Patients with autoimmune liver disease have glucose disturbances that mechanistically differ from steatotic liver disease.

Autoimmune liver diseases are associated with an increased risk of diabetes, yet the underlying mechanisms remain unknown. In this cross-sectional study, we investigated the glucose-regulatory disturbances in patients with autoimmune hepatitis (AIH, n = 19), primary biliary cholangitis (PBC, n = 15), and primary sclerosing cholangitis (PSC, n = 6). Healthy individuals (n = 24) and patients with metabolic dysfunction-associated steatotic liver disease (MASLD, n = 18) were included as controls. Blood samples were collected during a 120-min oral glucose tolerance test. We measured the concentrations of glucose, C-peptide, insulin, glucagon, and the two incretin hormones, glucose insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). We calculated the homeostasis model assessment of insulin resistance (HOMA-IR), whole body insulin resistance (Matsuda index), insulin clearance, and insulinogenic index. All patient groups had increased fasting plasma glucose and impaired glucose responses compared with healthy controls. Beta-cell secretion was increased in AIH, PBC, and MASLD but not in PSC. Patients with AIH and MASLD had hyperglucagonemia and hepatic, as well as peripheral, insulin resistance and decreased insulin clearance, resulting in hyperinsulinemia. Patients with autoimmune liver disease had an increased GIP response, and those with AIH or PBC had an increased GLP-1 response. Our data demonstrate that the mechanism underlying glucose disturbances in patients with autoimmune liver disease differs from that underlying MASLD, including compensatory incretin responses in patients with autoimmune liver disease. Our results suggest that glucose disturbances are present at an early stage of the disease.NEW & NOTEWORTHY Patients with autoimmune liver disease but without overt diabetes display glucose disturbances early on in their disease course. We identified pathophysiological traits specific to these patients including altered incretin responses.

Immediate cardiopulmonary responses to consecutive pulmonary embolism: a randomized, controlled, experimental study.

BACKGROUND: Acute pulmonary embolism (PE) induces ventilation-perfusion mismatch and hypoxia and increases pulmonary pressure and right ventricular (RV) afterload, entailing potentially fatal RV failure within a short timeframe. Cardiopulmonary factors may respond differently to increased clot burden. We aimed to elucidate immediate cardiopulmonary responses during successive PE episodes in a porcine model. METHODS: This was a randomized, controlled, blinded study of repeated measurements. Twelve pigs were randomly assigned to receive sham procedures or consecutive PEs every 15 min until doubling of mean pulmonary pressure. Cardiopulmonary assessments were conducted at 1, 2, 5, and 13 min after each PE using pressure-volume loops, invasive pressures, and arterial and mixed venous blood gas analyses. ANOVA and mixed-model statistical analyses were applied. RESULTS: Pulmonary pressures increased after the initial PE administration (p < 0.0001), with a higher pulmonary pressure change compared to pressure change observed after the following PEs. Conversely, RV arterial elastance and pulmonary vascular resistance was not increased after the first PE, but after three PEs an increase was observed (p = 0.0103 and p = 0.0015, respectively). RV dilatation occurred following initial PEs, while RV ejection fraction declined after the third PE (p = 0.004). RV coupling exhibited a decreasing trend from the first PE (p = 0.095), despite increased mechanical work (p = 0.003). Ventilatory variables displayed more incremental changes with successive PEs. CONCLUSION: In an experimental model of consecutive PE, RV afterload elevation and dysfunction manifested after the third PE, in contrast to pulmonary pressure that increased after the first PE. Ventilatory variables exhibited a more direct association with clot burden.

Comparing the effects of continuous positive airway pressure via mask or helmet interface on oxygenation and pulmonary complications after major abdominal surgery: a randomized trial.

The risk of pulmonary complications is high after major abdominal surgery but may be reduced by prophylactic postoperative noninvasive ventilation using continuous positive airway pressure (CPAP). This study compared the effects of intermittent mask CPAP (ICPAP) and continuous helmet CPAP (HCPAP) on oxygenation and the risk of pulmonary complications following major abdominal surgery. Patients undergoing open abdominal aortic aneurysm repair or pancreaticoduodenectomy were randomized (1:1) to either postoperative ICPAP or HCPAP. Oxygenation was evaluated as the partial pressure of oxygen in arterial blood fraction of inspired oxygen ratio (PaO2/FIO2) at 6 h, 12 h, and 18 h postoperatively. Pulmonary complications were defined as X-ray verified pneumonia/atelectasis, clinical signs of pneumonia, or supplementary oxygen beyond postoperative day 3. Patient-reported comfort during CPAP treatment was also evaluated. In total, 96 patients (ICPAP, n = 48; HCPAP, n = 48) were included, and the type of surgical procedure were evenly distributed between the groups. Oxygenation did not differ between the groups by 6 h, 12 h, or 18 h postoperatively (p = 0.1, 0.08, and 0.67, respectively). Nor was there any difference in X-ray verified pneumonia/atelectasis (p = 0.40) or supplementary oxygen beyond postoperative day 3 (p = 0.53). Clinical signs of pneumonia tended to be more frequent in the ICPAP group (p = 0.06), yet the difference was not statistically significant. Comfort scores were similar in both groups (p = 0.43), although a sensation of claustrophobia during treatment was only experienced in the HCPAP group (11% vs. 0%, p = 0.03). Compared with ICPAP, using HCPAP was associated with similar oxygenation (i.e., PaO2/FIO2 ratio) and a similar risk of pulmonary complications. However, HCPAP treatment was associated with a higher sensation of claustrophobia.

Predicting factors for pulmonary embolism response team activation in a general pulmonary embolism population.

Pulmonary embolism response teams (PERT) aim to improve treatment of acute pulmonary embolism (PE). PERT focus on intermediate- and high-risk PE patients, but recent multicenter studies show that low-risk PE patients compose one in five of all PERT cases. Conversely, not all intermediate- and high-risk PE patients elicit a PERT activation. The factors leading to PERT activations remain unknown. This study aims to describe the patient characteristics associated with PERT activation for low-risk PE patients and characteristics precluding PERT activation for intermediate/high-risk PE patients. We analysed data from all patients with confirmed PE diagnosed in the Massachusetts General Hospital Emergency Department from August 2013 to February 2017 and cross-referred these data with patients who received a PERT activation and patients who did not. Patients were stratified into low-risk or intermediate/high-risk PE. Univariate analyses were performed within each risk group comparing patients with a PERT activation and patients without. Fifteen percent (56/374) of low-risk PE patients triggered a PERT activation. Patient characteristics associated with PERT activation were: (1) vascular disease, (2) pulmonary diseases, (3) thrombophilia, (4) current use of anticoagulants, (5) central PE and (6) concurrent DVT. Thirty-five percent (110/283) of intermediate/high-risk PE patients did not elicit a PERT activation. Patient characteristics precluding a PERT activation were: (1) vascular disease, (2) malignancies and (3) asymptomatic presentation. Low-risk PE patients with PERT activations had more extensive clot burden, complex comorbidities, or had failed anticoagulation treatment. Intermediate/high-risk PE patients without PERT activations tended to have malignancies or vascular disease.

Oxygen Therapy Lowers Right Ventricular Afterload in Experimental Acute Pulmonary Embolism.

OBJECTIVES: To investigate if oxygen could unload the right ventricle and improve right ventricle function in a porcine model mimicking intermediate-high risk acute pulmonary embolism. DESIGN: Controlled, blinded, animal study. SETTING: Tertiary university hospital, animal research laboratory. SUBJECTS: Female, Danish pigs (n = 16, approximately 60 kg). INTERVENTIONS: Acute autologous pulmonary embolism was induced until doubling of baseline mean pulmonary arterial pressure. Group 1 animals (n = 8) received increasing Fio2 (40%, 60%, and 100%) for time intervals of 15 minutes returning to atmospheric air between each level of Fio2. In group 2 (n = 8), the effects of Fio2 40% maintained over 75 minutes were studied. In both groups, pulmonary vasodilatation from inhaled nitric oxide (40 parts per million) was used as a positive control. MEASUREMENTS AND MAIN RESULTS: Effects were evaluated by biventricular pressure-volume loop recordings, right heart catheterization, and arterial and mixed venous blood gasses. Pulmonary embolism increased mean pulmonary arterial pressure from 15 ± 4 to 33 ± 6 mm Hg (p = 0.0002) and caused right ventricle dysfunction (p < 0.05) with troponin release (p < 0.0001). In group 1, increasing Fio2 lowered mean pulmonary arterial pressure (p < 0.0001) and pulmonary vascular resistance (p = 0.0056) and decreased right ventricle volumes (p = 0.0018) and right ventricle mechanical work (p = 0.034). Oxygenation was improved and pulmonary shunt was lowered (p < 0.0001). Maximal hemodynamic effects were seen at Fio2 40% with no additional benefit from higher fractions of oxygen. In group 2, the effects of Fio2 40% were persistent over 75 minutes. Supplemental oxygen showed the same pulmonary vasodilator efficacy as inhaled nitric oxide (40 parts per million). No adverse effects were observed. CONCLUSIONS: In a porcine model mimicking intermediate-high risk pulmonary embolism, oxygen therapy reduced right ventricle afterload and lowered right ventricle mechanical work. The effects were immediately present and persistent and were similar to inhaled nitric oxide. The intervention is easy and safe. The study motivates extended clinical evaluation of supplemental oxygen in acute pulmonary embolism.

Impact of Preload on Right Ventricular Hemodynamics in Acute Pulmonary Embolism.

OBJECTIVES: To compare the hemodynamic effects of increased versus decreased preload in a porcine model of acute intermediate-risk pulmonary embolism. DESIGN: Randomized, controlled animal study. SETTING: Tertiary medical center, animal research laboratory. SUBJECTS: Female, Danish slaughter pigs (n = 22, ~ 60 kg). INTERVENTIONS: Acute pulmonary embolism was induced by large emboli made from clotting of autologous blood. Sixteen animals were randomized to either fluid loading (n = 8, isotonic saline, 1 L/hr for 2 hr) or diuretic treatment (n = 8, furosemide, 40 mg every 30 min, total 160 mg) and compared with a vehicle group (n = 6, no treatment). MEASUREMENTS AND MAIN RESULTS: Hemodynamics were evaluated at baseline, after pulmonary embolism and after each dose by biventricular pressure-volume loops, invasive pressures, diuretic output, respiratory variables, and blood analysis. Pulmonary embolism increased mean pulmonary arterial pressure (p < 0.0001), pulmonary vascular resistance (p = 0.008), right ventricular arterial elastance (p = 0.003), and right ventricular end-systolic volume (p = 0.020) while right ventricular stroke volume and right ventricular ejection fraction were decreased (p = 0.047 and p = 0.0003, respectively) compared with baseline. Fluid loading increased right ventricular end-diastolic volume (+31 ± 13 mL; p = 0.004), right ventricular stroke volume (+23 ± 10 mL; p = 0.009), cardiac output (+2,021 ± 956 mL; p = 0.002), and right ventricular ejection fraction (+7.6% ± 1.5%; p = 0.032), whereas pulmonary vascular resistance decreased (-202 ± 65 dynes; p = 0.020) compared with vehicle. Diuretic treatment decreased right ventricular end-diastolic volume (-84 ± 11 mL; p < 0.001), right ventricular stroke volume (-40 ± 6 mL; p = 0.001), cardiac output (-3,327 ± 451 mL; p = 0.005), and mean pulmonary arterial pressure (-7 ± 1 mm Hg; p < 0.001) and increased right ventricular end-systolic elastance (+0.72 ± 0.2 mm Hg/mL; p < 0.001) and systemic vascular resistance (+1,812 ± 767 dynes; p < 0.001) with no effects on mean arterial pressure. CONCLUSIONS: In a porcine model of acute intermediate-risk pulmonary embolism, fluid loading increased right ventricular preload and right ventricular stroke volume, whereas diuretics decreased right ventricular preload and right ventricular stroke volume without affecting mean arterial pressure.

Tunneled Peritoneal Catheter for Refractory Ascites in Cirrhosis: A Randomized Case-Series.

BACKGROUND AND OBJECTIVES: Refractory ascites markedly worsens prognosis in cirrhosis. Large volume paracentesis (LVP) is standard treatment, but complications are common. In a randomized controlled case-series, we assessed a permanent tunneled peritoneal catheter versus LVP in patients with cirrhosis and ascites. MATERIALS AND METHODS: Random allocation was computer-generated, and concealment used opaque envelopes. Patients were included from January 2017 to December 2018. Inclusion criteria were cirrhosis and recurrent ascites and expected survival of more than 3 months. RESULTS: Thirteen patients were enrolled (PleurX =6 versus LVP = 7). Seven were female, ranging in age from 51 to 80 years. No procedure-related complications occurred. Two patients died due to variceal bleeding (PleurX-group) and sepsis (LVP-group). One patient was withdrawn due to hyponatremia (PleurX-group). Two patients were withdrawn due to bacterial peritonitis and infection of unknown origin (control-group). In the PleurX-group, all patients colonized the catheter, two developed bacterial peritonitis. The most common bacterial colonization was Staph. Epidermidis (n = 4). CONCLUSIONS: In selected patients, the PleurX catheter mobilizes ascites and may be an alternative to LVP. The risk of infection should be considered in each case. The impact of colonization and risk of infections needs further investigation. The present trial does not allow for statistical conclusions.

The soluble mannose receptor is released from the liver in cirrhotic patients, but is not associated with bacterial translocation.

BACKGROUND & AIMS: Intestinal bacterial translocation is involved in activation of liver macrophages in cirrhotic patients. Macrophages play a key role in liver inflammation and are involved in the pathogenesis of cirrhosis and complications. Bacterial translocation may be determined by presence of bacterial DNA and macrophage activation, by the soluble mannose receptor. We hypothesize that the soluble mannose receptor is released from hepatic macrophages in cirrhosis and associated with bacterial DNA, portal pressure and complications. METHODS: We investigated 28 cirrhotic patients set for transjugular intrahepatic portosystemic shunt insertion as a result of refractory ascites (n=17), acute (n=3), or recurrent variceal bleeding (n=8). We analysed plasma from the portal and hepatic veins for bacterial DNA and soluble mannose receptor with qPCR and ELISA. RESULTS: The median soluble mannose receptor level was elevated in the hepatic vein compared with the portal vein (0.57(interquartile range 0.31) vs 0.55(0.40) mg/L, P=.005). The soluble mannose receptor levels were similar in bacterial DNA-positive and -negative patients. The soluble mannose receptor level in the portal and hepatic veins correlated with the portal pressure prior to transjugular intrahepatic portosystemic shunt insertion (r=.52, P<.008, both) and the levels correlated with Child-Pugh score (r=.63 and r=.56, P<.004, both). We observed higher soluble mannose receptor levels in patients with acute variceal bleeding compared to other indications (P<.05). CONCLUSION: This study showed hepatic soluble mannose receptor excretion with a higher level in the hepatic than the portal vein, though with no associations to bacterial DNA. We observed associations between soluble mannose receptor levels and portal pressure and higher levels in patients with acute variceal bleeding indicating the soluble mannose receptor as a marker of complications of cirrhosis, but not bacterial translocation.

Assessment of response to beta-blockers by expression of ßArr2 and RhoA/ROCK2 in antrum mucosa in cirrhotic patients.

BACKGROUND & AIMS: Non-selective beta-blockers (NSBB) are first choice for prevention of variceal bleeding. But possible deleterious effects in refractory ascites and frequent non-response are clinical drawbacks. Since levels of vasoactive proteins in antrum mucosa reflect vascular dysfunction in cirrhosis, these expression levels might also reflect hemodynamic response to NSBB. METHODS: Biopsies from the gastric and duodenal mucosa of 25 patients with cirrhosis were collected and the hepatic venous pressure gradient (HVPG) was measured before and after an acute propranolol challenge. Transcription and protein expression of Ras homolog family member A (RhoA), Rho-kinase (ROCK)2, beta-arrestin2 (ßArr2), endothelial nitric oxide synthase (eNOS) and the phosphorylation of downstream effectors VASP and moesin were analyzed using PCR and Western blot. Further 21 patients on NSBB were evaluated on their follow up for events of variceal bleeding defined as non-response. RESULTS: Ten patients showed HVPG <10mmHg, further seven patients showed significant hemodynamic response to NSBB, whereas eight patients were non-responders. The mucosal transcription of vasoactive proteins was higher in antrum mucosa compared to corpus and duodenum. The transcriptional levels of vasoactive proteins were higher in patients with HVPG >10mmHg and HVPG >16mmHg. Interestingly, mRNA levels of RhoA and ROCK2 were lower in patients with large varices at endoscopy. Moreover, RhoA and ROCK2 transcription correlated with the decrease of HVPG after acute NSBB challenge. Finally, acute and long-term non-responders showed lower expression of ßArr2 in antrum mucosa. CONCLUSION: This study shows for the first time that the expression of ßArr2 in antrum mucosa biopsies might reflect the hemodynamic response to NSBB and their long-term protective effect. This finding might offer an easy approach at upper endoscopy to facilitate the decision to treat with NSBB if varices are present.

Effect of paracentesis on metabolic activity in patients with advanced cirrhosis and ascites.

OBJECTIVE: Patients with decompensated cirrhosis often suffer from malnutrition. To enable appropriate nutritional supplementation a correct estimation of resting energy expenditure (REE) is needed. It is, however, unclear whether the volume of ascites should be included or not in the calculations of the REE. MATERIAL AND METHODS: In 19 patients with cirrhosis and ascites, measurements of REE by indirect calorimetry were performed before paracentesis, after paracentesis, and four weeks after paracentesis. Moreover, handgrip strength (HGS), dual X-ray absorptiometry (DXA), and biochemistry were assessed. RESULTS: Calculated and measured REE differed more than 10% in 63% of the patients at baseline. By including the weight of ascites in the calculation of REE, the REE was overestimated by 283 (-602-1381) kJ/day (p = 0.69). By subtracting the weight of ascites in the calculation of REE, it was underestimated by -379 (-1915 - 219) kJ/day, (p = 0.06). Patients in whom measured REE decreased after paracentesis had higher middle arterial pressure (MAP) (p = 0.02) and p-sodium (p = 0.02) at baseline. Low HGS (M: <30 kg; W < 20 kg) was evident in 68% of the patients. T-scores revealed osteopenia and osteoporosis in 58% and 16%, respectively. Reduced vitamin D levels (<50 nmol/l) were found in 68%. CONCLUSIONS: The presence of ascites seems to increase REE, why we suggest that when REE is calculated, the weight of ascites should be included. Indirect calorimetry is, however, preferable for REE estimation. More than two-third of patients with ascites suffer from muscle weakness and/or osteopenia.

Cardiac and proinflammatory markers predict prognosis in cirrhosis.

BACKGROUND & AIMS: Inflammation and cardiac dysfunction plays an important role in the development of complications leading to increased mortality in patients with cirrhosis. Novel cardiac markers such as prohormone of ANP (proANP), copeptin and high-sensitivity troponin T (hs-TnT) and proinflammatory markers including soluble urokinase-type plasminogen activator receptor (suPAR) and high-sensitive C-reactive protein (hs-CRP) are related to these complications. We aimed to investigate if cardiac and proinflammatory markers are related to severity of liver disease, cardiac and haemodynamic changes, and long-term survival. METHODS: One hundred and ninety-three stable cirrhotic patients (Child class: A = 46; B = 97; C = 50) had a full haemodynamic investigation performed with measurement of splanchnic and systemic haemodynamics and measurement of circulating levels of proBNP, proANP, copeptin, hs-TnT, LBP, IL 6, IL 8, IP 10, VEGF, hs-CRP and suPAR. RESULTS: Soluble urokinase-type plasminogen activator receptor soluble urokinase-type plasminogen activator receptor, hs-CRP, and hs-TnT were significantly different throughout the Child classes (P < 0.01; P < 0.01; P < 0.02). All markers except copeptin correlated with indicators of disease severity in cirrhosis; ProANP and suPAR correlated with hepatic venous pressure gradient (r = 0.24 and r = 0.34; P < 0.001) and systemic vascular resistance (r = -0.24 and r = -0.33; P < 0.001). Cardiac (proANP, hs-TnT; P < 0.01) and proinflammatory (hs-CRP, suPAR; P < 0.05) markers were associated with mortality in a univariate Cox analysis, however, the strongest predictors of mortality in a multivariate Cox analysis were hs-TnT, ascites and hepatic venous pressure gradient (reg.coeff.: 0.34, P < 0.001; 0.16, P < 0.001; 0.06, P = 0.04). CONCLUSION: Markers of cardiac dysfunction and inflammation are significantly associated with disease severity, degree of portal hypertension and survival in cirrhosis. In particular, hs-TnT and suPAR seem to contain prognostic information.

A Porcine Model of Acute Autologous Pulmonary Embolism.

Acute pulmonary embolism (PE) is a potentially life-threatening condition that causes abrupt obstruction of the pulmonary arteries, leading to acute right heart failure. Novel diagnostic methods and catheter-directed therapies are being developed rapidly, and there is an obvious need for a realistic PE animal model that can be used for pathophysiological evaluation and preclinical testing. This protocol introduces a porcine model employing large autologous pulmonary emboli. Instrumentations are performed with minimally invasive techniques, creating a close-chest model that enables the investigation of various treatment options with high reproducibility. Three hours after drawing blood to create autologous emboli ex vivo, the induction of PE caused an immediate increase in the mean pulmonary arterial pressure (17 ± 3 mmHg to 33 ± 6 mmHg, p < 0.0001) and heart rate (50 ± 9 beats·min-1 to 63 ± 6 beats·min-1, p < 0.0003) accompanied by a decreased cardiac output (5.0 ± 0.8 L/min to 4.5 ± 0.9 L/min, p < 0.037) compared to baseline. The CT pulmonary angiography revealed multiple emboli, and the pulmonary obstruction percentage was increased compared to baseline (0% [0-0] to 57.1% [38.8-63.3], p < 0.0001). In the acute phase, the phenotype is comparable to intermediate-risk PE. The model represents a realistic and well-characterized phenotype of intermediate-risk PE and creates an opportunity to test novel diagnostic methods, interventional and pharmaceutical treatments, and hands-on training for healthcare workers in interventional procedures.

No difference in portal and hepatic venous bacterial DNA in patients with cirrhosis undergoing transjugular intrahepatic portosystemic shunt insertion.

BACKGROUND: Bacterial translocation (BT) with immune activation may lead to hemodynamical alterations and poor outcomes in patients with cirrhosis. AIMS: We investigated bacterial DNA (bDNA), a marker of BT, and its relation to portal pressure and markers of inflammation in the portal and hepatic veins in patients with cirrhosis undergoing TIPS insertion. METHODS: We analysed plasma for bDNA and markers of inflammation in 28 patients [median portal pressure gradient 15 (11-19) mmHg] during TIPS treatment for refractory ascites (n = 19) or acute variceal bleeding (n = 9). Advanced cirrhosis was present in the majority [Child-Pugh class (A/B/C): 1/14/13], and most often caused by alcohol (n = 21). RESULTS: bDNA was detectable in one or both samples in 16 of 28 patients (57%). bDNA was present in 39% of the samples from the portal vein vs 43% of the samples in the hepatic vein (P = 0.126). Antibiotics had no effect on bDNA or markers of inflammation. Markers of inflammation did not differ between the hepatic and portal veins with the exceptions of soluble urokinase plasminogen activating receptor (suPAR) and vascular endothelial growth factor (VEGF), both higher in the hepatic vein (P = 0.031 and 0.003 respectively). CONCLUSIONS: No transhepatic gradient of bDNA was evident, suggesting that no major hepatic elimination of bDNA occurs in advanced liver disease. bDNA, in contrast to previous reports was largely unrelated to a panel of markers of inflammation and without relation to portal pressure.

Lactate metabolism in chronic liver disease.

BACKGROUND: In the healthy liver there is a splanchnic net-uptake of lactate caused by gluconeogenesis. It has previously been shown that patients with acute liver failure in contrast have a splanchnic release of lactate caused by a combination of accelerated glycolysis in the splanchnic region and a reduction in hepatic gluconeogenesis. AIMS: The aims of the present study were to investigate lactate metabolism and kinetics in patients with chronic liver disease compared with a control group with normal liver function. METHODS: A total of 142 patients with chronic liver disease and 14 healthy controls underwent a liver vein catheterization. Blood samples from the femoral artery and the hepatic and renal veins were simultaneously collected before and after stimulation with galactose. RESULTS: The fasting lactate levels, both in the hepatic vein and in the femoral artery, were higher in the patients than in the controls (P < 0.001) and there were a hepatic net-uptake of lactate in both groups. Fasting lactate concentrations correlated directly with the portal pressure, mean arterial blood pressure, and SaO2 and negatively with ICG clearance. CONCLUSIONS: Lactate levels are elevated in cirrhotic patients compared to controls relating to portal pressure and aspects of liver dysfunction and the lactate levels seem to increase with the severity of cirrhosis. This may not be caused by decreased gluconeogenesis but merely be due to accelerated glycolysis in the splanchnic region. Future studies should focus on the impact of chronic liver disease on lactate kinetics.

Different injection techniques in the assessment of central haemodynamics in patients with cirrhosis.

OBJECTIVE: Patients with cirrhosis often present with an abnormal distribution of blood volume with a reduced central blood volume (CBV) and central circulation time (CCT). In this group of patients it is important to determine the central haemodynamics as accurately as possible. The purpose of the present study was to compare an alternative injection technique by injecting technetium-labelled human serum albumin ((99m)Tc-HSA) from a deposit within the catheter lumen with the conventional injection technique by injecting iodine-labelled human serum albumin ((125)I-HSA) directly from a syringe. MATERIALS AND METHODS: In 192 patients with cirrhosis, CCT, CBV, and cardiac output (CO) were determined according to kinetic principles. Injection of the two radiolabelled HSA were performed simultaneously and followed by arterial blood sampling every second for the first minute. RESULTS: CCT was significantly shorter, and CO and CBV were significantly lower when determined by the alternative catheter deposit injection technique compared to determination by the traditional syringe deposit injection technique. The mean difference (bias) between CCT measured with the two methods was 0.38 s with limits of agreement ranging from - 0.83 s to 1.59 s. CONCLUSION: This study demonstrates that different injection techniques result in a minor but significant difference of the measured haemodynamics. When highly accurate measurements of the central haemodynamics are needed, we recommend using the alternative injection technique by injection of the indicator from a deposit within the catheter in order to reduce overestimation of CCT.

Are patients with eosinophilic esophagitis treated at an academic hospital comparable to a patient from a population-based cohort? Not in Denmark.

Background and Aim: Little are known about differences in eosinophilic esophagitis (EoE) patients in the general population compared with patients treated at academic hospitals. This might affect the generalizability of study results. The aims of the study were to compare clinical features, and complications of EoE between patients from a population-based cohort (DanEoE) and patients from an academic hospital cohort in Copenhagen (EoE-Cph). Methods: The DanEoE cohort is a population- and register-based cohort including all 236 adult EoE patients diagnosed in the North Denmark Region in 2007-2017 previously described in detail. The new EoE-Cph cohort consists of 245 consecutively referred adult patients to a dedicated EoE center in an Academic Hospital in the Danish capital in 2013-2020. Data were collected from medical registries and medical files. Results: Patients in the academic cohort were at symptom debut 12 (SD 16) years younger (P = 0.001). At the time of diagnosis they were 5.4 (SD 15) years younger (P < 0.001). Where Gastro-esophageal reflux disease (GORD) was present in one-third of the population-based cohort, this was only observed in 14% of the EoE-Cph group (P < 0.05). Food bolus obstruction before diagnosis was 24% less common in the EoE-Cph patients (P < 0.001). Conclusion: Results indicated that EoE patients referred to a Danish EoE center is a selected subgroup with disease debut at a younger age, less comorbid GORD, and rarely food bolus obstruction before diagnosis. This suggests that study results from academic hospitals might not have generalizability to the average EoE patient in a population.

Suboptimal diagnostic accuracy of ultrasound and CT for compensated cirrhosis: Evidence from prospective cohort studies.

INTRODUCTION: Abdominal ultrasound (US) and CT are important tools for the initial evaluation of patients with liver disease. Our study aimed to determine the accuracy of these methods for diagnosing cirrhosis. METHODS: In all, 377 participants from 4 prospective cohort studies evaluating patients with various liver diseases were included. All patients were included between 2017 and 2022 and had undergone a liver biopsy as well as US and/or CT. Using the histological assessment as the gold standard, we calculated diagnostic accuracy for US and CT. Liver biopsies were evaluated by expert histopathologists and diagnostic scans by experienced radiologists. RESULTS: The mean age was 54 ± 14 years and 47% were female. Most patients had NAFLD (58.3%) or alcohol-associated liver disease (25.5%). The liver biopsy showed cirrhosis in 147 patients (39.0%). Eighty-three patients with cirrhosis had Child-Pugh A (56.4% of patients with cirrhosis) and 64 had Child-Pugh B/C (43.6%). Overall, the sensitivity for diagnosing cirrhosis by US was 0.71 (95% CI 0.62-0.79) and for CT 0.74 (95% CI 0.64-0.83). The specificity was high for US (0.94, 95% CI 0.90-0.97) and for CT (0.93, 95% CI 0.83-0.98). When evaluating patients with Child-Pugh A cirrhosis, sensitivity was only 0.62 (95% CI 0.49-0.74) for US and 0.60 (95% CI 0.43-0.75) for CT. For patients with Child-Pugh B/C, sensitivity was 0.83 (95% CI 0.70-0.92) for US and 0.87 (95% CI 0.74-0.95) for CT. When limiting our analysis to NAFLD (20% with cirrhosis), the sensitivity for US was 0.45 (95% CI 0.28-0.64) and specificity was 0.97 (95% CI 0.93-0.99). CONCLUSION: US and CT show moderate sensitivity and may potentially overlook compensated cirrhosis underlining the need for additional diagnostic testing.

Postprandial dysfunction in fatty liver disease.

Fatty liver disease has mainly been characterized under fasting conditions. However, as the liver is essential for postprandial homeostasis, identifying postprandial disturbances may be important. Here, we investigated postprandial changes in markers of metabolic dysfunction between healthy individuals, obese individuals with non-alcoholic fatty liver disease (NAFLD) and patients with cirrhosis. We included individuals with biopsy-proven NAFLD (n = 9, mean age 50 years, mean BMI 35 kg/m2 , no/mild fibrosis), cirrhosis with hepatic steatosis (n = 10, age 62 years, BMI 32 kg/m2 , CHILD A/B) and healthy controls (n = 10, age 23, BMI 25 kg/m2 ), randomized 1:1 to fasting or standardized mixed meal test (postprandial). None of the patients randomized to mixed meal test had type 2 diabetes (T2D). Peripheral blood was collected for 120 min. After 60 min, a transjugular liver biopsy and liver vein blood was taken. Plasma levels of glucose, insulin, C-peptide, glucagon, and fibroblast growth factor 21 (FGF21) were measured. Postprandial peak glucose and C-peptide were significantly increased in NAFLD, and cirrhosis compared with healthy. Patients with NAFLD and cirrhosis had hyperglucagonemia as a potential sign of glucagon resistance. FGF21 was increased in NAFLD and cirrhosis independent of sampling from the liver vein versus peripheral blood. Glucagon levels were higher in the liver vein compared with peripheral blood. Patients with NAFLD and cirrhosis without T2D showed impaired glucose tolerance, hyperinsulinemia, and hyperglucagonemia after a meal compared to healthy individual. Postprandial characterization of patients with NAFLD may be important to capture their metabolic health.

Cardiac sympathetic imaging with mIBG in cirrhosis and portal hypertension: relation to autonomic and cardiac function.

Autonomic and cardiac dysfunction is frequent in cirrhosis and includes increased sympathetic nervous activity, impaired heart rate variability (HRV), and baroreflex sensitivity (BRS). Quantified (123)I-metaiodobenzylguanidine (mIBG) scintigraphy reflects cardiac noradrenaline uptake, and in patients with cardiac failure it predicts outcome. In this study, we aimed to investigate cardiac sympathetic neuronal function in cirrhosis by mIBG scintigraphy in relation to cardiovascular function. Ten patients with alcoholic cirrhosis and 10 age- and sex-matched healthy controls participated in the study. Heart/mediastinum (H/M) ratios of mIBG uptake were calculated 15 and 230 min after intravenous injection of mIBG. Furthermore, washout rate (WOR) of mIBG was calculated. The patients underwent a liver vein catheterization with determination of splanchnic and systemic hemodynamics and measurement of HRV and BRS. mIBG-scintigraphy revealed significantly increased WOR in patients with cirrhosis compared with controls (P < 0.005), whereas H/M uptakes were equal in the groups. Forty percent of the patients had reduced uptake of mIBG in the infero-lateral segment of the left ventricle. WOR correlated significantly with central circulation time, an estimate of central hypovolemia (r = -0.64, P < 0.05) and frequency-corrected QT(F) interval (r = 0.71, P = 0.01). Patients with cirrhosis had significantly decreased HRV and BRS correlating with indicators of abnormal cathecholamine uptake by mIBG although the catecholamine level was normal in the patients. In conclusion, in alcoholic cirrhosis, mIBG scintigraphy reveals autonomic dysfunction and impaired myocardial distribution of sympathetic nervous activity. It is associated to indicators of central hypovolemia, QT interval, and decreased HRV and BRS. Measurement of myocardial catecholamine uptake by mIBG may add important information on autonomic and cardiac dysfunction in cirrhosis.

Few complications after paracentesis in patients with cirrhosis and refractory ascites.

INTRODUCTION: The relevance of needle type and ultrasound guidance in connection with complications and technical problems in paracentesis in cirrhotic patients has only been sparsely described. The aim of this study was to evaluate paracentesis in cirrhotic patients with refractory ascites, focusing on technique, complications, amount of ascites drained and prognosis. MATERIAL AND METHODS: This was a retrospective study based on 51 cirrhotic patients with refractory ascites undergoing paracentesis. A total of 209 paracenteses were performed using a pigtail catheter and an intravenous catheter. Ultrasound-guided puncture or no ultrasound-guided punctured were compared with regard to amount of drained ascites, technical problems and complications both immediate and within a week of the procedure. The impact of coagulopathy was also investigated. RESULTS: 12% immediate and 5% late complications occurred, most of which were minor. No significant differences in the frequency of complications were found when comparing a pigtail to an intravenous catheter (8% versus 21%, OR = 2.81 95% CI (0.86; 9.13)), nor did the amount of drained ascites differ significantly. Ultrasound guidance did not significantly decrease the frequency of complications (7% versus 9%, OR 1.34 95% CI (0.37; 4.84)). Coagulopathy did not significantly affect the risk of complications. CONCLUSION: Paracentesis in patients with cirrhosis is associated with a low frequency of serious complications, regardless of the technique deployed. Although the material is of limited size, it appears that coagulopathy does not increase the risk of complications following this procedure.