Metabolic syndrome is associated with poor treatment response to antiviral therapy in chronic hepatitis C genotype 3 patients

Eur J Gastroenterol Hepatol. 2014 Mar 17. [Epub ahead of print]

Aziz H¹, Gill U, Raza A, Gill ML.

Abstract

INTRODUCTION: Hepatitis C viral (HCV) infection is caused by an RNA virus. HCV infection is considered to induce systemic disease that causes steatosis, alters lipid metabolism, and results in metabolic syndrome. This study aimed to investigate the therapeutic outcome in HCV genotype 3 patients with metabolic syndrome.

MATERIALS AND METHODS: A total of 621 HCV-positive patients who visited the hospital for treatment were screened. Among these, 441 patients were enrolled for antiviral therapy. These enrolled patients were assessed for metabolic syndrome according to the International Diabetes Federation criteria. Group A included patients with metabolic syndrome and group B included patients without metabolic syndrome. All patients received peginterferon-α2a (180 μg/week) and ribavirin (10 mg/kg/day) for 6 months.

RESULTS: The prevalence of metabolic syndrome in chronic HCV patients was 37.9%. We observed that metabolic syndrome was more common among female compared with male participants (43.9 vs. 28.8%, P=0.005). It was found that sustained virologic response (SVR) rates were significantly higher in the patients in group B (without metabolic syndrome) compared with the patients in group A who had metabolic syndrome (72.2 vs. 43.7%, P<0.05). Older patients were at a higher risk for metabolic syndrome and a correlation of metabolic syndrome with nonresponse to antiviral therapy was observed. An interesting correlation among metabolic syndrome, age, and SVR was found: with age, SVR decreases, while metabolic syndrome increases.

CONCLUSION: Metabolic syndrome has an influence on therapeutic outcomes in terms of SVR. Moreover, this information can identify patients who might have a low chance of attaining an SVR and a timely decision may protect the patients from the adverse effects of therapy.

PMID: 24642690 [PubMed - as supplied by publisher]

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Nonalcoholic Fatty Liver Disease: Prevalence, Influence on Age and Sex, and Relationship with Metabolic Syndrome and Insulin Resistance

International Journal of Gerontology
Volume 7, Issue 4 , Pages 194-198, December 2013

Hui-Yun Cheng, Horng-Yuan Wang, Wen-Hsiung Chang, Shee-Chan Lin, Cheng-Hsin Chu, Tsang-En Wang, Chuan-Chuan Liu, Shou-Chuan Shih

Received 14 April 2012; received in revised form 20 August 2012; accepted 1 February 2013. published online 28 May 2013.

Summary

Background/purpose

Nonalcoholic fatty liver disease (NAFLD) is a common condition comprising a wide spectrum of liver damage strongly associated with type 2 diabetes, obesity, and hyperlipidemia. The pathogenesis of fatty liver is multifactorial, and it has been suggested that the presence of insulin resistance (IR) is an essential requirement for the accumulation of hepatocellular fat. Although NAFLD may affect people of any age, in general, increasing age is associated with increasing prevalence. The aim of this study was to determine the prevalence of fatty liver and its influence on age and sex; and to assess the association of different degrees of fatty liver to IR and metabolic syndrome.

Materials and methods

The study was performed in 8350 alcohol- and virus-negative individuals who underwent routine physical check-up at the health evaluation centre of Mackay Memorial Hospital, from February 2004 to May 2009. They underwent clinical examination, anthropometry, biochemical tests including serum fasting insulin, and routine liver ultrasonography. Steatosis was graded as absent, mild, moderate, or severe.

Results

The overall prevalence of fatty liver was 34.40% with the prevalence of fatty liver being significantly higher in males than in females (22.34 vs. 12.06%, p = 0.015). A progressive increase in the means of a homeostasis model assessment of IR (HOMA-IR), body mass index, systolic blood pressure, plasma triglyceride, alanine aminotransferase, low-density lipoprotein-cholesterol and glucose level and decrease in high-density lipoprotein-cholesterol (p < 0.001 and p < 0.05) was observed from the group without steatosis to the groups with mild, moderate, and severe steatosis. Severe steatosis was associated with the clustering of risk factors for metabolic syndrome. Individuals with metabolic syndrome and a more pronounced HOMA-IR had a higher prevalence of moderate to severe steatosis (p < 0.001 and p < 0.05) compared to those with HOMA-IR below the median.

Conclusion

Fatty liver can be considered as the hepatic consequence of metabolic syndrome, specifically IR. There is a high prevalence of metabolic syndrome and fatty liver among the elderly population. Metabolic disorders are closely related to fatty liver; moreover, fatty liver appears to be a good predictor for the clustering of risk factors for metabolic syndrome.

Keywords: hepatic metabolic syndrome, insulin resistance, nonalcoholic fatty liver disease

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The Metabolic Syndrome and Chronic Liver Disease

Curr Pharm Des. 2013 Dec 5. [Epub ahead of print]

Rosselli M, Lotersztajn S, Vizzutti F, Arena U, Pinzani M, Marra F.

Dipartimento di Medicina Sperimentale e Clinica Largo Brambilla, 3 I-50134 Florence, Italy. fabio.marra@unifi.it.

Abstract

The prevalence of the metabolic syndrome (MetS), a cluster of cardiovascular risk factors associated with obesity and insulin resistance, is dramatically increasing in Western and developing countries. This disorder is not only associated with a higher risk of appearance of type 2 diabetes and cardiovascular events, but impacts on the liver in different ways. Nonalcoholic fatty liver disease (NAFLD) is considerd the hepatic manifestation of the MetS, and is characterized by triglyceride accumulation and a variable degree of hepatic injury, inflammation, and repair. In the presence of significant hepatocellular injury and inflammation, the picture is defined 'steatohepatitis' (NASH), that has the potential to progress to advanced fibrosis and cirrhosis. Diagnosis of NASH is based on a liver biopsy, and active search for noninvasive tests is ongoing. Progression of steatohepatitis to advanced fibrosis or cirrhosis has been shown in at least one third of patients followed with paired biopsies. Presence of NASH is associated with lower life expectancy, both due to liver-related death and an increase in cardiovascular events. The appearance of NAFLD is mainly dependent on increased flow of fatty acids derived from an excess of lipolysis from insulin-resistant adipose tissue. Development of NASH is based on lipotoxicity and is influenced by signals derived from outside the liver and from intrahepatic activation of inflammatory and fibrogenic pathways. The presence of the MetS is also associated with worse outcomes in patients with cirrhosis due to any causes, and has complex interactions with hepatitis C virus infection. Moreover, the MetS poses a higher risk of development of hepatocellular carcinoma, not necessarily through the development of NASH-related cirrhosis. In conclusion, the presence of metabolic alterations has a severe and multifaceted impact on the liver, and is responsible for a higher risk of liver-dependent and -independent mortality.

PMID: 24320032 [PubMed - as supplied by publisher]

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Metabolic Syndrome Is Associated With Fibrosis Development In Chronic Hepatitis B Virus Inactive Carriers

Journal of Gastroenterology and Hepatology

Accepted Article (Accepted, unedited articles published online and citable. The final edited and typeset version of record will appear in future.)

Clinical Hepatology

Álvaro Mena^*, José D Pedreira, Ángeles Castro, Soledad López, Pilar Vázquez,  Eva Poveda

DOI: 10.1111/jgh.12432

This article is protected by copyright. All rights reserved.

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/jgh.12432

Publication History
Accepted manuscript online: 13 NOV 2013 05:42AM EST
Manuscript Accepted: 16 SEP 2013

Keywords: HBV;  inactive carriers;  metabolic syndrome; fibrosis;  FibroScan

Abstract\

Background and Aim

There are few data of fibrosis development in chronic hepatitis B (CHB) patients classified as inactive carriers. The aim of this study is to determinate the prevalence of significant fibrosis and probable cirrhosis measured by FibroScan in real inactive CHB carriers and investigate the relationship with virological, epidemiological and metabolic factors.

Methods

Cross-sectional cohort study including CHB inactive carriers. Liver stiffness measurement was performed with transient elastography (FibroScan). Significant fibrosis (≥F2) was defined as stiffness >7.5 kPa, and probable cirrhosis as >11.8 kPa. Factors associated with significant fibrosis were explored with univariate and multivariate adjusted logistic regression analyses.

Results

96 CHB inactive carriers were analyzed. Of them, 24 (25%) had significant fibrosis and 7 (7%) probable cirrhosis; mean stiffness was 6.2±2.3 kPa.

Of them, 24% had metabolic syndrome, with higher FibroScan value than those without (8.4 kPa vs 5.5 kPa, p<0.001).

Factors associated with significant fibrosis were (odds ratio, 95% confidence interval, p value): central obesity (7.1, 1.8-27.9, 0.005), elevated fasting glucose (4.3, 1.3-27.9, 0.036), reduced HDL-cholesterol (5.2, 1.2-23.6, 0.032) and elevated triglycerides (6.2, 1.4-28.3, 0.019). Factors as age, sex, transaminases, HBV-DNA or genotype were not related with liver fibrosis.

The presence of metabolic syndrome has a 69% of positive predictive value and 89% of negative predictive value for significant fibrosis.

Conclusion

Different components of metabolic syndrome are associated with fibrosis development in CHB inactive carriers. In the absence of metabolic syndrome, significant fibrosis is uncommon in this population.

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Altered Metabolic Markers Diminish Response to Telaprevir-Based Triple Therapy for Hepatitis C

Source: DGNews  |  Presented at AASLD

By Brian Hoyle

WASHINGTON, DC -- November 6, 2013 -- Altered glucose metabolism, diabetes, and metabolic syndrome have been linked with a markedly diminished sustained virologic response (SVR) in patients with chronic hepatitis C virus (HCV) infections being treated with telaprevir-based triple therapy, according to results of an observational study presented at the 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD).

“Astonishingly, metabolic markers had a marked influence on SVR rates in this real-world setting, which was not reported before,” noted presenter Elmar Jaeckel, MD, Hannover Medical School, Hannover, Germany, in a poster presented here on November 5.

In this study, patients were allowed the choice of 2 currently approved and available protease inhibitors, utilising dual therapy with pegylated interferon alfa-2a and ribavirin or triple therapy with the inclusion of telaprevir. The choice of therapy, drug dose, and duration of therapy were at the discretion of the physician.

Dr. Jaeckel and colleagues examined 5,716 patients treated in private practice by German gastroenterologists since 2011 with the dual therapy (n = 4,501) or the telaprevir-based triple therapy (n = 1,873). The results presented here are interim data from 421 patients treated with the triple-drug combination who had completed follow-up.

The 421 patients were evaluated for metabolic risk markers and their influence on early virologic response (EVR, defined as HCV-RNA <10 IU/mL at week 4 after therapy), rapid virologic response (RVR; negative HCV-RNA at week 4 after therapy), and SVR (HCV-RNA <10 IU/mL at least 12 weeks after therapy).

SVR, it was observed, was greatly influenced by the metabolic markers. Patients with pre-diabetic alterations of glucose metabolism (evident as fasting glucose levels over 100 mg/dL) displayed diminished SVR compared with those with unaltered glucose metabolism (43.9% vs 64.1%; P = .020). The same trend held for those with glycated haemoglobin (HbA1c) of 6.0% or greater (30.8%) versus those with 6.0% or less (59.7%) (P = .057).

SVR rates were decreased in those diagnosed with diabetes mellitus compared with those without diabetes (27.3% vs 55.7%; P = .009). SVR was also reduced according to triglyceride levels >150 mg/dL (37.5% vs 55.8%;P = .050), HDL levels under 40 mg/dL (23.5% vs 60.5%; P = .006), and hypertension (43.8% vs 56.8%; P = .009).

EVR was not appreciably influenced by risk markers of metabolic syndrome. RVR, however, was diminished for patients with HbA1c level ≥ 6% compared with those with a level under 6% (30.8% vs 67.3%; P = .016), diabetes mellitus (40.9% vs 66.0%; P = .018), and high-density lipoprotein levels below 40 mg/dL (35.7% vs 67.1%; P = .028).

Patients in this interim analysis were predominantly male (63.2%), with a median age of 48.7 years. Median body mass index (BMI) was 25.9, with 25.2% of patients having a BMI ≥ 28. Duration of infection was 17.2 years, with a viral load exceeding 400,000 IU/mL in 73.6% of patients. Blood glucose levels exceeded 100 mg/dL in 20.7% of patients.

Metabolic syndrome has been linked with reduced efficacy of dual therapy involving pegylated interferon alfa-2a and ribavirin. No such association was reported, however, in phase 3 studies involving triple therapy with telaprevir.

The researchers expressed hope that the novelty of the findings, despite prior phase 3 studies, will help identify hard-to-treat patients who will need other, more efficacious, therapies.

Funding for this study was provided by Roche Pharma AG, Grenzach-Wyhlen, Germany.

[Presentation title: Elevated Glucose, Metabolic Syndrome and Diabetes Predict Lower Treatment Response to Triple Therapy With Telaprevir. Abstract 1948]

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Association Between the Hepatitis B and C Viruses and Metabolic Diseases in Patients Stratified by Age

Liver International

Wen-Cheng Li, Yi-Yen Lee, I-Chuan Chen, Cheng Sun, Feng-Hsiang Chiu, Chung-Hsun Chuang

Liver International. 2013;33(8):1194-1202.

Abstract and Introduction

Abstract

Background Hepatitis B/C viruses cause liver disease and metabolic disturbances.

Aims The purpose of this study was to evaluate the association between hepatitis B/C infection and metabolic syndrome (MS).

Methods In total, 26 305 subjects were included in this multicentre, cross-sectional study. Systolic and diastolic blood pressures, body mass index and waist circumference were measured. Total cholesterol, high- and low-density lipoprotein cholesterol, triglyceride, fasting blood glucose and uric acid were determined, and hepatitis B serum antigen (HBsAg) and anti-HCV antibodies were assayed using commercial kits.

Results MS was diagnosed in 2712 (23.0%) females, including 131 and 166 positive for HBsAg and anti-HCV respectively. In the men, 4594 (31.6%) were diagnosed with MS, including 326 positive for HBsAg and 131 positive for anti-HCV. No significant difference in the prevalence of MS was identified in any group, except men and women >45 years who were anti-HCV positive. Various metabolic alterations in both men and women >45 years were noted, including waist circumference, body mass index, fasting blood glucose and systolic and diastolic blood pressure. Notably, high- and low-density lipoproteins were significantly lower in positive subjects compared to those weakly positive and/or negative for anti-HCV.

Conclusions There were obvious metabolic derangements in patients coinflicted with MS and hepatitis C infections, particularly those >45 years of age. There is a pressing need to identify strategies to improve/resolve metabolic derangements to maximize sustained virological response rates in patients infected with HCV (and potentially HBV).

Introduction

Approximately 170 million (3% of the world's population) people are infected with the hepatitis C virus (HCV), and an overwhelming 2 billion people are currently infected with the hepatitis B virus (HBV) worldwide.^[1–3] HBV and HCV are particularly prevalent in Asia and Taiwan. Over time, the hepatitis C and B viruses cause liver disease that often progresses from chronic hepatitis to fibrosis, cirrhosis and in some cases, hepatocellular carcinoma.^{[1, 2]} In addition to being hepatotropic, the HCV is also known to cause metabolic disturbances, referred to as HCV-associated dysmetabolic syndrome (HCADS) characterized by steatosis, hypocholesterolaemia and insulin resistance (IR)/diabetes.^[1]

The 'classic' metabolic syndrome (MS), which includes glucose abnormalities, central obesity, dyslipidaemia and hypertension, is increasingly common in Eastern countries, largely because of an obesity epidemic caused by the Westernization of many countries.^[4] It is now widely accepted that patients with chronic HCV have a higher incidence of IR and type 2 diabetes mellitus than in patients with other liver diseases.^[1] Further, several studies have suggested an association between chronic HCV and MS, reporting a prevalence of MS ranging from 4.1% to 44%.^[5–7] It is also reported that insulin resistance, type 2 diabetes mellitus and HCADS negatively impact sustained virological responses (SVRs) to pegylated interferon- with ribavirin, and that MS is an independent predictor of a suboptimal SVR.^[1] To date, the prevalence of full-blown MS (regardless of whether it is the classic form or the viral form, as described by Bugianesi et al.) among patients infected with HCV remains unknown.^[8] Unlike HCV, the link between HBV and MS is not as well studied, despite the fact that infection with HBV is more common than HCV.

The purpose of this large, multi-centre, cross-sectional study was to evaluate the association between infection with either HBV or HCV and metabolic diseases, including MS and diabetes mellitus. The prevalence of both HBV and HCV infections, as well as type 2 diabetes, IR, obesity and MS, continue to increase at an alarming rate. There is therefore a pressing need to identify strategies for improving/resolving metabolic derangements to maximize SVR rates in patients infected with HCV (and potentially HBV). The findings of this study are anticipated to impact the prevention and long-term management of a multitude of HCV-positive individuals in the near future.

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Infection, CVD more prevalent among liver transplant recipients with metabolic syndrome

Provided by Healio

June 3, 2013

ORLANDO, Fla. — The presence of metabolic syndrome post-liver transplantation increased the risk for infection and cardiovascular disease, according to data presented at Digestive Disease Week.

In a retrospective cohort study, researchers evaluated 158 patients who underwent liver transplantation between 2002 and 2007 at a single medical facility, with follow-up through September 2012. The presence of metabolic syndrome (MetS) before transplant and at 6 and 12 months post-transplant was determined in each case.

Before transplantation, 25% of the cohort had MetS, which increased at 6 months (51% of cases) and 12 months post-transplant (61%). Thirty-one percent of participants who did not have prior MetS developed it de novo at 6 months, while 54% developed it by 12 months.

Investigators observed a significant association between MetS at 6 months and infection-related hospitalizations within the first post-transplant year (53% of those with compared with 31% of those without MetS; P=.005). Hospitalizations due to cardiovascular disease (CVD) also were more common among those with post-transplant MetS (26% of cases at 5 years post-transplant vs. 13%; P=.05).

Patients with MetS and nonalcoholic fatty liver disease (NAFLD) were not at increased risk for either infection- or cardiovascular-related hospitalization compared with those with MetS alone. NAFLD, however, significantly increased the risk for CVD among patients without MetS (14% vs. 0% of those without NAFLD; P=.03). Neither MetS nor NAFLD significantly impacted post-transplant survival, according to Kaplan-Meier analysis.

“We were able to show there was a statistically significant association with early infectious morbidity, as well as later cardiovascular morbidity, if you have symptoms of [MetS],” researcher Nicholas Kim, MD, an internal medicine resident at the University of Wisconsin, told Healio.com. “Our data suggest that it’s important to prevent metabolic syndrome from developing post-liver transplant. It’s a very common complication due to a variety of reasons, but if we are able to prevent it, we might be able to reduce the amount of early infectious complications and later cardiovascular complications after liver transplant.”

For more information:

Kim N. Tu1019: Development of the Metabolic Syndrome and Its Outcomes After Liver Transplantation. Presented at: Digestive Disease Week 2013; May 18-21, Orlando, Fla.

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