Adiponectin serum level changes and its dynamic relationship with hepatitis C during viral clearance

ABSTRACT

Recent evidences suggest that adiponectin is a multifunctional hormone, inversely associated with cardiovascular risk factors, such as blood pressure, low-density lipoprotein cholesterol and triglycerides levels. Literature data are conflicting on the serum adiponectin levels in chronic hepatitis C patients. Here we analyze the interesting study of Chang and coworkers, on the dynamic relationship between adiponectin levels and insulin resistance, in chronic hepatitis C patients during viral clearance.

KEYWORDS:

• adiponectin
• genetic
• hepatitis C
• insulin resistance
• viral clearance

This article refers to:

The evolving relationship between adiponectin and insulin sensitivity in hepatitis C patients during viral clearance

Hepatitis C virus (HCV) infection is a global health problem.¹ The World Health Organization has estimated that around 150 million persons worldwide may be infected. About 20–30% of chronic HCV (CHC) patients present a range of metabolic features including insulin resistance (IR), impaired glucose tolerance or type 2 diabetes mellitus (T2DM), disequilibrium of lipid metabolism and hepatic fat accumulation.^2,3 In the last two decades, adipose tissue was defined as active endocrine organ, which produces several polypeptide factors called “adipokines” (adipose tissue cytokines), involved in the regulation of glucose and lipid metabolism.⁴

Adiponectin is the major insulin-sensitizing adipokine, mainly secreted by hepatocytes and adipocytes and secreted in three forms: low molecular weight trimers, medium molecular weight hexamers, and high molecular weight multimers that have more biological activity than other two forms.⁵

Recent evidences suggest that adiponectin is a multifunctional hormone, inversely associated with cardiovascular risk factors, such as blood pressure, low-density lipoprotein cholesterol and triglycerides levels. Increased central fat mass reduces the circulating levels of adiponectin, which result low also in the presence of IR and T2DM.^6,7 It is well known also that hypoadiponectinemia enhances hepatic steatosis, inflammation, fibrosis, and finally hepato-carcinogenesis.⁸ Conversely, adiponectin exhibits anti-inflammatory, antihyperglycemic and antiatherogenic properties, which could be beneficial in the prevention and the treatment of disorders associated with overweight/obesity.⁹

Literature data are conflicting on the serum adiponectin levels in CHC patients, reporting them as higher, lower, or equal to controls, and suggesting also that lower adiponectin concentrations are associated with HCV genotype and gender.¹⁰ It has been recently highlighted that liver steatosis is negatively related to adiponectin in CHC patients.¹¹ These findings indicate that adiponectin levels may be suitable in clinical practice, as a marker of the degree of CHC-related steatosis. However, its role in the CHC-induced steatosis has not been completely characterized yet. It has been hypothesized that the pathogenic link between hypoadiponectinemiaand steatosis is related to the ability of adiponectin to protect hepatocytes from triglycerides accumulation by increasing the β-oxidation of free fatty acids and thus decreasing de novo free fatty acids production.¹¹

In this issue of Virulence, the Authors of the article entitled “The evolving relationship between adiponectin and insulin sensitivity in hepatitis C patients during viral clearance,” describe a prospective study that aims to elucidate the impact of HCV infection on adiponectin levels and the associated metabolic changes, evaluated before, during and after anti-viral therapy.¹² The study include 747 consecutive CHC patients and 546 of these complete anti-HCV therapy cycle with weight-based pegylated interferon-α-2b and ribavirin, 407 (54.5%) and 295 (39.5%) patients were respectively infected by HCV genotype 1 and 2. The Authors found the association between adiponectin values and sex, triglycerides serum levels and hepatic steatosis, and interferon λ3 (IFNL3) genotype with IR assessed by homeostasis model assessment-estimated insulin resistance (HOMA-IR), before anti-HCV therapy. In patients with a sustained virological response (SVR; n = 455), at 24 weeks post-therapy, gender, body mass index, aspartate aminotransferase to platelet ratio index (APRI), HOMA-IR and liver steatosis were associated with adiponectin levels, and IFNL3 genotype was associated with HOMA-IR levels. Generalized estimating equation analysis demonstrated that SVR affected longitudinal trends in adiponectin levels. Compared with pre-therapy levels, adiponectin and APRI levels decreased 24 weeks post-therapy in SVR patients, regardless of baseline IR. However, HOMA-IR levels decreased in SVR patients with baseline IR, but increased in those without baseline IR. Compared with control patients, immune-histochemical studies showed that pre-therapy CHC patients had higher hepatic adiponectin expression associated with hepatic fibrosis. The Authors concluded that during CHC infection, adiponectin may influence insulin sensitivity through triglycerides concentration. After viral clearance, adiponectin levels were directly associated with insulin sensitivity and decreased upon improved hepatic fibrosis.

This study of Chang et al. provides valuable information on the dynamic relationship between adiponectin levels and IR in CHC patients during viral clearance. The most important finding is the association of triglycerides and IFNL3 genotype with IR, particularly in the presence of the IFNL3 genotype CC. Male gender, hepatic steatosis and SVR, resulted as independent factors for the longitudinal trend in adiponectin levels. In SVR patients, gender, BMI, APRI, HOMA-IR, and hepatic steatosis were associated with adiponectin levels, while neither HOMA-IR nor adiponectin levels appeared to independently influence SVR in patients infected by HCV genotype 1 or 2. Also the negative effects of male gender and hepatic steatosis on adiponectin levels were present during pre-, peri- and post-therapy stages. The Authors conclude that these data indicate that the impact of HCV infection on adiponectin serum concentration, is probably the consequence of metabolic changes induced by HCV infection.

This is a key point on the study of adiponectin and its relationship with HCV. As today, there are limited data on the potential therapeutic role of adiponectin in CHC. Several works highlight the anti-inflammatory activity of adiponectin and its potential role in the treatment of IR, metabolic syndrome and liver steatosis, that are common features of CHC.^9,13,14 In this way, the evaluation of the serum adiponectin pattern and its isoforms in CHC patients under new direct antiviral agents, will be useful to better understand the metabolic effects of HCV and to identify those molecules capable of inducing production of adiponectin, eventually paving the way to a potential therapy to treat HCV-induced steatosis. Additional studies with larger sample sizes are needed to better understand of the protective role of adiponectin in CHC.

On the other side, in this study adiponectin levels were directly associated with insulin sensitivity after SVR. In fact, the HOMA-IR levels increased in patients without baseline IR and decreased in patients with baseline IR, which was associated with the IFNL3 genotype. This adiponectin pattern, may represent also an useful biomarker to follow-up the metabolic co-morbidities associated with CHC.^10,15,16

Finally, many studies showed the influence of genetic factors in the development of liver steatosis in CHC. In this context, it is noteworthy to mention another adipokine, adiponutrin, encoded by the patatin-like phospholipase domain-containing 3 (PNPLA3) gene. Valenti et al. have showed that rs738409 single nucleotide polymorphism of PNPLA3, encoding for a protein variant (I148M), influences hepatic triglycerides accumulation, the susceptibility to fibrosis, the response to antiviral treatment and may represent a genetic determinant of adiponectin levels in CHC.^17,18 The relevance of genetics in the development of liver steatosis and adiponectin changes in CHC is confirmed in this study by the description of the role of IFNL3 genotype CC. The significant impact of relatively frequent genetic variants, such as the PNPLA3 I148M or the IFNLA3 genotype CC, suggests some important considerations: 1) genetic variants affecting tissue-specific proteins, like the adipokines, may have both localized or systemic effects, involving apparently separate systems, such as adipose tissue, liver, and immune system, and providing a mechanistic link to understand the pathogenesis of several multifactorial disorders; 2) in the future, diagnosis and management of liver disorders should take into account the genetic background of each patient, since this could have serious consequences on the evolution and the prognosis of the disease.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.