Protein-based oral rehydration solutions for patients with an ileostomy: A randomised, double-blinded crossover study.

BACKGROUND & AIM: Patients with an ileostomy are at increased risk of dehydration and sodium depletion. Treatments recommended may include oral rehydration solutions (ORS). We aimed to investigate if protein type or protein hydrolysation affects absorption from iso-osmolar ORS in patients with an ileostomy. METHODS: This was a randomised, double-blinded, active comparator-controlled 3 × 3 crossover intervention study. We developed three protein-based ORS with whey protein isolate, caseinate or whey protein hydrolysate. The solutions contained 40-48 g protein/L, 34-45 mmol sodium/L and had an osmolality of 248-270 mOsm/kg. The patients ingested 500 mL/d. The study consisted of three 4-week periods with a >2-week washout between each intervention. The primary outcome was wet-weight ileostomy output. Ileostomy output and urine were collected for a 24-h period before and after each intervention. Additionally, blood sampling, dietary records, muscle-strength tests, bioimpedance analyses, questionnaires and psychometric tests were conducted. RESULTS: We included 14 patients, of whom 13 completed at least one intervention. Ten patients completed all three interventions. Wet-weight ileostomy output did not change following either of the three interventions and did not differ between interventions (p = 0.38). A cluster of statistically significant improvements related to absorption was observed following the intake of whey protein isolate ORS, including decreased faecal losses of energy (-365 kJ/d, 95% confidence interval (CI), -643 to -87, p = 0.012), potassium (-7.8 mmol/L, 95%CI, -12.0 to -3.6, p = 0.001), magnesium (-4.0 mmol/L, 95%CI, -7.4 to -0.7, p = 0.020), improved plasma aldosterone (-4674 pmol/L 95%CI, -8536 to -812, p = 0.019), estimated glomerular filtration rate (eGFR) (2.8 mL/min/1.73 m2, 95%CI, 0.3 to 5.4, p = 0.03) and CO2 (1.7 mmol/L 95%CI, 0.1 to 3.3, p = 0.04). CONCLUSION: Ingestion of 500 mL/d of iso-osmolar solutions containing either whey protein isolate, caseinate or whey protein hydrolysate for four weeks resulted in unchanged and comparable ileostomy outputs in patients with an ileostomy. Following whey protein isolate ORS, we observed discrete improvements in a series of absorption proxies in both faeces and blood, indicating increased absorption. The protein-based ORS were safe and well-tolerated. Treatments should be tailored to each patient, and future studies are warranted to explore treatment-effect heterogeneity and whether different compositions or doses of ORS can improve absorption and nutritional status in patients with an ileostomy. GOV STUDY IDENTIFIER: NCT04141826.

Landmark analysis of the risk of recurrence after resection or ablation for HCC: A nationwide study.

BACKGROUND: The risk of HCC recurrence at particular landmarks since the initial treatment is unknown. With this registry-based study, we aimed to provide a nuanced description of the prognosis following resection or ablation for HCC, including landmark analyses. METHODS: Using the Danish nationwide health care registries, we identified all patients who received resection or ablation in 2000-2018 as the first HCC treatment. HCC recurrence was defined as a new HCC treatment > 90 days after the first treatment. We conducted competing risk landmark analyses of the cumulative risk of recurrence and death. RESULTS: Among 4801 patients with HCC, we identified 426 patients who received resection and 544 who received ablation. The 2 treatment cohorts differed in cirrhosis prevalence and tumor stage. The 5-year recurrence risk was 40.7% (95% CI 35.5%-45.8%) following resection and 60.7% (95% CI: 55.9%-65.1%) following ablation. The 1-year recurrence risk decreased over the landmarks from 20.4% (95% CI: 16.6%-24.6%) at the time of resection to 4.7% (95% CI: 0.9%-13.9%) at the 5-year landmark. For ablation, the risk decreased from 36.1% (95% CI: 31.9%-40.4%) at the time of treatment to 5.3% (95% CI: 0.4%-21.4%) at the 5-year landmark. The risk of death without recurrence was stable over the landmarks following both resection and ablation. CONCLUSIONS: In conclusion, the risk of recurrence or death following resection or ablation for HCC is high from the treatment date, but the risk of recurrence decreases greatly over the survival landmarks. This information is valuable for clinicians and their patients.

Population-Based Study of Alcohol-Related Liver Disease in England in 2001-2018: Influence of Socioeconomic Position.

INTRODUCTION: England has seen an increase in deaths due to alcohol-related liver disease (ALD) since 2001. We studied the influence of socioeconomic position on the incidence of ALD and the mortality after ALD diagnosis in England in 2001-2018. METHODS: This was an observational cohort study based on health records contained within the UK Clinical Practice Research Datalink covering primary care, secondary care, cause of death registration, and deprivation of neighborhood areas in 18.8 million residents. We estimated incidence rate and incidence rate ratios of ALD and hazard ratios of mortality. RESULTS: ALD was diagnosed in 57,784 individuals with a median age of 54 years and of whom 43% had cirrhosis. The ALD incidence rate increased by 65% between 2001 and 2018 in England to reach 56.1 per 100,000 person-years in 2018. The ALD incidence was 3-fold higher in those from the most deprived quintile vs those from the least deprived quintile (incidence rate ratio 3.30, 95% confidence interval 3.21-3.38), with reducing inequality at older than at younger ages. For 55- to 74-year-olds, there was a notable increase in the incidence rate between 2001 and 2018, from 96.1 to 158 per 100,000 person-years in the most deprived quintile and from 32.5 to 70.0 in the least deprived quintile. After ALD diagnosis, the mortality risk was higher for patients from the most deprived quintile vs those from the least deprived quintile (hazard ratio 1.22, 95% confidence interval 1.18-1.27), and this ratio did not change during 2001-2018. DISCUSSION: The increasing ALD incidence in England is a greater burden on individuals of low economic position compared with that on those of high socioeconomic position. This finding highlights ALD as a contributor to inequality in health.

Risk of alcohol-associated liver disease in the offspring of parents with alcohol-associated liver disease: A nationwide cohort study.

BACKGROUND AND AIMS: Offspring of patients with alcohol-associated liver disease (ALD) may have a higher risk of ALD. We examined their risk of ALD and survival with ALD. APPROACH AND RESULTS: We used Danish nationwide registries to identify the offspring of patients diagnosed with ALD in 1996-2018 and 20:1 matched comparators from the general population. They were followed for ALD diagnosis through 2018. We used landmark competing risk analysis to estimate the age-specific absolute and relative 10-year risks of ALD. ALD was diagnosed in 385 of 60,707 offspring and 2842 of 1,213,357 comparators during 0.7 and 14.0 million person-years of follow-up, respectively, yielding an incidence rate ratio of 2.73 (95% CI: 2.44-3.03). The risk of being diagnosed with ALD within the next 10 years peaked at age 55 years for offspring and age 57 years for comparators with 10-year risks of 1.66% (95% CI: 1.16-2.30) in offspring and 0.81% (95% CI: 0.68-0.97) in comparators at these ages. Offspring were younger at ALD diagnosis than comparators (median age of 47.4 vs. 48.9 years), yet slightly more of them had developed cirrhosis (60.3% vs. 58.7%). Survival after ALD diagnosis was similar in offspring and comparators, adjusted hazard ratio=1.03 (95% CI: 0.88-1.21), so on average offspring died younger due to their younger age at diagnosis. CONCLUSIONS: Offspring of patients with ALD had a low but increased risk of ALD. Screening offspring for chronic liver disease may be unnecessary, but other interventions to mitigate alcohol-associated harm should be considered.

Alcohol use and hepatocellular carcinoma risk in patients with alcohol-related cirrhosis.

OBJECTIVES: Insights into risk factors for hepatocellular carcinoma (HCC) among patients with alcohol-related cirrhosis (ALD cirrhosis) are important for decisions about HCC surveillance. We studied the effects of continued hazardous alcohol use in ALD cirrhosis on HCC risk. METHODS: Within a nationwide registry-based cohort of patients with ALD cirrhosis, we compared HCC risk between patients with a continued hazardous alcohol use and matched comparators. We used Fine-Gray regression to compare the risk of HCC and Cox regression to compare all-cause mortality. We also included patients with ALD cirrhosis in a clinical case-control study. Cases had HCC, and controls did not. Alcohol use was quantified using the AUDIT-C-questionnaire. Logistic regression was used to analyze the association between hazardous alcohol use and HCC risk. RESULTS: In the registry-based study, we included 8,616 patients with continued hazardous alcohol use and 8,616 matched comparators. Patients with a continued hazardous alcohol use had a lower HCC risk (subdistribution hazard ratio: 0.64, 95% confidence interval [CI]: 0.57 - 0.72) and higher mortality (hazard ratio: 1.62, 95% CI: 1.56 - 1.67). In the clinical study, we included 146 patients with ALD cirrhosis of whom 53 had newly diagnosed HCC. Hazardous alcohol use was insignificantly associated with a lower HCC risk (odds ratio: 0.61, 95% CI: 0.25 - 1.46). CONCLUSIONS: Hazardous alcohol use in patients with ALD cirrhosis is associated with higher mortality and, consequently, a lower HCC risk. Even if alcohol is carcinogenic, HCC surveillance will therefore likely be more effective in patients with ALD cirrhosis without a hazardous alcohol use.

Prevalence of Statin Use and Predictors of Statin Initiation Among Patients with Alcohol-Related Cirrhosis - A Danish Nationwide Cohort Study.

Purpose: Statins reportedly increase the survival of patients with cirrhosis due to alcohol-related liver disease (ALD cirrhosis), but this association might be confounded by socioeconomic status. We examined the prevalence of statin use and socioeconomic and demographic predictors of statin initiation and discontinuation among patients with ALD cirrhosis. Patients and Methods: Using Danish nationwide healthcare registries, we examined statin use among patients diagnosed with ALD cirrhosis in 1997-2018. We computed the prevalence of statin use and incidence of statin initiation and discontinuation, and we used multivariable Cox regression to identify predictors of statin initiation and discontinuation. Results: We identified 28,260 patients with ALD cirrhosis in 1997-2018. During this period, the prevalence of statin use rose sharply, reaching 19.0% in late 2018. Among patients diagnosed with ALD cirrhosis after 2010, 16.9% were using statins when they were diagnosed with cirrhosis. Among the patients who did not use statins initially, those with lower educational attainment were more likely to begin taking them than those with higher attainment. Also, cohabiting patients were more likely to begin than patients who lived alone, and employed patients were more likely to begin compared to patients outside the labour force. Among current statin users, unemployment predicted statin discontinuation. Conclusion: The use of statins has become increasingly prevalent among Danish patients with ALD cirrhosis, reaching 19.0% in 2018. Employment, cohabitation, and a short education predicted statin initiation after ALD cirrhosis diagnosis, and unemployment predicted statin discontinuation. Overall, statin use was not a marker of a high socioeconomic status.

Effects of Curative-Intent Treatments on Hepatocellular Carcinoma Survival in Alcohol-Related Cirrhosis: A Nationwide Study.

Purpose: The aim of curative-intent treatment for hepatocellular carcinoma (HCC) is to restore the patients' survival to what it would have been, had they not developed HCC. We examined the chances of such 'statistical cure' from HCC in patients with cirrhosis due to alcohol-related liver disease (ALD cirrhosis). Patients and Methods: Using nationwide Danish healthcare registries, all patients with ALD cirrhosis who were treated for HCC in 2004-2018 were identified and included in cohorts based on initial HCC treatment. We used cure fraction analyses to estimate the chance of being statistically cured by each HCC treatment. Results: We included 1087 patients with HCC due to ALD cirrhosis, of whom 51 (4.7%) were treated with resection and 215 (19.8%) were treated with ablation. The cure fraction, ie the fraction of patients who experienced no excess mortality from HCC, was 31.8% (95% CI: 0.0-67.5) following resection and 22.9% (95% CI: 2.6-43.2) following ablation. In patients who were still alive five years after the initial HCC treatment, the likelihood of having been statistically cured at that time was 69.0% after resection and 60.2% after ablation. For both treatments, a 90% chance of having been statistically cured was reached after seven years. Conclusion: Based on cure fraction analyses, resection for HCC statistically cures 31.8% of patients with HCC and underlying ALD cirrhosis, while ablation statistically cures 22.9% of patients. Seven years after curative-intent treatments for HCC, surviving patients are 90% likely to be statistically cured of HCC. This information is valuable to patients and the clinicians caring for them.

Effects of statins and aspirin on HCC risk in alcohol-related cirrhosis: nationwide emulated trials.

BACKGROUND AND AIMS: Observational studies have shown an association between statin or aspirin use and a decreased risk of HCC, but the effects of a well-defined treatment strategy remain unknown. We emulated trials of the effects of continuous statin or aspirin use on HCC risk in patients with cirrhosis due to alcohol-related liver disease (ALD cirrhosis). APPROACH AND RESULTS: We specified target trials for statins and, separately, aspirin and emulated them using Danish health care registries. All eligible patients with ALD cirrhosis diagnosed in 2000-2018 were included in either an exposed or an unexposed arm. Patients were followed until HCC or death without HCC. The 5-year risk of HCC was estimated using marginal structural models with inverse probability weighting. Using statins continuously for 5 years compared with not using statins resulted in a relative risk (RR) of HCC of 0.67 (95% CI: 0.45-0.91). The RR of death without HCC was 0.69 (95% CI: 0.65-0.77). For aspirin, the RR was 1.05 (95% CI: 0.60-1.42) for HCC and 1.02 (95% CI: 0.95-1.09) for death without HCC. CONCLUSIONS: In patients with ALD cirrhosis, 5 years of continuous statin use resulted in a 33% RR reduction of HCC (number needed to treat = 94) and a 31% RR reduction of death without HCC (number needed to treat = 7). Such strong causal effects are implausible and best explained by uncontrollable confounding, highlighting the need for randomized trials. Aspirin use likely does not affect the risk of HCC or death without HCC.

Thyroid Disease and Hepatocellular Carcinoma Survival: A Danish Nationwide Cohort Study.

Introduction: Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer mortality worldwide. Recent animal studies suggest that thyroid hormone treatment improves HCC prognosis. The aim of this study was to describe the association between thyroid disease and HCC prognosis in humans. Methods: We performed a nationwide cohort study including all persons with an HCC diagnosis from 2000 to 2018. Patients' age, sex, HCC treatment, and diagnoses of thyrotoxicosis, nontoxic goiter, and myxedema were obtained from Danish national healthcare registries. We used regression models to examine the association between thyroid disease and mortality hazard and restricted mean survival time after HCC diagnosis, adjusting for confounding by sex and age. Results: We included 4,812 patients with HCC and 107 patients with thyroid disease. Median follow-up time was 5 months (total 5,985 person-years). The adjusted mortality hazard ratio was 0.68 (95% CI: 0.47-0.96) for thyrotoxicosis and 0.60 (95% CI: 0.41-0.88) for nontoxic goiter. The restricted mean survival time during the 5 years following HCC diagnosis was 6.8 months (95% CI: 1.1-12.6) longer for HCC patients with thyrotoxicosis than for patients without thyroid disease, and it was 6.9 months (95% CI: 0.9-12.9) longer for HCC patients with nontoxic goiter than for patients without thyroid disease. Conclusions: In this large nationwide cohort study, thyrotoxicosis and nontoxic goiter were associated with prolonged HCC survival.

Socioeconomic inequalities in the incidence of alcohol-related liver disease: A nationwide Danish study.

BACKGROUND: There is socio-economic inequality in total alcohol-related harm, but knowledge of inequality in the incidence of specific alcohol-related diseases would be beneficial for prevention. Registry-based studies with nationwide coverage may reveal the full burden of socioeconomic inequality compared to what can be captured in questionnaire-based studies. We examined the incidence of alcohol-related liver disease (ALD) according to socioeconomic status and age. METHODS: We used national registries to identify patients with an incident diagnosis of ALD and their socioeconomic status in 2009-2018 in Denmark. We computed ALD incidence rates by socioeconomic status (education and employment status) and age-group (30-39, 40-49, 50-59, 60-69 years) and quantified the inequalities as the absolute and relative difference in incidence rates between low and high socioeconomic status. FINDINGS: Of 17,473 patients with newly diagnosed ALD, 78% of whom had cirrhosis, 86% had a low or medium-low educational level and only 20% were employed. ALD patients were less likely to be employed in the 10 years prior to diagnosis than controls. The incidence rate of ALD correlated inversely with educational level, from 181 (95% CI, 167-197) to 910 (95% CI, 764-1086) per million person-years from the highest to the lowest educational level. By employment status, the incidence rate per million person-years was 211 (95% CI, 189-236) for employed and 3449 (95% CI, 2785-4271) for unemployed. Incidence rates increased gradually with age leading to larger inequalities in absolute numbers for older age-groups. Although ALD was rare in the younger age-groups, the relative differences in incidence rates between high and low socioeconomic status were large for these ages. The pattern of socioeconomic inequality in ALD incidence was similar for men and women. INTERPRETATION: This study showed substantial socioeconomic inequalities in ALD incidence for people aged 30-69 years. FUNDING: The study was supported by grants from the Novo Nordisk Foundation (NNF18OC0054612) and the Research Fund of Bispebjerg Hospital.

[Epidemiology for alcohol-related liver disease].

Alcohol is the dominant cause of liver disease in Denmark. Around 1,000 persons, usually of 40 to 70 years of age, are diagnosed with alcohol-related liver disease (ALD) each year in Denmark. ALD is usually preceded by several years of heavy drinking, during which alcohol cessation could have prevented manifest ALD as argued in this review. There is a substantial inequality in ALD incidence by geography and socioeconomic status in Denmark. ALD is associated with a high mortality: The five-year mortality risk is 54%, although the prognosis for patients with ALD has improved in recent years.

Decreasing Incidence of Alcohol-Related Liver Disease in Denmark: A 25-Year Nationwide Study.

PURPOSE: Alcohol consumption has decreased in Denmark in recent years. We aimed to illustrate and investigate the developments in the incidence, hospital care, and mortality of alcohol-related liver disease (ALD) in Denmark during the last 25 years. PATIENTS AND METHODS: Through nationwide healthcare registries, we identified all Danish patients with incident ALD in 1994-2018. We computed standardized incidence rates by sex, age, and geography, age-specific incidence rates by birth cohort, and standardized prevalence. We enumerated inpatient admissions, days of admission, outpatient visits, and emergency room visits. Lastly, we estimated relative risks of mortality, standardized mortality rates, and the proportion of deaths caused by ALD. RESULTS: The standardized incidence rate decreased from its peak at 357 per 1,000,000 in 2009 to 240 per 1,000,000 in 2018, and the decrease was evident for both sexes and all age groups below 70 years. The standardized prevalence was stable around 0.22% from 2011 onwards. There was an almost fivefold geographic variation in standardized incidence by municipalities, and age-specific incidence rates decreased sequentially with each 5-year birth cohort after 1960. The number of inpatient admissions, days of admission, and emergency room visits decreased during the study period, while the number of outpatient visits was stable. For patients diagnosed in 2014-2018 compared to 1994-1998, the relative risk of 1-year mortality was 0.83 (95% confidence interval: 0.78-0.87), and the standardized mortality along with the proportion of deaths caused by ALD decreased during the study period. CONCLUSION: The incidence of ALD decreased from 357 to 240 per 1,000,000 over the last 10 years in Denmark. During the same period, the prevalence remained stable around 0.22% and mortality decreased. Additionally, the burden of ALD on hospital care decreased significantly between 1994 and 2018. We anticipate a further decrease in the incidence of ALD in the future.

Risk of hepatocellular carcinoma in Danish outpatients with alcohol-related cirrhosis.

BACKGROUND AND AIMS: Accurate estimates of hepatocellular carcinoma (HCC) risk in patients with cirrhosis are important to guide surveillance strategies. We described HCC risk among outpatients with alcohol-related cirrhosis and contrasted the risk of death from HCC with the risk of death from variceal bleeding or trauma. METHODS: This was a nationwide, registry-based historical cohort study between 2006 and 2018. We included all Danish outpatients with a hospital diagnosis of alcohol-related cirrhosis, except those with cancer, those with chronic viral hepatitis or autoimmune liver disease, and those older than 80 years. We followed them through 2018 and described the cumulative risk of HCC and the cumulative risk of death from HCC, variceal bleeding, or trauma. RESULTS: Of the 4,553 patients included, 181 developed HCC and 2,274 died. The cumulative risk of HCC was 0.9% (95% CI 0.7-1.3) after 1 year, 3.6% (95% CI 3.0-4.2) after 5 years, and 6.0% (95% CI 5.1-7.0) after 10 years, or approximately 0.7% per year. Male sex, older age, and decompensated cirrhosis predicted a higher HCC risk. After 10 years, 6.9% of deaths in the cohort could be attributed to HCC, whereas 6.5% could be attributed to variceal bleeding, and 5.0% to trauma. CONCLUSIONS: In 2006-2018, Danish outpatients with alcohol-related cirrhosis had an HCC risk of 0.7% per year, and they were nearly as likely to die from variceal bleeding or from trauma as from HCC. The implications are that many potentially harmful examinations are required for every HCC found through surveillance, so interventions targeting the prevention of other causes of death might be more cost-effective. LAY SUMMARY: We described the risk of hepatocellular carcinoma (HCC, the most common form of liver cancer originating in the liver) in Danish outpatients with cirrhosis due to harmful alcohol consumption. Accurate data on that risk are important for patient counselling and decisions about screening for HCC. The risk was about 0.7% per year, which is lower than might be expected and suggests that many potentially harmful screening examinations are required for every HCC found through surveillance.

Long-term effects and complications of the transjugular intrahepatic portosystemic shunt: a single-centre experience.

Background and aims: Accurate estimates of the long-term risks of adverse outcomes after transjugular intrahepatic portosystemic shunt (TIPS) treatment are needed. The aim of this cohort study was to estimate the risks of stent dysfunction, variceal bleeding, refractory ascites, hepatic encephalopathy (HE), and death after TIPS treatment. Methods: We extracted data from electronic medical records of 104 consecutive TIPS patients. Gore® Viatorr® TIPS endoprostheses were used in all patients. We conducted competing risks analysis of the risk of stent dysfunction and variceal bleeding, and Kaplan-Meier estimation of overall survival. Results: The overall 1-year survival after TIPS insertion was 82% (95% confidence interval [CI]: 73-88%), and the 1-year risk of stent dysfunction was 15% (95% CI: 9-22%). In patients who had a TIPS for variceal bleeding, the 1-year risk of rebleeding was 23% (95% CI: 13-35%). In patients who had a TIPS for refractory ascites, the risk of having an unsuccessful ascites outcome 1 year after TIPS for refractory ascites was 35% (95% CI: 21-52%). Overall, the 1-year risk of overt HE was 38% (95% CI: 32-43%). The risk of experiencing any of the defined complications during the first year was 56% (95% CI: 45-66%). Conclusion: TIPS is an effective treatment for variceal bleeding and refractory ascites in most cases, but more than half of the patients experience either death, stent dysfunction, recurrence of symptoms, or overt HE within the first year after the procedure.