[Gastrointestinal symptoms and dietary intake of patients with irritable bowel syndrome following a low FODMAP diet].

INTRODUCTION: High FODMAP (fermentable oligo-, di, monosaccharides and polyols) foods have been linked with worsening symptoms of IBS patients. The aim was to compare gastrointestinal symptoms and dietary intake of patients with irritable bowel syndrome following a low FODMAP diet, with or without individual nutrition therapy. MATERIALS AND METHODS: A total of 54 patients that met Rome IV criteria for IBS were randomized into two groups, guided group (individual nutrition therapy, n=28) and self-management group (learned about low FODMAP diet online, n=26). Both groups followed low FODMAP diet for 4 weeks. Four-day food records were used to assess dietary intake. Symptoms were assessed by the IBS-severity scoring system (ISB-SSS). RESULTS: The number of subjects who did not complete the study was 13, thereof five in the nutrition therapy and eight in the self-management group, leaving 23 and 18 subjects available for analysis, respectively. Symptoms declined from baseline to endpoint in both groups, by 183±101 points on average in the group receiving nutrition therapy (p< 0.001) and 132±110 points in the self-management group (p< 0.001), with no difference between groups. At baseline, about 80% of meals in both groups contained food high in FODMAP's. The corresponding proportion was 9% and 36% in week 3 in the nutrition therapy and self-management group, respectively (p< 0.001). CONCLUSION: Both groups experienced relieve of symptoms, but compliance to the low FODMAP diet was better in the group receiving individual nutrition therapy compared with the group who only received instructions on how to learn about low FODMAP diet online.

Rebound Acid Hypersecretion after Withdrawal of Long-Term Proton Pump Inhibitor (PPI) Treatment-Are PPIs Addictive?

Proton pump inhibitors (PPIs) are widely used in the long-term treatment of gastroesophageal reflux disease (GERD) and other upper gastrointestinal disorders, such as the healing of peptic ulcers and/or prophylactic treatment of peptic ulcers. PPIs are also widely used as symptomatic treatment in patients with functional dyspepsia. One of the adverse effects of the long-term use of PPI is rebound acid hypersecretion (RAHS), which can occur after the withdrawal of PPI therapy due to a compensatory increase in gastric acid production. Mechanisms of the RAHS have been well established. Studies have shown that pentagastrin-stimulated acid secretion after the discontinuation of PPIs increased significantly compared to that before treatment. In healthy volunteers treated with PPIs, the latter induced gastrointestinal symptoms in 40-50% of subjects after the discontinuation of PPI therapy but after stopping the placebo. It is important for practicing physicians to be aware and understand the underlying mechanisms and inform patients about potential RAHS before discontinuing PPIs in order to avoid continuing unnecessary PPI therapy. This is important because RAHS may lead patients to reuptake PPIs as symptoms are incorrectly thought to originate from the recurrence of underlying conditions, such as GERD. Mechanisms of RAHS have been well established; however, clinical implications and the risk factors for RAHS are not fully understood. Further research is needed to facilitate appropriate management of RAHS in the future.

The Epidemiology of Newly Recognized Causes of Drug-Induced Liver Injury: An Update.

The incidence and prevalence of drug-induced liver injury appear to be increasing globally, for example, with the introduction of checkpoint inhibitors. Several reviews have been published in the last decade on the epidemiology of DILI, both among hospitalized patients and in the general population, as well as from retrospective and prospective studies on DILI. Most of these reviews have not focused on newly recognized agents that have recently changed the landscape of DILI. Apart from liver injury associated with antibiotics, oncological agents, particularly checkpoint inhibitors, are increasingly being recognized as causing liver injury. The type of liver injury associated with these agents is not idiosyncratic but rather an indirect type of injury. Furthermore, recently, COVID-19 vaccines and green tea extract have been found to lead to liver injury. Checkpoint inhibitors have revolutionized the treatment of many malignancies, such as malignant melanoma, lung cancer, and renal cancer. Via the activation of T cells, they can increase immune activity against malignant cells, but at the same time, they can decrease immune tolerance and therefore lead to immune-related adverse effects in many organs. The most common adverse effect in clinical practice is liver injury. A recent prospective study demonstrated an 8% frequency of DILI due to the use of checkpoint inhibitors among patients with malignant melanoma and renal cancer. This rate is much higher than observed with drugs, leading to idiosyncratic liver injury. Shortly after the implementation of the worldwide vaccination program against COVID-19, several case reports were published on suspected vaccination-induced autoimmune-like hepatitis occurring shortly after the vaccination. At first, these reports were met with skepticism, but currently, around 100 reports have been published, and cases of positive recurrence have been reported. The clinical, biochemical, immunological, and histological features are indistinguishable from classic autoimmune hepatitis (AIH). These reactions are very similar to drug-induced autoimmune-like hepatitis (DI-ALH) due to drugs such as nitrofurantoin, minocycline, and infliximab, which do not relapse after a short course of corticosteroids, which is the general rule in classic autoimmune hepatitis (AIH). Green tea extract has been found to be a well-documented cause of acute hepatocellular liver injury with jaundice. A strong HLA association has been reported, showing a high prevalence of HLA-B*35:01 among patients suffering from green tea-induced liver injury. Overall, 3% of patients recruited in the DILIN study were supplemented with green tea extract as one of the ingredients. In a prospective population-based study from Iceland, green tea was implicated in approximately 8% of patients with DILI.

Incidence of cirrhosis in Iceland-impact of the TraP HepC nationwide HCV elimination program.

OBJECTIVE: In 2016, a nationwide elimination program for hepatitis C virus (HCV) was initiated in Iceland, entitled Treatment as Prevention for Hepatitis C (TraP HepC), providing unrestricted access to antiviral treatment. The aims were to describe the changes in etiology and epidemiology of cirrhosis in Iceland and to assess the trends in HCV-related cirrhosis following TraP HepC. METHODS: The study included all patients newly diagnosed with cirrhosis in 2016-2022. Diagnosis was based on liver elastography, histology, or 2 of 4 criteria: cirrhosis on imaging, ascites, varices, or elevated international normalized ratio (INR). RESULTS: Over the study period, 342 new cirrhosis patients were identified, 223 (65%) males, median age 62 years. The crude overall incidence was 13.8 cases per 100,000 inhabitants annually. The most common etiologies were alcohol-related liver disease (ALD) (40%), metabolic dysfunction-associated steatotic liver disease (MASLD) (28%), and HCV with or without alcohol overconsumption (15%). The number of HCV cirrhosis cases was unusually high in 2016 (n = 23) due to intensified case-finding, but decreased significantly over the study period (p < 0.001) to n = 1 (2021) and n = 2 (2022). The overall 5-year survival was 55% (95% CI 48.9-62.3%). The most common causes of death were hepatocellular carcinoma (26%) and liver failure (25%). CONCLUSION: During the past two decades, the incidence of cirrhosis has increased extraordinarily in Iceland, associated with increased alcohol consumption, obesity, and HCV. ALD and MASLD now collectively make up two thirds of cases in Iceland. Following a nationwide elimination program, incidence of HCV cirrhosis has dropped rapidly in Iceland.

Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis.

We report a multi-ancestry genome-wide association study on liver cirrhosis and its associated endophenotypes, alanine aminotransferase (ALT) and γ-glutamyl transferase. Using data from 12 cohorts, including 18,265 cases with cirrhosis, 1,782,047 controls, up to 1 million individuals with liver function tests and a validation cohort of 21,689 cases and 617,729 controls, we identify and validate 14 risk associations for cirrhosis. Many variants are located near genes involved in hepatic lipid metabolism. One of these, PNPLA3 p.Ile148Met, interacts with alcohol intake, obesity and diabetes on the risk of cirrhosis and hepatocellular carcinoma (HCC). We develop a polygenic risk score that associates with the progression from cirrhosis to HCC. By focusing on prioritized genes from common variant analyses, we find that rare coding variants in GPAM associate with lower ALT, supporting GPAM as a potential target for therapeutic inhibition. In conclusion, this study provides insights into the genetic underpinnings of cirrhosis.

The Safe Use of Analgesics in Patients with Cirrhosis: A Narrative Review.

Pain is prevalent in patients with cirrhosis. Due to potential alterations in drug metabolism, risk for adverse effects, and complications from cirrhosis, physicians are often faced with difficult choices when choosing appropriate analgesics in these patients. Overall, acetaminophen remains the preferred analgesic. Despite its potential for intrinsic liver toxicity, acetaminophen is safe when used at 2 g/d. In contrast, non-selective nonsteroidals should be avoided due to their multiple side effects, including worsening renal function, blunting diuretic response, and increasing risk of portal hypertensive and peptic ulcer bleeding. Celecoxib can be administered for short term (≤5 days) in patients with Child's A and Child's B cirrhosis (50% dose reduction). Opioids carry the risk of precipitating hepatic encephalopathy and should generally be avoided, when possible. If clinical situation demands their use, opioid use should be limited to short-acting agents for short duration. Gabapentin and pregabalin are generally safe. Duloxetine should be avoided in hepatic impairment. Topical diclofenac and lidocaine seem to be safe in patients with cirrhosis.

Hepatocellular Jaundice due to Hydroxycut in Monozygotic Twins.

Liver injury associated with the use of a number of different of herbal and dietary supplements are increasingly recognized. It is though often unclear which of the sometimes multiple ingredients are responsible for the liver injury. Several case reports have been published on suspected liver injury due to Hydroxycut, which is a multi-ingredient supplement often used to induce weight loss. However, the hepatotoxic potential of Hydroxycut has though been disputed, and steatotic liver disease has also been implicated in patients who are found to have elevated liver enzymes while on Hydroxycut. We report clinically apparent liver injury with jaundice associated with the use of Hydroxycut in monozygotic twins with remarkably similar type of liver injury. Both had the genotype HLA-B 35:01 allele, a risk factor for green-tea extract induced liver injury, which is included in Hydroxycut.

The incidence and prevalence of proton pump inhibitor usage among internal medicine patients after hospital admission: A retrospective cohort study.

BACKGROUND: The use of proton pump inhibitors (PPIs) has increased over the past decades. One potential gateway into new PPI use is following a hospital admission. The study aimed to examine the incidence of new PPI usage following admission to internal medicine services and the ratio of new persistent users. METHODS: A retrospective descriptive study was conducted among all adults who had been admitted to internal medicine wards at the National University Hospital of Iceland from 2010-2020. Data was obtained from the Icelandic Internal Medicine Database. The proportion of patients who started treatment with PPI within 3 months of discharge (new users) and the proportion of patients who continued to use it after 3 months (persistent users) were examined. RESULTS: Among 85.942 admissions during the study period, 7238 (15.6%) became new users, and of those 4942 (68%) were new persistent users. The incidence of new PPI use was highest for patients discharged from gastroenterology (32.2%), hematology (31.8%), and oncology (29.2%). Patients with new PPI use more commonly had a history of malignancy (19.5%) and liver disease (22.7%) and more commonly were admitted to the ICU during their hospitalization. The highest ratio of persistent usage was among patients discharged from geriatric medicine (84%). CONCLUSION: One in every six patients admitted to internal medicine wards filled out a prescription for PPI within 3 months from discharge, and a large proportion of them became persistent users. The high rate of new PPI users from oncology and hematology is noteworthy and requires further research.

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.

Review of human risk factors for idiosyncratic drug-induced liver injury: latest advances and future goals.

INTRODUCTION: Idiosyncratic drug-induced liver injury (DILI) is a common cause of acute liver injury and can lead to death from acute liver failure or require liver transplantation. Although the total burden of liver injury is high, the frequency of DILI caused by specific agents is often low. As the liver injury is by per definition idiosyncratic, the prediction of which patients will develop liver injury from specific drugs is currently a very difficult challenge. AREAS COVERED: The current paper highlights the most important studies on prediction of DILI published in 2019-2023, including studies on genetic, metabolomic, and demographic risk factors, concomitant medication, and the role of comorbid liver diseases. Risk stratification using demographic, metabolomic, and multigenetic risk factors is discussed. EXPERT OPINION: Great advances have been made in identifying genetic risk factors for DILI. Combining these risk factors with demographic information and other biomarkers into multigenetic risk models might become highly useful in risk stratifying patients exposed to DILI. However, a more detailed mapping of genetic risk factors is needed. Results of these studies need to be validated in the selected ethnic groups before applicability and cost-effectiveness can be determined.

Study design for development of novel safety biomarkers of drug-induced liver injury by the translational safety biomarker pipeline (TransBioLine) consortium: a study protocol for a nested case-control study.

A lack of biomarkers that detect drug-induced liver injury (DILI) accurately continues to hinder early- and late-stage drug development and remains a challenge in clinical practice. The Innovative Medicines Initiative's TransBioLine consortium comprising academic and industry partners is developing a prospective repository of deeply phenotyped cases and controls with biological samples during liver injury progression to facilitate biomarker discovery, evaluation, validation and qualification.In a nested case-control design, patients who meet one of these criteria, alanine transaminase (ALT) ≥ 5 × the upper limit of normal (ULN), alkaline phosphatase ≥ 2 × ULN or ALT ≥ 3 ULN with total bilirubin > 2 × ULN, are enrolled. After completed clinical investigations, Roussel Uclaf Causality Assessment and expert panel review are used to adjudicate episodes as DILI or alternative liver diseases (acute non-DILI controls). Two blood samples are taken: at recruitment and follow-up. Sample size is as follows: 300 cases of DILI and 130 acute non-DILI controls. Additional cross-sectional cohorts (1 visit) are as follows: Healthy volunteers (n = 120), controls with chronic alcohol-related or non-alcoholic fatty liver disease (n = 100 each) and patients with psoriasis or rheumatoid arthritis (n = 100, 50 treated with methotrexate) are enrolled. Candidate biomarkers prioritised for evaluation include osteopontin, glutamate dehydrogenase, cytokeratin-18 (full length and caspase cleaved), macrophage-colony-stimulating factor 1 receptor and high mobility group protein B1 as well as bile acids, sphingolipids and microRNAs. The TransBioLine project is enabling biomarker discovery and validation that could improve detection, diagnostic accuracy and prognostication of DILI in premarketing clinical trials and for clinical healthcare application.

Herb-Induced Liver Injury by Ayurvedic Ashwagandha as Assessed for Causality by the Updated RUCAM: An Emerging Cause.

Herb-induced liver injury (HILI) caused by herbal supplements, natural products, and products used in traditional medicine are important for differential diagnoses in patients with acute liver injury without an obvious etiology. The root of Withania somnifera (L.) Dunal, commonly known as ashwagandha, has been used in Ayurvedic medicine for thousands of years to promote health and longevity. Due to various biological activities, ashwagandha and its extracts became widespread as herbal supplements on the global market. Although it is generally considered safe, there are several reported cases of ashwagandha-related liver injury, and one case ended with liver transplantation. In this paper, we review all reported cases so far. Additionally, we describe two new cases of ashwagandha hepatotoxicity. In the first case, a 36-year-old man used ashwagandha capsules (450 mg, three times daily) for 6 months before he developed nausea, pruritus, and dark-colored urine. In the second case, a 30-year-old woman developed pruritus after 45 days of using ashwagandha capsules (450 mg). In both cases, serum bilirubin and liver enzymes (aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP) were increased. The liver injury pattern was hepatocellular (R-value 11.1) and mixed (R-value 2.6), respectively. The updated Roussel Uclaf Causality Assessment Method (RUCAM) (both cases with a score of seven) indicated a "probable" relationship with ashwagandha. Clinical and liver function improvements were observed after the discontinuation of ashwagandha supplement use. By increasing the data related to ashwagandha-induced liver injury, these reports support that consuming ashwagandha supplements is not without its safety concerns.

[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.

Nomenclature, diagnosis and management of drug-induced autoimmune-like hepatitis (DI-ALH): An expert opinion meeting report.

Drug-induced liver injury (DILI) can mimic almost all other liver disorders. A phenotype increasingly ascribed to drugs is autoimmune-like hepatitis (ALH). This article summarises the major topics discussed at a joint International Conference held between the Drug-Induced Liver Injury consortium and the International Autoimmune Hepatitis Group. DI-ALH is a liver injury with laboratory and/or histological features that may be indistinguishable from those of autoimmune hepatitis (AIH). Previous studies have revealed that patients with DI-ALH and those with idiopathic AIH have very similar clinical, biochemical, immunological and histological features. Differentiating DI-ALH from AIH is important as patients with DI-ALH rarely require long-term immunosuppression and the condition often resolves spontaneously after withdrawal of the implicated drug, whereas patients with AIH mostly require long-term immunosuppression. Therefore, revision of the diagnosis on long-term follow-up may be necessary in some cases. More than 40 different drugs including nitrofurantoin, methyldopa, hydralazine, minocycline, infliximab, herbal and dietary supplements (such as Khat and Tinospora cordifolia) have been implicated in DI-ALH. Understanding of DI-ALH is limited by the lack of specific markers of the disease that could allow for a precise diagnosis, while there is similarly no single feature which is diagnostic of AIH. We propose a management algorithm for patients with liver injury and an autoimmune phenotype. There is an urgent need to prospectively evaluate patients with DI-ALH systematically to enable definitive characterisation of this condition.

Liver injury in patients with COVID-19 in comparison to patients with the pandemic influenza A (H1N1) 2009: a population-based study.

BACKGROUND: Elevated liver tests in patients with COVID-19 are widely reported. Population-based studies utilizing a validated analysis of drug-induced liver injury (DILI), with a control group of other viral illnesses and follow-up are largely lacking. MATERIALS AND METHODS: All hospitalized patients in Iceland with SARS-CoV-2 in 2020 and pandemic influenza A (H1N1) in 2009 were included in this retrospective, population-based study. Liver tests were compared between the two groups and the correlation to inflammatory markers and persistence of alanine aminotransferase (ALT) elevations were assessed. Potential DILI cases were reviewed using the Roussel Uclaf Causality Assessment Method (RUCAM). RESULTS: 225 SARS-CoV-2-positive and 73 influenza A (H1N1)-positive patients were included. Liver test values were similar between the groups, except for aspartate aminotransferase (AST) which was significantly lower in COVID-19, with a mean difference of 26 U/L (95%CI 4.2-47). Ferritin elevation was positively correlated with ALT, AST and alkaline phosphatase. No patient had persistently elevated ALT in COVID-19 and none had a probable DILI. Only 3 patients had a possible DILI according to the RUCAM. CONCLUSIONS: Elevated liver enzymes are not specific for COVID-19. Hyperferritinemia was associated with elevated liver tests. DILI was very rare in COVID-19 and an unlikely cause of elevated liver enzymes in COVID-19. Abnormal liver tests are nonpersistent and generally not clinically important in these patients.