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Lu Y, Gou W, Zhang HF, Li YY. Effects of Liver Fibrosis on Islet Function in Patients with Chronic Hepatitis B Complicated with Impaired Fasting Glucose. Int J Gen Med 2023; 16:5161-5173. [PMID: 38021063 PMCID: PMC10640824 DOI: 10.2147/ijgm.s429455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 10/26/2023] [Indexed: 12/01/2023] Open
Abstract
Background Patients with chronic hepatitis B (CHB) and cirrhosis often have impaired fasting glucose (IFG). This study sought to investigate the impact of liver fibrosis on islet function in individuals diagnosed with CHB and IFG. Material and Methods Patients with chronic hepatitis B (CHB) and impaired fasting glucose (IFG) were selected for this study. They were divided into low-risk (L-R), intermediate-risk (M-R), and high-risk (H-R) liver fibrosis groups based on the FIB-4 score. The study compared islet function among different risk groups of liver fibrosis and analyze the correlation between liver fibrosis and islet function. Additionally, the patients were divided into a diabetes mellitus (DM) group and a non-DM (NDM) group based on the development of DM. The cumulative risk of progression to DM in patients with L-R, M-R, and H-R liver fibrosis was analyzed using the Kaplan-Meier method. Hazard ratios (HRs) and confidence intervals (CIs) were calculated for DM development through Cox regression analysis. Results In this study of 228 individuals, higher FIB-4 scores were observed in the DM group compared to the NDM group. Patients with H-R liver fibrosis displayed lower islet function and had a significantly higher risk of developing DM. The FIB-4 score and fasting plasma glucose (FPG) were identified as independent risk factors for DM progression in CHB patients with IFG. Conclusion Among patients with CHB and IFG, the severity of liver fibrosis is associated with islet function, and the FIB-4 score is a significant risk factor for DM development.
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Affiliation(s)
- Yan Lu
- Department of Clinical Medicine, Qingdao University, Qingdao City, Shandong Province, People’s Republic of China
| | - Wei Gou
- Department of Clinical Medicine, Qingdao University, Qingdao City, Shandong Province, People’s Republic of China
- Department of Metabolic Liver Disease, Qingdao Sixth People’s Hospital, Qingdao City, Shandong Province, People’s Republic of China
| | - Hai Feng Zhang
- Medical Department, Qingdao Sixth People’s Hospital, Qingdao City, Shandong Province, People’s Republic of China
| | - Yi Ying Li
- Medical Department, Qingdao Sixth People’s Hospital, Qingdao City, Shandong Province, People’s Republic of China
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Imamura Y, Kumagi T, Kuroda T, Koizumi M, Yoshida O, Kanemitsu K, Tada F, Tanaka Y, Hirooka M, Hiasa Y. Pancreas stiffness in liver cirrhosis is an indicator of insulin secretion caused by portal hypertension and pancreatic congestion. Hepatol Res 2021; 51:775-785. [PMID: 34018285 DOI: 10.1111/hepr.13672] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 05/03/2021] [Accepted: 05/10/2021] [Indexed: 12/21/2022]
Abstract
AIM Portal hypertension induces pancreatic congestion and impaired insulin secretion in patients with liver cirrhosis (LC). However, its mechanism is unclear, with no established noninvasive imaging method for the evaluation of its pathogeneses. The present study focused on pancreas stiffness, as assessed by shear wave elastography (SWE), and examined its association with portal hypertension and insulin secretion. METHODS Shear wave elastography and contrast-enhanced ultrasonography were utilized to evaluate pancreas stiffness and congestion, respectively. A glucagon challenge test was used for insulin secretion assessment. Furthermore, rat models of carbon tetrachloride (CCl4 )-induced LC and portal hypertension were used to identify the direct effects of pancreatic congestion. Immunohistochemistry staining of the pancreas was carried out on human autopsy samples. RESULTS Pancreas stiffness measured by SWE was higher in patients with LC than in controls and showed significant correlation with pancreatic congestion. The glucagon challenge test indicated a lower value for the change in C-peptide immunoreactivity in the LC group, which was inversely correlated with pancreas stiffness and congestion. Additionally, portal hypertension and insulin secretion dysfunction were confirmed in CCl4 rat models. Autopsy of human samples revealed congestive and fibrotic changes in the pancreas and the relationship between insulin secretion and their factors in patients with LC. CONCLUSIONS In patients with LC, pancreas stiffness measured by SWE could be a potential noninvasive test for evaluating pancreatic congestion and fibrosis due to portal hypertension. Moreover, it was associated with impaired insulin secretion, and could aid in guiding the treatment for hepatogenous diabetes.
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Affiliation(s)
- Yoshiki Imamura
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Teru Kumagi
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan.,Postgraduate Medical Education Center, Ehime University Hospital, Ehime, Japan
| | - Taira Kuroda
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Mitsuhito Koizumi
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Osamu Yoshida
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Kozue Kanemitsu
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Fujimasa Tada
- Department of Internal Medicine, Saiseikai Matsuyama Hospital, Ehime, Japan
| | - Yoshinori Tanaka
- Department of Gastroenterology, Matsuyama Shimin Hospital, Ehime, Japan
| | - Masashi Hirooka
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan
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The extracellular volume fraction of the pancreas measured by dual-energy computed tomography: The association with impaired glucose tolerance. Eur J Radiol 2021; 141:109775. [PMID: 34020172 DOI: 10.1016/j.ejrad.2021.109775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 04/29/2021] [Accepted: 05/07/2021] [Indexed: 11/21/2022]
Abstract
PURPOSE To investigate the clinical value of measuring the ECV fraction of the pancreas by DECT in association with an impaired glucose tolerance (IGT) estimated by the hemoglobin A1C (HbA1C) value in patients with or without cirrhosis. MATERIALS AND METHODS This retrospective study included patients who underwent contrast-enhanced dynamic CT with dual-energy mode between March 2018 and February 2019. The ECV fraction of the pancreas was calculated from iodine map images created from equilibrium-phase contrast-enhanced DECT images. The cross-sectional areas of the pancreas were also measured. RESULTS In total, 51 patients were analyzed (median age, 69 years old; 22 women). The ECV fraction of the pancreas showed a significant negative correlation with the HbA1c value in the cirrhotic group (ρ=-0.346, p = 0.048), while there was no significant correlation in the non-cirrhotic group (ρ=-0.086, p = 0.734). In the elevated HbA1C group, the ECV fraction of the pancreas in the cirrhotic patients (median, 0.247; interquartile range [IQR], 0.098) was significantly lower than that in the non-cirrhotic patients (0.332, IQR 0.113) (p = 0.024). In the elevated HbA1C group, the cross-sectional area of the pancreas was significantly larger in the cirrhotic patients than that in the non-cirrhotic patients (median [IQR]; 2945 [904] vs. 1885 [909] mm2, p = 0.019). CONCLUSION A reduction in the ECV fraction of the pancreas measured by DECT as well as the enlargement of the pancreatic parenchyma was observed in cirrhotic patients with IGT. These findings suggest that the measurement of the pancreatic ECV fraction by DECT may help clarify the pathophysiology of IGT in patients with cirrhosis.
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Orsi E, Grancini V, Menini S, Aghemo A, Pugliese G. Hepatogenous diabetes: Is it time to separate it from type 2 diabetes? Liver Int 2017; 37:950-962. [PMID: 27943508 DOI: 10.1111/liv.13337] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2016] [Accepted: 11/29/2016] [Indexed: 12/12/2022]
Abstract
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 A1c 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.
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Affiliation(s)
- Emanuela Orsi
- Diabetes Service, Endocrinology and Metabolic Diseases Unit, IRCCS "Cà Granda-Ospedale Maggiore Policlinico" Foundation, University of Milan, Milan, Italy.,Department of Medical Sciences, University of Milan, Milan, Italy
| | - Valeria Grancini
- Diabetes Service, Endocrinology and Metabolic Diseases Unit, IRCCS "Cà Granda-Ospedale Maggiore Policlinico" Foundation, University of Milan, Milan, Italy.,Department of Medical Sciences, University of Milan, Milan, Italy
| | - Stefano Menini
- Department of Clinical and Molecular Medicine, "La Sapienza" University, Rome, Italy.,Diabetes Unit, Sant'Andrea Hospital, Rome, Italy
| | - Alessio Aghemo
- Division of Gastroenterology and Hepatology, A.M. and A. Migliavacca Center for Liver Disease, IRCCS "Cà Granda-Ospedale Maggiore Policlinico" Foundation, University of Milan, Milan, Italy
| | - Giuseppe Pugliese
- Department of Clinical and Molecular Medicine, "La Sapienza" University, Rome, Italy.,Diabetes Unit, Sant'Andrea Hospital, Rome, Italy
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Plasma Glucose Level Is Predictive of Serum Ammonia Level After Retrograde Occlusion of Portosystemic Shunts. AJR Am J Roentgenol 2017; 209:W169-W176. [PMID: 28657848 DOI: 10.2214/ajr.16.17307] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
OBJECTIVE The purpose of this study was to evaluate predictors of reduction in ammonia levels by occlusion of portosystemic shunts (PSS) in patients with cirrhosis. MATERIALS AND METHODS Forty-eight patients with cirrhosis (21 women, 27 men; mean age, 67.8 years) with PSS underwent balloon-occluded retrograde transvenous obliteration (BRTO) at one institution between February 2008 and June 2014. The causes of cirrhosis were hepatitis B in one case, hepatitis C in 20 cases, alcohol in 15 cases, nonalcoholic steatohepatitis in eight cases, and other conditions in four cases. The Child-Pugh classes were A in 24 cases, B in 23 cases, and C in one case. The indication for BRTO was gastric varices in 40 cases and hepatic encephalopathy in eight cases. Testing was conducted before and 1 month after the procedure. Statistical analyses were performed to identify predictors of a clinically significant decline in ammonia levels after BRTO. RESULTS Occlusion of PSS resulted in a clinically significant decrease in ammonia levels accompanied by increased portal venous flow and improved Child-Pugh score. Univariate analyses showed that a reduction in ammonia levels due to BRTO was significantly related to lower plasma glucose levels, higher RBC counts, and higher hemoglobin concentration before the treatment. Furthermore, multivariate logistic regression identified preoperative plasma glucose level as the strongest independent predictor of a significant ammonia reduction in response to BRTO. In addition, although BRTO resulted in significantly declined ammonia levels in patients with normal glucose tolerance before the procedure, ammonia levels were not significantly decreased after shunt occlusion in patients with diabetes mellitus or impaired glucose tolerance before BRTO, according to 75-g oral glucose tolerance test results. CONCLUSION Preoperative plasma glucose level is a useful predictor of clinically significant ammonia reduction resulting from occlusion of PSS in patients with cirrhosis. Even if PSS are present, control of blood ammonia levels by BRTO alone may be difficult in patients with glucose intolerance.
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Kuroda T, Hirooka M, Koizumi M, Ochi H, Hisano Y, Bando K, Matsuura B, Kumagi T, Hiasa Y. Pancreatic congestion in liver cirrhosis correlates with impaired insulin secretion. J Gastroenterol 2015; 50:683-93. [PMID: 25283134 DOI: 10.1007/s00535-014-1001-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Accepted: 09/24/2014] [Indexed: 02/04/2023]
Abstract
BACKGROUND Although impaired glucose tolerance is common in cirrhosis, this condition's pathogenesis remains undefined. This study aimed to clarify pathogenesis related to the pancreas in cirrhotic patients, and to evaluate associations between insulin secretion and pancreatic congestion due to portal hypertension. METHODS Pancreatic perfusion parameters were analyzed by dynamic contrast-enhanced ultrasound (CE-US) in 41 patients (20 cirrhotic, 21 non-cirrhotic; age, 67.9 ± 13.3; female, 19), and prospectively compared to delta C-peptide immunoreactivity (ΔCPR). In a separate study, a retrospective chart review with human autopsy specimens was conducted, and vessels and islets of the pancreas were analyzed in 43 patients (20 cirrhotic, 23 controls; age, 71.5 ± 11.6; female, 15). RESULTS In the CE-US study, the clinical characteristics indicative of portal hypertension (e.g., ascites and varices) had significantly higher incidences in the cirrhotic group than in the control group. Pancreatic drainage times were greater in the cirrhotic group (p < 0.0001), and had a significant negative correlation with ΔCPR (R = 0.42, p = 0.0069). In the histopathological study, the islets were enlarged in the cirrhotic group (p < 0.0001). However, the percentage of insulin-positive area per islet was decreased in the cirrhotic group (p < 0.0001), and had a significant negative correlation with the wall thickness of the pancreatic vein (R = 0.63, p < 0.0001). CONCLUSIONS Pancreatic congestion was present in cirrhotic patients. Moreover, pancreatic congestion and insulin secretion were significantly correlated. This pathogenesis could be a key factor underlying the development of hepatogenous diabetes in cirrhotic patients.
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Affiliation(s)
- Taira Kuroda
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
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Occlusion of portosystemic shunts improves hyperinsulinemia due to insulin resistance in cirrhotic patients with portal hypertension. J Gastroenterol 2014; 49:1333-41. [PMID: 24096983 DOI: 10.1007/s00535-013-0893-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Accepted: 09/25/2013] [Indexed: 02/04/2023]
Abstract
BACKGROUND Liver cirrhosis (LC) is often complicated by hyperinsulinemia due to insulin resistance (IR), which is considered to be closely related to shunt formation and impaired liver function. This study evaluates whether balloon-occluded retrograde transvenous obliteration (B-RTO) can affect glucose and insulin metabolism in patients with LC. METHODS Twenty-five cirrhotic patients (mean age = 69.6 years; female/male = 12/13; hepatitis C virus/alcohol/nonalcoholic steatohepatitis = 14/6/5; Child-Pugh's class A/B = 10/15) with gastric varices and/or hepatic encephalopathy caused by portosystemic shunts (PSS) due to portal hypertension (PH) underwent B-RTO at our hospital. Testing was performed before and at 1 month after the procedure. RESULTS Shunt occlusion resulted in a decrease in extrahepatic collateral blood flow and an increase in portal venous flow, as well as a dramatic improvement in hepatic function markers. In addition, B-RTO significantly decreased homeostasis model assessment (HOMA) of IR without a statistical decline of HOMA of β-cell function. The 75-g oral glucose tolerance test (75-OGTT) revealed that occlusion of PSS reduced both fasting immunoreactive insulin (IRI) levels and the area under the curve for IRI. However, no significant change in preprandial or postprandial plasma glucose levels was observed. Furthermore, according to the criteria of the American Diabetes Association, B-RTO led to an improved 75-OGTT profile in 58.3 % of patients who had impaired glucose tolerance or diabetes mellitus before the procedure. CONCLUSIONS Shunt occlusion improves IR-related hyperinsulinemia through increased portal venous flow, ameliorated liver function, and consequent augmented hepatic insulin clearance in cirrhotic patients with PH.
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Kuriyama S, Miwa Y, Fukushima H, Nakamura H, Toda K, Shiraki M, Nagaki M, Yamamoto M, Tomita E, Moriwaki H. Prevalence of diabetes and incidence of angiopathy in patients with chronic viral liver disease. J Clin Biochem Nutr 2011; 40:116-22. [PMID: 18188413 PMCID: PMC2127229 DOI: 10.3164/jcbn.40.116] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2006] [Accepted: 09/26/2006] [Indexed: 12/26/2022] Open
Abstract
Patients with chronic liver disease (CLD) often develops glucose intolerance. We explored the prevalence of diabetes mellitus in viral CLD, and analyzed factors profoundly affecting the diabetic angiopathies. 229 CLD patients (124 chronic hepatitis and 105 liver cirrhosis) entered the study. The diagnosis of diabetes was made with the criteria by World Health Organization. Laboratory investigation included serum asparate aminotransferase, alanine aminotransferase, albumin, fasting blood sugar, hemoglobin A1c (HbA1c), fasting immunoreactive insulin, and HOMA-R (FBS*IRI/405). The incidence of macro- and microangiopathy were also examined. Forty (17.5%) CLD patients were diagnosed diabetes, giving a significantly higher incidence than that of general cohort (5.3%) (p<0.001). Among them, 12 (30%) had the triopathy, significantly lower than that in a matched group of diabetic patients without CLD (65%) (p<0.001). Significantly increased levels of HbA1c and HOMA-R were observed in diabetic CLD with angiopathy compared with diabetic CLD without. Incidence of diabetes was increased in viral CLD patients. The rate of diabetic angiopathies in CLD, however, was relatively low, this could be explained by low coagulability in these patients. Poor control of hyperglycemia, partly due to insulin resistance, might explain the onset of angiopathy in diabetic CLD.
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Affiliation(s)
- Shoko Kuriyama
- Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
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Holecek M. Three targets of branched-chain amino acid supplementation in the treatment of liver disease. Nutrition 2010; 26:482-90. [PMID: 20071143 DOI: 10.1016/j.nut.2009.06.027] [Citation(s) in RCA: 122] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2009] [Revised: 06/08/2009] [Accepted: 06/24/2009] [Indexed: 12/18/2022]
Abstract
The article explains the pathogenesis of disturbances in branched-chain amino acid (BCAA; valine, leucine, and isoleucine) and protein metabolism in various forms of hepatic injury and it is suggested that the main cause of decrease in plasma BCAA concentration in liver cirrhosis is hyperammonemia. Three possible targets of BCAA supplementation in hepatic disease are suggested: (1) hepatic encephalopathy, (2) liver regeneration, and (3) hepatic cachexia. The BCAA may ameliorate hepatic encephalopathy by promoting ammonia detoxification, correction of the plasma amino acid imbalance, and by reduced brain influx of aromatic amino acids. The influence of BCAA supplementation on hepatic encephalopathy could be more effective in chronic hepatic injury with hyperammonemia and low concentrations of BCAA in blood than in acute hepatic illness, where hyperaminoacidemia frequently develops. The favorable effect of BCAA on liver regeneration and nutritional state of the body is related to their stimulatory effect on protein synthesis, secretion of hepatocyte growth factor, glutamine production and inhibitory effect on proteolysis. Presumably the beneficial effect of BCAA on hepatic cachexia is significant in compensated liver disease with decreased plasma BCAA concentrations, whereas it is less pronounced in hepatic diseases with inflammatory complications and enhanced protein turnover. It is concluded that specific benefits associated with BCAA supplementation depend significantly on the type of liver disease and on the presence of inflammatory reaction. An important task for clinical research is to identify groups of patients for whom BCAA treatment can significantly improve the health-related quality of life and the prognosis of hepatic disease.
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Affiliation(s)
- Milan Holecek
- Department of Physiology, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Czech Republic.
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10
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Park SK, Cho YK, Park JH, Kim HJ, Park DI, Sohn CI, Jeon WK, Kim BI. Change of insulin sensitivity in hepatitis C patients with normal insulin sensitivity: a 5-year prospective follow-up study variation of insulin sensitivity in HCV patients. Intern Med J 2009; 40:503-11. [PMID: 19712201 DOI: 10.1111/j.1445-5994.2009.02042.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Hepatitis C virus (HCV) infection is associated with a high prevalence of diabetes mellitus (DM). Insulin resistance (IR) is known to play a crucial role in the development of DM in chronic hepatitis C (CHC) patients. We prospectively investigated changes of insulin sensitivity in CHC patients during a 5-year period and analysed the factors significantly associated with IR. METHODS Sixty-two CHC patients with normal insulin sensitivity (CHC group), and a healthy control group of 172 subjects matched by age, gender, body mass index and lifestyles were studied. We compared the initial baseline insulin sensitivity, metabolic parameters and incidence of IR at the end of the follow-up period between the two groups. The changes in insulin sensitivity, metabolic parameters and the development of IR were analysed as well as factors associated with the development of IR. RESULTS IR developed in 22.5% of 62 CHC patients and 5.2% of 172 normal individuals (P < 0.001). HCV infection per se and the genotype 1 were independent risk factors for the development of IR. The duration of infection > or = 120 months, initial fasting glucose 90-100 mg/dL, fasting insulin > or = 10 microIU/mL and the homeostasis model assessment (HOMA-IR) 2.3-2.7 were significantly associated with the development of IR in the CHC group. CONCLUSION HCV infection was an independent risk factor for the development of IR. All CHC patients, even those with normal insulin sensitivity, require careful monitoring for the development of IR.
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Affiliation(s)
- S K Park
- Division of Gastroenterology and hepatology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
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Zhang W, Fan Y, Zhu LQ, Cheng ZM. Relationship between abnormal glycometabolism and ultra-sensitive C-reactive protein in non-alcoholic fatty liver. Shijie Huaren Xiaohua Zazhi 2008; 16:319-321. [DOI: 10.11569/wcjd.v16.i3.319] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the relationship between abnormal glycometabolism and ultra-sensitive C-reactive protein (hsCRP) in non-alcoholic fatty liver (NAFLD).
METHODS: One hundred and ninety-one NAFLD patients were divided into normal glucose metabolism group and abnormal glucose metabolism group according to the oral glucose tolerance test (OGTT). Their serum hsCRP levels were measured.
RESULTS: The serum hsCRP levels in the abnormal glucose metabolism group were higher than those in the normal glucose metabolism group(4.01 ± 1.45 vs 0.96 ± 0.41, P < 0.01), which were positively correlated with the glucose tolerance (r = 0.74, P < 0.01).
CONCLUSION: Serum hsCRP levels are related with abnormal glycometabolism in NAFLD patients.
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Affiliation(s)
- Robert E Shangraw
- Department of Anesthesiology, School of Medicine, Oregon Health and Science University, Portland, OR 97201, USA
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Abstract
1. Diabetes mellitus is common in patients with cirrhosis; patients with DM undergoing liver transplantation often have many other co-morbid illnesses including obesity, coronary artery disease (CAD), autonomic neuropathy, gastroparesis, and nephropathy. 2. Long-term survival of patients with diabetes mellitus (DM) is significantly lower and morbidity higher when compared to non-diabetics mainly because of cardiovascular complications, infections, and renal failure. 3. Obesity, CAD, and renal failure are confounding factors that result in poor patient survival. 4. Patients with DM should undergo careful cardiovascular diagnostic work up, including routine coronary arteriogram, and necessary interventions before liver transplantation. This is especially important in those over 50 years old, and in those with retinopathy, nephropathy, and neuropathy. 5. Patients with coronary artery disease that is not amenable to surgery or stents, and those with impaired left ventricular function, should not be considered for liver transplantation. Other relative or absolute contraindications are those with proteinura and renal failure who are not candidates for combined liver/kidney transplantation, those with severe gastroparesis, especially when it is associated with diabetic autonomic neuropathy, and those with two or more risk factors such as CAD, morbid obesity, and renal failure. 6. Future studies should focus on risk stratification of patients with DM undergoing liver transplantation and better interventions to reduce the risk of diabetic complications before and after liver transplantation.
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Affiliation(s)
- Paul J Thuluvath
- Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
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Alavian SM, Hajarizadeh B, Nematizadeh F, Larijani B. Prevalence and determinants of diabetes mellitus among Iranian patients with chronic liver disease. BMC Endocr Disord 2004; 4:4. [PMID: 15555059 PMCID: PMC538272 DOI: 10.1186/1472-6823-4-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2004] [Accepted: 11/19/2004] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND: Alterations in carbohydrate metabolism are frequently observed in cirrhosis. We conducted this study to define the prevalence of diabetes mellitus (DM) and impaired glucose tolerance (IGT) in Iranian patients with chronic liver disease (CLD), and explore the factors associated with DM in these patients. METHODS: One hundred and eighty-five patients with CLD were enrolled into the study. Fasting plasma glucose and two-hour plasma glucose were measured in patients' sera. DM and IGT were diagnosed according to the latest American Diabetes Association criteria. RESULTS: The subjects included 42 inactive HBV carriers with a mean age of 42.2 +/- 12.0 years, 102 patients with HBV or HCV chronic hepatitis with a mean age of 41.2 +/- 10.9 years, and 41 cirrhotic patients with a mean age of 52.1 +/- 11.4 years. DM and IGT were diagnosed in 40 (21.6%) and 21 (11.4%) patients, respectively. Univariate analysis showed that age (P = 0.000), CLD status (P = 0.000), history of hypertension (P = 0.007), family history of DM (P = 0.000), and body mass index (BMI) (P = 0.009) were associated with DM. Using Multivariate analysis, age (OR = 4.7, 95%CI: 1.8-12.2), family history of DM (OR = 6.6, 95%CI: 2.6-17.6), chronic hepatitis (OR = 11.6, 95%CI: 2.9-45.4), and cirrhosis (OR = 6.5, 95%CI: 2.4-17.4) remained as the factors independently associated with DM. When patients with cirrhosis and chronic hepatitis were analyzed separately, higher Child-Pugh's score in cirrhotic patients (OR = 9.6, 95%CI: 1.0-88.4) and older age (OR = 7.2, 95%CI: 1.0-49.1), higher fibrosis score (OR = 59.5, 95%CI: 2.9-1211.3/ OR = 11.9, 95%CI: 1.0-132.2), and higher BMI (OR = 30.3, 95%CI: 3.0-306.7) in patients with chronic hepatitis were found to be associated with higher prevalence of DM. CONCLUSIONS: Our findings indicate that patients with cirrhosis and chronic hepatitis are at the increased risk of DM occurrence. Older age, severe liver disease, and obesity were associated with DM in these patients.
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Affiliation(s)
- Seyed M Alavian
- Department of Internal Medicine, Baghiatollah University of Medical Sciences, Tehran, Iran
- Tehran Hepatitis Center, Tehran, Iran
| | | | - Fariborz Nematizadeh
- Department of Internal Medicine, Baghiatollah University of Medical Sciences, Tehran, Iran
- Tehran Hepatitis Center, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center (EMRC), Tehran University of Medical Sciences, Tehran, Iran
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Carbon tetrachloride-induced cirrhosis in rats: Influence of the acute effects of the toxin on glucose metabolism. Hepatology 2003. [DOI: 10.1002/hep.510230325] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/28/2023]
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Nakaya Y, Harada N, Niwa Y, Takahashi A. Time course of change in respiratory quotient during prolonged starvation in carbon tetrachloride-induced cirrhotic rats. Nutr Res 2002. [DOI: 10.1016/s0271-5317(02)00377-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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18
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AlDosary AA, Ramji AS, Elliott TG, Sirrs SM, Thompson DM, Erb SR, Steinbrecher UP, Yoshida EM. Post-liver transplantation diabetes mellitus: an association with hepatitis C. Liver Transpl 2002; 8:356-61. [PMID: 11965580 DOI: 10.1053/jlts.2002.31745] [Citation(s) in RCA: 72] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
A retrospective study was performed on all liver transplant recipients from British Columbia from 1989 to March 2000 to determine the prevalence and predictive factors of diabetes mellitus (DM) post-liver transplantation. DM was defined as hyperglycemia requiring treatment with insulin or oral hypoglycemic agents. Patient characteristics, cause of liver disease at transplantation, and immunosuppression regimen were considered. Both univariate and multiple logistic regression analyses were performed. Posttransplantation DM (PTDM) occurred in 43 of 177 transplant recipients (24%). Of these, 13 transplant recipients had DM pretransplantation, whereas 30 patients developed de novo PTDM. The majority of patients were treated with insulin (80%). In univariate analysis, transplantation for hepatitis C virus (HCV) liver disease was associated with a greater incidence of PTDM (odds ratio [OR], 3.01; 95% confidence interval [CI], 1.46 to 6.23) and de novo PTDM (OR, 5.20; 95% CI, 2.25 to 11.99). Patients administered tacrolimus had a greater incidence of PTDM (OR, 2.04; 95% CI, 1.01 to 4.13), and there was a trend toward increased PTDM in older patients (mean age, 49 years). Recipient sex, steroid dosage, and acute rejection were not predictive of PTDM. The incidence of graft loss and death rates were similar between the two groups. On logistic regression, HCV was the only independent predictor of PTDM (OR, 4.12; 95% CI, 1.91 to 8.90) and de novo PTDM (OR, 6.02; 95% CI, 2.55 to 14.20). In conclusion, DM post-liver transplantation is a common occurrence and is associated with HCV.
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Affiliation(s)
- Ahmad A AlDosary
- Division of Endocrinology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
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19
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Rabe C, Pilz T, Klostermann C, Berna M, Schild HH, Sauerbruch T, Caselmann WH. Clinical characteristics and outcome of a cohort of 101 patients with hepatocellular carcinoma. World J Gastroenterol 2001; 7:208-15. [PMID: 11819762 PMCID: PMC4723524 DOI: 10.3748/wjg.v7.i2.208] [Citation(s) in RCA: 83] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To conduct a cohort study of 101 patients with hepatocellular carcinoma (HCC) presenting to a tertiary care medical referral center in Germany between 1997 and 1999.
METHODS AND RESULTS: Data were retrospectively analyzed by chart review. In 95 cases (72 males and 23 females) sufficient data were available for analysis. Twenty five (29%) of 85 patients were HBsAg or anti HBc positive, 21/85 (25%) were anti HCV positive, and 6/ 85 (7%) were positive for both HBV and HCV-markers. Age was significantly lower in HBV positive patients than in the other two groups. Thirty one (34%) of 90 patients had histories of alcohol abuse. In 79/94 (84%) patients, cirrhosis was diagnosed. Of these cirrhotic patients, 29/79 (37%) belonged to Child Pugh’s group (CHILD) A, 32/79 (40%) to CHILD B, and 18/79 (23%) to CHILD C. AFP was elevated in 61/91 (67%) patients. A single tumor nodule was found in 38/94 (40%), more than one nodule in 31/94 (34%), and 25/94 (26%) had a diffusely infiltrating tumor, i.e. the tumor margins could not be seen on imaging procedures. Portal vein thrombosis was present in 19/94 (20%). Imaging data consistent with lymph node metastases were found in 10/92 (11%), while distant metastases were found in 8/93 (9%). According to Okuda 28/94 (30%) were grouped to stage I, 53/94 (56%) were grouped to stage II, and 13/94 (14%) were grouped to stage III. Survival data were available for 83 patients. The Kaplan-Meier estimate for median survival was 84 months. Factors influencing survival were the Okuda score, the presence of portal vein thrombosis, and the presence of ascites. The presence of non complicated liver cirrhosis by itself, distant metastases, or infection with hepatitis viruses did not influence survival. AFP positivity by itself did not influence survival, though patients with an AFP value greater than 100 μg/L did experience shortened survival. Treatment besides tamoxifen or supportive care was associated with prolonged survival. The influence of therapy on survival was most pronounced in Okuda stage II patients. There was longer survival in those Okuda stage II patients who were treated with percutaneous ethanol injection.
CONCLUSION: Even in a low incidence area such as Germany, the majority of HCC is caused by viral hepatitis and therefore potentially preventable. Reflecting the high proportion of advanced stage tumors in our patients, the median survival was poor. Patients who received active therapy had a longer survival.
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Affiliation(s)
- C Rabe
- Sigmund Freud Str. 25, D 53105 Bonn,Germany
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20
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Blanco JJ, Herrero JI, Quiroga J, Sangro B, Gómez-Manero N, Pardo F, Cienfuegos JA, Prieto J. Liver transplantation in cirrhotic patients with diabetes mellitus: midterm results, survival, and adverse events. Liver Transpl 2001; 7:226-33. [PMID: 11244164 DOI: 10.1053/jlts.2001.22183] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Liver cirrhosis is frequently associated with diabetes mellitus (DM), and this metabolic complication is also frequent after orthotopic liver transplantation (OLT). The aim of our study is to investigate which factors are associated with DM before and after OLT and their impact on post-OLT evolution. We evaluated the prevalence of DM among 115 liver transplant candidates with cirrhosis and assessed their evolution after OLT (median follow-up, 41 months). Sixteen candidates had DM requiring pharmacological therapy (group A), 45 candidates had DM controlled with diet (group B), and 54 candidates did not have DM (group C). One-year and 3-year actuarial survival rates were 100% and 100% for group A, 91% and 85% for group B, and 77% and 74% for group C, respectively (P <.03). Post-OLT DM was more frequent in group A. The incidence of other metabolic complications, major infections, rejection, and arterial hypertension; the need for hospitalization; and renal and graft function of patients in groups A, B, and C were similar. The only risk factor for DM 1 year after OLT on multivariate analysis was pre-OLT DM requiring pharmacological treatment. The incidence of complications, need for hospitalization, and renal and graft function 1 year after OLT for patients with post-OLT DM were similar to those of patients without post-OLT DM. In conclusion, patients with cirrhosis who have DM have a greater risk for post-OLT DM, but their midterm survival is not worse than the survival of those without DM.
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Affiliation(s)
- J J Blanco
- Liver Unit, Clínica Universitaria, Av Pio XII SIN, 31008 Pamplona, Spain
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21
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Garrido Serrano A, Guerrero Igea FJ, Lepe Jiménez JA, Palomo Gil S, Grilo Reina A. [Hyperinsulinemia in cirrhotic patients infected with hepatitis C virus]. GASTROENTEROLOGIA Y HEPATOLOGIA 2001; 24:127-31. [PMID: 11261223 DOI: 10.1016/s0210-5705(01)70138-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
AIMS a) To prospectively study the frequency of diabetes mellitus in cirrhotic patients with hepatitis C virus (HCV) infection, comparing it with that in cirrhotic patients without HCV infection and b) to investigate basal insulinemia values in both groups, as well as the possible factors causing insulinemia. MATERIAL AND METHODS Fifty patients with cirrhosis due to HCV infection (group I) and 50 patients with cirrhosis due to other etiologic agents (group II) were studied. In both groups the percentage of diabetic patients, basal insulinemia values and the factors associated with insulin resistance were compared: age, anthropometric indexes, stage of cirrhosis according to Child-Pugh score, plasmatic ferritin concentrations and treatment with drugs inducing insulin resistance. RESULTS The percentage of diabetics in group I was 36% (18/50) compared with 18% (9/50) in group II (p < 0.05) and basal insulinemia values were 23.5 +/- 9.7 microU/ml compared with 15.7 +/- 9.9 microU/ml respectively (p < 0.05). No differences between the groups were found in the following variables: age (58.7 +/- 16.2 vs. 60.6 +/- 10.0 years), weight (73.2 +/- 10.7 vs 73.9 +/- 11.2 Kg), height (161.9 +/- 8.8 vs. 161.1 +/- 6.8 cm), body mass index (28.2 +/- 3.1 vs. 28.5 +/- 5.2 Kg/height m2) or Child-Pugh stage (A: 40 vs 34, B: 7 vs. 10, C: 3 vs. 6, NS). In contrast, serum ferritin concentrations were much higher in patients in group I than in those in group II [137.7 (12.4-410.2) vs. 87.6 (2.4-420.0) ng/ml p < 0.05]. At the time of inclusion in this study 10 patients in group I were receiving diuretics or non-selective beta adrenergic blockers compared with 24 patients in group II (p < 0.05). CONCLUSIONS Diabetes mellitus is more prevalent in patients with cirrhosis due to HVC than in those with cirrhosis due to other etiologic agents. Moreover, basal insulinemia values are higher in these patients, which could be explained by an increase in half insulin resistance associated with an increase in iron deposits.
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22
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Abstract
In the last year some relevant papers on nutrition and metabolism in chronic liver disease and transplantation have been published. Studies investigating the reliability of predicting energy expenditure in cirrhosis, and some relevant contributions to the understanding of metabolic consequences of liver transplantation, deserve particular mention. These include the first direct evidence that liver transplantation corrects the insulin resistance present in cirrhosis, as well as studies on the role of genetic polymorphism of the vitamin D receptor gene in bone loss after transplantation. Other papers have dealt with body composition, polyunsaturated fatty acid and antioxidant status in cirrhosis. However, relevant contributions in the field of nutritional support in cirrhosis are surprisingly lacking.
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Affiliation(s)
- E Cabré
- Department of Gastroenterology, Hospital Universitari Germans Trias i Pujol, Badalona, Catalonia, Spain
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23
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Konrad T, Steinmüller T, Vicini P, Toffolo G, Grewerus D, Schüller A, Bechstein WO, Usadel KH, Cobelli C, Mahon A, Wittmann W, Klar E, Golling M, Neuhaus P. Evidence for impaired glucose effectiveness in cirrhotic patients after liver transplantation. Metabolism 2000; 49:367-72. [PMID: 10726916 DOI: 10.1016/s0026-0495(00)90308-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
To evaluate the impact of acute and chronic liver disease and single immunosuppression (cyclosporine A [CSA] or FK506) on insulin sensitivity and glucose effectiveness in liver-grafted patients, we performed a frequently sampled intravenous glucose tolerance test (FSIGTT) in nondiabetic patients after orthotopic liver transplantation (OLT) with acute liver failure ([ALF] group, n = 9, with CSA therapy), in patients after OLT with chronic liver disease (CSA group, n = 8; FK506 group, n = 8), and in 9 healthy control subjects. Insulin sensitivity and glucose effectiveness were determined by analyzing glucose and insulin data from the FSIGTT with Bergman's minimal model technique for glucose. The intravenous glucose tolerance index ([KG] ie, the slope of the regression of the logarithm of blood glucose concentration) was not different between the ALF group (2.17 +/- 0.16 min(-1)) and controls (2.29 +/- 0.13 min(-1)), but was lower (P < .05) in both groups with chronic liver disease (CSA group, 1.46 +/- 0.1; FK506 group, 1.61 +/- 0.11 min(-1)) compared with the ALF group (P < .05). A positive relation for the KG and glucose effectiveness was found in all liver-grafted patients and controls. Insulin sensitivity was not different between all liver-grafted patients and controls. The body mass index (BMI) was the overall determinant of insulin sensitivity in all groups. Single immunosuppressive therapy does not impair insulin sensitivity in liver-grafted patients. The lower glucose effectiveness in liver-grafted patients with chronic liver disease but not in patients after ALF points to a defect in the regulation of glucose-mediated glucose uptake in peripheral tissue.
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Affiliation(s)
- T Konrad
- Department of Internal Medicine I, Johann Wolfgang Goethe-University, Frankfurt, Germany
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24
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Perseghin G, Mazzaferro V, Sereni LP, Regalia E, Benedini S, Bazzigaluppi E, Pulvirenti A, Leão AA, Calori G, Romito R, Baratti D, Luzi L. Contribution of reduced insulin sensitivity and secretion to the pathogenesis of hepatogenous diabetes: effect of liver transplantation. Hepatology 2000; 31:694-703. [PMID: 10706560 DOI: 10.1002/hep.510310320] [Citation(s) in RCA: 96] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
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.
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Affiliation(s)
- G Perseghin
- Department of Intermal Medicine I, Istituto Scientifico H San Raffaele, National Cancer Institute, Milan, Italy.
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25
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Schneiter P, Gillet M, Chioléro R, Jéquier E, Tappy L. Hepatic nonoxidative disposal of an oral glucose meal in patients with liver cirrhosis. Metabolism 1999; 48:1260-6. [PMID: 10535388 DOI: 10.1016/s0026-0495(99)90265-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Seven patients with liver cirrhosis and five healthy subjects were studied over 4 hours after ingestion of a glucose meal to determine whether alterations of hepatic nonoxidative glucose disposal participate in the pathogenesis of impaired glucose tolerance. Hepatic uridyl-diphosphoglucose (UDPG) turnover was calculated from the isotopic enrichment of urinary acetaminophen glucuronide during continuous infusion of 13C-galactose and used as an index of hepatic glycogen synthesis. Patients with cirrhosis had postprandial hyperglycemia and decreased glucose clearance, but hepatic UDPG turnover was not altered (1.84 +/- 0.29 mg/kg fat-free mass min v 1.76 +/- 0.15 in controls, nonsignificant). It is concluded that hepatic postprandial glycogen synthesis is unaltered in patients with advanced cirrhosis, demonstrating important hepatic functional reserve.
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Affiliation(s)
- P Schneiter
- Institut de physiologie, Université de Lausanne, Switzerland
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26
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Abstract
In the past year, some relevant papers on the mechanisms of malnutrition in cirrhosis have been published. Studies investigating the metabolic destiny of leucine after protein breakdown, which have contributed to a better understanding of the pathogenesis of muscle wasting and fat depletion in these patients, deserve particular mention. Also, the demonstration that chronically reducing hyperinsulinaemia in cirrhosis is able to improve insulin sensitivity opens novel pathogenic and therapeutic perspectives for such a metabolic derangement in these patients. Other papers dealt with unsaturated lipids, lipoperoxidation and antioxidants in chronic liver disease. However, randomized trials on parenteral or enteral nutrition in cirrhosis and liver transplantation are missing.
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Affiliation(s)
- E Cabré
- Department of Gastroenterology, Hospital Universitari Germans Trias i Pujol, Badalona, Catalonia, Spain
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27
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Tabaru A, Shirohara H, Moriyama A, Otsuki M. Effects of branched-chain-enriched amino acid solution on insulin and glucagon secretion and blood glucose level in liver cirrhosis. Scand J Gastroenterol 1998; 33:853-9. [PMID: 9754734 DOI: 10.1080/00365529850171521] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND The aim of this study was to determine whether therapeutically used branched-chain amino acids (BCAAs) solution influences glucose metabolism in liver cirrhosis (LC). METHODS BCAAs solution (200 ml) was infused in LC patients at different stages, and plasma concentrations of glucose and pancreatic hormones were determined. RESULTS In patients with mild LC, BCAAs caused a significant increase in glucose level (maximal increment, 12.5+/-2.5 mg/dl) with a great increase in insulin (maximal increment, 39.5+/-8.3 microU/ml) and a small increase in glucagon secretion (maximal increment, 101.0+/-16.0 pg/ml). In patients with advanced LC, BCAAs caused a great increase in glucagon secretion (220.5+/-19.4 pg/ml) with only a slight increase in glucose levels (5.8+/-2.2 mg/dl). CONCLUSION BCAAs solution causes hyperglycemia in mild LC due to insulin resistance, whereas it causes only a slight increase in severe LC due to hepatic glucagon resistance. Thus, there is a possibility that BCAAs solution may lead to hypoglycemia in advanced LC with hepatic glycogen depletion.
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Affiliation(s)
- A Tabaru
- Third Dept. of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
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28
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Marchesini G, Bugianesi E, Ronchi M, Flamia R, Thomaseth K, Pacini G. Zinc supplementation improves glucose disposal in patients with cirrhosis. Metabolism 1998; 47:792-8. [PMID: 9667223 DOI: 10.1016/s0026-0495(98)90114-7] [Citation(s) in RCA: 46] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Zinc deficiency is common in cirrhosis, and was proved to affect nitrogen metabolism. In experimental animals, zinc status may also affect glucose disposal, and acute zinc supplementation improves glucose tolerance in healthy subjects. This study was aimed at measuring the effects of long-term oral zinc supplements on glucose tolerance in cirrhosis. The time courses of glucose, insulin, and C-peptide in response to an intravenous (i.v.) glucose load were analyzed by the minimal-model technique before and after long-term oral zinc supplements (200 mg three times per day for 60 days) in 10 subjects with advanced cirrhosis and impaired glucose tolerance or diabetes. The test was performed using a simplified procedure, based on 20 blood samples collected within 4 hours from the glucose load. Normal values were obtained in 25 age-matched healthy subjects. Zinc levels were low to normal or reduced before treatment, and were normalized by oral zinc. Glucose disappearance improved by greater than 30% in response to treatment. There were no changes in pancreatic insulin secretion and systemic delivery, or in the hepatic extraction of insulin. Insulin sensitivity (SI), which was reduced by 80% before treatment, did not change. Glucose effectiveness (SG) was nearly halved in cirrhosis before treatment (0.013 [SD 0.007] min(-1) v. 0.028 [SD 0.009] in controls; P < .001), and increased to 0.017 (SD 0.009) after zinc (P < .05 v. baseline). The return to normal of plasma zinc levels after long-term zinc treatment in advanced cirrhosis improves glucose tolerance via an increase of the effects of glucose per se on glucose metabolism. Poor zinc status may contribute to the impaired glucose tolerance and diabetes of cirrhosis.
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Affiliation(s)
- G Marchesini
- Dipartimento di Medicina Interna, Cardioangiologia, Epatologia, Università di Bologna, Italy
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29
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Petrides AS, Stanley T, Matthews DE, Vogt C, Bush AJ, Lambeth H. Insulin resistance in cirrhosis: prolonged reduction of hyperinsulinemia normalizes insulin sensitivity. Hepatology 1998; 28:141-9. [PMID: 9657106 DOI: 10.1002/hep.510280119] [Citation(s) in RCA: 71] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Insulin resistance is present in nearly all patients with cirrhosis, but its etiology remains unknown. Chronic hyperinsulinemia has been suspected as a potential candidate, and we therefore tested the hypothesis that, in cirrhosis, prolonged reduction of the hyperinsulinemia restores insulin sensitivity. Whole-body insulin sensitivity (euglycemic insulin-clamp technique), glucose turnover (6,6-2H2-glucose isotope dilution), glucose oxidation (indirect calorimetry), non-oxidative glucose disposal, and fractional glycogen synthase activity in muscle (biopsies) were measured in eight clinically stable patients with cirrhosis before and at the end of a 4-day continuous subcutaneous infusion of the somatostatin-analogue octreotide (200 microg/24 h) designed to continuously reduce plasma insulin levels. Baseline data were compared with results obtained in healthy individuals matched for sex, age, and weight (n = 8). During the baseline (pre-octreotide) study, patients demonstrated a significant decrease in insulin-mediated glucose uptake compared with controls (5.75 +/- 0.21 vs. 7.98 +/- 0.84 mg/kg/min; P < .03), which was entirely accounted for by an impairment in non-oxidative glucose disposal (P < .04). Four-day infusion of octreotide to cirrhotic patients: 1) reduced postabsorptive and meal-stimulated plasma insulin levels by approximately 35% to 45% without significantly affecting glucose tolerance; 2) did not significantly alter plasma free fatty acids (FFA), growth hormone, and glucagon levels in the postabsorptive state and during the meal test; 3) normalized insulin-mediated whole-body glucose disposal (7.63 +/- 0.72 mg/kg/min post-octreotide; P = not significant vs. control). Restoration of insulin-mediated glucose utilization was entirely caused by normalization of non-oxidative glucose disposal; 4) was associated with a considerably more pronounced stimulation by insulin of the fractional glycogen synthase in muscle compared with pre-octreotide results (increment above baseline pre: 0.035 +/- 0.010 vs. post: 0.060 +/- 0.023 nmol/min/mg protein; P < .04). Fractional glycogen activity significantly correlated with non-oxidative glucose disposal during insulin infusion (r = .69; P < .03). Prolonged reduction of hyperinsulinemia for 96 hours in cirrhotic patients normalizes insulin-mediated glucose uptake and glycogen synthesis in muscle. We conclude that chronic hyperinsulinemia causes insulin resistance in cirrhosis.
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Affiliation(s)
- A S Petrides
- Department of Medicine and Gastroenterology, Academic Hospital of the Ruhr University, Bochum, Germany
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30
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Petrides AS, Matthews DE, Esser U. Effect of moderate exercise on insulin sensitivity and substrate metabolism during post-exercise recovery in cirrhosis. Hepatology 1997; 26:972-9. [PMID: 9328322 DOI: 10.1002/hep.510260426] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
We examined whether a single bout of moderate exercise has a beneficial effect on insulin sensitivity and fuel homeostasis in cirrhosis. Clinically stable cirrhotic patients and age-, sex-, and weight-matched controls participated in insulin clamp studies (either euglycemic hyperinsulinemic or hyperglycemic hyperinsulinemic) in combination with indirect calorimetry and [6,6-2H2]glucose. Three to seven days later, studies were repeated following a single bout of exercise (30 minutes of treadmill exercise at 60% of maximal aerobic capacity). After an overnight fast, following exercise, both cirrhotic and control individuals showed a shift in fuel utilization to enhanced lipid oxidation, decreased glucose oxidation, and increased nonoxidative glucose disposal rates (i.e., glycogen synthesis in muscle) when compared with pre-exercise rates but differences were statistically significant only in the patient group. During euglycemic hyperinsulinemia, insulin-mediated glucose disposal was significantly reduced in cirrhotic patients (3.43 +/- 0.26 vs. 7.36 +/- 0.48 mg/kg/min, P < .01). Following exercise, glucose uptake increased significantly in cirrhotic patients when compared with pre-exercise levels (P < .05) but remained unchanged in the control group. The increase in total body glucose disposal in cirrhotic patients was entirely accounted for by an increase in nonoxidative glucose disposal (0.81 +/- 0.20 vs. 0.51 +/- 0.15 mg/kg/min, P < .05). During combined hyperglycemia/hyperinsulinemia, however, insulin sensitivity was unaffected by exercise in both patients and control individuals. In summary, in cirrhotic patients, a single bout of moderate exercise 1) causes a shift in substrate utilization with an increase in lipid oxidation in the postexercise period that is significantly more pronounced than in controls, and 2) increases insulin sensitivity only during euglycemia but not during the more physiological condition of hyperglycemia. Single bouts of moderate exercise therefore may not have a beneficial effect on the metabolic status of patients with chronic liver disease.
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Affiliation(s)
- A S Petrides
- Department of Medicine, University of Tennessee Health Science Center, Memphis, USA
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31
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Riggio O, Merli M, Leonetti F, Giovannetti P, Foniciello M, Folino S, Tamburrano G, Capocaccia L. Impaired nonoxidative glucose metabolism in patients with liver cirrhosis: effects of two insulin doses. Metabolism 1997; 46:840-3. [PMID: 9225841 DOI: 10.1016/s0026-0495(97)90132-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Glucose intolerance is encountered in the majority of cirrhotic patients. This alteration has been attributed to a defective insulin-mediated glucose uptake in peripheral tissue, where nonoxidative glucose disposal seems to be chiefly impaired. To further investigate insulin action under euglycemic conditions, we studied how physiological (100 microU/mL) and pharmacological (1,000 microU/mL) plasma insulin concentrations affect whole-body insulin-mediated glucose uptake, as well as oxidative and nonoxidative glucose disposal, in cirrhotic patients and controls. To this aim, a sequential two-step insulin euglycemic clamp combined with indirect calorimetry was performed in eight cirrhotic patients and six control subjects. During the first step of the clamp, total glucose uptake was reduced by 40% in cirrhotic patients versus controls (4.42 +/- 1.39 v 7.63 +/- 1.60 mg/kg/min, P = .002). By increasing insulin to pharmacological levels, glucose disposal increased in both groups. However, the maximum rate of glucose metabolism achieved in cirrhotic patients was lower than in controls at all times (10.29 +/- 2.04 v 12.82 +/- 0.51 mg/kg/min, P = .012). Glucose oxidation was lower in cirrhotics in the basal state, but similar in both groups during insulin/glucose infusion. On the other hand, the reduced nonoxidative glucose disposal observed in cirrhotic patients was not normalized even by increasing insulin to pharmacological levels. In conclusion, in liver cirrhosis a reduced insulin sensitivity is associated with a reduced insulin responsiveness that is mainly caused by defective nonoxidative glucose disposal.
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Affiliation(s)
- O Riggio
- University La Sapienza, Rome, Italy
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32
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Shangraw RE, Hexem JG. Glucose and potassium metabolic responses to insulin during liver transplantation. LIVER TRANSPLANTATION AND SURGERY : OFFICIAL PUBLICATION OF THE AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES AND THE INTERNATIONAL LIVER TRANSPLANTATION SOCIETY 1996; 2:443-54. [PMID: 9346691 DOI: 10.1002/lt.500020607] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Insulin regulates glucose and potassium metabolism by acting differently upon peripheral tissues (e.g., skeletal muscle) and the splanchnic bed, including the liver. Liver disease is accompanied by "insulin resistance" of glucose metabolism, whereby glucose intolerance occurs despite relatively increased plasma insulin concentration. However, it is unknown whether insulin resistance extends to potassium metabolism. Further, it is uncertain whether the hyperglycemia and alterations of plasma potassium concentration observed during liver transplantation result from changes in circulating insulin concentration, altered sensitivity to insulin, or both, as the diseased liver is removed and replaced with a graft organ. The present study evaluated the role of the liver in maximal insulin responsiveness of whole-body glucose and potassium metabolism, using a hyperinsulinemic clamp technique, to identify the mechanism(s) underlying post-reperfusion hyperglycemia and intraoperative hyperkalemia. Two protocols were employed: in protocol 1 (n = 10), no exogenous insulin was administered. In protocol 2 (n = 10), an intravenous insulin bolus (666 mU . kg-1) was administered after anesthesia induction, followed by an infusion at 500 mU.m-2.min-1, which continued until 3 hours after portal vein unclamping. Plasma concentrations of glucose and potassium were regulated by glucose and potassium chloride infusion (euglycemic eukalemic clamp). Insulin-stimulated exogenous glucose and potassium uptakes were determined in protocol 2 before skin incision and during the dissection, anhepatic, and neohepatic stages. In both protocols, serial measurements of hemodynamic arterial blood gases, glucose, free fatty acids, potassium, insulin, and glucagon concentrations were made. Without insulin (protocol 1), progressive hyperglycemia peaked after portal vein unclamping (post-reperfusion hyperglycemia), with no concomitant decrease in plasma insulin concentration. Intraoperative plasma potassium concentration did not change. Insulin infusion (protocol 2) produced a stable hyperinsulinemia (approximately 2000 microU/mL). Hyperinsulinemia did not eliminate post-reperfusion hyperglycemia. Insulin-stimulated glucose uptake, in mg . kg-1 . min-1, was 8.10 +/- 0.78 (mean +/- SE) before skin incision, 7.62 +/- 0.82 during the hepatic dissection, 4.40 +/- 0.75 during the anhepatic stage, and 4.06 +/- 0.74 at 3 hours after portal vein unclamping. Insulin-stimulated potassium uptake, in mEq . kg-1 . hr-1, was 0.24 +/- 0.02 before skin incision, 0.21 +/- 0.04 during hepatic dissection, 0.07 +/- 0.02 during the anhepatic stage, and 0.21 +/- 0.04 and 0.19 +/- 0.05 at 30 minutes and 3 hours, respectively, after portal vein unclamping. We conclude that post-reperfusion hyperglycemia is not due to inadequate insulin stimulation. Liver disease-induced insulin resistance of glucose metabolism is exacerbated by hepatectomy and is not reversed during the intraoperative neohepatic stage. Liver disease does not impair maximal insulin-stimulated potassium uptake. The liver, even with end-stage disease, accounts for approximately 70% of insulin-stimulated potassium uptake.
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Affiliation(s)
- R E Shangraw
- Department of Anesthesiology, Oregon Health Sciences University, Portland 97201-3098, USA.
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Navasa M, Bustamante J, Marroni C, González E, Andreu H, Esmatjes E, García-Valdecasas JC, Grande L, Cirera I, Rimola A, Rodés J. Diabetes mellitus after liver transplantation: prevalence and predictive factors. J Hepatol 1996; 25:64-71. [PMID: 8836903 DOI: 10.1016/s0168-8278(96)80329-1] [Citation(s) in RCA: 125] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
AIMS/METHODS To investigate the prevalence and risk factors for the development of diabetes mellitus after orthotopic liver transplantation, we reviewed 27 variables (including previous history of diabetes mellitus, data related to pre-transplant liver disease, and postoperative events) in 102 patients who survived longer than 1 year after orthotopic liver transplantation. RESULTS Fourteen patients had diabetes mellitus prior to liver transplantation and all but one were alive 2 and 3 years after transplantation, with all survivors continuing to have diabetes mellitus 1, 2 and 3 years after transplantation. Among the 88 patients without pre-transplant diabetes mellitus, the prevalence of post-transplant diabetes mellitus was 27% at 1 year, 9% at 2 years and 7% at 3 years, probably related to a significant reduction in the daily prednisone dose (13 +/- 4 mg at 1 year, 7 +/- 6 mg at 2 years and 2 +/- 4 mg at 3 years, p < 0.001). Patients with post-transplant diabetes mellitus 1 year after transplantation had a higher number of rejection episodes during the first postoperative year than those without post-transplant diabetes mellitus (1.5 +/- 1.1 vs 1.1 +/- 0.7, p < 0.05) and also had higher, but not statistically significant, cumulative steroid dose and blood cyclosporine levels. Mortality of patients with post-transplant diabetes mellitus was significantly higher during the second postoperative year in comparison with patients without post-transplant diabetes mellitus: 4/24 vs 2/64 (17% vs 3%; p < 0.05). CONCLUSIONS Liver transplantation does not significantly modify pre-transplant diabetes mellitus. Diabetes mellitus frequently develops de novo after liver transplantation, although this complication is usually transient and probably related to immunosuppressive drug administration. The prognosis of patients with post-transplant diabetes mellitus is worse than that of those without this complication.
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Affiliation(s)
- M Navasa
- Liver Unit, Hospital Clínic i Provincial, University of Barcelona, Spain
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Petrides AS, Vogt C, Schulze-Berge D, Matthews D, Strohmeyer G. Pathogenesis of glucose intolerance and diabetes mellitus in cirrhosis. Hepatology 1994; 19:616-27. [PMID: 8119686 DOI: 10.1002/hep.1840190312] [Citation(s) in RCA: 184] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Glucose intolerance and diabetes mellitus are both prevalent in cirrhosis, yet the pathogenesis of impaired glucose metabolism remains unknown. Therefore insulin secretion (hyperglycemic clamp, +125 mg/dl), insulin sensitivity (euglycemic hyperinsulinemic insulin clamp, +10 microU/ml and +50 microU/ml), whole-body glucose oxidation (indirect calorimetry) and glucose turnover ([6,6-2H2]glucose isotope dilution) were evaluated in a homogenous group of cirrhotic patients with glucose intolerance (n = 7) or frank diabetes mellitus (n = 6). The results were compared with those obtained in control subjects (n = 8). In glucose-intolerant patients, whole-body glucose uptake (mainly reflecting glucose utilization by muscle) was significantly impaired in patients during both insulin infusions as a result of decreased stimulation of the two major intracellular pathways of glucose disposal--nonoxidative glucose disposal (i.e., glycogen synthesis) and glucose oxidation. Hepatic glucose production was normal in the basal state and was normally suppressed during stepwise insulin infusion (by 65% and 85%, respectively, p = NS vs. controls). Hyperglycemia-induced increases of plasma C-peptide concentrations were comparable to those in controls (p = NS). In diabetic patients, insulin-mediated glucose uptake was significantly reduced, mainly because of impaired non-oxidative glucose disposal. Glucose oxidation appeared to be reduced, too. Hepatic glucose production was significantly increased in the basal state (3.03 +/- 0.24 vs. 2.34 +/- 0.10 mg/kg min, p < 0.02) and during insulin infusion (+50 microU/ml: 0.67 +/- 0.17 vs. 0.13 +/- 0.08 mg/kg min, p < 0.05) compared with that in controls. Both the first and second phases of beta-cell secretion were significantly reduced in response to steady-state hyperglycemia (both p < 0.01 vs. control values). In conclusion, glucose intolerance in cirrhosis results from two abnormalities that occur simultaneously: (a) insulin resistance of muscle and (b) an inadequate response (even when comparable to that of controls) of the beta-cells to appropriately secrete insulin to overcome the defect in insulin action. Diabetes mellitus in insulin-resistant cirrhotic patients develops as the result of progressive impairment in insulin secretion together with the development of hepatic insulin resistance leading to fasting hyperglycemia and a diabetic glucose tolerance profile.
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Affiliation(s)
- A S Petrides
- Department of Internal Medicine, Heinrich-Heine University, Düsseldorf, Germany
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