Comparison of three algorithms of non-invasive markers of fibrosis in chronic hepatitis C

Aliment Pharmacol Ther 2012; 35: 92–104

Summary

Background Preliminary data suggest that performance of non‐invasive markers for liver fibrosis in hepatitis C may improve when combined. Three algorithms based on the combination of Fibrotest, Forns’ index and AST‐to‐platelet ratio (APRI) have been proposed: Sequential Algorithm for Fibrosis Evaluation (SAFE biopsy); Fibropaca algorithm; Leroy algorithm. Aim To compare three algorithms to diagnose significant fibrosis (≥F2 by METAVIR) and cirrhosis (F4). Methods A total of 1013 HCV monoinfected cases undergoing liver biopsy were consecutively enrolled in seven centres. Fibrotest, APRI and Forns’ index were measured at the time of liver biopsy, considered the reference standard. Results Overall, performance of combination algorithms was significantly higher than the single non‐invasive methods (P < 0.0001). SAFE biopsy and Fibropaca algorithm saved a significantly higher number of liver biopsies than the single methods (P < 0.0001). For ≥F2, Fibropaca algorithm saved more biopsies than SAFE biopsy (51.7% vs. 43.8%, P = 0.0003), but with lower accuracy (87.6% vs. 90.3%, P = 0.05). Regarding F4, the number of saved liver biopsies did not differ between SAFE biopsy and Fibropaca algorithm (79.1% vs. 76.2%, P = 0.12). However, SAFE biopsy showed a lower accuracy when compared with Fibropaca algorithm (91.2% vs. 94%, P = 0.02). As to Leroy algorithm, although it showed a good performance for ≥F2 (93.5% accuracy), it saved less liver biopsies than SAFE biopsy and Fibropaca algorithm (29.2% vs. 43.8% and 51.7% respectively, P < 0.0001). Conclusions SAFE biopsy and the Fibropaca algorithm have excellent performance for liver fibrosis in hepatitis C, allowing a significant reduction in the need for liver biopsies. They can be useful in clinical practice and for large‐scale screening.     

Transient elastography and biomarkers for liver fibrosis assessment and follow-up of inactive hepatitis B carriers

Background Non invasive methods for fibrosis evaluation remain to be validated longitudinally in hepatitis B. Aim To evaluate longitudinally transient elastography (TE) and biomarkers for liver fibrosis assessment and follow‐up of hepatitis B virus (HBV) inactive carriers. Methods Three hundred and twenty‐nine consecutive HBeAg‐negative HBV patients (201 inactive carriers) who underwent TE, Fibrotest and aspartate to platelet ratio index (APRI) the same day were studied. Results TE (median 4.8 vs. 6.8 kPa, P < 0.0001), Fibrotest (0.16 vs. 0.35, P < 0.0001) and APRI values (0.28 vs. 0.43, P < 0.0001) were significantly lower in inactive carriers than in the remaining patients whereas they did not differ among inactive carriers according to HBV DNA levels. In 82 inactive carriers with repeated examinations, although differences were observed among individual patients, TE values did not differ significantly over time (median intra‐patient changes at end of follow‐up relative to baseline: ?0.2 kPa, P = 0.12). Conversely, significant fluctuations were observed for Fibrotest (+0.03, P = 0.012) and APRI (?0.01, P < 0.05). Eleven inactive carriers (5.5%) had initial elevated TE values (>7.2 kPa) confirmed during follow‐up in two with significant fibrosis (F2 and F3) on liver biopsy. Conclusion Non‐invasive tools, particularly TE, could be useful, in addition to HBV DNA and transaminase levels, for follow‐up of HBV inactive carriers as well as better selection of patients who require a liver biopsy.     

Assessment of asymptomatic liver fibrosis in alcoholic patients using fibroscan: prospective comparison with seven non-invasive laboratory tests

Background Systematic screening for liver fibrosis in heavy‐drinking patients is a challenge. Aims To assess Fibroscan for non‐invasive diagnosis of asymptomatic liver fibrosis in alcohol abuse patients, to determine diagnostic liver stiffness cut‐off values and to compare performance of Fibroscan with seven non‐invasive laboratory tests. Methods One hundred and three alcoholic patients were studied. Liver fibrosis was staged by METAVIR system. Fibroscan, Fibrotest, Fibrometer, Hepascore, APRI, PGA, PGAA and hyaluronic acid tests were performed. Liver stiffness cut‐offs were determined using receiver‐operating characteristic (ROC) curves. Results Liver stiffness was correlated with fibrosis (r = 0.72, P < 0.014), with median at 5.7, 6.3, 8.4, 15 and 47.3 kPa for F0 (n = 8), F1 (n = 18), F2 (n = 24), F3 (n = 20) and F4 (n = 33) stage fibrosis respectively. For Fibroscan, areas under ROC curves (AUROCs) were 0.84 (95% CI: 0.73–0.95) (F ≥ 1), 0.91 (0.85–0.98) (F ≥ 2), 0.90 (0.82–0.97) (F ≥ 3) and 0.92 (0.87–0.98) (F = 4), yielding diagnostic stiffness cut‐offs of 5.9 (F ≥ 1), 7.8 (F ≥ 2), 11 (F ≥ 3) and 19.5 (F4) kPa. Sensitivity, specificity, PPV and NPV were 80%, 90.5%, 93% and 70% for F ≥ 2, and 85.7%, 84.2%, 68.6% and 87.9% for F = 4. Performance of Fibroscan was higher than seven laboratory tests, for which AUROCs ranged from 0.66 to 0.77 (F ≥ 1), from 0.54 to 0.82 (F ≥ 2), from 0.43 to 0.88 (F ≥ 3) and from 0.56 to 0.89 (F = 4), with significant difference only vs. APRI (P < 0.001) and Hepascore (P = 0.04). Combining Fibroscan with each tests did not improve performance. Conclusions Fibroscan is effective to assess liver fibrosis in alcoholic patients. Instant screening of liver fibrosis in heavy drinkers is feasible without liver biopsy.     

Use of the AST to platelet ratio index in HCV/HIV co-infected patients

Aliment Pharmacol Ther 2011; 33: 566–577

Summary

Background The AST to platelet ratio index (APRI), a non‐invasive marker of liver fibrosis, has not been well studied in HCV/HIV (hepatitis C virus/human immunodeficiency virus) co‐infected patients with advanced HIV. Aim To compare the accuracy of APRI in HCV/HIV co‐infected patients to that in HCV mono‐infected patients and to determine the impact of CD4+ T‐cell counts on its performance. Methods We identified 106 consecutive HCV/HIV co‐infected patients and 105 matched HCV mono‐infected patients who underwent liver biopsy at Harborview Medical Center over a 5‐year period. Performance characteristics were calculated and receiver operating characteristic (ROC) analysis conducted. Results The area under the ROC curve (AUROC) of APRI for predicting significant fibrosis was similar when comparing those with and without HIV co‐infection (0.77 vs. 0.86, P = 0.18), but was lower in HIV co‐infected patients with CD4 counts <250 cells/mm³ (0.64 vs. 0.86, P = 0.05). In HIV co‐infected patients with CD4 counts ≥250, APRI had higher negative predictive value (93% vs. 88%, P = 0.57), positive predictive value (63% vs. 40%, P = 0.43) and specificity (95% vs. 88%, P = 0.05) than in those with lower CD4 counts. Conclusions The AST to platelet ratio index (APRI) performance characteristics appear to be suboptimal in HCV/HIV co‐infected patients with CD4 counts <250 and they require further study in this population at increased risk for advanced liver disease.     

Systematic review: non-invasive methods of fibrosis analysis in chronic hepatitis C

Background  Accurate determination of the presence and degree of liver fibrosis is essential for prognosis and for planning treatment of patients with chronic hepatitis C virus (HCV). Non-invasive methods of assessing fibrosis have been developed to reduce the need for biopsy.
Aim  To perform a review of these non-invasive measures and their ability to replace biopsy for assessing hepatic fibrosis in patients with chronic HCV.
Methods  A systematic review of PUBMED and EMBASE was performed through 2008 using the following search terms: HCV, liver, elastography, hepatitis, Fibroscan, SPECT, noninvasive liver fibrosis, ultrasonography, Doppler, MRI, Fibrotest, Fibrosure, Actitest, APRI, Forns and breath tests, alone or in combination.
Results  We identified 151 studies: 87 using biochemical, 57 imaging and seven breath tests either alone or in combination.
Conclusions  Great strides are being made in the development of accurate non-invasive methods for determination of fibrosis. Although no single non-invasive test or model developed to date can match that information obtained from actual histology (i.e. inflammation, fibrosis, steatosis), combinations of two modalities of non-invasive methods can reliably differentiate between minimal and significant fibrosis, and thereby avoid liver biopsy in a significant percentage of patients.     

Optimized stepwise combination algorithms of non-invasive liver fibrosis scores including Hepascore in hepatitis C virus patients

Background  Non-invasive liver fibrosis scores such as Hepascore (HS) have been proposed as an alternative to liver biopsy in hepatitis C virus (HCV)-infected patients.
Aim  To validate HS as an alternative to liver biopsy and Fibrotest (FT) and propose five optimized combination algorithms to improve diagnostic accuracy.
Methods  The cohort included 467 patients with HCV. There were 274/467 (59%) men, and mean age was 47 ± 12 years.
Results  Hepascore area under ROC curves (AUC) for ≥F2, F3F4 and F4 diagnosis were 0.82, 0.84 and 0.90 respectively, in the same range as FT. HS and FT were concordant in 387/467 (82%) for fibrosis staging. Among these patients, 342/387 (88%) were concordant with liver biopsy. AUCs of aspartate aminotransferase (AST) to Platelets Ratio Index (APRI) and Forns for ≥F2 were 0.76 and 0.73 (0.65–0.79) respectively. The algorithm combining APRI and HS had the highest rate of avoided liver biopsies (45%) with a high diagnostic accuracy (91%).
Conclusions  Hepascore is an accurate non-invasive marker for ≥F2 and F4 diagnosis in HCV patients. In a pragmatic approach, a stepwise optimized algorithm combining APRI and FT or HS considerably increases diagnostic accuracy and avoided liver biopsies.     

Clinical predictors of fibrosis in patients with chronic liver disease

Aliment Pharmacol Ther 31 , 1085–1094

Summary

Background Patients with chronic liver disease and components of metabolic syndrome may be at higher risk for fibrosis. Aim To assess the impact of clinicodemographic factors on hepatic fibrosis in CLD. Methods Of 1028 chronic liver disease patients, 964 were included in the analysis. Extensive clinico‐demographic and histological data were available. Significant baseline fibrosis (METAVIR stage ≥2) and fibrosis progression (increase of ≥1 stage in subsequent biopsy) were compared between groups using univariate and multivariate analyses. Results Compared with HCV and HBV, NAFLD patients were more obese (higher BMI and waist circumference), diabetic, hypertensive and hyperlipidaemic. Significant fibrosis occurred in 55%, 43% and 20% of HCV, HBV and NAFLD, respectively. Factors independently associated with fibrosis in NAFLD included DM, elevated AST and ALT. For viral hepatitis, independent predictors of fibrosis were low platelet count (HBV and HCV), age (HBV) and elevated AST and ALT (HCV). A second biopsy was available for 96 patients with follow‐up of about 4 years. Factors independently associated with progression of fibrosis were HCV infection, higher ALT and lower platelet count. Conclusions Diabetes mellitus is an independent risk factor for fibrosis only in NAFLD. Elevated aminotransferases and/or low platelet counts are independently associated with significant baseline fibrosis or progression of fibrosis, in patients with chronic liver disease.     

Assessment of liver fibrosis before and after antiviral therapy by different serum marker panels in patients with chronic hepatitis C

Aliment Pharmacol Ther 2011; 33: 138–148

Summary

Background Liver biopsy is the reference standard to assess liver fibrosis in chronic hepatitis C. Aim To validate and compare the diagnostic performance of non‐invasive tests for prediction of liver fibrosis severity and assessed changes in extracellular matrix markers after antiviral treatment. Methods The performances of Forns’ score, AST to platelet ratio index (APRI), FIB‐4 index and Enhanced Liver Fibrosis (ELF) score were validated in 340 patients who underwent antiviral therapy. These scores were determined 24 weeks after treatment in 161 patients. Results Forns’ score, APRI, FIB‐4 and ELF score showed comparable diagnostic accuracies for significant fibrosis [area under the receiver operating characteristic curve (AUROC) 0.83, 0.83, 0.85 and 0.81, respectively]. To identify cirrhosis, FIB‐4 index showed a significantly better performance over APRI and ELF score (AUROC 0.89 vs. 0.83 and 0.82, respectively). ELF score decreased significantly in patients with sustained virological response (SVR) (P < 0.0001) but remained unchanged in nonresponders. Non‐1 hepatitis C virus (HCV) genotype, baseline lower HCV RNA, glucose, hyaluronic acid and higher cholesterol levels were independently associated with SVR. Conclusions Simple panel markers and ELF score are accurate at identifying significant fibrosis and cirrhosis in chronic hepatitis C. A decrease in ELF score after antiviral treatment reflects the impact of viral clearance in hepatic extracellular matrix and probably in the improvement of liver fibrosis.     

丙型肝炎病人丙肝病毒RNA载量、肝脏纤维化与25羟基维生素D水平的相关性分析

目的 考察25羟基维生素D[25(OH)D]水平在丙型肝炎中的表达水平,分析25(OH)D与丙肝病毒RNA(HCV RNA)载量、肝脏纤维化之间的关联和影响关系.方法 选取慢性丙型肝炎病人267例作为观察组,另选取正常体检者100例作为对照组,检测丙氨酸氨基转氨酶(ALT)、天冬氨酸氨基转移酶(AST)和谷氨酰转肽酶(GGT).采用荧光定量 PCR 仪测定HCV RNA载量,采用肝脏纤维化指数(Fibrotest分级)进行评价肝纤维化程度.结果 观察组ALT和AST、GGT显著高于对照组(P<0.01),观察组25(OH)D显著低于对照组(P<0.01);观察组>50~≤75 nmol·L-1项下25 (OH)D人数显著多于对照组(P<0.01);血清25 (OH) D与HCV RNA载量呈负相关(r=-0.922,P<0.01),血清25 (OH) D与Fibrotest分级呈负相关(r=-0.957,P<0.01).结论 25(OH)D是丙肝的保护因素,临床对丙肝病人适当补充25(OH)D或可改善病人的临床症状.     

Development of a non‐invasive algorithm with transient elastography (Fibroscan) and serum test formula for advanced liver fibrosis in chronic hepatitis B

Aliment Pharmacol Ther 31 , 1095–1103

Summary

Background Non‐invasive assessments of liver fibrosis in chronic hepatitis B were well established. Aim To develop a combined algorithm of liver stiffness measurement (LSM) and serum test formula to predict advanced liver fibrosis in chronic hepatitis B. Methods We reported an alanine aminotransferase (AST)‐based LSM algorithm for liver fibrosis in 156 chronic hepatitis B patients, which formed the training cohort to evaluate the performance of APRI (AST‐to‐platelet‐ratio‐index), Forns index, FIB‐4 and Fibroindex against liver histology. The best combined LSM‐serum formula algorithm would be validated in another cohort of 82 chronic hepatitis B patients. Results In the training cohort, LSM has the best performance of diagnosing advanced (≥F3) fibrosis [area under the receiver operating characteristics curve (AUROC) 0.88, 95% confidence interval (CI) 0.85–0.91], while Forns index has the best performance among the various serum test formulae (AUROC 0.70, 95% CI 0.62–0.78). In the combined algorithm, low LSM or low Forns index could be used to exclude advanced fibrosis as both of them had high sensitivity (>90%). To confirm advanced fibrosis, agreement between high LSM and high Forns index could improve the specificity (from 99% to 100% and from 87% to 98% in the training and validation cohorts respectively). Conclusion A combined LSM–Forns algorithm can improve the accuracy to predict advanced liver fibrosis in chronic hepatitis B.     

多项无创模型指数诊断慢性乙型肝炎肝纤维化的价值比较

目的分析无创模型指数对慢性乙型肝炎肝纤维化的诊断价值。方法未曾接受抗病毒治疗的1038例慢性乙型肝炎患者,均接受肝活检,并检测血液、B超等指标。计算天冬氨酸转氨酶与血小板比值(APRI)、4因子肝纤维化指数(FIB-4)、γ-谷氨酰转肽酶与血小板计数比值(GPR)、S指数(S)、年龄-脾脏/血小板比值(ASPRI)、年龄-血小板指数(API)及FV等不同无创模型指数,并利用受试者工作特征(ROC)曲线下面积(AUROC)分析不同无创模型指数对肝纤维化的诊断价值。结果诊断肝纤维化(F2~3):FIB-4在谷丙转氨酶(ALT)<参考值上限(ULN)时价值最好,AUROC为0.795,但在ALT>5ULN时AUROC明显下降(Z=2.442,P<0.05);ASPRI、S、GPR、FV在2ULN≤ALT≤5ULN时价值最好,AUROC分别为0.809、0.828、0.830、0.873。诊断早期肝硬化(F4):API、FIB-4、GPR、S、ASPRI、FV的AUROC在不同的ALT水平时均>0.800,其中,在不同ALT水平下,ASPRI和FV的AUROC分别为0.898和0.900、0.892和0.928、0.887和0.920、0.895和0.918,均具有较高的诊断价值。结论ASPRI、S、GPR、FIB-4、FV诊断肝纤维化和肝硬化均有价值,ASPRI、FV诊断早期肝硬化价值较高,FIB-4诊断肝纤维化的价值受ALT水平影响较大。     

Dual cut-off transient elastography to assess liver fibrosis in chronic hepatitis B: a cohort study with internal validation

Aliment Pharmacol Ther 2011; 34: 353–362

Summary

Background  Transient elastography has gained popularity to stage liver fibrosis in chronic viral hepatitis, however, diagnostic cut‐offs for severe fibrosis in chronic hepatitis B are poorly defined. Aim  To evaluate an algorithm with two distinct cut‐offs for positive and negative prediction of significant fibrosis and cirrhosis in chronic hepatitis B patients. Methods  Two cohorts of treatment‐naïve patients with chronic hepatitis B (125 training and 92 validations) were consecutively and concurrently examined by percutaneous liver biopsy and transient elastography. Fibrosis was staged by Metavir (significant fibrosis = F ≥ 2; cirrhosis = F4) in ≥2 cm long liver tissue cores. Results  A >13.1 kPa positive and a ≤9.4 kPa negative cut‐off for cirrhosis had a >90% sensitivity and specificity, with an accuracy of 94%. The corresponding cut‐offs for F ≥ 2 were >9.4 and ≤6.2 kPa, thus classifying 56% of patients with an overall accuracy of 90%. In the validation cohort, F4 and F ≥ 2 were predicted by the above transient elastography cut‐offs with an overall accuracy >90%. In 165 patients with higher than upper limit of normal transaminase activity the dual cut‐off algorithm of transient elastography was as accurate as in the 52 patients with normal alanine aminotransferase values in the prediction and exclusion of cirrhosis, only. Conclusions  A dual cut‐off algorithm allowed for correctly classifying both significant fibrosis and cirrhosis in the majority of the patients with chronic hepatitis B, independent of alanine aminotransferase values, thus reducing the need for liver biopsy investigations.     

Protective effect of isochlorogenic acid B on liver fibrosis in non‐alcoholic steatohepatitis of mice

Liver fibrosis is a common symptom of non‐alcoholic steatohepatitis (NASH) and a worldwide clinical issue. The miR‐122/HIF‐1α signalling pathway is believed to play an important role in the genesis of progressive fibrosis. Isochlorogenic acid B (ICAB), naturally isolated from Laggera alata, is verified to have antioxidative and hepatoprotective properties. The aim of this study was to investigate the effect of ICAB on liver fibrosis in NASH and its potential protective mechanisms. NASH was induced in a mouse model with a methionine‐ and choline‐deficient (MCD) diet for 4 weeks, and ICAB was orally administered every day at three doses (5, 10 and 20 mg/kg). Pathological results indicated that ICAB significantly improved the pathological lesions of liver fibrosis. The levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and hepatic hydroxyproline (Hyp), cholesterol (CHO) and triglyceride (TG) were also significantly decreased by ICAB. In addition, ICAB inhibited hepatic stellate cells (HSCs) activation and the expressions of hepatic genes involved in liver fibrosis including LOX, TGF‐β1, MCP‐1, COL1α1 and TIMP‐1. ICAB also attenuated liver oxidative stress through Nrf2 signalling pathway. What is more, the decreased levels of miR‐122 and over‐expression of hepatic HIF‐1α could be reversed by ICAB treatment. These results simultaneously confirmed that ICAB had a significant protective effect on fibrosis in NASH by inhibiting oxidative stress via Nrf2 and suppressing multiple profibrogenic factors through miR‐122/HIF‐1α signalling pathway.     

丙型肝炎患者HCV RNA载量、肝脏纤维化与25羟基维生素D水平的相关性分析

目的：考察25羟基维生素D水平在丙型肝炎中的表达水平,分析25羟基维生素D 与HCV RNA载量、肝脏纤维化之间的关联。方法：选取我院2014年1月至于2015年1月感染科收治的慢性丙型肝炎患者267例作为丙肝组,另选取我院体检科正常体检者100例作为对照组,检测患者谷丙转氨酶(ALT)、天冬氨酸氨基转移酶(AST)和谷氨酰转肽酶(GGT)。采用荧光定量 PCR 仪测定 HCV RNA载量,采用Fibrotest分级进行评价肝纤维化程度,统计和分析。结果：丙肝组ALT和AST、GGT显著高于对照组(p＜0.01),丙肝组25(OH)D显著低于对照组(p＜0.01);丙肝组50-75nM 25(OH)D人数显著高于对照组(p＜0.01);血清25 ( OH) D与HCV病毒载量呈负相关(r=-0.922,p＜0.01),血清25 ( OH) D与Fibrotest分级呈负相关(r=-0.957,p＜0.01)。结论：25(OH)D是丙肝的保护因素,临床对丙肝患者适当补充25(OH)D或可改善患者的临床症状。     

Prospective evaluation of transient elastography for the diagnosis of hepatic fibrosis in Asians: comparison with liver biopsy and aspartate transaminase platelet ratio index

Background  Transient elastography (TE) is a reliable non-invasive predictor of hepatic fibrosis, but data on TE in Asians are limited.
Aim  To evaluate prospectively the accuracy of TE for diagnosis of hepatic fibrosis in Asians compared with APRI (aspartate transaminase to platelet ratio index).
Methods  One hundred and twenty consecutive patients who underwent liver biopsy were enrolled. TE (Fibroscan) was performed by two independent operators. Fibrosis was graded by two independent pathologists using the METAVIR classification. Area under receiver operating curves (AUROC) were used to evaluate the accuracy of TE and APRI in diagnosing significant fibrosis (F ≥ 2) and cirrhosis (F4).
Results  Predominant aetiologies were hepatitis B (48%), non-alcoholic steatohepatitis (14%) and hepatitis C (8%). TE was unsuccessful in five patients (4.2%) because of small inter-costal space (three patients), obesity and ascites. There was good correlation between TE and fibrosis ( r  = 0.606). AUROC for diagnosis of significant fibrosis was 0.856 (95% CI 0.779–0.932) for TE and 0.673 (95% CI 0.568–0.777) for APRI. AUROC for diagnosis of cirrhosis was 0.924 (95% CI 0.857–0.990) for TE and 0.626 (95% CI 0.437–0.815) for APRI. Optimal TE value was 9.0 kPa for diagnosis of significant fibrosis and 16.0 kPa for cirrhosis with specificity/sensitivity/PPV/NPV/accuracy of 82.6%/85.2%/80.9%/86.7%/84.1% and 88.9%/82.7%/32.0%/98.8%/83.2%, respectively.
Conclusions  Transient elastography is a reliable predictor of hepatic fibrosis in Asians. Failure of TE in Asians is commonly because of small inter-costal space. TE is superior to APRI for non-invasive diagnosis of hepatic fibrosis and cirrhosis.     

Meta-analysis: insulin sensitizers for the treatment of non-alcoholic steatohepatitis

Aliment Pharmacol Ther 2010; 32: 1211–1221

Summary

Background Non‐alcoholic fatty liver disease generally has a benign course; however, patients with non‐alcoholic steatohepatitis (NASH) may progress to cirrhosis and hepatocellular carcinoma. Currently, there is a lack of consensus about optimal NASH treatment. Aim To assess the efficacy of insulin‐sensitizing agents on histological and biochemical outcomes in randomized control trials of biopsy‐proven NASH. Methods Multiple online databases and conference abstracts were searched. Random effects meta‐analyses were performed, with assessment for heterogeneity and publication bias. Results Nine trials were included; five trials using thiazolidinediones (glitazones), three using metformin and one trial using both drugs. There was no publication bias. Compared with controls, glitazones resulted in improved steatosis (WMD = 0.57, 95% CI 0.36–0.77, P = <0.001), hepatocyte ballooning (WMD = 0.36, 95% CI 0.24–0.49, P < 0.001) and ALT (WMD = 16.4, 95% CI 7.7–25.0, P < 0.001), but not inflammation (P = 0.09) or fibrosis (P = 0.11). In patients without diabetes, glitazones significantly improved all histological and biochemical outcomes, most importantly including fibrosis (WMD = 0.29, 95% CI 0.078–0.51, P = 0.008). Metformin failed to improve any pooled outcome. Conclusions Treatment of NASH with glitazones, but not metformin, demonstrates a significant histological and biochemical benefit, especially in patients without diabetes. Additional studies are needed to investigate long‐term outcomes of glitazone therapy in patients without diabetes.     

Cenicriviroc for the treatment of non-alcoholic steatohepatitis and liver fibrosis

Introduction: Nonalcoholic fatty liver disease (NAFLD) has an increasing prevalence worldwide. At present, no specific pharmacotherapy is approved for NAFLD. Simple steatosis and nonalcoholic steatohepatitis (NASH) can progress to liver fibrosis that is associated with mortality in NAFLD. The recruitment of inflammatory monocytes and macrophages via chemokine receptor CCR2 as well as of lymphocytes and hepatic stellate cells via CCR5 promote the progression of NASH to fibrosis.

Areas covered: I summarize preclinical and clinical data on the efficacy and safety of the dual CCR2/CCR5 inhibitor cenicriviroc (CVC, also TBR-652 or TAK-652) for the treatment of NASH and fibrosis. In animal models of liver diseases, CVC potently inhibits macrophage accumulation in the liver and ameliorates fibrosis. In a phase 2b clinical trial (CENTAUR) on 289 patients with NASH and fibrosis, CVC consistently demonstrated liver fibrosis improvement after 1 year of therapy and had an excellent safety profile, leading to the implementation of a phase 3 trial (AURORA).

Expert opinion: Preclinical and clinical data support the development of CVC as a safe and potent antifibrotic agent. However, open questions around CVC are the durability of antifibrotic responses, divergent effects on NASH versus fibrosis, potential long-term concerns and the expected path to approval.     

瞬时弹性成像联合APRI在慢性乙型肝炎肝纤维化诊断中的应用价值

目的 评价瞬时弹性成像(FibroScan) 联合天冬氨酸转移酶(AST)与血小板指数(PLT)的比值(APRI)在判断慢性乙型肝炎患者肝纤维化程度中的作用。 方法 选择152例临床确诊为慢性乙型肝炎患者,进行常规实验室检查、FibroScan检查和肝脏活组织检查,探究FibroScan及APRI的诊断价值,并绘制FibroScan、APRI以及联合诊断模型的受试者工作特征曲线(ROC曲线),分析三者与肝脏纤维化病理分期的相关性。 结果 FibroScan 与 APRI对显著纤维化(S2~S4期)的曲线下面积(AUROC值)和95% 可信区间(95%CI)分别为0.752(0.672~0.832),0.717(0.630~0.805),对S3~S4期的 AUROC值分别为0.937(0.890~0.985),0.911(0.836~0.986),对S4期的AUROC值分别为0.973(0.947~0.998),0.934(0.862~1.000);两者联合后对S2~S4期的AUROC值为0.811(0.732~0.890)。结论 FibroScan联合APRI诊断模型可以进一步提高对显著期肝纤维化的诊断效能,对临床选择抗病毒治疗,干预肝纤维化进程具有一定的指导意义。     

Reliability of liver stiffness measurement in non-alcoholic fatty liver disease: the effects of body mass index

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.