The Impact of Sex on the Response to Proton Pump Inhibitor Treatment.

Proton pump inhibitor (PPI) treatment is responsible for substantial gastrin elevation secondary to reduced intragastric acidity. Due to the increasing global prevalence of PPI users, concerns have been raised about the clinical significance of continuous gastrin elevation and its potential long-term side effects. Hypergastrinemia secondary to PPIs has trophic effects on gastric mucosa, leading to enterochromaffin-like cell hyperplasia and gastric (fundic) polyp formation, and it is believed to provoke acid rebound following PPI withdrawal that induces PPI overutilization. Previous studies have found higher gastrin release following PPI therapy in females compared with males, and sex differences have also been demonstrated in pharmacokinetic parameters and dose requirements for acid reflux. It is conceivable that females might be at increased risk of PPI overuse, because they often receive higher milligram-per-kilogram doses. The prevalence of PPI use is more common among females, and the female sex is a risk factor for adverse drug reactions. This non-systematic review outlines the current knowledge of the impact of biological sex on the response to PPIs. The aim is to highlight the female sex as a potential risk factor that could be a step toward precision medicine and should be considered in future research on the response to PPI treatment.

Primær skleroserende kolangitt.

Primary sclerosing cholangitis is a severe liver disease and a leading cause of liver transplantation in Scandinavia. This clinical review article examines recently revised recommendations on diagnosis, follow-up and treatment of patients with this disease. Treatment of symptoms, assessment of fibrosis and monitoring for the development of cancer in the liver and bowel are central.

[Current use of proton pump inhibitors and when to limit, stop or not start treatment].

Proton pump inhibitors (PPIs) are potent inhibitors of gastric acid secretion that have changed treatment practice for gastric acid-related disorders. The major adequate indications for their use are treatment of gastro-esophageal reflux disease, peptic ulcers, eradication of Helicobacter pylori infection in combination with antibiotics and prophylaxis for patients on non-steroidal anti-inflammatory or antiplatelet drugs. Since their introduction, clinical success has been accompanied by widespread use of PPIs, which has steadily increased over the last decades without concomitant increase in the incidence of acid-related disorders. PPIs are now among the most widely prescribed class of medications worldwide and around 10% of Icelanders are current PPI users. This increase has been linked to PPI prescription without an indication, or continued use for longer duration than recommended. In recent years, concerns have been raised about PPI overuse and the associated increased risk of harm, not only in terms of increased costs but also the potential risk of physical dependence and long-term side effects of PPIs. The article is based on search in PubMed, the authors' own clinical experience and research, and is intended to provide practice advice on the use of PPIs with focus on appropriate prescription and deprescription of PPIs.

Noninvasive evaluation of fibrosis in adult biliary diseases.

PURPOSE OF REVIEW: Liver fibrosis is highly associated with disease progression and clinical outcome in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), the major chronic biliary diseases in adults. Establishment of validated tools for the noninvasive evaluation of liver fibrosis in PBC and PSC for use in patient follow-up, and effect evaluation in clinical trials, has been a top research priority over recent years. RECENT FINDINGS: Two studies in large PBC patient panels investigated liver stiffness measurement by vibration-controlled transient elastography (VCTE) and two studies in PSC demonstrated enhanced liver fibrosis (ELF) variation over time, confirming VCTE and ELF as good prognostic markers. Currently, magnetic resonance elastography (MRE), quantitative MRI mapping and novel serum extracellular matrix and extracellular vesicle markers show promising results for fibrosis and prognostic assessment in biliary diseases. SUMMARY: In this article, we will briefly review recent studies supporting recommendations to assess liver fibrosis and prognosis using the ELF test and VCTE during clinical follow-up in both PBC and PSC. We will discuss emerging evidence for MRE and other imaging techniques, and novel serum fibrosis markers, for which sufficient data or availability is currently limited precluding recommendations for clinical use.

Improvement of cholestatic episodes in patients with benign recurrent intrahepatic cholestasis (BRIC) treated with rifampicin. A long-term follow-up.

OBJECTIVE: Patients with benign recurrent intrahepatic cholestasis (BRIC) suffer from recurrent episodes of cholestatic jaundice. Treatment options remain limited and are mainly symptomatic. In case reports rifampicin, plasmapheresis, and nasobiliary drainage have been reported to be effective. In this case series, we present long-term experience indicating disease-modifying effects of non-invasive treatment with rifampicin for recurrent cholestasis in BRIC type 1 (BRIC1). MATERIALS AND METHODS: We included all adult BRIC1 patients diagnosed and followed up at a single centre in Bergen, Norway. Data regarding clinical and biochemical features during BRIC attacks with and without rifampicin treatment were retrieved from medical journals and a data registry. RESULTS: Five males with BRIC1 were included. Median age at diagnosis was 22 years (range 15-41). Together they had suffered from 65 cholestatic attacks (including four documented abortive attacks). Twenty-eight attacks were treated with rifampicin alone over the last 12 years; all cases showed symptomatic relief and reduction in the levels of bilirubin and alkaline phosphatase in blood. The attacks treated with rifampicin seemed to have shorter duration and were less likely to result in complications or hospitalization compared to attacks prior to the introduction of rifampicin. No side effects attributable to rifampicin were noted. CONCLUSIONS: Episodic treatment of recurrent BRIC1 attacks with rifampicin seems to ameliorate severity and shorten the duration of attacks. Timely diagnosis and effective treatment are of major importance in BRIC, not only to decrease complications but also improving patients' quality of life.

Population pharmacokinetics of esomeprazole in patients with preterm preeclampsia.

Esomeprazole is a proton pump inhibitor being investigated for treatment of preeclampsia. Esomeprazole pharmacokinetics during pregnancy are unknown. We used data from 10 pregnant participants with preterm preeclampsia, and 49 non-pregnant participants to develop a population pharmacokinetic model of esomeprazole. A two-compartment model described the data well. In pregnant participants after single dose, clearance was 42.2% (14.9-61.6%) lower compared to non-pregnant, most likely due to inhibition of CYP2C19. In non-pregnant participants after repeated dosing, clearance was 54.9% (48.2-63.5%) lower in extensive metabolizers and bioavailability was 33% (10.0-52.0%) higher compared to single dosing, which could be due to autoinhibition of CYP2C19. During pregnancy, the CYP2C19 autoinhibition effect with repeated dosing is expected to lead to much lower increase in exposure compared to non-pregnant individuals, since CYP2C19 is already inhibited due to pregnancy.

Pharmacokinetics of single and repeated oral doses of esomeprazole and gastrin elevation in healthy males and females.

OBJECTIVE: Gastrin elevation secondary to proton pump inhibitor (PPI) therapy is well documented. Recent studies have demonstrated a sex-related difference where females on PPIs have significantly higher baseline gastrin levels than males. The aim of the study was to analyse the pharmacokinetics of esomeprazole and short-term effect on serum gastrin levels and evaluate potential sex-related difference. MATERIALS AND METHODS: Healthy volunteers received 40 mg of esomeprazole daily for five days. After the 1st and 5th dose blood samples for fasting gastrin and pharmacokinetic analysis were collected at scheduled time-points for eight hours. Esomeprazole was analysed by liquid chromatography and gastrin concentrations were measured using radioimmunoassay. RESULTS: A total of 30 volunteers were enrolled. Females had higher median baseline gastrin (pM) than males 12 (IQR 10-15) vs. 7 (IQR 4-11) (p = .03). In the study cohort, median gastrin levels rose from 10 (IQR 6-14) to 15 (IQR 13-20) (p = .0002). The serum levels for esomeprazole increased by an average of 299.8 ng/mL (p < .001) from day 1 to day 5. Comparison of the esomeprazole pharmacokinetic parameters between males and females revealed no significant sex-related differences. No significant correlation was found between the AUC and the gastrin level on day 5 (p = .15). CONCLUSIONS: In healthy volunteers, serum gastrin increased significantly after a four-day PPI-therapy. There was also a significant increase in serum esomeprazole from day 1 to day 5. The increase in gastrin and esomeprazole concentration was not related to sex and no significant sex-related difference was found in terms of pharmacokinetic parameters. European Clinical Trial Database (2015-002230-41).

Predictors of Gastrin Elevation Following Proton Pump Inhibitor Therapy.

GOALS: The goal of this study was to elucidate the most important predictors for elevation of gastrin in patients on long-term PPI therapy through analysis of data from 2 published studies in Icelandic patients with erosive GERD. BACKGROUND: Gastrin elevation is a known but variable consequence of proton pump inhibitor (PPI) therapy. Concerns have been raised about the clinical importance of chronic PPI induced gastrin elevation. STUDY: This cross-sectional analysis included patients with endoscopically verified erosive esophagitis receiving long-term PPI therapy. PPI exposure in dosage over weight (mg/kg) and dosage over body surface area (mg/m) was compared with fasting gastrin levels in two separate multiple linear regression models. Data was collected on age, gender, weight, H. pylori infection, smoking, PPI duration and type. RESULTS: Overall data from 157 patients (78 females) were analyzed. Median serum gastrin levels were higher in females than males (92 vs. 60 pg/mL; P=0.001). Simple linear regression showed a correlation between serum gastrin levels and gender (P=0.0008) as well as PPI exposure in mg/kg (P=0.0001) and mg/m (P=0.0001). Multiple linear regression analysis showed that PPI exposure, both in mg/kg (ß=0.95 [CI=0.4-1.5]; P=0.001) and mg/m (ß=0.02 [CI=0.0-0.0]; P=0.0015) along with female gender (ß=0.2 [CI=0.0-0.4]; P=0.02) predicted higher gastrin values. CONCLUSIONS: Dosage and female gender seem to play an important role in the development of gastrin elevation on PPI therapy. A significant correlation was found between fasting serum gastrin and dosage of PPIs over weight and body surface area.

Problems Associated with Deprescribing of Proton Pump Inhibitors.

Proton pump inhibitors (PPIs) are recommended as a first-line treatment for gastroesophageal reflux disease (GERD) and other acid related disorders. In recent years, concerns have been raised about the increasing prevalence of patients on long-term PPI therapy and inappropriate PPI use. It is well known that short-term PPI therapy is generally well tolerated and safe; however, their extensive long-term use is a major global issue. One of these long-standing concerns is PPI-induced gastrin elevation secondary to hypoacidity. Hypergastrinemia is believed to play a role in rebound hyperacidity when PPIs are discontinued resulting in induced dyspeptic symptoms that might result in the reinstitution of therapy. Gastrin exerts tropic effects in the stomach, especially on enterochromaffin-like (ECL) cells, and concerns have also been raised regarding the potential progression to dysplasia or tumor formation following long-term therapy. It is well known that a substantial number of patients on long-term PPI therapy can discontinue PPIs without recurrence of symptoms in deprescribing trials. What is unknown is how sustainable deprescribing should be undertaken in practice and how effective it is in terms of reducing long-term outcomes like adverse drug events, morbidity and mortality. Moreover, there is no clear consensus on when and how deprescribing strategies should be attempted in practice. This review sought to summarize the harms and benefits of long-term PPI therapy with special focus on gastrin elevation and its relation to deprescribing studies and future interventions that may improve PPI use.

Study of Gender Differences in Proton Pump Inhibitor Dose Requirements for GERD: A Double-Blind Randomized Trial.

GOALS: To determine the proportion of patients with gastroesophageal reflux disease who are on proton pump inhibitors (PPIs) who could reduce their prior dosage by half, and identify predictors of successful step-down. BACKGROUND: Appropriate hypergastrinemia results from gastric acid inhibition. A gender difference in fasting gastrin with higher levels among women than among men on long-term PPI therapy has been demonstrated. STUDY: Patients with endoscopically verified erosive esophagitis on long-term PPI therapy were randomized double blindly to step down their dose by half or continue with the same dose for 8 weeks. Fasting gastrin levels were measured before and after treatment. The primary endpoint was successful step-down throughout the study period. RESULTS: Overall, 100 patients were randomized, 49 (24 females) to continue with the same dose as before and 51 (25 females) to step down. Female patients had higher gastrin levels compared with male patients: 78 pg/mL (IQR, 50 to 99) versus 50 pg/mL (IQR, 36 to 74) (P=0.007). Among those randomized to the step-down intervention only 3/25 (12%) women failed to complete the 2 months of lower-dose therapy versus 9/25 (36%) men (P=0.09). Female gender (P=0.048) was the strongest predictor for successful step-down (odds ratio=1.27; 95% CI, 1.01-1.60). The chance of failing to maintain symptom control was twice as high in the reduction group (24%) as compared with the control group (13%) (P=0.2). CONCLUSIONS: Female patients on long-term PPI therapy were 3 times more likely to tolerate half of their prior dose. Female gender had higher probability for successful step-down. These results indicate that women with gastroesophageal reflux disease might manage with lower doses of PPIs as compared with men.European Clinical Trial Database (https://eudract.ema.europa.eu/), number 2013-002067-26.

The effects of long-term therapy with proton pump inhibitors on meal stimulated gastrin.

BACKGROUND: Dyspepsia develops in healthy volunteers after withdrawal of proton-pump inhibitors. This phenomenon, attributed to rebound acid hypersecretion, is thought to be mediated by reflex hypergastrinemia. AIMS: To measure fasting and postprandial gastrin in patients on long-term proton-pump inhibitor treatment and correlate gastrin levels with the duration of treatment and other potential predictors. METHODS: In this cross sectional study patients, with erosive esophagitis, on long-term proton-pump inhibitor treatment and healthy controls underwent gastrin measurements at baseline and four times following a meal and Helicobacter pylori status was determined. RESULTS: A total of 100 patients and 50 controls were studied. Pre- and postprandial gastrin levels were higher in patients (p<0.001). No significant correlation was found between the area under the gastrin-curve and the treatment duration. Female patients had significantly higher gastrin levels than males pre- and postprandial, whereas such differences was not found in the control group. Female gender was the only independent predictor of s-gastrin levels (OR 2.50 compared to males, 95% CI: 1.08-5.76, p=0.032) in the patient group. CONCLUSION: Gastrin values were higher in patients compared to controls. There was no correlation between gastrin levels and treatment duration. Female patients had significantly higher gastrin values than males.