Management of vascular access for extracorporeal life support: A cohort study.

Extracorporeal membrane oxygenation (ECMO) is required for patients with refractory cardiac or respiratory failure. Inadequate securement of ECMO cannulae may lead to adverse events, ranging from line kinking to catastrophic accidents, such as air entrainment into the circuit or massive bleeding. Furthermore, the micro-motion of the cannulae at the entry site might increase the risk of local infections. Since 2015, we implemented a written protocol for management of ECMO cannulae and tubing, which specifically includes the securement of each cannula with three sutureless devices. The aim of the present study was to retrospectively assess cannulae micro-motion and the rate of bleeding events at the insertion site. Secondarily we aimed to evaluate the impact of prone positioning maneuvers during ECMO on these events. We performed a single-centre retrospective analysis of prospectively collected data on nursing care of ECMO cannulae. We included adult patients treated with veno-venous (V-V) or veno-arterial (V-A) ECMO between 2015 and 2018 in our general intensive care unit. The distance between the insertion site and the end of the wire-wound part of the cannula was recorded daily. Variations of this distance (defined as "cannula micro-motion") were recorded. Forty-five ECMO consecutive adult patients (40 V-V and 5 V-A) were included. No accidental cannula dislodgement was recorded. Median daily "cannula micro-motion" was 0.0 (-0.5 to 0.2) cm, without any significant difference between ECMO configuration, cannula type, and insertion site. Twelve patients (26%) presented at least one bleeding episode at cannula insertion site, none of which required surgical intervention. In the subgroup of patients who underwent prone positioning, no difference in cannulae micro-motion was recorded. An ECMO nursing protocol for cannulae management providing sutureless devices for cannula and tubing securement allows safe line stabilization, with the potential to reduce complications related to ECMO vascular access.

Intravenous fluid therapy in patients with severe acute pancreatitis admitted to the intensive care unit: a narrative review.

Patients with acute pancreatitis (AP) often require ICU admission, especially when signs of multiorgan failure are present, a condition that defines AP as severe. This disease is characterized by a massive pancreatic release of pro-inflammatory cytokines that causes a systemic inflammatory response syndrome and a profound intravascular fluid loss. This leads to a mixed hypovolemic and distributive shock and ultimately to multiorgan failure. Aggressive fluid resuscitation is traditionally considered the mainstay treatment of AP. In fact, all available guidelines underline the importance of fluid therapy, particularly in the first 24-48 h after disease onset. However, there is currently no consensus neither about the type, nor about the optimal fluid rate, total volume, or goal of fluid administration. In general, a starting fluid rate of 5-10 ml/kg/h of Ringer's lactate solution for the first 24 h has been recommended. Fluid administration should be aggressive in the first hours, and continued only for the appropriate time frame, being usually discontinued, or significantly reduced after the first 24-48 h after admission. Close clinical and hemodynamic monitoring along with the definition of clear resuscitation goals are fundamental. Generally accepted targets are urinary output, reversal of tachycardia and hypotension, and improvement of laboratory markers. However, the usefulness of different endpoints to guide fluid therapy is highly debated. The importance of close monitoring of fluid infusion and balance is acknowledged by most available guidelines to avoid the deleterious effect of fluid overload. Fluid therapy should be carefully tailored in patients with severe AP, as for other conditions frequently managed in the ICU requiring large fluid amounts, such as septic shock and burn injury. A combination of both noninvasive clinical and invasive hemodynamic parameters, and laboratory markers should guide clinicians in the early phase of severe AP to meet organ perfusion requirements with the proper administration of fluids while avoiding fluid overload. In this narrative review the most recent evidence about fluid therapy in severe AP is discussed and an operative algorithm for fluid administration based on an individualized approach is proposed.

Complete, Durable Remission of Advanced Hepatocellular Carcinoma under Treatment with Viscum album Extracts: A Case Report.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths. Early-stage disease is treated with curative intent, but most patients present with advanced HCC, which carries a poor prognosis. Viscum album extracts (VAE) are used by cancer patients as an adjunct treatment or palliation. CASE PRESENTATION: A 51-year-old female presented with relapsing multifocal HCC. She declined palliative treatment and commenced intravenous VAE treatment in conjunction with intravenous hepato-protective L-ornithine-L-aspartate (LOLA). She experienced a significant improvement of life-quality and performance status. After 3 months, a significant regression was noted on computerized tomography, and α-fetoprotein was in normal range. Imaging 11 months later confirmed a complete regression. The VAE and LOLA treatment continues to date. The patient had no other cancer-directed therapy. The regression is sustained for more than 5 years at publication, confirmed by regular imaging and serology. The patient is experiencing an unrestricted quality of life. CONCLUSION: Complete regression of advanced HCC is rare. Responses of HCC to VAE treatment have been reported before. However, this is the first documented case with a complete and durable regression of an HCC under treatment with VAE. Further studies should evaluate VAE treatment in HCC, especially when administered in forms as reported here.

Improved survival of patients with hepatocellular carcinoma and compensated hepatitis C virus-related cirrhosis who attained sustained virological response.

BACKGROUND: Few studies examined the outcome of patients with hepatitis C virus (HCV)-related cirrhosis who developed hepatocellular carcinoma (HCC). The relative weight as determinant of death for cancer vs end-stage liver disease (ESLD) and the benefit of HCV eradication remain undefined. This multicentre, retrospective analysis evaluates overall survival (OS), rate of decompensation and tumour recurrence in compensated HCC patients treated with interferon (IFN) according to HCV status since HCC diagnosis. METHODS: Two groups of patients with HCV-related cirrhosis and HCC were followed since HCC diagnosis: (i) compensated cirrhotics with prior sustained virological response (SVR) on IFN-based regimens (N=19); (ii) compensated cirrhotics without SVR (viraemic) (N=156). RESULTS: Over a median follow-up of 3.0 years since the onset of HCC, OS was longer for HCC patients with SVR than for viraemic patients (log-rank P=.004). The 5-year OS rate was 65.9% in patients with SVR vs 31.9% in viraemic patients. Similar trends were reported for hepatic decompensation (log-rank P=.01) and tumour recurrence (log-rank P=.01). These findings were confirmed at multivariable and propensity score analysis. At propensity analysis, 0/19 compensated patients with SVR died for ESLD vs 7/19 (37%) viraemic patients (P=.004). HCC mortality was similar in the two groups. CONCLUSIONS: Hepatocellular carcinoma patients with prior SVR and compensated cirrhosis at the time of tumour diagnosis have prolonged OS than viraemic patients. Given the lack of cirrhosis progression, no SVR patient ultimately died for ESLD while this condition appears the main cause of death among viraemic patients.

Long-Term Ursodeoxycholic Acid Therapy Does Not Alter Lithocholic Acid Levels in Patients with Cystic Fibrosis with Associated Liver Disease.

OBJECTIVE: To evaluate the fasting and postprandial serum bile acid composition in patients with cystic fibrosis-associated liver disease (CFLD) after chronic administration of ursodeoxycholic acid (UDCA) (20 mg/kg/day). The aim was to specifically focus on the extent of biotransformation of UDCA to its hepatotoxic metabolite, lithocholic acid, because of recent concerns regarding the safety of long-term, high-dose UDCA treatment for CFLD. STUDY DESIGN: Twenty patients with CFLD (median age 16 years, range: 2.4-35.0) prescribed UDCA therapy for at least 2 years were studied. Total and individual serum bile acids were measured by stable-isotope dilution mass spectrometry, in fasting and 2-hour postprandial samples taken during chronic UDCA (20 mg/kg/day) administration. RESULTS: During chronic UDCA administration (median duration 8 years, IQR: 6-16), UDCA became the predominant serum bile acid in all patients (median, IQR: 3.17, 1.25-5.56 µmol/L) and chenodeoxycholic acid concentrations were greater than cholic acid (1.86, 1.00-4.70 µmol/L vs 0.40, 0.24-2.71 µmol/L). The secondary bile acids, deoxycholate and lithocholate, were present in very low concentrations in fasted serum (<0.05 µmol/L). After UDCA administration, 2-hour postprandial concentrations of both UDCA and chenodeoxycholic acid significantly increased (P < .01), but no significant changes in serum lithocholic acid concentrations were observed. CONCLUSION: These data do not support recent suggestions that enhanced biotransformation of UDCA to the hepatotoxic secondary bile acid lithocholic occurs when patients with CFLD are treated with relatively high doses of UDCA.

Survival of patients with HCV cirrhosis and sustained virologic response is similar to the general population.

BACKGROUND & AIMS: Life expectancy of patients with compensated hepatitis C virus (HCV) cirrhosis achieving sustained virologic response (SVR) is limited by liver events as compared to the general population. Thus, survival benefit of SVR remains to be measured. METHODS: The study includes prospective surveillance data from three cohorts of Italian patients with compensated HCV cirrhosis who achieved SVR on an interferon-based (IFN) regimen, compared to simultaneously observed non-SVR, untreated and decompensated patients. Overall survival was calculated from the date of start of IFN to death. The number of deaths expected during the at-risk period was determined by applying age- and sex-specific mortality rates recorded in Italy for person-years adequate for the enrolment period. The standardized mortality ratio (SMR) determined the relative risk of death over that of the age and sex matched general population. RESULTS: Overall, 28/181 patients followed-up for a median period of 9.6years (range 1-25years) died. The 10 and 20-year overall survival rates for the whole series were 90.9% (95% CI, 84.3-94.8) and 62.9% (95% CI, 45.9-75.9), respectively. The number of expected deaths in the corresponding age and sex matched general population was 28.1, corresponding to a SMR=1.00 (95% CI, 0.72-1.35), with an SMR for non-SVR patients of 3.85 (95% CI, 3.43-4.30), for untreated of 3.01 (95% CI, 2.64-3.42) and for decompensated of 6.70 (95% CI, 5.39-8.22). CONCLUSIONS: Patients with compensated HCV cirrhosis achieving SVR by IFN obtain a main benefit levelling their survival curve to that of the general population. Wider applicability of IFN-free regimens will possibly make this achievement more generalizable.

Analysis of peripheral blood dendritic cells as a non-invasive tool in the follow-up of patients with chronic hepatitis C.

Hepatitis C virus (HCV) has a high propensity to establish chronic infections. Failure of HCV-infected individuals to activate effective antiviral immune responses is at least in part related to HCV-induced impairment of dendritic cells (DCs) that play a central role in activating T cell responses. Although the impact of HCV on DC phenotype and function is likely to be more prominent in the liver, major HCV-induced alterations are detectable in peripheral blood DCs (pbDCs) that represent the most accessible source of DCs. These alterations include numerical reduction, impaired production of inflammatory cytokines and increased production of immunosuppressive IL10. These changes in DCs are relevant to our understanding the immune mechanisms underlying the propensity of HCV to establish persistent infection. Importantly, the non-invasive accessibility of pbDCs renders the analysis of these cells a convenient procedure that can be serially repeated in patient follow-up. Accordingly, the study of pbDCs in HCV-infected patients during conventional treatment with pegylated interferon and ribavirin indicated that restoration of normal plasmacytoid DC count may represent an additional mechanism contributing to the efficacy of the dual therapy. It also identified the pre-treatment levels of plasmacytoid DCs and IL10 as putative predictors of response to therapy. Treatment of chronic HCV infection is changing, as new generation direct-acting antiviral agents will soon be available for use in interferon-free therapeutic strategies. The phenotypic and functional analysis of pbDCs in this novel therapeutic setting will provide a valuable tool for investigating mechanisms underlying treatment efficacy and for identifying predictors of treatment response.

ABCB4 mutations in adult patients with cholestatic liver disease: impact and phenotypic expression.

BACKGROUND: The ABCB4 gene encodes the MDR3 protein. Mutations of this gene cause progressive familial intrahepatic cholestasis type 3 (PFIC3) in children, but their clinical relevance in adults remains ill defined. The study of a well-characterized adult patient series may contribute to refining the genetic data regarding cholangiopathies of unknown origin. Our aim was to evaluate the impact of ABCB4 mutations on clinical expression of cholestasis in adult patients. METHODS: We consecutively evaluated 2602 subjects with hepatobiliary disease. Biochemical evidence of a chronic cholestatic profile (CCP) with elevated serum gamma-glutamyltransferase activity or diagnosis of intrahepatic cholestasis of pregnancy (ICP) and juvenile cholelithiasis (JC) were inclusion criteria. The personal/family history of additional cholestatic liver disease (PFH-CLD), which includes ICP, JC, or hormone-induced cholestasis, was investigated. Mutation screening of ABCB4 was carried out in 90 patients with idiopathic chronic cholestasis (ICC), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), ICP, and JC. RESULTS: Eighty patients had CCP. PSC and ICC patients with PFH-CLD had earlier onset of disease than those without it (p = 0.003 and p = 0.023, respectively). The mutation frequency ranged from 50% (ICP, JC) to 17.6% (PBC). Among CCP patients, presence or absence of PFH-CLD was associated with ABCB4 mutations in 26.8 vs 5.1% (p = 0.013), respectively; in the subset of ICC and PSC patients, the corresponding figures were 44.4 vs 0% (p = 0.012) and 28.6 vs 8.7% (p = 0.173). CONCLUSIONS: Cholangiopathies attributable to highly penetrant ABCB4 mutant alleles are identifiable in a substantial proportion of adults that generally have PFH-CLD. In PSC and ICC phenotypes, patients with MDR3 deficiency have early onset of disease.

Interferon lambda-3 is not associated with clinical outcome in patients with HCV-induced compensated cirrhosis: a long-term cohort study.

BACKGROUND: Interferon Lambda-3 (IFN-λ3) gene polymorphism is associated with spontaneous clearance of hepatitis C virus (HCV) and response to IFN-based therapy (IFN). However, very few data are available about its value in predicting sustained virologic response (SVR) in patients with cirrhosis, and whether IFN-λ3 genotype influences liver disease progression remains unclear. METHODS: We determined IFN-λ3 genotype by PCR in a cohort of patients with compensated HCV-related cirrhosis, enrolled between 1989 and 1992. Person-years follow-up was calculated for each individual from the date of enrolment to the development of first episode of decompensation, HCC, liver transplant, death or end of follow-up. The follow-up of patients who achieved SVR was censored at the time of IFN initiation. Kaplan-Meier curves and Cox regression analyses were used to assess the association between IFN-λ3 genotype and clinical outcome. RESULTS: IFN-λ3 was determined in 264 patients (52% males, mean age 57±8 years, 67% HCV genotype (G)1, while CC, CT and TT genotypes were 36%, 50% and 14%, respectively. During a median follow-up of 14.8 years, 149 (56%) patients received IFN. Overall, SVR was achieved in 31 (21%) patients, 40% among those with CC genotype (22% in G1 and 61% in G2, respectively) compared to 10% and 13% among patients with CT and TT genotypes (p<0.0001). Univariate and multivariate analyses found no association between IFN-λ3 (CC vs. non-CC genotype) and disease progression. CONCLUSION: IFN-λ3 determination is fundamental for allocating cirrhotic patients to be treated with IFN, while it has no value in predicting the outcome of the disease.

Telomere dysfunction in peripheral blood mononuclear cells from patients with primary biliary cirrhosis.

BACKGROUND: Chromosomal instability in peripheral blood mononuclear cells has a role in the onset of primary biliary cirrhosis. We hypothesized that patients with primary biliary cirrhosis may harbour telomere dysfunction, with consequent chromosomal instability and cellular senescence. AIM: To evaluate the clinical significance of telomerase activity and telomere length in peripheral blood mononuclear cells from patients with primary biliary cirrhosis. STUDY DESIGN: In this population-based case control study, 48 women with primary biliary cirrhosis (25 with cirrhosis), 12 with chronic hepatitis C matched by age and severity of disease, and 55 age-matched healthy women were identified. Mononuclear cells from the peripheral blood of patients and controls were isolated. Telomere length and telomerase activity were measured. RESULTS: Telomere length and telomerase activity did not differ between cases (5.9 ± 1.5 kb) and controls (6.2 ± 1.4 kb, pc=0.164). Telomere shortening and advanced-stage disease strongly correlated with telomerase activity. Patients with advanced disease retained significantly less telomerase activity than those with early-stage disease (0.6 ± 0.9 OD vs. 1.5 ± 3.7 OD, p=0.03). Telomere loss correlated with age, suggesting premature cellular ageing in patients with primary biliary cirrhosis. CONCLUSION: Our data strongly support the telomere hypothesis of human cirrhosis, indicating that telomere shortening and telomerase activity represent a molecular mechanism in the evolution of human cirrhosis in a selected population of patients.

Cholesterol metabolism after bariatric surgery in grade 3 obesity: differences between malabsorptive and restrictive procedures.

OBJECTIVE: Malabsorptive bariatric surgery (biliopancreatic diversion and biliointestinal bypass [BIBP]) reduces serum cholesterol levels more than restrictive surgery (adjustable gastric banding [AGB]), and this is thought to be due to greater weight loss. Our aim was to evaluate the changes of cholesterol metabolism induced by malabsorptive and restrictive surgery independent of weight loss. RESEARCH DESIGN AND METHODS: In a nonrandomized, self-selected, unblinded, active-comparator, bicenter, 6-month study, glucose metabolism (blood glucose and serum insulin levels and homeostasis model assessment of insulin resistance [HOMA-IR] index) and cholesterol metabolism (absorption: serum campesterol and sitosterol levels; synthesis: serum lathosterol levels; catabolism: rate of appearance and serum concentrations of serum 7-α- and serum 27-OH-cholesterol after infusions of deuterated 7-α- and 27-OH-cholesterol in sequence) were assessed in grade 3 obesity subjects undergoing BIBP (n = 10) and AGB (n = 10). Evaluations were performed before and 6 months after surgery. RESULTS: Subjects had similar values at baseline. Weight loss was similar in the two groups of subjects, and blood glucose, insulin levels, HOMA-IR, and triglycerides decreased in a similar way. In contrast, serum cholesterol, LDL cholesterol, non-HDL cholesterol, serum sitosterol, and campesterol levels decreased and lathosterol levels increased only in BIBP subjects, not in AGB subjects. A significant increase in 7-α-OH-cholesterol occurred only with BIBP; serum 27-OH-cholesterol decreased in both groups. CONCLUSIONS: Malabsorptive surgery specifically affects cholesterol levels, independent of weight loss and independent of glucose metabolism and insulin resistance. Decreased sterol absorption leads to decreased cholesterol and LDL cholesterol levels, accompanied by enhanced cholesterol synthesis and enhanced cholesterol catabolism. Compared with AGB, BIBP provides greater cholesterol lowering.

The use of stable and radioactive sterol tracers as a tool to investigate cholesterol degradation to bile acids in humans in vivo.

Alterations of cholesterol homeostasis represent important risk factors for atherosclerosis and cardiovascular disease. Different clinical-experimental approaches have been devised to study the metabolism of cholesterol and particularly the synthesis of bile acids, its main catabolic products. Most evidence in humans has derived from studies utilizing the administration of labeled sterols; these have several advantages over in vitro assay of enzyme activity and expression, requiring an invasive procedure such as a liver biopsy, or the determination of fecal sterols, which is cumbersome and not commonly available. Pioneering evidence with administration of radioactive sterol derivatives has allowed to characterize the alterations of cholesterol metabolism and degradation in different situations, including spontaneous disease conditions, aging, and drug treatment. Along with the classical isotope dilution methodology, other approaches were proposed, among which isotope release following radioactive substrate administration. More recently, stable isotope studies have allowed to overcome radioactivity exposure. Isotope enrichment studies during tracer infusion has allowed to characterize changes in the degradation of cholesterol via the "classical" and the "alternative" pathways of bile acid synthesis. Evidence brought by tracer studies in vivo, summarized here, provides an exceptional tool for the investigation of sterol metabolism, and integrate the studies in vitro on human tissue.

Oxysterols in bile acid metabolism.

Increasing body of evidence is available indicating that oxysterols are more much than intermediates of metabolic pathways. Oxysterols play a role in the regulation of cholesterol synthesis, transport and efflux. A scavenger effect of cholesterol 27-hydroxylase on elevated serum cholesterol levels is well demonstrated. Bile acid synthesis occurs through two main pathways, the classic and the alternative ones. Since plasma concentrations of 27-hydroxycholesterol were clearly shown to reflect its production rate the alternative pathway of bile acid synthesis can be easily explored. Conversely this was not true for 7α-hydroxycholesterol and also the direct evaluation of the classic pathway by kinetic studies is more difficult since the rate of plasma appearance during continuous infusion of deuterated isotopomers may not exactly measure its production rate. Hepatic cholesterol 7alpha-hydroxylase activity is absent during fetal life in humans and upregulates after birth. Both the classic and alternative pathways become mature after the age of 4 years. It has been clearly demonstrated that in patients with liver disease the classic pathway is impaired while the alternative one is preserved. Conversely, in obese patients, preliminary data suggest an increase of the production rate of 27-hydroxycholesterol, a possible mechanism to counteract the increase of atherosclerotic risk.

Severe hepatic encephalopathy in a patient with liver cirrhosis after administration of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker combination therapy: a case report.

INTRODUCTION: A combination therapy of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers has been used to control proteinuria, following initial demonstration of its efficacy. However, recently concerns about the safety of this therapy have emerged, prompting several authors to urge for caution in its use. In the following case report, we describe the occurrence of a serious and unexpected adverse drug reaction after administration of a combination of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers to a patient with nephrotic syndrome and liver cirrhosis with severe portal hypertension. CASE PRESENTATION: We administered this combination therapy to a 40-year-old Caucasian man with liver cirrhosis in our Hepatology Clinic, given the concomitant presence of glomerulopathy associated with severe proteinuria. While the administration of one single drug appeared to be well-tolerated, our patient developed severe acute encephalopathy after the addition of the second one. Discontinuation of the therapy led to the disappearance of the side-effect. A tentative rechallenge with the same drug combination led to a second episode of acute severe encephalopathy. CONCLUSION: We speculate that this adverse reaction may be directly related to the effect of angiotensin II on the excretion of blood ammonia. Therefore, we suggest that patients with liver cirrhosis and portal hypertension are at risk of developing clinically relevant encephalopathy when angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker combination therapy is administered, thus indicating the need for a careful clinical follow-up. In addition, the incidence of this serious side-effect should be rigorously evaluated in all patients with liver cirrhosis administered with this common treatment combination.

Sustained virologic response prevents the development of esophageal varices in compensated, Child-Pugh class A hepatitis C virus-induced cirrhosis. A 12-year prospective follow-up study.

UNLABELLED: The incidence of de novo development of esophageal varices (EV) in patients with compensated liver cirrhosis has been determined by few studies in the short term and never in the long term. The aims of the present study were to determine the incidence and the risk factors associated with the development of EV and to assess whether antiviral treatment and achievement of sustained virologic response (SVR) may prevent de novo EV development in patients with HCV-induced cirrhosis. We studied 218 patients with compensated EV-free, HCV-induced cirrhosis consecutively enrolled between 1989 and 1992 at three referral centers in Milan, Italy. Endoscopic surveillance was performed at 3-year intervals according to international guidelines. SVR was defined as undetectable serum HCV-RNA 24 weeks after treatment discontinuation. During a median follow-up of 11.4 years, 149/218 (68%) patients received antiviral treatment and 34 (22.8%) achieved SVR. None of the SVR patients developed EV compared with 22 (31.8%) of the 69 untreated subjects (P < 0.0001) and 45 (39.1%) of the 115 non-SVR patients (P < 0.0001). On multivariate analysis, HCV genotype 1b (hazard ratio [HR] 2.40; 95% confidence interval [CI] 1.17-4.90) and baseline model for end-stage liver disease (MELD) score (HR 1.20; 95% CI 1.07-1.35 for 1 point increase) were independent predictors of EV. CONCLUSION: In the long term, the achievement of SVR prevents the development of EV in patients with compensated HCV-induced cirrhosis. Therefore, in these patients, endoscopic surveillance can be safely delayed or avoided. Genotype 1b infection and MELD score identify the subset of patients at higher risk of EV development who need tailored endoscopic surveillance.

Predicting mortality risk in patients with compensated HCV-induced cirrhosis: a long-term prospective study.

OBJECTIVES: The identification of prognostic factors associated with mortality is crucial in any clinical setting. METHODS: We enrolled in a prospective study 352 patients with compensated hepatitis C virus (HCV)-induced cirrhosis, consecutively observed between 1989 and 1992. At entry, patients underwent upper endoscopy to detect esophageal varices, and were then surveilled by serial clinical and ultrasonographic examination. The model for end-stage liver disease (MELD) score was calculated with information collected at enrollment. Baseline predictors and intercurrent events associated with mortality were assessed using the Cox regression model. RESULTS: During a median follow-up of 14.4 years, 194 subjects received a single course of interferon monotherapy, 131 patients developed decompensation (ascites, bleeding, hepatic encephalopathy), 109 patients had hepatocellular carcinoma (HCC), 9 had liver transplant, and 158 died. Esophageal varices were associated with development of decompensation (hazard ratio (HR), 2.09; 95% confidence interval (CI), 1.33-3.30) and liver-related death (HR, 2.27; 95% CI, 1.41-3.66). A MELD score of > 10 predicted overall mortality (HR, 2.15; 95% CI, 1.50-3.09). Overall survival of patients with MELD < or = 10 was 80% at 10 years. HCC occurrence increased the risk of decompensation fivefold (HR, 5.52; 95% CI, 3.77-8.09). Hepatic and overall mortality hazard ratios were 8.62 (95% CI, 5.57-13.3) and 3.80 (95% CI, 2.67-5.42), respectively, for patients who developed HCC, and 16.9 (95% CI, 9.97-28.6) and 7.08 (95% CI, 4.88-10.2) for those who experienced decompensation. CONCLUSIONS: In patients with compensated HCV-induced cirrhosis, the presence of esophageal varices at baseline predicted decompensation and mortality. The development of HCC during follow-up strongly hastens the occurrence of decompensation, which is the main determinant of death. Patients with a MELD score < or = 10 at study entry had a prolonged life expectancy.

Plasma oxysterols in normal and cholestatic children as indicators of the two pathways of bile acid synthesis.

BACKGROUND: No information is available on the hepatic and extrahepatic pathways of bile acid synthesis in normal children and in pediatric cholestatic liver diseases. METHODS: To explore the changes of the two pathways of bile acid synthesis during development, plasma concentrations of 7alpha-hydroxycholesterol and 27-hydroxycholesterol were measured in 50 healthy children (1 month-14 years) and compared to 18 adult controls. We also measured plasma oxysterols in 31 patients with pediatric cholestatic liver disease. RESULTS: A progressive increase of plasma concentrations of both 27-hydroxycholesterol and 7alpha-hydroxycholesterol was found with age. In children with cystic fibrosis-associated liver disease plasma concentrations of 27-hydroxycholesterol were significantly lower compared to age-matched controls (5.6+/-0.5 vs. 12.8+/-1.1 microg/dl; p<0.001) and paralleled significantly lower concentrations of total cholesterol. In infants with biliary atresia plasma concentrations of 27-hydroxycholesterol were significantly higher compared to age-matched controls (8.8+/-0.8 vs. 4.4+/-0.6 microg/dl, p<0.001) paralleling significantly higher concentrations of total cholesterol while 7alpha-hydroxycholesterol resulted significantly lower (1.2+/-0.2 vs. 2.3+/-0.3 microg/100 mg of total cholesterol; p=0.011). CONCLUSIONS: Our data suggest that both pathways of bile acid synthesis reach a state of maturity only after the age of 4 years and are significantly influenced also in children by liver function and intestinal absorption of cholesterol.

Clinical features and management of primary biliary cirrhosis.

Primary biliary cirrhosis (PBC), which is characterised by progressive destruction of intrahepatic bile ducts, is not a rare disease since both prevalence and incidence are increasing during the last years mainly due to the improvement of case finding strategies. The prognosis of the disease has improved due to both the recognition of earlier and indolent cases, and to the wide use of ursodeoxycholic acid (UDCA). New indicators of prognosis are available that will be useful especially for the growing number of patients with less severe disease. Most patients are asymptomatic at presentation. Pruritus may represent the most distressing symptom and, when UDCA is ineffective, cholestyramine represents the mainstay of treatment. Complications of long-standing cholestasis may be clinically relevant only in very advanced stages. Available data on the effects of UDCA on clinically relevant end points clearly indicate that the drug is able to slow but not to halt the progression of the disease while, in advanced stages, the only therapeutic option remains liver transplantation.

Primary biliary cirrhosis is not an additional risk factor for bone loss in women receiving regular calcium and vitamin D supplementation: a controlled longitudinal study.

BACKGROUND AND GOALS: Alterations in bone metabolism in primary biliary cirrhosis (PBC) are generally considered to be highly prevalent and severe, but no data are available from prospective studies with adequate control groups. The aims of this study were: (1) to measure changes in bone mineral density (BMD) over time; (2) to correlate the degree of bone loss with the severity of liver disease; and (3) to characterize bone disease in PBC patients receiving regular calcium and vitamin D supplementation. STUDY: We enrolled 118 women with PBC (mean age+/-SD: 56+/-11 y; 72% postmenopausal; 43% with cirrhosis), and measured BMD (lumbar spine, DXA-Hologic) at entry and serially over the following 5 years. The controls were 472 healthy women selected from a large observational group matched for age and menopausal status (mean age+/-SD: 55+/-10 y; 73% postmenopausal). RESULTS: Mean BMD was 0.851+/-0.142 g/cm2 in the PBC group and 0.857+/-0.158 g/cm2 in the control group; the prevalence of osteoporosis was 28% and 29%, respectively. BMD significantly correlated with age and postmenopausal status, but not with liver cirrhosis or serum bilirubin levels. The biochemical markers of bone turnover were high in about 50% of the patients. The yearly bone loss in the PBC group was 0.008 g/cm2 (95% confidence interval: 0.014-0.003) similar to that calculated in the control group. CONCLUSIONS: Among patients with PBC, the prevalence of osteoporosis and the yearly rate of BMD loss are similar to those observed in the general population, and are not associated with the severity of liver disease.