Alpha-1 Antitrypsin Augmentation and the Liver Phenotype of Adults With Alpha-1 Antitrypsin Deficiency (Genotype Pi∗ZZ).

BACKGROUND & AIMS: α1-Antitrypsin (AAT) is a major protease inhibitor produced by hepatocytes. The most relevant AAT mutation giving rise to AAT deficiency (AATD), the 'Pi∗Z' variant, causes harmful AAT protein accumulation in the liver, shortage of AAT in the systemic circulation, and thereby predisposes to liver and lung injury. Although intravenous AAT augmentation constitutes an established treatment of AATD-associated lung disease, its impact on the liver is unknown. METHODS: Liver-related parameters were assessed in a multinational cohort of 760 adults with severe AATD (Pi∗ZZ genotype) and available liver phenotyping, of whom 344 received augmentation therapy and 416 did not. Liver fibrosis was evaluated noninvasively via the serum test AST-to-platelet ratio index and via transient elastography-based liver stiffness measurement. Histologic parameters were compared in 15 Pi∗ZZ adults with and 35 without augmentation. RESULTS: Compared with nonaugmented subjects, augmented Pi∗ZZ individuals displayed lower serum liver enzyme levels (AST 71% vs 75% upper limit of normal, P < .001; bilirubin 49% vs 58% upper limit of normal, P = .019) and lower surrogate markers of fibrosis (AST-to-platelet ratio index 0.34 vs 0.38, P < .001; liver stiffness measurement 6.5 vs 7.2 kPa, P = .005). Among biopsied participants, augmented individuals had less pronounced liver fibrosis and less inflammatory foci but no differences in AAT accumulation were noted. CONCLUSIONS: The first evaluation of AAT augmentation on the Pi∗ZZ-related liver disease indicates liver safety of a widely used treatment for AATD-associated lung disease. Prospective studies are needed to confirm the beneficial effects and to demonstrate the potential efficacy of exogenous AAT in patients with Pi∗ZZ-associated liver disease.

Quantification of circulating alpha-1-antitrypsin polymers associated with different SERPINA1 genotypes.

OBJECTIVES: Alpha-1-antitrypsin deficiency is a genetic disorder caused by mutations in the SERPINA1 gene encoding alpha-1-antitrypsin (AAT), the major serine protease inhibitor in plasma. Reduced AAT levels are associated with elevated risk of developing emphysema mainly due to uncontrolled activity of neutrophil elastase in the lungs. The prevalent Z-AAT mutant and many rare pathogenic AAT variants also predispose to liver disease due to their accumulation as polymeric chains in hepatocytes. Part of these polymers are secreted into the bloodstream and could represent biomarkers of intra-hepatic accumulation. Moreover, being inactive, they further lower lung protection against proteases. Aim of our study is to accurately quantify the percentage of circulating polymers (CP) in a cohort of subjects with different SERPINA1 genotypes. METHODS: CP concentration was measured in plasma or Dried Blood Spot (DBS) by a sensitive sandwich ELISA based on capture by the polymer-specific 2C1 monoclonal antibody. RESULTS: CP were significantly elevated in patients with the prevalent PI*SZ and PI*ZZ genotypes, with considerable intra-genotype variability. Notably, higher percentage of polymers was observed in association with elevated C-reactive protein. CP levels were also increased in carriers of the Mmalton variant, and of Mprocida, I, Plowell and Mherleen in heterozygosity with Z-AAT. CONCLUSIONS: These findings highlight the importance of implementing CP quantification in a clinical laboratory. Indeed, the variable amount of CP in patients with the same genotype may correlate with the variable severity of the associated lung and liver diseases. Moreover, CP can reveal the polymerogenic potential of newly discovered ultrarare AAT variants.

Mediterranean-Oriented Dietary Intervention Is Effective to Reduce Liver Steatosis in Patients with Nonalcoholic Fatty Liver Disease: Results from an Italian Clinical Trial.

Results: One hundred and fifty five subjects aged 20-59 years underwent (i) liver ultrasound (US), (ii) clinical and anthropometric evaluations, (iii) blood tests, and (iv) assessment of dietary habits. According to US evaluation, 73 of them had severe, moderate, or mild liver steatosis (NAFLD patients) and 82 had no liver steatosis (healthy controls). Fifty-eight NAFLD patients and 73 controls completed the study. Among NAFLD patients, 26 (45%) downgraded steatosis severity, 12 of which achieved complete steatosis regression (21%). Three of the healthy controls developed NAFLD. The NAFLD patients improved their dietary habits and reduced BMI and waist circumference, during the study period, more than healthy controls. Liver steatosis remission/regression was independent of changes in BMI or liver enzymes and was more frequent among patients with mild steatosis at baseline. Conclusions: Mediterranean dietary advices, without a personalised meal planning, were efficient in reducing/remitting NAFLD, especially among patients with mild disease, which argues in favour of early identification and lifestyle intervention. This trial is registered with NCT03300661.

Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency.

OBJECTIVE: Alpha-1 antitrypsin deficiency (AATD) is a common, potentially lethal inborn disorder caused by mutations in alpha-1 antitrypsin (AAT). Homozygosity for the 'Pi*Z' variant of AAT (Pi*ZZ genotype) causes lung and liver disease, whereas heterozygous 'Pi*Z' carriage (Pi*MZ genotype) predisposes to gallstones and liver fibrosis. The clinical significance of the more common 'Pi*S' variant remains largely undefined and no robust data exist on the prevalence of liver tumours in AATD. DESIGN: Baseline phenotypes of AATD individuals and non-carriers were analysed in 482 380 participants in the UK Biobank. 1104 participants of a multinational cohort (586 Pi*ZZ, 239 Pi*SZ, 279 non-carriers) underwent a comprehensive clinical assessment. Associations were adjusted for age, sex, body mass index, diabetes and alcohol consumption. RESULTS: Among UK Biobank participants, Pi*ZZ individuals displayed the highest liver enzyme values, the highest occurrence of liver fibrosis/cirrhosis (adjusted OR (aOR)=21.7 (8.8-53.7)) and primary liver cancer (aOR=44.5 (10.8-183.6)). Subjects with Pi*MZ genotype had slightly elevated liver enzymes and moderately increased odds for liver fibrosis/cirrhosis (aOR=1.7 (1.2-2.2)) and cholelithiasis (aOR=1.3 (1.2-1.4)). Individuals with homozygous Pi*S mutation (Pi*SS genotype) harboured minimally elevated alanine aminotransferase values, but no other hepatobiliary abnormalities. Pi*SZ participants displayed higher liver enzymes, more frequent liver fibrosis/cirrhosis (aOR=3.1 (1.1-8.2)) and primary liver cancer (aOR=6.6 (1.6-26.9)). The higher fibrosis burden was confirmed in a multinational cohort. Male sex, age ≥50 years, obesity and the presence of diabetes were associated with significant liver fibrosis. CONCLUSION: Our study defines the hepatobiliary phenotype of individuals with the most relevant AATD genotypes including their predisposition to liver tumours, thereby allowing evidence-based advice and individualised hepatological surveillance.

Liver Phenotypes of European Adults Heterozygous or Homozygous for Pi∗Z Variant of AAT (Pi∗MZ vs Pi∗ZZ genotype) and Noncarriers.

BACKGROUND & AIMS: Homozygosity for the Pi∗Z variant of the gene that encodes the alpha-1 antitrypsin peptide (AAT), called the Pi∗ZZ genotype, causes a liver and lung disease called alpha-1 antitrypsin deficiency. Heterozygosity (the Pi∗MZ genotype) is a risk factor for cirrhosis in individuals with liver disease. Up to 4% of Europeans have the Pi∗MZ genotype; we compared features of adults with and without Pi∗MZ genotype among persons without preexisting liver disease. METHODS: We analyzed data from the European Alpha-1 Liver Cohort, from 419 adults with the Pi∗MZ genotype, 309 adults with the Pi∗ZZ genotype, and 284 individuals without the variant (noncarriers). All underwent a comprehensive evaluation; liver stiffness measurements (LSMs) were made by transient elastography. Liver biopsies were analyzed to define histologic and biochemical features associated with the Pi∗Z variant. Levels of serum transaminases were retrieved from 444,642 participants, available in the United Kingdom biobank. RESULTS: In the UK biobank database, levels of serum transaminases were increased in subjects with the Pi∗MZ genotype compared with noncarriers. In the Alpha-1 Liver Cohort, adults with Pi∗MZ had lower levels of gamma-glutamyl transferase in serum and lower LSMs than adults with the Pi∗ZZ variant, but these were higher than in noncarriers. Ten percent of subjects with the Pi∗MZ genotype vs 4% of noncarriers had LSMs of 7.1 kPa or more (adjusted odds ratio, 4.8; 95% confidence interval, 2.0-11.8). Obesity and diabetes were the most important factors associated with LSMs ≥7.1 kPa in subjects with the Pi∗MZ genotype. AAT inclusions were detected in liver biopsies of 63% of subjects with the Pi∗MZ genotype, vs 97% of subjects with the Pi∗ZZ genotype, and increased with liver fibrosis stages. Subjects with the Pi∗MZ genotype did not have increased hepatic levels of AAT, whereas levels of insoluble AAT varied among individuals. CONCLUSIONS: Adults with the Pi∗MZ genotype have lower levels of serum transaminases, fewer AAT inclusions in liver, and lower liver stiffness than adults with the Pi∗ZZ genotype, but higher than adults without the Pi∗Z variant. These findings should help determine risk of subjects with the Pi∗MZ genotype and aid in counseling.

Elderly-onset vs adult-onset ulcerative colitis: a different natural history?

BACKGROUND: Incidence of ulcerative colitis (UC) in elderly population is increasing because of ageing and because of its minimal impact on life span. Data on natural history, outcomes and therapeutic strategies are limited. Our aim is to characterize UC in elderly-onset patients followed at our Inflammatory Bowel Disease outpatient clinic and compare with adult-onset UC. METHODS: From January 2000 to June 2019, 94 patients with UC diagnosed after the age of 65 years (elderly group, E-O) were identified and matched 1-1 according to gender and calendar year of diagnosis with patients diagnosed with UC at age between 40 and 64 years (adult age, A-O). RESULTS: Comorbidity Index (3.8 vs 1.6, p < 0.0005) was higher for elderly UC patients. Symptoms at presentation were similar between the two groups, although abdominal pain was more common in adults, and weight loss was more common in the elderly. At diagnosis, left colitis (61% vs 39%) and proctitis (14% vs 26%) (p = 0.011) were more frequent in the elderly. Therapy and clinical behaviour were similar. Surgery was more frequently performed in the elderly (20% vs 9%, p = 0.02), while biological therapy was less used (2.1% vs 22%, p < 0.0005). Complications were more frequent in the elderly. Extraintestinal manifestations were lower in elderly patients (9.6% vs 19.2%, p = 0.061). Time to first relapse was similar between the two groups. Mortality (p < 0.0005) was higher in elderly patients. CONCLUSIONS: Ulcerative Colitis has similar presentation and behaviour in elderly and adults patients. However, the elderly are more fragile because of comorbidities, increased risk of infections and disease-related complications.

An Italian expert consensus on the management of alpha1-antitrypsin deficiency: a comprehensive set of algorithms.

BACKGROUND: Alpha1-antitrypsin deficiency (AATD) is a genetic-based risk condition, mainly affecting the lungs and liver. Despite its wide distribution, it is largely underdiagnosed, thus being considered a rare disease, and is consequently managed in ad-hoc reference centers. Unfortunately, an easy-to-use algorithm for managing such a complex disease is still lacking. METHODS: An expert consensus meeting was conducted among experts in the management of AATD to build a comprehensive algorithm, including diagnosis, monitoring, AAT therapy, rehabilitation and lung transplantation, and liver disease, that could serve as a guide for physicians and treating centers. A panel of AATD specialists evaluated the results of their work. RESULTS: Diagnosis is the most delicate phase, and awareness about this condition should be raised among GPs. A set of recommendations has been written about the most suitable follow-up visits. Augmentation therapy with AAT may be useful to reduce the progression of emphysema and lung function decline in selected patients. Exercise capacity may be improved by pulmonary rehabilitation and, in selected cases, by lung volume reduction or lung transplantation. Support therapies are needed for those who develop liver disease, and, in selected cases, liver transplantation may be considered. Patients should be carefully educated about their lifestyle, including smoking cessation, body weight control, and reduced alcohol intake. CONCLUSIONS: The proposed algorithm obtained the endorsement of the Italian Society of Pneumology (SIP). However, further studies and additional clinical data are required to confirm the validity of these recommendations.

Amoxicillin-Clavulanate-Induced Ischaemic Colitis.

Ischaemic colitis (IC) is the most frequent form of ischaemia of the digestive tract. Due to the worldwide increasing use of medications, there is a growing interest in drug-induced IC. This study reports a rare case of IC directly due to amoxicillin-clavulanate intake. The objective of the study was to describe the evolution of this novel manifestation. An 18-year-old man, non-smoker, with an insignificant medical history, presented with diarrhoea and cramping abdominal pain that started the day following the end of a 10-day amoxicillin-clavulanate course for recent upper respiratory tract infection. Stool cultures including Clostridium difficile toxin testing were negative. Colonoscopy documented an erosive-ulcerative colitis of the sigmoid and the descending colon. Histological examination of the colon biopsies revealed an IC with focal pseudomembranous areas in the descending-sigmoid colon. Thrombophilia screening tests were negative. The patient was discharged from the hospital without symptoms, and another colonoscopy was performed 3 weeks after the previous one, which documented normal endoscopic and histological findings. Amoxicillin-clavulanate IC is a very rare condition and should be suspected once infectious diseases, vascular/haemodynamic causes and a prothrombotic/hypercoagulable state have been excluded. Immediate discontinuation of the antibiotic leads to rapid disease remission.

Lack of association of coeliac disease with idiopathic and ischaemic dilated cardiomyopathies.

OBJECTIVE: A prevalence of coeliac disease higher than in the general population has been reported not only in patients with idiopathic dilated cardiomyopathy, a presumable autoimmune disease, but also in patients with ischaemic or valvular cardiomyopathy. The evidence is controversial, however, and the concept itself of an association unrelated to aetiology is intriguing and warrants further testing. The aim of our study was to assess the prevalence of coeliac disease in a cohort of patients with dilated cardiomyopathy screened for the presence of serum anti-transglutaminase antibodies. We provisionally assessed the sensitivity and specificity of two commercially available kits for tissue transglutaminase antibodies detection. MATERIAL AND METHODS: We screened for anti-transglutaminase antibodies in 350 consecutive patients with idiopathic (n = 182) and with ischaemic (n = 168) dilated cardiomyopathy using the previously validated method for anti-transglutaminase antibody assay. Coeliac disease diagnosis has been confirmed by duodenal histopathology in patients testing positive at serological screening. RESULTS: Two coeliac patients (0.6% prevalence) have been identified, one with idiopathic and one with ischaemic dilated cardiomyopathy. They presented with iron deficiency anaemia and with recurrent abdominal pain and diarrhoea, respectively, and both had villous atrophy at histopathology. After 1 year on a gluten-free diet, the echocardiographic parameters did not improve in either patient. CONCLUSIONS: Our results indicate that the prevalence of coeliac disease in patients with dilated cardiomyopathies is similar to that reported for the Italian general population. The confounding factor of conditions associated with both coeliac disease and dilated cardiomyopathies may explain the association unrelated to aetiology reported in previous studies mostly based on small sample size.

A randomised, open label, controlled trial on the effect of interferon plus amantadine compared with interferon alone for treatment of chronic hepatitis C.

BACKGROUND: Combination of the antiviral drug amantadine with interferon (IFN) may be more effective than IFN monotherapy for treatment of chronic hepatitis C. METHODS: We randomised 93 patients with chronic hepatitis C to IFNIFN 6 MU 3 times/week for 24 weeks, followed by IFN 3 MU 3 times/week for further 24 weeks given in combination with amantadine 100 mg t.i.d. (regimen A, n=48) or as monotherapy (regimen B, n=45). Control liver biopsies were obtained 6 months post treatment. RESULTS: At the end of the trial a similar proportion of patients had normal serum ALT levels (35% for regimen A, and 44% for regimen B) as measured by intention to treat criteria. Sustained biochemical response at 6 months post treatment was 15 and 20%, and sustained virological response was 10 and 20% for regimen A and B, respectively. The effect on liver histology was also similar: the inflammatory components of the Knodell score decreased by 1.3+/-0.6 points for regimen A and by 1.6+/-0.6 for regimen B, and score for fibrosis remained unchanged with both regimens. CONCLUSIONS: Combination of IFN therapy with amantadine does not enhance the effect of IFN as shown by biochemical, virological and histological criteria.

Efficacy and tolerability of combination therapy with interferon-alfa plus ribavirin in patients with chronic hepatitis C virus infection: a single-center study in relapsers and nonresponders to previous treatment with high-dose interferon-alfa monotherapy.

BACKGROUND: In chronic hepatitis C virus (HCV) infection, interferon (IFN) monotherapy usually is carried out at doses of 3 to 6 million units (MU) 3 times per week, but treatment efficacy is low. OBJECTIVE: The aim of our study was to assess the efficacy and tolerability of IFN-alfa2b in combination with ribavirin in relapsers and nonresponders to high-dose IFN treatment (5 to 6 MU 3 times per week). We measured the biochemical and virologic responses to treatment and the risk for relapse during the 24 weeks following the end of treatment. METHODS: Patients with chronic HCV infection (relapsers and nonresponders to a previous treatment with high-dose IFN) received IFN-alfa2b, 3 MU 3 times per week, and ribavirin, 1000 or 1200 mg/d for 24 or 48 weeks. The patients were then followed up for an additional 24 weeks. Sustained response was defined as normal serum alanine aminotransferase (ALT) level and undetectable HCV RNA 24 weeks after treatment was stopped. RESULTS: Forty-three patients (32 men, 11 women; mean [SD] age, 45 [2] years; 10 relapsers, 33 nonresponders) were included in the study. Four patients were withdrawn from the study at week 4 of treatment because of treatment-related adverse events, and 1 dropped out. At the end of the treatment period, normalization of serum ALT levels and undetectable HCV RNA levels were seen in 58.1% and 30.2% of patients, respectively. No significant difference in virologic response at the end of treatment was found between nonresponders (10/33 [30.3%]) to previous IFN therapy and relapsers (3/10 [30.0%]). At the end of follow-up, 3 (7.0%) treated patients had sustained response (2 nonresponders to the first IFN course and 1 relapser). All of the patients with sustained response were treated for 24 weeks. CONCLUSION: Based on the results of our study, combination therapy with IFN-alfa and ribavirin may be of value in a limited number of patients with chronic HCV infection who do not respond to, or relapse after, a first course of treatment with high-dose IFN monotherapy.

Addicts with chronic hepatitis C: difficult to reach, manage or treat?

AIM: To assess the acceptance, safety and efficacy of care and treatment for chronic hepatitis C (CHC) in drug addicts. METHODS: We designed a multidisciplinary, phase IV prospective cohort study. All illicit drug users (IDUs) visited a Territorial Addiction Service (SerT) in the District of Brescia, and hepatitis C antibody (HCVAb) testing positive were offered as part of a standardised hepatologic visit in our Gastroenterology Unit. Patients with confirmed CHC and without medical contraindications were administered peginterferon alfa-2b 1.5 µg/kg per week plus ribavirin (800-1400 mg/d) for 16-48 wk. All IDUs were unselected because of ongoing addiction and read and signed an informed consent form. Virologic responses at weeks 4 and 12 of therapy, at the end of treatment and 24 wk after the end of treatment were the main measures of efficacy. Adherence was estimated according to the 80/80/80 criteria. RESULTS: From November 2007 to December 2009, 162 HCVAb+ IDUs were identified. Sixty-seven patients (41% of the initial cohort) completed the diagnostic procedure, and CHC was diagnosed in 54 (33% of the total). Forty-nine patients were offered therapy, and 39 agreed (80% of acceptance rate). The prevalent HCV genotype was type 1, and the HCV RNA baseline level was over 5.6 log/mL in 61% of cases. Five patients dropped out, two because of severe adverse events (SAEs) and three without medical need. Twenty-three and 14 patients achieved end of treatment responses (ETRs; 59%) and sustained virologic responses (SVRs; 36%), respectively. Thirty-one patients were fully compliant with the study protocol (80% adherence). The prevalence of host and viral characteristics negatively affecting the treatment response was high: age over 40 years (54%), male gender (85%), overweight body type (36%), previous unsuccessful antiviral therapy (21%), HCV genotype and viral load (60% and 62%, respectively), earlier contact with HBV (40%) and steatosis and fibrosis (44% and 17%, respectively). In a univariate analysis, alcohol intake was associated with a non-response (P = 0.0018, 95%CI: 0.0058-0.4565). CONCLUSION: Drug addicts with CHC can be successfully treated in a multidisciplinary setting using standard antiviral combination therapy, despite several "difficult to reach, manage and treat" characteristics.

Three new alpha1-antitrypsin deficiency variants help to define a C-terminal region regulating conformational change and polymerization.

Alpha1-antitrypsin (AAT) deficiency is a hereditary disorder associated with reduced AAT plasma levels, predisposing adults to pulmonary emphysema. The most common genetic AAT variants found in patients are the mildly deficient S and the severely deficient Z alleles, but several other pathogenic rare alleles have been reported. While the plasma AAT deficiency is a common trait of the disease, only a few AAT variants, including the prototypic Z AAT and some rare variants, form cytotoxic polymers in the endoplasmic reticulum of hepatocytes and predispose to liver disease. Here we report the identification of three new rare AAT variants associated to reduced plasma levels and characterize their molecular behaviour in cellular models. The variants, called Mpisa (Lys259Ile), Etaurisano (Lys368Glu) and Yorzinuovi (Pro391His), showed reduced secretion compared to control M AAT, and accumulated to different extents in the cells as ordered polymeric structures resembling those formed by the Z variant. Structural analysis of the mutations showed that they may facilitate polymerization both by loosening 'latch' interactions constraining the AAT reactive loop and through effects on core packing. In conclusion, the new AAT deficiency variants, besides increasing the risk of lung disease, may predispose to liver disease, particularly if associated with the common Z variant. The new mutations cluster structurally, thus defining a region of the AAT molecule critical for regulating its conformational state.

Hypoglycemia, an atypical early sign of hepatocellular carcinoma.

BACKGROUND: Hypoglycemia is extremely uncommon as the first presentation of hepatocellular carcinoma, and it occurs predominantly as a paraneoplastic manifestation. METHODS: We report a case of a 38-year-old-man positive for hepatitis B surface antigen with high-serum viremia who presented with symptoms of acute severe hypoglycemia. RESULTS: Laboratory tests confirmed hypoglycemia (serum glucose 1.54 mmol/L) with undetectable serum-C peptide (<0.5 µIU/mL) and slightly increased serum insulin concentration (35 µIU/mL). Alpha-fetoprotein serum level was 75,625 ng/mL. Abdominal ultrasonography and computed tomography revealed a big vascularized mass of 13 cm in diameter occupying most of the right lobe of the liver and an (18)F-fluoro-2-deoxy-D-glucose positron-emission tomography revealed a predominant uptake of glucose by the tumor mass. CONCLUSIONS: These findings indicate that hepatocellular carcinoma-associated hypoglycemia may be due exclusively to increased glucose utilization by the tumor mass.

Increased serum gamma-glutamyl-transpeptidase concentration is associated with nonalcoholic steatosis and not with cholestasis in patients with chronic hepatitis C.

BACKGROUND AND AIM: Increased pretreatment gamma-glutamyl-transpeptidase (gammaGT) is common in patients with chronic hepatitis C and with little or no alcohol consumption. The mechanism involved in this phenomenon is unclear, and the aim of this study was to investigate factors associated with increased gammaGT levels, specifically looking at the role of cholestasis that frequently accompanies hepatitis C. METHODS: Fifty patients with chronic hepatitis C enrolled in two trials of antiviral treatment, 25 with normal and 25 with elevated pretreatment gammaGT levels, were retrospectively selected. In addition to the common liver function and virological tests, other values measured were serum bile acid concentration and composition by gas-chromatography as a sensitive index of cholestasis, and liver biopsy scores for cholestasis and steatosis in addition to siderosis, fibrosis and inflammation. RESULTS: Total mean serum bile acid concentration was 11.6 +/- 1.4 micromol/L and 8.5 +/- 1.2 micromol/L (not significant) in patients with elevated and with normal gammaGT, respectively, and individual bile acid composition was similar in the two groups. By univariate analysis, serum gammaGT level was linearly related to total serum bile acid (P < 0.05) and to cholestasis score (P < 0.001) among other variables, but steatosis score (P < 0.001) and Knodell score (P < 0.04) were the only variables independently associated with elevated serum gammaGT level by multivariate analysis. CONCLUSIONS: Increased serum gammaGT level in patients with chronic hepatitis C is associated with liver steatosis and fibrosis, and indicates more advanced liver disease rather than reflecting the cholestasis that often accompanies this condition.

Ursodeoxycholic acid does not affect ethinylestradiol bioavailability in women taking oral contraceptives.

OBJECTIVE: Contraception is recommended for female patients during ursodeoxycholic acid (UDCA) treatment for the potential teratogenic effect of this bile acid, and the aim of our study was to determine whether this treatment affects the bioavailability of ethinylestradiol (EE2). METHODS: In this double-blind, randomised study, we measured EE2 pharmacokinetics in eight healthy volunteers randomly allocated to receive oral contraceptive (30 microg EE2 and 75 microg gestodene) plus either UDCA (8-10 mg/kg per day) or placebo for 21 days during the first of three consecutive menstrual cycles. After a washout period during the second cycle, the subjects received the alternative treatment during the third menstrual cycle. Serum EE2 and UDCA were measured using radioimmunoassay and gas chromatography-mass spectrometry, respectively. RESULTS: The profile for serum EE2 concentration was similar during UDCA (mean maximum serum concentration 177 pg/ml, SEM 59) and during placebo treatment (153 pg/ml, SEM 62), and mean area under the curve (AUC) was 1374 pg/h per ml (SEM 580) and 1320 pg/h per ml (SEM 551) during the two regimens, respectively. The point estimates and 90% confidence intervals of UDCA/placebo ratios for EE2 AUC and for maximum serum concentration were 1.1 (0.8-1.5) and 1.2 (1.0-1.4), respectively. Mean serum triglycerides concentration increased from 58.3 mg/dl (SEM 6.8) at enrolment to 91.4 mg/dl (SEM 10.7) during placebo (P < 0.01) and to 88.6 mg/dl (SEM 13.7) during UDCA treatment (P < 0.05). During UDCA treatment, serum enrichment with this bile acid and with the metabolite iso-UDCA was 29% (16%) and 3% (2%), respectively. CONCLUSION: Co-administration with UDCA does not affect the bioavailability of EE2 in healthy volunteers, indicating that contraceptive efficacy is not affected.