G. Ronchi

Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic liver disease

Objective: Transient elastography (TE) is gaining popularity as a non-invasive method for predicting liver fibrosis, but intraobserver and interobserver agreement and factors influencing TE reproducibility have not been adequately assessed. This study investigated these aspects. Setting: Tertiary referral liver unit. Patients: Over a 4-month period, 200 patients with chronic liver disease (CLD) with varying aetiology consecutively underwent TE and liver biopsy. Interventions: TE was performed twice by two different operators either concomitantly or within 3 days of the bioptic procedure (METAVIR classification). Main outcome measures: Intraobserver and interobserver agreement were analysed using the intraclass correlation coefficient (ICC) and correlated with different patient-related and liver disease-related covariates. Results: 800 TE examinations were performed, with an indeterminate result rate of 2.4%. The overall interobserver agreement ICC was 0.98 (95% CI 0.977 to 0.987). Increased body mass index (>25 kg/m2), steatosis, and low staging grades (fibrosis (F) stage <2) were significantly associated with reduced ICC (p<0.05). Intraobserver agreement ICC was 0.98 for both raters. Using receiver operating characteristic curves, three diagnostic TE thresholds were identified: >7.9 kPa for F⩾2, >10.3 for F⩾3 and >11.9 for F = 4. TE values assessed by the two raters fell within the same cut-off of fibrosis in 88% of the cases for F⩾2, in 92% for F⩾3 and 91% for F = 4. Conclusions: TE is a highly reproducible and user-friendly technique for assessing liver fibrosis in patients with CLD. However, because TE reproducibility is significantly reduced (p<0.05) in patients with steatosis, increased BMI and lower degrees of hepatic fibrosis, caution is warranted in the clinical use of TE as a surrogate for liver biopsy.

The natural history of compensated cirrhosis due to hepatitis C virus: A 17-year cohort study of 214 patients†

Large databases of consecutive patients followed for sufficiently long periods are needed to establish the rates, chronology, and hierarchy of complications of cirrhosis as well as the importance of other potential causes of liver disease. In accordance with this goal, a cohort of patients with compensated cirrhosis due to hepatitis C virus (HCV) was followed for 17 years. Two hundred and fourteen HCV RNA–seropositive patients with Child‐Pugh class A cirrhosis who had no previous clinical decompensation were prospectively recruited and followed up with periodic clinical and abdominal ultrasound examinations. During 114 months (range 1–199), hepatocellular carcinoma (HCC) developed in 68 (32%), ascites in 50 (23%), jaundice in 36 (17%), upper gastrointestinal bleeding in 13 (6%), and encephalopathy in 2 (1%), with annual incidence rates of 3.9%, 2.9%, 2.0%, 0.7%, and 0.1%, respectively. Clinical status remained unchanged in 154 (72%) and progressed to Child‐Pugh class B in 45 (21%) and class C in 15 (7%). HCC was the main cause of death (44%) and the first complication to develop in 58 (27%) patients, followed by ascites in 29 (14%), jaundice in 20 (9%), and upper gastrointestinal bleeding in 3 (1%). The annual mortality rate was 4.0% per year and was higher in patients with other potential causes of liver disease than in those without them (5.7% vs. 3.6%; P = .04). In conclusion, hepatitis C–related cirrhosis is a slowly progressive disease that may be accelerated by other potential causes of liver disease. HCC was the first complication to develop and the dominant cause for increased mortality. (HEPATOLOGY 2006;43:1303–1310.)

The diagnostic and economic impact of contrast imaging techniques in the diagnosis of small hepatocellular carcinoma in cirrhosis

Background Contrast-enhanced ultrasound (CE-US), contrast CT scan and gadolinium dynamic MRI are recommended for the characterisation of liver nodules detected during surveillance of patients with cirrhosis with US. Aim To assess the sensitivity, specificity, diagnostic accuracy and economic impact of all possible sequential combinations of contrast imaging techniques in patients with cirrhosis with 1–2 cm liver nodules undergoing US surveillance. Patients/methods 64 patients with 67 de novo liver nodules (55 with a size of 1–2 cm) were consecutively examined by CE-US, CT, MRI, and a fine-needle biopsy (FNB) as diagnostic standard. Undiagnosed nodules were re-biopsied; non-malignant nodules underwent enhanced imaging follow-up. The typical radiological feature of hepatocellular carcinoma (HCC) was arterial phase hypervascularisation followed by portal/venous phase washout. Results HCC was diagnosed in 44 (66%) nodules (2, <1 cm; 34, 1–2 cm; 8, >2 cm). The sensitivity of CE-US, CT and MRI for 1–2 cm HCC was 26, 44 and 44%, with 100% specificity, the typical vascular pattern of HCC being identified in 22 (65%) by a single technique versus 12 (35%) by at least two techniques carried out at the same time point (p=0.028). Compared with the cheapest dual examination (CE-US+CT), the cheapest single technique of stepwise imaging diagnosis of HCC was equally expensive (€26 440 vs €28 667), but led to a 23% reduction of FNB procedures (p=0.031). Conclusions In patients with cirrhosis with a 1–2 cm nodule detected during surveillance, a single imaging technique showing a typical contrast pattern confidently permits the diagnosis of HCC, thereby reducing the need for FNB examinations.

A morphometric and immunohistochemical study to assess the benefit of a sustained virological response in hepatitis C virus patients with cirrhosis.

Although annular fibrosis is the hallmark of cirrhosis, other microscopic changes that affect liver function such as sinusoid capillarization or loss of metabolic zonation are common. A sustained virological response (SVR) may halt fibrosis deposition in hepatitis C virus (HCV)‐infected patients, but its impact on the other cirrhosis‐associated lesions is unknown. The aim of this study was to assess the impact of an SVR on cirrhosis‐related histopathological features. Paired pre‐ and posttreatment liver biopsies from 38 HCV patients with cirrhosis with an SVR were analyzed. Fibrosis was staged using the METAVIR scoring system, and the area of fibrosis was measured using morphometry. Ductular proliferation, metabolic zonation, sinusoid capillarization, and hepatic stellate cell activation were assessed by anti‐cytokeratin‐7, anti‐glutamine synthetase (GS), anti‐cytochrome P4502E1 (CYP2E1), anti‐CD34, and anti α‐smooth muscle actin (αSMA). After 61 months from an SVR, cirrhosis regression was observed in 61%, and the collagen content decreased in 89%. Although periportal and lobular necroinflammation vanished, portal inflammation persisted in 66%. Ductular proliferation decreased in 92%. Before treatment, metabolic zonation was lost, as shown by GS and CYP2E1, in 71% and 88%, respectively, with normalization in 79% and 73%, after an SVR. Conversely, no changes in sinusoidal capillarization were observed after treatment, as assessed by CD34 (P = 0.41) and αSMA (P = 0.95). Finally, no differences in all the immunohistochemical scores emerged whether or not cirrhosis persisted. Conclusion: Cirrhosis regression and decreased fibrosis are frequently observed among HCV patients with cirrhosis with an SVR. Despite ductular proliferation vanishing and lobular zonation restoration, portal inflammation and sinusoidal capillarization may not regress after viral eradication. (HEPATOLOGY 2012)

A 28-Year Study of the Course of Hepatitis Δ Infection: A Risk Factor for Cirrhosis and Hepatocellular Carcinoma

BACKGROUND & AIMS Chronic infection with hepatitis Delta virus (HDV) is a risk factor for cirrhosis and hepatocellular carcinoma (HCC); predictors of disease outcome are, however, poorly defined. We tracked the course of HDV infection in 299 patients over a mean period of 233 months. METHODS We analyzed data from patients who had been HDV positive for at least 6 months (230 males; mean age, 30 years) admitted from 1978 to 2006 to Maggiore Hospital, Milan. HDV infection was defined by the presence of HDV antigen in liver tissue or serum HDV RNA in anti-HDV/hepatitis B surface antigen seropositive patients. At enrollment, 7 patients had acute hepatitis, 101 had mild-moderate chronic hepatitis, 76 had severe chronic hepatitis, and 104 had histologic or clinical cirrhosis. Ninety patients were treated with interferon, 62 with corticosteroids, and 12 with nucleoside analogues; 135 received no therapy. RESULTS Over a mean period of 233 months, 82 patients developed cirrhosis. Among the 186 total patients with cirrhosis, 46 developed HCC, 43 ascites, 44 jaundice, and 1 encephalopathy. Female sex, alcohol abuse, and HDV replication were associated with liver decompensation; HBV replication and interferon were associated with HCC development. By the end of the study, 186 patients were still alive, 63 had died, and 29 had received liver transplants. The main cause of death was liver failure (n = 37, 59%); HDV replication was the only independent predictor of mortality. CONCLUSIONS Persistent HDV replication leads to cirrhosis and HCC at annual rates of 4% and 2.8%, respectively, and is the only predictor of liver-related mortality.

Transient elastography predicts fibrosis progression in patients with recurrent hepatitis c after liver transplantation

Objective: Transient elastography (TE) allows non-invasive evaluation of the severity of liver disease in patients with chronic hepatitis C. This procedure, however, warrants further validation in the setting of liver transplantation (LT), including patients under follow-up for recurrent hepatitis C. Setting: Tertiary referral hospital. Patients: 95 patients (75 males) transplanted for end-stage liver disease due to hepatitis C virus. Interventions: Paired liver biopsy (LB) and TE were carried out 6–156 (median, 35) months after LT. 40 patients with recurrent hepatitis C sequentially evaluated 6–21 months apart. Main outcome measures: Clinical, laboratory and graft histological features influencing TE results. Results: Median TE values were 7.6 kPa in the 90 patients with a successful TE examination, being 5.6 kPa in the 30 patients with Ishak fibrosis score (S) of 0–1, 7.6 kPa in the 38 with S2–3; 16.7 kPa in the 22 with S4–6, (p<0.0001). Areas under the ROC curves were 0.85 (95% CI, 0.76 to 0.92) for S⩾3, 0.90 (95% CI, 0.82 to 0.95) for S⩾4 with 7.9 and 11.9 kPa optimal TE cut-off (81% and 82% sensitivity, 88% and 94% negative predictive value, respectively). Fibrosis, necroinflammatory activity and higher than 200 IU/l gamma-glutamyl transpeptidase levels independently influenced TE results. During post-LT follow-up, TE results changed in parallel with grading (r = 0.63) and staging (r = 0.71), showing 86% sensitivity and 92% specificity in predicting staging increases. Conclusions: TE accurately predicts fibrosis progression in LT patients with recurrent hepatitis C, suggesting that protocol LB might be avoided in patients with improved or stable TE values during follow-up.

Etiology-related determinants of liver stiffness values in chronic viral hepatitis B or C

BACKGROUND & AIMS Transient elastography (TE) has gained popularity for the non-invasive assessment of severity of chronic viral hepatitis, but a comprehensive evaluation of the factors that might account for discrepancy in diagnostic accuracy between TE and the standard of care liver biopsy (LB) is still needed. METHODS Patients with chronic hepatitis-B (HBV, n=104) or -C (HCV, n=453) underwent percutaneous LB concomitantly with TE (FibroScan®; Echosens, Paris, France). Liver cell necroinflammatory activity (A) and fibrosis (F) were assessed by METAVIR. Perisinusoidal fibrosis was rated with a 0-3 score. Determinants of TE results were investigated by a linear regression model whereas discordance between TE and LB results was assessed by logistic regression. RESULTS Fibrosis (p<0.0001) and liver cell necroinflammatory activity (p<0.0001) were independently associated with TE results in both HBV and HCV patients, whereas steatosis (p<0.0001) was independently associated with TE in HCV only. Fibrosis overestimation was predicted by severe/moderate necroinflammatory activity in HBV and by older age (41-60 or>60years vs.<40), >2 UNL AST and>2 UNL GGT, as well as severe/moderate necroinflammatory activity and severe/moderate steatosis in HCV. In the latter patients, however, moderate/severe necroinflammatory activity and steatosis were the only independent predictors of fibrosis overestimation. CONCLUSIONS Fibrosis and necroinflammatory activity are the main determinants of TE in chronic viral hepatitis. Since TE staging of fibrosis is influenced by necroinflammatory activity and steatosis, a diagnostic LB is deemed necessary for a reliable intra-patient TE monitoring of the course of viral hepatitis.

Ultrasound-assisted percutaneous liver biopsy: Superiority of the Tru-Cut over the Menghini needle for diagnosis of cirrhosis

A total of 1192 consecutive patients with diffuse liver disease were randomized to have percutaneous liver biopsy specimens taken with the Menghini or the Tru-Cut needle, to compare tissue yield, safety, and accuracy of the two needles for diagnosing cirrhosis. The sites of puncture were determined by prebiopsy ultrasound scans. Adequate samples were obtained from 94% with the Tru-Cut needle and from 79.2% with the Menghini needle (p less than 0.001). Accuracy in diagnosing cirrhosis was 89.5% for the Tru-Cut needle and 65.5% for the Menghini needle (p less than 0.05). Complication rates were very low and similar for both needles. Under these conditions, the Tru-Cut needle is superior to the Menghini needle for diagnosing cirrhosis.

Diagnosis of Hepatocellular Carcinoma in Cirrhosis by Dynamic Contrast Imaging: The Importance of Tumor Cell Differentiation

Dynamic contrast imaging techniques are considered the standard of care for the radiological diagnosis of hepatocellular carcinoma (HCC) in cirrhosis. However, the accuracy of radiological diagnosis depends largely on the degree of arterial hypervascularization, which increases with tumor size. Owing to the interplay and prognostic relevance of tumor vascularization and cell differentation, we asked ourselves whether tumor grade also affects the outcome of radiological diagnosis. Sixty‐two HCCs (47 of which measured 1‐2 cm) were consecutively detected in 59 patients with compensated cirrhosis under surveillance with ultrasound and confirmed by way of echo‐guided biopsy and concurrent investigations with contrast‐enhanced ultrasound (CE‐US), computed tomography (CT), and gadolinium magnetic resonance imaging (MRI). Tumor cell differentiation was evaluated using Edmondson‐Steiner criteria in liver cores of 0.9‐5.0 cm (median 1.6 cm). Eighteen (29%) HCCs were grade I (1.5 cm), 28 (45%) were grade II (1.5 cm), 16 (26%) were grade III (1.8 cm), and none were grade IV. Contrast wash‐in and wash‐out were concurrently demonstrated in 21 (34%) tumors by way of CE‐US, including three (16%) grade I and 18 (41%) grade II‐III (P = 0.08); in 32 (52%) tumors by way of CT, including three (16%) grade I and 29 (66%) grade II‐III (P = 0.0006); and 28 (47%) tumors by way of MRI, including three grade I (16%) and 25 (57%) grade II‐III (P = 0.01). Among 1‐ to 2‐cm tumors, the radiological diagnosis was achieved in two of 16 grade I and 17of 31 grade II‐III tumors (P = 0.006). Conclusion: Tumor grade, a relevant predictor of disease severity, influences the accuracy of dynamic contrast techniques in the diagnosis of HCC. HEPATOLOGY 2010

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