Conservative management of Anderson Type II odontoid fractures in octogenarians: is radiological union what we are searching for?

OBJECTIVE: The C2 odontoid fractures represent one of the most common cervical spine injuries. Stabilization and immobility are required for a correct treatment. However, in some cases surgical treatment is recommended. There are still no guidelines for Type II odontoid fractures management. The present study aims at determining how non-union could impact on mortality, functional and clinical outcomes in octogenarian patients conservatively treated. MATERIALS AND METHODS: The present investigation is a retrospective case series. All patients with diagnosis of Type II odontoid fractures, over 80 years and conservatively treated in our institution between January 2016 to April 2020 were potentially eligible for the study. The primary outcome was the bony fusion of the fracture after 3 months of conservative treatment. The secondary outcomes were clinical, functional outcomes and mortality. RESULTS: Sixty-four patients were eligible for the study according to inclusion and exclusion criteria. Computer Tomography (CT) evaluation performed 3 months after trauma showed complete fracture healing in 31 patients (48.4%, Fused), while 33 patients (51.6%) were evaluated as non-fused. Among these, 6 months after the CT evaluation, 14 patients were classified as stable, while 19 were classified as unstable. There were no statistically significant changes in clinical and functional outcomes reported in our patient series between patients with complete radiological healing and patients who reported stable fibrous non-union. CONCLUSIONS: In a selected group of elderly patients with a high risk for surgery, the conservative treatment of odontoid Type II fractures can be considered a viable management strategy. The achievement of a stable non-union allows for clinical and functional results comparable to complete fracture healing.

Long-term outcomes of direct acting antivirals in post-transplant advanced hepatitis C virus recurrence and fibrosing cholestatic hepatitis.

Long-term functional outcomes of sofosbuvir-based antiviral treatment were evaluated in a cohort study involving 16 Italian centres within the international compassionate use programme for post-transplant hepatitis C virus (HCV) recurrence. Seventy-three patients with cirrhosis (n=52) or fibrosing cholestatic hepatitis (FCH, n=21) received 24-week sofosbuvir with ribavirin±pegylated interferon or interferon-free sofosbuvir-based regimen with daclatasvir/simeprevir+ribavirin. The patients were observed for a median time of 103 (82-112) weeks. Twelve of 73 (16.4%) died (10 non-FCH, 2 FCH) and two underwent re-LT. Sustained virological response was achieved in 46 of 66 (69.7%): 31 of 47 (66%) non-FCH and 15 of 19 (79%) FCH patients. All relapsers were successfully retreated. Comparing the data of baseline with last follow-up, MELD and Child-Turcotte-Pugh scores improved both in non-FCH (15.3±6.5 vs 10.5±3.8, P<.0001 and 8.4±2.1 vs 5.7±1.3, P<.0001, respectively) and FCH (17.3±5.9 vs 10.1±2.8, P=.001 and 8.2±1.6 vs 5.5±1, P=.001, respectively). Short-treatment mortality was higher in patients with baseline MELD≥25 than in those with MELD<25 (42.9% vs 4.8%, P=.011). Long-term mortality was 53.3% among patients with baseline MELD≥20 and 7.5% among those with MELD<20 (P<.0001). Among deceased patients 75% were Child-Turcotte-Pugh class C at baseline, while among survivors 83.9% were class A or B (P<.0001). Direct acting antivirals-based treatments for severe post-transplant hepatitis C recurrence, comprising fibrosing cholestatic hepatitis, significantly improve liver function, even without viral clearance and permit an excellent long-term survival. The setting of severe HCV recurrence may require the identification of "too-sick-to-treat patients" to avoid futile treatments.

Safety and efficacy of direct-acting antivirals for the treatment of chronic hepatitis C in a real-world population aged 65 years and older.

The availability of direct-acting antiviral agents (DAA) regimens has expanded the pool of patients eligible for treatment. However, data on the virologic response and tolerability of DAAs in elderly patients are lacking. We evaluated the efficacy and safety of DAAs in patients with advanced fibrosis/cirrhosis in real-life practice with the focus on those aged ≥65 years. Between January and December 2015, all consecutive patients with HCV-related advanced fibrosis/cirrhosis treated with DAA at eleven tertiary referral centres in Emilia Romagna (Italy) were enrolled. Regimen choice was based on viral genotype and stage of disease, according to guidelines. The primary end point was sustained virologic response 12 weeks after the end of treatment (SVR12). Overall, 282 of 556 (50.7%) patients evaluated were elderly, most of them with cirrhosis. Antiviral therapy was stopped prematurely in four (1.4%) patients. Two patients, both with cirrhosis, died during treatment due to worsening of liver/renal function. SVR12 was achieved by 94.7% and was comparable to that obtained in patients aged <65 (P=.074). Similar data were also reported in subgroup of patients aged ≥75 years. All patients with advanced fibrosis achieved virologic response. SVR12 was 80.8% in Child-Pugh-Turcotte (CTP)-B cirrhosis and 95.4% in CTP-A (P=.013). According to genotype, the SVR12 was achieved in 172 of 181 (95%) with genotype 1b cirrhosis and in 44 of 48 (91.7%) with genotype 2 cirrhosis. In conclusions, in a real-world setting, DAAs are safe and effective in elderly patients with HCV-related advanced fibrosis/cirrhosis, but SVR12 is lower with worsening CTP class.

Randomised clinical trial: alisporivir combined with peginterferon and ribavirin in treatment-naïve patients with chronic HCV genotype 1 infection (ESSENTIAL II).

BACKGROUND: Alisporivir (ALV) is an oral, host-targeting agent with pangenotypic anti-hepatitis C virus (HCV) activity and a high barrier to resistance. AIM: To evaluate efficacy and safety of ALV plus peginterferon-α2a and ribavirin (PR) in treatment-naïve patients with chronic HCV genotype 1 infection. METHODS: Double-blind, randomised, placebo-controlled, Phase 3 study evaluating ALV 600 mg once daily [response-guided therapy (RGT) for 24 or 48 weeks or 48 weeks fixed duration] or ALV 400 mg twice daily RGT with PR, compared to PR alone. Following a Food and Drug Administration partial clinical hold, ALV/placebo was discontinued and patients completed treatment with PR only. At that time, 87% of patients had received ≥12 weeks and 20% had received ≥24 weeks of ALV/PR triple therapy. RESULTS: A total of 1081 patients were randomised (12% cirrhosis, 55% CT/TT IL28B). Addition of ALV to PR improved virological response in a dose-dependent fashion. Overall, sustained virological response (SVR12; primary endpoint) was 69% in all ALV groups vs. 53% in PR control. Highest SVR12 (90%) was achieved in patients treated with ALV 400 mg twice daily and PR for >24 weeks. Seven cases of pancreatitis were reported, with similar frequency between ALV/PR and PR control groups (0.6% vs. 0.8% respectively). Adverse events seen more frequently with ALV/PR than with PR alone were anaemia, thrombocytopenia, hyperbilirubinaemia and hypertension. CONCLUSIONS: Alisporivir, especially the 400 mg twice daily regimen, increased efficacy of PR therapy in treatment-naïve patients with HCV genotype 1 infection. The mechanism of action and pangenotypic activity suggest that alisporivir could be useful in interferon-free combination regimens.

HCV genotype 1 subtypes (1a and 1b): similarities and differences in clinical features and therapeutic outcome.

AIM: To evaluate similarities and differences in HCV-1 subtypes 1a and 1b in the presenting clinical features and the response to peg-interferon and ribavirin (Peg/RIBA). PATIENTS AND METHODS: A total of 1,233 naïve patients with HCV genotype-1 infection, 159 (13%) with subtype 1a and 1,074 (87%) with subtype 1b were treated with Peg-IFN/RIBA at 12 Italian centers. Covariates included in the logistic model were age, gender, BMI, serum alanine aminotransferase, serum gamma-glutamiltranspeptidase (γGT), platelets counts, liver fibrosis, the occurrence of type 2 diabetes, baseline viremia, and IL28B genotype. RESULTS: At multivariate analysis, baseline characteristics differentiating patients with HCV-1a versus HCV-1b were young age, male gender, no F4 fibrosis, and no diabetes. SVR was achieved by 37% of patients with subtype 1b and 45% of those with subtype 1a, a nonsignificant difference of 8% (p = 0.069). In patients with subtype 1a, predictors of SVR were IL28B CC (OR 5.78, CI 1.98-16.83), RVR (OR 4.18, CI 1.66-10.55), female gender (OR 2.83, CI 1.83-6.78), and HCVRNA (OR 0.55, CI 0.32-0.96). In patients with subtype 1b, the ranking of predictors was levels RVR (OR 6.49, CI 4.32-9.73), IL28B CC (OR 3.32, CI 2.15-4.58), γGT (OR 1.59, CI 0.14-2.22), HCVRNA (OR 0.61, CI 0.47-0.79), and age (OR 0.01, CI 0.02-0.42). CONCLUSION: In Italy HCV-1 subtype 1a prevails in young male patients with less advanced liver damage, findings that imply a more recent spreading of the infection with this viral strain. The two HCV-1 subtypes appear equally responsive to Peg-IFN/RIBA, with IL28B genotyping and monitoring of RVR mostly influencing the therapeutic response.

Alisporivir with peginterferon/ribavirin in patients with chronic hepatitis C genotype 1 infection who failed to respond to or relapsed after prior interferon-based therapy: FUNDAMENTAL, a Phase II trial.

Alisporivir (ALV) is an oral, investigational host-targeting agent, with pangenotypic activity against hepatitis C virus (HCV). This randomized, double-blind, placebo-controlled, Phase II study explored the efficacy and safety of ALV with peginterferon-α2a/ribavirin (PR) in patients with chronic HCV genotype 1 infection in whom prior PR had failed (43% relapsers, 34% null responders and 23% partial responders). Four-hundred-and-fifty-nine patients were randomized (1:1:1:1) to ALV 600 mg once daily (QD), ALV 800 mg QD, ALV 400 twice daily (BID) or placebo plus PR for 48 weeks. When the global ALV trial programme was put on clinical hold, all patients in this study had received ≥31 weeks of randomized treatment; patients completed 48 weeks on PR alone. All ALV groups demonstrated superior rates of complete early virologic response (cEVR; primary endpoint) vs PR alone (P ≤ 0.0131), with highest cEVR rate seen with ALV 400 mg BID (74% vs 36% with PR alone; P < 0.0001). Respective SVR12 rates (key secondary endpoint) were 65% vs 26% in prior relapsers, 63% vs 5% in partial responders and 68% vs 3% in null responders. In patients who received >40 weeks of randomized treatment, the SVR12 rate was 89% for ALV 400 mg BID vs 30% for PR alone (P = 0.0053). Rates of viral breakthrough and relapse were lowest with ALV 400 mg BID. One case of pancreatitis (fully recovered) occurred with ALV/PR. Common AEs were headache, fatigue, anaemia, neutropenia and nausea. Hypertension was infrequent, but more common with ALV. ALV merits further investigation in interferon-free regimens in combination with direct-acting antiviral agents.

Small (

PURPOSE: We prospectively compared gadoliniumenhanced magnetic resonance imaging (dynamic MRI), superparamagnetic iron oxide (SPIO) (ferucarbotran) MRI and multidetector-row computed tomography (MDCT) and the combination of dynamic MRI plus MDCT vs. dynamic MRI plus SPIO-MRI (double-contrast MRI: DC-MRI) for the detection of small (1 cm and the highest specificity (83.3%) superior to dynamic MRI (p<0.0001). In the per-lesion analysis, SPIO-MRI demonstrated a positive predictive value higher than dynamic MRI (p=0.0059) and than both the combinations dynamic MRI/MDCT and DC-MRI (p=0.0021 and p=0.0087, respectively). DC-MRI showed the highest sensitivity (97.7%) and accuracy (78.9%), detecting hypovascular and atypical HCCs >1 cm. Furthermore its per-patient negative predictive value was the highest (100%), and significantly higher than all the other methods. CONCLUSIONS: DC-MRI is the most sensitive and accurate method and can be confidently used as a single-step procedure for the detection of small HCCs, with the exception of lesions <1 cm.

Generation of a novel antibody probe to the apical sodium-dependent bile acid transporter that inhibits ileal bile acid absorption.

Intestinal bile acid absorption is mediated by a sodium-dependent transporter located in the brush border apical membrane of ileocytes. The transmembrane topology and the role of individual amino acid residues in the bile acid transport process have been investigated by means of various experimental approaches, leading to multiple hypotheses. We raised a monoclonal antibody against a segment of the transporter comprising vicinal cysteine residues, in order to evaluate its functional role. A 14 amino acid peptide, corresponding to amino acids 104-117 of the transporter, was synthesized, and a monoclonal anti-peptide antibody was raised. In vitro uptake-inhibition studies in the presence of the monoclonal anti-peptide antibody were performed using ileal brush border membrane vesicles. Rabbit ileum was perfused in vivo with 5 mM taurocholic acid in the presence of the monoclonal antibody, and bile acid absorption inhibition was evaluated. The anti-peptide monoclonal antibody significantly reduced the in vitro uptake and in vivo absorption of taurocholic acid. The present data demonstrate the functional relevance of the 104-117 peptide segment and report the generation of a novel antibody against the apical sodium-dependent bile acid transporter (ASBT) that may be used as a therapeutic agent in hypercholesterolemia and in cholestatic pruritus.

Clinical trial: peg-interferon alfa-2b and ribavirin for the treatment of genotype-1 hepatitis C recurrence after liver transplantation.

BACKGROUND: Treatment of hepatitis C virus (HCV) recurrence after liver transplantation (LT) is difficult with low response rates. AIM: To assess the safety and efficacy of pegylated-interferon (PEG-IFN) alfa-2b + ribavirin (RBV) in patients with post-LT recurrent genotype-1 HCV and to establish stopping rules according to response. METHODS: Fifty-three patients with post-LT HCV recurrence were enrolled. Patients received PEG-IFN alfa-2b 1.0 micro/kg/week plus RBV 8-10 mg/kg/day for 24 weeks. Those with 'early virological response at week 24' (EVR24) continued treatment for 24 weeks (group A). Patients without EVR24 were randomized to continue (group B) or to discontinue (group C). RESULTS: Overall sustained virological response (SVR) was 26% (14/53). Alanine aminotransferase, rapid virological response, EVR12, EVR24, undetectable serum HCV-RNA at weeks 12 (cEVR12) and 24 (cEVR24) were related to SVR. cEVR12 and cEVR24 (OR: 14.7; 95% CI: 2.02-106.4) were independent predictors of SVR. All patients with SVR, had cEVR12. No patient in groups B and C achieved end-of-treatment response. One patient in group B had SVR. CONCLUSIONS: Pegylated-interferon alfa-2b was effective in one of four of patients with HCV genotype 1 after LT. Treatment should be discontinued in patients with no virological response at week 12. Further studies are needed to evaluate whether a longer treatment period may be beneficial in patients with > or =2 log10 drop in HCV-RNA at week 24.

Hepatobiliary phospholipid transporter ABCB4, MDR3 gene variants in a large cohort of Italian women with intrahepatic cholestasis of pregnancy.

BACKGROUND: Intrahepatic cholestasis of pregnancy is a multifactorial disorder of pregnancy associated with a genetic background. AIM: To evaluate the genetic contribution of ABCB4, MDR3 gene in the development of intrahepatic cholestasis of pregnancy in a large cohort of Italian subjects. METHODS: This study represents an extension of a previous multicentre-prospective study including three Italian referral centres. In all, we enrolled 96 women at the 3rd trimester of pregnancy. Genomic DNA was extracted from peripheral venous blood leucocytes by standard procedures. Polymerase chain reaction was used to amplify exon 14, 15 and 16 of MDR3 gene. RESULTS: We found 3 non-synonymous heterozygous mutations in exon 14 (E528D, R549H, G536A), 1 in exon 15 (R590Q) and 2 in exon 16 (R652G, T6671). MDR3 gene variants in exons 14, 15 and 16 occurred in 7/96 of pregnant mothers with intrahepatic cholestasis of pregnancy (7.2%), and in none of 96 pregnant controls matched for age and parity. All seven patients had normal gamma-glutamyl transpeptidase, normal bilirubin, but high levels of both alanine transferase and serum bile acids. One had cholesterol biliary lithiasis. The outcome of pregnancy was normal in four cases (with vaginal delivery), while there was one fetal distress. CONCLUSIONS: MDR3 mutations are responsible for the development of intrahepatic cholestasis of pregnancy in only a small percentage of Italian women. Further genetic studies are warranted, however, to clarify the role of different mutations in intrahepatic cholestasis of pregnancy.

Transjugular intrahepatic portosystemic shunt: a case report of rescue management of unrestrainable variceal bleeding in a pregnant woman.

Liver cirrhosis complications in pregnant women are frequent and death rate secondary to variceal bleeding is relevant. Both sclerotherapy and banding ligation seem to be safe procedures in pregnancy; when bleeding is not arrested endoscopically an emergency transjugular intrahepatic portosystemic shunt should be considered, but data regarding pregnant cirrhotic women are scarce. We describe the case of a pregnant woman at 14 weeks of gestation who underwent management of acute variceal bleeding by transjugular intrahepatic portosystemic shunt. Transjugular intrahepatic portosystemic shunt may represent a rescue treatment for failed attempts of band ligation or sclerotherapy.

Clinical trial: modulation of human placental multidrug resistance proteins in cholestasis of pregnancy by ursodeoxycholic acid.

BACKGROUND: The effects of ursodeoxycholic acid on human placental bile acids and bilirubin transporters in intrahepatic cholestasis of pregnancy are still undefined. AIM: To evaluate whether ursodeoxycholic acid affects MRP2, MRP3 and MRP4 expression in the placenta. MATERIALS AND METHODS: Forty-three pregnant women were enrolled; fourteen subjects had physiological pregnancies. Intrahepatic cholestasis of pregnancy patients were divided into two groups: (i) 13 received ursodeoxycholic acid (20 mg/kg/day) and (ii) 16 untreated. Total bile acid and bilirubin in serum and cord blood were determined in each subject. Multidrug resistance proteins expression (immunoblot, quantitative real-time PCR) was evaluated in placentas collected at delivery. anova test was used for statistical analysis of data. RESULTS: Ursodeoxycholic acid administration significantly improved maternal serum bile acid and cord blood bilirubin and bile acid levels. MRP2 protein and RNA expression was significantly increased in placentas from treated patients compared to controls (P < 0.001 and P < 0.01, respectively). MRP3 protein expression was not significantly different between the groups while RNA expression was significantly decreased in treated patients (P < 0.01). MRP4 did not show significant differences between the groups. CONCLUSIONS: Ursodeoxycholic acid administration induces placental MRP2 expression, and reduces bilirubin and bile acid levels in cord blood.

High incidence of allograft dysfunction in liver transplanted patients treated with pegylated-interferon alpha-2b and ribavirin for hepatitis C recurrence: possible de novo autoimmune hepatitis?

BACKGROUND: Interferon may trigger autoimmune disorders, including autoimmune hepatitis, in immunocompetent patients. To date, no such disorders have been described in liver transplanted patients. METHODS: 9 of 44 liver transplanted patients who had been receiving pegylated-interferon alpha-2b and ribavirin for at least 6 months for hepatitis C virus (HCV) recurrence, developed graft dysfunction despite on-treatment HCV-RNA clearance in all but one case. Laboratory, microbiological, imaging and histological evaluations were performed to identify the origin of graft dysfunction. The International Autoimmune Hepatitis scoring system was also applied. RESULTS: In all cases infections, anastomoses complications and rejection were excluded, whereas the autoimmune hepatitis score suggested a "probable autoimmune hepatitis" (score from 10 to 14). Three patients developed other definite autoimmune disorders (overlap anti-mitochondrial antibodies (AMA)-positive cholangitis, autoimmune thyroiditis and systemic lupus erythematosus, respectively). In all cases, pre-existing autoimmune hepatitis was excluded. Anti-lymphocyte antibodies in immunosuppressive induction treatment correlated with the development of the disorder, whereas the use of granulocyte colony-stimulating factor to treat interferon-induced neutropenia showed a protective role. Withdrawal of antiviral treatment and treatment with prednisone resulted in different outcomes (five remissions and four graft failures with two deaths). CONCLUSIONS: De novo autoimmune hepatitis should be considered in differential diagnosis along with rejection in liver transplanted patients developing graft dysfunction while on treatment with interferon.

Ursodeoxycholic acid improves gastrointestinal motility defects in gallstone patients.

AIM: To simultaneously evaluate the presence of defects in gallbladder and gastric emptying, as well as in intestinal transit in gallstone patients (GS) and the effect of chronic ursodeoxycholic acid (UDCA) administration on these parameters and on serum bile acids and clinical outcome in GS and controls (CTR). METHODS: After a standard liquid test meal, gallbla-dder and gastric emptying (by ultrasound), oroileal transit time (OITT) (by an immunoenzymatic technique) and serum bile acids (by HPLC) were evaluated before and after 3 mo of UDCA (12 mg/kg bw/d) or placebo administration in 10 symptomatic GS and 10 matched healthy CTR. RESULTS: OITT was longer in GS than in CTR (P < 0.0001); UDCA significantly reduced OITT in GS (P < 0.0001), but not in CTR. GS had longer gastric half-emptying time (t(1/2)) than CTR (P < 0.0044) at baseline; after UDCA, t(1/2) significantly decreased (P < 0.006) in GS but not in CTR. Placebo administration had no effect on gastric emptying and intestinal transit in both GS and CTR. CONCLUSION: The gallstone patient has simultaneous multiple impairments of gallbladder and gastric emptying, as well as of intestinal transit. UDCA administration restores these defects in GS, without any effect in CTR. These results confirm the pathogenetic role of gastrointestinal motility in gallstone disease and suggest an additional mechanism of action for UDCA in reducing bile cholesterol supersaturation.

A statistical model predicting high hepatocyte proliferation index and the risk of developing hepatocellular carcinoma in patients with hepatitis C virus-related cirrhosis.

BACKGROUND: Incidence of hepatocellular carcinoma in hepatitis C virus-related cirrhosis is 4% per year. Although cost-effective, current screening could be improved. AIM: To develop a statistical model including non-invasive parameters able to identify patients at high risk of developing hepatocellular carcinoma. METHODS: One hundred and fifty-eight patients (73F:85M) with compensated chronic hepatitis C virus liver disease underwent evaluation, including argyrophilic nucleolar organizer regions proliferation index, and were followed up for 56.18 +/- 1.44 months. RESULTS: Fifty-six patients had chronic hepatitis without cirrhosis and low argyrophilic nucleolar organizer regions proliferation index (< or =25%), 65 had hepatitis C virus-related cirrhosis and low argyrophilic nucleolar organizer regions proliferation index and 37 had hepatitis C virus-related cirrhosis and high argyrophilic nucleolar organizer regions proliferation index (>25%). Groups were similar for gender and viral genotype distribution. None of the patients with chronic hepatitis without cirrhosis developed hepatocellular carcinoma, compared with 6.1% of low argyrophilic nucleolar organizer regions proliferation index and 30.6% of high argyrophilic nucleolar organizer regions proliferation index (P = 0.002). By multivariable logistic regression analysis, the following parameters were independently associated with hepatocellular carcinoma development and used for the development of the statistical model: platelets (OR 0.98), gamma-globulins (OR 0.111), alanine aminotransferase/aspartate aminotransferase ratio (OR 0.07), serum ferritin (OR 1.0) and ultrasonographic pattern (coarse OR 2.9, coarse nodular OR 10.12). The statistical model properly allocated 95.9% of patients with low argyrophilic nucleolar organizer regions proliferation index and 72.2% of patients with high argyrophilic nucleolar organizer regions proliferation index. CONCLUSIONS: The model, to be validated in large prospective studies, may help tailoring screening according to the risk of hepatocellular carcinoma development.

Intrahepatic cholestasis of pregnancy: three novel MDR3 gene mutations.

BACKGROUND: The aetiology of intrahepatic cholestasis of pregnancy is unknown, but more than 10 different MDR3 gene mutations have recently been identified. AIM: To evaluate the genetic contribution of the MDR3 gene in the pathogenesis of intrahepatic cholestasis of pregnancy in Italian subjects. METHODS: We performed a multicentre prospective case-control study, enrolling 80 women with intrahepatic cholestasis of pregnancy at the third trimester of pregnancy and 80 pregnant women without intrahepatic cholestasis of pregnancy. Genomic DNA was extracted from peripheral venous blood leucocytes using standard procedures. The polymerase chain reaction was used to amplify exon 14 of the MDR3 gene and the polymerase chain reaction products were sequenced using a Big Dye Terminator Cycle Sequencing kit. RESULTS: Three novel non-synonymous heterozygous mutations in exon 14 were found (4%; E528D, R549H, G536R) among the 80 intrahepatic cholestasis of pregnancy patients, whereas the pregnant controls were all negative for exon 14 polymorphisms. The three patients involved had normal GGT and bilirubin, but high levels of both ALT and serum bile acids. One had cholesterol bile stones. The outcome of pregnancy was normal for two (with vaginal delivery), while foetal distress was recorded in the third. CONCLUSIONS: These three novel mutations add further information on the involvement of the MDR3 gene in intrahepatic cholestasis of pregnancy. As in other studies, we found only heterozygous mutations that could cause an impaired transport protein function, not its absence (which is responsible for more severe liver disease). Different genetic backgrounds might justify the presence of novel MDR3 gene mutations.

Higher doses of peginterferon alpha-2b administered twice weekly improve sustained virological response in difficult-to-treat patients with chronic hepatitis C: results of a pilot randomized study.

SUMMARY: Beside substantial progress in treatment of chronic hepatitis C (CHC) particular patients (genotype 1/4, high viral load, previous nonresponse, cirrhosis) remain difficult to treat. The aim of our pilot randomized study was to compare efficacy and tolerability of standard doses of Peginterferon alpha-2b + ribavirin with higher doses of Peginterferon alpha-2b administered twice weekly + ribavirin. Sixty-five outpatients with CHC were subsequently enrolled. Group A (n = 22) received recommended doses of Peginterferon alpha-2b and group B (n = 43), received high doses twice weekly. Groups were comparable for baseline characteristics. All genotype 1/4 patients had high baseline viraemia. Sustained virological response (SVR) was significantly higher in group B among naïve patients (72%vs 25%, P = 0.024). A significantly higher rate of SVR was observed in group B both considering only genotype 1/4 patients, (46%vs 13%, P = 0.03) and grouping together genotype 1/4 naive and relapsers (57%vs 11%, P = 0.039). Discontinuation rate was 32% (7 of 22) in group A and 21% (9 [corrected] of 43) in group B. Our response rates are the highest reported for genotype 1/4 with high viraemia. Our pilot study supports the need of randomized studies to evaluate both viral kinetics and efficacy of high dose and twice weekly administration of Peginterferon alpha-2b in genotype 1/4 patients with high viraemia who may need personalized treatment schedules.

Measurement of hepatic functional mass by means of 13C-methacetin and 13C-phenylalanine breath tests in chronic liver disease: comparison with Child-Pugh score and serum bile acid levels.

AIM: To evaluate and compare the clinical usefulness of 13C-phenylalanine and 13C-methacetin breath tests in quantitating functional hepatic mass in patients with chronic liver disease and to further compare these results with those of conventional tests, Child-Pugh score and serum bile acid levels. METHODS: One hundred and forty patients (50 HCV-related chronic hepatitis, 90 liver cirrhosis patients) and 40 matched healthy controls were studied. Both breath test and routine liver test, serum levels of cholic and chenodeoxycholic acid conjugates were evaluated. RESULTS: Methacetin breath test, expressed as 60 min cumulative percent of oxidation, discriminated the hepatic functional capacity not only between controls and liver disease patients, but also between different categories of chronic liver disease patients. Methacetin breath test was correlated with liver function tests and serum bile acids. Furthermore, methacetin breath test, as well as serum bile acids, were highly predictive of Child-Pugh scores. The diagnostic power of phenylalanine breath test was always less than that of methacetin breath test. CONCLUSION: Methacetin breath test represents a safe and accurate diagnostic tool in the evaluation of hepatic functional mass in chronic liver disease patients.

Breath tests with stable isotopes: have they a role in liver transplantation?

Evaluation of liver function is crucial in the overall management of patients with liver disease. In particular, patients with end-stage liver disease need accurate prognostic indicators to plan liver transplantation, and in this case, to manage their presence in the waiting list. Availability of predictors of clinical outcome is further essential after liver transplant, mainly to correctly diagnose and adequately treat complications, such as acute rejection, drug toxicity, liver dysfunction. Breath tests using labelled substrates selectively metabolized within the liver may represent an accurate diagnostic and prognostic tool in these clinical conditions, possibly with an adjuntive role to the most commonly used prognostic models (Child-Pugh and MELD scores). Promising results have been in fact recently obtained by the use of different substrates (aminopyrine, methacetin, erythromycin, methionine) which explore different metabolic function of the hepatocyte. The usefulness of breath tests has been documented in liver disease patients both before and after liver transplantation, in the early as well as in the late phase.