Abstract 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.
Background and Aims
Nonalcoholic fatty liver disease is epidemiologically associated with hepatic and metabolic disorders. The aim of this study was to examine whether hepatic fat accumulation has a ...causal role in determining liver damage and insulin resistance.
Methods
We performed a Mendelian randomization analysis using risk alleles in PNPLA3, TM6SF2, GCKR and MBOAT7, and a polygenic risk score for hepatic fat, as instruments. We evaluated complementary cohorts of at‐risk individuals and individuals from the general population: 1515 from the liver biopsy cohort (LBC), 3329 from the Swedish Obese Subjects Study (SOS) and 4570 from the population‐based Dallas Heart Study (DHS).
Results
Hepatic fat was epidemiologically associated with liver damage, insulin resistance, dyslipidemia and hypertension. The impact of genetic variants on liver damage was proportional to their effect on hepatic fat accumulation. Genetically determined hepatic fat was associated with aminotransferases, and with inflammation, ballooning and fibrosis in the LBC. Furthermore, in the LBC, the causal association between hepatic fat and fibrosis was independent of disease activity, suggesting that a causal effect of long‐term liver fat accumulation on liver disease is independent of inflammation. Genetically determined hepatic steatosis was associated with insulin resistance in the LBC and SOS. However, this association was dependent on liver damage severity. Genetically determined hepatic steatosis was associated with liver fibrosis/cirrhosis and with a small increase in risk of type 2 diabetes in publicly available databases.
Conclusion
These data suggest that long‐term hepatic fat accumulation plays a causal role in the development of chronic liver disease.
Summary
Background
Sarcopenia recognises insulin resistance and obesity as risk factors, and is frequently associated with cardiometabolic disorders, including non‐alcoholic fatty liver disease ...(NAFLD).
Aim
To test the prevalence of sarcopenia and its relation with the severity of fibrosis (main outcome) and the entire spectrum of liver histology in patients with NAFLD.
Methods
We considered 225 consecutive patients with histological diagnosis of NAFLD (Kleiner score). The skeletal muscle index (%) (total appendicular skeletal muscle mass (kg)/weight (kg) × 100), a validated measure of sarcopenia, was assessed by bioelectrical impedance analysis. Sarcopenia was defined as a skeletal muscle mass index ≤37 in males and ≤28 in females.
Results
The prevalence of sarcopenia showed a linear increase with the severity of fibrosis, and severe fibrosis (F3–F4) was more than doubled in sarcopenia (48.3% vs. 20.4% in fibrosis ≤F2, P < 0.001). After adjusting for confounders, the association of sarcopenia with severe fibrosis was maintained (OR 2.36, CI 1.16–4.77, P = 0.01), together with age > 50 (OR 6.53, CI 2.95–14.4, P < 0.001), IFG/Diabetes (OR 2.14, CI 1.05–4.35, P = 0.03) and NASH (OR 13.3, CI 1.64–108.1, P = 0.01). Similarly, a significant association was found between sarcopenia and NASH (P = 0.01), steatosis severity (P = 0.006), and ballooning (P = 0.01), but only the association with severe steatosis was maintained (OR 2.02, CI 1.06–3.83, P = 0.03) after adjusting for confounders.
Conclusions
In Western patients with NAFLD, with high prevalence of metabolic disorders and advanced liver disease, sarcopenia was associated with the severity of fibrosis and steatosis, independently of hepatic and metabolic risk factors. Studies are needed to assess the impact of interventions to reduce sarcopenia on NAFLD progression.
Hepatocellular carcinoma (HCC) is the most frequent primary neoplasm of the liver, and is the fourth most common malignancy worldwide. It is also the third leading cause of cancer-related deaths. ...Most cases of HCC develop on a pre-existing chronic liver disease, usually due to hepatitis C virus (HCV), hepatitis B virus (HBV), or alcohol. However, between 15% and 50% of HCC develops in the absence of a known etiology of liver disease, and different lines of evidence identify in non-alcoholic fatty liver disease (NAFLD) a possible relevant risk factor for occurrence of HCC. Insulin resistance (IR), steatosis, oxidative stress and imbalances in adipokine/cytokine interplay, the most important factors involved in NAFLD pathogenesis and progression, could also have a determinant role in liver carcinogenesis by promoting cellular growth and DNA damage. Recently, behavioral therapy and various insulin sensitizing agents have been tested in the treatment of NAFLD. A number of studies suggest that these approaches improve IR and reduce steatosis, necroinflammation and fibrosis. A potential role of these therapeutic strategies in the prevention of hepatocarcinogenesis can thus be envisaged.
Summary
Background
The accuracy of available non‐invasive tools for staging severe fibrosis in patients with nonalcoholic fatty liver disease (NAFLD) is still limited.
Aim
To assess the diagnostic ...performance of paired or serial combination of non‐invasive tools in NAFLD patients.
Methods
We analysed data from 741 patients with a histological diagnosis of NAFLD. The GGT/PLT, APRI, AST/ALT, BARD, FIB‐4, and NAFLD Fibrosis Score (NFS) scores were calculated according to published algorithms. Liver stiffness measurement (LSM) was performed by FibroScan.
Results
LSM, NFS and FIB‐4 were the best non‐invasive tools for staging F3‐F4 fibrosis (AUC 0.863, 0.774, and 0.792, respectively), with LSM having the highest sensitivity (90%), and the highest NPV (94%), and NFS and FIB‐4 the highest specificity (97% and 93%, respectively), and the highest PPV (73% and 79%, respectively). The paired combination of LSM or NFS with FIB‐4 strongly reduced the likelihood of wrongly classified patients (ranging from 2.7% to 2.6%), at the price of a high uncertainty area (ranging from 54.1% to 58.2%), and of a low overall accuracy (ranging from 43% to 39.1%). The serial combination with the second test used in patients in the grey area of the first test and in those with high LSM values (>9.6 KPa) or low NFS or FIB‐4 values (<−1.455 and <1.30, respectively) overall increased the diagnostic performance generating an accuracy ranging from 69.8% to 70.1%, an uncertainty area ranging from 18.9% to 20.4% and a rate of wrong classification ranging from 9.2% to 11.3%.
Conclusion
The serial combination of LSM with FIB‐4/NFS has a good diagnostic accuracy for the non‐invasive diagnosis of severe fibrosis in NAFLD.
Linked ContentThis article is linked to Khan paper. To view this article visit https://doi.org/10.1111/apt.14267.
Summary
Background
Data on HCV‐related hepatocellular carcinoma (HCC) early recurrence in patients whose HCC was previously cured, and subsequently treated by direct‐acting antivirals (DAAs), are ...equivocal.
Aim
To assess the risk of HCC early recurrence after DAAs exposure in a large prospective cohort of HCV‐cirrhotic patients with previous successfully treated HCC, also looking for risk factors for cancer early recurrence.
Methods
We enrolled 143 consecutive patients with complete response after curative treatment of HCC, subsequently treated with DAAs and monitored by the web‐based RESIST‐HCV database. Clinical, biological, and virological data were collected. The primary endpoint was the probability of HCC early recurrence from DAA starting by Kaplan‐Meier method.
Results
Eighty‐six per cent of patients were in Child‐Pugh class A and 76% of patients were BCLC A. Almost all patients (96%) achieved sustained virological response. Twenty‐four HCC recurrences were observed, with nodular or infiltrative pattern in 83% and 17% of patients, respectively. The 6‐, 12‐ and 18‐month HCC recurrence rates were 12%, 26.6% and 29.1%, respectively. Main tumour size and history of prior HCC recurrence were independent risk factors for HCC recurrence by Cox multivariate model.
Conclusions
Probability of HCC early recurrence in patients who had HCC previously cured remains high, despite HCV eradication by DAAs. Risk was comparable but not higher to that reported in literature in DAA‐untreated patients. Previous HCC recurrence and tumour size can be used to stratify the risk of HCC early recurrence. Further studies are needed to assess impact of DAAs on late recurrence and mortality.
Transient elastography (TE) is adequate for a diagnosis of cirrhosis, but its accuracy for milder stages of fibrosis is much less satisfactory. The objective of this study was to compare the ...performance and the discordance rate of acoustic radiation force impulse (ARFI) and TE with liver biopsy in a cohort of chronic hepatitis C (CHC) patients.
One hundred thirty-nine consecutive patients with CHC were enrolled in two tertiary centers, and evaluated for histological (Metavir score) and biochemical features. All patients underwent TE and ARFI.
TE was unreliable in nine patients (6.5%), while in no cases (0%) were ARFI invalid measurements recorded (P=0.029). By area under receiver operating characteristic curve (AUROC), the best cutoff values for TE and ARFI for significant fibrosis (≥F2) were ≥6.5 kPa (AUROC: 0.78) and ≥1.3 m/s (AUROC: 0.86), respectively. For severe fibrosis (F3-F4), these cutoff values were 8.8 kPa (AUROC: 0.83) for TE and 1.7 m/s (AUROC: 0.94) for ARFI. For cirrhosis, TE had its best cutoff at ≥11 kPa (AUROC: 0.80) and ARFI at ≥2.0 m/s (AUROC: 0.89). By pairwise comparison of AUROC, ARFI was significantly more accurate than TE for a diagnosis of significant and severe fibrosis (P=0.024 and P=0.002, respectively), while this difference was only marginal for cirrhosis (P=0.09). By partial AUROC analysis, ARFI performance results significantly higher for all three stages of fibrosis. The average concordance rates of TE and ARFI vs. liver biopsy were 45.4 and 54.7%, respectively. By multivariate analysis, ARFI was not associated with alanine aminotransferase (ALT), body mass index, Metavir grade, and liver steatosis, while TE was significantly correlated with the ALT value (P=0.027).
In a cohort of patients with CHC, ARFI imaging was more accurate than TE for the non-invasive staging of both significant and severe classes of liver fibrosis.
Aliment Pharmacol Ther 2011; 34: 757–766
Summary
Background Hyperuricemia has been associated with metabolic disorders. In this line recent studies observed an independent link between higher uric ...acid serum levels and clinical diagnosis of non‐alcoholic fatty liver disease (NAFLD).
Aims We aimed to assess the potential association between uric acid serum levels and histological liver damage in a homogeneous cohort of biopsy‐proven NAFLD patients.
Methods Consecutive NAFLD patients (n = 166), assessed by liver biopsy (Kleiner score), anthropometric, biochemical and metabolic features, were included. Enzymatic colorimetric test was used for serum uric acid assays (Roche Diagnostics GmbH, Mannheim, Germany). Hyperuricemia was diagnosed when uric acid serum levels were >7 mg/dL in men, and >6 mg/dL in women.
Results Mean uric acid serum level was 5.75 mg/dL, and about 20% of patients had hyperuricemia, that was independently associated with younger age (OR 0.951, 95% CI 0.918–0.984, P = 0.004), lobular inflammation (OR 2.144, 95% CI 1.055–4.357, P = 0.03) and steatosis grade (OR 1.859, 95% CI 1.078–3.205, P = 0.02), by multivariate logistic regression analysis. Female gender (OR 2.656, 95% CI 1.190–5.928, P = 0.01), higher HOMA index (OR 1.219, 95% CI 1.043–1.426, P = 0.01), and hyperuricemia (OR 4.906, 95% CI 1.683–14.296, P = 0.004) were linked to NAFLD activity score (NAS) ≥ 5 by multiple logistic regression analysis. Conversely, higher HOMA index (OR 1.140, 95% CI 1.001–1.229, P = 0.04), and NAS (OR1.954, 95% CI 1.442–2.649, P < 0.001) were independently associated with significant fibrosis by logistic regression analysis.
Conclusions In NAFLD patients, hyperuricemia is independently associated with the severity of liver damage, representing, in this setting of patients, together with insulin resistance, a potential new therapeutic target in future intervention trials.
Summary
Background Liver stiffness measurement (LSM) using transient elastography (TE) is used to stage fibrosis in patients with liver disease, diagnostic reliability and the factors affecting its ...performance in patients with non‐alcoholic fatty liver disease (NAFLD) are incompletely understood.
Aim To assess LSM.
Methods Consecutive NAFLD patients (n = 169), assessed by liver biopsy (Kleiner score), anthropometrical, biochemical and metabolic features, underwent LSM using TE with standard M probe.
Results Liver stiffness measurement was not reliable in 23 patients (14%) due to obesity. Among patients with a reliable TE, a LSM value >7.25 kPa was the best cut‐off for predicting significant fibrosis at biopsy (AUC 0.794); however, this cut‐off still failed to rule out F2‐F4 fibrosis in 31% (false‐negative rate) or rule in F3‐F4 in 29% (false‐positive rate). Similarly a LSM value >8.75 kPa was the best cut‐off for severe fibrosis (F3‐F4) (AUC 0.870), with a rate of false‐negatives 24% and of false‐positives 2%. Body mass index was the major determinant of these diagnostic errors in predicting significant and severe fibrosis both by overestimating or underestimating the stage of fibrosis.
Conclusions In NAFLD patients, even when liver stiffness measurement is feasible, high BMI values negatively affect the diagnostic reliability. Improved performance of transient elastography could be obtained using specifically designed probes.
Summary
Anecdotal reports suggest that patients with chronic hepatitis C virus (HCV) hepatitis and overt or occult hepatitis B virus (HBV) coinfection may reactivate HBV when HCV is suppressed or ...cleared by direct‐acting antivirals (DAAs). We assessed the prevalence of overt or previous HBV coinfection and the risk of HBV reactivation in patients with HCV cirrhosis treated with DAAs. This was a retrospective cohort of 104 consecutive patients with HCV cirrhosis treated with DAAs. Serum HCV‐RNA and HBV‐DNA were tested at weeks 4, 8 and 12 of DAAs therapy and at week 12 of follow‐up. At the start of DAAs, eight patients (7.7%) were HBsAg positive/HBeAg negative with undetectable HBV‐DNA and low levels of quantitative HBsAg (four on nucleos(t)ide analogues NUCs and four inactive carriers), 37 patients (35.6%) had markers of previous HBV infection (25 anti‐HBc positive, 12 anti‐HBc/anti‐HBs positive) and 59 (56.7%) had no evidence of HBV infection. Sixty‐seven patients (64.4%) were HCV‐RNA negative at week 4 and 98 (94.2%) achieved sustained virological response. All four HBsAg‐positive patients treated with NUCs remained HBV‐DNA negative, but three of four untreated patients showed an increase in HBV‐DNA of 2‐3 log without a biochemical flare and achieved HBV‐DNA suppression when given NUCs. During or after DAAs, by conventional assay, HBV‐DNA remained not detectable in all 37 anti‐HBc‐positive patients but in three of them (8.1%) HBV‐DNA became detectable with a highly sensitive PCR. HBV reactivation is likely to occur in untreated HBV/HCV‐coinfected cirrhotic patients when they undergo HCV treatment with DAAs. Pre‐emptive therapy with NUCs should be considered in this setting. Anti‐HBc‐positive patients rarely reactivate HBV without clinical or virological outcomes.
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