Salvatore Petta

Non-alcoholic fatty liver disease pathogenesis: The present and the future

Non-alcoholic fatty liver disease is the clinical hepatic expression of metabolic syndrome. The prevalence of non-alcoholic fatty liver disease is around 20-30%, and with a rapid increase in the metabolic risk factors in the general population, non-alcoholic fatty liver disease has become the most common cause of liver disease worldwide. A fraction (20-30%) of non-alcoholic fatty liver disease patients develop a potentially progressive hepatic disorder, namely non-alcoholic steatohepatitis, leading to end-stage liver disease. The pathogenesis of non-alcoholic fatty liver disease is not entirely understood, and even if insulin resistance is a major pathogenetic key, many other factors are implicated in both liver fat accumulation and disease progression to non-alcoholic steatohepatitis. In this review we aim to examine the literature, principally concerning human non-alcoholic fatty liver disease pathogenesis, and to identify the newest, most promising clinical and basic research data.

Insulin resistance and diabetes increase fibrosis in the liver of patients with genotype 1 HCV infection.

OBJECTIVES:Metabolic factors may affect the course of chronic hepatitis C (CHC). Insulin resistance (IR) determines steatosis, but its direct role in affecting progression of hepatic fibrosis is less clear. We aimed to assess whether increasing degrees of IR, up to overt diabetes, are linked to steatosis and higher stages of fibrosis in patients with CHC resulting from genotype 1 HCV (G1-HCV).METHODS:Two hundred one consecutive patients with G1-HCV infection were evaluated by liver biopsy and anthropometric and metabolic measurements, including IR, by the homeostasis model assessment (HOMA). Nondiabetic patients were defined as insulin resistant if HOMA-IR was >2.7. All biopsies were scored by one pathologist for staging and grading (Scheuer), and graded for steatosis.RESULTS:Ninety-six patients were noninsulin resistant (group 1), 76 were insulin resistant without diabetes (group 2), and 29 were diabetic (group 3). At multivariate analysis, fibrosis of ≥3 was independently associated with high necroinflammatory activity (odds ratio [OR] 2.994, 95% confidence interval [CI] 1.422–6.098), low platelets (OR 0.994, 95% CI 0.981–0.999), low cholesterol (OR 0.987, 95% CI 0.976–0.998), high ferritin (OR 1.002, 95% CI 1.001–1.004), and a high prevalence of IR (OR 2.692, 95% CI 1.463–4.954). Diabetic patients were twice as likely to have severe fibrosis (60%) than those with IR but no diabetes (30%) (P = 0.006). The degree of steatosis and that of fibrosis were weakly associated with each other (P = 0.42).CONCLUSIONS:In subjects with CHC resulting from G1-HCV, IR and overt diabetes are major determinants of advanced fibrosis, regardless of the degree of steatosis, mainly in the presence of severe necroinflammation.

Carotid atherosclerosis and chronic hepatitis C: A prospective study of risk associations

There are contrasting results in studies of cardiovascular risk in patients with genotype 1 chronic hepatitis C (G1 CHC). We evaluated the prevalence of carotid atherosclerosis compared with a control population in order to assess the potential association between atherosclerosis, host and viral factors, and liver histological features. In all, 174 consecutive biopsy‐proven G1 CHC patients were evaluated by anthropometric and metabolic measurements and 174 patients attending an outpatient cardiology unit were used as controls. Intima‐media thickness (IMT) and carotid plaques, defined as focal thickening of >1.3 mm at the level of common carotid, were evaluated using ultrasonography. All G1 CHC biopsies were scored by one pathologist for staging and grading, and graded for steatosis. Carotid plaques were found in 73 (41.9%) G1 CHC patients compared with 40 (22.9%) control patients (P < 0.001). Similarly, G1 CHC patients had a greater IMT compared with control patients (1.04 ± 0.21 versus 0.90 ± 0.16; P < 0.001). Multivariate logistic regression analysis showed that older age (odds ratio [OR] 1.047, 95% confidence interval [CI]: 1.014‐1.082, P = 0.005), and severe hepatic fibrosis (OR 2.177, 95% CI: 1.043‐4.542, P = 0.03), were independently linked to the presence of carotid plaques. In patients ≤55 years, 15/67 cases with F0‐F2 fibrosis (22.3%) had carotid plaques, compared with 11/21 (52.3%) with F3‐F4 fibrosis (P = 0.008). By contrast, in patients >55 years the prevalence of carotid plaques was similar in those with or without severe fibrosis (25/43, 58.1% versus 22/43, 51.1%; P = 0.51). Conclusion: Severe hepatic fibrosis is associated with a high risk of early carotid atherosclerosis in G1 CHC patients. (HEPATOLOGY 2012)

Insulin resistance is a risk factor for esophageal varices in hepatitis C virus cirrhosis

Indirect methods to predict the presence of esophageal varices (EV) in patients with cirrhosis are not sensitive enough to be used as a surrogate for endoscopy. We tested the effectiveness of liver stiffness measurement (LSM) by transient elastography and the presence of insulin resistance (IR), a marker associated with fibrosis progression, in the noninvasive prediction of portal hypertension. One hundred four consecutive patients with newly diagnosed Child A hepatitis C virus (HCV) cirrhosis underwent upper gastrointestinal endoscopy to search for EV. Clinical, anthropometric, biochemical, ultrasonographic, and metabolic features, including IR by the homeostasis model assessment (HOMA), and LSM by transient elastography, were recorded at the time of endoscopy. EVs were detected in 63 of 104 patients (60%). In 10 patients (16%), the EVs were medium‐large (≥F2). By multivariate analysis, the presence of EVs was independently associated with a low platelet count/spleen diameter ratio (OR, 0.998; 95% CI, 0.996‐0.999) and a high HOMA‐IR score (OR, 1.296; 95%CI, 1.018‐1.649), not with LSM (OR, 1.009; 95%CI, 0.951‐1.070). It is noteworthy that nine of ten patients with medium‐large EVs had a platelet/spleen ratio of less than 792 or an HOMA‐IR of greater than 3.5. The independent association between low platelet count/spleen diameter ratio (OR, 0.998; 95%CI, 0.996‐1.000), high HOMA‐IR score (OR, 1.373; 95%CI, 1.014‐1.859) and presence of EV was confirmed in the subgroup of 77 nondiabetic subjects. Conclusions: In patients with Child A HCV cirrhosis, two simple, easy‐to‐get tests, namely the platelet/spleen ratio and insulin resistance measured by HOMA‐IR, regardless of the presence of diabetes, significantly predict the presence of EV, outweighing the contribution given by transient elastography. (HEPATOLOGY 2009;49:195‐203)

Hepatitis C and diabetes: the inevitable coincidence?

Type 2 diabetes (T2D) and HCV infection are common conditions involving, respectively, at least 170 and 130 million people worldwide. However, the distribution of such cases does not overlap in the same age groups in different geographic areas. Following pioneering reports of increased prevalence of T2D in HCV-positive cirrhosis, interest concerning the relationship between HCV and T2D has escalated. HCV is able to induce insulin resistance (IR) directly and the role of specific viral genotypes responsible for such effect is disputed. IR has consistently been found to be closely linked to fibrosis in HCV infection, although also typically associated with T2D in prefibrotic stages. HCV infection could be associated with a reduced prevalence of metabolic syndrome owing to virus-associated reduction in BMI (reported in population but not clinical studies) and hypobetaliproteinemia. A three- to ten-fold increased risk of HCV infection was reported among diabetic patients in comparison with different control groups and a meta-analysis showed a 1.8-fold excess risk of T2D among HCV-positive compared with HBV-positive patients. Moreover, HCV positivity is associated with an increased risk of T2D in patients receiving liver or kidney transplantations. T2D and IR are independent predictors of a more rapid progression of liver fibrosis and impaired response to antiviral treatment in chronic hepatitis C. Patients with cirrhosis and T2D have an increased susceptibility to hepatic encephalopathy and hepatocellular carcinoma (HCC). However, the beneficial effects of antiviral treatment on IR and T2D are controversial. Theoretically, glycemic control in chronic hepatitis C, and particularly in cirrhotic patients, could improve the prognosis and the response to antivirals, although the evidence for this is limited. Future studies should elucidate the relationship between insulin signaling, HCV and interferon signaling, entity of cardiovascular risk in patients with HCV infection, the potential role of ‘metabolic’ strategies added to antiviral treatment schedules, the impact of IR on liver failure, portal hypertension and HCC, particularly in patients managed in a transplant setting.

Anti-tissue transglutaminase antibodies in patients with abnormal liver tests: is it always coeliac disease?

BACKGROUND:Coeliac disease (CD) is found in 5–10% of patients with chronically abnormal liver tests and no obvious cause of liver disease. In this population the efficacy of screening for CD by anti-tissue transglutaminase (anti-tTG) may be impaired by the high rate of positive anti-tTG found in chronic liver disease.AIMS:To evaluate the prevalence of coeliac disease and the role of anti-tTG in patients with non-viral, non-autoimmune chronic and no obvious cause of liver damage.METHODS:Out of 2,512 consecutive patients with abnormal liver tests, 168 (118 men, 50 women; mean age 40.7 ± 12.6 years) were defined, on the basis of clinical data and liver biopsy, as NAFLD or cryptogenic chronic hepatitis. All were tested by recombinant IgA and IgG anti-tissue transglutaminase. Patients with a positive serology underwent endoscopy with duodenal biopsies.RESULTS:NAFLD was diagnosed in 121 patients, in 6 associated with cirrhosis, while 47 patients were considered as cryptogenic hepatitis in the absence of steatosis. Anti-tTG were positive in 20/168 patients (3 IgA alone; 11 IgG alone; 6 both IgA and IgG). Coeliac disease was found at endoscopy and confirmed by histopathology only in the 6 patients (3.6%) with both IgA and IgG anti-tTG positivity. Four of the patients with CD had NAFLD (3.3%), in 2 of them associated with cirrhosis; while 2 of those with cryptogenic hepatitis (4.2%) had CD.CONCLUSIONS:The prevalence of CD in patients with chronically abnormal liver tests of unexplained etiology is 4%, with no relation with the degree of liver steatosis. Screening should be done by testing for IgA and IgG antibodies and then evaluating by endoscopy and biopsy only patients positive for both.

How to optimize HCV therapy in genotype 1 patients: predictors of response

The advent of triple therapy (TT) with first‐generation protease inhibitors boceprevir (BOC) and telaprevir (TVR) in addition to pegylated interferon and ribavirin (PEG‐IFN/RBV) has resulted in a significant improvement in the sustained virological response (SVR) rate and potentially in life years gained compared to dual therapy (DT), when treating naïve or treatment‐experienced patients with genotype 1 (G1) chronic hepatitis C (CHC). This benefit is partly offset by the increased complexity of treatment, and the increased costs and risks of therapy, making it necessary to optimize the indications for TT. Naïve patients with mild fibrosis and the IL28B CC polymorphism and/or with a rapid virological response (RVR) to DT can still benefit from DT, while TT is preferable in all others. Phase 3 trials have clearly shown that a 1 log10 decrease in HCVRNA after 4 weeks of DT associated with a favourable IL28B genotype and a low stage of fibrosis, and a pattern of previous response to DT in treatment‐experienced patients are the strongest predictors of an SVR to TT. Moreover, an extended rapid virological response (eRVR) is associated with an SVR rate >90%, so that the overall duration of treatment can be shortened in a high proportion of patients. Further efforts to optimize the current TT regimens both by increasing efficacy and improving tolerance are still needed. Most important, in the future, treatment can probably be personalized based on data from post‐marketing surveillance of TT providing information about patient groups that were underrepresented in phase 3 studies such as those with cirrhosis.

Serum BLyS/BAFF predicts the outcome of acute hepatitis C virus infection

Summary.u2002 B‐lymphocyte stimulator/B activating factor (BLyS/BAFF) is a tumour necrosis factor‐family cytokine that plays a key role in generating and maintaining the mature B‐cell pool. BLyS/BAFF expression by macrophages is stimulated by interferon‐γ and interleukin‐10, and its serum levels are increased in chronic hepatitis C (CHC). The aim of this study was to assess serum levels of BLyS/BAFF in patients with acute hepatitis C (AHC) and correlate them with disease outcome. We studied 28 patients with AHC (14 males, mean age 59.3u2003±u200315u2003years), followed for at least 7u2003months since onset, comparing them with 86 CHC patients and 25 healthy blood donors (HBD). BLyS/BAFF levels were assessed at baseline (within 4u2003weeks of onset) and during follow‐up. BLyS/BAFF median levels were significantly higher in AHC (1485u2003pg/mL) than in CHC (1058u2003pg/mL) and in HBD (980u2003pg/mL) (Pu2003<u20030.001). BLyS/BAFF levels were higher in AHC patients evolving to chronicity (1980u2003pg/mL) than in those with a self‐limited course (1200u2003pg/mL), (Pu2003=u20030.02). By logistic regression analysis, higher BLyS/BAFF levels were independently associated with persistence of HCV infection (OR 29.7; 95%u2003CI: 1.73–508.20). High serum levels of BLyS/BAFF at onset of AHC can predict its evolution to chronic infection.

Optimal therapy in hepatitis C virus genotypes 2 and 3 patients

Current guidelines recommend that patients with genotype 2 (G2) and 3 (G3) chronic hepatitis C be treated with pegylated interferon (PEG‐IFN) plus low doses of ribavirin (800u2003mg/day) for 24 weeks, resulting in a sustained virological response (SVR) rate of approximately 80%. Considering these high response rates, several recent randomized trials have assessed whether shorter treatment (12–16 weeks) could be cost‐effective in these patients. The results of these studies vary but suggest better responsiveness in G2 patients, and overall, do not strongly support reducing treatment to <24 weeks in all patients. On the other hand, the presence of a rapid virological response (RVR) (defined as an undetectable hepatitis C virus‐RNA at 4 weeks of treatment) was always reported to be the best positive predictor of achieving SVR in both G2 and G3 patients. These results suggest that in a subgroup of subjects with RVR (G2>G3, viral load <400u2003000u2003IU, low fibrosis, no metabolic cofactors), shorter treatment is as effective as standard regimens, and that it can be proposed mainly if problems of poor tolerance or adherence are foreseen. It is possible that the SVR rate in non‐RVR patients and non‐responder patients could also be improved by prolonging therapy, but this must be specifically investigated in other studies along with the role of IL28B polymorphisms.

Visceral adiposity index and exercise in non-alcoholic fatty liver disease: authors’ reply

We thank Prof. Filik for his interest in our recent article. 2 He points to the fact that the interpretation of our results could be affected by lack of data on physical activity and diet. In response to this issue, we are aware that both physical activity and diet are able to affect not only anthropometric and metabolic parameters of visceral adiposity index (VAI) but also the severity of liver disease. Unfortunately, data on both physical activity and diet in our patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD) are not available, even if we are confident that their variations should not significantly affect our results. In fact, in our study, we evaluated histological liver damage and metabolic features of NAFLD patients who had not yet undergone lifestyle intervention. In any case, we found useful a further prospective evaluation of the impact of baseline diet and physical activity on both VAI and liver disease severity. These data, in fact, together with follow-up data, could help validate VAI as a surrogate marker of metabolic and liver disease improvement after therapeutic approaches in NAFLD patients.