Application of ultrasonography-elastography score to suspect porto-sinusoidal vascular disease in patients with portal vein thrombosis.

BACKGROUND: Porto-sinusoidal vascular disease (PSVD) and portal vein thrombosis (PVT) are causes of portal hypertension characterized respectively by an intrahepatic and a pre-hepatic obstacle to the flow in the portal system. As PVT may be a consequence of PSVD, in PVT patients at presentation, a pre-existing PSVD should be suspected. In these patients the identification of an underlying PSVD would have relevant implication regarding follow-up and therapeutic management, but it could be challenging. In this setting ultrasonography may be valuable in differential diagnosis. The aim of the study was to use ultrasonography to identify parameters to discriminate between PSVD and "pure" PVT and then to suspect PVT secondary to a pre-existing PSVD. METHODS: Fifty-three patients with histologically proven PSVD and forty-eight patients affected by chronic PVT were enrolled and submitted to abdominal ultrasonography with elastography by acoustic radiation force impulse (ARFI). RESULTS: ARFI was higher and superior mesenteric vein (SMV) diameter was wider in PSVD patients than in PVT patients. Thus, a prognostic score was obtained as linear combinations of the two parameters with a good discrimination capacity between PSVD and PVT (the area under the curve = 0.780; 95% confidence interval: 0.690-0.869). CONCLUSIONS: A score based on ARFI and SMV diameter may be useful to suspect an underlying PSVD in patients with PVT and to identify a subgroup of patients to be submitted to liver biopsy.

Fibroblast Growth Factor 21 in Chronic Hepatitis C: A Potential Non-Invasive Biomarker of Liver Status upon Viral Eradication.

Fibroblast growth factor 21 (FGF-21), previously recognized as a marker of liver damage and a potential drug target in non-alcoholic fatty liver disease (NAFLD), has unclear implications in hepatitis C virus (HCV) infections. This study aimed to investigate the relationship between FGF-21 levels and liver health in patients with HCV undergoing direct-acting antiviral (DAA) treatment. Forty-five patients were assessed for liver stiffness, blood chemistry, and other relevant metrics before and after achieving sustained viral response (SVR), defined as the absence of detectable HCV-RNA after 24 weeks of treatment. Post-treatment, all patients showed a decrease in liver stiffness and improved liver enzyme levels (AST and ALT), alongside an increase in FGF-21 levels. Interestingly, the increase in FGF-21 correlated negatively with liver stiffness but showed no correlation with hepatic steatosis. The observed elevation in FGF-21 levels at SVR following DAA therapy for chronic HCV infection can be attributed to the restoration of hepatic function, including its synthetic capabilities. Specifically, the mitigation of liver fibrosis post-HCV eradication is expected to lead to improvements in liver function, such as enhanced albumin and FGF-21 production. This improvement in synthetic function likely drives the increase in FGF-21 levels, rather than changes in liver fat content. We suggest a potential role of FGF-21 as a marker of fibrosis and hepatic cytotoxicity and as a drug target beyond NAFLD, to be confirmed by additional studies.

A Low Daily Intake of Simple Sugars in the Diet Is Associated with Improved Liver Function in Cirrhotic Liver Transplant Candidates.

(1) Background: We investigated, for the first time, whether dietary simple sugar intake affects MELD score changes over time in a cohort of cirrhotic liver transplant candidates. (2) Methods: the MELD score, dietary habits using a 3-day food diary, and visceral adipose tissue index (VATI) measured with CT scan were assessed in 80 consecutive outpatient cirrhotic patients at baseline, after counseling to follow current nutritional guidelines. The MELD score was reassessed after six months and the DELTA-MELD was calculated as the MELD at the second assessment minus the MELD at baseline. (3) Results: Compared with the baseline, the MELD score of cirrhotic patients at the end of the study was decreased, stable, or increased in 36%, 8% and 56% of patients, respectively. In separate multiple linear regression models, DELTA-MELD was positively and independently correlated with the daily intake of simple sugars expressed in g/kg body weight (p = 0.01) or as a percentage of total caloric intake (p = 0.0004) and with the number of daily portions of fruit, added sugar, jam, and honey (p = 0.003). These associations were present almost exclusively in patients with VATI above the median value. (4) Conclusions: In cirrhotic patients with high amounts of visceral adipose tissue the consumption of simple sugars and fructose should be limited to improve their clinical outcome.

Acute hepatitis-like presentation with cholestasis of CBFB-MYH11-positive acute myeloid leukemia in an adult male: a case report.

BACKGROUND: Liver involvement in adults with acute myeloid leukemia is uncommon. Most of the case reports describe acute liver failure or obstructive jaundice, while acute hepatitis is rarely mentioned. We report a patient with acute myeloid leukemia who presented with clinical, biochemical, and radiological signs of acute hepatitis that totally regressed after chemotherapy. CASE PRESENTATION: A 38-year-old Caucasian man presented with fever, cough, and mild fatigue. Laboratory workup showed anemia, thrombocytopenia, severe leukocytosis, transaminitis, and hyperbilirubinemia. Imaging of the abdomen (ultrasound and magnetic resonance) showed hepatomegaly, splenomegaly, upper limits portal veins diameters, increased thickness of the gallbladder wall, and significant abdominal lymph nodes. Peripheral blood smear and bone marrow evaluation were consistent with acute myeloid leukemia, and liver biopsy showed massive sinusoidal and portal infiltration by leukemic cells. After remission-inducing chemotherapy, there was complete normalization of liver function tests, and liver, spleen, and portal vein size. CONCLUSIONS: This case highlights the importance of taking acute myeloid leukemia into account as a possible cause of liver damage to make a rapid diagnosis and start appropriate treatment that may lead to hematological remission and hepatic dysfunction resolution.

Safety and efficacy of directly-acting antiviral therapy for chronic hepatitis C virus in elderly people.

INTRODUCTION: In Italy, the prevalence of hepatitis C virus (HCV) infection is higher in the elderly, although the efficacy and safety of treatment in this population has not been extensively studied. Moreover, little is known about how much pharmacological interaction affects eligibility to treatment and to what extent the treatment affects subsequent outcomes. METHODS: We retrospectively analyzed the efficacy and safety of directly acting antivirals (DAAs), drug-to-drug interactions, and post-treatment outcomes in 138 patients with HCV aged 70 years or older, who were consecutively treated in our center between 2015 and 2020. RESULTS: The mean age was 77 years old (range = 70-95 years old). The Cumulative Illness Rating Scale of pretherapy severity was classified as moderate to severe in 65% of patients. Fifty-five patients (40%) presented compensated cirrhosis, eight of which were complicated by hepatocellular carcinoma (HCC) and all were cured before treatment. One hundred two patients (74%) were taking two or more drugs (range = 0-5 concomitant drugs registered) and in 29 patients (21%) we found potential drug-to-drug interaction. In 11 of those 29 patients (38%), we were forced to change the chronic therapy, when all therapeutic regimens were equal in terms of efficacy and interactions, to avoid potentially serious drug interactions. One serious adverse event occurred in our sample population (i.e., diverticular bleeding due to interaction with direct oral anticoagulants [DOACs]), whereas mild side effects occurred in 37% of patients. The undetectability of HCV RNA at the end of treatment was achieved in 97% of patients, whereas a sustained virological response (SVR) 12 and SVR 24 were obtained in 98% of patients. When comparing pretherapy with post-therapy data, after a medium follow-up of 15 months (median = 1 year, minimum = 2 months, and maximum = 4 years), we observed a reduction in the incidence of episodes of liver decompensation in patients with cirrhosis and a slight increase in the incidence of HCC (with 6 recurrent and 5 de novo HCC), diagnosed within 13 months from the end of therapy. In all patients, we found a significant improvement in all ultrasound variables and a significant reduction in the elastographic measurements. No significant differences in outcomes were observed dividing the population into patients aged ≥ 80 and < 80 years old. CONCLUSIONS: Directly acting antiviral therapy was found to be safe and effective in elderly people, and, despite the large number of concomitant drugs, pharmacological interactions appeared to not affect the adherence to therapy or the incidence of adverse events. Side effects were mostly independent from the type of DAA used and from the burden of comorbidity. In long-term follow-up, the benefit of DAA therapy mainly concerned liver pathology and should be strongly advised in patients with cirrhosis. The therapy was found to not affect extrahepatic comorbidities but allowed to end follow-up in noncirrhotic patients with savings in terms of resources. Finally, patients should not be excluded based on age if they have a good performance status.

The Effects of 12-Week Beta-Hydroxy-Beta-Methylbutyrate Supplementation in Patients with Liver Cirrhosis: Results from a Randomized Controlled Single-Blind Pilot Study.

BACKGROUND AND AIM: Sarcopenia is considered an important risk factor for morbidity and mortality in liver cirrhosis. Beta-hydroxy-beta-methylbutyrate (HMB) has the potential to increase muscle mass and performance by stimulating protein synthesis and reducing muscle catabolism. The present study aimed at evaluating the effect of HMB supplementation on muscle mass and function in patients with liver cirrhosis. Changes in frailty during the study were also estimated, and the safety of HMB supplementation was verified. METHODS: This is a randomized, single-blind, placebo-controlled pilot trial. Twenty-four patients (14 HMB and 10 placebo) affected by liver cirrhosis were enrolled in the study. Each patient received dedicated counseling, which included nutrition and physical activity recommendations for chronic liver disease patients. Patients were randomized to receive 3 g/day of HMB or placebo (sorbitol powder) for 12 consecutive weeks. A diet interview, anthropometry, electrical bioimpedance analysis (BIA), quadriceps ultrasound, physical performance battery, Liver Frailty Index (LFI), and cognitive tests were completed at enrolment (T0), at 12 weeks (T1), and 24 weeks after enrolment (T2). RESULTS: At baseline, the two groups were similar in demography, severity of liver disease, muscle mass, muscle function, and cognitive tests. LFI at baseline was higher in patients in the HMB group vs. those in the placebo group (4.1 ± 0.4 vs. 3.4 ± 0.6, p < 0.01). After treatment, a statistically significant increase in muscle function was seen in the HMB group (chair stand test: 14.2 ± 5 s vs. 11.7 ± 2.6 s, p < 0.05; six-minute walk test: 361.8 ± 68 m vs. 409.4 ± 58 m, p < 0.05). Quadriceps muscle mass measured by ultrasound also increased (4.9 ± 1.8 vs. 5.4 ± 1.8 mm, p < 0.05) after HMB, while LFI decreased (4.1 ± 0.4 vs. 3.7 ± 0.4, p < 0.05). HMB was well tolerated by patients, and no adverse events were documented. CONCLUSIONS: Our study suggests the efficacy of 12-week beta-hydroxy-beta-methylbutyrate supplementation in promoting improvements in muscle performance in compensated cirrhotic patients. LFI was also ameliorated. Further studies with a greater number of patients are required to reinforce this hypothesis.

Low serum magnesium concentration is associated with the presence of viable hepatocellular carcinoma tissue in cirrhotic patients.

This study aimed to ascertain, for the first time, whether serum magnesium (Mg) concentration is affected by the presence of hepatocellular carcinoma (HCC). We retrospectively enrolled consecutive cirrhotic patients with a diagnosis of HCC (n = 130) or without subsequent evidence of HCC during surveillance (n = 161). Serum levels of Mg were significantly (P < 0.001) lower in patients with HCC than in those without (median [interquartile range]: 1.80 [1.62-1.90] mg/dl vs. 1.90 [1.72-2.08] mg/dl). On multivariate logistic regression, low serum Mg was associated with the presence of HCC (OR 0.047, 95% CI 0.015-0.164; P < 0.0001), independently from factors that can influence magnesaemia and HCC development. In a subset of 94 patients with HCC, a linear mixed effects model adjusted for confounders showed that serum Mg at diagnosis of HCC was lower than before diagnosis of the tumor (ß = 0.117, 95% CI 0.039-0.194, P = 0.0035) and compared to after locoregional treatment of HCC (ß = 0.079, 95% CI 0.010-0.149, P = 0.0259), with two thirds of patients experiencing these changes of serum Mg over time. We hypothesize that most HCCs, like other cancers, may be avid for Mg and behave like a Mg trap, disturbing the body's Mg balance and resulting in lowering of serum Mg levels.

Minimally invasive aortic valve replacement: short-term efficacy of sutureless compared with stented bioprostheses.

OBJECTIVES: Sutureless aortic valve prostheses have been introduced to facilitate the implant process, speed up the operating time and improve haemodynamic performance. The goal of this study was to assess the potential advantages of using sutureless prostheses during minimally invasive aortic valve replacement in a large multicentre population. METHODS: From 2011 to 2019, a total of 3402 patients in 11 hospitals underwent isolated aortic valve replacement with minimal access approaches using a bioprosthesis. A total of 475 patients received sutureless valves; 2927 received standard valves. The primary outcome was the incidence of 30-day deaths. Secondary outcomes were the occurrence of major complications following procedures performed with sutureless or standard bioprostheses. Propensity matched comparisons was performed based on a multivariable logistic regression model. RESULTS: The annual number of sutureless valve implants increased over the years. The matching procedure paired 430 sutureless with 860 standard aortic valve replacements. A total of 0.7% and 2.1% patients with sutureless and standard prostheses, respectively, died within 30 days (P = 0.076). Cross-clamp times [48 (40-62) vs 63 min (48-74); P = 0.001] and need for blood transfusions (27.4% vs 33.5%; P = 0.022) were lower in patients with sutureless valves. No difference in permanent pacemaker insertions was observed in the overall population (3.3% vs 4.4% in the standard and sutureless groups; P = 0.221) and in the matched groups (3.6% vs 4.7% in the standard and sutureless groups; P = 0.364). CONCLUSIONS: The use of sutureless prostheses is advantageous and facilitates the adoption of a minimally invasive approach, reducing cardiac arrest time and the number of blood transfusions. No increased risk of permanent pacemaker insertion was observed.

Directly acting antivirals are safe and effective in HCV positive patients aged 80 years and older: a multicenter real-life study.

Background: Treatment of chronic Hepatitis C with directly acting antivirals (DAAs) can bring to sustained virologic response (SVR) in approximately 95% of patients. Efficacy and safety of DAAs in aging patients has not been widely analyzed. We aimed to determine safety and efficacy of DAA-based regimens in a cohort of elderly patients in a real-life setting.Research Design and Methods: We retrospectively investigated safety and efficacy of DAAs in HCV patients of 80 years or older treated in three Hepatology Units.Results and Expert opinion: During the study period, 170 patients older than 80 years received DAAs. Their mean age was 82,3 years. The predominant HCV genotype was 1 (100 patients, 59%). Among the 93 cirrhotic patients (54,7%), 18 had CPT score > A5. Different DAAs regimens were used. Concomitant drugs were common: 163 patients (95,8%) taking at least one drug. In 11 patients, usual therapy had to be changed to start antiviral treatment. Two serious adverse events occurred. Four patients terminated treatment prematurely. In total, 45 patients (26,5%) testified mild side effects. HCV-RNA undetectability at week 12 of treatment follow-up was achieved in 168/170 patients. DAA treatment in HCV patients of 80 years or older is efficacious and safe. Drug-drug interaction should be judiciously evaluated before starting therapy.

Minimally invasive redo aortic valve replacement with a sutureless valve implant.

Reoperations for a dysfunctional mechanical aortic valve prosthesis are usually performed with a repeat sternotomy. Reopening the chest may be associated with a heart structure tear, bleeding, excessive transfusion, and a possible unfavorable outcome. Experience performing a redo aortic valve replacement with a minimally invasive approach and avoiding lysis of the pericardial adhesions is growing. We describe a redo aortic valve replacement procedure performed because of subvalvular pannus formation in a patient with a mechanical prosthesis. A partial J-shaped hemisternotomy at the 3rd intercostal space was performed; the ascending aorta was exposed and the valve was replaced with a sutureless bioprosthesis. The video tutorial shows the surgical approach, cardiopulmonary bypass solutions, and sutureless valve deployment.

Minimally invasive tricuspid valve surgery without caval occlusion: Short and midterm results.

OBJECTIVE: The use of minimally invasive or transcatheter interventions rather than standard full sternotomy operations to treat tricuspid valve (TV) disease is increasing. The debate however is still open regarding venous drainage management during cardiopulmonary bypass (CPB) and wheatear or not superior and inferior vena cava should be occluded during the opening of the right atrium to avoid air entrance in the venous line. The aim of the present study is to report operative outcomes and midterm follow-up results of minimally invasive TV surgery performed without caval occlusion. METHODS: A retrospective outcome evaluation from institutional records was performed with prospective data entry. Considered were consecutive patients who underwent right mini-thoracotomy TV surgery isolated or combined with mitral valve surgery during the period from June 2013 to February 2020. A telephone and echocardiographic follow-up was performed. RESULTS: During the study period, 68 consecutive patients underwent minimally invasive TV surgery without occlusion of cava veins. The mean age was 69 ± 14 years and 48 (70%) were female. All operations were performed safely without air-lock during CPB. A perioperative cerebral stroke occurred in one patient. The survival at a 5- and 8-year follow-up was 100% and 79%, respectively. No severe tricuspid regurgitation was evident at echocardiographic follow-up. CONCLUSION: Our results show that performing tricuspid surgery without caval occlusion is safe. The air was captured by the active vacuum drainage system without causing damage. Midterm follow-up data confirm that a minimally invasive approach does not alter the quality of surgery.

Severe rectal prolapse and solitary rectal ulcer in a young anorectic woman with myxoid degeneration of visceral adipose tissue.

Rectal prolapse is a disorder in which the rectum protrudes from the anal canal. Solitary rectal ulcer may coexist. Both conditions have been associated with chronic constipation and excessive straining during defecation. Rectal prolapse has been rarely reported in women suffering from anorexia nervosa. Lack of rectal support because of loss of ischiorectal fat has been proposed as one of the possible mechanisms in this condition, together with chronic constipation and abuse of laxative. We report the case of an anorexic woman with a severe rectal prolapse and bleeding requiring urgent Altmeier's procedure. Surgery was complicated by dehiscence of the anastomosis and volvulus, requiring ileostomy and laciniae debridement. Pathological analysis of all the surgical samples taken from different abdominal sites highlighted changes in the visceral adipose tissue consisting in nodular aggregates of small adipocytes dispersed in a myxoid matrix surrounding blood vessels within abundant fibrosis. The morphologic features resemble those observed in primordial fetal fat and are comparable to those observed in cancer associated cachexia. The diffuse myxoid degeneration of visceral adipose tissue may play a role in the pathogenesis of rectal prolapse in patients with anorexia nervosa. Besides starvation, the mechanism sustaining myxoid degeneration of the adipose tissue is not entirely clear. Whenever possible improving nutritional and clinical conditions should be ideal before any surgical approach.

Clinico-immunological outcomes of HCV-cured cryoglobulinemia: Lower relapse rate with interferon-based than interferon-free therapy.

Sustained virological response (SVR) obtained with interferon (IFN) or with direct-acting antivirals (DAAs) is commonly followed by response of hepatitis C virus (HCV)-associated mixed cryoglobulinemia vasculitis (MCV), but relapse of MCV despite SVR has been reported in several patients after DAAs and rarely after IFN. Since relapses could have been overlooked in studies with IFN, we retrospectively compared the outcomes of MCV in SVR patients treated with DAAs (n = 70) or IFN (n = 39) followed-up, respectively, for 30.5 (range 11-51) or 48 months. Groups were comparable for demographics and clinics and response rates of MCV were similar (92% and 86%); however, DAA-treated patients less efficiently reduced cryoglobulins (P = .006) and circulating B-cell clones (P = .004), and had more frequently relapses of MCV (18% vs 3%, P = .028) and need for rituximab therapy (P = .01). Although largely inferior on an intention-to-treat basis, IFN may be superior to DAAs on clinico-immunological outcomes possibly owing to its antiproliferative activity.

Small hepatic veins Budd-Chiari syndrome and paroxysmal nocturnal hemoglobinuria - The association of two rare entities: a case report.

Small hepatic veins Budd-Chiari syndrome is a rare disorder characterized by hepatic venous outflow obstruction limited to the small intrahepatic veins, with normal appearance of the large hepatic veins at imaging. In this case only a liver biopsy can demonstrate the presence of a small vessels outflow block. Paroxysmal nocturnal haemoglobinuria (PNH) is one of the most severe acquired thrombophilic state and represents one of the main aetiological factors of Budd-Chiari syndrome. In patient affected by PNH with liver impairment and/or ascites, Budd-Chiari syndrome must be always taken into consideration and, if necessary, a liver biopsy performed to exclude the small hepatic veins involvement. We report a case of small hepatic veins Budd-Chiari syndrome secondary to paroxysmal nocturnal haemoglobinuria.

Reduced Lysosomal Acid Lipase Activity in Blood and Platelets Is Associated With Nonalcoholic Fatty Liver Disease.

OBJECTIVES: To investigate whether blood total lysosomal acid lipase activity (BT-LAL) levels are uniquely associated with the noncirrhotic and cirrhotic stages of nonalcoholic fatty liver disease (NAFLD) and with protection from NAFLD in metabolically/genetically predisposed subjects and a normal liver. To clarify which enzyme-carrying circulating cells are involved in reduced BT-LAL of NAFLD. METHODS: In a cross-sectional study, BT-LAL was measured by a fluorigenic method in patients with NAFLD (n = 118), alcoholic (n = 116), and hepatitis C virus-related disease (n = 49), in 103 controls with normal liver and in 58 liver transplant recipients. Intracellular platelet and leukocyte LAL was measured in 14 controls and 28 patients with NAFLD. RESULTS: Compared with controls, (i) BT-LAL and LAL in platelets, but not in leukocytes, were progressively reduced in noncirrhotic NAFLD and in nonalcoholic steatohepatitis-related cirrhosis; (ii) platelet and leukocyte counts did not differ in patients with noncirrhotic NAFLD; and (iii) BT-LAL did not differ in alcoholic and hepatitis C virus noncirrhotic patients. BT-LAL progressively increased in controls with metabolic syndrome features according to their PNPLA3 rs738409 steatosis-associated variant status (II vs IM vs MM), and their BT-LAL was higher than that of noncirrhotic NAFLD, only when carriers of the PNPLA3 unfavorable alleles were considered. Liver transplant recipients with de novo NAFLD compared with those without de novo NAFLD had lower BT-LAL. DISCUSSION: LAL in blood and platelets is progressively and uniquely reduced in NAFLD according to disease severity. High BT-LAL is associated with protection from NAFLD occurrence in subjects with metabolic and genetic predisposition. Low LAL in platelets and blood could play a pathogenetic role in NAFLD.

Daclatasvir, sofosbuvir with or without ribavirin for 24 weeks in hepatitis C genotype 3 cirrhosis: A real-life study.

INTRODUCTION AND AIM: Cirrhotic patients with hepatitis C virus genotype 3 infection show unsatisfactory outcomes after 12 weeks' treatment with direct antiviral agents. The National Italian Drug Agency allows 24 weeks of therapy in difficult-to-treat patients, including genotype 3 cirrhotics. Aim of this study was to evaluate efficacy and safety of a 24-week course of sofosbuvir plus daclatasvir±ribavirin in this population. MATERIALS AND METHODS: 106 consecutive cirrhotics (70.8% males, mean age 55.3±7.6 years) in 8 tertiary hepatology centers received sofosbuvir plus daclatasvir for 24 weeks. Ribavirin was administered in 85 (80.2%) based expected tolerability, at a mean dose of 964±202mg/day. Baseline Child-Pugh class was A 91.5%, B 6.6%, C 1.9%; mean baseline MELD was 8.5±2.7. RESULTS: All patients completed 12-week follow-up post-treatment, and 104 (98.1%) obtained sustained virological response (100% in ribavirin -treated patients vs. 90.4% without ribavirin; p=0.04). No worsening in renal and liver function was observed, no serious adverse events occurred. Two virological failures showed resistance associated variants (Y93H and S282T). CONCLUSION: An extended 24-week treatment with sofosbuvir plus daclatasvir+ribavirin obtained 100% efficacy in genotype 3 hepatitis C cirrhosis, with very limited side effects. The role of ribavirin seems crucial in this setting and should be administered if clinically feasible.

A two gene-based risk score predicts alcoholic cirrhosis development in males with at-risk alcohol consumption.

Background: Alcoholic cirrhosis represents 1% of all cause-of-deaths worldwide. Its incidence is higher in males and results from the combination of environmental and genetic factors. Among all the genetic determinants of alcoholic cirrhosis, the patatin-like phospholipase domain protein 3 (PNPLA3) rs738409 represents the most widely validated determinant. Recent cross-sectional studies on alcohol abusers identified transmembrane-6 superfamily member 2 (TM6SF2) rs58542926, membrane bound O-acyltransferase domain containing 7 (MBOAT7) rs641738, and cluster of differentiation 14 (CD14) rs2569190 as new genetic risk factors for alcoholic cirrhosis. We aimed to develop a gene-based risk score to predict the incidence of alcoholic cirrhosis in males with at-risk alcohol consumption. Materials and methods: A total of 416 male at-risk alcohol drinkers were retrospectively examined. The association between alcoholic cirrhosis incidence and PNPLA3, CD14, TM6SF2, and MBOAT7 variants was tested. Age at onset of at-risk alcohol consumption, age, and body mass index (BMI) were included as covariates to determine the prediction score for alcoholic cirrhosis incidence by evaluating time-dependent receiver operating characteristic curves. Results: We found that PNPLA3, CD14, and TM6SF2 were associated with alcoholic cirrhosis prevalence. PNPLA3 and CD14 were also associated with its incidence. The best predictive score formula was (age at onset of at-risk alcohol consumption × 0.1) + (number of CD14 allele T) + (number of PNPLA3 allele M) + (BMI × 0.1). A threshold of 7.27 was identified as cutoff for the predictive risk of alcoholic cirrhosis development in 36 years from the onset of at-risk alcohol consumption with 70.1% sensitivity and 78.7% specificity. Conclusion: We developed the first score for alcoholic cirrhosis prediction that combines clinical and genetic factors.

Long-lasting persistence of large B-cell clones in hepatitis C virus-cured patients with complete response of mixed cryoglobulinaemia vasculitis.

BACKGROUND & AIMS: Hepatitis C virus (HCV)-related mixed cryoglobulinaemia vasculitis (MCV) is characterized by the expansion of rheumatoid factor-producing B-cell clones. The aim of this study was to assess whether B-cell clones may persist in these patients after the clearance of the virus with antiviral therapy, and whether their persistence influences clinical outcomes. METHODS: Forty-five HCV-cured MCV patients were followed up for a median of 18.5 (range 9-38) months after the clearance of HCV. Circulating B-cell clones were detected using flow cytometry either by the skewing of kappa/lambda ratio or by the expression of a VH 1-69-encoded idiotype. RESULTS: The clinical response of vasculitis was 78% complete, 18% partial and 4% null. However, cryoglobulins remained detectable in 42% of patients for more than 12 months. Circulating B-cell clones were detected in 18 of 45 patients, and in 17 of them persisted through the follow-up; nine of the latter patients cleared cryoglobulins and had complete response of vasculitis. Several months later, two of these patients had relapse of MCV. CONCLUSIONS: B-cell clones persist in MCV patients long after HCV infection has been cleared but halt the production of pathogenic antibody. These 'dormant' cells may be reactivated by events that perturb B-cell homeostasis and can give rise to the relapse of cryoglobulinaemic vasculitis.