Introduction
Hepatitis C virus (HCV) is a single-stranded RNA virus belonging to the Flaviviridae family. Approximately 64–103 million people are infected with HCV worldwide, making HCV one of the major causes of chronic liver disease.1 Acute infection may resolve spontaneously in 15%–45% of cases, but the remaining 55%–85% of infected individuals (75%–85% according to serologic surveys) fail to clear the virus and become chronically infected.1,2 In a significant number of patients, chronic hepatitis C (CHC) will progress to cirrhosis and hepatocellular carcinoma (HCC), which represent the end-stage HCV-related liver disease, and are among the leading causes for liver transplantation in the Western world.2 Approximately 350,000 to 500,000 people die each year from hepatitis C-related liver diseases around the world.1
The primary host cells for HCV are hepatocytes, although replication may also occur in other cell types, such as peripheral blood mononuclear cells and B and T lymphocytes.3,4 HCV interferes with the hepatic lipid metabolism throughout its life cycle. Viral entry into hepatocytes occurs following its binding to low-density lipoprotein receptors.5,6 Once internalized, HCV interferes with the host lipid metabolism for its replication and assembly, which consequently leads to hepatic steatosis. Finally, the virus is released from the hepatocyte via the very low-density lipoprotein secretion pathway.7
Hepatic steatosis is a condition in which there is excessive accumulation of triglycerides within the hepatocytes. The most common causes are alcohol consumption (alcoholic fatty liver disease) and insulin resistance (IR) within the metabolic syndrome (MS) (non-alcoholic fatty liver disease - NAFLD), but other causes, including malnutrition, total parenteral nutrition, severe weight loss, gastrointestinal bypasses, some inherited metabolic conditions (e.g., abetalipoproteinemia), glycogen storage diseases, lipodystrophy, alpha 1-antitrypsin deficiency, pregnancy, drugs and toxins, as well as human immunodeficiency virus (HIV) and chronic HCV infection, are also responsible for a number of cases.
NAFLD is one of the most common causes of chronic liver disease in the Western world. It represents a spectrum of conditions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), where steatosis is associated with hepatic inflammation and various degrees of fibrosis and cirrhosis, which develops as a consequence of long-standing NASH.8 NAFLD is estimated to affect around 25%–30% of the general population, while NASH is reported in 2%–3% of the population.9
Strong epidemiological, biochemical, and therapeutic evidence implicate IR as the primary pathophysiological derangement and the key mechanism leading to hepatic steatosis. Indeed, NAFLD is regarded as a hepatic manifestation of the MS.
MS represents a combination of well-known and established cardiovascular disease related risk factors. Multiple definitions of MS exist with several revisions; and although criteria differ, the essential components of MS include insulin resistance/hyperglycemia, dyslipidemia, hypertension, and visceral obesity.10–14 These factors have a tendency of clustering together, and individuals with MS have a 2-fold increase in cardiovascular outcomes and a 1.5-fold increase in all-cause mortality.15
Hepatic steatosis in CHC infection results from the combination of several host and viral factors that directly interfere with lipid metabolism within the hepatocytes or cause different metabolic derangements through IR. Host factors include the before mentioned components of MS, such as obesity and type 2 diabetes mellitus (T2DM); but also include alcohol consumption, medication use, and genetic predisposition (e.g., interleukin (IL) 28B polymorphism).16,17 Viral factors include genotype (genotype 3 causing the most pronounced steatosis), HCV RNA load, and gene mutations.16–18
HCV and insulin resistance
Glucose metabolism impairment, development of IR, and T2DM can often be found accompanying CHC and is commonly measured using the homeostatic model assessment (HOMA) index. Euglycemic insulin clamp studies have shown that IR in CHC has both a hepatic and a peripheral component and induces an array of host metabolic changes.19,20 Besides promoting steatosis and fibrosis progression, the presence of IR has been shown to impair treatement response and, vice-versa, regress following successful treatment outcome.
Several studies have assessed IR in hepatitis C patients before and after interferon therapy. Petit et al. report that IR in nondiabetic HCV-infected patients was related to grading of liver fibrosis and may occur early in the course of HCV infection.21 In a study including 260 HCV-infected subjects, Hui et al. found that HCV may induce IR irrespective of the severity of liver disease and that genotype 3 had a significantly lower HOMA-IR than other genotypes.22 On the other hand, another study found that median HOMA-IR was significantly higher in patients with genotype 1 related steatosis than in those with genotype 3 related steatosis.23 Irrespective of the genotype, higher HCV RNA levels were associated with the presence of IR and, accordingly, the severity of hepatic steatosis,24,25 where treatment and clearance of HCV improved IR.26–28 Regarding the impact of HCV infection on the development of T2DM, a meta-analysis of 34 studies found a positive correlation between HCV infection and increased risk of T2DM in comparison to the general population in both retrospective and prospective studies.29 Studies investigating the association between HCV and IR, and their key findings, are summarized in Table 1.
Table 1.The association between hepatitis C virus (HCV) and insulin resistance
| Methods/Study population | Findings and conclusions | Author |
| 15 CHC patients assessed before and after IFNα therapy | Glucose tolerance improved after IFNα treatment | Tanaka et al.,30 1997 |
| 13 nondiabetic CHC patients before and after IFNα therapy | HCV-induced liver injury related to deterioration of insulin sensitivity and impaired glucose homeostasis | Konrad et al.,31 2000 |
| 103 nondiabetic CHC patients | IR related to grading of liver fibrosis and occurred at an early stage of HCV infection | Petit et al.,21 2001 |
| 160 patients with CHC | Circulating insulin levels increased with fibrosis in overweight patients with CHC | Hickman et al.,32 2003 |
| 260 CHC patients | HCV may induce IR irrespective of the severity of liver disease. Genotype 3 associated with lower HOMA-IR | Hui et al.,22 2003 |
| 141 nondiabetic CHC patients | IR was significantly higher in patients with genotype 1 related steatosis than in genotype 3 | Fartoux et al.,23 2005 |
| 159 patients with CHC genotype 1 (113) and non-1 genotype (46) treated with IFN/RBV | SVR independently related to genotype, IR, and fibrosis | Romero-Gómez et al.,33 2005 |
| 90 patients with CHC and 90 with NAFLD | Basal and postload IR were lower in CHC patients than in NAFLD | Svegliati-Baroni et al.,34 2007 |
| 17 CHC patients not receiving pharmacological treatment | 70% overweight or obese, 77% presented with IR | Vázquez-Vandyck et al.,35 2007 |
| 89 CHC patients receiving IFNα or IFNα/RBV | HCV clearance improved IR, β-cell function, and hepatic IRS1&2 expression | Kawaguchi et al.,26 2007 |
| 232 CHC and 56 HCV eradicated patients | CHC patients had higher prevalence of T2DM and IR | Imazeki et al.,36 2008 |
| 162 CHC patients assessed before treatment | Higher HCV RNA levels associated with the presence of IR and hepatic steatosis | Hsu et al.,24 2008 |
| 346 untreated, nondiabetic CHC patients with genotype 1 or 3 | HOMA-IR rather than steatosis was independently associated with fibrosis regardless of genotype | Cua et al.,37 2008 |
| 201 CHC patients with genotype 1 | IR and overt diabetes were related to advanced fibrosis, regardless of steatosis | Petta et al.,38 2008 |
| 82 CHC patients treated with either IFN/RBV (59) or pegylated-IFN/RBV (23) | Patients with lower HOMA-IR were more likely to achieve SVR | Poustchi et al.,39 2008 |
| 34 postliver transplant patients evaluated (14 HCV positive and 20 HCV negative) | Higher IR in the HCV positive group. Higher HCV RNA levels were associated with higher HOMA-IR | Delgado-Borrego et al.,40 2008 |
| 500 CHC patients | IR was present in 32.4% of nondiabetic CHC, associated with genotypes 1 and 4 as well as high HCV RNA levels. Fibrosis was associated with IR independent from steatosis | Moucari et al.,25 2008 |
| Meta-analysis including 34 studies of HCV infected patients | T2DM risk was higher in HCV-infected in both retrospective and prospective studies | White et al.,29 2008 |
| 275 nondiabetic treatment-naïve CHC patients | IR was increased in 37% of patients, contributing to fibrosis progression, and was more prevalent in obese patients with steatosis. No connections with genotype or viremia. | Tsochatzis et al.,41 2009 |
| 28 CHC patients treated with pegylated-IFNα2a/RBV | Disappearance of HCV RNA at 6 months after treatment independently reduced IR | Kim et al.,27 2009 |
| 38 CHC patients and healthy controls | IR was positively correlated with HCV infection and liver fibrosis | Mohamed et al.,42 2009 |
| 14 patients with CHC (without MS) and 7 healthy controls | HCV infection was associated with peripheral and hepatic IR | Vanni et al.,19 2009 |
| 170 HCV mono-infected nad 170 HIV/HCV co-infected patients | IR was associated with liver fibrosis and steatosis in HCV mono-infected. | Halfon et al.,43 2009 |
| 96 CHC non-genotype 3 patients with advanced fibrosis treated with pegylated-IFN/RBV | HCV suppression was correlated with improvement in IR independent from potential confounders | Delgado-Borrego et al.,28 2010 |
| 188 patients in with different stages of HCV infection | IR, regardless of presence of T2DM, was significantly associated with HCC in patients with CHC | Hung et al.,44 2010 |
| 40 CHC genotype 1 patients enrolled in a study of danoprevir | HOMA-IR improvement was correlated with a decrease in viral load | Moucari et al.,45 2010 |
| 92 untreated consecutive male CHC patients | IR was detected in 63 (69%) patients. IR was associated with steatosis. | Ahmed et al.,46 2011 |
| 1,038 treatment-naive CHC patients enrolled in albinterferon alpha-2b vs. pegylated-IFNα2a study | SVR was independently associated with significant reduction in HOMA-IR in patients with genotype 1, not in genotypes 2 or 3 | Thompson et al.,47 2012 |
| 50 noncirrhotic, nondiabetic CHC patients (27 untreated, 23 treated with pegylated-IFN/RBV) | IR was not strongly associated with SVR. HCV therapy may improve IR regardless of virologic response | Brandman et al.,48 2012 |
| 140 CHC patients treated with pegylated-IFNα2a/RBV for 48 weeks | SVR was significantly lower in the IR-HCV group compared with the non-IR-HCV. Plasma insulin levels and HOMA-IR were decreased significantly in patients with SVR | Ziada et al.,49 2012 |
| 431 CHC patients receiving pegylated-IFNα2a/RBV or pegylated-IFNα2b/RBV | SVR prevented development of de novo IR in nondiabetic patients with CHC | Aghemo et al.,50 2012 |
| 155 anti-HCV positive patients without T2DM, hypercortisolism, thyroid disease, hyperlipidemia or infective diseases | 79 (51%) patients had elevated HOMA-IR | Kiran et al.,51 2013 |
| 102 nondiabetic and non-cirrhotic CHC patients (69% genotype 1) | 25% of subjects had IR. HCV viral load and genotype did not influence IR | Mukhtar et al.,52 2013 |
| 30 CHC patients and 8 healthy controls underwent a fasting test | 9 CHC patients had elevated HOMA-IR. Total ketone body change rate was lower in CHC patients. Mitochondrial β-oxidation impairment due to HCV infection suggested | Sato et al.,53 2013 |
| 44 treatment naive patients with genotype 1 or 3 | IR was found in 27 (61%) and significant steatosis in 37 (84%) patients. No difference in IR between genotypes. IR associated with higher levels of liver fibrosis and steatosis. | Péres et al.,54 2013 |
HCV and hepatic steatosis
Hepatic steatosis was reported to be a histologic feature of non-A, non-B (NANB) hepatitis several years before hepatitis C testing was available, and it was considered common enough to be used as a diagnostic aid in the absence of serological diagnostic tests for hepatitis C.55,56 Steatosis occurs in 40%–86% of patients with chronic hepatitis C, and its frequency varies with genotype.16–18 As already mentioned, steatosis is more common in genotype 3 infection, where it occurs in 73% of patients, while the prevalence of steatosis in patients infected with other genotypes is around 50%.16–18 Infection with HCV genotype 3 is also associated with higher steatosis scores than in other genotypes, even in the absence of the metabolic risk factors associated with NAFLD, and there is a significant correlation between the degree of steatosis and the HCV RNA viral load.57,58 It has also been demonstrated in patients infected with HCV genotype 3 that steatosis can improve and even disappear following successful treatment with interferon (IFN) and ribavirin (RBV).58 Recent studies investigating the role of a single-nucleotide polymorphism near the IL28B gene found that steatosis is less prevalent in carriers of the IL28B CC genotype, who also show less pronounced disturbances of lipid metabolism and a favorable response to IFN therapy.59
Studies investigating the association between HCV and hepatic steatosis, and their key findings, are summarized in Table 2.
Table 2.The association between HCV and hepatic steatosis
| Methods/Study population | Findings and conclusions | Authors |
| 240 LBS from patients with acute hepatitis A (86 patients), B (78 patients), and NANB (76 patients) | Steatosis was found in 26% of NANB hepatitis patients compared to 10% of hepatitis A and 6% of B patients | Kryger et al.,60 1982 |
| 181 LBS from 94 patients with chronic NANB hepatitis | Microvesicular steatosis was found in 59% of patients and was considered a typical sign of the chronic NANB | Wiese et al.,56 1985 |
| LBS from 39 patients with chronic NANB hepatitis during evaluation and follow-up | Fatty metamorphosis noted in 20 (51%) patients | Di Bisceglie et al.,61 1991 |
| LBS from 50 patients with CHC and 21 patients with autoimmune chronic hepatitis | Steatosis was more common in patients with CHC (72% vs. 19%) | Bach et al.,62 1992 |
| 54 LBS from 45 patients with CHC | Fatty change present in 29/54 (54%) specimens | Scheuer et al.,63 1992 |
| LBS from 358 anti-HCV positive patients | Steatosis was a prominent feature in patients with chronic HCV infection | Giusti et al.,64 1993 |
| Comparison of 317 HCV and 299 HBV LBS | Large-droplet fat droplets more likely to be seen in HCV | Lefkowitch et al.,65 1993 |
| LBS from 55 asymptomatic anti-HCV positive blood donors | Steatosis present in 47% | McMahon et al.,66 1994 |
| LBS from 148 patients with chronic hepatitis of which 121 (81.8%) were HCV-positive | Steatosis found in 60% of HCV-positive and in 52% of HCV-negative patients. No significant association between steatosis and HCV was found | Fiore et al.,67 1996 |
| LBS from 90 patients with CHC compared according to genotype | Steatosis was more prevalent in patients with HCV genotype 3a compared to genotypes 1a or 1b | Mihm et al.,68 1997 |
| LBS from 60 CHC patients compared to 18 patients with chronic hepatitis B and 41 with nonalcoholic steatohepatitis | Fat deposition occurred more often in patients with CHC than in chronic hepatitis B (52% versus 22%) | Czaja et al.,69 1998 |
| LBS from 43 CHC patients | Steatosis was observed in 21 (48.8%) patients | Fujie et al.,70 1999 |
| LBS from 148 CHC untreated patients | 91 patients (61%) had steatosis of various grade | Hourigan et al.,71 1999 |
| LBS from 101 HCV-infected patients without other risk factors for a fatty liver | Steatosis was found in 41 (40.6%) patients. HCV genotype 3 was associated with higher steatosis scores | Rubbia-Brandt et al.,57 2000 |
| LBS from 170 CHC patients | Steatosis was found in 90 (52.9%) patients | Ong et al.,72 2001 |
| LBS from 180 consecutive CHC patients and 41 additional subjects with a known duration of infection | 86 (48%) patients showed steatosis. Genotype 3a was associated with a higher prevalence | Adinolfi et al.,73 2001 |
| LBS from 100 male patients with untreated noncirrhotic CHC | Hypobetalipoproteinemia and genotype 3 were associated with steatosis in CHC patients | Serfaty et al.,74 2001 |
| Pre- and post-treatment LBS from 28 HCV genotype 1 and 34 genotype 3 patients | Steatosis was initially present in 16 (57%) patients with HCV genotype 1 and 21 (62%) patients with genotype 3. Achieving SVR greatly reduced steatosis in genotype 3 patients, but not in genotype 1 | Kumar et al.,75 2002 |
| LBS from 97 CHC patients | Steatosis was present in 171 patients (57.6%) with BMI and genotype 3a as independent predictors | Monto A et al.,76 2002 |
| Paired LBS from 98 CHC patients prior to antiviral treatment | 41 (42%) showed signs of steatosis. Prevalence and grade of steatosis were strongly associated with HCV genotype 3 | Westin et al.,77 2002 |
| LBS from 124 CHC patients | 90 (73%) specimens showed signs of steatosis. Genotype 3 was associated with increased steatosis grade | Hui et al.,78 2002 |
| Paired LBS (mean interval time of 48 months) were evaluated in 96 patients with CHC | Steatosis was initially found in 51 (54%) of patients. Worsening of steatosis was observed in 34% of patients, stability in 50%, and improvement in 16% | Castéra et al.,79 2003 |
| LBS from 1,428 treatment naïve patients were assessed at baseline and 24 weeks after treatment with peginterferon or interferon α-2b and ribavirin | At baseline, steatosis was present in 935 of 1428 patients (65%), including 175 of 210 patients (83%) with genotype 3 versus 760 of 1218 (62%) with other genotypes. Steatosis was associated with genotype 3, fibrosis and lower SVR | Poynard et al.,56 2003 |
| LBS from 290 CHC patients | 135 patients (46.6%) had steatosis, and it was associated with HCV genotype 3, higher grade of necroinflammation, and higher BMI | Asselah et al.,80 2003 |
| LBS from 755 CHC patients | Steatosis was found in 315 (42%) and fibrosis in 605 patients. Steatosis was independently associated with fibrosis, genotype 3, BMI, ongoing alcohol abuse and age | Rubbia-Brandt et al.,81 2004 |
| LBS from 574 CHC patients | Steatosis was present in 277 (48%) of patients. Severity of steatosis was associated with BMI, HCV genotype 3, age, and duration of infection | Patton et al.,82 2004 |
| Paired LBS (median interval of 61 months) from 135 untreated CHC patients with a METAVIR score of A1F1 or lower on first liver biopsy | Steatosis was the only independent factor predictive of progression of fibrosis regardless of genotype | Fartoux et al.,83 2005 |
| LBS from two cohorts with a total of 325 genotype 1 HCV infected patients were analyzed for the presence and severity of steatosis in relation to the rs12979860 polymorphism at the IL28B locus | Steatosis was found in 67.4% (89/132) of IL28B non-CC patients compared to 39.6% (19/48) of CC patients | Tilmann et al.,59 2011 |
| LBS from 92 untreated males with CHC | Steatosis was found in 54% of patients and was associated with IR | Ahmed et al.,46 2011 |
| LBS from 152 liver transplant recipients with HCV followed up for a median of 2.09 years | Steatosis was frequent (29.6%) in the early post-transplant period and its presence within the first year carried a higher risk of fibrosis progression | Brandman et al.,84 2011 |
| LBS from 148 CHC patients | Steatosis was found in 40 patients (27%). No correlation with fibrosis or response to combined antiviral therapy was found | Rafi et al.,85 2011 |
| LBS from 50 HCV positive patients | 28 (56%) patients had steatosis, and it was associated with age and triglycerides levels | Ouakaa-Kchaou et al.,86 2011 |
| LBS from 50 patients with HCV genotype 2 and 256 with HCV genotype 3 | Steatosis was present in 72% of patients. Advanced liver fibrosis and hepatic steatosis were more common in HCV genotype 3 | Melo et al.,87 2014 |
| LBS from 330 patients with chronic hepatitis (66 HBV, 198 HCV, and 66 HBV-HCV co-infected) | Steatosis prevalence was comparable between the HBV-HCV co-infected and HCV groups (47.0% vs 49.5%, respectively). HBV group showed lowest steatosis rates (33.3%) | Zampino R et al.,88 2014 |
| 110 HBV infected, 111 HCV infected and 136 NAFLD patients were evaluated using steatosis biomarkers (SteatoTest > 0.38 as a surrogate for steatosis > 5%) | Prevalence of steatosis was 21% in chronic hepatitis B, 43% in CHC and 82% in NAFLD patients | Pais et al.,89 2015 |
Pathogenesis of insulin resistance and steatosis in HCV infection
The pathogenesis of IR and steatosis in HCV infection is a very intriguing problem, and extensive research of this topic has been undertaken. Different pathogenetic mechanisms have been proposed to explain the development of IR in HCV infected patients.90–95
In vitro and animal studies have greatly contributed to our understanding of both lipid and glucose metabolism alterations induced by HCV. Glucose transporter 2 (GLUT2), responsible for transporting glucose to hepatocytes, is downregulated by the HCV core protein, while the overproduction of tumor necrosis factor alpha (TNF-α), induced by HCV infection, inhibits insulin receptor substrate (IRS) and phosphatidylinositol 3 kinase (PI3K) via suppressor of cytokine signaling (SOCS)-3. These impairments of intracellular insulin signaling could block GLUT-4 activation, reducing the uptake of glucose by cells.96–98
Other cytokines besides TNF-α, such as IL-6 as well as a number of adipokines, have been shown to play a part in IR and steatosis pathogenesis of NAFLD, and evidence on their influence in HCV-induced metabolic changes continue to grow.99,100 HCV infection has also been suggested to cause mitochondrial dysfunction and endoplasmic reticulum impairment, while the genotype 3 HCV core protein has been shown to downregulate peroxisome proliferator activating receptor (PPARγ) and upregulate SOCS-7, leading to further impairment of insulin signaling.101–103
As for human studies, in a landmark study using liver biopsy specimens (LBS) obtained from nonobese, nondiabetic HCV-infected patients, HCV inhibited the insulin-stimulated tyrosine phosphorylation of hepatic insulin receptor substrate-1 (IRS-1), resulting in inhibition of the PI3K-Akt pathway, a key transducer of the insulin metabolic signal.104,105 HCV core protein was thus shown to impair hepatocyte insulin signaling by increasing cytokine production, predominantly TNF-α, activating SOCS, and inhibiting IRS through several mechanisms.
All these mechanisms are probably responsible for hepatic IR. However, there is also evidence of significant peripheral IR in HCV infection. Milner et al., using a hyperinsulinemic-euglycemic clamp, found no difference in hepatic glucose production and nonesterified free fatty acids suppresion with insulin between CHC patients and controls, suggesting IR is predominantly in muscles.20 Vanii et al. approximated the contribution of peripheral IR in CHC to reach 80%.19 The role of liver-derived circulating factors (hepatokines), as possible mediators of the liver-muscle crosstalk, has yet to be fully elucidated.106
The development of steatosis is also probably a result of several mechanisms. Both HCV induced and host related IR as well as metabolic factors are important for its development; it is also, however, a consequence of derangements of lipid metabolism caused directly by HCV.16
The influence of HCV on cholesterol and lipogenesis pathways of hepatocytes is a crucial part of its life cycle. HCV core protein plays a major role in the replication process by inducing accumulation of lipid droplets as well as lipogenic gene and protein activity, consequently manifesting as hepatic steatosis.107 Main mechanisms of HCV-induced hepatic steatosis include promotion of lipogenesis, impairment of mitochondrial lipid oxidation, and decreased microsomal triglyceride transfer protein (MTTP) activity.108,109
The activity of the HCV core protein decreases the expression and activity of the nuclear PPAR-α/γ, which, besides being strongly involved in lipid and lipoprotein metabolism, seem to have a protective effect against hepatic inflammation and fibrosis. The analysis of PPAR-α expression in LBS of 86 untreated patients with HCV and controls found it to be deeply impaired.110 The HCV core protein also induces hepatic fat accumulation by activating the sterol regulatory element-binding protein-1c (SREBP-1c), a transcription factor regulating lipogenesis.111 A study in transgenic mice expressing the full HCV protein repertoire showed maturational activation and nuclear translocation of SREBP-1c, resulting in increased lipogenic enzyme transcription.112 The factors involved in pathogenesis of metabolic changes in HCV infection as well as clinical outcomes are shown in Fig. 1.
Clinical consequences of hepatitis C associated steatosis and IR
The presence of both steatosis and IR in CHC may affect fibrosis and therapy outcomes as well as promote atherosclerosis and hepatic malignancy.
Liver fibrosis severity and progression are associated with hepatic steatosis and can be used as a clinically relevant parameter regarding starting and prioritizing treatment in CHC patients.77,82,113,114
IR, independent of other factors, is significantly associated with HCC development in patients with CHC.44
Of further clinical relevance, primarily in areas where IFN-free regimens with direct-acting antivirals are not yet the standard of care, is the fact that IR has been shown to affect negatively responses to IFN treatment, effectively lowering sustained viral response (SVR) rates irrespective of genotype.115
A review by Negro lists a number of conflicting studies regarding the impact of chronic HCV infection on cardiovascular morbidity.116 It is not yet clear if the reported conditions and observations, such as increased incidence of coronary artery disease, stroke rate, and carotid plaque formation, are a result of a systemic chronic inflammation, direct viral action, or a consequence of IR.
The intricacies of the pathogenesis of IR, hepatic steatosis, and metabolic syndrome are not yet fully understood, and the fact that HCV is able to induce such changes and play a part in such a complex interplay of metabolic processes means it should remain an important focus of research, even as new therapies promise to make hepatitis C an easily managable condition.
Conclusions
Many epidemiological, clinical, and experimental studies have shown that HCV infection is strongly associated with liver steatosis, IR, and the development of T2DM. Our overview of available clinical data further establishes this premise and, with very few exceptions, shows the presence and strength of this association across various groups of patients, providing a strong foothold for future consideration of this topic. The severity of hepatic steatosis in CHC arises from the combination of several host features (like visceral obesity, genetic predisposition, medication use, and alcohol consumption) and viral factors (including genotype, viral load, and gene mutations), which interfere with lipid metabolism within the hepatocytes or promote IR in the liver and peripheral tissues.
The presence and severity of HCV associated steatosis and IR impact liver fibrosis severity and progression, lower rates of response to interferon-based therapy, promote HCC development, and probably increase cardiovascular morbidity.
The recognition of the link between HCV, steatosis, and MS is important for improved patient treatment and care, and many unresolved issues make it an intriguing area of future research.
Abbreviations
- CHC:
chronic hepatitis C
- GLUT:
glucose transporter
- HBV:
hepatitis B virus
- HCV:
hepatitis C virus
- HCC:
hepatocellular carcinoma
- HOMA:
homeostatic model assessment
- HIV:
human immunodeficiency virus
- IRS:
insulin receptor substrate
- IR:
insulin resistance
- IFNα:
interferon-α
- IL:
interleukin
- LBS:
liver biopsy specimens
- MS:
metabolic syndrome
- MTTP:
microsomal triglyceride transfer protein
- NANB:
non-A, non-B
- NAFLD:
non-alcoholic fatty liver disease
- NASH:
non-alcoholic steatohepatitis
- PPAR:
peroxisome proliferator activating receptor
- PI3K:
phosphatidylinositol 3-kinase
- RBV:
ribavirin
- SREBP-1c:
sterol regulatory element-binding protein-1c
- SOCS-3:
suppressor of cytokine signaling 3
- SVR:
sustained viral response
- TNF-α:
tumor necrosis factor-α
- T2DM:
type 2 diabetes mellitus
Declarations
Conflict of interest
None
Authors’ contributions
Concept and literature search (DK and LVJ), drafting the manuscript (DK, LVJ and SS), and critical revision with intellectual content (LVJ, MD, MVS, IBC).