Mirella Fraquelli

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.

Accuracy of Ultrasonography, Spiral CT, Magnetic Resonance, and Alpha-Fetoprotein in Diagnosing Hepatocellular Carcinoma: A Systematic Review

BACKGROUND AND AIM:In patients with chronic liver disease, the accuracy of ultrasound scan (US), spiral computed tomography (CT), magnetic resonance imaging (MRI), and alpha-fetoprotein (AFP) in diagnosing hepatocellular carcinoma (HCC) has never been systematically assessed, and present systematic review was aimed at this issue.METHODS:Pertinent cross-sectional studies having as a reference standard pathological examinations of the explanted liver or resected segment(s), biopsies of focal lesion(s), and/or a period of follow-up, were identified using MEDLINE, EMBASE, Cochrane Library, and CancerLit. Pooled sensitivity, specificity, and likelihood ratios (LR) were calculated using the random effect model. Summary receiver operating characteristic (SROC) curve and predefined subgroup analyses were made when indicated.RESULTS:The pooled estimates of the 14 US studies were 60% (95% CI 44–76) for sensitivity, 97% (95% CI 95–98) for specificity, 18 (95% CI 8–37) for LR+, and 0.5 (95% CI 0.4–0.6) for LR−; for the 10 CT studies sensitivity was 68% (95% CI 55–80), specificity 93% (95% CI 89–96), LR+ 6 (95% CI 3–12),and LR− 0.4 (95% CI 0.3–0.6); for the nine MRI studies sensitivity was 81% (95% CI 70–91), specificity 85% (95%CI 77–93), LR+ 3.9 (95%CI 2–7), and LR− 0.3 (95% CI 0.2–0.5). The sensitivity and specificity of AFP varied widely, and this could not be entirely attributed to the threshold effect of the different cutoff levels used.CONCLUSIONS:US is highly specific but insufficiently sensitive to detect HCC in many cirrhotics or to support an effective surveillance program. The operative characteristics of CT are comparable, whereas MRI is more sensitive. High-quality prospective studies are needed to define the actual diagnostic role of AFP.

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.

Hereditary hemochromatosis in adults without pathogenic mutations in the hemochromatosis gene.

BACKGROUND AND METHODS Hereditary hemochromatosis in adults is usually characterized by mutations in the HFE gene on the short arm of chromosome 6. Most patients have a substitution of tyrosine for cysteine at position 282 (C282Y). We studied a large family from Italy that includes persons who have a hereditary iron-overload condition indistinguishable from hemochromatosis but without apparent pathogenic mutations in the HFE gene. We performed biochemical, histologic, and genetic studies of 53 living members of the family, including microsatellite analysis of chromosome 6 and direct sequencing of the HFE gene. RESULTS Of the 53 family members, 15 had abnormal serum ferritin levels, values for transferrin saturation that were higher than 50 percent, or both. Thirteen of the 15 had elevated body iron levels, diagnosed on the basis of the clinical evaluation and liver biopsy, and underwent iron-removal therapy. The other two, both children, did not undergo liver biopsy or iron-removal therapy. None of the 15 members had the C282Y mutation of the HFE gene; 5 of the 15 (as well as 5 healthy relatives) had another mutation of this gene, a substitution of aspartate for histidine at position 63, but none were homozygous for it. No other mutations were found after sequencing of the entire HFE gene for all family members. Microsatellite analysis showed no linkage of the hemochromatosis phenotype with the short arm of chromosome 6, the site of the HFE gene. CONCLUSIONS Hereditary hemochromatosis can occur in adults who do not have pathogenic mutations in the hemochromatosis gene.

Heterogeneity of Hemochromatosis in Italy

BACKGROUND & AIMS Patients with hemochromatosis show variable phenotype expression. We evaluated the frequency of hemochromatosis gene (HFE) mutations and the contribution of HFE genotype, ancestral haplotype, ethnic background, and additional factors (alcohol intake, hepatitis viruses, and beta-thalassemia trait) to the severity of iron overload in a large series of Italian patients with a hemochromatosis phenotype. METHODS HFE genotype was studied in 188 patients. Phenotype evaluation was available in 153 men and 20 women and was based mainly on iron removed. HFE genotype was determined by a polymerase chain reaction restriction assay and ancestral haplotype through D6S265 and D6S105 microsatellite analysis. RESULTS The frequency of C282Y homozygotes was 64%, with a decreasing gradient from north to south. C282Y homozygotes showed more severe iron overload than the other HFE genotypes. In the same group, ancestral haplotype was associated with a more severe phenotype. Additional factors may favor the development of a relatively mild hemochromatosis phenotype in patients nonhomozygous for the C282Y mutation. CONCLUSIONS Hemochromatosis in Italy is a nonhomogenous disorder in which genetic and acquired factors are involved. In patients with a single or no HFE mutation, further studies will enable a differentiation between true genetic disorders and interactions between genetic and acquired factors.

Physical state of meal affects gastric emptying, cholecystokinin release and satiety.

To verify the influence of food consistency on satiety mechanisms we evaluated the effects of the same meal in solid-liquid (SM) and homogenized (HM) form on satiety sensation, gastric emptying rate and plasma cholecystokinin (CCK) concentration. Eight healthy men, aged 21-28 (mean 24.5) years were given two meals (cooked vegetables 250 g, cheese 35 g, croutons 50 g and olive oil 25 g, total energy 2573 kJ, with water 300 ml) differing only in physical state: SM and HM. The subjects consumed the meals in randomized order on non-consecutive days. The sensations of fullness, satiety and desire to eat were evaluated by means of a questionnaire, gastric emptying was assessed by ultrasonographic measurement of antral area, and plasma CCK concentration was measured by radioimmunoassay. The vegetable-rich meal was significantly more satiating (P < 0.05) when in the HM form than when eaten in a SM state. Furthermore, the overall gastric emptying time was significantly slowed (255 (SEM 11) min after HM v. 214 (SEM 12) min after SM; P < 0.05) and CCK peak occurred later (94 (SEM 12) min after HM v. 62 (SEM 11) min after SM; NS) when the food was consumed in the HM form. Independently of the type of meal, antral area was significantly related to fullness sensations (r2 0.46, P = 0.004). These results demonstrate that meal consistency is an important physical food characteristic which influences both gastric emptying rate and satiety sensation. Moreover, the relationship observed between antral area and fullness sensation confirms that antral distension plays a part in the regulation of eating behaviour.

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.

Position paper of the Italian Association for the Study of the Liver (AISF): The multidisciplinary clinical approach to hepatocellular carcinoma

Patients with hepatocellular carcinoma should be managed with a multidisciplinary approach framed in a network where all the diagnostic techniques and therapeutic resources are available in order to provide the optimal level of care. Given this assumption, the Coordinating Committee of the Italian Association for the Study of the Liver nominated a panel of experts to elaborate practical recommendations for the multidisciplinary management of hepatocellular carcinoma aiming to provide: (1) homogeneous and efficacious diagnostic and staging work-up, and (2) the best treatment choice tailored to patient status and tumour stage at diagnosis. The 2010 updated American Association for the Study of Liver Disease Guidelines for hepatocellular carcinoma were selected as the reference document. For each management issue, the American Association for the Study of Liver Disease recommendations were briefly summarised and discussed, according to both the scientific evidence published after their release and the clinical expertise of the Italian centres taking care of these patients. The Italian Association for the Study of the Liver expert panel recommendations are finally reported.

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.

Haemochromatosis in patients with beta-thalassaemia trait.

Severe iron overload has been reported in patients with the β‐thalassaemia trait. Studies performed before the discovery of the haemochromatosis gene (HFE) have yielded conflicting results: some suggest that iron overload might arise from the interaction of the β‐thalassaemia trait with heterozygosity for haemochromatosis, some with homozygosity for haemochromatosis and others that it was unrelated to haemochromatosis. We have studied the clinical phenotype, iron indices and HFE genotypes of 22 unrelated patients with the β‐thalassaemia trait and haemochromatosis, the inheritance of chromosome 6p and 1q haplotypes in families of non‐homozygous C282Y probands and serum measures of iron status in relatives heterozygous for C282Y with or without the β‐thalassaemia trait. We demonstrate that the β‐thalassaemia trait aggravates the clinical picture of C282Y homozygotes, favouring higher rates of iron accumulation and the development of severe iron‐related complications. We suggest that the coexistence of the β‐thalassaemia trait might also increase the risk of iron overload in patients with HFE genotypes at a mild risk of haemochromatosis. Our findings do not support the hypothesis that the association of the β‐thalassaemia trait with a single C282Y or H63D allele might lead to iron overload and suggest that other non‐HFE‐related inherited factors are present in haemochromatosis patients with incomplete HFE genotypes.