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Background: Congestion is associated with poor prognosis in cardiac amyloidosis (CA). The cardio-hepatic interaction and the prognostic impact of secondary liver affection by cardiac congestion in CA are poorly understood and require further characterisation. Methods: Participants of the amyloidosis cohort study AmyKoS at the Interdisciplinary Amyloidosis Centre of Northern Bavaria with proven transthyretin (ATTR-CA) and light chain CA (AL-CA) underwent serial work-up including laboratory tests, echocardiography, and in-depth hepatic assessment by vibration-controlled transient elastography (VCTE) and 13C-methacetin breath test. Results: In total, 74 patients with AL-CA (n = 17), ATTR-CA (n = 26) and the controls (n = 31) were analysed. ATTR-CA patients showed decreased microsomal liver function expressed by maximal percentage of dose rate (PDRpeak) related to hepatic congestion. Reduced PDRpeak in AL-CA could result from altered pharmacokinetics due to changed hepatic blood flow. Liver stiffness as a combined surrogate of chronic liver damage and congestion was identified as a predictor of all-cause mortality. Statistical modelling of the cardio-hepatic interaction revealed septum thickness, NT-proBNP and PDRpeak as predictors of liver stiffness in both CA subtypes; dilatation of liver veins and the fibrosis score FIB-4 were only significant for ATTR-CA. Conclusions: Non-invasive methods allow us to characterise CA-associated hepatic pathophysiology. Liver stiffness might be promising for risk stratification in CA.
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OBJECTIVE: Progressive hepatic fibrosis can be considered the final stage of chronic liver disease. Hepatic stellate cells (HSC) play a central role in liver fibrogenesis. Thyroid hormones (TH, e.g. thyroxine; T4 and triiodothyronine; T3) significantly affect development, growth, cell differentiation and metabolism through activation of TH receptor α and/or ß (TRα/ß). Here, we evaluated the influence of TH in hepatic fibrogenesis. DESIGN: Human liver tissue was obtained from explanted livers following transplantation. TRα-deficient (TRα-KO) and wild-type (WT) mice were fed a control or a profibrogenic methionine-choline deficient (MCD) diet. Liver tissue was assessed by qRT-PCR for fibrogenic gene expression. In vitro, HSC were treated with TGFß in the presence or absence of T3. HSC with stable TRα knockdown and TRα deficient mouse embryonic fibroblasts (MEF) were used to determine receptor-specific function. Activation of HSC and MEF was assessed using the wound healing assay, Western blotting, and qRT-PCR. RESULTS: TRα and TRß expression is downregulated in the liver during hepatic fibrogenesis in humans and mice. TRα represents the dominant isoform in HSC. In vitro, T3 blunted TGFß-induced expression of fibrogenic genes in HSC and abrogated wound healing by modulating TGFß signalling, which depended on TRα presence. In vivo, TRα-KO enhanced MCD diet-induced liver fibrogenesis. CONCLUSION: These observations indicate that TH action in non-parenchymal cells is highly relevant. The interaction of TRα with TH regulates the phenotype of HSC via the TGFß signalling pathway. Thus, the TH-TR axis may be a valuable target for future therapy of liver fibrosis.
Subject(s)
Fibroblasts , Hepatic Stellate Cells , Animals , Mice , Humans , Hepatic Stellate Cells/metabolism , Thyroid Hormones/metabolism , Thyroid Hormones/pharmacology , Thyroid Hormone Receptors alpha/genetics , Thyroid Hormone Receptors alpha/metabolism , Transforming Growth Factor betaABSTRACT
OBJECTIVE: At high altitude (HA), acute mountain sickness (AMS) is accompanied by neurologic and upper gastrointestinal symptoms (UGS). The primary aim of this study was to test the hypothesis that delayed gastric emptying (GE), assessed by 13 C-octanoate breath testing (OBT), causes UGS in AMS. The secondary aim was to assess post-gastric mechanisms of OBT, which could confound results under these conditions, by determination of intermediary metabolites, gastrointestinal peptides, and basal metabolic rate. METHODS: A prospective trial was performed in 25 healthy participants (15 male) at 4559 m (HA) and at 490 m (Zurich). GE was assessed by OBT (428 kcal solid meal) and UGS by visual analogue scales (VAS). Blood sampling of metabolites (glucose, free fatty acids (FFA), triglycerides (TG), beta-hydroxyl butyrate (BHB), L-lactate) and gastrointestinal peptides (insulin, amylin, PYY, etc.) was performed as well as blood gas analysis and spirometry. STATISTICAL ANALYSIS: variance analyses, bivariate correlation, and multilinear regression analysis. RESULTS: After 24 h under hypoxic conditions at HA, participants developed AMS (p < 0.001). 13 CO2 exhalation kinetics increased (p < 0.05) resulting in reduced estimates of gastric half-emptying times (p < 0.01). However, median resting respiratory quotients and plasma profiles of TG indicated that augmented beta-oxidation was the main predictor of accelerated 13 CO2 -generation under these conditions. CONCLUSION: Quantification of 13 C-octanoate oxidation by a breath test is sensitive to variation in metabolic (liver) function under hypoxic conditions. 13 C-breath testing using short-chain fatty acids is not reliable for measurement of gastric function at HA and should be considered critically in other severe hypoxic conditions, like sepsis or chronic lung disease.
Subject(s)
Altitude , Gastrointestinal Diseases , Breath Tests/methods , Caprylates , Carbon Dioxide , Carbon Isotopes , Female , Gastric Emptying , Humans , Insulin , Male , Perception , Prospective StudiesABSTRACT
BACKGROUND: Neuralgic amyotrophy (NA) has been described as a possible extrahepatic manifestation of hepatitis E virus (HEV) infection. Usually, HEV-associated NA occurs bilaterally. The clinical characteristics determining the course of HEV-associated NA have still not been defined. METHODS: In this retrospective multicentric case series, 16 patients with HEV-associated NA were studied and compared to 176 HEV patients without NA in terms of their age, sex, and ALT levels. RESULTS: Neither gender distribution (75% vs. 67% male) nor age (47 vs. 48 years median) differed significantly between the NA patients and controls. Eight NA patients (50%) presented with bilateral involvement-seven of these had right-side dominance and one had left-side dominance. Thirteen cases (81%) were hospitalized. Eight of these patients stayed in hospital for five to seven days, and five patients stayed for up to two weeks. The time from the onset of NA to the HEV diagnosis, as well as the diagnostic and therapeutic proceedings, showed a large variability. In total, 13 (81%) patients received treatment: 1/13 (8%) received intravenous immunoglobulins, 8/13 (62%) received glucocorticoids, 3/13 (23%) received ribavirin, and 6/13 (46%) received pregabalin/gabapentin. Patients with ages above the median (47 years) were more likely to be treated (p = 0.001). CONCLUSION: HEV-associated NA causes a relevant morbidity. In our case series neither the type of treatment nor the time of initiation of therapy had a significant effect on the duration of hospitalization or the course of the disease. The clinical presentation, the common diagnostic and therapeutic procedures, and the patients' characteristics showed large variability, demonstrating the necessity of standardized protocols for this rare but relevant disease.
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INTRODUCTION: 13 C-breath tests are valuable, noninvasive diagnostic tests that can be widely applied for the assessment of gastroenterological symptoms and diseases. Currently, the potential of these tests is compromised by a lack of standardization regarding performance and interpretation among expert centers. METHODS: This consensus-based clinical practice guideline defines the clinical indications, performance, and interpretation of 13 C-breath tests in adult and pediatric patients. A balance between scientific evidence and clinical experience was achieved by a Delphi consensus that involved 43 experts from 18 European countries. Consensus on individual statements and recommendations was established if ≥ 80% of reviewers agreed and <10% disagreed. RESULTS: The guideline gives an overview over general methodology of 13 C-breath testing and provides recommendations for the use of 13 C-breath tests to diagnose Helicobacter pylori infection, measure gastric emptying time, and monitor pancreatic exocrine and liver function in adult and pediatric patients. Other potential applications of 13 C-breath testing are summarized briefly. The recommendations specifically detail when and how individual 13 C-breath tests should be performed including examples for well-established test protocols, patient preparation, and reporting of test results. CONCLUSION: This clinical practice guideline should improve pan-European harmonization of diagnostic approaches to symptoms and disorders, which are very common in specialist and primary care gastroenterology practice, both in adult and pediatric patients. In addition, this guideline identifies areas of future clinical research involving the use of 13 C-breath tests.
Subject(s)
Breath Tests/standards , Consensus , Gastric Emptying , Helicobacter Infections/diagnosis , Helicobacter pylori , Liver Function Tests/standards , Pancreatic Function Tests/standards , Adult , Breath Tests/methods , Carbon Isotopes , Child , Delphi Technique , Europe , Humans , Liver/physiology , Liver Function Tests/methods , Pancreas, Exocrine/physiology , Pancreatic Function Tests/methods , Urea/analysisABSTRACT
PURPOSE: We aimed to investigate the feasibility, accuracy and safety of percutaneous endobiliary cholangio-forceps biopsy of biliary strictures in our institution. METHODS: A total of 13 percutaneous transhepatic endobiliary biopsies (7 men and 6 women, mean age 66.85±16.76 years) were performed between January 2015 and March 2019 using a transluminal forceps biopsy device. Technical success, rate of complications, number of biopsy specimens, procedure and fluoroscopy time, mean radiation exposure were evaluated; sensitivity and accuracy were calculated. RESULTS: Technical success, i.e., acquisition of at least three (median, 3.00; range, 3-5) macroscopic representative samples, could be achieved in all 13 biopsies. Access was gained via the right liver lobe in 12 of 13 cases (92.3%). All patients presented blood work indicative of cholestasis prior the intervention, with mean bilirubin 4.72±3.72 µmol/L, mean γ-glutamyl transferase 574.16 ± 360.92 IU/L, and median alkaline phosphatase 407 IU/L (165-1366 IU/L). In 12 of 13 cases (92.3%), biopsied material was sufficient for the pathologist to make a histopathologic diagnosis. Analysis revealed cases of malignancy in eight of 13 cases (61.5%), all of which turned out to be cases of cholangiocarcinoma. In four benign cases (30.8%), diagnosis was considered to be confirmed by further imaging or clinical follow-ups, which showed no signs of progressive disease. There was one case (7.7%) of a false-negative result with proof of malignancy in subsequent surgical tissue extraction. A calculation of diagnostic performance yielded a sensitivity rate of 88.9% and an accuracy rate of 92.3%. There was one case of minor and one case of major complication in our study collective, leading to an overall complication rate of 15.4%. CONCLUSION: Percutaneous transhepatic biliary drainage (PTBD)-based forceps biopsy via the transhepatic drainage tract in patients with biliary obstruction of unknown origin is a technically feasible and safe technique with good diagnostic value rates. The procedure should be considered in patients not suitable for endoscopic strategies with indication for establishment of PTBD.
Subject(s)
Bile Ducts/pathology , Biopsy/instrumentation , Cholestasis/pathology , Constriction, Pathologic/diagnosis , Surgical Instruments/adverse effects , Adult , Aged , Aged, 80 and over , Bile Duct Neoplasms/diagnosis , Bile Duct Neoplasms/pathology , Cholangiocarcinoma/diagnosis , Cholangiocarcinoma/pathology , Cholestasis/blood , Cholestasis/diagnostic imaging , Cholestasis/etiology , Drainage/methods , Feasibility Studies , Female , Fluoroscopy/statistics & numerical data , Humans , Liver/enzymology , Liver/pathology , Male , Middle Aged , Radiation Exposure/statistics & numerical data , Retrospective Studies , Safety , Sensitivity and SpecificityABSTRACT
Anorexia nervosa (AN) is an eating disorder characterized by a low food intake and often exceeding exercise, leading to a particularly low body × weight proportion. Patients with AN usually report less hunger than healthy controls. Endogenous endocannabinoids (eCBs), specifically the anandamide, have been associated to hunger, as a meal initiator, but research regarding AN and eCB and inconclusive. In this pilot study, we investigated plasma levels of eCB in inpatients with AN during fasting and after eating, both during the acute AN phase and after weight recovery. After an 8-hr fasting period, blood sample was collected from all participants. After that, participants were given a muffin test meal. Blood samples for the investigation of endogenous eCBs anandamide (N-arachidonoylethanolamide [AEA]) and 2-arachidonoylglycerol (2-AG) were then collected after 120 and 240 min. Participants were only allowed to eat and drink what was offered them during the research. AN reported less hunger than controls during fasting and at the end of the experiment. Also, plasma levels of AEA were significantly smaller in AN in comparison with controls in all time points. No significant difference was found for 2-AG plasma levels. After recovery, no significant difference was found for eCB levels. These findings could be interpreted as an AEA deregulation in AN before and after food intake, which persists after weight recovery. These findings may have implications to the pharmacological treatment of AN and to relapse occurring in the disorder.
Subject(s)
Anorexia Nervosa/blood , Anorexia Nervosa/therapy , Endocannabinoids/blood , Fasting/blood , Humans , Pilot Projects , Young AdultABSTRACT
BACKGROUND & AIMS: It is not clear how rapid ascent to a high altitude causes the gastrointestinal symptoms of acute mountain sickness (AMS). We assessed the incidence of endoscopic lesions in the upper gastrointestinal tract in healthy mountaineers after a rapid ascent to high altitude, their association with symptoms, and their pathogenic mechanisms. METHODS: In a prospective study, 25 mountaineers (10 women; mean age, 43.8 ± 9.5 y) underwent unsedated, transnasal esophagogastroduodenoscopy in Zurich (490 m) and then on 2 test days (days 2 and 4) at a high altitude laboratory in the Alps (Capanna Regina Margherita, 4559 m). Symptoms were assessed using validated instruments for AMS (the acute mountain sickness score and the Lake Louise scoring system) and visual analogue scales (scale, 0-100). Levels of messenger RNAs (mRNAs) in duodenal biopsy specimens were measured by quantitative polymerase chain rection. RESULTS: The follow-up endoscopy at high altitude was performed in 19 of 25 patients on day 2 and in 23 of 25 patients on day 4. The frequency of endoscopic lesions increased from 12% at baseline to 26.3% on day 2 and to 60.9% on day 4 (P < .001). The incidence of ulcer disease increased from 0 at baseline to 10.5% on day 2 and to 21.7% on day 4 (P = .014). Mucosal lesions were associated with lower hunger scores (37.3 vs 67.4 in patients without lesions; P = .012). Subjects with peptic lesions had higher levels of HIF2A mRNA, which encodes a hypoxia-induced transcription factor, and ICAM1 mRNA, which encodes an adhesion molecule, compared with subjects without lesions (fold changes, 1.38 vs 0.63; P = .001; and 1.37 vs 0.66; P = .011, respectively). CONCLUSIONS: In a prospective study of 25 mountaineers, fast ascent to a high altitude resulted in rapid onset of clinically meaningful mucosal lesions and ulcer disease. Duodenal biopsy specimens from these subjects had increased levels of HIF2A mRNA and ICAM1 mRNA, which might contribute to the formation of hypoxia-induced peptic lesions. Further studies are needed of the mechanisms of this process.
Subject(s)
Altitude Sickness , Acute Disease , Adult , Altitude , Altitude Sickness/diagnosis , Endoscopy, Digestive System , Female , Humans , Hypoxia , Prospective StudiesABSTRACT
According to the data of the GLOBOCAN-network of the World Health Organization, there were 952,000 (6.8% of the total) new cases of gastric cancer in 2012, making it the fifth most common malignancy in the world. It represents a substantive change since the very first estimates in 1975 when stomach cancer was the most common neoplasm. More than 70% of cases (677,000 cases) occur in developing countries, and half the world total occurs in Eastern Asia, mainly in China. Gastric cancer is the third leading cause of cancer death in both sexes worldwide (Globocan, Estimated cancer incidence, mortality and prevalence worldwide in 2012, http://globocan.iarc.fr , 2012). Annually, worldwide 723,000 patients die of this tumor entity. Interestingly, a strong change in incidence rates in relation to the anatomical-topographic localization of the primary tumors in the stomach and esophagus has been experienced. While the frequency of proximal gastric carcinoma and adenocarcinoma of the cardiac and subcardiac region in Europe and North America has been constantly rising, distal gastric carcinomas have become less common (Torre et al. in JAMA 65:87-108, 2015). Furthermore, the relative incidence of esophageal adenocarcinoma (mostly localized in the distal esophagus) has strongly increased (Jemal et al. in JAMA 58:71-96, 2008; Crew and Neugut 31:450-464, 2004; Pohl and Welch 97:142-146, 2005).
Subject(s)
Adenocarcinoma/therapy , Stomach Neoplasms/therapy , Adenocarcinoma/epidemiology , Adenocarcinoma/pathology , Chemoradiotherapy, Adjuvant , Gastrectomy , Global Health , Humans , Incidence , Prevalence , Stomach Neoplasms/epidemiology , Stomach Neoplasms/pathology , Treatment OutcomeABSTRACT
BACKGROUND: Whether gastrointestinal motor and sensory function is primary cause or secondary effect of abnormal body weight is uncertain. Moreover, studies relating continuous postprandial sensations of satiation to measurable pathology are scarce. This work assessed postprandial gastrointestinal function and concurrent sensations of satiation across a wide range of body weight and after weight change. METHODS: Patients with anorexia nervosa (AN) and obesity (OB) were investigated in reference to normal weight controls (HC). AN were additionally investigated longitudinally. Gastric emptying, antral contractions and oro-cecal transit after ingestion of a solid meal were investigated by MRI and 13C-lactose-ureide breath test. The dependency of self-reported sensations of satiation on the varying degree of stomach filling during gastric emptying was compared between groups. RESULTS: 24 AN (BMI 14.4 (11.9-16.0) kg/m2), 16 OB (34.9 (29.6-41.5) kg/m2) and 20 HC (21.9 (18.9-24.9) kg/m2) were studied. Gastric half-emptying time (t50) was slower in AN than HC (p = 0.016) and OB (p = 0.007), and a negative association between t50 and BMI was observed between BMI 12 and 25 kg/m2 (p = 0.007). Antral contractions and oro-cecal transit were not different. For any given gastric content volume, self-reported postprandial fullness was greater in AN than in HC or OB (p < 0.001). After weight rehabilitation, t50 in AN tended to become shorter (p = 0.09) and postprandial fullness was less marked (p < 0.01). CONCLUSIONS: A relationship between body weight and gastric emptying as well as self-reported feelings of satiation is present. AN have slower gastric emptying and heightened visceral perception compared to HC and OB. Longitudinal follow-up after weight rehabilitation in AN suggests these abnormalities are not a primary feature, but secondary to other factors that determine abnormal body weight. TRIAL REGISTRATION: Registered July 20, 2009 at ClinicalTrials.gov ( NCT00946816 ).
Subject(s)
Anorexia Nervosa/physiopathology , Body Weight/physiology , Digestion/physiology , Obesity/physiopathology , Sensation/physiology , Adolescent , Adult , Case-Control Studies , Eating/physiology , Female , Gastric Emptying/physiology , Humans , Male , Middle Aged , Postprandial Period/physiology , Young AdultABSTRACT
BACKGROUND: In adult patients with Duchenne muscular dystrophy (DMD) life-threatening constipation has been reported. Since gastrointestinal function in DMD has not been rigorously studied we investigated objective and subjective manifestations of gastrointestinal disturbances in DMD patients. METHODS: In 33 patients with DMD, age 12-41 years, eating behavior and gastrointestinal symptoms were evaluated by questionnaires. Gastric emptying half time (T1/2) and oro-cecal transit time (OCTT) were evaluated by analyzing 13CO2 exhalation curves after ingestion of 13C labeled test meals. Colonic transit time (CTT) was measured by abdominal radiography following ingestion of radiopaque markers. RESULTS: The median (quartiles) T1/2 was 187 (168, 220) minutes, the OCTT was 6.3 (5.0, 7.9) hours, both substantially longer than normal data (Goetze 2005, T1/2: 107±10; Geypens 1999, OCTT 4.3±0.1 hours). The median CTT was 60 (48, 82) hours despite extensive use of laxative measures (Meier 1995, upper limit of normal: 60 hours). T1/2 and OCTT did not correlate with symptoms evaluated by the Gastroparesis Cardinal Symptom Index (GCSI) (Spearman r = -0.3, p = 0.1; and r = -0.15, p = 0.4, respectively). CTT was not correlated with symptoms of constipation assessed by ROME III criteria (r = 0.12, p = 0.5). CONCLUSIONS: DMD patients have a markedly disturbed gastrointestinal motor function. Since objective measures of impaired gastrointestinal transport are not correlated with symptoms of gastroparesis or constipation our findings suggest that measures assuring adequate intestinal transport should be taken independent of the patient's perception in order to prevent potentially life threatening constipation, particularly in older DMD patients.
Subject(s)
Constipation/etiology , Constipation/physiopathology , Gastrointestinal Tract/physiopathology , Gastrointestinal Transit , Muscular Dystrophy, Duchenne/complications , Muscular Dystrophy, Duchenne/physiopathology , Adolescent , Adult , Cecum/physiopathology , Child , Colon/physiopathology , Female , Gastric Emptying , Gastrointestinal Diseases/etiology , Gastrointestinal Diseases/physiopathology , Gastrointestinal Motility , Humans , Male , Stomach/physiopathology , Young AdultABSTRACT
BACKGROUND: The gastric accumulation of enteral formulas in tube-fed patients leads to an increased risk of vomiting and regurgitation. Gastric secretion-induced coagulation of proteins in enteral formulas might lead to gastric accumulation of solid protein particles that further increase the risk of upper digestive intolerance. This study used magnetic resonance imaging to noninvasively assess the half-emptying time (t50) of enteral formulas differing in protein composition. METHODS: Three isocaloric (450 kcal) and isovolumetric (300 mL) enteral formulas, 1 with a noncoagulating P4 protein blend and 2 with coagulating casein-dominant protein blends, were compared in a double-blind, randomized, 3-way crossover study in 21 healthy volunteers. Gastric content emptying curves were fitted with the LinExp model to compute t50 and the parameter κ with κ > 1 reflecting the accumulation of gastric secretion. t50 and κ were compared between all 3 enteral formulas. The formula that emptied fastest was identified by an ordinal mixed model using the ranks of t50. RESULTS: As indicated by values for κ > 1, all enteral formulas induced gastric secretion. No differences were detected for t50. However, the noncoagulating formula emptied fastest in 74% of all participants (P = .004). CONCLUSION: This study demonstrates that a noncoagulating enteral formula can empty faster from the stomach compared with coagulating formulas in a large cohort of healthy volunteers. Investigations on the efficiency of the noncoagulating P4 protein blend in patients requiring tube feeding will further elucidate its potential for reducing upper digestive intolerance during enteral nutrition. Trial NTR2979.
Subject(s)
Caseins/pharmacology , Enteral Nutrition/methods , Food, Formulated , Gastric Emptying , Stomach , Vomiting/prevention & control , Whey Proteins/pharmacology , Adult , Caseins/chemistry , Cross-Over Studies , Double-Blind Method , Enteral Nutrition/adverse effects , Female , Food, Formulated/adverse effects , Gastric Juice/chemistry , Gastric Juice/metabolism , Healthy Volunteers , Humans , Magnetic Resonance Imaging/methods , Male , Stomach/chemistry , Stomach/physiology , Vomiting/etiology , Whey Proteins/chemistry , Young AdultABSTRACT
BACKGROUND: A subclinical, hepatic involvement in manifest and premanifest Huntington's disease (HD) was recently demonstrated by using the (1) (3) C-methionine breath test (MeBT). In this longitudinal pilot study, we investigated whether there is evidence for progressive hepatic mitochondrial dysfunction in premanifest HD. METHODS: The MeBT was performed within a group of 25 well-characterized premanifest HD mutation carriers at baseline and in a 14.5-month follow-up. RESULTS: The total group of mutation carriers (P = 0.033; Cohen's d = 0.6) and the subgroup of mutation carriers from our PreHD-B subgroup (nearer to disease onset; P = 0.030; Cohen's d = 1.12) revealed a lower amount of exhaled (13) CO2 in the follow-up. CONCLUSIONS: This study demonstrates in vivo progressive, subclinical, hepatic involvement in premanifest HD. Limitations of the study, such as high variance in breath test results, are discussed.
Subject(s)
Huntington Disease/complications , Liver Diseases/etiology , Mitochondrial Diseases/etiology , Adult , Disease Progression , Female , Follow-Up Studies , Humans , Huntingtin Protein , Huntington Disease/genetics , Liver Diseases/diagnosis , Male , Middle Aged , Mitochondria/pathology , Nerve Tissue Proteins/genetics , Statistics as Topic , Trinucleotide Repeats/genetics , Young AdultABSTRACT
Reduced insulin sensitivity might increase the susceptibility to acute mountain sickness (AMS). The diabetogenic side effects of dexamethasone should therefore be considered for AMS treatment. To examine whether reduced insulin sensitivity is predictive of AMS and how it is affected by dexamethasone at high altitude, we analyzed endocrine and metabolic parameters obtained from healthy mountaineers in Zurich (LA; 490 m), and 2 and 4 days after fast ascent to the Capanna Regina Margherita (HA2, HA4; 4559 m). 14 of 25 participants developed AMS and were treated with dexamethasone starting in the evening of HA2. Before and after ingestion of an 1800 kJ meal, plasma was analyzed for erythropoietin (EPO) and cholecystokinin (CCK). Insulin sensitivity (HOMA-S) and beta cell activity were calculated. HOMA-S (p<0.01) and EPO levels (p<0.05) were lower in Zurich in the group developing AMS and given dexamethasone, i.e., before treatment and exposure to hypoxia. CCK was lower (p<0.01) and glucose and insulin were higher on HA4 in the dexamethasone group compared to the untreated group. Individuals with low baseline insulin sensitivity and low baseline EPO levels were more susceptible to AMS. Reduced CCK may contribute to the beneficial effect of dexamethasone on high altitude anorexia. However, reduced insulin sensitivity questions the widespread use of dexamethasone to prevent/treat AMS.
Subject(s)
Altitude Sickness/blood , Altitude , Insulin Resistance/physiology , Adult , Altitude Sickness/drug therapy , Blood Glucose/metabolism , Cholecystokinin/blood , Dexamethasone/therapeutic use , Energy Intake , Erythropoietin/blood , Female , Glucocorticoids/therapeutic use , Homeostasis , Humans , Hydrocortisone/blood , Hypoxia/blood , Hypoxia/complications , Insulin-Secreting Cells/physiology , Interleukin-6/blood , Islet Amyloid Polypeptide/blood , Male , Middle Aged , Models, Biological , Oxygen/blood , Retrospective Studies , Time Factors , Young AdultABSTRACT
UNLABELLED: Human iron homeostasis is regulated by intestinal iron transport, hepatic hepcidin release, and signals from pathways that consume or supply iron. The aim of this study was to characterize the adaptation of iron homeostasis under hypoxia in mountaineers at the levels of (1) hepatic hepcidin release, (2) intestinal iron transport, and (3) systemic inflammatory and erythropoietic responses. Twenty-five healthy mountaineers were studied. Blood samples and duodenal biopsies were taken at baseline of 446 m as well as on day 2 (MG2) and 4 (MG4) after rapid ascent to 4559 m. Divalent metal-ion transporter 1 (DMT-1), ferroportin 1 (FP-1) messenger RNA (mRNA), and protein expression were analyzed in biopsy specimens by quantitative reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. Serum hepcidin levels were analyzed by mass spectrometry. Serum iron, ferritin, transferrin, interleukin (IL)-6, and C-reactive protein (CRP) were quantified by standard techniques. Serum erythropoietin and growth differentiation factor 15 (GDF15) levels were measured by enzyme-linked immunosorbent assay (ELISA). Under hypoxia, erythropoietin peaked at MG2 (P < 0.001) paralleled by increased GDF15 on MG2 (P < 0.001). Serum iron and ferritin levels declined rapidly on MG2 and MG4 (P < 0.001). Duodenal DMT-1 and FP-1 mRNA expression increased up to 10-fold from baseline on MG2 and MG4 (P < 0.001). Plasma CRP increased on MG2 and MG4, while IL-6 only increased on MG2 (P < 0.001). Serum hepcidin levels decreased at high altitude on MG2 and MG4 (P < 0.001). CONCLUSION: This study in healthy volunteers showed that under hypoxemic conditions hepcidin is repressed and duodenal iron transport is rapidly up-regulated. These changes may increase dietary iron uptake and allow release of stored iron to ensure a sufficient iron supply for hypoxia-induced compensatory erythropoiesis.
Subject(s)
Adaptation, Physiological , Altitude , Hypoxia/metabolism , Iron/metabolism , Adult , Altitude Sickness/drug therapy , Basic Helix-Loop-Helix Transcription Factors/biosynthesis , C-Reactive Protein/metabolism , Cation Transport Proteins/blood , Dexamethasone/therapeutic use , Duodenum/metabolism , Female , Ferritins/blood , Growth Differentiation Factor 15/blood , Hepcidins/blood , Humans , Interleukin-6/blood , Liver , Male , Middle Aged , RNA, Messenger/metabolism , Transferrin/metabolismABSTRACT
OBJECTIVE: In this cross-sectional study, we investigated whether there is evidence for hepatic mitochondrial dysfunction in manifest and/or premanifest Huntington disease (HD) by using the ¹³C-methionine breath test. METHODS: The ¹³C-methionine breath test was performed within a group of 21 patients with early manifest HD without medication, 30 premanifest mutation carriers, as well as 36 healthy controls. Premanifest mutation carriers were stratified into the 2 groups preHD-A (further from predicted onset) and preHD-B (nearer) based on a calculation of the probability of estimated disease onset within 5 years. The ¹³C-methionine breath test was performed after an overnight fasting, breath samples were analyzed by nondispersive isotope-selective infrared spectroscopy, and results expressed as percentage dose recovered after 90 minutes of testing time. Statistical analyses comprised analysis of covariance and post hoc t tests. RESULTS: Patients with manifest HD and mutation carriers from our preHD-B group revealed a lower amount of exhaled ¹³CO2 compared with healthy controls (p < 0.001 and p = 0.017, respectively). In a stepwise linear regression model, breath test results correlate to functional and cognitive scores of the Unified Huntington's Disease Rating Scale in manifest and also in premanifest HD. For all mutation carriers together, there was a weak but significant correlation of breath test results to ratio caudate volume/total intracranial volume. CONCLUSION: This study demonstrates for the first time in vivo a subclinical, hepatic involvement in manifest and premanifest HD.
Subject(s)
Huntington Disease/complications , Liver Diseases/etiology , Adult , Breath Tests , Carbon Radioisotopes , Cross-Sectional Studies , Female , Humans , Liver Diseases/diagnosis , Male , Methionine , Middle Aged , Mitochondria/pathology , Radiopharmaceuticals , Young AdultABSTRACT
BACKGROUND: Several factors, such as dysphagia, an increased motor activity, increased metabolic rate and a hypermetabolic state have been discussed as contributing to weight loss even at the early stages of Huntington's Disease (HD). Aim of this pilot study was to investigate gastric emptying as a possible reason for weight loss in HD. METHODS: 11 HD participants at early stages of the disease and matched controls were investigated by using the well-established and non-invasive 13C-octanoate breath test. The "Gastroparesis Cardinal Symptom Index" and the "Short-Form Leeds Dyspepsia Questionnaire" were used for clinical evaluation of gastroparesis or dyspepsia. RESULTS: When compared to standard values ââgiven in literature and controls all HD patients had normal breath test results. There was no evidence of gastroparesis or dyspepsia. There was a correlation of breath test results with the cognitive and functional performance of HD participants. CONCLUSION: According to our data, there is no evidence of impaired gastric emptying in early HD. We can not exclude that gastric emptying contributes to weight loss at more advanced stages of the disease.
ABSTRACT
BACKGROUND: Mitochondrial dysfunction due to respiratory chain impairment is a key feature in pathogenesis of Friedreich ataxia. Friedreich ataxia affects the nervous system, heart and pancreas. METHODS: We assessed hepatic mitochondrial function by (13)C-methionine-breath-test in 16 Friedreich ataxia patients and matched healthy controls. RESULTS: Patients exhaled significantly smaller amounts of (13)CO(2) over 90 minutes. Maximal exhaled percentage dose of (13)CO(2) recovery was reduced compared to controls. CONCLUSIONS: (13)C-methionine-breath-test indicates subclinical hepatic mitochondrial dysfunction in Friedreich ataxia but did not correlate with GAA repeat lengths, disease duration or disease severity.
Subject(s)
Breath Tests/methods , Friedreich Ataxia/diagnosis , Mitochondria, Liver/metabolism , Adult , Carbon Radioisotopes , Cross-Sectional Studies , Exhalation , Female , Friedreich Ataxia/metabolism , Friedreich Ataxia/physiopathology , Humans , Liver Diseases/diagnosis , Liver Diseases/etiology , Liver Diseases/metabolism , Male , Methionine , Middle AgedABSTRACT
Chronic HCV (hepatitis C virus)-associated cirrhosis represents a major indication for liver transplantation. Bile acids contribute to hepatic stellate cell activation as a key event in fibrogenesis. The aim of the present study was to investigate the role of bile acids and polymorphisms in bile acid level-regulating genes on fibrosis progression. A total of 206 subjects with chronic HCV infection were included for ABCB11 (ATP-binding cassette, subfamily B, member II) 1331T>C and NR1H4 (nuclear receptor) -1G>T genotyping, 178 of which were analysed for fibrosis stage. Exclusion criteria were HBV (hepatitis B virus) or HIV coinfection, alcohol >40 g/day and morbid obesity. A total of 358 patients with NAFLD (non-alcoholic fatty liver disease) were genotyped for comparison with a non-viral liver disease. Caucasian individuals (n = 110), undergoing liver resection for focal hepatic metastasis, served as controls. The ABCB11 1331C allele was significantly overrepresented in HCV patients compared with controls {allelic frequency 62.9%; OR (odds ratio), 1.41 [95% CI (confidence interval), 1.012-1.965]}. Median plasma bile acid levels were not significantly increased in the CC compared with TT genotype [7.2 (1-110) µmol/l compared with 3.5 (1-61) µmol/l; values are medians (range). A significant association between the presence of cirrhosis and ABCB11 genotype (CC compared with CT or TT, P=0.047) was observed in the χ2 test and independent of other risk factors of age, gender, body mass index and disease duration in multivariate analysis (P = 0.010). No such association could be observed in fatty liver patients with regard to advanced fibrosis (F ≥ 2). The common ABCB11 1331CC genotype, which is present in 40% of HCV patients and renders the carrier susceptible to increased bile acid levels, is associated with cirrhosis.