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1.
Gastroenterology ; 2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33819485

RESUMO

BACKGROUND & AIMS: Limited understanding of pruritus mechanisms in cholestatic liver diseases hinders development of anti-pruritic treatments. Previous studies implicated lysophosphatidic acid (LPA) as a potential mediator of cholestatic pruritus. METHODS: Pruritogenicity of LPC, LPA's precursor, was examined in naïve mice, cholestatic mice, and nonhuman primates. LPC's pruritogenicity involving keratinocyte-TRPV4 was studied using genetic and pharmacological approaches, cultured keratinocytes, ion channel physiology and structural-computational modeling. Activation of pruriceptor-sensory neurons by microRNA-146a (miR-146a), secreted from keratinocytes, was identified by in-vitro and ex-vivo Ca2+-imaging assays. Sera from primary biliary cholangitis (PBC) patients were used for measuring the levels of LPC and miR-146a. RESULTS: LPC was robustly pruritic in mice. TRPV4 in skin keratinocytes was essential for LPC-induced itch and itch in mice with cholestasis. 3D-structural modeling, site-directed mutagenesis and channel function analysis suggested a TRPV4 C-terminal motif for LPC binding and channel activation. In keratinocytes, TRPV4-activation by LPC induced extracellular release of miR-146a, which activated TRPV1+-sensory neurons to cause itch. Both LPC and miR-146a levels were elevated in sera of PBC patients with itch and correlated with itch intensity. Moreover, LPC and miR-146a were also increased in sera of cholestatic mice and elicited itch in nonhuman primates. CONCLUSIONS: We identified LPC as a novel cholestatic pruritogen that induces itch through epithelia-sensory neuron crosstalk, whereby it directly activates skin keratinocyte-TRPV4, which rapidly release miR-146a to activate skin-innervating TRPV1+-pruriceptor sensory neurons. Our findings support the new concept of the skin, as a sensory organ, playing a critical role in cholestatic itch, beyond liver, peripheral sensory neurons and central neural pathways supporting pruriception.

3.
Eur J Immunol ; 2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33788264

RESUMO

The pathogenesis of auto-immune complications triggered by SARS-CoV2 has not been completely elucidated. Here, we performed an analysis of the cellular immune status, cell ratios and monocyte populations of patients with COVID-19 treated on the intensive care unit (ICU) (cohort 1, N = 23) and normal care unit (NCU) (cohort 2, n = 10) compared with control groups: patients treated on ICU for non-infectious reasons (cohort 3, n = 30) and patients treated on NCU for infections other than COVID-19 (cohort 4, n = 21). Patients in cohort 1 presented significant differences in comparison with the other cohorts, including reduced frequencies of lymphocytes, reduced CD8+T-cell count, reduced percentage of activated and intermediate monocytes and an increased B/T8 cell ratio. Over time, patients in cohort 1 who died presented with lower counts of B, T, CD4+T, CD8+T-lymphocytes, NK-cells and activated monocytes. The B/T8 ratio was significantly lower in the group of survivors. In cohort 1 significantly higher levels of IgG1 and IgG3 were found, whereas cohort 3 presented higher levels of IgG3 compared to controls. Among many immune changes, an elevated B/T8 cell ratio and a reduced rate of activated monocytes were mainly observed in patients with severe COVID-19. Both parameters were associated with death in cohort 1. This article is protected by copyright. All rights reserved.

5.
J Hypertens ; 2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33734143

RESUMO

OBJECTIVE: To identify potentially targetable psychosocial factors associated with nonadherence to prescribed antihypertensive medications in patients presenting with hypertensive urgencies at an emergency department. METHODS: This prospective study included patients treated with antihypertensive drugs who presented with hypertensive urgencies (SBP ≥180 mmHg and/or DBP ≥110 mmHg) at the emergency department of a tertiary referral clinic between April 2018 and April 2019. Health literacy was assessed using the Newest Vital Sign test. The Hospital Anxiety and Depression Scale (HADS) was used to quantify symptoms of anxiety and depression. Patients were classified nonadherent if less than 80% of the prescribed antihypertensive drugs were detectable in urine or plasma using liquid chromatography-high-resolution mass spectrometry. RESULTS: A total of 104 patients (62% women) presenting with hypertensive urgencies with a median SBP of 200 mmHg (IQR 190-212) and DBP of 97.5 mmHg (IQR 87-104) were included. Twenty-five patients (24%) were nonadherent to their antihypertensive medication. Nonadherent patients were more often men (66 versus 23%, P = 0.039), prescribed higher numbers of antihypertensive drugs (median 3, IQR 3-4 versus 2, IQR 1-3; P < 0.001), and more often treated with calcium channel blockers (76 versus 25%; P < 0.001) and/or diuretics (64 versus 40%; P = 0.030). There was no difference in health literacy (P = 0.904) or the scores on the HADS subscales for depression (P = 0.319) and anxiety (P = 0.529) between adherent and nonadherent patients. CONCLUSION: Male sex, higher numbers of antihypertensive drugs, and treatment with diuretics and/or calcium channel blockers were associated with nonadherence. We did not identify a specific psychosocial characteristic associated with nonadherence.

6.
J Gastrointestin Liver Dis ; 30(1): 66-72, 2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33723560

RESUMO

BACKGROUND AND AIMS: Colonic diverticulosis (CD) is among the most common conditions of the large bowel. Several factors have been associated with an increased risk of CD and its complications, including advanced age, obesity, physical inactivity, and a low-fiber diet. Available data is conflicting and a comprehensive analysis of different bowel, dietary and environmental habits linked with CD is lacking. We aimed to investigate the relationship between potential risk factors and CD prevalence using full data from a colonoscopy-based cross-sectional study in Europe. METHODS: The study was conducted at three tertiary referral centers in Germany and Lithuania. It included consecutive adult patients referred for routine colonoscopy who completed a detailed questionnaire on our considered multiple risk factors for diverticulosis and diverticulitis, including dietary and environmental factors, and bowel habits. RESULTS: The study included 1,333 patients, 696 women and 635 men. Colonic diverticulosis was diagnosed in 858 (64%) of patients. Multivariate analysis revealed that age (OR: 1.08, 95%CI: 1.06-1.10, p<0.001) and obesity (OR: 1.05, 95%CI: 1.02-1.09, p=0.004) were associated with CD. We also revealed new risk factors for CD: increased frequency of bowel movements (OR: 0.10, 95%CI: 0.03-0.33, p<0.001) and feeling of incomplete bowel emptying (OR: 2.05, 95%CI: 1.47-2.87, p<0.001). Older participants had reduced odds (OR: 0.921, 95 CI: 0.89-0.95, p<0.05) of diverticulitis compared to younger subjects. Feeling of incomplete bowel emptying after defecation was associated with increased odds (OR: 2.769, 95% CI 1.35-5.7, p<0.006) for diverticulitis. Moreover, participants with a higher educational status had increased odds (OR: 2.453, 95%CI: 1.31-4.59, p=0.005) for diverticulitis compared to the lower education group. CONCLUSIONS:  Study shows that older age, obesity, frequency of bowel movements, and feeling of incomplete bowel emptying are associated with the risk of CD. Furthermore, older age, feeling of incomplete bowel emptying, and higher education were associated with the risk of diverticulitis among CD patients.

7.
Clin Res Hepatol Gastroenterol ; 45(2): 101476, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33684791
8.
Liver Int ; 2021 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-33641234

RESUMO

BACKGROUND & AIMS: Bacterial infections (BI) affect the natural course of cirrhosis and were suggested to be a landmark event marking the transition to the decompensated stage. Our specific aim was to evaluate the impact of BI on the natural history of compensated cirrhosis. METHODS: We analyzed 858 patients with cirrhosis, evaluated for the INCA trial (EudraCT 2013-001626-26) in 2 academic medical centers between February 2014 and May 2019. Only patients with previously compensated disease were included. They were divided into 4 groups: compensated without BI, compensated with BI, 1st decompensation without BI, and 1st decompensation with BI. RESULTS: About 425 patients (median 61 [53-69] years) were included in the final prospective analysis. At baseline, 257 patients were compensated (12 [4.7%] with BI), whereas 168 patients presented with their 1st decompensation (42 [25.0%] with BI). In patients who remained compensated MELD scores were similar in those with and without BI. Patients with their first decompensation and BI had higher MELD scores than those without BI. Amongst patients who remained compensated, BI had no influence on transplant-free survival, whereas patients with their 1st decompensation and concurrent BI had significantly reduced transplant-free survival as compared with those without BI. The development of BI or decompensation during follow-up had a greater impact on survival than each of these complications at baseline. CONCLUSIONS: In compensated patients with cirrhosis, the 1st decompensation associated to BI has worse survival than decompensation without BI. By contrast, BI without decompensation does not negatively impact survival of patients with compensated cirrhosis.

9.
Lancet ; 397(10275): 704, 2021 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33610214
10.
Gut ; 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33632708

RESUMO

OBJECTIVE: Alpha-1 antitrypsin deficiency (AATD) is a common, potentially lethal inborn disorder caused by mutations in alpha-1 antitrypsin (AAT). Homozygosity for the 'Pi*Z' variant of AAT (Pi*ZZ genotype) causes lung and liver disease, whereas heterozygous 'Pi*Z' carriage (Pi*MZ genotype) predisposes to gallstones and liver fibrosis. The clinical significance of the more common 'Pi*S' variant remains largely undefined and no robust data exist on the prevalence of liver tumours in AATD. DESIGN: Baseline phenotypes of AATD individuals and non-carriers were analysed in 482 380 participants in the UK Biobank. 1104 participants of a multinational cohort (586 Pi*ZZ, 239 Pi*SZ, 279 non-carriers) underwent a comprehensive clinical assessment. Associations were adjusted for age, sex, body mass index, diabetes and alcohol consumption. RESULTS: Among UK Biobank participants, Pi*ZZ individuals displayed the highest liver enzyme values, the highest occurrence of liver fibrosis/cirrhosis (adjusted OR (aOR)=21.7 (8.8-53.7)) and primary liver cancer (aOR=44.5 (10.8-183.6)). Subjects with Pi*MZ genotype had slightly elevated liver enzymes and moderately increased odds for liver fibrosis/cirrhosis (aOR=1.7 (1.2-2.2)) and cholelithiasis (aOR=1.3 (1.2-1.4)). Individuals with homozygous Pi*S mutation (Pi*SS genotype) harboured minimally elevated alanine aminotransferase values, but no other hepatobiliary abnormalities. Pi*SZ participants displayed higher liver enzymes, more frequent liver fibrosis/cirrhosis (aOR=3.1 (1.1-8.2)) and primary liver cancer (aOR=6.6 (1.6-26.9)). The higher fibrosis burden was confirmed in a multinational cohort. Male sex, age ≥50 years, obesity and the presence of diabetes were associated with significant liver fibrosis. CONCLUSION: Our study defines the hepatobiliary phenotype of individuals with the most relevant AATD genotypes including their predisposition to liver tumours, thereby allowing evidence-based advice and individualised hepatological surveillance.

11.
Gastroenterology ; 160(5): 1481-1482, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33346006
13.
Liver Int ; 2020 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-33159831

RESUMO

BACKGROUND AND AIMS: Liver stiffness measurements (LSM), commonly performed by transient elastography (TE) or two-dimensional shear wave elastography (2D-SWE), are used to quantify liver fibrosis. Active hepatitis, a hallmark of autoimmune hepatitis (AIH), could bias LSM. This bias might be overcome by measurement spleen 2D-SWE. Here, we compare liver and spleen 2D-SWE to TE and liver biopsy (LB) in prospectively recruited patients with AIH. METHODS: We analysed liver and spleen 2D-SWE in relation to liver TE in 90 patients treated ≥ 6 months for AIH. Liver and spleen 2D-SWE were also compared to LB in 63 individuals with AIH. Finally, we evaluated these tools in 220 patients with AIH and during 18 months follow-up. RESULTS: Liver 2D-SWE correlated with surrogate markers of active hepatitis (ALT and IgG, both P < .001) but there was no link between spleen 2D-SWE and ALT. Liver 2D-SWE, but not spleen 2D-SWE, was associated with histopathological inflammatory score (P < .01). When compared to LB, the optimal cut-offs for detecting cirrhosis by liver and spleen 2D-SWE were 16.1 kPa (AUROC 0.93) and 29.8 kPa (AUROC 0.95), respectively. In patients with active hepatitis the combined diagnostic approach including liver and spleen 2D-SWE had significantly better AUROC for detecting cirrhosis than liver 2D-SWE alone. CONCLUSIONS: Liver and spleen 2D-SWE are reliable complementary methods for the diagnosis of advanced fibrosis in AIH. Spleen 2D-SWE seems to be less biased by inflammation and could facilitate fibrosis assessment in therapy-naïve patients or in the presence of active hepatitis.

14.
Nat Commun ; 11(1): 5958, 2020 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-33235214

RESUMO

Aging is a key risk factor for chronic diseases of the elderly. MicroRNAs regulate post-transcriptional gene silencing through base-pair binding on their target mRNAs. We identified nonlinear changes in age-related microRNAs by analyzing whole blood from 1334 healthy individuals. We observed a larger influence of the age as compared to the sex and provide evidence for a shift to the 5' mature form of miRNAs in healthy aging. The addition of 3059 diseased patients uncovered pan-disease and disease-specific alterations in aging profiles. Disease biomarker sets for all diseases were different between young and old patients. Computational deconvolution of whole-blood miRNAs into blood cell types suggests that cell intrinsic gene expression changes may impart greater significance than cell abundance changes to the whole blood miRNA profile. Altogether, these data provide a foundation for understanding the relationship between healthy aging and disease, and for the development of age-specific disease biomarkers.

17.
Ann Hepatol ; 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-33045414

RESUMO

Intestinal permeability is getting more and more attention in gastrointestinal research. Although well recognized, its exact role in health and disease is yet to be defined. There are many methods of quantifying intestinal permeability, but most of them fail to deliver tangible information about the morphological integrity of the intestinal barrier. In this review we aim to describe imaging options for the assessment of intestinal barrier integrity and their potential relevance for clinical practice. Our focus is on confocal laser endomicroscopy, which is at this time the only method for visualizing not only functional but also morphological aspects of the gut barrier in vivo.

18.
Nutrients ; 12(9)2020 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-32906634

RESUMO

Secondary sclerosing cholangitis in critically ill patients (SC-CIP) occurs after long-term intensive care treatment. This study aimed to assess the gut-liver axis in SC-CIP. Stool microbiome composition, gut permeability, bacterial translocation and serum bile acid profiles of 18 SC-CIP patients compared to 11 patients after critical illness without liver disease (CIP controls), 21 patients with cirrhosis and 21 healthy controls were studied. 16S rDNA was isolated from stool and sequenced using the Illumina technique. Diamine oxidase, zonulin, soluble CD14 (sCD14) and lipopolysaccharide binding protein were measured in serum and calprotectin in stool. Serum bile acids were analyzed by high-performance liquid chromatography-mass spectrometry (HPLC-MS). Reduced microbiome alpha diversity and altered beta diversity were seen in SC-CIP, CIP controls and cirrhosis compared to healthy controls. SC-CIP patients showed a shift towards pathogenic taxa and an oralization. SC-CIP, CIP controls and cirrhotic patients presented with impaired gut permeability, and biomarkers of bacterial translocation were increased in SC-CIP and cirrhosis. Total serum bile acids were elevated in SC-CIP and cirrhosis and the bile acid profile was altered in SC-CIP, CIP controls and cirrhosis. In conclusions, observed alterations of the gut-liver axis in SC-CIP cannot solely be attributed to liver disease, but may also be secondary to long-term intensive care treatment.

19.
JHEP Rep ; 2(6): 100168, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32964201

RESUMO

Background & Aims: NAFLD is a growing health concern. The aim of the Fatty Liver Assessment in Germany (FLAG) study was to assess disease burden and provide data on the standard of care from secondary care. Methods: The FLAG study is an observational real-world study in patients with NAFLD enrolled at 13 centres across Germany. Severity of disease was assessed by non-invasive surrogate scores and data recorded at baseline and 12 months. Results: In this study, 507 patients (mean age 53 years; 47% women) were enrolled. According to fibrosis-4 index, 64%, 26%, and 10% of the patients had no significant fibrosis, indeterminate stage, and advanced fibrosis, respectively. Patients with advanced fibrosis were older, had higher waist circumferences, and higher aspartate aminotransferase and gamma-glutamyltransferase as well as ferritin levels. The prevalence of obesity, arterial hypertension, and type 2 diabetes increased with fibrosis stages. Standard of care included physical exercise >2 times per week in 17% (no significant fibrosis), 19% (indeterminate), and 6% (advanced fibrosis) of patients. Medication with either vitamin E, silymarin, or ursodeoxycholic acid was reported in 5%. Approximately 25% of the patients received nutritional counselling. According to the FibroScan-AST score, 17% of patients presented with progressive non-alcoholic steatohepatitis (n = 107). On follow-up at year 1 (n = 117), weight loss occurred in 47% of patients, of whom 17% lost more than 5% of body weight. In the weight loss group, alanine aminotransferase activities were reduced by 20%. Conclusions: This is the first report on NAFLD from a secondary-care real-world cohort in Germany. Every 10th patient presented with advanced fibrosis at baseline. Management consisted of best supportive care and lifestyle recommendations. The data highlight the urgent need for systematic health agenda in NAFLD patients. Lay summary: FLAG is a real-world cohort study that examined the liver disease burden in secondary and tertiary care. Herein, 10% of patients referred to secondary care for NAFLD exhibited advanced liver disease, whilst 64% had no significant liver scarring. These findings underline the urgent need to define patient referral pathways for suspected liver disease.

20.
Front Oncol ; 10: 1578, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32984017

RESUMO

Patients with pre-existing comorbidities and immunosuppression are at greater risk for SARS-CoV-2 infection and severe manifestations of COVID-19. This also includes cancer patients, who are shown to have a poor prognosis after infection. Here, we describe the case of a 72-year old male patient with B-cell depletion after maintenance treatment with rituximab for non-Hodgkin-lymphoma who had a prolonged COVID-19 course and initial false negative test results. Our case highlights the diagnostic pitfalls in diagnosing COVID-19 in B-cell depleted patients and discuss the role of B-cell depletion in the course and treatment of COVID-19. Furthermore, we investigated peripheral blood monocytes and SARS-CoV-2 specific T cells in our patient. In conclusion, our case report can help physicians to avoid diagnostic pitfalls for COVID-19 in hemato-oncological patients under chemoimmunotherapy and tries to explain the role of B-cell depletion and SARS-CoV-2 specific T cells in this context.

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