A low FODMAP diet plus traditional dietary advice versus a low-carbohydrate diet versus pharmacological treatment in irritable bowel syndrome (CARBIS): a single-centre, single-blind, randomised controlled trial.

BACKGROUND: Dietary advice and medical treatments are recommended to patients with irritable bowel syndrome (IBS). Studies have not yet compared the efficacy of dietary treatment with pharmacological treatment targeting the predominant IBS symptom. We therefore aimed to compare the effects of two restrictive dietary treatment options versus optimised medical treatment in people with IBS. METHODS: This single-centre, single-blind, randomised controlled trial was conducted in a specialised outpatient clinic at the Sahlgrenska University Hospital, Gothenburg, Sweden. Participants (aged ≥18 years) with moderate-to-severe IBS (Rome IV; IBS Severity Scoring System [IBS-SSS] ≥175) and no other serious diseases or food allergies were randomly assigned (1:1:1) by web-based randomisation to receive a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) plus traditional IBS dietary advice recommended by the UK National Institute for Health and Care Excellence (hereafter the LFTD diet), a fibre-optimised diet low in total carbohydrates and high in protein and fat (hereafter the low-carbohydrate diet), or optimised medical treatment based on predominant IBS symptom. Participants were masked to the names of the diets, but the pharmacological treatment was open-label. The intervention lasted 4 weeks, after which time participants in the dietary interventions were unmasked to their diets and encouraged to continue during 6 months' follow-up, participants in the LFTD group were instructed on how to reintroduce FODMAPs, and participants receiving pharmacological treatment were offered diet counselling and to continue with their medication. The primary endpoint was the proportion of participants who responded to the 4-week intervention, defined as a reduction of 50 or more in IBS-SSS relative to baseline, and was analysed per modified intention-to-treat (ie, all participants who started the intervention). Safety was analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02970591, and is complete. FINDINGS: Between Jan 24, 2017, and Sept 2, 2021, 1104 participants were assessed for eligibility and 304 were randomly assigned. Ten participants did not receive their intervention after randomisation and thus 294 participants were included in the modified intention-to-treat population (96 assigned to the LFTD diet, 97 to the low-carbohydrate diet, and 101 to optimised medical treatment). 241 (82%) of 294 participants were women and 53 (18%) were men and the mean age was 38 (SD 13). After 4 weeks, 73 (76%) of 96 participants in the LFTD diet group, 69 (71%) of 97 participants in the low-carbohydrate diet group, and 59 (58%) of 101 participants in the optimised medical treatment group had a reduction of 50 or more in IBS-SSS compared with baseline, with a significant difference between the groups (p=0·023). 91 (95%) of 96 participants completed 4 weeks in the LFTD group, 92 (95%) of 97 completed 4 weeks in the low-carbohydrate group, and 91 (90%) of 101 completed 4 weeks in the optimised medical treatment group. Two individuals in each of the intervention groups stated that adverse events were the reason for discontinuing the 4-week intervention. Five (5%) of 91 participants in the optimised medical treatment group stopped treatment prematurely due to side-effects. No serious adverse events or treatment-related deaths occurred. INTERPRETATION: Two 4-week dietary interventions and optimised medical treatment reduced the severity of IBS symptoms, with a larger effect size in the diet groups. Dietary interventions might be considered as an initial treatment for patients with IBS. Research is needed to enable personalised treatment strategies. FUNDING: The Healthcare Board Region Västra Götaland, the Swedish Research Council, the Swedish Research Council for Health, Working Life and Welfare, AFA Insurance, grants from the Swedish state, the Wilhelm and Martina Lundgren Science Foundation, Skandia, the Dietary Science Foundation, and the Nanna Swartz Foundation.

Development of celiac-safe foods: prevention of transglutaminase 2 (TG2) deamidation of gluten in healthy non-celiac volunteers.

In celiac disease, intestinal transglutaminase (TG2) produces immunogenic peptides by deamidation of gluten proteins. These products drive the celiac immune response. We have previously identified an interaction between gliadin and a food additive, E304i, which prevents gliadin processing (both deamidation and transamidation) by TG2, in vitro. In this study, we investigated if E304i could prevent TG2 processing of gluten in flours and if the effect was evident after simulated gastrointestinal digestion. We also confirmed the outcome in vivo in a human cross-over intervention study in healthy non-celiac participants. TG2 transamidation experiments (in vitro) of digested wheat and rye flours supplemented with E304i at 30 mg/g indicated full prevention of TG2 processing. In the intervention study, participant serum levels of deamidated gliadin peptides (dGDPs) increased after the intake of reference wheat rolls (80 g per day for a week; 41% ± 4% compared to washout), while the intake of the intervention E304i/zinc sulfate wheat rolls generated a modest response (80 g per day for a week; 8 ± 10% of control). The difference between the groups (32.8 ± 15.6%) was significant (p = 0.00003, n = 9), confirming that E304i /zinc addition to wheat rolls prevented TG2 deamidation of gluten. In conclusion, this study shows that E304i /zinc addition to wheat rolls prevents TG2 deamidation of gluten in non-celiac participants. Clinical trial registration: clinicaltrials.gov, identifier (NCT06005376).

Natural history of symptoms and prognostic information of the rapid drink challenge and solid bolus swallows in esophagogastric junction outflow obstruction defined by manometry.

BACKGROUND/INTRODUCTION: Esophagogastric junction outflow obstruction (EGJOO) is a condition characterized by poor relaxation of the lower esophageal sphincter (LES), which can manifest as dysphagia and chest pain. The best treatment of EGJOO is unknown as some patients improve without any specific therapy, whereas some patients undergo invasive therapy. Currently, prognostic factors are lacking. We aimed to assess the long-term prognosis and predictors of dysphagia and chest pain by the rapid drink challenge and solid bolus swallows in EGJOO. METHODS: We retrospectively assessed high-resolution esophageal manometries (HRM) performed at our center between 2015 and 2018. The patients completed a dysphagia and chest pain questionnaire a median of 34 months after the HRM/baseline assessment, including the Impaction dysphagia questionnaire-10 (IDQ-10) complemented with questions regarding chest pain and esophageal treatments. Symptoms were compared with HRM findings. RESULTS: In all, 980 HRMs were analyzed and 66 (6.5%) were identified as having HRM findings compatible with EGJOO. Of these, 27 patients with EGJOO (41%) completed the follow-up questionnaires and had no exclusion criteria, and 70% of these patients had dysphagia and 44% chest pain at least once a week. Dysphagia at follow-up was more common in patients with elevated integrated relaxation pressure (IRP) on all three HRM metrics (water swallows, solid bolus swallows, and rapid drink challenge) (p = 0.03, odds ratio: 8.4 (95% CI: 1.2-56.0)), but this was not seen for chest pain (p = 0.45). Abnormal motility patterns on rapid drink challenge or solid bolus swallows were not associated with dysphagia or chest pain at follow-up. CONCLUSIONS: Having a high IRP on three HRM metrics-water swallows, solid bolus swallows, and rapid drink challenge-is associated with a worse prognosis in patients with EGJOO and could potentially be used to select candidates suitable for invasive procedures.

The influence of muscle performance and fatigue on prognosis in patients with compensated liver disease.

BACKGROUND: Poor muscle function is associated with a negative prognosis in advanced liver disease but the impact in compensated chronic liver disease is unknown. Similar prognostic uncertainty applies to fatigue. We aimed to assess the prognostic value of muscle performance and fatigue in a cohort of patients with compensated chronic liver disease. METHODS: We followed 241 patients with compensated chronic liver disease included in a study between 2010 and 2014. Subjects were 52 ± 15 years (mean ± SD; 134 females). All subjects performed four muscle function tests: "Timed Up and Go" test, walking speed, handgrip strength, and standing heel-rises. Fatigue was evaluated by fatigue impact scale. Follow up data was acquired through hospital records and registries. RESULTS: During follow up of 6.75 ± 1.4 years, 13 patients died (5.5%) and 11 (4.5%) patients underwent liver transplantation. A timed up and go over 10 s was not significantly associated with a lower survival (Kaplan-Meier, log rank test p = 0.132), or with transplant free survival (p = 0.543), Fig. 3. It was also not specifically associated with liver related causes of death (p = 0.597). The other physical functioning tests and fatigue were not significantly associated with mortality or transplant-free survival (p > 0.05 for all) except for maximal walking speed (2.2 vs. 1.9 m/s, p = 0.007). CONCLUSIONS: Our study suggests that muscle function and fatigue are not key prognostic factors in compensated chronic liver disease. However, further confirmation in future studies is needed.

Prevalence and impact of disorders of Gut-Brain interaction in Sweden.

BACKGROUND: Previous epidemiologic studies in Sweden have only covered some of the disorders of gut-brain interaction (DGBI) and are not representative of the general population. This study aimed to define the prevalence and impact of DGBI in Sweden. METHODS: We used Swedish data from the Rome Foundation Global Epidemiology Study which include information on DGBI diagnoses, psychological distress, quality of life (QoL), healthcare utilization, and the impact of stress on GI symptoms. KEY RESULTS: The prevalence of having any DGBI was 39.1% (95% CI 37.0-41.2); esophageal disorders 6.1% (5.1-7.3), gastroduodenal disorders 10.7% (9.3-12.0), bowel disorders 31.6% (29.6-33.6), and anorectal disorders 6.0% (5.1-7.2). Subjects with a DGBI more commonly reported anxiety and/or depression, reduced mental and physical QoL, and more frequent doctor visits due to health problems. Subjects with a DGBI reported bothersome gastrointestinal (GI) symptoms to a greater extent and more than 1/3 had visited a doctor due to GI problems and of those 1/3 had seen multiple doctors. Prescription medications were available among 36.4% (31.0-42.0) who had bothersome GI symptoms and a DGBI, with sufficient symptom relief in 73.2% (64.0-81.1). Psychological factors and eating were reported to worsen GI symptoms and stress during the last month was greater in subjects with a DGBI. CONCLUSIONS AND INFERENCES: DGBI prevalence and its impact in Sweden is in line with global data, including increased healthcare utilization. GI symptoms are commonly affected by psychological factors and eating, and a high proportion of those on prescription medication report sufficient GI symptom relief.

Type of Rectal Barostat Protocol Affects Classification of Hypersensitivity and Prediction of Symptom Severity in Irritable Bowel Syndrome.

Background/Aims: Visceral hypersensitivity is an important pathophysiologic mechanism in irritable bowel syndrome (IBS). We compared 2 barostat distension protocols and their ability to distinguish between IBS patients and healthy controls, identify subjects with rectal hypersensitivity, and their associations with gastrointestinal symptom severity. Methods: We retrospectively reviewed all patients at our unit that had undergone barostat investigations 2002-2014. Protocol 1 (n = 369) used phasic isobaric distensions with stepwise increments in pressure and protocol 2 (n = 153) used pressure controlled ramp inflations. Both protocols terminated when subjects reported pain or maximum pressure was reached. Thresholds for first sensation, urgency, discomfort and pain were established. Age- and gender-matched controls were used for comparison. The gastrointestinal symptom rating scale-IBS, and the hospital anxiety and depression scale were used for symptom reports. Results: A significantly higher proportion of patients was classified as having hypersensitivity in protocol 1 vs protocol 2 for all thresholds (P < 0.001). Patients with visceral hypersensitivity, defined based on rectal pain thresholds in protocol 1 had more severe gastrointestinal symptoms overall as well as anxiety, whereas these associations were weaker or in most cases absent when visceral hypersensitivity was defined based on rectal pain thresholds in protocol 2. Conclusion: Our study indicates that a rectal barostat protocol using phasic isobaric distensions with stepwise pressure increments is more sensitive in IBS patients with respect to identifying subjects with rectal hypersensitivity and a link with IBS symptoms.

Global Prevalence and Impact of Rumination Syndrome.

BACKGROUND & AIMS: Rumination syndrome is a Disorder of Gut-Brain Interaction (DGBI) of unknown etiology. We aimed to assess its global prevalence and potential associations with other medical conditions. METHODS: Data were collected via the Internet in 26 countries. Subjects were evenly distributed by country, sex, and age groups and were invited for a "health survey" using the Rome IV diagnostic questionnaire and a supplementary questionnaire addressing factors potentially associated with DGBI. RESULTS: In all, 54,127 subjects completed the survey (51% male; mean age, 44.3 years). The overall prevalence of rumination syndrome was 3.1% (95% confidence interval [CI], 3.0-3.3%). It was highest in Brazil (5.5% CI, 4.5-6.5) and lowest in Singapore (1.7% CI, 1.1-2.2). The mean age of people with rumination syndrome was 44.5 years (standard deviation, 15.6) and it was more common in females (54.5% vs 45.5%). Factors independently associated with rumination syndrome were depression (odds ratio [OR], 1.46), anxiety (OR, 1.8), body mass index (OR, 1.04), and female sex (OR, 1.19). Subjects with multiple DGBI were at increased risk of having rumination syndrome, with the highest risk in subjects with 4 gastrointestinal regions with DGBI (OR, 15.9 compared with none). Quality of life (QoL) was lower in subjects with rumination syndrome compared with the rest of the cohort (PROMIS-10 score: physical QoL mean 12.9 vs 14.5; mental QoL mean 12.0 vs 13.6). CONCLUSIONS: The prevalence of rumination syndrome is higher than reported in most previous population studies and is likely underdiagnosed in clinical practice. Awareness of rumination syndrome should be raised among clinicians to improve care for these patients.

Muscle performance and fatigue in compensated chronic liver disease.

Background: A common and debilitating symptom in patients with chronic liver disease is fatigue (CLD). Muscle dysfunction has been suggested to be a key mechanism of fatigue in CLD. Objective: We aimed to evaluate fatigue and the potential association with muscle performance and physical activity in outpatients with CLD. Methods: Two-hundred seventy outpatients with CLD were included, (52 ± 15 years, mean ± SD; 151 females) with autoimmune hepatitis (n = 49), primary biliary cholangitis (n = 45), primary sclerosing cholangitis (n = 46), chronic hepatitis B (n = 57) or C (n = 73). Patients with a Child-Pugh >6 were excluded. The questionnaire Fatigue Impact Scale (FIS) was used to evaluate fatigue, and physical activity was evaluated through a self-reported level of physical activity. Muscle function was assessed with four muscle tests, walking speed, handgrip strength, standing heel-rise test (SHT) and 'Timed Up and Go' test (TUG). Results: The median total FIS score was 30 (40% had FIS > 40, considered high-fatigue). Diminished muscle performance was observed in the SHT (% of predicted value: 53 ± 26%) and with maximum grip strength (85 ± 20%). The FIS score was significantly different between groups of CLDs (p = .004). In multivariate analysis the TUG (p = .001), SHT (p = .005), antidepressants (p < .001), and level of physical activity (p = .001) were associated with fatigue (R2 = 29%). Subjects with higher levels of physical activity had lower FIS (p < .001). Conclusions: In patients with CLD, fatigue was associated with low muscle performance and reduced level of physical activity, which could be a potential therapeutic target.

Visceral sensitivity remains stable over time in patients with irritable bowel syndrome, but with individual fluctuations.

BACKGROUND: Visceral hypersensitivity in irritable bowel syndrome (IBS), measured with rectal balloon distensions, using a barostat, has been suggested to be a phenomenon that is reduced due to habituation at repeated investigations. We investigated the stability of rectal sensitivity in patients with IBS who had undergone a previous rectal barostat study and assessed variations in symptom pattern and severity in relation to rectal sensory function. METHOD: Irritable bowel syndrome patients, who had previously been undergone a rectal barostat study, were included. All patients underwent a second study 8-12 years later. Symptoms were characterized by use of questionnaires. KEY RESULTS: We included 26 subjects (17 females, median age at the index investigation 44.5 (21-61) years). Pressure and volume sensory thresholds were unchanged at the follow-up compared with the index investigation (P > 0.05 for all). At the index investigation, 8/26 patients had rectal hypersensitivity of which four were reclassified as normosensitive, and sixfrom normo- to hypersensitive, meaning that 10/26 patients were hypersensitive at the follow-up investigation. IBS-QOL had improved significantly in six of nine domains at follow-up (P < 0.05 for all). There were no differences in anxiety, depression, IBS symptom severity, or somatization (P > 0.05) at follow-up. None of these were associated with change in rectal sensitivity at follow-up. CONCLUSIONS AND INFERENCES: Rectal hypersensitivity and IBS symptoms remained stable at the group level over 8-12 years in IBS patients, even though individual fluctuations were noted. Our findings contradict previous findings indicating that visceral hypersensitivity is an unstable trait.

Oesophageal symptoms are common and associated with other functional gastrointestinal disorders (FGIDs) in an English-speaking Western population.

BACKGROUND: The prevalence and frequency of oesophageal symptoms suggestive of a functional oesophageal disorder according to the Rome IV criteria are unknown. OBJECTIVE: We aimed to describe the prevalence and risk factors for oesophageal symptoms compatible with functional oesophageal disorders in the general population. METHODS: Data were analysed from a population-based online survey of 6300 individuals aged ≥ 18 years in the USA, UK and Canada with equal demographic proportions across countries. Questions included the Rome IV diagnostic questionnaire, demographics, medication, somatization, quality of life, and organic gastrointestinal (GI) disease. Multivariate analysis was used to identify factors independently related to oesophageal symptoms. RESULTS: Data from 5177 participants (47.8% female; mean age 46.7 years) were available for analysis. Symptom prevalence was 8.1% for globus, 6.5% for heartburn, 4.5% for dysphagia and 5.2% for chest pain, and 17.0% reported at least one oesophageal symptom. Oesophageal symptoms were independently associated with younger age, female gender, previous abdominal surgery and the presence of other functional GI disorders. Reporting oesophageal symptoms was associated with reduced quality of life. CONCLUSION: Oesophageal symptoms are common in the general population and important predictors include other functional GI disorders, age and gender. Oesophageal symptoms are associated with poorer quality of life.

Impact of cardiac dysfunction on health-related quality of life in cirrhotic liver transplant candidates.

OBJECTIVE: Cardiac dysfunction, in particular left ventricular diastolic dysfunction, is common in cirrhosis. We aimed to investigate the impact of cardiac dysfunction on health-related quality of life (QoL) in liver cirrhosis. MATERIALS AND METHODS: A total of 88 cirrhotic liver transplant candidates with an available echocardiogram and ECG completed the Short form-36 (SF-36) and Fatigue Impact Scale. In a subgroup of 61 patients, levels of cardiac biomarkers, in particular serum N-terminal pro-brain natriuretic peptide, adiponectin, and high-sensitive troponin T, were also measured. RESULTS: Although left ventricular systolic diameter was related to a lower SF-36 physical component summary, neither left ventricular diastolic dysfunction nor any other echocardiographic feature was found to be associated with any other SF-36 or Fatigue Impact Scale domain (P>0.05 for all). On linear regression analysis after adjustment for confounders, a prolonged QTc interval was found to be related to a lower SF-36 mental component summary score (ß=-9.7, P=0.009) and increased physical fatigue (ß=10.5, P=0.004). Neither serum N-terminal pro-brain natriuretic peptide, high-sensitivity troponin T, nor adiponectin levels were found to be related to QoL (P>0.05 for all). Serum adiponectin levels did not differ among patients with versus those without echocardiographic cardiac alterations (P>0.05 for all). CONCLUSION: A prolonged QTc interval, but not any echocardiographic abnormalities or cardiac biomarkers, seems to be predictive of QoL in cirrhosis.

Prevalence of pre-transplant electrocardiographic abnormalities and post-transplant cardiac events in patients with liver cirrhosis.

BACKGROUND: Although cardiovascular disease is thouht to be common in cirrhosis, there are no systematic investigations on the prevalence of electrocardiographic (ECG) abnormalities in these patients and data on the occurrence of post-transplant cardiac events in comparison with the general population are lacking. We aimed to study the prevalence and predictors of ECG abnormalities in patients with cirrhosis undergoing liver transplantation and to define the risk of cardiac events post-transplant compared to the general population. METHODS: Cirrhotic patients undergoing first-time liver transplantation between 1999-2007 were retrospectively enrolled. ECGs at pre-transplant evaluation were reviewed using the Minnesota classification and compared to healthy controls. Standardized incidence ratios for post-transplant cardiac events were calculated. RESULTS: 234 patients with cirrhosis were included, 186 with an available ECG (36% with alcoholic and 24% with viral cirrhosis; mean follow-up 4 years). Cirrhotics had a prolonged QTc interval, a Q wave, abnormal QRS axis deviation, ST segment depression and a pathologic T wave more frequently compared to controls (p < 0.05 for all). Arterial hypertension, older age, cirrhosis severity and etiology were related to ECG abnormalities. Compared to the general Swedish population, patients were 14 times more likely to suffer a cardiac event post-transplant (p < 0.001). A prolonged QTc interval and Q wave were related to post-transplant cardiac events (p < 0.05 for all). CONCLUSIONS: Pre-transplant ECG abnormalities are common in cirrhosis and are associated with cardiovascular risk factors and cirrhosis severity and etiology. Post-transplant cardiac events are more common than in the general population.

Pre-transplant renal impairment predicts posttransplant cardiac events in patients with liver cirrhosis.

BACKGROUND: Cardiovascular disease and renal impairment are common in cirrhotic transplant candidates. We aimed to investigate potential association between pretransplant renal function impairment and cardiac events after liver transplantation. METHODS: Adult cirrhotic patients undergoing first-time liver transplantation between 1999 and 2007 in a single institution with available glomerular filtration rate (GFR), assessed by Cr-EDTA clearance at pre-transplant evaluation, were retrospectively enrolled (n=202). Impaired renal function was defined as GFR less than 60 mL/min/1.73 sqm. Pretransplant QT-time corrected by heart rate (QTc) and left-ventricular dysfunction was also registered. Mortality and cardiac events were analyzed, until death or last follow-up (end 2009). RESULTS: Renal impairment was present in 24% (48/202). Cardiac events occurred in 28% (56/202) after transplantation, mean follow-up time of 3.8 years (2.2). Events were more common in patients with renal impairment compared with those without (48% versus 21%, P<0.001). In Cox regression analysis, pretransplant renal impairment was found to be an independent predictor of posttransplant cardiac events (HR 2.19, 95% CI 1.25-3.85) and reduced cardiac event-free survival (HR 2.27, 95% CI 1.31-3.94). Prolonged QTc interval was an independent predictor of posttransplant cardiac events in the subgroup with pretransplant electrocardiogram and echocardiogram (n=166 and n=112, HR 4.75, 95% CI 2.07-10.9); however, left-ventricular diastolic dysfunction was not (P>0.05). A pretransplant score comprising renal impairment, prolonged QTc interval, and age older than 52 was developed for prediction of 3- and 12-month cardiac events (c-statistic 0.73 and 0.75, respectively). CONCLUSIONS: Pretransplant renal impairment is a predictor of cardiac event after liver transplantation together with prolonged QTc interval.

Gastrointestinal symptoms in patients with cirrhosis: a longitudinal study before and after liver transplantation.

OBJECTIVE: Gastrointestinal (GI) symptoms are common in cirrhosis and have an impact on quality of life. Their pathophysiology and their relation to energy intake have not been fully elucidated and the effect of liver transplantation on GI symptoms has not been studied. We aimed to prospectively evaluate GI symptoms and their determinants before and after transplantation and their potential relation with energy intake in cirrhosis. METHODS: A total of 108 cirrhotic liver transplant candidates completed the Gastrointestinal Symptom Rating Scale (GSRS) and the hospital anxiety and depression scale. Fasting serum glucose and insulin were measured in all patients. Serum thyrotropin, free T3/T4, cortisol, free testosterone, estradiol, dehydroepiandrosterone sulfate, interleukin-6 and tumor necrosis factor-α were measured in a subgroup of 80 patients. Transplant recipients were followed for 1 year. A separate cohort of 40 cirrhotic patients underwent a high-caloric satiation drinking test (SDT). RESULTS: GI symptoms were more severe in cirrhotics compared to controls from the general population. In regression analysis, the total GSRS score was independently related to lactulose, anxiety and low free testosterone (p < 0.05 for all). Four out of six GSRS domain scores improved significantly 1 year post-transplant (p < 0.05) but the total GSRS score remained higher compared to controls. GI symptoms predicted ingestion of fewer calories at SDT compared to other patients and controls (p < 0.05). CONCLUSIONS: Psychological distress, lactulose treatment and low testosterone are predictors of GI symptoms which are common among cirrhotic transplant candidates. They are also associated with decreased energy intake as measured by a SDT. GI symptoms remain of concern post-transplant.

Hepatic encephalopathy is related to anemia and fat-free mass depletion in liver transplant candidates with cirrhosis.

BACKGROUND: Although muscle wasting may lead to decreased ammonia detoxification in cirrhosis, the potential role of lean mass depletion in hepatic encephalopathy (HE) has not been explored. Anemia, hormonal abnormalities, and psychological distress may contribute to cognitive dysfunction, but data on their potential relation to HE are limited. METHODS: Data on 108 cirrhotic liver transplant candidates enrolled in a prospective study on fatigue were retrospectively analyzed. HE was assessed clinically and with the number connection tests (NCT) A and B. Psychosocial distress was assessed with a validated questionnaire. Fasting serum glucose, insulin, ammonia, and the glomerular filtration rate (GFR) were measured. Fat and fat-free mass was evaluated with dual-energy X-ray absorptiometry. Serum cortisol, testosterone, dehydroepiandrosterone, thyroid function tests, interleukin-6, and tumor necrosis factor-α (TNF-α) were measured in a subgroup of 80 patients. RESULTS: A total of 28% of patients had (overt or minimal) HE. Anemia was present in 59%, diabetes in 29%, renal impairment in 16%, and fat-free mass depletion in 14%. In multivariate analysis, fat-free mass depletion was an independent predictor of HE and NCT-A; renal impairment of NCT-A and -B; and anemia of NCT-B (p < 0.05 for all). HE was also independently related to international normalized ratio and TNF-α (p < 0.05 for both), but not to other hormonal abnormalities or psychological distress. Plasma ammonia was independently associated to anemia (beta = 15.24, p = 0.049), fasting insulin (beta = 0.26, p < 0.05), and GFR (beta = -0.43, p = 0.003). CONCLUSIONS: Anemia and fat-free mass depletion are predictors of HE in cirrhotic liver transplant candidates along with liver failure, renal impairment, and systemic inflammation.

Impact of peri-transplant heart failure & left-ventricular diastolic dysfunction on outcomes following liver transplantation.

BACKGROUND & AIMS: Assess the prevalence of peri-transplant heart failure and its potential relation to post-transplant morbidity and mortality. METHODS: A retrospective study was performed on 234 consecutive cirrhotic patients undergoing liver transplantation in a single European center from 1999 to 2007 (mean age 52, 30% women, 36% with alcoholic liver disease, 24% with viral hepatitis, 18% cholestatic liver disease). Left ventricular diastolic dysfunction was defined as E/A ratio ≤ 1. We used the Boston classification for heart failure to assess the prevalence of peri-transplant heart failure. Patients were followed up for a mean of 4 years post-transplant (0.5-9 years). RESULTS: Eighteen per cent of patients demonstrated diastolic dysfunction pretransplant. During the peri-transplantation period highly possible heart failure occurred in 27%. In logistic regression analysis, heart failure was independently related to lower mean arterial blood pressure (OR 0.94, 95% CR 0.91-0.98) and prolonged corrected QT time on ECG (OR 9.10, 95% CI 3.77-21.93) pretransplant. Peri-transplant mortality amounted to 5%, and was independently related to heart failure (OR 15.11, 95% CI 1.76-129.62) and the peri-transplant need of dialysis (OR 14.18, 95% CI 1.65-121.89). Heart failure was also associated with longer stay in the intensive care unit and peri-transplant cardiac events (P < 0.05). Long-term transplant-free mortality was independently related to diastolic dysfunction at baseline (Hazard ratio 4.82, 95% CI 1.78-13.06). CONCLUSION: Heart failure occurs in approximately a quarter of patients with cirrhosis following liver transplantation and it is an independent predictor of mortality and morbidity.

Factors related to fatigue in patients with cirrhosis before and after liver transplantation.

BACKGROUND & AIMS: We performed a prospective study to evaluate fatigue and identify potential determinants among patients with cirrhosis. We also studied the effects of liver transplantation on fatigue in these patients. METHODS: A total of 108 patients with cirrhosis being evaluated before liver transplantation completed the fatigue impact scale (FIS), the hospital anxiety and depression (HAD) scale, and the short-form 36 (SF-36). Results were compared with controls from the general population. Fasting serum levels of insulin and glucose were measured in all patients. Levels of serum thyrotropin, free T(3) and T(4), cortisol, free testosterone, dehydroepiandrosterone sulfate, estradiol, interleukin-6, and tumor necrosis factor-α were measured in a subgroup of 80 patients. Transplant recipients were followed for 1 year. RESULTS: Compared with controls, patients with cirrhosis had more pronounced fatigue, on the basis of higher FIS domain and total scores (P < .05), which were related to all SF-36 domains (r = -0.44 to -0.77, P < .001). All FIS scores improved significantly after liver transplantation, although physical fatigue levels remained higher than in controls (P < .05). In multivariate analysis, pretransplant FIS scores were only related to depression, anxiety, cirrhosis severity, and low serum levels of cortisol (P < .05 for all). Impaired renal function and anemia were independent predictors of physical fatigue (P < .05). CONCLUSIONS: Fatigue is common among patients with cirrhosis and associated with impaired quality of life. Psychological distress, severity of cirrhosis, and low levels of cortisol determine general fatigue, whereas anemia and impaired renal function also contribute to physical fatigue. Physical fatigue remains of concern for patients who have received liver transplants for cirrhosis.

Increased risk for malignant neoplasms among patients with cirrhosis.

BACKGROUND & AIMS: It is not clear how cirrhosis affects the risks for hepatocellular carcinoma (HCC) and non-HCC cancers, which are rare among these patients. We assessed the risk for malignant neoplasms in patients with cirrhosis. METHODS: Patients diagnosed with cirrhosis in Gothenburg, Sweden, from 1994 to 2005 were identified and linked to the National Cancer and Death registers. We studied data from 1019 patients with cirrhosis: 68% men, 48% with alcoholic liver disease (ALD), 10% with hepatitis C virus (HCV), and 12% with HCV + ALD. Standardized incidence ratios for malignant neoplasms were calculated (corrected for sex, age, and calendar year according to data from the general Swedish population). The follow-up period was 3290 person-years. RESULTS: Overall, 114 (11%) patients developed HCC; HCC occurred more frequently among patients with HCV than other diseases (P < .05). HCC risk did not differ among patients with HCV, with or without ALD (P > .05). Compared with the general population, cirrhotic patients had increased risk for HCC (26-fold); cholangiocarcinoma (13-fold); and esophageal (8-fold), pancreatic (5-fold), and colorectal and lung cancers (each 4-fold). The risk for cholangiocarcinoma increased mainly among patients with non-ALD cirrhosis, whereas the risk for extrahepatic malignancies increased mainly among patients with ALD and cirrhosis. CONCLUSIONS: The overall risk for non-HCC malignancies is more than 2-fold greater for patients with cirrhosis (mostly in biliary and gastrointestinal malignancies) than of the general population. The risk for non-HCC cancers differs between patients with ALD and non-ALD cirrhosis. The increased risk for HCC among patients with cirrhosis is associated with HCV; it is the same among patients with HCV, with or without ALD.