Fabio Salvatore Macaluso

The severity of steatosis influences liver stiffness measurement in patients with nonalcoholic fatty liver disease

In nonalcoholic fatty liver disease, the influence of severity of steatosis on liver stiffness measurement (LSM) is poorly studied and still debated. We assessed the impact of steatosis severity and its ultrasonographic (US) sign, severe bright liver echo pattern, on LSM values and on transient elastography accuracy for the diagnosis of liver fibrosis in a cohort of consecutive patients with nonalcoholic fatty liver disease. Patients (n = 253) were assessed by clinical, US, and histological (Kleiner score) features. Transient elastography was performed using the M probe. Among patients with low amounts of fibrosis (F0‐F1 and F0‐F2), median LSM values, expressed in kilopascals, were significantly higher in subjects with severe steatosis (≥66% at liver biopsy) compared to those without (F0‐F1 6.9 versus 5.8, P = 0.04; F0‐F2 7.4 versus 6.0, P = 0.001) as well as in patients with severe bright liver echo pattern on US compared to their counterparts (F0‐F1 7.3 versus 5.6, P = 0.001; F0‐F2 7.6 versus 6.0, P < 0.001). In subjects without significant fibrosis (F0‐F1) and without severe fibrosis (F0‐F2), a higher rate of false‐positive LSM results was observed in patients with steatosis ≥66% compared to those without (F0‐F1 23.6% versus 14.9%, F0‐F2 33.3% versus 13.2%) and in patients with severe bright liver echo pattern on US (F0‐F1 22.2% versus 15.4%, F0‐F2 28.8% versus 15.6%) compared to their counterparts. Conclusions: In patients with nonalcoholic fatty liver disease, the presence of severe steatosis, detected by histology or by US, should always be taken into account in order to avoid overestimations of liver fibrosis assessed by transient elastography. (Hepatology 2015;62:1101‐1110)

Cost-effectiveness of sofosbuvir-based triple therapy for untreated patients with genotype 1 chronic hepatitis C.

We assessed the cost‐effectiveness of sofosbuvir (SOF)‐based triple therapy (TT) compared with boceprevir (BOC)‐ and telaprevir (TVR)‐based TT in untreated genotype 1 (G1) chronic hepatitis C (CHC) patients discriminated according to IL28B genotype, severity of liver fibrosis, and G1 subtype. The available published literature provided the data source. The target population was made up of untreated Caucasian patients, aged 50 years, with G1CHC and these were evaluated over a lifetime horizon by Markov model. The study was carried out from the perspective of the Italian National Health Service. Outcomes included discounted costs (in euros at 2013 value), life‐years gained (LYG), quality‐adjusted life year (QALY), and incremental cost‐effectiveness ratio (ICER). Cost of SOF was assumed to be €3,500 per week, i.e., the price generating a willingness‐to‐pay threshold of €25,000 per LYG compared with TVR in the entire population of untreated G1 patients. The robustness of the results was evaluated by one‐way deterministic and multivariate probabilistic sensitivity analyses. SOF was cost‐effective compared with BOC in all strategies with the exception of cirrhosis and IL28B CC patients. In comparison with TVR‐based strategies, SOF was cost‐effective in IL28B CT/TT (ICER per LYG €22,229) and G1a (€19,359) patients, not cost‐effective in IL28B CC (€45,330), fibrosis F0‐F3 (€26,444), and in cirrhosis (€34,906) patients, and dominated in G1b patients. The models were sensitive to SOF prices and to likelihood of sustained virological response. Conclusion: In untreated G1 CHC patients, SOF‐based TT may be a cost‐effective alternative to first‐generation protease inhibitors depending on pricing. The cost‐effectiveness of SOF improved in IL28B CT/TT and G1a patients. SOF was dominated by TVR in G1b patients even if, in clinical practice, this issue could be counterbalanced by the good tolerability profile of SOF and by the shorter treatment duration. (Hepatology 2014;59:1692–1705)

Hepatic steatosis and insulin resistance are associated with severe fibrosis in patients with chronic hepatitis caused by HBV or HCV infection.

Background and aims: Steatosis and insulin resistance (IR) are the major disease modifying in patients with chronic hepatitis C (CHC). Only few studies evaluated these features in patients with chronic hepatitis B (CHB). We aimed to assess the prevalence and the factors related to steatosis and IR in CHB patients, compared with CHC subjects, and to evaluate the potential association between these features and fibrosis severity.

Steatosis affects the performance of liver stiffness measurement for fibrosis assessment in patients with genotype 1 chronic hepatitis C

BACKGROUND & AIMS In Chronic Hepatitis C (CHC), the influence of steatosis on liver stiffness measurement (LSM) is still debated. We assessed the impact of steatosis and its ultrasonographical sign - bright liver echo pattern (BLEP) - on LSM values and on transient elastography (TE) accuracy for the diagnosis of liver fibrosis, in a cohort of consecutive patients with Genotype 1 (G1) CHC. METHODS Patients (n=618) were assessed by clinical, ultrasonographic and histological (Scheuer score) features. TE was performed using the M probe. RESULTS Male gender (p=0.04), steatosis as continuous variable (p<0.001), severity of necroinflammation (p=0.02) and stage of fibrosis (p<0.001) were associated with LSM by multivariate linear regression analysis. Among patients within the same fibrosis stages (F0-F2 and F3-F4; F0-F3 and F4), mean LSM values, expressed in kPa, were significantly higher in subjects with moderate-severe steatosis (⩾20% at liver biopsy) compared with those without, as well as in patients with BLEP on US compared with their counterpart. In subjects without severe fibrosis (F0-F2) and without cirrhosis (F0-F3), a higher rate of false-positive LSM results was observed in patients with steatosis ⩾20% compared with those without (F0-F2: 35.3% vs. 17.9%; F0-F3: 38.9% vs. 16.6%), and in patients with BLEP on US (F0-F2: 28.0% vs. 18.3%; F0-F3: 29.7% vs. 17.8%) compared with their counterpart. CONCLUSIONS In patients with G1 CHC, the presence of moderate-severe steatosis, detected by histology or by US, should always be taken into account in order to avoid overestimations of liver fibrosis assessed by TE.

Cardiovascular diseases and HCV infection: a simple association or more?

HCV infection, metabolic disorders and cardiovascular alterations, considered alone or in combination, are common conditions in a large proportion of the general population. Consequently, determining whether the association of HCV infection with cardiometabolic disorders is simply coincidental or, conversely, caused by pathogenetic mechanisms (in)directly linking chronic HCV infection to these disorders, would be of extreme relevance. Several clinical studies have shown that metabolic disorders—namely, type 2 diabetes,1 insulin resistance (IR)2 and hepatic steatosis3—are highly prevalent in patients with chronic hepatitis C (CHC) compared with non-infected patients. Experimental and clinical studies have shown that HCV is able to directly influence glucose and lipid metabolism and thus can perturb the metabolic homeostasis of the host, leading to extrahepatic consequences.4 ,5 However, unlike the classic forms of metabolic disturbances, CHC is associated with a favourable lipoprotein profile—that is, reduced levels of apolipoprotein B containing lipoproteins, such as low density lipoprotein and very low density lipoprotein cholesterol.6 The discordance between the increased prevalence of IR, steatosis and diabetes, and the favourable lipoprotein profile in CHC compared with non-infected individuals, may account for the similar prevalence of metabolic syndrome (ie, the presence of at least three of the following: visceral obesity, hyperglycaemia, arterial hypertension, low levels of high density lipoprotein cholesterol and high triglycerides levels)7 reported in data from the database of the third National Health and Nutrition Examination Survey (NHANES-III).8 These data raise the question of whether HCV infection per se and/or via induction of metabolic/inflammatory dysfunctions is associated with an increased cardiovascular risk. With this in mind, cross sectional and prospective studies have evaluated the presence and occurrence of both cardiovascular alterations and cardiovascular mortality in HCV infected patients compared with non-infected patients, with contrasting results.6 ,9–34 This review was prompted by …

Association of vitamin D serum levels and its common genetic determinants, with severity of liver fibrosis in genotype 1 chronic hepatitis C patients.

Lower 25‐hydroxyvitamin D [25(OH)D] serum levels have been associated with the severity of liver fibrosis in genotype 1 chronic hepatitis C patients (G1CHC). In addition, a recent genome‐wide study identified genetic variants (rs12785878, near dehydrocholesterol reductase, DHCR7; rs10741657, near CYP2R1; and rs7041, near vitamin D‐binding protein, GC) affecting 25(OH)D serum levels in healthy populations. We aimed to assess the association between vitamin D serum levels and its genetic determinants, with the severity of liver fibrosis. Two hundred and sixty patients with biopsy‐proven G1CHC were consecutively evaluated. The 25(OH)D serum levels were measured by high‐pressure liquid chromatography. All patients were genotyped for DHCR7 rs12785878, CYP2R1 rs10741657 and GC rs7041 single nucleotide polymorphisms. DHCR7 GG genotype (P = 0.003) and the severity of fibrosis (P = 0.03) were independent factors associated with lower 25(OH)D serum levels in multiple linear regression analysis. Interestingly, 53.8% (7/13) of patients with DHCR7 GG genotype had severe liver fibrosis, compared to 27.1% (67/247) of those with DHCR7 TT/TG genotype (P = 0.03). By multivariate logistic regression analysis, severe fibrosis was independently associated with older age (OR, 1.056; 95% CI, 1.023–1.089, P = 0.001), low cholesterol (OR, 0.984; 95% CI, 0.974–0.994, P = 0.002), high triglycerides (OR, 1.008; 95% CI, 1.002–1.015, P = 0.01), low 25(OH)D (OR, 0.958; 95% CI, 0.919–0.999, P = 0.04), DHCR7 GG genotype (OR, 4.222; 95% CI, 1.106–16.120; P = 0.03), moderate–severe steatosis (OR, 2.588; 95% CI, 1.355–4.943; P = 0.004) and moderate–severe necroinflammatory activity (grading) (OR, 2.437; 95% CI, 1.307–4.763; P = 0.001). No associations were found between liver fibrosis and both CYP2R1 and GC genotypes. In patients with G1CHC, GG homozygosis for DHCR7 gene and lower 25(OH)D levels are independently associated with the severity of liver fibrosis.

Genetic background in nonalcoholic fatty liver disease: A comprehensive review.

In the Western world, nonalcoholic fatty liver disease (NAFLD) is considered as one of the most significant liver diseases of the twenty-first century. Its development is certainly driven by environmental factors, but it is also regulated by genetic background. The role of heritability has been widely demonstrated by several epidemiological, familial, and twin studies and case series, and likely reflects the wide inter-individual and inter-ethnic genetic variability in systemic metabolism and wound healing response processes. Consistent with this idea, genome-wide association studies have clearly identified Patatin-like phosholipase domain-containing 3 gene variant I148M as a major player in the development and progression of NAFLD. More recently, the transmembrane 6 superfamily member 2 E167K variant emerged as a relevant contributor in both NAFLD pathogenesis and cardiovascular outcomes. Furthermore, numerous case-control studies have been performed to elucidate the potential role of candidate genes in the pathogenesis and progression of fatty liver, although findings are sometimes contradictory. Accordingly, we performed a comprehensive literature search and review on the role of genetics in NAFLD. We emphasize the strengths and weaknesses of the available literature and outline the putative role of each genetic variant in influencing susceptibility and/or progression of the disease.

Metabolic Factors and Chronic Hepatitis C: A Complex Interplay

In the last years, several lines of evidence showed how metabolic factors may influence the natural history of patients with chronic hepatitis C. Chronic HCV infection is able to perturb the metabolic homeostasis of the host, in a context of complex interactions where pre-existent metabolic status and genetic background play an important role, allowing us to state that HCV infection is a systemic disease. In this review, we discuss the most recent lines of evidence on the main metabolic factors that are known to be associated with CHC, namely, insulin resistance/type 2 diabetes, steatosis, visceral obesity, atherosclerosis, vitamin D, menopause, fructose and coffee intake, lipoproteins, methylenetetrahydrofolate reductase status, and hyperuricaemia. In particular, we focus on the pathophysiological mechanisms underlying the correlation between HCV infection and metabolic disorders, the impact of metabolic factors on the progression of liver and non-liver-related diseases, and, on the contrary, the possible influence of chronic HCV infection on metabolic features. In this setting, the importance of a multifaceted evaluation of CHC patients and a prompt correction of modifiable metabolic risk factors should be emphasized.

Serum γ-glutamyl Transferase Levels, Insulin Resistance and Liver Fibrosis in Patients with Chronic Liver Diseases

Background and Aims Serum levels of γ-glutamyl-transpeptidase(γ-GT) were associated with liver disease severity and metabolic alterations, which in turn are able to affect hepatic damage. In patients with nonalcoholic fatty liver disease (NAFLD), genotype 1 chronic hepatitis C (G1CHC) and chronic hepatitis B (CHB), we assessed the link between liver fibrosis and γ-GT serum levels, and we evaluated if normal or high γ-GT serum levels affect the association between insulin resistance (IR) and severity of liver fibrosis. Methods 843 consecutive patients with chronic liver disease (CLD)(193 NAFLD, 481 G1CHC, 169 CHB) were evaluated by liver biopsy (Kleiner and Scheuer scores) and clinical and metabolic measurements. IR was diagnosed if HOMA>3. A serum γ-GT concentration of >36 IU/L in females and >61 IU/L in males was considered the threshold value for identifying high levels of γ-GT. Results By multivariate logistic regression analysis, abnormal γ-GT serum levels were independently linked to severe liver fibrosis in patients with NAFLD (OR2.711,CI1.120–6.564,p = 0.02), G1CHC (OR3.461,CI2.138–5.603,p<0.001) and CHB (OR2.778,CI1.042–7.414,p = 0.04), together with IR and liver necroinflammation, and with a negative predictive value>80%. Interestingly, among patients with high or normal γ-GT values, even if IR prevalence was significantly higher in patients with severe fibrosis compared to those without, IR remained significantly associated with severe fibrosis in patients with abnormal γ-GT values only (OR4.150,CI1.079–15.970,p = 0.03 for NAFLD; OR2.250,CI1.211–4.181,p = 0.01 for G1CHC; OR3.096,CI2.050–34.220,p = 0.01 for CHB). Conclusions In patients with CLD, IR is independently linked to liver fibrosis only in patients with abnormal γ-GT values, without differences according to liver disease etiology, and suggesting a role of γ-GT as a marker of metabolic-induced liver damage. These data could be useful for the clinical and pharmacologic management of patients with CLD.

Clinical features and outcomes of patients with drug-induced autoimmune hepatitis: A retrospective cohort study

BACKGROUND Drugs and herbal products can induce autoimmune hepatitis. We assessed frequency and clinical outcomes of patients suffering from drug-induced autoimmune hepatitis. METHODS All patients with drug-induced liver injury admitted between 2000 and 2011 were retrospectively studied. Diagnoses of drug-induced autoimmune hepatitis and idiopathic autoimmune hepatitis were made according to simplified criteria. After discharge, all patients had regular follow-up and were contacted to update outcomes. RESULTS Among 10,270 in-hospital patients, 136 (1.3%) were diagnosed with drug-induced liver injury. Among them, 12 (8.8%) were diagnosed as drug-induced autoimmune hepatitis (41.7% males, age range 17-73); 8 (66.7%) were with jaundice at admission. Liver biopsies showed a pattern compatible with drug-induced autoimmune hepatitis, featured by severe portal inflammation and lymphoplasmacytic infiltrate. Drug-induced autoimmune hepatitis group had a shorter duration of drug intake, and higher values of transaminases and gamma globulins. All patients received immunosuppressive therapy with subsequent clinical remission, and five achieved a steroid-free long-term remission. CONCLUSIONS A diagnosis of drug-induced autoimmune hepatitis was quite rare in our cohort, and clinical pattern was similar to idiopathic autoimmune hepatitis. Severe portal inflammation, prominent portal-plasma cells, rosette formation and severe focal necrosis were significantly more frequent in drug-induced autoimmune hepatitis as compared to drug-induced liver injury.