The relationship between transient elastography and histological collagen proportionate area for assessing fibrosis in chronic viral hepatitis

Background

Collagen proportionate area (CPA) has a better correlation with hepatic venous pressure gradient (HVPG) than with Ishak stage. Liver stiffness measurement (LSM) is proposed as non invasive marker of portal hypertension/disease progression. Our aim was to compare LSM and CPA with Ishak staging in chronic viral hepatitis, and HVPG in HCV hepatitis after transplantation.

Methods

One hundred and sixty-nine consecutive patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections pre/post liver transplantation (LT), had a liver biopsy combined with LSM (transient elastography), CPA (biopsies stained with Sirius Red and evaluated by digital image analysis and expressed as CPA) and HVPG (measured contemporaneously with transjugular biopsies in LT HCV patients).

Results

LSM was dependent on CPA in HBV (r ² = 0.61, p < 0.0001), HCV (r ² = 0.59, p < 0.0001) and LT groups (r ² = 0.64, p < 0.0001). In all three groups, CPA and Ishak were predictors of LSM, but multivariately CPA was better related to LSM (HBV: r ² = 0.61, p < 0.0001; HCV: r ² = 0.59, p < 0.0001; post-LT: r ² = 0.68, p < 0.0001) than Ishak stage. In the LT group, multiple regression analysis including HVPG, LSM, aspartate aminotransferase to platelet ratio index (APRI) and Ishak stage/grade, showed that only CPA was related to HVPG (r ² = 0.41, p = 0.01), both for HVPG ≥6 mmHg (OR 1.34, 95 % CI 1.14–1.58; p < 0.0001) or ≥10 mmHg (OR 1.25, 95 % CI 1.06–1.47; p = 0.007).

Conclusion

CPA was related to LSM in HBV or HCV hepatitis pre/post-LT. CPA was better related to LSM than Ishak stage. In the LT HCV group, CPA was better related to HVPG than Ishak stage/grade, LSM or APRI. CPA may represent a better comparative histological index for LSM, rather than histological stages.     

Hepatic vein arrival time as assessed by contrast-enhanced ultrasonography is useful for the assessment of portal hypertension in compensated cirrhosis

The measurement of the hepatic venous pressure gradient (HVPG) for the estimation of portal hypertension (PH) in cirrhosis has some limitations, including its invasiveness. Hepatic vein arrival time (HVAT), as assessed by microbubble contrast-enhanced ultrasonography (CEUS), is negatively correlated with the histological grade of liver fibrosis because of the associated hemodynamic abnormalities. Anatomical and pathophysiological changes in liver microcirculation are the initial events leading to PH. However, the direct relationship between HVAT and PH has not been evaluated. The present study measured both HVPG and HVAT in 71 consecutive patients with compensated cirrhosis and analyzed the relationship between the two parameters (i.e., the derivation set). Results were validated in 35 compensated patients with cirrhosis at another medical center (i.e., the validation set). The derivation set had HVPG and HVAT values of 11.4 ± 5.0 mmHg (mean ± standard deviation; range, 2-23) and 14.1 ± 3.4 seconds (range, 8.4-24.2), respectively; there was a statistically significant negative correlation between HVPG and HVAT (r(2) = 0.545; P < 0.001). The area under the receiver operating characteristic curve (AUROC) was 0.973 for clinically significant PH (CSPH; HVPG, ≥10 mmHg), and the sensitivity, specificity, positive predictive value, negative predictive value, and positive and negative likelihood ratios for CSPH for an HVAT cut-off value of 14 seconds were 92.7%, 86.7%, 90.5%, 89.7%, 6.95, and 0.08, respectively. In addition, a shorter HVAT was associated with worse Child-Pugh score (P < 0.001) and esophageal varices (P = 0.018). In the validation set, there was also a significant negative correlation between HVAT and HVPG (r(2) = 0.538; P < 0.001), and AUROC = 0.953 for CSPH. HVAT was significantly correlated with PH. These results indicate that measuring HVAT is useful for the noninvasive prediction of CSPH in patients with compensated cirrhosis. (HEPATOLOGY 2012;56:1053-1062).     

Hepatic venous pressure gradient as a predictor of fibrosis in chronic liver disease because of hepatitis B virus

Background: Liver biopsy has been considered to be a gold standard for assessing hepatic fibrosis. Sample variability, interobserver variability and step‐wise evaluation limit its use. Hepatic venous pressure gradient (HVPG) correlates with hepatic fibrosis in chronic liver disease (CLD) because of hepatitis C. Aim: To evaluate the utility of HVPG for assessing hepatic fibrosis in patients with hepatitis B virus (HBV)‐related CLD. Patients and Methods: Sixty‐one patients with HBV‐related CLD who underwent both liver biopsy and hepatic haemodynamic studies were studied. Results: Forty‐nine (80.3%) patients had clinically significant portal hypertension (PHT) (HVPG≥10 mmHg), 39 (63.9%) severe PHT (i.e. HVPG≥12 mmHg), six (9.8%) HVPG≤5 mmHg and another six (9.8%) had preclinical PHT (i.e. HVPG>5 but <10 mmHg). A positive correlation between HVPG and fibrosis score was found (r=0.436, P<0.001). In patients with HVPG<10 or <12 mmHg there was a significant correlation with fibrosis score (r=0.603, P=0.029 and r=0.887, P<0.001 respectively). A positive correlation also existed in patients with HVPG≥10 mmHg and in patients with HVPG≥12 mmHg (r=0.512, P≤0.001 and r=0.543, P<0.001 respectively). Receiver operating characteristic curve of HVPG for the prediction of advanced fibrosis (stage≥3) had an area under curve of 0.906. HVPG value above 13.0 mmHg had a sensitivity of 79% and a specificity of 89% for predicting advanced fibrosis on histology. Conclusions: HVPG correlates well with the degree of histological fibrosis in patients with HBV‐related CLD.     

Von Willebrand factor as new noninvasive predictor of portal hypertension, decompensation and mortality in patients with liver cirrhosis

von Willebrand factor antigen (vWF-Ag) is elevated in patients with liver cirrhosis, but the clinical significance is unclear. We hypothesized that vWF-Ag levels may correlate with portal pressure, measured by hepatic venous pressure gradient (HVPG), and predict clinically significant portal hypertension (CSPH; HVPG ≥10 mmHg), decompensation and mortality. Portal hemodynamics were assessed by HVPG measurement, whereas vWF-Ag levels were measured by enzyme-linked immunosorbent assay. During follow-up, complications of liver cirrhosis, death or transplantation were recorded. Two hundred and eighty-six patients (205 male and 81 female; mean age, 56 years) with liver cirrhosis were included. vWF-Ag correlated with HVPG (r = 0.69; P < 0.0001) and predicted CSPH independently of Child Pugh score. Higher vWF-Ag levels were associated with varices (odds ratio [OR] = 3.27; P < 0.001), ascites (OR = 3.93; P < 0.001) and mortality (hazard ratio: 4.41; P < 0.001). Using a vWF-Ag cut-off value of ≥241%, the AUC for detection of CSPH in compensated patients was 0.85, with a positive predictive value and negative predictive value of 87% and 80%, respectively. Compensated patients had 25% mortality after 53 months if the vWF-Ag was <315% compared to 15 months in patients with vWF-Ag >315% (P < 0.001). Decompensated patients had a mortality of 25% after 37 and 7 months if their vWF-Ag was <315% and >315%, respectively (P = 0.002). In compensated patients with a vWF-Ag >315% median time to decompensation or death was 32 months compared with 59 months in patients with vWF-Ag <315%. vWF-Ag equals Model for End-Stage Liver Disease (MELD) in mortality prediction (area under the curve [AUC] = 0.71 for vWF-Ag versus AUC = 0.65 for MELD; P = 0.2). Conclusion: vWF-Ag is a new, simple and noninvasive predictor of CSPH. A vWF-Ag cut-off value at 315% can clearly stratify patients with compensated and decompensated liver cirrhosis in two groups with completely different survival. vWF-Ag may become a valuable marker for the prediction of mortality in patients with liver cirrhosis in clinical practice. (HEPATOLOGY 2012).     

Prognostic value of a single HVPG measurement and Doppler-ultrasound evaluation in patients with cirrhosis and portal hypertension

Background

In patients with cirrhosis the onset of clinically significant portal hypertension (CSPH; i.e., hepatic venous pressure gradient (HVPG) ???10?mmHg) is associated with an increased risk of complications. However, most cirrhotic patients already have CSPH at presentation, and limited information is available on further risk stratification in this population. This study assessed the prognostic value of a single HVPG measurement and Doppler-ultrasound (US) evaluation in patients with cirrhosis and CSPH.

Methods

Eighty-six consecutive patients with cirrhosis (73% compensated) and untreated CSPH (mean HVPG 17.8?±?5.1?mmHg) were included. All were studied by paired HVPG and US, and followed up for a minimum of 12?months (mean 28?±?20?months).

Results

Sixteen (25.3%) patients developed a first decompensation, and 11.6% died on follow-up. HVPG (per 1?mmHg increase OR 1.22, 95% CI 1.05?C1.40, p?=?0.007) and bilirubin (per 1?mg/ml increase OR 2.42, 95% CI 0.93?C6.26, p?=?0.06) independently predicted first decompensation, and Model for End-Stage Liver Disease (MELD) score (per 1 point increase OR 1.24, 95% CI 1.03?C1.51, p?=?0.03) and HVPG (per 1?mmHg increase OR 1.08, 95% CI 1.01?C1.26, p?=?0.05) independently predicted mortality. The best HVPG cutoff predicting these events was 16?mmHg. Ultrasonographic parameters lacked independent predictive value. The ultrasonographic detection of abdominal collaterals had a high positive likelihood ratio (7.03, 95% CI 2.23?C22.16) for the prediction of HVPG ???16?mmHg, implying an increase of the probability of belonging to this higher-risk population from 58 to 91%.

Conclusions

HVPG holds an independent predictive value for first decompensation and death in patients with CSPH. The ultrasonographic detection of collaterals allows the non-invasive identification of patients with HVPG ???16?mmHg, who are at higher risk.     

Histological-hemodynamic correlation in cirrhosis-a histological classification of the severity of cirrhosis

BACKGROUND/AIMS: While the definitive diagnosis of cirrhosis is histological, it is the degree of portal hypertension, as determined by the hepatic venous pressure gradient (HVPG), that is an important determinant of the severity of cirrhosis. An HVPG > or =10 mmHg (termed clinically significant portal hypertension or CSPH) is predictive of the development of complications of cirrhosis, including death. This study aimed to determine the relationship between specific histological parameters and HVPG in cirrhosis. METHODS: Forty-three patients with biopsy-proven cirrhosis and HVPG measurements within 6 months of the biopsy were included in the study. The following parameters were scored semiquantitatively and without knowledge of HVPG results: sinusoidal fibrosis, septal thickness, loss of portal tracts and central veins, nodule size, inflammation, steatosis, and iron. RESULTS: Septal thickness (p=0.03), small nodularity (p=0.003), loss of portal tracts (p=0.01), inflammation (p=0.04) and alcoholic etiology (p=0.01) correlated with the presence of CSPH. However, small nodularity and septal thickness were the only parameters independently predictive of CSPH (r=0.658, p<0.05). CONCLUSIONS: We describe a subclassification of histological cirrhosis based on the severity of portal hypertension that consists of a combination of nodule size and septal thickness, with small nodularity and thick septa being independent predictors of the presence of CSPH.     

Use of transient elastography (FibroScan®) for the noninvasive assessment of portal hypertension in HIV/HCV-coinfected patients

The hepatic venous pressure gradient (HVPG) is the gold standard for assessing portal pressure and correlates with the occurrence of portal hypertension (PH)-related complications. Transient elastography (TE) is a new, highly accurate noninvasive technique, which enables us to evaluate hepatic fibrosis to detect advanced fibrosis and cirrhosis. We performed a hepatic haemodynamic study and TE in 38 HIV/HCV-coinfected patients. The association between HVPG and liver stiffness was assessed by linear regression. The diagnostic value of TE was assessed by receiver operating characteristic (ROC) curves. We considered clinically significant PH as an HVPG ≥ 10 mmHg and severe PH as an HVPG ≥ 12 mmHg. A total of 38 HIV/HCV-coinfected patients were included. Twenty-eight patients (73.7%) had clinically significant PH (HVPG ≥ 10 mmHg), and 23 (60.5%) of these had severe PH (HVPG ≥ 12 mmHg). We found a statistically significant association between liver stiffness (kPa) and HVPG (r(2) = 0.46, P < 0.001, straight line equation HVPG=7.4 + 0.204*TE). The areas under the ROC curves were 0.80 [95% confidence interval (CI), 0.64-0.97] and 0.80 (95% CI, 0.66-0.94) for the prediction of HVPG ≥ 10 and ≥ 12 mmHg, respectively. Our data suggest that TE can predict the presence of clinically significant and severe PH in HIV/HCV-coinfected patients.     

PRO-C3: a new and more precise collagen marker for liver fibrosis in patients with chronic hepatitis C

Objective: Detecting significant fibrosis and cirrhosis remains important in treatment and follow-up of patients with chronic hepatitis C Infection (CHC). The aim of this study was to assess the ability of PRO-C3 to identify significant fibrosis (Ishak score?≥3) and cirrhosis (Ishak score?≥5) both as a single test and as a part of algorithms.

Materials and methods: PRO-C3 was assessed in baseline samples from the NORDynamIC trial. 270 patients were stratified into groups according to baseline biopsy. Baseline APRI, FIB-4 and GUCI scores were available for comparison in 232 patients.

Results: PRO-C3 increased with Ishak scores (p?=?.001). Area under the curve (AUC) for significant fibrosis was 0.75 (95% CI 0.68–0.81) and 0.76 (95% CI 0.68–0.84) for cirrhosis. FIB-4, APRI and GUCI had similar AUCs. In a PRO-C3 algorithm including age, platelet count, body mass index (BMI) and international normalised ratio (INR), the diagnostic efficacy improved to 0.85 (CI 0.80–0.89) and 0.90 (IQR 0.84–0.96) for significant fibrosis and cirrhosis, respectively.

Conclusions: In our study, PRO-C3 was an independent predictor of fibrosis stage, and may play an important role in managing CHC patients.     

Comparison and correlation of fibrosis stage assessment by collagen proportionate area (CPA) and the ELF panel in patients with chronic liver disease

BackgroundFibrosis progression is the common consequence of most chronic liver diseases.AimsTo evaluate the performance of Collagen Proportionate Area (CPA) and ELF using Ishak’s score in patients with chronic liver diseases.MethodsRetrospective analysis of medical data from patients on whom a liver biopsy was performed as part of the diagnostic assessment. CPA was calculated by using digital image analysis and then compared with Ishak and ELF scores.Results143 patients (84 men (59%); mean age 48.8 ± 12.8 years) were evaluated. Patients were mainly affected by viral hepatitis (92 HCV and 8 HBV). CPA and ELF values increased with worsening Ishak stage (P < 0.001) and their median values were significantly different among Ishak stages (P < 0.001). There was a significant correlation between CPA and ELF (r = 0.5). In AUROC analysis, CPA and ELF had similar diagnostic accuracy in identifying cirrhosis, but CPA had higher diagnostic accuracy than ELF in identifying significant or absent fibrosis. High ELF scores were observed in non-cirrhotic patients who suffered non-liver related deaths.ConclusionsThis study demonstrated that CPA and ELF values successfully identified patients with advanced fibrosis or cirrhosis, thus confirming the role of ELF as a clinical method for non-invasive assessment of fibrosis stage in chronic hepatitis.     

An inexpensive and worldwide available digital image analysis technique for histological fibrosis quantification in chronic hepatitis C

Hepatic fibrosis staging is based on semiquantitative scores. Digital imaging analysis (DIA) appears more accurate because fibrosis is quantified in a continuous scale. However, high cost, lack of standardization and worldwide unavailability restrict its use in clinical practice. We developed an inexpensive and widely available DIA technique for fibrosis quantification in hepatitis C, and here, we evaluate its reproducibility and correlation with semiquantitative scores, and determine the fibrosis percentage associated with septal fibrosis and cirrhosis. 282 needle biopsies staged by Ishak and METAVIR scores were included. Images of trichrome‐stained sections were captured and processed using Adobe^® Photoshop^® CS3 and Adobe^® Bridge^® softwares. The percentage of fibrosis (fibrosis index) was determined by the ratio between the fibrosis area and the total sample area, expressed in pixels calculated in an automated way. An excellent correlation between DIA fibrosis index and Ishak and METAVIR scores was observed (Spearman's r = 0.95 and 0.92; P < 0.001, respectively). Excellent intra‐observer reproducibility was observed in a randomly chosen subset of 39 biopsies with an intraclass correlation index of 0.99 (95% CI, 0.95–0.99). The best cut‐offs associated with septal fibrosis and cirrhosis were 6% (AUROC 0.97, 95% CI, 0.95–0.99) and 27% (AUROC 1.0, 95% CI, 0.99–1), respectively. This new DIA technique had high correlation with semiquantitative scores in hepatitis C. This method is reproducible, inexpensive and available worldwide allowing its use in clinical practice. The incorporation of DIA technique provides a more complete evaluation of fibrosis adding the quantification to architectural patterns.     

Correlation of transient elastography with hepatic venous pressure gradient in patients with cirrhotic portal hypertension: A study of 326 patients from India

AIM To study the diagnostic accuracy of transient elastography(TE) for detecting clinically significant portal hypertension(CSPH) in Indian patients with cirrhotic portal hypertension.METHODS This retrospective study was conducted at the Institute of Liver, Gastroenterology, and Panceatico-Biliary Sciences, Sir Ganga Ram Hospital, New Delhi, on consecutive patients with cirrhosis greater than 15 years of age who underwent hepatic venous pressure gradient(HVPG) and TE from July 2011 to May 2016. Correlation between HVPG and TE was analyzed using the Spearman's correlation test. Receiver operating characteristic ( ROC) curves were prepared for determining the utility of TE in predicting various stages of portal hypertension. The best cut-off value of TE forthe diagnosis of CSPH was obtained using the Youden index.RESULTS The study included 326 patients [median age 52(range 16-90) years; 81% males]. The most common etiology of cirrhosis was cryptogenic(45%) followed by alcohol(34%). The median HVPG was 16.0(range 1.5 to 30.5) mm Hg. Eighty-five percent of patients had CSPH. A significant positive correlation was noted between TE and HVPG(rho 0.361, P 0.001). The area under ROC curve for TE in predicting CSPH was 0.740(95%CI: 0.662-0.818)(P 0.01). A cut-off value of TE of 21.6 k Pa best predicted CSPH with a positive predictive value(PPV) of 93%.CONCLUSION TE has a fair positive correlation with HVPG; thus, TE can be used as a non-invasive modality to assess the degree of portal hypertension. A cut-off TE value of 21.6 k Pa identifies CSPH with a PPV of 93%.     

Intrahepatic angiogenesis increases portal hypertension in hepatitis B patients with cirrhosis

Aim

It remains unclear whether intrahepatic angiogenesis increases portal hypertension (PH) in hepatitis B with cirrhosis. We aim to investigate the relationship between intrahepatic angiogenesis and PH in hepatitis B patients with cirrhosis.

Methods

Sixty hepatitis B patients with cirrhosis and 40 healthy subjects were included in this study. Angiogenesis markers vascular endothelial growth factor receptor‐2 (VEGFR2), von Willebrand factor (vWF), and fibrosis marker α‐smooth muscle actin (α‐SMA) were observed by immunohistochemistry. Sirius Red staining was also used to determine liver fibrosis. Correlations between levels of intrahepatic angiogenesis and Child–Pugh classes, liver fibrosis degree, and portal vein pressure were examined. We also analyzed the relationship between levels of intrahepatic angiogenesis and complications of PH, including esophageal varices (EV), ascites, and hypersplenism.

Results

Correlation was observed between the levels of VEGFR2 (r = 0.590, P < 0.01), vWF (r = 0.524, P < 0.01) in tissue, and Child–Pugh classes. Significant correlations were observed between levels of VEGFR2 and α‐SMA (r = 0.710, P < 0.01), VEGFR2 and Sirius Red (r = 0.841, P < 0.01), vWF and α‐SMA (r = 0.768, P < 0.01), and vWF and Sirius Red (r = 0.825, P < 0.01). Patients with hepatic venous pressure gradient (HVPG) ≥12 mmHg showed higher levels of VEGFR2 and vWF expression compared to those with (HVPG) <12 mmHg (2.60 ± 1.28% vs. 1.09 ± 0.73%; 5.85 ± 2.45% vs. 2.31 ± 1.34%, P < 0.01), respectively. Moreover, complications of PH, including size of esophageal varices (P < 0.01), presence of ascites (P < 0.01), and spleen volume (P < 0.01) were significantly affected by the levels of intrahepatic angiogenesis.

Conclusion

Intrahepatic angiogenesis increases PH in hepatitis B patients with cirrhosis. The study provides the potential ways to intervene in the progresses for therapeutic benefits in cirrhosis and PH.

     

Plasma Nogo-A and placental growth factor levels are associated with portal hypertension in patients with liver cirrhosis

BACKGROUND Clinically significant portal hypertension(CSPH) and severe portal hypertension(SPH) increase the risk for decompensation and life-threatening complications in liver cirrhosis. Pathologic angiogenesis might contribute to the formation of these conditions. Placental growth factor(PlGF) and Nogo-A protein are biomarkers of pathological angiogenesis, but data on their role in liver cirrhosis and portal hypertension is scarce.AIM To determine plasma levels of PlGF and Nogo-A in patients with liver cirrhosis,CSPH, SPH and potential to predict portal hypertension.METHODS A cohort of 122 patients with hepatitis C virus and/or alcohol-induced liver cirrhosis with characterized hepatic venous pressure gradient(HVPG) were included in the study. Demographic data, medical history, Child-Turcotte-Pugh and Model of End Stage liver disease score, clinical chemistry, liver stiffnessvalues were recorded on the day of the procedure prior HVPG measurement. The degree of portal hypertension was determined by the invasive HVPG measurement. Nogo-A and PlGF plasma levels were evaluated using enzyme linked immunosorbent assay. The control group consisted of 30 healthy age-and sex-matched individuals.RESULTS Peripheral PlGF levels were higher and Nogo-A levels were lower in patients with liver cirrhosis(23.20 vs 9.85; P 0.0001 and 2.19 vs 3.12; P = 0.004 respectively). There was a positive linear correlation between peripheral levels of PlGF and HVPG(r = 0.338, P = 0.001) and negative linear correlation between the peripheral Nogo-A levels and HVPG(r =-0.267, P = 0.007). PlGF levels were higher in CSPH and SPH(P = 0.006; P 0.0001) whereas Nogo-A levels were lower(P = 0.01; P 0.033). Area under the curve for the diagnosis of CSPH for PlGF was 0.68(P = 0.003) and for Nogo-A-0.67(P = 0.01); for SPH 0.714(P 0.0001) and 0.65(P = 0.014) respectively. PlGF levels were higher and Nogo-A levels were lower in patients with esophageal varices(P 0.05). PlGF cut-off value of 25 pg/mL distinguished patients with CSPH at 55.7% sensitivity and76.7% specificity; whereas Nogo-A cut-off value of 1.12 ng/mL was highly specific(93.1%) for the diagnosis of CSPH.CONCLUSION Plasma PlGF levels were higher while Nogo-A levels were lower in patients with liver cirrhosis and portal hypertension. Biomarkers showed moderate predictive value in determining CSPH and SPH.     

Hepatic recompensation according to Baveno VII criteria is linked to a significant survival benefit in decompensated alcohol-related cirrhosis

Background & Aims

Removing the primary aetiological factor in decompensated cirrhosis may lead to a restoration of hepatic function. In this study, we investigated the clinical implications of recompensation and the subsequent survival in patients with decompensated alcohol-related cirrhosis.

Methods

The rate of recompensation was evaluated in patients with decompensated alcohol-related cirrhosis and persistent alcohol abstinence undergoing a hepatic venous pressure gradient (HVPG) measurement. Recompensation was defined according to Baveno VII criteria as resolution of ascites and hepatic encephalopathy, absence of variceal bleeding and improvement in liver function.

Results

Two hundred and four abstinent patients with decompensated alcohol-related cirrhosis (age: 57.2 [IQR:50.1–63.7] years; 75.0% male; median MELD: 15 [IQR:11–19]) and a median HVPG of 20 (IQR:18–24) mmHg were included. During a median follow-up of 24.4 (IQR:10.9–50.4) months, 37 patients (18.1%) achieved abstinence-induced recompensation. Lower baseline HVPG, lower Child-Pugh score, lower BMI, higher albumin and higher mean arterial pressure were linked to a higher probability of recompensation. After adjusting for age, disease severity, portal hypertension and systemic inflammation, achieving recompensation resulted in a significant and considerable reduction in liver-related mortality (adjusted HR: 0.091 [95% CI: 0.012–0.677]; p = .019). Only 13 patients (6.4%) developed hepatocellular carcinoma, with a tendency towards a lower risk upon recompensation (HR: 0.398 [95% CI: 0.084–1.878]; p = .245), yet this finding did not reach statistical significance and requires further investigation.

Conclusions

Alcohol abstinence led to recompensation in 18.1% of our cohort of HVPG-characterised patients with decompensated alcohol-related cirrhosis. Achieving hepatic recompensation resulted in a >90% risk reduction in liver-related mortality.     

Alcohol Abstinence Improves Prognosis Across All Stages of Portal Hypertension in Alcohol-Related Cirrhosis

Background and AimsAlcohol-related liver disease is a leading cause of liver-related mortality. The effect of alcohol abstinence on the natural history of alcohol-related cirrhosis across distinct stages of portal hypertension has not been thoroughly investigated. In this study, we assessed the clinical implications of abstinence in patients with alcohol-related cirrhosis and clinically significant portal hypertension.MethodsAlcohol abstinence, hepatic decompensation, and mortality were assessed in patients with alcohol-related cirrhosis who underwent a baseline hepatic venous pressure gradient (HVPG) measurement and were diagnosed with clinically significant portal hypertension (HVPG ≥10 mm Hg).ResultsA total of 320 patients with alcohol-related cirrhosis (median age: 57 [interquartile range (IQR), 49.7-63.1] years; 75.6% male; 87.5% decompensated) and a median HVPG of 20 (IQR, 17-23) mm Hg were followed up for a median of 36 (IQR, 14-80) months. Overall, 241 (75.3%) patients remained abstinent, while 79 (24.7%) patients had active alcohol consumption. Alcohol abstinence was linked to a significantly reduced risk of hepatic decompensation (adjusted hazard ratio [aHR], 0.391; P < .001), as well as liver-related (aHR, 0.428; P < .001) and all-cause (aHR, 0.453; P < .001) mortality, after adjusting for baseline HVPG, MELD, and previous decompensation. Importantly, alcohol abstinence significantly reduced the cumulative incidence of hepatic decompensation in both groups with HVPG 10–19 mm Hg (P < .001) and HVPG ≥20 mm Hg (P = .002). The 3-year decompensation probability was 32.4% vs 60.0% in HVPG 10–19 mm Hg and 57.5% vs 82.6% in HVPG ≥20 mm Hg for abstinent patients vs active drinkers, respectively.ConclusionsAlcohol abstinence improves prognosis across all stages of portal hypertension in alcohol-related cirrhosis, including in patients who have already progressed to high-risk portal hypertension. (ClinicalTrials.gov, Number: NCT03267615).     

6-thioguanine associated nodular regenerative hyperplasia in patients with inflammatory bowel disease may induce portal hypertension

BACKGROUND: Recent studies suggest an association between 6-thioguanine (6-TG) therapy and hepatic nodular regenerative hyperplasia (NRH) in patients with inflammatory bowel disease (IBD). An influence of 6-TG on portal pressure remains to be determined. The aim of the study was to examine the functional relevance of long-term 6-TG treatment on hepatic hemodynamics in IBD patients and its association with NRH. METHODS: Patients treated with 6-TG for IBD underwent measurement of the hepatic venous pressure gradient (HVPG) and liver biopsy. 6-TG therapy was stopped when NRH was diagnosed. If elevated, HVPG measurement was repeated after 1 yr. RESULTS: Twenty-six patients (15 women, 11 men; median age 41 yr, range 23-76) treated with 6-TG for 38 months (median; range 12-45) were included. Among 24 patients with sufficient liver biopsy, 6 patients (25%) were diagnosed with NRH. In these 6 patients, the HVPG was higher (median HVPG 7 mmHg, range 3-14) than in the 18 patients without NRH (median 3 mmHg, range 2-5; P < 0.001). In the patients with NRH, two had clinically significant portal hypertension (CSPH) (13 and 14 mmHg, respectively); in one patient the HVPG was slightly elevated (7 mmHg). No overt clinical signs of portal hypertension were observed. One year after stopping 6-TG therapy, HVPG decreased in all 3 patients with initially elevated HVPG levels. CONCLUSIONS: We demonstrate that IBD patients under long-term 6-TG therapy are at a substantial risk for developing NRH. NRH results in elevation of HVPG and may cause CSPH. Discontinuation of 6-TG therapy extenuates portal hypertension and may thus reduce the risk of complications.     

Prospective comparison of Fibroscan,King’s score and liver biopsy for the assessment of cirrhosis in chronic hepatitis C infection

Summary. Historically, liver biopsy (LB) was the sole method to evaluate the severity of hepatic fibrosis in patients with chronic hepatitis C infection. However, LB is expensive and associated with a risk of severe complications. Therefore, noninvasive tests have been developed to assess the severity of liver fibrosis. The accuracy of Fibroscan (FS) and King’s score (KS) was evaluated individually and in combination using liver histology as the reference standard. One hundred and eighty‐seven patients were identified who had undergone a biopsy with a diagnosis of chronic hepatitis C virus (HCV) mono‐infection (HCV RNA‐positive by RT‐PCR), attending King’s College Hospital (n = 88) or the Royal Free Hospital (n = 99) (London) between May 2006 and December 2007. Liver fibrosis was scored using the Ishak method; significant fibrosis was defined as Ishak fibrosis stage F3–F6, and cirrhosis defined as Ishak fibrosis F5–F6. The diagnostic accuracy of each test was assessed by area under receiver operator characteristic curves (AUROC). Median age was 49 years (43–54) and 115 (61%) were male. The AUROC for FS, KS and FS + KS for the diagnosis of Ishak F3–F6 were 0.83, 0.82 and 0.85, respectively and for the diagnosis of cirrhosis (≥F5) were 0.96, 0.89 and 0.93, respectively. The negative predictive values for the diagnosis of cirrhosis using the optimal cut‐off results for fibrsocan (10.05 kPa), KS (24.3) and the two combined (26.1) were 98%, 91% and 94%, respectively. The noninvasive markers and, particularly, FS were effective tests for the prediction of cirrhosis in chronic hepatitis C. Both KS and FS also had clinical utility for the prediction of Ishak fibrosis stages F3–F6.     

Non-invasive diagnosis and follow-up of portal hypertension

Compensated advanced chronic liver disease (cACLD) describes the spectrum of advanced fibrosis/cirrhosis in asymptomatic patients at risk of developing clinically significant portal hypertension (CSPH, defined by a hepatic venous pressure gradient (HVPG) ≥10 mmHg). Patients with cACLD are at high risk of liver-related morbidity and mortality. In patients at risk of chronic liver disease, cACLD is strongly suggested by a liver stiffness (LSM) value >15 kPa or clinical/biological/radiological signs of portal hypertension, and ruled out by LSM <10 kPa, or Fibrotest® ≤0.58, or Fibrometer® ≤0.786. Patients with chronic liver disease (excluding vascular diseases) with a LSM <10 kPa are at low risk of developing portal hypertension complications. The presence of CSPH can be strongly suspected when LSM is ≥20 kPa. In a patient without clinical, endoscopic or radiological features of portal hypertension, measurement of the HVPG is recommended before major liver or intra-abdominal surgery, before extra-hepatic transplantation and in patients with unexplained ascites.Endoscopic screening for oesophageal varices can be avoided in patients with LSM <20 kPa and a platelet count >150 G/L (favourable Baveno VI criteria) at the time of diagnosis. There is no non-invasive method alternative for oeso-gastroduodenal endoscopy in patients with unfavourable Baveno criteria (liver stiffness ≥20 kPa or platelet count ≤50 G/l). Platelet count and liver stiffness measurements must be performed once a year in patients with cACLD with favourable Baveno VI criteria at the time of diagnosis. A screening oeso-gastroduodenal endoscopy is recommended if Baveno VI criteria become unfavourable.     

Collagen proportionate area correlates to hepatic venous pressure gradient in non-abstinent cirrhotic patients with alcoholic liver disease

AIM To explore the relationship between collagen proportionate area(CPA) and portal hypertension-related clinical manifestations in alcoholic liver disease(ALD).METHODS Retrospective study with chart review of patients with ALD adressed to our center between January 2012 and December 2013 for a transjugular liver biopsy(TJLB) and hepatic hemodynamic study. Patients were included if they met the following criteria:(1) Medical indication for a liver biopsy in the setting of ALD;(2) recent( 15 d) clinical, radiological, endoscopic and biological data available; and(3) estimated follow-up of at least 6 mo. Liver tissue from cirrhotic subjects obtained from transjugular liver biopsies was stained with Picro Sirius red and computer-assisted digital image analysis to determine fibrosis density using CPA was performed. RESULTS We included 61 patients with alcoholic ALD, subdivided in 41 active alcohol drinkers and 20 durably abstinent patients. Nine healthy liver donors served as controls. Mean CPA in patients with ALD was 7.1%, with no difference between active drinkers and abstinent patients(P = 0.17). Using a fibrosis density cutoff of 5%, we observed a positive correlation between high fibrosis density and the hepatic venous pressure gradient(HVPG) only in active drinkers(P = 0.02). At 12-mo of follow-up, in the group of active alcohol drinkers, patients reaching a composite outcome showed a higher HVPG value as compared to those who did not(18.5 mm Hg vs 14.5 mm Hg P 0.04) whereas CPA values were similar(6.9% vs 11%, P = 0.23).CONCLUSION In active alcoholic ALD, CPA correlates to portal pressure but only HVPG predicts clinical events, pointing to the role of alcohol as a modulator of portal hypertension.     

HIV–HCV co‐infected patients with low CD4+ cell nadirs are at risk for faster fibrosis progression and portal hypertension

Summary. Patients co‐infected with the human immunodeficiency virus (HIV) and the hepatitis C virus (HCV) are fraught with a rapid fibrosis progression rate and with complications of portal hypertension (PHT) We aimed to assess the influence of immune function [Centers of Disease Control and Prevention (CDC) stage] on development of PHT and disease progression in HIV–HCV co‐infection. Data of 74 interferon‐naïve HIV–HCV co‐infected patients undergoing liver biopsy, measurement of portal pressure and of liver stiffness and routine laboratory tests (including CD4+ cell count, HIV and HCV viral load) were analysed. Time of initial exposure (risk behaviour) was used to assess fibrosis progression. Fibrosis progression, time to cirrhosis and portal pressure were correlated with HIV status (CDC stage). HIV–HCV patients had rapid progression of fibrosis [0.201 ± 0.088 METAVIR fibrosis units/year (FU/y)] and accelerated time to cirrhosis (24 ± 13 years), high HCV viral loads (4.83 × 10⁶ IU/mL) and a mean HVPG at the upper limit of normal (5 mmHg). With moderate or severe immunodeficiency, fibrosis progression was even higher (CDC‐2 = 0.177 FU/y; CDC‐3 = 0.248 FU/y) compared with patients with higher CD4+ nadirs (CDC‐1 = 0.120 FU/y; P = 0.0001). An indirect correlation between CD4+ cell count and rate of fibrosis progression (R = ?0.6654; P < 0.001) could be demonstrated. Hepatic venous pressure gradient (HVPG) showed early elevation of portal pressure with median values of 4, 8 and 12 mmHg after 10, 15 and 20 years of HCV infection for CDC‐3 patients. Patients treated with highly active anti‐retroviral therapy (HAART) had similar rates of progression and portal pressure values than patients without HAART. Progression of HCV disease is accelerated in HIV–HCV co‐infection, being more pronounced in patients with low CD4+ cell count. A history of a CD4+ cell nadir <200/μL is a risk factor for rapid development of cirrhosis and PHT. Thus, HCV treatment should be considered early in patients with HIV–HCV co‐infection and largely preserved CD4+ cell counts.