Incidence and prevalence of primary biliary cholangitis in the Netherlands - A nationwide cohort study.

Background & Aims: Although primary biliary cholangitis (PBC) is considered a rare disorder, accurate determination of its incidence and prevalence remains challenging due to limited comprehensive population-based registries. We aimed to assess the incidence and prevalence of PBC in the Netherlands over time through the nationwide Dutch PBC Cohort Study (DPCS). Methods: DPCS retrospectively included every identifiable patient with PBC in the Netherlands from 1990 onwards in all 71 Dutch hospitals. Incidence and prevalence were assessed between 2008-2018 by Poisson regression between sex and age groups over time. Results: On the 1st of January 2008, there were 1,458 patients with PBC in the Netherlands. Between 2008-2018, 2,187 individuals were newly diagnosed, 46 were transplanted and 468 died. The yearly incidence of PBC in 2008 was 1.38, increasing to 1.74 per 100,000 persons in 2018. When compared to those aged <45 years, females aged 45-64 years (adjusted incidence rate ratio 4.21, 95% CI 3.76-4.71, p <0.001) and males ≥65 years (adjusted incidence rate ratio 14.41, 95% CI 9.62-21.60, p <0.001) were at the highest risk of being diagnosed with PBC. The male-to-female ratio of patients newly diagnosed with PBC during the study period was 1:14 in those <45 years, 1:10 in patients aged 45-64 years, and 1:4 in those ≥65 years. Point prevalence increased from 11.9 in 2008 to 21.5 per 100,000 persons in 2018. Average annual percent change in this time period was 5.94% (95% CI 5.77-6.15, p <0.05), and was the highest among the population aged ≥65 years (5.69%, 95% CI 5.32-6.36, p <0.001). Conclusions: In this nationwide cohort study, we observed an increase in both the incidence and prevalence of PBC in the Netherlands over the past decade, with marked age and sex differences. Impact and implications: This nationwide Dutch primary biliary cholangitis (PBC) Cohort Study, including all hospitals in the Netherlands, showed that the incidence and prevalence of PBC have increased over the last decade. The age-dependent PBC incidence rate differed for males (highest risk ≥65 years) and females (highest risk between 45 and 65 years), which may be related to a difference in the timing of exposure to environmental triggers of PBC. The largest increase in PBC prevalence over time was observed in the population aged ≥65 years, which may have implications for the use of second-line therapies. These results therefore indicate that further studies are needed to elaborate on the advantages and disadvantages of add-on therapies in the elderly population.

Liver stiffness improvement in hepatitis C patients after successful treatment.

BACKGROUND: Successful treatment of chronic hepatitis C with direct-acting antiviral agents (DAAs) is expected to lead to improvement in liver fibrosis in most of the patients. However, limited data are available on the improvement of advanced liver fibrosis and cirrhosis, measured by transient elastography after treatment. This study assessed the change in liver stiffness measurements after successful treatment with DAAs in patients with pre-treatment advanced fibrosis or cirrhosis. METHODS: This observational retrospective cohort study included 514 mono-infected chronic hepatitis C patients, treated with all possible DAA-regimes in the Amsterdam region, the Netherlands. Liver stiffness was measured using FibroScan® at baseline and during follow-up. Cut-off values for staging liver fibrosis were ≥ 9.5 kPa for advanced fibrosis (F3) and ≥ 14.6 kPa for cirrhosis (F4). RESULTS: Liver stiffness decreased significantly from a median of 15.6 kPa (IQR 11.4-25.4) to 9.4 kPa (IQR 6.2-17.0) in 197 patients with pre-treated advanced fibrosis or cirrhosis. In 50.3% of these patients, liver stiffness improved to a value fitting with mild to moderate fibrosis (< 9.5 kPa, F0-F2) after successful treatment. Multivariate analysis demonstrated that a pre-treatment FibroScan® value of ≥ 20.0 kPa was associated with persisting advanced fibrosis or cirrhosis after treatment (OR 29.07, p < 0.001). CONCLUSION: Liver stiffness improves significantly after successful direct-acting antiviral agent treatment in chronic hepatitis C patients with advanced fibrosis or cirrhosis prior to DAA treatment. Long-term outcomes regarding occurrence of hepatocellular carcinoma (HCC) in these patients are required to determine whether they can be safely discharged from HCC surveillance.

Sofosbuvir plus simeprevir for the treatment of HCV genotype 4 patients with advanced fibrosis or compensated cirrhosis is highly efficacious in real life.

Chronic hepatitis C virus (HCV) infection is a major cause of chronic liver disease and liver-related death. Recently, multiple regimens of different direct-acting antiviral agents (DAAs) have been registered. Although treatment with sofosbuvir (SOF) and simeprevir (SMV) is registered for the treatment of genotype 4 patients in some countries, data on efficacy of this combination are lacking. We aimed to assess the efficacy of SOF and SMV with or without RBV during 12 weeks in a real-life cohort of genotype 4 HCV patients. A retrospective multicentre observational study was conducted in 4 hospitals in Amsterdam, the Netherlands, including patients with advanced liver fibrosis or liver cirrhosis treated with SOF plus SMV with or without RBV during 12 weeks for a genotype 4 chronic HCV infection from 1 January 2015 to 1 August 2015. Sustained viral response (SVR) was established at week 12 after end of treatment. A total of 53 patients with genotype 4 HCV infection, treatment naïve and experienced, were included. SVR was achieved in 49 of 53 patients (92%). The four failures all had a virological relapse and did not receive ribavirin. Three were nonresponder to earlier interferon-based treatment, and one was treatment naive. In this real-life cohort of patients with HCV genotype 4 infection and advanced liver fibrosis/cirrhosis, we show that treatment with SOF and SMV is effective. The addition of RBV could be considered in treatment-experienced patients as recommended in guidelines.

Magnetic resonance colonography with a limited bowel preparation and automated carbon dioxide insufflation in comparison to conventional colonoscopy: patient burden and preferences.

OBJECTIVES: To evaluate patient burden and preferences for MR colonography with a limited bowel preparation and automated carbon dioxide insufflation in comparison to conventional colonoscopy. METHODS: Symptomatic patients were consecutively recruited to undergo MR colonography with automated carbon dioxide insufflation and a limited bowel preparation followed within four weeks by colonoscopy with a standard bowel cleansing preparation. Four questionnaires regarding burden (on a five-point scale) and preferences (on a seven-point scale) were addressed after MR colonography and colonoscopy and five weeks after colonoscopy. RESULTS: Ninety-nine patients (47 men, 52 women; mean age 62.3, SD 8.7) were included. None of the patients experienced severe or extreme burden from the MR colonography bowel preparation compared to 31.5% of the patients for the colonoscopy bowel preparation. Colonoscopy was rated more burdensome (25.6% severe or extreme burden) compared to MR colonography (5.2% severe or extreme burden) (P<0.0001). When discarding the bowel preparations, the examinations were rated equally burdensome (P=0.35). The majority of patients (61.4%) preferred MR colonography compared to colonoscopy (29.5%) immediately after the examinations and five weeks later (57.0% versus 39.5%). CONCLUSION: MR colonography with a limited bowel preparation and automated carbon dioxide insufflation demonstrated less burden compared to colonoscopy. The majority of patients preferred MR colonography over colonoscopy.

Dutch guidance for the treatment of chronic hepatitis C virus infection in a new therapeutic era.

BACKGROUND: A new era for the treatment of chronic hepatitis C is about to transpire. With the introduction of the first-generation protease inhibitors the efficacy of hepatitis C treatment improved significantly. Since then, the therapeutic agenda has moved further forward with the recent approval of sofosbuvir and the expected approval of agents such as simeprevir and daclatasvir. This paper, developed parallel to the approval of sofosbuvir, is to serve as a guidance for the therapeutic management of chronic hepatitis C. METHODS: We performed a formal search through PubMed, Web of Science and ClinicalTrials.gov to identify all clinical trials that have been conducted with EMA-approved new agents in hepatitis C; for this version (April 2014) we focused on sofosbuvir. For each disease category, the evidence was reviewed and recommendations are based on GRADE. RESULTS: We identified 11 clinical trials with sofosbuvir and for each disease category recommendations for treatment are made. Not all disease categories were studied extensively and therefore in some cases we were unable to provide recommendations. CONCLUSION: The recent approval of sofosbuvir will most likely change the therapeutic landscape of chronic hepatitis C. The use of sofosbuvir-containing regimens can shorten the duration of therapy, increase efficacy and result in less side effects, compared with standard of care. The efficacy relative to standard of care needs to be weighed against the increased costs of sofosbuvir. With future approval of the other direct-acting antivirals, the outcome of hepatitis C treatment will likely improve further and this guidance will be updated.

Magnetic resonance colonography with automated carbon dioxide insufflation: Diagnostic accuracy and distension.

OBJECTIVES: To evaluate the diagnostic performance of MR colonography using automated carbon dioxide (CO2) insufflation for colonic distension, with colonoscopy serving as the reference standard. METHODS: Ninety-eight symptomatic patients underwent MR colonography with faecal tagging and automated CO2 insufflation. Three readers (one expert (reader 1), and two less experienced (readers 2 and 3)) evaluated the images for the presence of colorectal lesions. Bowel distension was evaluated on a 4-point scale. Results were verified with colonoscopy and histopathological analysis. RESULTS: Per-patient sensitivity for lesions ≥10mm was 91.7% (11 of 12) (reader 1), 75.0% (9 of 12) (reader 2), and 75% (9 of 12) (reader 3). Specificity was 96.5% (82 of 85) (reader 1), 97.7% (83 of 85) (reader 2), 95.3% (81 of 85) (reader 3). Per-patient sensitivity for lesions ≥6mm was 85.7% (18 of 21) (reader 1), 57.1% (12 of 21) (reader 2), and 57.1% (12 of 21) (reader 3). Specificity was 86.8% (66 of 76), 98.7% (75 of 76), 90.8% (69 of 76), respectively. Per-patient sensitivity for advanced neoplasia of ≥10mm and ≥6mm was 88.9% (8 of 9) for all readers. Specificity for ≥10mm and ≥6mm was 98.9% (87 of 88) (reader 1), 97.7% (86 of 88) (reader 2), 96.6% (85 of 88) (reader 3). 94.4% of the colon segments were adequate to optimal distended with dual positioning. CONCLUSION: MR colonography can accurately detect lesions ≥10mm, and advanced neoplasia ≥6mm. Sufficient distension was achieved using automated CO2 insufflation for colonic distension in MR colonography.

Plasma HCV-RNA decline in the first 48 h identifies hepatitis C virus mono-infected but not HCV/HIV-coinfected patients with an undetectable HCV viral load at week 4 of peginterferon-alfa-2a/ribavirin therapy.

During peginterferon-alfa-2a/ribavirin therapy, plasma hepatitis C virus (HCV)-RNA decreases with a rapid first phase and a slower second phase. We compared the viral load decrease and slope in the first 48 h in patients with a rapid viral response (RVR, i.e. HCV-RNA < 50 IU/mL at week 4) with patients not achieving an RVR. From 23 HCV-infected (14 mono-infected and nine HCV/HIV-coinfected) genotype 1 or 4 positive peginterferon-alfa-2a/ribavirin-treated patients, plasma HCV-RNA was determined at baseline, 48 h, weeks 1, 2, 4, 8, 12, 48 and 72. The HCV viral load decrease (Delta0-48), the slope (lambda(1)) and the efficiency factor (epsilon) were determined in the first 48 h after the start of therapy. Five (36%) HCV mono-infected patients and three (33%) HIV/HCV-coinfected patients achieved an RVR whereas six (43%) HCV mono-infected patients and five (56%) HIV/HCV-coinfected patients reached a sustained viral response (SVR). In contrast to HIV/HCV-coinfected patients, five HCV mono-infected patients with an RVR showed both a larger Delta0-48 and steeper lambda(1) (-1.77log(10) IU/mL +/- 0.66 and -2.04/day +/- 0.76) compared to nine non-RVR patients (-0.66log(10) IU/mL +/- 0.39; P = 0.019 and -0.76/day +/- 0.41; P = 0.019). When divided by SVR, a greater Delta0-48 and steeper lambda(1) were also seen in both HCV mono-infected and HIV/HCV-coinfected patients. Thus, in the first 48 h after the start of therapy, HCV mono-infected patients with an RVR have a larger viral load decrease, steeper viral slope and a higher efficiency factor as compared with non-RVR patients.

Laparoscopic resection of a symptomatic gastric diverticulum: a minimally invasive solution.

Gastric diverticula are rare and occasionally symptomatic. A sensation of fullness in the upper abdomen immediately after meals is the most common symptom. Dyspepsia and vomiting are less common. Ulceration with hemorrhage or perforation has been reported. If it is thought that complaints can be ascribed to the diverticulum and if proton pump inhibitors do not relieve symptoms, surgical resection is an option. Knowledge of the pitfalls in diagnosis and treatment of a gastric diverticulum are essential for successful and complete relief of symptoms. We report a successful laparoscopic approach as a minimally invasive solution to a symptomatic gastric diverticulum.

Reproducibility of ambulatory intragastric pH monitoring.

Ambulatory 24-hour intragastric pH monitoring is nowadays the standard technique for assessing intragastric acidity. For (patho)physiological and pharmacological studies the method has to be sensitive and reproducible. Intragastric acidity was measured continuously by means of intragastric electrodes in the gastric corpus. In order to assess the reproducibility of the test, we repeated it test twice on separate days under standardized conditions in 8 healthy subjects. Subjects were fully ambulatory and no medication was administered. We found no significant difference between 24-hour median pH values during both study days [1.45 (range 1.20-1.90) and 1.40 (1.20-2.00), day 1 and 2, respectively]. There was a significant overall correlation between consecutive 30-min median pH values during 24 hours (r = 0.97, p < 0.0001). Over 24 hours and during the day the technique was able to detect consistent pH changes of > 0.1 pH units, but during the night only changes of > 0.3 pH units could be detected, due to nocturnal pH fluctuations in two subjects. This study shows that ambulatory 24-hour intragastric pH monitoring is reproducible and is able to detect small changes in gastric acidity.

Effects of indomethacin on intragastric pH and meal-stimulated serum gastrin secretion in rheumatoid arthritis patients.

The effects of oral indomethacin on intragastric pH and serum gastrin were investigated in rheumatoid arthritis patients. Nine patients (1 male, 8 female) without a history of peptic ulcer disease and 6 patients with a history of peptic ulcer disease (5 male, 1 female) were studied. To obviate Helicobacter pylori infection as a confounding factor, only patients with positive H. pylori serology were included. After a 5-day period of placebo treatment and after a 5-day period of indomethacin (50 mg t.d.s.; total dose 750 mg), 24-h intragastric pH and basal and meal-stimulated serum gastrin levels were measured in a double-blind placebo controlled cross-over study. There were no differences in the median 24-h pH values between placebo and indomethacin users irrespective of peptic ulcer disease history. Indomethacin resulted in a higher basal and stimulated gastrin response than placebo in patients with a history of peptic ulcer disease. The basal and incremental responses were lower in patients with a history of peptic ulcer disease than in patients without a history of peptic ulcer disease, both during indomethacin and placebo. The same basal and stimulated incremental serum gastrin responses were found during placebo and indomethacin treatment in patients without a history of peptic ulcer disease. No correlation was established between median 2-h post-prandial intragastric pH and post-prandial incremental serum gastrin concentration. We conclude that indomethacin does not influence the intragastric pH of rheumatoid arthritis patients irrespective of history of peptic ulcer disease.

Attenuation of the gastric acid and serum gastrin-lowering effects of the prostaglandin E2 analog enprostil.

Enprostil, a synthetic prostaglandin E2 analog, has been shown to decrease gastric acid secretion and plasma gastrin levels during short-term treatment. However, effects of prolonged treatment with enprostil on these parameters in humans are unknown. We have studied the effects of 35 micrograms enprostil twice daily on 24-hour intragastric pH, basal gastrin, and meal-stimulated gastrin release in 10 healthy volunteers. Enprostil, 35 micrograms, was ingested twice daily for 4 weeks. Subjects were studied on day 0 (preentry) and days 1 and 29, when enprostil was taken 30 minutes before the first and third standard test meals at 9 AM and 5 PM. Enprostil significantly increased 24-hour median pH (p < 0.02) on day 1 but not on day 29. Enprostil had no significant effect on basal gastrin levels compared with placebo. However, on day 1, but not on day 29, postprandial gastrin levels were significantly lower compared with preentry (p < 0.05). On day 29 post-prandial gastrin levels after the second standard test meal were significantly higher compared with preentry data (p < 0.05). In conclusion, 35 micrograms enprostil twice daily reduced gastric acidity and serum gastrin levels on the first day of treatment, but this effect attenuated and even transiently reversed during a 4-week treatment period.

Does smoking influence the pharmacokinetics and pharmacodynamics of the H2-receptor antagonist famotidine?

Twelve healthy habitual cigarette smokers and eight non-smokers participated in a double-blind placebo controlled study to determine the effect of smoking on the pharmacokinetics and pharmacodynamics of the H2-receptor antagonist famotidine. In smokers, cigarette smoking was standardised and started 1 h before (A), or 2 h after (B) drug administration, or was prohibited (C). Intragastric pH-levels (IGpH) were measured with an ambulatory pH-recorder. Famotidine (40 mg orally) significantly raised median 22 h IGpH in non-smokers and smokers in all study periods. The smoking sequence (A, B, C) did not significantly influence median 22 h IGpH in both placebo-treated and famotidine-treated smokers, and no significant difference in median 22 h IGpH was shown between smokers and non-smokers. Plasma drug concentrations were similar in the various experiments, although famotidine was detected earlier in plasma from non-smokers compared with smokers (P less than 0.05). Smoking did not interfere significantly with the pharmacokinetics and pharmacodynamics of famotidine.

Weekend treatment with 20 and 40 mg omeprazole: effect on intragastric pH, fasting and postprandial serum gastrin, and serum pepsinogens.

Weekend treatment with 20 mg omeprazole reduces ulcer relapse rates but the results may improve with a higher dose regimen. We have evaluated three day weekend treatment with 20 and 40 mg doses of omeprazole in eight healthy subjects in a double blind crossover study. Twenty four hour ambulatory intragastric pH and basal and meal stimulated serum gastrin and serum pepsinogens A and C values were studied. The investigations began on the Friday before the third weekend course of omeprazole and were repeated on alternate days, except Sundays, for two weeks. When compared with values before the study, median 24 hour intragastric pH and basal and meal stimulated gastrin concentrations were significantly (p less than 0.01-0.05), but transiently, raised with both doses of omeprazole. Basal pepsinogen A and C values were significantly (p less than 0.01) increased on all study days, but did not return to their pre-study values before the next weekend dose, except for pepsinogen C in subjects treated with 20 mg omeprazole. A dose dependent effect was found for all parameters studied (p less than 0.05). In conclusion, weekend treatment with 20 and 40 mg omeprazole produces pronounced and dose dependent increases in intragastric pH, basal and meal stimulated serum gastrin, and basal serum pepsinogen A and C without inducing prolonged hypoacidity or hypergastrinaemia. Weekend treatment with 40 mg omeprazole merits further study in the prevention of peptic ulcer relapse.

Repeated intravenous bolus injections of omeprazole: effects on 24-hour intragastric pH, serum gastrin, and serum pepsinogen A and C.

We determined the effect of four times daily dosing with intravenous omeprazole on 24-h intragastric acidity, serum gastrin, and serum pepsinogen A and C in 10 fasting subjects (median age, 23.5 years). Two dose regimens (80-20-20-20 mg and 80-40-40-40 mg) were compared in a randomized placebo-controlled crossover study. Intragastric pH was continuously monitored during 24 h, using combined glass electrodes, and blood samples were taken every 6 h. Repeated boluses of omeprazole every 6 h significantly increased (p less than 0.01) the median 24-h intragastric pH compared with placebo (median pH, 3.7 (140 mg/day), 4.3 (200 mg/day), and 1.4 (placebo)) but failed to continuously raise pH levels above 4.0 in 8 (140 mg/day) or 9 (200 mg/day) of 10 subjects. No advantage of the 200-mg dose over the 140-mg dose was demonstrated. A cumulative effect of intravenous omeprazole was shown after repeated boluses but also a marked interindividual variation in response, which was correlated with the omeprazole area under the plasma concentration time curve. A significant elevation of serum gastrin coincided with the increased pH levels, which was followed after 12-18 h by a significant increase of both serum pepsinogens.

The effect of intravenous amino acids on intragastric pH during continuous intragastric pH-monitoring.

The present study was undertaken to determine the onset and duration of gastric acid stimulation by amino acids measured by continuous intragastric pH-monitoring. A 3-hour intravenous infusion of 250 ml of an amino acid solution (Vamin 18) was given to 20 healthy volunteers. The results were compared with data obtained during basal conditions and during a 3-hour intravenous infusion of a 5% glucose solution. One hour after starting the amino acid infusion the decrease in intragastric pH-levels reached statistical significance (p less than 0.02). This increased intragastric acidity lasted for one hour after stopping the amino acid infusion. Serum gastrin levels remained unchanged. These results indicate that continuous intragastric pH-monitoring is capable of demonstrating stimulation of gastric acidity during and for one hour after an amino acid infusion. These findings may be important for patients on parenteral nutrition.

Effect of intravenous omeprazole on intragastric pH during intravenous infusion of amino acids.

Intravenous amino acids stimulate gastric acid secretion by an unknown mechanism. In patients on parenteral nutrition, this amino acid-induced gastric acid secretion might contribute to the failure of H2-receptor antagonists to raise intragastric pH above 4.0, a level thought to be needed to prevent stress ulceration. Therefore we studied the effect of single and repeated doses of the H+/K(+)-ATPase blocker omeprazole on the intragastric pH during a 3-hr infusion of amino acids in 10 healthy volunteers; 5% glucose was used as a control infusion. Amino acids significantly decreased intragastric pH when compared to glucose infusion (P less than 0.05). After intravenous administration of 40 mg, 80 mg and 2 X 40 mg omeprazole, this amino acid-induced fall in pH was significantly inhibited (P less than 0.01). No advantage of the 80-mg dose over the 40-mg dose could be demonstrated. The repeated dose of 40 mg showed a tendency to higher pH values compared to the single-dose experiments, which reached significance in the amino acid experiments only (P less than 0.05). Neither during the infusion of amino acids nor the glucose infusion omeprazole was able to continuously raise intragastric pH above 4.0. In conclusion, this study shows that intravenous omeprazole prevents gastric acid stimulation by intravenous amino acids but fails to continuously raise intragastric pH above 4.

Effect of single and repeated intravenous doses of omeprazole on pentagastrin stimulated gastric acid secretion and pharmacokinetics in man.

Single intravenous doses of 10, 20, 40, and 80 mg and repeated once daily intravenous doses of 10 and 20 mg omeprazole induced a powerful and long lasting inhibition of pentagastrin stimulated gastric acid secretion (PAO) in healthy male volunteers. Single intravenous doses of 10, 20, 40, and 80 mg omeprazole inhibited PAO by 30% (p less than 0.01), 45% (p less than 0.01), 61% (p less than 0.01), and 80% (p less than 0.01), respectively when measured 1.5 h after dose, and by 20% (NS), 27% (NS), 36% (p less than 0.01) and 59% (p less than 0.01), respectively when measured 24 h after dose. Six days after repeated once daily intravenous doses of 10 and 20 mg omeprazole, PAO was inhibited by 63% (p less than 0.01) and 82% (p less than 0.01), respectively when measured 1.5 h after dose, and by 32% (p less than 0.01) and 43% (p less than 0.01), respectively when measured 24 h after dose. The inhibition of PAO by 10 mg administered intravenously as a single bolus injection was comparable with the inhibition by 20 mg as a single oral dose. Repeated once daily administration of 10 mg intravenously and 20 mg orally also resulted in comparable reductions in PAO. The reduction in PAO after repeated once daily oral administration of 20 mg was comparable with the effect of a single intravenous dose of 40 mg. Terminal half lives were short, but significantly (p less than 0.05) prolonged after a single intravenous injection of 80 mg. Repeated once daily intravenous administration of 10 and 20 mg did not result in prolongation of terminal half lives. It is concluded that intravenous administration of omeprazole causes a potent and long acting inhibition of pentagastrin stimulated gastric acid secretion in man. Its potency is augmented after repeated once daily administration.