The prevalence and disease course of autoimmune liver diseases in Greenland.

Autoimmune liver diseases are rare serious diseases causing chronic inflammation and fibrosis in the liver parenchyma and bile ducts. Yet, the prevalence and burden of autoimmune liver diseases are largely unexplored in Arctic native populations. We investigated the prevalence and management of autoimmune liver diseases in Greenland using nationwide cross-sectional register data and subsequent medical chart reviews validating diagnoses and extracting liver histology examinations and medical treatments. The overall prevalence of autoimmune liver diseases in Greenland was 24.6 per 100,000 (95% CI: 14.7-41.3). This was based on 7 patients with autoimmune hepatitis (AIH) (12.3 per 100,000), 3 patients with primary biliary cholangitis (PBC) (5.3 per 100,000), 4 patients with AIH/PBC overlap disease (7.0 per 100,000), and no patients with primary sclerosing cholangitis. All diagnoses were confirmed by liver histology examinations. Medical treatments adhered to internal recommendations and induced complete remission in most patients with AIH, and complete or partial remission in 1 patient with PBC and 3 patients with AIH/PBC overlap disease. One patient had established cirrhosis at the time of diagnosis, while 2 patients progressed to cirrhosis. In conclusion, the prevalence of autoimmune liver diseases was lower in Greenland than in Scandinavia and among Alaska Inuit.

High-dose oral thiamine versus placebo for chronic fatigue in patients with primary biliary cholangitis: A crossover randomized clinical trial.

BACKGROUND & AIMS: Fatigue has high negative impact on many patients with primary biliary cholangitis (PBC) and treatment options are limited. Recently we showed favorable effects of four weeks of high-dose thiamine treatment on fatigue in patients with inflammatory bowel disease. We aimed to investigate the effect and safety of high-dose (600-1800 mg daily) oral thiamine treatment on chronic fatigue in patients with PBC. METHODS: Randomized, double-blinded, placebo-controlled crossover trial including patients with severe PBC-related fatigue. Participants were allocated 1:1 to either group 1) 4 weeks of high-dose thiamine, 4 weeks of washout, and 4 weeks of placebo; or group 2) 4 weeks of placebo, washout, and high-dose thiamine, respectively. Fatigue severity was quantified using the fatigue subscale of the PBC-40 questionnaire. The primary outcome was a fatigue reduction of ≥ 5 points after 4 weeks of high-dose thiamine treatment. RESULTS: We enrolled 36 patients; 34 completed the study. The overall mean reduction in fatigue was 5.0 points (95% CI: 2.5 to 7.5; p < 0.001) for the combined group 1 and group 2. Crossover analysis showed a mean increase in fatigue of 0.3 points (95% CI: -4.2 to 3.8) after high-dose thiamine treatment compared to a 1.4 points (95% CI: 6.2 to -3.4) mean reduction after placebo (p = 0.55). Only mild and transient adverse events were recorded. CONCLUSION: Four weeks of high-dose oral thiamine treatment in patients with PBC was well tolerated and safe. However, high-dose thiamine was not superior to placebo in reducing PBC-related fatigue. TRIAL REGISTRATION: The trial was registered in the ClinicalTrials.gov (NCT04893993) and EudraCT (2020-004935-26).

Atorvastatin for patients with cirrhosis. A randomized, placebo-controlled trial.

BACKGROUND: Patients with cirrhosis and portal hypertension face a high risk of complications. Besides their anti-inflammatory and antifibrotic effects, statins may reduce portal pressure and thus the risk of complications and mortality. We aimed to investigate the effects of atorvastatin on hospital admissions, mortality, inflammation, and lipidomics in cirrhosis with portal hypertension. METHODS: We performed a double-blinded, randomized, placebo-controlled clinical trial among patients with cirrhosis and portal hypertension. Atorvastatin (10-20 mg/d) was administered for 6 months. We measured splanchnic hemodynamics, analyzed inflammatory markers, and performed lipidomics at baseline and after 6 months. RESULTS: Seventy-eight patients were randomized, with 38 patients allocated to atorvastatin and 40 patients to placebo. Fifty-nine patients completed 6 months of intervention. Comparisons between changes in each group were calculated. Liver-related complications and mortality were similar between the groups. The HVPG and Model for End-stage Liver Disease score did not change between groups (p=0.95 and 0.87, respectively). Atorvastatin decreased 3 of 42 inflammatory markers, CD62-L-selectin, matrix metalloproteinases-2, and TNF-α (p-values: 0.005, 0.011, and 0.023, respectively), while lipidomics was not significantly changed. CONCLUSIONS: In patients with cirrhosis, atorvastatin was safe to use, but did not reduce mortality, the risk of liver-related complications, or the HVPG. Atorvastatin induced minor anti-inflammatory effects and minor effects on lipids during a 6-month treatment period.

Signs of non-alcoholic fatty liver disease in indigenous Arctic populations - a systematic review.

INTRODUCTION: The increasing prevalence of obesity and type 2 diabetes mellitus has become a global healthcare concern spreading to indigenous Arctic populations. As non-alcoholic fatty liver disease (NAFLD) is strongly associated with the metabolic syndrome, it has become a leading cause of chronic liver disease. However, data are sparse on the prevalence of NAFLD in indigenous Arctic populations who may have a different risk profile for diabetes complications. METHODS: We conducted a systematic review to estimate the prevalence of NAFLD or signs of NAFLD in indigenous Arctic people inhabiting Greenland, Alaska, Canadian territories and Eastern Russia. Also, we wanted to discuss how Arctic research in metabolic disease such as NAFLD may move forward. RESULTS: Through the pre-specified search of Ovid MEDLINE and Embase, 3,070 unique references were identified and six studies including 5,487 persons qualified for data extraction. The prevalence of NAFLD or signs of NAFLD varied between 21% and 65%. The risk of bias was considerable particularly due to the inclusion of small and heterogeneous studies. CONCLUSION: Only limited published research exists on NAFLD in indigenous Arctic populations. This review reports that the prevalence of NAFLD or signs of NAFLD in the indigenous Arctic populations residing in Arctic Regions may be similar to the global level, emphasising the need for further health research in indigenous Arctic populations.

The Prevalence of Inflammatory Bowel Disease in Greenland.

BACKGROUND: Inflammatory bowel disease (IBD) is sparsely investigated in Arctic populations. The aim of this study was to estimate the prevalence of ulcerative colitis (UC) and Crohn's disease (CD) in Greenland. METHODS: Cross-sectional nationwide data on demography, anthropometry, biochemistry, and pharmacotherapy were extracted from the electronic medical records in Greenland. Diagnoses of UC and CD were based on International Classification of Diseases-Tenth Revision and International Classification of Primary Care-Second Edition coding and treatment with mesalazine. Data from Statistics Greenland were used for prevalence calculations. RESULTS: In total, 254 patients in Greenland experienced IBD, with 214 cases of UC and 40 cases of CD. The overall IBD prevalence was 0.45%, distributed as 0.38% with UC and 0.07% with CD. The IBD prevalence was similar across the 5 regions of Greenland. However, a higher prevalence was observed in the region main towns with the largest populations (0.53%) compared with the small towns along the coastline (0.29%). UC patients were prescribed mesalazine treatment with a frequency of 78%. Furthermore, 10% of all IBD patients received treatment with nonspecific immunomodulators and 7% received biologics. CONCLUSIONS: This study estimates the prevalence and uncovers characteristics of IBD in Greenland. Although CD may be underdiagnosed or less prevalent, the overall prevalence of IBD in Greenland parallels Scandinavian countries and North America. These results boost the knowledge on autoimmune diseases in arctic populations and may guide clinicians in their management of IBD in Greenland. Furthermore, the results may encourage research in IBD across the Arctic regions.

The burden of inflammatory bowel disease has never been investigated in Greenland. This nationwide, cross-sectional, register-based study estimates the prevalence of ulcerative colitis and Crohn's disease in Greenland and reports that the overall prevalence of inflammatory bowel disease in Greenland parallels Western countries.

Development and validation of the Cirrhotic Ascites Severity model-A patient-reported outcome-based model to predict 1-year mortality.

Ascites formation is a sign of decompensation of cirrhosis and heralds a poor prognosis. The widely used standard binary classification of ascites as diuretic-responsive or refractory does not cover the spectrum of ascites and has limited prognostic information. We developed the Cirrhotic Ascites Severity (CIRAS) model to predict 1-year mortality among 465 patients randomized to placebo in the satavaptan trials investigating treatment of cirrhotic ascites. We used multivariable logistic regression to derive the CIRAS model based on these variables: ascites discomfort score (≤50 or >50), plasma sodium (≥140, 133-139, 125-132, or <125 mmoL/L), and a composite of ascites accumulation and diuretic treatment. We validated the prediction model in 697 trial participants randomized to satavaptan treatment. The 1-year all-cause mortality was 19.6%. The area under the receiver operator curve was higher for the CIRAS model than for the standard ascites classification into refractory and diuretic-responsive in both the development cohort (0.68 [95% confidence interval (CI): 0.62-0.75] vs. 0.62 [0.57-0.68]), and the validation cohort (0.68 [0.64-0.72] vs. 0.55 [0.51-0.60]). The CIRAS model had similar discrimination to the Child-Pugh score and nearly as good as the Model for End-Stage Liver Disease (MELD), MELD-Na, and MELD 3.0. Conclusions: The CIRAS model based on simple ascites-relevant data is an easily applicable and patient-centered way to describe the severity and prognosis of all ascites grades. It carries more prognostic information than today's label of "refractory ascites" and forms the basis for earlier and better clinical decisions related to ascites management.

Effects and safety of natriuretic peptides as treatment of cirrhotic ascites: A systematic review and meta-analysis.

BACKGROUND: Natriuretic peptides are involved in the cascade of pathophysiological events occurring in liver cirrhosis, counterbalancing vasoconstriction and anti-natriuretic factors. The effects of natriuretic peptides as treatment of cirrhotic ascites have been investigated only in small studies, and definitive results are lacking. AIM: To examine the effects and safety of natriuretic peptides in cirrhosis patients with ascites. METHODS: We searched MEDLINE, Web of Science, Scopus, Cochrane Library and Embase for all available studies applying intravenous administration of any natriuretic peptide to patients suffering from cirrhotic ascites. Inclusion was not limited by treatment duration or dose, or by follow-up duration. Both randomised controlled trials and non-randomised studies were eligible for inclusion. The primary outcome was change in renal sodium excretion. Secondary outcomes included safety measures and changes in renal water excretion, plasma aldosterone concentration, and plasma renin activity. RESULTS: Twenty-two studies were included. Atrial natriuretic peptide (ANP) was the only intensively studied treatment. Sodium excretion increased in response to continuous ANP infusion and was more pronounced when infusion rates of > 30 ng/kg/min were administered compared with ≤ 30 ng/kg/min (P < 0.01). Moreover, natriuresis was significantly higher in study subgroups with mild/moderate ascites compared with moderate/severe and refractory ascites (P < 0.01). ANP infusions increased renal water excretion, although without reaching a statistically significant dose-response gradient. Plasma aldosterone concentration and plasma renin activity were significantly lower at baseline in study subgroups achieving a negative sodium balance in response to an ANP administration compared with treatment non-responders (P < 0.01). Blood pressure decreases occurred less frequently when ANP doses ≤ 30 ng/kg/min were applied. The quality of evidence for a natriuretic response to ANP was low, mainly due to small sample sizes and considerable between-study heterogeneity. Data were sparse for the other natriuretic peptides; B-type natriuretic peptide and urodilatin. CONCLUSION: Intravenous ANP infusions increase sodium excretion in patients with cirrhotic ascites. Continuous infusion rates > 30 ng/kg/min are the most effective. However, safety increases with infusion rates ≤ 30 ng/kg/min.

Non-alcoholic fatty liver disease in patients with type 2 diabetes in Greenland: a register-based cross-sectional study.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide due to its close association to the metabolic syndrome of type 2 diabetes mellitus (T2DM), obesity and insulin resistance. However, the prevalence and severity of NAFLD in Greenland remain unexplored. We aimed to estimate the prevalence of liver steatosis and fibrosis among Greenlanders and Danes with T2DM living in Greenland using biochemical surrogate markers. We included 1409 Greenlanders and 182 Danes with T2DM in this register-based cross-sectional study. Greenlanders had higher BMI and plasma lipid levels and lower HbA1c levels compared with Danes (p<0.05). Their median alanine aminotransferase (ALAT) levels were similar. However, more Greenlanders had elevated ALAT levels (20.5% vs. 11.5%, p<0.05). Greenlanders had lower FIB-4 scores than Danes, 0.91 (IQR: 0.66-1.27) vs. 0.97 (IQR: 0.78-1.34), without difference in FIB-4 score categories (p=0.27). The prevalence of advanced fibrosis was low in both populations (1.7-2.6%). In conclusion, Greenlanders with T2DM had better glycaemic control despite higher BMI and plasma lipids. A larger proportion of Greenlanders had elevated plasma ALAT levels, while FIB-4 scores were lower than Danes. These findings suggest that Greenlanders with T2DM may be less likely to develop liver complications than Danes with T2DM in Greenland.

[Christmas article: Footwear fashion amongst medical doctors - are clogs fashion or history?]

INTRODUCTION The medical costume has long been subject to interest and debate. In particular, the scene in footwear fashion amongst medical doctors (MDs) has transformed in recent years. The aim of this study was to investigate footwear trends in a specialized hospital setting. We hypothesized, that the footwear differs between 1) medical specialities, 2) senior and junior MDs, and 3) male and female MDs. METHODS In this crosssectional study, we observed the footwear fashion at morning conferences for seven medical specialities at Aarhus University Hospital. Data on sex, seniority, footwear type, presence of socks, and abrasion of footwear were noted for individual MDs. RESULTS In total, data on 153 MDs was registered. 48% wore clogs, 42% sneakers, and 9% sandals. There was a significant difference between the investigated specialities (p = 0.02) with rheumatologists and anaesthesiologists being the least in favour of clogs (15% and 19%) as opposed to radiologists, surgeons and gynaecologists (63%, 58% and 56%). Further, senior MDs preferred clogs more than junior MDs (p = 0.004), and seniority was associated with having worn-out shoes (OR = 4.4; 95% CI: 1.2 16.9). Finally, the footwear differed between male and female MDs (p = 0.005), however, this difference seemed primarily driven by the female preference for sandals. CONCLUSION The fashion in footwear is changing amongst MDs. The traditional clog is less preferred by the younger generation and in certain specialities. FUNDING none. TRIAL REGISTRATION Clinicaltrials.gov (NCT04740281).

Ularitide as treatment of refractory ascites in cirrhosis- a study protocol for a randomised trial.

INTRODUCTION Ascites is a frequent complication to cirrhosis. When ascites becomes refractory to standard diuretic pharmacotherapy, patients are facing a median survival of less than one year and most likely a need for frequent hospitalisations due to large-volume paracentesis or complications. An unmet need exists for new and improved treatments of refractory ascites and the present study investigates the potential of the natriuretic peptide ularitide for this indication. METHODS We aim to investigate the effects, safety and tolerability of ularitide as treatment of refractory ascites in cirrhosis patients in a randomised, double-blind, placebo-controlled trial. Participants receive ularitide or placebo as a continuous intravenous infusion during hospitalisation as an add-on to any diuretic treatment. Clinical end points include increase in diuresis and natriuresis, reduction in body weight and waist circumference, safety end points, as well as changes in plasma concentrations of renal and systemic response biomarkers and hormones. CONCLUSION This study will provide evidence concerning the potential of ularitide in treating cirrhosis patients with refractory ascites. FUNDING This investigator-initiated trial is supported by ADS AIPHIA Development Services AG. TRIAL REGISTRATION Clinicaltrials.gov (NCT04311489) and EU Drug Regulating Authorities Clinical Trials (EudraCT: 2019-002268-28). The trial will be conducted in accordance with good clinical practice, the Declaration of Helsinki and applicable demands from Danish authorities.

Macrophage Activation Markers, CD163 and CD206, in Acute-on-Chronic Liver Failure.

Macrophages facilitate essential homeostatic functions e.g., endocytosis, phagocytosis, and signaling during inflammation, and express a variety of scavenger receptors including CD163 and CD206, which are upregulated in response to inflammation. In healthy individuals, soluble forms of CD163 and CD206 are constitutively shed from macrophages, however, during inflammation pathogen- and damage-associated stimuli induce this shedding. Activation of resident liver macrophages viz. Kupffer cells is part of the inflammatory cascade occurring in acute and chronic liver diseases. We here review the existing literature on sCD163 and sCD206 function and shedding, and potential as biomarkers in acute and chronic liver diseases with a particular focus on Acute-on-Chronic Liver Failure (ACLF). In multiple studies sCD163 and sCD206 are elevated in relation to liver disease severity and established as reliable predictors of morbidity and mortality. However, differences in expression- and shedding-stimuli for CD163 and CD206 may explain dissimilarities in prognostic utility in patients with acute decompensation of cirrhosis and ACLF.

Macrophage Activation Markers, Soluble CD163 and Mannose Receptor, in Liver Fibrosis.

Macrophages are essential components of the human host immune system, which upon activation facilitates a broad pallet of immunomodulatory events including release of pro- or anti-inflammatory cytokines and chemokines, restoration of immune homeostasis and/or wound healing. Moreover, some macrophage phenotypes are crucially involved in fibrogenesis through stimulation of myofibroblasts, while others promote fibrolysis. During the last decades, the role of resident liver macrophages viz. Kupffer cells and recruited monocytes/macrophages in acute and chronic liver diseases has gained interest and been extensively investigated. Specifically, the scavenger receptors CD163 and mannose receptor (CD206), expressed by macrophages, are of utmost interest since activation by various stimuli induce their shedding to the circulation. Thus, quantifying concentrations of these soluble biomarkers may be of promising clinical relevance in estimating the severity of inflammation and fibrosis and to predict outcomes such as survival. Here, we review the existing literature on soluble CD163 and soluble mannose receptor in liver diseases with a particular focus on their relationship to hepatic fibrosis in metabolic associated fatty liver disease, as well as in chronic hepatitis B and C.

Disease mutations reveal residues critical to the interaction of P4-ATPases with lipid substrates.

Phospholipid flippases (P4-ATPases) translocate specific phospholipids from the exoplasmic to the cytoplasmic leaflet of membranes. While there is good evidence that the overall molecular structure of flippases is similar to that of P-type ATPase ion-pumps, the transport pathway for the "giant" lipid substrate has not been determined. ATP8A2 is a flippase with selectivity toward phosphatidylserine (PS), possessing a net negatively charged head group, whereas ATP8B1 exhibits selectivity toward the electrically neutral phosphatidylcholine (PC). Setting out to elucidate the functional consequences of flippase disease mutations, we have identified residues of ATP8A2 that are critical to the interaction with the lipid substrate during the translocation process. Among the residues pinpointed are I91 and L308, which are positioned near proposed translocation routes through the protein. In addition we pinpoint two juxtaposed oppositely charged residues, E897 and R898, in the exoplasmic loop between transmembrane helices 5 and 6. The glutamate is conserved between PS and PC flippases, whereas the arginine is replaced by a negatively charged aspartate in ATP8B1. Our mutational analysis suggests that the glutamate repels the PS head group, whereas the arginine minimizes this repulsion in ATP8A2, thereby contributing to control the entry of the phospholipid substrate into the translocation pathway.