Roadmap to DILI research in Europe. A proposal from COST action ProEuroDILINet.

In the current article the aims for a constructive way forward in Drug-Induced Liver Injury (DILI) are to highlight the most important priorities in research and clinical science, therefore supporting a more informed, focused, and better funded future for European DILI research. This Roadmap aims to identify key challenges, define a shared vision across all stakeholders for the opportunities to overcome these challenges and propose a high-quality research program to achieve progress on the prediction, prevention, diagnosis and management of this condition and impact on healthcare practice in the field of DILI. This will involve 1. Creation of a database encompassing optimised case report form for prospectively identified DILI cases with well-characterised controls with competing diagnoses, biological samples, and imaging data; 2. Establishing of preclinical models to improve the assessment and prediction of hepatotoxicity in humans to guide future drug safety testing; 3. Emphasis on implementation science and 4. Enhanced collaboration between drug-developers, clinicians and regulatory scientists. This proposed operational framework will advance DILI research and may bring together basic, applied, translational and clinical research in DILI.

Development of severe alcohol related liver disease over four decades in Iceland: impact of increased access and use of alcohol.

OBJECTIVE: Limited data exist on the association between per capita alcohol consumption and incidence of alcohol related liver disease (ARLD). The aims were to analyse this relationship and assess prevalence of ARLD in Iceland and among patients treated for alcohol use disorder (AUD) and its impact on outcomes. METHODS: A retrospective study on all patients diagnosed with severe ARLD: alcohol related cirrhosis (ARC) and alcohol related hepatitis (ARH) in Iceland 1984-2020. Medical records were scrutinized for clinical features, severity of ARLD, proportion undergoing treatment for AUD, data on abstinence and long-term outcomes. RESULTS: A total of 314 patients, males 76%, median age 56 years, fulfilled the predetermined criteria for ARLD. Median MELD was 17, 73% with Child-Pugh B/C and 70/314 (22%) who had ARH. Incidence of ARLD increased from 0.77 cases per 100 000 inhabitants annually 1984-2000 to 6.1 per 100 000 in 2016-2020. Per capita alcohol consumption increased from 4.3 Liters to 7.5 L in in the same time periods. Overall 220/314 (70%) with ARLD had undergone treatment for AUD. Of all individuals who had AUD treatment during the study period (n = 21.845), 1% were diagnosed with ARLD. Patients who underwent treatment for AUD after the ARLD diagnosis had better prognosis than those who had treatment prior to ARLD diagnosis (hazard ratio 2.5 [95% CI 1.3-5.0]). CONCLUSIONS: The incidence of ARLD increased 8-fold during the study period coinciding with 74% increase in per capita alcohol consumption. Patients with prior diagnosis of AUD had worse prognosis that needs special attention.

Incidence and outcomes in patients with acute cholangitis: a population-based study.

OBJECTIVE: The importance of early ERCP (endoscopic retrograde cholangiopancreatography) in patients with acute cholangitis (AC) is controversial. The aims were to compare outcomes in those who had early ERCP within 24 h from diagnosis and those who had ERCP undertaken later and examine the general prognosis of AC patients. METHODS: A prospective endoscopic database was used to identify all patients who underwent ERCP 2010-2021 at Landspitali University Hospital, diagnosed with cholangitis (k83.0) or calculus of bile duct with cholangitis (k80.3) according to ICD-10 diagnostic codes. Tokyo guidelines were used to verify the diagnosis and severity. Sepsis was analyzed by the Sepsis-3 criteria. RESULTS: A total of 240 patients met the inclusion criteria, 107 women (45%), median age 74 years, mostly due to gallstones (75%) and malignancy (19%), 61 (25%) underwent ERCP early. Overall 30-day mortality was 3.3% and was not significantly different between the early and late ERCP groups (4.9% vs 2.5% respectively). Patients who underwent early ERCP were more likely to have severe cholangitis according to the Tokyo guidelines criteria than those who underwent ERCP later (31% vs 18%, p = 0.047) but had a shorter median hospital stay (4 vs. 6 days, p = 0.006). Sepsis was more common among those who had ERCP early than those who had late ERCP (33% vs 19%, p = 0.033). CONCLUSIONS: The results indicate that for patients with AC the timing of ERCP is an important factor influencing the hospital stay, with shorter hospital stay for patients receiveing ERCP within 24 h, despite more severe cholangitis at diagnosis.

Incidence and prognosis of patients with small intestinal neuroendocrine tumors in a population based nationwide study.

BACKGROUND & AIMS: Small intestinal neuroendocrine tumours (SI-NETs) are the most frequent malignant tumours of the small intestine. Population based studies on SI-NETs are scarce. We aimed to examine the incidence, presentation of disease and prognosis of SI-NET and to determine patient prognosis in those undergoing emergency or elective surgery. METHODS: This was a retrospective population-based study. Information on all patients diagnosed with neuroendocrine tumours of the small intestine (excluding duodenum) from the beginning of the Icelandic Cancer Registry and the pathology departments in the country (1966-2017). Detailed phenotypic information was obtained from medical records on symptoms at diagnosis, treatment, recurrence and survival. RESULTS: A total of 113 patients with SI-NETs were identified, 3 patients were excluded due to lack of data and/or diagnostic error, leaving 110 patients for final analysis. The incidence of SI-NET was 0.78/100,000 and did not increase during the study period. A total of 42 % (n = 46) of patients were diagnosed incidentally. Long-term prognosis, after a landmark of 12 months, was better in patients who were diagnosed incidentally (HR 0.52; p = 0.03). Overall 89 % (n = 98) of cases underwent surgical resection of the primary tumor, 31 % (n = 30) patients acute or semi-acute surgery and 69 % (n = 68) elective surgery. Emergency surgery was associated with a 6-fold risk of death in the first 12 months after surgery (HR: 5.99; p = 0.01) and associated with more severe surgical complications. However, there was no difference in the long-term risk of death after the first 12 months (HR: 1.39; p = 0.27). CONCLUSIONS: The incidence of SI-NETs has not changed significantly in the last decades. Incidentally diagnosed SI-NET was associated with a favorable long-term prognosis. Emergency surgery in patients with SI-NET was associated with a significantly worse short-term risk of mortality compared to those who underwent elective surgery.

Dili is rare amongst patients without liver metastases receiving cancer treatment in Iceland: a population-based cohort study.

BACKGROUND: There is limited information on the frequency of idiosyncratic drug-liver injury (DILI) among cancer patients. The aim of the study was to evaluate the frequency of DILI due to cancer treatment in a population-based setting. MATERIAL AND METHODS: All patients diagnosed with genitourinary cancer, breast cancer or metastatic malignant melanoma in 2007-2018 were matched with a database containing laboratory results for all major hospitals in Iceland. Medical chart review was performed for cases with ALT/AST ≥5× upper limit of normal (ULN), ALP ≥2× ULN or bilirubin ≥2× ULN. Patients with liver-, and/or bone metastases and isolated elevations of ALP and patients with other etiologies of liver enzyme elevations were excluded. Cases with a RUCAM score of probable or highly probable were included. RESULTS: Among 4956 patients, 840 patients had liver enzyme elevations. Overall, nine (0.2%) cases of DILI were identified, seven women (78%), median age 59 years (IQR 52-66). Four patients had kidney cancer, four breast cancer and one metastatic prostate cancer. In eight cases, a single agent was implicated: Pazopanib (n = 3), axitinib, docetaxel, gemcitabine, letrozole and paclitaxel. In all cases, the treatment was interrupted or discontinued due to the liver injury. No patient developed jaundice or liver failure and no death was linked to DILI. Time to normalization of liver enzymes was 17 days (IQR 25-120). CONCLUSION: DILI was found to be rare and no cases of severe liver injury occurred. However, approximately 90% of patients switched to another treatment which might have affected prognosis.

Drug-induced liver injury: Pathogenesis, epidemiology, clinical features, and practical management.

Drug-induced liver injury (DILI) is an important but rare adverse event which can range from mild liver enzyme elevations to liver failure, transplantation or death. A large proportion of commonly used medications, in addition to herbal and dietary supplements, can cause liver injury. DILI has been categorized as direct or idiosyncratic but indirect liver injury has emerged as a third type of drug-induced liver injury. These types of liver injury may warrant different clinical approach and treatment. Associations of HLA genotypes and risk of DILI have highlighted the importance of the immune system in the pathogenesis of DILI. Furthermore, novel agents affecting the immune response can lead to liver injury, often associated with autoimmune features in serologic tests and liver biopsies. Overall, the diagnosis of DILI remains a challenge as it is requires detailed case evaluation in addition to reviewing the hepatotoxic potentials and clinical signatures of the implicated agents. Biochemical profiles vary between agents and although individual drugs tend to portray a consistent clinicopathologic signature, many drugs have multiple signatures. Thanks to multicenter prospective studies on DILI and websites in the public domain such as LiverTox, physicians are provided with tools to investigate suspected DILI cases to increase the likelihood of establishing adiagnosis. The pathogenesis of DILI, epidemiology and current challenges in the diagnosis and management of the disease are reviewed in the paper.

Incidence of diverticular bleeding: a population-based study.

OBJECTIVE: To determine the incidence of diverticular bleeding (DB) and examine the time trend of the incidence. Furthermore to study prognosis with regard to therapy and rebleeding. METHODS: A retrospective, population-based study of patients with DB in a National University Hospital from 2006 to 2016. Patients were identified in an electronically stored colonoscopy database. Definite diverticular bleeding was defined as active bleeding, a nonbleeding visible vessel or adherent clot. Presumptive diverticular bleeding was defined as acute painless rectal bleeding leading to hospitalization with visible diverticula but no evidence of bleeding and no other colonic lesions or bleeding sites identified on endoscopy. A 30-day re-bleeding was determined after discharge. RESULTS: A total of 3683 colonoscopy reports were reviewed, including 345 patients (males 51%) with presumptive 95% (n = 327) or definitive 5% (n = 18) diverticular bleeding. Overall 96% were treated conservatively, 3% endoscopically and 0.3% surgically. Only 5.8% of patients had a 30-day rebleed. After exclusion, 315 patients were included in the incidence calculations. The mean cumulative incidence of diverticular bleeding was 14/100,000 inhabitants per year. A time trend analysis of the incidence of DB revealed no significant change in incidence during the study period. CONCLUSIONS: The mean incidence of colonic diverticular bleeding was found to be approximately 14 cases per 100,000 inhabitants and year. The incidence does not seem to have changed in the past decade. The vast majority of patients with diverticular bleeding did not require endoscopic therapy and could be managed with conservative treatment.

Treatment as Prevention for Hepatitis C (TraP Hep C) - a nationwide elimination programme in Iceland using direct-acting antiviral agents.

A nationwide programme for the treatment of all patients infected with hepatitis C virus (HCV) was launched in Iceland in January 2016. By providing universal access to direct-acting antiviral agents to the entire patient population, the two key aims of the project were to (i) offer a cure to patients and thus reduce the long-term sequelae of chronic hepatitis C, and (ii) to reduce domestic incidence of HCV in the population by 80% prior to the WHO goal of HCV elimination by the year 2030. An important part of the programme is that vast majority of cases will be treated within 36 months from the launch of the project, during 2016-2018. Emphasis is placed on early case finding and treatment of patients at high risk for transmitting HCV, that is people who inject drugs (PWID), as well as patients with advanced liver disease. In addition to treatment scale-up, the project also entails intensification of harm reduction efforts, improved access to diagnostic tests, as well as educational campaigns to curtail spread, facilitate early detection and improve linkage to care. With these efforts, Iceland is anticipated to achieve the WHO hepatitis C elimination goals well before 2030. This article describes the background and organization of this project. Clinical trial number: NCT02647879.

Helicobacter pylori infection in Icelandic children.

OBJECTIVE: The prevalence of Helicobacter pylori (HP) infection is decreasing in the western world. The seroprevalence among 25-50-year-old Icelandic adults was recently shown to be 30-40%. Information on the seroprevalence in Nordic children is limited. We aimed at ascertaining the infection prevalence among healthy Icelandic children. METHODS: The infection status in stored frozen blood samples from two cross-sectional studies on the health of 7-9-year-old children (n = 125) and 16-18-year-old adolescents (n = 80) was determined by enzyme-linked immunosorbent assay (ELISA). Information on family demographics and GI symptoms was obtained by standardized questionnaires. RESULTS: Overall, 3.4% (7/205) of the children were infected with H. pylori. The prevalence was 2.6% (5/190), missing data n = 3, among children with both parents born in a low prevalence country compared to 17% (2/12) among those with at least one parent born in a high prevalence area (p = .026). When at least one parent was born in a high prevalence country, the odds ratio for being H. pylori seropositive was 2.2 (95% CI, 1.02-54.67), when adjusted for the educational status of the mother. There was no significant association between H. pylori infection and gastrointestinal symptoms. CONCLUSION: Prevalence of H. pylori infection in Iceland has become very low, suggesting a great reduction in transmission from older generations. There was an association between H. pylori infection and origin from high prevalence areas but not with gastrointestinal symptoms. The results mirror recent studies of children of Scandinavian ancestry.

The incidence and outcome of ischemic colitis in a population-based setting.

OBJECTIVE: Population-based studies on patients with ischemic colitis (IC) are limited. We aimed to determine the incidence, risk factors and outcome of patients with IC. METHODS: A retrospective nationwide study was conducted on adult patients with histologically confirmed IC in 2009-2013 in Iceland. IC patients were matched for age and gender with patients hospitalized with lower gastrointestinal bleeding. Data were collected on clinical presentation, comorbidities, smoking habits, management and outcome. RESULTS: Eighty-nine patients, 61 (69%) females and mean age of 65 years (±17), fulfilled the predetermined criteria. Females were older than males, 68 years (±14) vs. 59 years (±20) (p = .0170). The mean cumulative incidence was 7.3 cases per 100,000 inhabitants. A total of 57 (64%) patients presented with abdominal pain, hematochezia and diarrhea. IC was localized in the left colon in 78 (88%) patients. Overall, 62 (70%) patients had cardiovascular disease vs. 53 (60%) of control group (NS) and 55 (62%) had a history of smoking vs. 53 (60%) in control group (NS). Ten (11%) patients required surgery and/or died within 30-days from hospital admission. At the end of follow-up, 7 (9%) patients had experienced recurrence of IC with an estimated 3-year recurrence rate of 15%. CONCLUSIONS: IC is a common clinical phenomenon that affects a wide range of age groups, but is most prominent among elderly women. It typically presents with a clinical triad of abdominal pain, hematochezia and diarrhea. Most cases are mild and self-limiting with a good prognosis.

Use of statins in patients with liver disease.

Statins are generally well tolerated and shown to have a good safety profile. In clinical trials a similar proportion of patients randomized to statins and placebo treated developed abnormal liver tests. However, idiosyncratic drug-induced liver injury (DILI) is a rare adverse reaction and clinical trials are underpowered to detect uncommon side effects. Although probably very rare, idiosyncratic DILI due to statins has been reported among other drugs in all major prospective and retrospective series on DILI. A summary of 40 cases of statin hepatoxicity has been published and, a series of 76 cases suspected statin induced liver injury has recently been published. In the last mentioned series, three patients died and/or underwent liver transplantation and three cases had a rechallenge with the same statin which produced a similar pattern of liver injury. Statin therapy appears to be safe in the treatment of non-alcoholic fatty liver disease, in compensated patients with chronic hepatitis B or C. Statins have also been shown to have an inhibitory effect on hepatitis C virus replication in vitro. Retrospective data as well as data from a recent randomized controlled trial suggest that statin therapy might be a useful adjunct to standard combination antiviral therapy in patients with chronic hepatitis C. Statin therapy seems to be related to a reduced risk for hepatocellular carcinoma in patients with chronic liver disease, but randomized data are lacking.

Bleeding-related symptoms in colorectal cancer: a 4-year nationwide population-based study.

BACKGROUND: Little is known about the major presenting features of patients with colorectal cancer (CRC) in a population-based setting, especially regarding bleeding-related symptoms. AIM: To determine the proportion of CRC patients presenting with bleeding-related symptoms, to compare bleeders and nonbleeders and to explore the role of anticoagulants in bleeders. METHODS: This was a nationwide, population-based, retrospective study, investigating all patients diagnosed with CRC in Iceland from 2008 to 2011. Bleeding-related symptoms were defined as overt bleeding, iron deficiency anaemia or a positive faecal occult blood test. Obstructive symptoms were defined as a confirmed diagnosis of ileus or dilated intestines on imaging. RESULTS: Data were available for 472/496 (95%) patients, males 51%, mean age 69 (±13) years. In all, 348 (74%) patients had bleeding-related symptoms; of these 348 patients, 61% had overt bleeding. Bleeders were less likely than nonbleeders to have metastases at diagnosis, 19% vs. 34% (P < 0.001). Overt bleeders were less likely than nonbleeders to have obstructive symptoms, 2% vs. 16% respectively (P < 0.0001). Occult bleeders were more likely to have proximal cancer (69%) than both overt (17%) and nonbleeders (44%) (P < 0.0001); however, they were less likely than nonbleeders to have metastases (22% vs. 35%, P < 0.05). Bleeders were more likely to use warfarin than nonbleeders (9% vs. 3%, P < 0.05); the use of low-dose aspirin was the same (24%). CONCLUSIONS: The majority of patients with CRC present with bleeding-related symptoms. Bleeders with CRC present earlier than nonbleeders. Warfarin use may induce bleeding in some patients, resulting in an earlier diagnosis.

Risk factors for Clostridium difficile toxin-positive diarrhea: a population-based prospective case-control study.

Increased incidence and severity of Clostridium difficile infections (CDIs) is of major concern. However, by minimizing known risk factors, the incidence can be decreased. The aim of this investigation was to calculate the incidence and assess risk factors for CDI in our population. A 1-year prospective population-based nationwide study in Iceland of CDIs was carried out. For risk factor evaluation, each case was matched with two age- and sex-matched controls that tested negative for C. difficile toxin. A total of 128 CDIs were identified. The crude incidence was 54 cases annually per 100,000 population >18 years of age. Incidence increased exponentially with older age (319 per 100,000 population >86 years of age). Community-acquired origin was 27 %. Independent risk factors included: dicloxacillin (odds ratio [OR]: 7.55, 95 % confidence interval [CI]: 1.89-30.1), clindamycin (OR: 6.09, 95 % CI: 2.23-16.61), ceftriaxone (OR: 4.28, 95 % CI: 1.59-11.49), living in a retirement home (OR: 3.9, 95 % CI: 1.69-9.16), recent hospital stay (OR: 2.3, 95 % CI: 1.37-3.87). Proton pump inhibitors (PPIs) were used by 60/111 (54 %) versus 91/222 (41 %) (p = 0.026) and ciprofloxacin 19/111 (17 %) versus 19/222 (9 %) (p = 0.027) for cases and controls, respectively. In all, 75 % of primary CDIs treated with metronidazole recovered from one course of treatment. CDI was mostly found among elderly patients. The most commonly identified risk factors were broad-spectrum antibiotics and recent contact with health care institutions. PPI use was significantly more prevalent among CDI patients.

The predictors of complications in patients with drug-induced liver injury caused by antimicrobial agents.

BACKGROUND: Antimicrobials are the leading cause of idiosyncratic drug-induced liver injury in most series. AIM: To determine the incidence and the predictors of complications in patients with drug-induced liver injury caused by antimicrobial agents requiring hospitalization. METHODS: Medical records of patients with drug-induced liver injury caused by antimicrobial agents were identified by ICD-10, for the period between 2002 and 2006. Clinical information and blood tests during hospitalization were recorded. The causality assessment of drug-induced liver injury was determined by the Roussel UCLAF causality assessment method (RUCAM) scale. RESULTS: Of 47 594 in-patient admissions per year, the annual incidence of drug-induced liver injury was 0.03%. Male: female ratio was 7:3 with a median age of 47 years. Eighty reactions of drug-induced liver injury were caused by anti-tuberculosis drugs (85%) and by antibiotics (15%). The median (IQR) of RUCAM scale was 6 (5-8). A total of 36% had HIV infection and 9% of patients had diabetes mellitus. Median (IQR) duration of hospitalization was 9 (5-15) days. Serious complications and death were found in 27.5% and 26%, respectively. By a multivariable logistic analysis, the presence of jaundice was found to be significantly associated with an unfavourable outcome. CONCLUSION: Although rare, antimicrobial agents-related drug-induced liver injury requiring hospitalization has a high mortality rate. The presence of jaundice predicts poor outcome.

Predictors of subjective fatigue in chronic gastrointestinal disease.

BACKGROUND: Fatigue is a common, but poorly understood symptom in patients with chronic gastrointestinal (GI) diseases. AIM: To evaluate factors of importance for fatigue in patients with chronic GI diseases, and to compare it with fatigue in the general population. METHODS: In all, 399 patients attending a GI out-patient clinic completed questionnaires assessing fatigue, sleep disturbances, psychological general well-being and GI symptom severity. The patients were divided into two diagnostic groups: functional GI disorders (n = 112) and organic GI diseases (n = 287). The severity of fatigue was also evaluated in an age- and gender-matched group of 399 individuals from the general population. RESULTS: Both patient groups had more severe fatigue than controls and patients with functional GI disorders were more fatigued than patients with an organic GI disease. Fatigue was associated with psychological general well-being, GI symptom severity, gender, employment status and sleep disturbances. In a linear regression analysis, psychological general well-being (vitality, general health, self-control), sleep disturbances and employment status were independently associated with the severity of fatigue (adjusted R(2) = 55%). CONCLUSIONS: Fatigue is a troublesome symptom in a subgroup of patients with chronic GI diseases. These patients have a high symptom burden as regards both GI and psychological symptoms, as well as sleep disturbances.

Nutrient-dependent enhancement of rectal sensitivity in irritable bowel syndrome (IBS).

Food-related gastrointestinal symptoms are common in irritable bowel syndrome (IBS), but the mechanisms behind this are unclear. Enhanced colorectal sensitivity after duodenal lipid administration in IBS patients has been demonstrated. However, the effects of a regular meal on colorectal sensitivity in these patients and the importance of the composition of the meal are not known. On two separate days, 10 IBS patients and 11 controls randomly received a liquid meal (800 kcal), containing 60% calories from fat (fatty meal) or carbohydrate (carbohydrate meal). Using a barostat rectal sensitivity was assessed during four separate distension sequences before, immediately after and 30 and 60 min after the meal. In the patients, the discomfort (P = 0.04) and the pain thresholds (P = 0.007) were gradually reduced after the fatty meal, whereas only a tendency in the same direction was seen after the carbohydrate meal. In patients VAS ratings for pain increased after the fatty meal (P = 0.03), but not after carbohydrates. In the controls, sensory thresholds were not affected by the meals. In IBS, a liquid meal enhances rectal sensitivity, and this seems to be partly nutrient dependent as a fatty meal has more pronounced effects than a carbohydrate meal. This might be of relevance for their postprandial symptoms.

Effects of long-term treatment with oxytocin in chronic constipation; a double blind, placebo-controlled pilot trial.

BACKGROUND: Oxytocin and its receptor have been found throughout the gastrointestinal (GI) tract, where it affects gut function. Clinically, we have noticed an improvement of bowel habits during lactation in constipated women. The aim of this study was to examine whether oxytocin has an effect on bowel symptoms and psychological well being in women with refractory constipation. METHODS: Fifty-nine women with refractory constipation were included in a double blind, multicentre study. After a 2-week run-in period, they were randomly allocated to nasal inhalation of either placebo or oxytocin treatment twice daily for 13 weeks, followed by a 2 weeks, posttreatment period. The patients completed a questionnaire every day concerning bowel habits, abdominal pain and discomfort, and Gastrointestinal Symptoms Rating Scale (GSRS) and Psychological General Well-being (PGWB) twice during the study; namely, during the baseline period and at the end of the treatment period. RESULTS: Both oxytocin and placebo led to improvement of the constipation according to the GSRS and led to improvement in the sensation of incomplete evacuation and anorectal obstruction, without significant differences between the groups. Abdominal pain and discomfort responded weakly to oxytocin, with no effect of the placebo. In a subgroup of patients with IBS and concomitant depression, a weak improvement in depressed mood was observed after oxytocin administartion. CONCLUSION: Nasal administration of oxytocin had no significant advantage over placebo concerning an effect on constipation. However, it seems to have a positive effect on abdominal pain and discomfort and depressed mood. These findings should be further explored.

High interdigestive and postprandial motilin levels in patients with the irritable bowel syndrome.

Motilin shows cyclic variation with the different phases of the migrating motor complex (MMC). Altered motilin levels have been found in irritable bowel syndrome (IBS) patients, but in these studies motilin levels were analysed without the knowledge of the phases of MMC. We included 13 healthy controls (HC) and 24 patients with IBS [12 diarrhoea-predominant (IBS-D) and 12 constipation-predominant (IBS-C)]. We performed interdigestive and postprandial antroduodenojejunal manometry and blood samples for analysis of motilin were drawn. Group differences in plasma levels of motilin were analysed during mid-phase II, just before the start of phase III (pre-III), during phase I, immediately before the meal and 30 and 60 min after the 500 kcal mixed meal. Higher motilin levels were observed in IBS vs HC in both the interdigestive and postprandial periods (P < 0.05). No significant differences between IBS-C and IBS-D were observed. The cyclic variation of motilin during MMC and the meal response was similar in IBS and controls. IBS patients, irrespective of the predominant bowel habit, demonstrate higher motilin levels than HCs in all phases of the MMC and also after a meal. These findings may bear some pathophysiological importance in IBS and relate to the gastrointestinal dysmotility often seen in these patients.

Altered visceral perceptual and neuroendocrine response in patients with irritable bowel syndrome during mental stress.

BACKGROUND AND AIMS: Stress often worsens the symptoms of irritable bowel syndrome (IBS). We hypothesised that this might be explained by altered neuroendocrine and visceral sensory responses to stress in IBS patients. SUBJECTS AND METHODS: Eighteen IBS patients and 22 control subjects were assessed using rectal balloon distensions before, during, and after mental stress. Ten controls and nine patients were studied in supplementary sessions. Rectal sensitivity (thresholds and intensity-visual analogue scale (VAS)) and perceived stress and arousal (VAS) were determined. Plasma levels of corticotropin releasing factor (CRF), adrenocorticotropic hormone (ACTH), cortisol, noradrenaline, and adrenaline were analysed at baseline, immediately after stress, and after the last distension. Heart rate was recorded continuously. RESULTS: Thresholds were increased during stress in control subjects (p<0.01) but not in IBS patients. Both groups showed lower thresholds after stress (p<0.05). Repeated distensions without stress did not affect thresholds. Both groups showed increased heart rate (p<0.001) and VAS ratings for stress and arousal (p<0.05) during stress. Patients demonstrated higher ratings for stress but lower for arousal than controls. Basal CRF levels were lower in patients (p<0.05) and increased significantly during stress in patients (p<0.01) but not in controls. Patients also responded with higher levels of ACTH during stress (p<0.05) and had higher basal levels of noradrenaline than controls (p<0.01). Controls, but not patients, showed increased levels of adrenaline and noradrenaline in response to stress (p<0.05). CONCLUSIONS: Stress induced exaggeration of the neuroendocrine response and visceral perceptual alterations during and after stress may explain some of the stress related gastrointestinal symptoms in IBS.

Delay in gastric emptying in patients with chronic renal failure.

BACKGROUND: Gastrointestinal (GI) symptoms are common in patients with chronic renal failure (CRF). Delayed gastric emptying might be a possible pathophysiological mechanism. The aims of this study were to evaluate gastric emptying in patients with CRF and to correlate the findings with GI symptoms and evaluate the impact of Helicobacter pylori infection in CRF patients on gastric emptying. METHODS: Thirty-nine patients with CRF (17 F, 22 M) were compared with 131 healthy subjects (74 F, 57 M). A standardized breakfast was given with 20 spherical, radiopaque markers (ROMs). The emptying was followed by fluoroscopy after 4, 5 and 6 h. Gastric emptying was assessed by calculating the individual mean percentual gastric retention of markers, 4 to 6 h after the meal. The perceived severity of GI symptoms was assessed with a validated questionnaire. Because of gender differences in gastric emptying, men and women were compared separately and a percentile of 95 was chosen as the upper reference value. H. pylori infection was assessed using a serological method. RESULTS: Delayed gastric emptying was found in 14 out of 39 (36%) of the CRF patients. There was no relationship between delayed gastric emptying and age, GI symptoms, H. pylori infection or underlying renal disease. However, a higher proportion of patients in peritoneal dialysis demonstrated delayed gastric emptying compared with predialytic patients (6 of 9 versus 2 of 13, P = 0.026). Men with CRF had a higher gastric retention compared with healthy men (16.6 (0-63.3)% versus 0 (0-2.1)%, P < 0.0001), and 10 men with CRF had delayed gastric emptying (P < 0.0001). There was no significant difference in mean gastric retention between women with CRF and healthy women (13.3 (0-55.4)% versus 10.8 (0-30.0)%, P = 0.93), but 4 women with CRF had delayed gastric emptying (P = 0.02). Eighteen of the CRF patients had GI symptoms (6 F, 12 M) and 21 were asymptomatic (11 F, 10 M). There was no difference in mean gastric retention in patients with CRF with and without GI symptoms (M: 13.3 (0-55.0)% versus 47.5 (5.0-65.0)%, P = 0.51, F: 16.6 (0-63.3)% versus 13.3 (0-59.2)%, P = 0.96). Gastric emptying in CRF patients with and without H. pylori infection showed no difference. CONCLUSIONS: Delayed gastric emptying is common in patients with chronic renal failure, particularly in men. The delay was not associated with the presence of GI symptoms, underlying renal disease or H. pylori infection. However, the dialytic status might have an impact on gastric emptying in patients with CRF.