH) in obesity has been well-documented. However, circulating alpha-MSH concentrations in obese men and their relationship with clinical indicators of obesity and glucose metabolism have not as yet been evaluated. METHODS: We measured the plasma concentrations of alpha-MSH in 15 obese and 15 non-obese male subjects. The relationship of the plasma concentrations of alpha-MSH with body mass index (BMI), body fat mass (measured by bioelectric impedance), body fat distribution (measured by computed tomography), insulin levels, insulin resistance (assessed by the glucose infusion rate (GIR) during an euglycemic hyperinsulinemic clamp study) and with the serum concentrations of leptin and TNF-alpha were also evaluated. RESULTS: In obese men, the plasma alpha-MSH concentrations were significantly increased compared with those in non-obese men (P< 0.02). The plasma levels of alpha-MSH were positively correlated with BMI (r= 0.560, P< 0.05), fasting insulin levels (r=0.528, P< 0.05) and with visceral fat area (r=0.716, P<0.01), but negatively correlated with GIR (r= -0.625, P< 0.02) in obese male subjects. There were significant correlations between plasma concentrations of alpha-MSH and visceral fat area (r=0.631, P< 0.02), and GIR (r = -0.549, P< 0.05) in non-obese male subjects. Circulating concentrations of alpha-MSH were not significantly correlated with the serum concentrations of leptin and TNF-alpha in both obese and non-obese men. CONCLUSION: Circulating concentrations of alpha-MSH are significantly increased and correlated with insulin resistance in obese men.     

Impaired insulin signaling in the liver of transgenic rats with low circulating growth hormone levels.

GH is known to regulate glucose and lipid metabolism as well as body growth. Controversy exists as to whether GH-deficient adults are indeed insulin sensitive or insulin resistant. In GH-deficient animal models, however, no clear observation indicating insulin resistance has been made, while increased insulin sensitivity has been reported in those animals. We have produced human GH (hGH) transgenic rats characterized by low circulating hGH levels and virtually no endogenous rat GH secretion. Although the body length of the transgenic rat is normal, they develop massive obesity and insulin resistance, indicating that the transgenic rat is a good model for the analysis of insulin resistance under GH deficiency. In this study, we have examined how GH deficiency affects the early steps of insulin signaling in the liver of the transgenic rat. Circulating glucose and insulin concentrations were significantly higher in the transgenic rats than in their littermates. In addition, impaired glucose tolerance was observed in the transgenic rat. The amount of insulin receptor was smaller in the liver of the transgenic rat, resulting in decreased tyrosine phosphorylation in response to insulin stimulation. The amounts of insulin receptor substrate-1 and -2 (IRS-1 and -2) and insulin-stimulated phosphorylation of IRSs were also smaller in the transgenic rat. Despite the decrease in tyrosine phosphorylation levels of IRSs being mild to moderate (45% for IRS-1 and 16% for IRS-2), associated phosphatidylinositol 3-kinase (PI3-kinase) activity was not increased by insulin stimulation at all in the transgenic rat. To elucidate whether this discrepancy resulted from the alteration in binding of the p85 subunit of PI3-kinase to phosphotyrosine residues of the IRSs, we determined the amount of p85 subunit in the immunocomplexes with anti-phosphotyrosine antibody. Insulin did not affect the amount of p85 subunit associated with phosphotyrosine in the transgenic rats, while it significantly increased in the controls, indicating that alteration may have occurred at the sites of phosphorylated tyrosine residues in IRSs. These results suggest that GH deficiency in the transgenic rat leads to impairment in at least the early steps of insulin signaling in the liver with a resultant defect in glucose metabolism.     

Increased serum soluble tumor necrosis factor receptor levels are associated with insulin resistance in liver cirrhosis

Insulin resistance is present in nearly all patients with liver cirrhosis, but its etiology remains unclear. Recent studies have shown that tumor necrosis factor-alpha (TNF-alpha) system is involved in the insulin resistance of human obesity. Serum concentrations of TNF-alpha, and 2 soluble TNF receptors (sTNF-RI and sTNF-RII) are increased in cirrhotic patients. This study explored whether TNF-alpha system activity was associated with insulin resistance in liver cirrhosis. A total of 26 male nondiabetic patients with liver cirrhosis (mean age, 59 +/- 3 years; body mass index, 23.7 +/- 0.4 kg/m2) and 25 male control subjects (age, 65 +/- 2 years; body mass index, 24.4 +/- 0.5 kg/m2) were studied. Serum insulin, c-peptide, TNF-alpha, sTNF-RI, and sTNF-RII concentrations were determined by immunoassay. The insulin resistance was estimated by homeostasis assessment model (HOMA IR). In cirrhotic patients, serum levels of TNF-alpha, sTNF-RI, and sTNF-RII were all higher than those in the controls, and correlated with disease severity. Also, the serum c-peptide, insulin concentrations, and the HOMA IR were higher in liver cirrhosis with comparable blood glucose to control subjects, indicating a degree of insulin insensitivity. In the whole population, there was a moderate, but statistically significant, correlation between serum sTNF-RI or sTNF-RII, and HOMA IR. Also, body mass index was associated with HOMA IR, but not related to serum TNF-alpha, and sTNF-Rs levels. In multiple regression analysis, both sTNF-RII and body mass index jointly contributed to 30% variance of HOMA IR. Our study demonstrated that elevated sTNF-RII levels were associated with insulin resistance in liver cirrhosis. The data indicated that TNF-alpha system might play a role in modulating insulin action in patients with liver cirrhosis.     

Serum growth hormone-binding protein, insulin-like growth factor-I, and growth hormone in patients with liver cirrhosis.

We determined serum growth hormone-binding protein (GHBP), insulin-like growth factor-I (IGF-I), and growth hormone (GH) levels in patients with cirrhosis and in age-matched control subjects, and investigated their relationships. Serum GHBP levels in cirrhotic patients (14.6% +/- 3.9%) (means +/- SD) were significantly lower than those in normal subjects (20.4% +/- 4.7%). GHBP levels had positive correlations with cholinesterase (r = .58, P less than .001) and Normotest (r = .66, P less than .001), both of which represent liver function in cirrhotic patients. Basal GH levels in cirrhotic patients (range, 0.35 to 13.0 micrograms/L; median, 3.9 micrograms/L) were significantly higher than those in normal subjects (0.015 to 6.0 micrograms/L; 0.19 microgram/L). GHBP levels in cirrhotic patients correlated positively with IGF-I levels (r = .39, P less than .01), and negatively with GH levels (r = -.33, P less than .01). These results may indicate that the serum GHBP level reflects the number of hepatic GH receptors, and that the high basal GH level observed in cirrhotic patients is, at least in part, attributable to decreased clearance of GH by these receptors.     

Plasma betatrophin levels in patients with liver cirrhosis

AIM: To investigate the plasma levels of betatrophin in patients with cirrhosis.METHODS: Forty patients diagnosed at the clinic with liver cirrhosis according to biological, ultrasonographic,or histological criteria were included.The severity of cirrhosis was classified according to Pugh's modification of Child's classification and MELD score. Insulin resistance(IR) was assessed by the Homeostasis Model Assessment. A total of 20 patients showed a MELD score higher than 14. The control group consisted in 15 sex-and aged-matched subjects.Fasting blood samples were obtained for subsequent analysis. Serum insulin was determined by Liaison automated immune chemiluminiscence assay(DiaSorin S.p.A.) using a sandwich assay. The sensitivity of the assay was 0.2 μU/mL. The intra and interassay variation coefficients were 4% and 10%,respectively. The normal values were between 2 and17 μU/mL. Human active betatrophin was analyzed by specific quantitative sandwich ELISA(Aviscera Bioscience). The sensitivity of the assay was 0.4 ng/mL, and the intra and interassay reproducibility were 6% and 10%, respectively.RESULTS: Plasma betatrophin levels were significantly increased in patients with cirrhosis compared with those in healthy subjects(P = 0.0001). Betatrophin levels were also associated with disease severity, being higher in Child-Pugh C patients compared to Child-Pugh B(P 0.0005) and in patients who displayed a MELD score higher than 14 points compared to patients with lower punctuation(P = 0.01). In addition, we found a positive correlation between plasma betatrophin levels and the severity of cirrhosis according to Child-Pugh classification(r = 0.53; P 0.01) or MELD score(r = 0.45; P 0.01). In the overall cohort, a moderate correlation between serum betatrophin and plasmatic bilirrubin(r= 0.39; P 0.01) has been observed, as well as an inverse correlation between betatrophin and albumin(r =-0.41; P 0.01) or prothrombin time(r =-0.44;P 0.01). Moreover, insulin resistance was observed in82.5% of the cirrhotic patients. In this group of patients,betatrophin levels were significantly higher than those in the group of patients without IR(P 0.05).CONCLUSION: Plasma betatrophin is increased in patients with cirrhosis. This increase is related to the severity of cirrhosis, as well as with the emergence of insulin resistance.     

重组人生长激素治疗肝硬化低蛋白血症的影响因素及意义

目的探讨重组人生长激素对不同血清白蛋白含量肝硬化患者低蛋白血症的临床疗效及意义。方法将92例血清白蛋白含量低于35g/L的肝硬化患者根据血清白蛋白含量分为3组：轻度低水平组（30.0～35.0g/L）、中度低水平组（25.0～30.0g/L）、重度低水平组（20.0～25.0g/L）,每组随机分为两组,治疗组给予重组人生长激素4IU肌注,1次/2日;对照组给予20%人血白蛋白100ml静滴,1次/2日,两组疗程均为30d。治疗组和对照组均给予相同方案的保肝、对症治疗。分别于治疗后15d、30d、60d、90d测定相应观察指标。结果治疗后30d两组患者血清白蛋白含量均上升,治疗组于治疗后第90d后仍维持高点水平,且肝功能好转,而对照组60d后白蛋白含量开始降低;血清白蛋白浓度大于25.0g/L时,治疗组观察指标改善尤为明显。结论重组人生长激素可明显提高肝硬化低蛋白血症患者血清白蛋白水平,中远期疗效好,并可改善肝功能;肝硬化患者血清白蛋白浓度对生长激素的疗效具有显著影响。