Pathogenesis and significance of hepatitis C virus steatosis: An update on survival strategy of a successful pathogen

Table 1 Steatosis is associated with fibrosis

Method and findings	Conclusion	Ref.
98 CHC patients who had undergone repeat liver biopsies before antiviral treatment (median follow-up 5.8 yr)	In HCV patients with genotype 3 infection, steatosis was a risk factor for fibrosis progression	[68]
297 consecutive patients with HCV	Steatosis and inflammation scores were the only parameters independently predicting fibrosis	[70]
96 non-cirrhotic treatment-naive CHC patients	In untreated CHC patients fibrosis progression was strongly associated with worsening of steatosis	[71]
1428 CHC treatment-naïve patients included in a French therapeutic trial	The variables independently associated with steatosis were genotype 3 , higher age, triglycerides and body mass index (BMI) values and septal fibrosis	[72]
131 biopsy-proven CHC individuals	Hepatic steatosis was related to genotype, fibrosis degree, and serum leptin level	[73]
160 CHC patients	Irrespective of viral genotype, patients who had steatosis showed significantly more fibrosis than non-steatosic	[74]
Cross sectional study evaluating: 233 hepatic biopsies from 219 CHC patients and hepatectomy specimens from 65 patients transplanted for HCV-related cirrhosis. Longitudinal study: 41 patients with two biopsies and 10 patients with three biopsies performed over 2-8 yr	Steatosis was associated with fibrosis independently of necroinflammation, but declined in cirrhosis	[75]
Retrospective study conducted on 324 US patients with CHC from a university medical center and a regional VA medical center	Steatosis was independently associated with advanced fibrosis stage	[76]
135 treatment-naive CHC patients who had undergone repeat liver biopsies after a median interval of 61 months after the baseline biopsy	Irrespective of HCV genotype, steatosis was a chief contributor to fibrosis progression in mild CHC and the probability of such a fibrosis worsening is directly dependent on the proportion of steatotic hepatocytes	[77]
116 CHC patients undergoing liver biopsy	The MTHFR C677T polymorphism, responsible for hyperhomocysteinemia, contributed to increasing steatogenesis and steatosis which in its turn, hastened hepatic fibrosis progression	[78]
Meta-analysis on individual data from 3068 patients with biopsy- proven CHC recruited from 10 centers in Europe, Australia, and United States	Steatosis was significantly and independently associated with fibrosis in CHC. Hepatic inflammation may mediate fibrogenesis in patients with liver steatosis	[79]
180 patients infected with genotype 1b HCV	At multivariate analysis, fibrosis was significantly related to age, alanine transaminase, diabetes, hepatitis B core antibody, steatohepatitis and grading	[80]
Overall, 600 consecutive individuals: 500 with CHC; and 100 with CHB	IR, was associated with 1 and 4 HCV genotypes and high viral load. The association of significant fibrosis with IR occurs independent of steatosis	[81]
153 chronic hepatitis C patients enrolled in the Swiss hepatitis c cohort study and for whom a liver biopsy and plasma samples were available	By multiple regression analysis, CTGF levels were independently associated with steatosis, a past history of alcohol abuse, plasma leptin and HCV RNA levels; when only patients with genotypes non-3 were considered, CTGF levels were independently associated with a past history of alcohol abuse, plasma leptin levels and steatosis	[82]
107 consecutive CHC patients	Multiple regression analysis revealed that, HOMA-IR, fibrosis and oxidative stress were independently associated with steatosis, whereas steatosis was independently associated with oxidative stress and HOMA-IR. Steatosis and HAI were also independent predictors of fibrosis	[83]
143 AA and 157 CA adults with untreated chronic HCV genotype 1 infection	In 3-variable models including race and biopsy adequacy, the factors significantly associated with fibrosis progression were age when infected, steatosis, ALT level, and necroinflammatory score	[84]
228 HCV treatment-naive patients who met the inclusion/exclusion criteria	Genotype 1 and presence of steatosis were found to be associated significantly with MS. After adjusting for confounding variables, MS remained independently associated with a lack of SVR	[85]
346 untreated, nondiabetic patients solely infected with either genotype 1 or 3	HOMA-IR rather than steatosis was independently associated with fibrosis for both HCV genotype 1 and genotype 3. Exclusion of cirrhotic subjects did not alter the findings with respect to the greater contribution of IR compared to hepatic steatosis, as a predictor of fibrosis	[86]
Retrospective study of 460 patients with CHC	Elevated AST, alpha fetoprotein, and presence of grade 2 and 3 steatosis are independent parameters associated with stage 3 and 4 fibrosis in patients with CHC	[87]
112 HCV RNA positive subjects who had two liver biopsies performed	On multivariate analysis, only baseline steatosis was significantly associated with fibrosis. Kaplan-Meier analysis demonstrated that steatosis impacted on time to progression to both significant fibrosis and cirrhosis	[88]
Of 253 HCV RNA-positive persons who underwent at least one liver biopsy	The presence of T2D, steatosis and duration of HCV infection were independent predictors of advanced fibrosis	[89]
Metanalysis of 12 published studies, including 1989 HIV/HCV co-infected patients	In co-infected patients, HS was associated with higher body mass index, diabetes mellitus, elevated alanine aminotransferase, necroinflammatory activity and fibrosis	[90]
Liver biopsy samples were collected from 59 patients with HCV without a sustained virologic response (SVR) or cirrhosis	There were no associations between fibrosis progression and histologic features including inflammation, fibrosis, or steatosis	[91]
170 genotype 1 CHC patients	At multivariate analysis Severe (F3-F4 fibrosis), , was independently associated with older age, IR, steatosis > 10%, and moderate-severe necroinflammatory activity in CHC patients	[92]
92 untreated consecutive adults with chronic HCV infection admitted for liver biopsy	In multivariate analyses, fibrosis was associated with high AST level, age ≥ 40 yr, and steatosis	[93]
152 LT recipients with HCV were followed up with repeated liver biopsies for a median of 2.09 yr after index biopsy	In the multivariate analysis, steatosis at 1 yr was an independent predictor of subsequent F2 to F4 fibrosis. Steatosis was a stronger predictor of fibrosis in the setting of sirolimus use	[94]
755 consecutive chronic hepatitis C patients (178 with genotype 3), admitted to three referral hospitals in Switzerland	Fibrosis was associated with steatosis in genotype 3 infected individuals alone	[95]
574 CHC patients with chronic hepatitis C from a single United States center	In CHC owing to genotype 1 infection HCV, fibrosis was associated with steatosis severity	[96]
Clinical data and liver histology findings in 510 HCV patients were analysed	Age at liver biopsy, BMI and duration of HCV were independent risk factors for increased fibrosis in HCV patients. Steatosis as a risk factor for fibrosis is evident in HCV genotype-1	[97]
60 HCV patients compared to 41 NASH patients and 18 CHB individuals	Compared to patients who had mild steatosis, those CHC individuals with moderate steatosis exhibited higher fibrosis stages	[98]
251 CHC women	Severity of fibrosis was associated with a longer duration of infection, a higher BMI, advanced steatosis and the menopause	[99]
Ninety HCV infected patients undergoing liver biopsy	Steatosis was not found to be independently associated with fibrosis	[100]
Liver biopsies from 66 out of 306 HCV/HIV non-cirrhotic patients without cirrhosis at baseline who underwent a second biopsy were case-matched with a control group selected from a cohort of 233 HCV mono-infected patients	Progression of fibrosis was similar in HIV/HCV-co-infected compared to HCV mono-infected individuals and no clinical or laboratory predictor of worsening liver disease was identified	[101]

AA: African American; CA: Caucasian American; CHB: Chronic hepatitis B; CHC: Chronic hepatitis C; CTGF: Connective tissue growth factor; HAI: Hepatic activity index; HOMA-IR: Homeostasis model of insulin resistance; HS: Hepatic steatosis; LT: Liver transplantation; T2D: Type 2 diabete; HCV: Hepatitis C virus; HIV: Human immunodeficiency virus.