Development and validation of a scoring system to predict response to obeticholic acid in primary biliary cholangitis.

BACKGROUND & AIMS: Obeticholic acid (OCA) is the only licensed second-line therapy for primary biliary cholangitis (PBC). With novel therapeutics in advanced development, clinical tools are needed to tailor the treatment algorithm. We aimed to derive and externally validate the OCA response score (ORS) for predicting the response probability of individuals with PBC to OCA. METHODS: We used data from the Italian RECAPITULATE (N 441) and the IBER-PBC (N 244) OCA real-world prospective cohorts to derive/validate a score including widely available variables obtained either pre-treatment (ORS), or also after 6 months of treatment (ORS+). Multivariable Cox's regressions with backward selection were applied to obtain parsimonious predictive models. The predicted outcomes were biochemical response according to POISE (ALP/ULN<1.67 with a reduction of at least 15%, and normal bilirubin), or ALP/ULN<1.67, or NORMAL RANGE criteria (NR: normal ALP, ALT and bilirubin) up to 24 months. RESULTS: Depending on the response criteria, ORS included age, pruritus, cirrhosis, ALP/ULN, ALT/ULN, GGT/ULN and bilirubin. ORS+ also included ALP/ULN and bilirubin after 6 months of OCA therapy. Internally validated c-statistics for ORS were of 0.75, 0.78 and 0.72 for POISE, ALP/ULN<1.67 and NR response, which raised to 0.83, 0.88, 0.81 with ORS+, respectively. The respective performances in validation were of 0.70, 0.72 and 0.71 for ORS, and 0.80, 0.84, 0.78 for ORS+. Results were consistent across groups with mild/severe disease. CONCLUSIONS: We developed and externally validated a scoring system capable to predict OCA response according to different criteria. This tool will enhance a stratified second-line therapy model to streamline standard care and trial delivery in PBC.

The role of antiplatelet therapies on incidence and mortality of hepatocellular carcinoma.

AIM: To evaluate the impact of antiplatelet therapy (APT)on the incidence of hepatocellular carcinoma (HCC) and mortality following its treatment. METHODS: A systematic literature search was performed using PubMed and Cochrane Central Register of Controlled Trials Databases. Two HCC clinical settings were explored: (i) incidence, and (ii) death after any HCC treatment. Odds ratios (OR) and 95% confidence intervals (95%CI) were calculated to compare the pooled data between patients who received or did not receive APT. RESULTS: A total of 20 studies were identified, of whom 15 focused on HCC incidence, including 2,685,009 patients, and five on post-treatment death, including 3281 patients. APT was associated with an overall reduced risk of HCC incidence (OR: 0.63; 95%CI = 0.51-0.79; p < 0.001) as well as of post-treatment mortality (OR: 0.54; 95%CI = 0.35-0.83; p = 0.006). CONCLUSIONS: Current data suggest that APT correlated with higher HCC incidence and poor overall survival following tumour treatment.

Non-alcoholic fatty liver disease and the risk of fibrosis in Italian primary care services: GPS-NAFLD Study: GPS-NAFLD Study.

BACKGROUND AND AIMS: The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing globally. This study aimed to determine the prevalence of NAFLD and the probability of liver fibrosis in Italian primary care services. METHODS: We carried out a population-based and nested case-control study including all individuals aged 18 years and above registered at Italian primary care services. Data were collected from the general practitioners' network from 2010 to 2017. NAFLD cases were identified via the ICD-9-CM and Hepatic Steatosis Index score > 36 and were matched each up to 10 controls. Other causes of liver diseases were excluded. The risk of fibrosis was assessed using the FIB-4 and NAFLD fibrosis scores (NFS). RESULTS: NAFLD was present in 9% of the primary care population with high regional variability. Among NAFLD subjects: 25% had diabetes, 10% had chronic kidney disease, 11% had cardiovascular disease and 28% were obese. Furthermore, 30% had at least two comorbidities and 13% had cirrhosis. Once cirrhosis was excluded, the risk of any degree of fibrosis was 13.8% with NFS and 20.5% with FIB-4 in subjects <65 years. CONCLUSIONS: Even if there is an identification gap in primary care, recorded cases with NAFLD have a high frequency of associated comorbidities. Despite regional variability, a close relation between cirrhosis and NAFLD exists (OR: 3.48, 95% CI: 3.23-3.76). Therefore, the use of non-invasive tests should be promoted in primary care as a useful tool for the early identification of fibrosis risk, independently of evidence of steatosis.

The role of elastography in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide and its prevalence is even higher in patients with risk factors such as type 2 diabetes and obesity. Liver biopsy is the gold standard for diagnosis of non-alcoholic steatohepatitis (NASH), particularly for the assessment of fibrosis stage that is a key prognostic factor. Noninvasive methods for assessment of liver fibrosis are a huge need in contemporary hepatology in order to stratify patient's risk of advanced and progressive liver disease. In this perspective different imaging techniques have been developed in last decades and showed high performance in liver fibrosis evaluation. Strengths and weaknesses of all imaging methods are summarized in this review.

A Comparative Study of Serum Angiogenic Biomarkers in Cirrhosis and Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a global health problem associated with chronic liver disease. Its pathogenesis varies according to the underlying etiological factors, although in most cases it develops from liver cirrhosis. The disease progression is accompanied by pathological angiogenesis, which is a prerequisite that favors the development of HCC. AIMS: This study aims at contributing to our understanding of the role of angiogenic factors in the progression of liver disease. For this purpose, we evaluate the clinical significance of serum angiogenic markers (VEGF, Ang-1, Ang-2, the angiopoietin receptor Tie1/2, HGF, and PECAM-1) first in cirrhotic and HCC patients separately, and then comparing cirrhotic patients with and without HCC. MATERIALS AND METHODS: We enrolled 62 patients, out of whom 33 were diagnosed with HCC and 29 with liver cirrhosis without signs of neoplasia. Patients underwent venous blood sampling before and after receiving treatments for the diagnosed disease. Serum markers were evaluated using ELISA assays for Tie1 and the Bio-Plex Multiplex system for the remaining ones. Biomarker levels were investigated as a function of clinical scores for disease staging (MELD and Fibrosis Index, FI). RESULTS: In cirrhotic patients, Ang-1 and Ang-2 correlate with MELD (ρAng-1 = -0.73, p = 2E-5) and FI (ρAng-1 = -0.52, p = 7E-3, ρAng-2 = 0.53, p = 3E-3). A reduction of Ang-2 levels (p = 0.047) and of the Ang-2/Ang-1 ratio (p = 0.031) is observed in cirrhotic patients diagnosed with viral hepatitis after antiviral treatments. In HCC patients, Ang-1 negatively correlates with FI (ρ = -0.63, p = 1E-4), and PECAM-1 positively correlates with MELD (ρ = 0.44, p = 0.01). A significant Ang-1 reduction was observed in deceased patients during the study compared to ones who survived (p = 0.01). In HCC patients, VEGF levels were increased after tumor treatment (p = 0.037). Notably, HGF levels in cirrhotic patients with HCC are significantly raised (p = 0.017) compared to that in those without HCC. CONCLUSIONS: Our results suggest that serum angiogenic markers, with emphasis on Ang-1/2, can contribute to the development of quantitative tools for liver disease staging and therapy monitoring. The comparison between cirrhotic patients with and without HCC suggests that HGF levels are potentially useful for monitoring the insurgence of HCC after a cirrhosis diagnosis. High Ang-1 levels in HCC patients appear to have a protective role as well as prognostic significance.

Use of imaging techniques for non-invasive assessment in the diagnosis and staging of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease and represent a common finding in highly prevalent metabolic disorders (i.e. type 2 diabetes, metabolic syndrome, obesity). Non-alcoholic steatohepatitis (NASH) requires liver biopsy for grading and staging the liver damage by the assessment of steatosis, inflammation and fibrosis. In parallel with the development of numerous 'liquid' biomarkers and algorithms that combine anthropometric and laboratory parameters, innovative hepatic imaging techniques have increasingly been developed to attempt to overcome the need for biopsy, both in diagnosis and staging of NAFLD, and in possible use in the follow-up of the disease. In this review, we focused on the different imaging techniques trying to highlight the strengths and disadvantages of different approaches, particularly for ultrasound techniques, in stratifying liver injury and fibrosis in patients with NAFLD / NASH.

Congenital extrahepatic portosystemic shunt: description of four cases and review of the literature.

Congenital extrahepatic portosystemic shunt (CEPS), also known as Abernethy malformation, is a rare condition in which the splenomesenteric blood drains directly into a systemic vein, bypassing the liver through a complete or partial shunt. The diagnosis is frequently made during childhood in the setting of neonatal cholestasis, hypergalactosemia, failure to thrive, mental retardation or other congenital defects. In adulthood, CEPS is usually found incidentally during diagnostic work-up for abdominal pain, liver test abnormalities, liver nodules, portopulmonary hypertension, portopulmonary syndrome or portosystemic encephalopathy. The diagnosis depends on imaging and portal venography, but sometimes only liver biopsy can be resolutive, demonstrating the absence of venules within the portal areas. Here we report four recent cases of Abernethy malformation diagnosed in young adults, in which ultrasound (US) was the initial imaging technique and allowed to suspect the diagnosis. Furthermore, we reviewed clinical presentations, associated anomalies and treatment of the 310 cases of CEPS previously reported in the literature.

Contrast-enhanced ultrasonography in chronic glomerulonephritides: correlation with histological parameters of disease activity.

PURPOSE: To compare contrast-enhanced ultrasonography (CEUS)-derived time-intensity (TI) curves with histological findings in kidneys of patients affected by chronic glomerulonephritides (GN) in the early stage of disease. METHODS: Research ethics committee approval and patient written informed consent were obtained. Thirty-one patients who showed clinical and laboratory signs of GN, with preserved renal function, were consecutively enrolled. They underwent kidney CEUS, from which TI curves were obtained, and kidney biopsy. TI curves were compared with clinical data, ultrasound (US) Doppler, and histological parameters. RESULTS: The persistence of contrast agent signal during the wash-out phase was found to be correlated with the degree of disease activity (p = 0.016) and in particular with the presence of mesangial hyperplasia (p = 0.008). No correlation was observed between TI curves and clinical or Doppler US-derived parameters. CONCLUSIONS: The persistence of contrast agent signal in the wash-out phase of CEUS appears to reflect a disturbance of perfusion in glomerular capillaries in the early stages of GN. We found that the histological element directly correlated with the prolonged wash-out was mesangial hyperplasia.

Autoimmunity and lymphoproliferation markers in naïve HCV-RNA positive patients without clinical evidences of autoimmune/lymphoproliferative disorders.

BACKGROUND: HCV can lead to both chronic liver disease and B-cell lymphoproliferative disorders. A strong association exists between HCV and mixed cryoglobulinaemia (MC). METHODS: Anti-nuclear antibodies (ANA), rheumatoid factor Ig-G (RF-IgG), free light chain κ and λ (FLC-κ, FLC-λ) levels and κ/λ ratio were evaluated in 50/420 subjects unexpectedly resulted anti-HCV positive after routine screenings for non-hepathological procedures. RESULTS: Three/fifty patients had HCV-RNA undetectable in the serum and were excluded from the analysis. Thirty-nine/fifty patients had laboratory evidence of circulating cryoglobulins without liver disease and MC-related symptoms. Among them, 17 resulted ANA-positive. The mean cryocrit was higher in ANA-positive patients, while no other demographic/clinical differences were observed between the groups. Significantly higher levels of RF-IgG were observed in ANA-positive vs ANA-negative patients. κ and λ FLC were higher in ANA-positive patients. A ROC analysis, based on ANA-positivity vs ANA-negativity, confirmed a high sensitivity and specificity of RF-IgG test. CONCLUSIONS: Published data concerning MC come mostly from symptomatic vasculitis. We analyzed HCV-patients without MC symptoms, founding cryoglobulins in the majority of them. The increased levels of FR-IgG and FLC in CGs-ANA-positive patients, suggest these test could be used to identify a state of silent autoimmune and/or lymphoproliferative condition before the transition to a frank disease in naïve HCV-patients without symptoms of extrahepatic manifestations.

Single hepatocellular carcinoma smaller than 2 cm: are ethanol injection and radiofrequency ablation equally effective?

BACKGROUND/AIM: The impact of radiofrequency ablation (RFA) and percutaneous ethanol injection (PEI) on survival in patients with small hepatocellular carcinoma (HCC) is unclear. We compared their efficacy in cirrhotics with single HCC ≤2 cm. PATIENTS AND METHODS: Two hundred forty-four cirrhotics with single HCC ≤2 cm treated with PEI (108 cases) or RFA (136 cases) were enrolled in the study. Eighty-one patients in each group were selected for propensity score matching analysis. RESULTS: The five-year survival was not significantly different (64.7% in PEI and 72.9% in RFA group) but the 5-year recurrence (73.3% in PEI and 49% in RFA group, p=0.023) and local tumor progression (49% in PEI and 30.1% in RFA group, p=0.018) were higher in the PEI group. CONCLUSION: PEI and RFA are equally effective in treating HCCs smaller than 2 cm in terms of 5-year survival, despite higher cumulative and local recurrence rates, in patients treated with PEI.

Anti-nuclear antibody detection in cryoprecipitates: distinctive patterns in hepatitis C virus-infected patients.

BACKGROUND: Anti-nuclear antibodies are immunoglobulins directed against nuclear antigens. They are associated with many autoimmune disorders, but are frequently found in patients infected with hepatitis C virus, possibly indicating an underlying common origin. Likewise, mixed cryoglobulinemia often accompanies autoimmune diseases and hepatitis C infection. AIM: To compare anti-nuclear antibodies and immunoglobulin content of cryoprecipitates from hepatitis C virus-positive patients in order to assess their predictive value in the onset of hepatitis C virus-driven extrahepatic disorders. METHODS: Serum from 40 hepatitis C virus-positive patients and 50 controls with rheumatoid arthritis was processed for cryoglobulin detection: all subjects presented with Type III mixed cryoglobulinemia. Immunoglobulin content and immunoglobulin subclasses of cryoprecipitates were assessed by immunofixation and tested by ELISA for rheumatoid factor. Cryoprecipitates were also analysed for anti-nuclear antibodies by indirect immuno-fluorescence to identify specific patterns typical of each condition. RESULTS: Anti-nuclear antibody patterns differed significantly; 26 infected subjects (65%) were IgG3 positive: of these, 25 were also anti-nuclear antibody-positive (96.1%). CONCLUSIONS: IgG3 are autoreactive clones unrelated to viral recognition and possibly involved in autoimmune disorders. Altogether, these results may represent useful diagnostic device for early detection of hepatitis C virus-induced autoimmune diseases.

Long-term effectiveness of resection and radiofrequency ablation for single hepatocellular carcinoma ≤3 cm. Results of a multicenter Italian survey.

BACKGROUND & AIMS: The aim of this study was to compare liver resection and radiofrequency ablation in patients with single hepatocellular carcinoma ≤3 cm and compensated cirrhosis. METHODS: The study involved 544 Child-Pugh A cirrhotic patients (246 in the resection group and 298 in the radiofrequency group) observed in 15 Italian centers. Overall survival and tumor recurrence rates were analyzed using the Kaplan Meier method before and after propensity score matching. Cox regression models were used to identify factors associated with overall survival and tumor recurrence. RESULTS: Two cases of perioperative mortality were observed in the resection group and the rate of major complications was 4.5% in the resection group and 2.0% in the radiofrequency group (p=0.101). Four-year overall survival rates were 74.4% in the resection group and 66.2% in the radiofrequency group (p=0.353). Four-year cumulative HCC recurrence rates were 56% in the resection group and 57.1% in the radiofrequency group (p=0.765). Local tumor progression was detected in 20.5% of ablated patients and in one resected patient (p<0.001). After propensity score matching, both survival and tumor recurrence were still not significantly different although a trend towards lower recurrence was observed in resected patients. Older age and higher alpha-fetoprotein levels were independent predictors of poor overall survival while older age and higher alanine-aminotransferase levels resulted to be independent factors associated with higher recurrence rate. CONCLUSIONS: In spite of a higher rate of local tumor progression, radiofrequency ablation can provide results comparable to liver resection in the treatment of single hepatocellular carcinoma ≤3 cm occurring in compensated cirrhosis.

Long-term effectiveness of radiofrequency ablation for solitary small hepatocellular carcinoma: a retrospective analysis of 363 patients.

BACKGROUND: Radiofrequency Ablation is the most widely performed percutaneous treatment for Hepatocellular Carcinoma. This multicentre study was aimed at assessing the complication, overall survival and disease-free survival rates in cirrhotic patients with single Hepatocellular Carcinoma nodule ≤3 cm undergoing Radiofrequency Ablation. METHODS: Data of 365 patients (59% males; mean age 67 ± 8 years), Child-Pugh A/B, with single Hepatocellular Carcinoma nodule ≤3 cm (tumours >2-3 cm = 127/236), showing complete necrosis after Radiofrequency Ablation between 1998 and 2010 in 7 Italian Centers were retrospectively reviewed. Complication, overall survival and disease-free survival rates were analyzed as main clinical end-points. RESULTS: Major complications were observed in 8 patients (2.2%) and minor complications in 23 patients (6.3%). The 3-, and 5-year overall survival rates were 80% and 64%. One hundred and seven patients (29.5%) died, being 41 deaths (38.3%) Hepatocellular Carcinoma-related. At multivariate analysis only age (p = 0.04; OR 2.29), ascites (p < 0.001; OR 3.74) and Child-Pugh class ≥B8 (p = 0.003; OR 2.42) were confirmed as independent predictors for overall survival. The disease-free survival rates at 3- and 5-year were 50%, and 41.8%. CONCLUSIONS: Radiofrequency Ablation is an effective and safe tool for the treatment of single Hepatocellular Carcinoma ≤3 cm providing excellent 5-year overall survival and disease-free survival rates. Patient's age and liver status appeared as main determinants of outcome.

Ethanol injection is highly effective for hepatocellular carcinoma smaller than 2 cm.

AIM: To analyze the long-term prognosis in a cohort of western cirrhotic patients with single hepatocellular carcinoma treated with ethanol injection. METHODS: One-hundred forty-eight patients with solitary hepatocellular carcinoma were enrolled. The tumor diameter was lower than 2 cm in 47 patients but larger in the remaining 101 patients. The impact of some pre-treatment clinical and laboratory parameters and of tumor recurrence on patients' survival was assessed. RESULTS: Among the pre-treatment parameters, only a tumor diameter of less than 2 cm was an independent prognostic factor of survival. The occurrence of new nodules in other liver segments and the neoplastic portal invasion were linked to a poorer prognosis at univariate analysis. Patients with a single hepatocellular carcinoma smaller than 2 cm showed a better 5-year cumulative survival (73.0% vs 47.9%) (P = 0.009), 3-year local recurrence rate (29.1% vs 51.5%) (P = 0.011), and 5-year distant intrahepatic recurrence rate (52.9% vs 62.8%) (P = 0.054) compared to patients with a larger tumor. CONCLUSION: The 5-year survival rate of patients with single hepatocellular carcinoma < 2 cm undergoing ethanol injection is excellent and comparable to that achieved using radiofrequency ablation.