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

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

Metformin Stimulates Intestinal Glycolysis and Lactate Release: A single-Dose Study of Metformin in Patients With Intrahepatic Portosystemic Stent.

The pharmacodynamic effects of metformin remain elusive, but several lines of evidence suggest a critical role of direct effects in the gastrointestinal (GI) tract. We investigated if metformin stimulates intestinal glucose metabolism and lactate release in the prehepatic circulation. We included eight patients with transjugular intrahepatic portosytemic stent in an open label study. Portal and arterialized peripheral blood was obtained before and 90 minutes after ingestion of 1,000 mg metformin. Metformin increased lactate concentrations by 23% (95% confidence interval (CI): 6-40) after 90 minutes in the portal vein. The plasma concentration of glucose, insulin, and C-peptide was higher in the portal vein compared with arterialized blood (P < 0.05, all) and was lowered at both sampling sites following metformin ingestion (P < 0.01, all). Plasma concentration of GLP-1 was 20% (95% CI: 2-38) higher in the portal vein at baseline and metformin increased the concentration with 11% (1.5 pM, P = 0.05). The median concentration of growth differentiation factor 15 was 10% (95% CI: 1-19) higher in the portal vein compared with arterialized blood. Ninety minutes after metformin administration, the median portal vein concentration increased to around 3,000 ng/mL with a mean portal/arterial ratio of 1.5 (95% CI: 1.2-1.8). Non-targeted metabolomics showed that metformin acutely affected benzoate-hippurate metabolism. A single-dose of metformin directly affects substrate metabolism in the upper GI tract in humans with direct stimulation of nonoxidative glucose metabolism. These data suggest glucose lowering effects of metformin can be intrinsically linked with the GI tract without hepatic uptake of the drug.

The Danish comorbidity in liver transplant recipients study (DACOLT): a non-interventional prospective observational cohort study.

BACKGROUND: Liver transplantation is the only curative treatment for patients with end-stage liver disease. Short-term survival has improved due to improved surgical techniques and greater efficacy of immunosuppressive drugs. However, long-term survival has not improved to the same extent as the short-term survival, and the 10-year survival after liver transplantation is 60%. In addition to liver- and transplant-related causes, comorbidities such as cardiovascular, pulmonary, renal, and metabolic diseases have emerged as leading causes of morbidity and mortality in liver transplant recipients. The objective of this study is to assess the burden of comorbidities and identify both liver- and transplant-related risk factors as well as traditional risk factors that contribute to the pathogenesis of comorbidity in liver transplant recipients. METHODS/DESIGN: The Danish Comorbidity in Liver Transplant Recipients (DACOLT) study is an observational, longitudinal study. We aim to include all adult liver transplant recipients in Denmark (n = approx. 600). Participants will be matched by sex and age to controls from the Copenhagen General Population Study (CGPS) and the Copenhagen City Heart Study (CCHS). Physical and biological measures including blood pressure, ankle-brachial index, spirometry, exhaled nitric oxide, electrocardiogram, transthoracic echocardiography, computed tomography (CT) angiography of the heart, unenhanced CT of chest and abdomen and blood samples will be collected using uniform protocols in participants in DACOLT, CGPS, and CCHS. Blood samples will be collected and stored in a research biobank. Follow-up examinations at regular intervals up to 10 years of follow-up are planned. DISCUSSION: There is no international consensus standard for optimal clinical care or monitoring of liver transplant recipients. This study will determine prevalence, incidence and risk factors for comorbidity in liver transplant recipients and may be used to provide evidence for guidelines on management, treatment and screening and thereby contribute to improvement of the long-term survival. Trial registration ClinicalTrials.gov: NCT04777032; date of registration: March 02, 2021.

TERT promoter mutated circulating tumor DNA as a biomarker for prognosis in hepatocellular carcinoma.

BACKGROUND AND AIMS: Plasma circulating tumor DNA (ctDNA) with tumor-specific mutations is an attractive biomarker. The telomerase reverse transcriptase (TERT) C228T promoter mutation is the most prevalent tumor-associated mutation in hepatocellular carcinoma (HCC). We evaluated the presence and prognostic value of the TERT C228T mutation in plasma and tissue in a Danish HCC cohort. METHODS: We analyzed ctDNA from 95 HCC patients and 45 liver cirrhotic patients without HCC for the TERT mutation using droplet digital polymerase chain reaction. We also analyzed DNA from the corresponding primary tumor tissues in 34 HCC patients. RESULTS: The plasma TERT C228T mutation was detected in 42/95 HCC patients (44%) but in none of the non-HCC patients. The TERT mutation was detected in 23/34 tumor samples (68%). The TERT mutation was associated with increased mortality when detected in plasma (adjusted HR 2.16 (1.20-3.88), p = .010) but not in tumor tissue (adjusted HR 1.11 (0.35-3.56), p = .860). There was a positive correlation between the presence of the TERT mutation in plasma and an advanced TNM stage (p < .0001) and vascular invasion (p = .005). Analysis of the TERT mutation in plasma and tumor DNA from the same patient was concordant in 21/34 samples (62%; kappa value 0.31, p = .014). Non-concordance was associated with an early TNM stage. CONCLUSION: The plasma TERT mutation was detected in 44% of HCC patients and in none of non-HCC cirrhotic patients; and was associated with increased mortality. We propose the TERT C228T mutation in ctDNA as a promising HCC biomarker for prognosis.

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

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

[18 F]-Fluoro-2-deoxy-D-galactose positron emission tomography/computed tomography as complementary imaging tool in patients with hepatocellular carcinoma.

BACKGROUND & AIMS: Positron emission tomography (PET) with the liver-specific tracer [18 F]-fluoro-2-deoxy-D-galactose (18 F-FDGal) can be used for imaging of hepatocellular carcinoma (HCC). Curative intended and locoregional treatments of HCC require absence of extrahepatic disease. The aim of this prospective study was to determine whether adding 18 F-FDGal PET/CT to standard work-up changes the planned treatment in patients with HCC deemed suitable for curative or locoregional treatment. METHODS: Fifty patients with HCC were included at our tertiary liver centre. The primary study outcome was a change in treatment strategy. A subgroup of 29 patients was also examined with [18 F]-fluoro-2-deoxy-D-glucose (18 F-FDG) PET/CT for comparison. RESULTS: 18 F-FDGal PET/CT detected eight extrahepatic HCC metastases in six patients (12%), which were primarily not detected by ceCT or MRI. These findings led to a change in treatment in five patients (10%). One of the eight extrahepatic HCC foci was also detected by 18 F-FDG PET/CT. A total of 85 malignant intrahepatic foci were examined, 12 of these were new findings by 18 F-FDGal PET/CT which had a sensitivity of 71%, highest for large foci. None of the additional intrahepatic foci found by 18 F-FDGal PET changed the planned treatment. CONCLUSIONS: For the detection of extrahepatic HCC metastases, 18 F-FDGal PET/CT was superior both to standard clinical work-up with contrast-enhanced CT, and/or MRI, and to 18 F-FDG PET/CT in patients deemed suitable for locoregional treatment. 18 F-FDGal PET/CT led to a change in the planned treatment in 10% of the patients whereas 18 F-FDG PET/CT did not change the planned treatment in any patient.

Preliminary experience on safety of regorafenib after sorafenib failure in recurrent hepatocellular carcinoma after liver transplantation.

Regorafenib is one option for second-line treatment of hepatocellular carcinoma (HCC), improving overall survival (OS) of sorafenib-tolerant patients who develop progression. We aim to evaluate the safety and outcomes of regorafenib as second-line treatment for HCC recurrence after liver transplantation (LT). This is a retrospective, multicenter, international study including regorafenib-treated LT patients (2015-2018), with analysis of baseline characteristics and evolutionary events during sorafenib/regorafenib treatment. Twenty-eight LT patients (57 years, 7% cirrhotics, 54% performance status 1) were included. Median time from LT to regorafenib initiation was 3.9 (1.1-18.5) years; median time on sorafenib was 11.3 (0.7-76.4) months and 14 (1-591) days from sorafenib discontinuation to regorafenib. During regorafenib (6.3 months), all patients had at least one adverse event (AE), the most common grade 3/4 AEs were fatigue (n = 7) and dermatological reaction (n = 5). While no liver rejection was observed, plasma levels of immunosuppressive drugs increased in five. Twenty-four patients developed progression (38% extrahepatic growth, 33% new extrahepatic lesions/vascular invasion). Median OS from regorafenib initiation was 12.9 (95% CI, 6.7-19.1) and 38.4 months (95% CI, 18.5-58.4) for the sorafenib initiation. This is the first study showing safety of regorafenib after LT, thus providing the rational of considering regorafenib in the clinical decision-making in sorafenib-tolerant patients with HCC recurrence after LT.

ß-Blockers Improve Presinusoidal Portal Hypertension.

BACKGROUND: Presinusoidal portal hypertension is a clinically important cause of gastric and gastroesophageal varices. Whereas ß-blockers have an established prophylactic role against bleeding from esophageal and gastric varices in portal hypertension due to cirrhosis, the effect on presinusoidal portal hypertension is unknown. AIMS: To evaluate the hemodynamic effect of ß-blockers in non-cirrhotic patients with presinusoidal portal hypertension. METHODS: We measured the blood pressure gradient from spleen pulp to free hepatic vein in 12 patients with presinusoidal portal hypertension by combined hepatic vein catheterization and spleen pulp puncture while on and off ß-blocker treatment (random sequence). RESULTS: The ß-blockers reduced the gradient from a mean off-treatment value of 32 mm Hg to a on-treatment value of 26 mm Hg (P < 0.05) with a reduction of at least 20% in five patients (42%). CONCLUSIONS: ß-blocker treatment caused a clinically significant reduction in the pressure gradient from spleen pulp to the free hepatic vein. This finding supports the recommendation for prophylactic ß-blockage in patients with presinusoidal portal hypertension.

Metabolic liver function in humans measured by 2-18F-fluoro-2-deoxy-D-galactose PET/CT-reproducibility and clinical potential.

BACKGROUND: PET/CT with the radioactively labelled galactose analogue 2-18F-fluoro-2-deoxy-D-galactose (18F-FDGal) can be used to quantify the hepatic metabolic function and visualise regional metabolic heterogeneity. We determined the day-to-day variation in humans with and without liver disease. Furthermore, we examined whether the standardised uptake value (SUV) of 18F-FDGal from static scans can substitute the hepatic systemic clearance of 18F-FDGal (K met, mL blood/min/mL liver tissue/) quantified from dynamic scans as measure of metabolic function. Four patients with cirrhosis and six healthy subjects underwent two 18F-FDGal PET/CT scans within a median interval of 15 days for determination of day-to-day variation. The correlation between K met and SUV was examined using scan data and measured arterial blood concentrations of 18F-FDGal (blood samples) from 14 subjects from previous studies. Regional and whole-liver values of K met and SUV along with total metabolic liver volume and total metabolic liver function (total SUV, average SUV multiplied by total metabolic liver volume) were calculated. RESULTS: No significant day-to-day differences were found for K met or SUV. SUV had higher intraclass correlation coefficients than K met (0.92-0.97 vs. 0.49-0.78). The relationship between K met and SUV was linear. Total metabolic liver volume had non-significant day-to-day variation (median difference 50 mL liver tissue; P = 0.6). Mean total SUV in healthy subjects was 23,840 (95% CI, 21,609; 26,070), significantly higher than in the patients (P < 0.001). CONCLUSIONS: The reproducibility of 18F-FDGal PET/CT was good and SUV can substitute K met for quantification of hepatic metabolic function. Total SUV of 18F-FDGal is a promising tool for quantification of metabolic liver function in pre-treatment evaluation of individual patients.

Time-trends in incidence and prognosis of hepatocellular carcinoma in Denmark: A nationwide register-based cohort study.

BACKGROUND & AIMS: There are no recent data on incidence or survival of hepatocellular carcinoma (HCC) in Denmark. We examined current HCC epidemiology. METHODS: We used data from nationwide registries to identify all Danish citizens diagnosed with HCC in 1994-2016. We computed annual standardized incidence rates for the entire 1994-2016 period, and we compared survival for patients diagnosed in 2004-2014; data on HCC stage were available for that period alone and coded according to the TNM classification. RESULTS: The incidence rate for 1994-2016 was 3.7 (95% CI 3.6-3.8) per 100 000 population per year. It was stable around 3.0 in 1994-2007, climbed steadily to 5.7 in 2008-2011, and remained high in 2012-2016. The proportion of non-cirrhotic patients with HCC was 21%, with a slightly decreasing time trend. Median survival time rose from 2.7 months in 2004-2006 to 7.7 months in 2013-2014, but only patients with early HCC (stage I or II HCC or a "probably early HCC") saw improvements after 2007 (confounder-adjusted mortality hazard ratio for 2013-2014 vs 2007-2009=0.67, 95% 0.50-0.90). The proportion of patients with early HCC rose from 17% in 2004-2006 to 30% in 2013-2014. CONCLUSIONS: HCC incidence increased between 2007 and 2011. Concurrently, the HCC stage at diagnosis and patient survival improved. The likely reasons for the changes include easier access to HCC workup, changing diagnostic criteria for HCC, increased prevalence of risk factors for HCC, and improved treatment of patients with HCC.

Outcome in patients treated with isolated liver transplantation for familial transthyretin amyloidosis to prevent cardiomyopathy.

BACKGROUND: Familial transthyretin (TTR) amyloidosis is caused by different TTR mutations resulting in different clinical phenotypes of the disease. The Leu111Met mutation causes severe restrictive cardiomyopathy. Liver transplantation (LTx) is an established treatment option for patients with TTR amyloidosis; however, information on outcome after isolated LTx in patients with Leu111Met mutation amyloidosis is limited. METHODS: Between 2005 and 2012, six patients with TTR Leu111Met amyloidosis underwent isolated orthotopic LTx. None suffered from neuropathy. Prior to LTx, patients presented with echocardiographic manifestations of early cardiac amyloid involvement and in five endomyocardial biopsy was positive for TTR amyloid. RESULTS: Median age at LTx was 45.5 yr (range 39-54), and four were male (67%). All patients were alive at a median follow-up of 56.6 months (range 18-104). No surgical complications occurred. Two patients (33%) underwent cardiac transplantation during follow-up due to progressive cardiomyopathy. The remaining four patients experienced no echocardiographic or clinical deterioration of cardiac function following LTx. CONCLUSION: Isolated LTx appears to be a valuable treatment option for patients with familial TTR amyloidosis due to Leu111Met mutation. Appropriate timing of LTx is of utmost importance to avoid development of severe amyloid cardiomyopathy and the need for combined heart and liver transplantation.

The lumped constant for the galactose analog 2-18F-fluoro-2-deoxy-D-galactose is increased in patients with parenchymal liver disease.

UNLABELLED: The galactose analog 2-(18)F-fluoro-2-deoxy-d-galactose ((18)F-FDGal) is a suitable PET tracer for measuring hepatic galactokinase capacity in vivo, which provides estimates of hepatic metabolic function. As a result of a higher affinity of galactokinase toward galactose, the lumped constant (LC) for (18)F-FDGal was 0.13 in healthy subjects. The aim of the present study was to test the hypothesis of a significantly different LC for (18)F-FDGal in patients with parenchymal liver disease. METHODS: Nine patients with liver cirrhosis were studied in connection with a previous study with determination of hepatic intrinsic clearance of ¹8F-FDGal (V*(max/K*(m)). The present study determined the hepatic removal kinetics of galactose, including hepatic intrinsic clearance of galactose (V(max)/K(m)) from measurements of hepatic blood flow and arterial and liver vein blood galactose concentrations at increasing galactose infusions. LC for ¹8F-FDGal was calculated as (V*(max)/K*(m))/(V(max)/K(m)). On a second day, a dynamic ¹8-FDGal PET study with simultaneous infusion of galactose (mean arterial galactose concentration, 6.1 mmol/L of blood) and blood samples from a radial artery was performed, with determination of hepatic systemic clearance of ¹8F-FDGal (K*(+gal) from linear analysis of data (Gjedde-Patlak method). The maximum hepatic removal rate of galactose was estimated from ¹8F-FDGal PET data (V(max)(PET)) using the estimated LC. RESULTS: The mean hepatic V(max) of galactose was 1.18 mmol/min, the mean K(m) was 0.91 mmol/L of blood and the mean V(max)/K(m) was 1.18 L of blood/min. When compared with values of healthy subjects, K(m) did not differ (P = 0.77), whereas both V(max) and V(max)/K(m) were significantly lower in patients (both P < 0.01). Mean LC for ¹8LF-FDGal was 0.24, which was significantly higher than the mean LC of 0.13 in healthy subjects (P < 0.0001). Mean K*(+gal) determined from the PET study was 0.019 L of blood/min/L of liver tissue, which was not significantly different from that in healthy subjects (P = 0.85). Mean hepatic V(max)(PET) was 0.57 mmol/min/L of liver tissue, which was significantly lower than the value in healthy subjects (1.41 mmol/min/L of liver tissue (P < 0.0001). CONCLUSION: Disease may change the LC for a pet tracer, and this study demonstrated the importance of using the correct LC.

Regional metabolic liver function measured in patients with cirrhosis by 2-[¹8F]fluoro-2-deoxy-D-galactose PET/CT.

BACKGROUND & AIMS: There is a clinical need for methods that can quantify regional hepatic function non-invasively in patients with cirrhosis. Here we validate the use of 2-[(18)F]fluoro-2-deoxy-d-galactose (FDGal) PET/CT for measuring regional metabolic function to this purpose, and apply the method to test the hypothesis of increased intrahepatic metabolic heterogeneity in cirrhosis. METHODS: Nine cirrhotic patients underwent dynamic liver FDGal PET/CT with blood samples from a radial artery and a liver vein. Hepatic blood flow was measured by indocyanine green infusion/Fick's principle. From blood measurements, hepatic systemic clearance (Ksyst, Lblood/min) and hepatic intrinsic clearance (Vmax/Km, Lblood/min) of FDGal were calculated. From PET data, hepatic systemic clearance of FDGal in liver parenchyma (Kmet, mL blood/mL liver tissue/min) was calculated. Intrahepatic metabolic heterogeneity was evaluated in terms of coefficient-of-variation (CoV, %) using parametric images of Kmet. RESULTS: Mean approximation of Ksyst to Vmax/Km was 86% which validates the use of FDGal as PET tracer of hepatic metabolic function. Mean Kmet was 0.157 mL blood/mL liver tissue/min, which was lower than 0.274 mL blood/mL liver tissue/min, previously found in healthy subjects (p<0.001), in accordance with decreased metabolic function in cirrhotic livers. Mean CoV for Kmet in liver tissue was 24.4% in patients and 14.4% in healthy subjects (p<0.0001). The degree of intrahepatic metabolic heterogeneity correlated positively with HVPG (p<0.05). CONCLUSIONS: A 20-min dynamic FDGal PET/CT with arterial sampling provides an accurate measure of regional hepatic metabolic function in patients with cirrhosis. This is likely to have clinical implications for the assessment of patients with liver disease as well as treatment planning and monitoring.

Long-term outcome in patients treated with combined heart and liver transplantation for familial amyloidotic cardiomyopathy.

BACKGROUND: The amyloidogenic transthyretin (ATTR) mutation Leu111Met causes a primarily cardiac amyloidosis: Familial amyloidotic cardiomyopathy (FAC). Combined heart-liver transplantation (CHLTx) is the preferred treatment for patients with heart failure due to familial amyloidosis, but information on outcome of patients with Leu111Met mutation is limited. The aim of this study was to evaluate the long-term outcome of CHLTx in patients with FAC. METHODS AND MATERIALS: Between 1998 and 2009, CHLTx was performed in 7 FAC patients (four men). Six patients underwent simultaneous transplantation. All patients suffered from severe cardiomyopathy. RESULTS: Mean recipient age at transplantation was 48.3 ± 4.2 yr. Mean follow-up was 55 months. No peroperative mortality occured. Two patients died within the first year (infection, multi-organ failure) of transplantation. Cumulative survival at 4.5 yr was 71%. No significant liver rejections occurred. One patient experienced an episode of cardiac rejection requiring treatment (H2R). For the surviving five patients, most recent left ventricular ejection fraction was 0.61 ± 0.02, and plasma creatinine was 129 ± 47 µM. None developed significant allograft vasculopathy or neuropathy after transplantation. No recurrence of cardiac amyloid was found. CONCLUSIONS: CHLTx in selected patients with FAC due to Leu111Met mutation offers acceptable long-term survival, almost comparable with isolated cardiac transplantation. Allograft rejection was rare.

Mechanical characteristics of distension-evoked peristaltic contractions in the esophagus of systemic sclerosis patients.

BACKGROUND: Systemic sclerosis (SS) patients with severe esophageal affection have impaired peristalsis. However, motor function evaluated in vivo by manometry and fluoroscopy does not provide detailed information about the individual contraction cycles. AIMS: To apply, for the first time in gastrointestinal (GI) patients, a method and principles modified from cardiac research to study esophageal muscle behavior in SS patients. METHODS: Muscle contraction cycles were analyzed using pressure-cross-sectional area (P-CSA) loops during distension pressure up to 5 kPa. The probe with bag and electrodes for CSA measurements was positioned 7 and 15 cm above the lower esophageal sphincter (LES) in eleven healthy volunteers and eleven SS patients. The P-CSA, the wall tension, Δtension (afterload tension - preload tension), contraction velocity, work output (area of the tension-CSA loops), and power output (preload tension × CSA rate) were analyzed. RESULTS: The P-CSA loops consisted of phases with relaxation and contraction behavior. The tension-stretch ratio loops in patients were shifted to the left at both distension sites, indicative of a stiffer wall in patients. Lower contraction amplitudes and smaller P-CSA loops were observed for the SS patients. The work output, power output, Δtension, and contraction velocity were lower in patients (P < 0.001). Association was found between disease duration and the work output, Δtension, and velocity at pressure steps higher than 3 kPa (P < 0.05). CONCLUSIONS: Distension-evoked esophageal contraction can be studied in vivo and analyzed with advanced methods. Increased esophageal stiffness and impaired muscle function that depended on disease duration were observed for SS patients. The analysis may be useful for characterization of other diseases affecting GI function.

Spontaneous and bolus-induced motility in the chronically obstructed guinea-pig small intestine in vitro.

Partial obstruction of the small intestine results in dysmotility and morphometric changes proximal to the site of obstruction. However, our understanding of the relation between the morphometric remodeling and change in the motility pattern during chronic obstruction is sparse. The aim of this study was to investigate the effect of partial chronic intestinal obstruction on motility, morphology, and collagen content proximal and distal to the site of obstruction. Twenty guinea-pigs with partial intestinal obstruction and eight sham-operated controls lived for four weeks. Spontaneous and bolus-induced motility was recorded in isolated intestinal segments proximal and distal to the site of obstruction using a perfused low-compliance pressure-measuring system in vitro. After the motility experiments, the specimens were fixed at 2 kPa luminal distension pressure and sampled for histomorphometric determination of luminal radius, layer thickness, and wall thickness. Total wall collagen was also determined. The area under the curve (AUC) of spontaneous contractions and the amplitude, frequency, and AUC for the bolus-induced motility were higher in the proximal segments of the banded animals compared to distal segments and to the intestinal segments in the control animals (P < 0.05). The radius-to-thickness ratio was lowest in the proximal segments of the obstructed animals (P < 0.01). The collagen content was three times higher proximal to the site of obstruction when compared to distal locations and to the controls (P < 0.01). The AUC at 2 ml bolus injections plotted against the radius-to-thickness ratio showed a strong association (r = 0.97 for control, and r = 0.99 for obstruction, P < 0.01). No correlation was found between the collagen content and AUC. In conclusion, partial intestinal obstruction in guinea pigs caused pronounced changes in morphology and motility. An association was found between the radius-to-thickness ratio and bolus-induced motility.

Gastric emptying: a comparison of three methods.

OBJECTIVE: A better understanding of the clinical relevance of delayed gastric emptying (e.g. in diabetes) requires a simple, easily accessible and inexpensive method for measuring it. Two "new" methods for measuring gastric emptying of liquids (the paracetamol absorption test and the 13C-acetate breath test) are compared with the gold standard (gastric emptying scintigraphy (GES)). MATERIAL AND METHODS: The three techniques were used simultaneously in 10 healthy subjects. A gastric emptying time-retention curve was drawn for each technique and the results were compared at the 75%, 50% and 25% retention quartiles. RESULTS: Agreement was found between the paracetamol absorption test and GES (p=0.95; Hotelling's T 2 test). Using the Wagner-Nelson one compartment correction produced a retention curve for the 13C-acetate breath test statistically significantly below GES (p<0.01). CONCLUSION: In healthy subjects, the paracetamol absorption test produced results comparable to those of liquid GES, but not to the results of the 13C-acetate breath test.

Biomechanical remodeling of the chronically obstructed Guinea pig small intestine.

Small intestinal obstruction is a frequently encountered clinical problem. To understand the mechanisms behind obstruction and the clinical consequences, data are needed on the relation between the morphologic and biomechanical remodeling that takes place in the intestinal wall during chronic obstruction. We sought to determine the effect of partial obstruction on mechanical and morphologic properties of the guinea pig small intestine. Partial obstruction was created surgically in 2 groups of animals living for 2 and 4 weeks. Controls were sham operated and lived for 4 weeks. A combined impedance planimetry-high-frequency ultrasound system was designed to measure the luminal cross-sectional area and wall thickness. These measures were used to compute the circumferential stress and strain of the excised intestinal segments. The incremental elastic modulus was obtained by using nonlinear fitting of the stress-strain curve. Histologic analysis and the measurements of total wall collagen were also performed. The luminal cross-sectional area, wall thickness, and elastic modulus in circumferential direction increased in a time-dependent manner proximal to the obstruction site (P < 0.01), whereas no differences in these parameters were found distal to the obstruction site (P > 0.25). The circumferential stress-strain curves of the proximal segments in 2- and 4-week groups shifted to the left, indicating the intestinal wall became stiffer. Histologic examination revealed a massive increase in the thickness of the muscle layer especially the circular smooth muscle layer (P < 0.05). The collagen content proximal to the obstruction site was significantly larger in the partially obstructed animals compared to controls (P < 0.05). No difference was found distal to the obstruction site. Strong correlation was found between the collagen content and the elastic modulus at stress levels of 70 kPa stress (P < 0.01) and 10 kPa (P < 0.05) proximal to the obstruction site suggesting that the alteration of collagen has great impact on the mechanical remodeling. The morphologic and biomechanical remodeling likely influence the function of the intestine affected by partial obstructed intestine.