Clinical impact of MRI on indeterminate findings on contrast-enhanced CT suspicious of HCC.

OBJECTIVES: In patients evaluated for hepatocellular carcinoma (HCC), magnetic resonance imaging (MRI) is often used secondarily when multiphase contrast-enhanced computed tomography (ceCT) is inconclusive. We investigated the clinical impact of adding MRI. MATERIALS AND METHODS: This single-institution retrospective study included 48 MRI scans (44 patients) conducted from May 2016 to July 2023 due to suspicion of HCC on a multiphase ceCT scan. Data included medical history, preceding and subsequent imaging, histology when available, and decisions made at multidisciplinary team meetings. RESULTS: In case of possible HCC recurrence, 63% of the MRI scans were diagnostic of HCC. For 80% of the negative MRI scans, the patients were diagnosed with HCC within a median of 165 days in the suspicious area of the liver. In case of possible de-novo HCC in patients with cirrhosis, 22% of the scans were diagnostic of HCC and 33% of the negative MRI scans were of patients diagnosed with HCC within a median of 109 days. None of the non-cirrhotic patients with possible de-novo HCC and negative MRI scans (64%) were later diagnosed with HCC, but 3/5 of the indeterminate scans were of patients diagnosed with HCC in a biopsy. CONCLUSIONS: Secondary MRI to a multiphase ceCT scan suspicious of HCC is highly valuable in ruling out HCC in non-cirrhotic patients and in diagnosing HCC non-invasively in cirrhotic patients and patients with prior HCC. Patients with cirrhosis or prior HCC are still at high risk of having HCC if MRI results are inconclusive or negative.

Similar insulin regulation of splanchnic FFA and VLDL-TG in men with nonalcoholic hepatic steatosis and steatohepatitis.

This study aimed to determine whether obese men with nonalcoholic fatty liver disease (NAFLD) display differences between those with simple steatosis versus steatohepatitis (NASH) in splanchnic and hepatic FFA and VLDL-triglycerides (VLDL-TG) balances. The study involved 17 obese men with biopsy-proven NAFLD (9 with NASH and 8 with simple steatosis). We used hepatic vein catheterization in combination with [3H]palmitate and [14C]VLDL-TG tracers to measure splanchnic palmitate and VLDL-TG uptake and release rates during basal and hyperinsulinemic conditions. Indocyanine green was used to measure splanchnic plasma flow. Splanchnic palmitate uptake was similar in the two groups and significantly reduced during hyperinsulinemia (NASH: 62 (48-77) versus 38 (18-58) µmol/min; simple steatosis: 62 (46-78) versus 45 (25-65) µmol/min, mean (95% CI), basal versus clamp periods, respectively, P = 0.02 time-effect). Splanchnic palmitate release was also comparable between groups and nonsignificantly diminished during hyperinsulinemia. The percent palmitate delivered to the liver originating from visceral adipose tissue lipolysis was similar and unchanged by hyperinsulinemia. Splanchnic uptake and release of VLDL-TG were similar between groups. Hyperinsulinemia suppressed VLDL-TG release (P <0.05 time-effect) in both groups. Insulin-mediated glucose disposal was similar in the two groups (P = 0.54). Obese men with NASH and simple steatosis have similar splanchnic uptake and release of FFA and VLDL-TG and a similar proportion of FFA from visceral adipose tissue lipolysis delivered to the liver. These results demonstrate that the splanchnic balances of FFA and VLDL-TG do not differ between obese men with NASH and those with simple steatosis.

Landmark analysis of the risk of recurrence after resection or ablation for HCC: A nationwide study.

BACKGROUND: The risk of HCC recurrence at particular landmarks since the initial treatment is unknown. With this registry-based study, we aimed to provide a nuanced description of the prognosis following resection or ablation for HCC, including landmark analyses. METHODS: Using the Danish nationwide health care registries, we identified all patients who received resection or ablation in 2000-2018 as the first HCC treatment. HCC recurrence was defined as a new HCC treatment > 90 days after the first treatment. We conducted competing risk landmark analyses of the cumulative risk of recurrence and death. RESULTS: Among 4801 patients with HCC, we identified 426 patients who received resection and 544 who received ablation. The 2 treatment cohorts differed in cirrhosis prevalence and tumor stage. The 5-year recurrence risk was 40.7% (95% CI 35.5%-45.8%) following resection and 60.7% (95% CI: 55.9%-65.1%) following ablation. The 1-year recurrence risk decreased over the landmarks from 20.4% (95% CI: 16.6%-24.6%) at the time of resection to 4.7% (95% CI: 0.9%-13.9%) at the 5-year landmark. For ablation, the risk decreased from 36.1% (95% CI: 31.9%-40.4%) at the time of treatment to 5.3% (95% CI: 0.4%-21.4%) at the 5-year landmark. The risk of death without recurrence was stable over the landmarks following both resection and ablation. CONCLUSIONS: In conclusion, the risk of recurrence or death following resection or ablation for HCC is high from the treatment date, but the risk of recurrence decreases greatly over the survival landmarks. This information is valuable for clinicians and their patients.

Prevalence of hyperthyroidism and hypothyroidism in liver transplant recipients and associated risk factors.

The prevalence of hyperthyroidism and hypothyroidism and associated risk factors are unknown in liver transplant recipients. We aimed to determine the prevalence of hyperthyroidism and hypothyroidism and associated risk factors in liver transplant recipients and to compare it with controls from the general population. As part of the Danish Comorbidity in Liver Transplant Recipients (DACOLT) Study, all Danish liver transplant recipients over the age of 20 were invited for measurements of concentrations of thyrotropin and thyroid hormones. The prevalence of hyperthyroidism and hypothyroidism was compared to age- and sex-matched controls from the Copenhagen General Population Study. Using logistic regression adjusted for age, sex, smoking, and body-mass index, we investigated potential risk factors. We recruited 489 liver transplant recipients and 1808 controls. Among liver transplant recipients, 14 (2.9%) had hyperthyroidism compared with 21 (1.2%) of controls (adjusted odds ratio [aOR] 2.24, 95% confidence interval [CI] 1.05-4.75, P = 0.04), while 42 (5.7%) had hypothyroidism compared with 139 (7.7%) of controls (aOR 0.68, 95% CI 0.43-1.08, P = 0.10). Female sex, and autoimmune hepatitis and primary sclerosing cholangitis as causes of transplantation were associated with hyperthyroidism after adjustments. Age, female sex, and autoimmune liver diseases as cause of transplantation were associated with hypothyroidism after adjustments. DACOLT is registered in ClinicalTrials.gov (NCT04777032).

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

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

The role of N-terminal pro-brain natriuretic peptide, chromogranin A, and 5-hydroxyindoleacetic acid in screening for carcinoid heart disease.

Carcinoid heart disease (CHD) is a serious complication for patients with neuroendocrine tumors (NETs), and early detection is crucial. We aimed to investigate N-terminal pro-brain natriuretic peptide (NT-proBNP), chromogranin A (CgA), and plasma 5-hydroxyindoleacetic acid (P-5-HIAA) as a screening tool for detection of CHD. We prospectively included patients with disseminated small intestinal NETs (SI-NETs) and performed transthoracic echocardiography (TTE), questionnaires, and biochemical assessment of NT-proBNP, CgA, and P-5-HIAA. The presence and severity of CHD was assessed using a scoring system based on echocardiographic characteristics. A total of 93 patients were included in the final analysis. Fifteen (16%) were diagnosed with CHD. The median NT-proBNP (219 ng/L vs. 124 ng/L, p = .05), CgA (3930 pmol/L vs. 256 pmoL/L, p < .0001), and P-5-HIAA (1160 nmol/L vs. 210 nmoL/L, p < .0001) were significantly higher in patients with CHD compared to non-CHD patients. For NT-proBNP, the area under the receiver operating characteristic (AUROC) curve for detection of CHD was 0.67 (95% CI: 0.50-0.84), and at a 260 ng/L cutoff level, the sensitivity and specificity were 46% and 79%. For CgA, the AUROC was 0.91 (95% CI: 0.84-0.97), and at a cutoff level of 598 pmol/L, the sensitivity and specificity were 100% and 69%. For P-5-HIAA, the AUROC was 0.89 (95% CI: 0.80-0.98), and at a cutoff level of 752 nmol/L, the sensitivity and specificity were 92% and 85%. In conclusion, CgA and P-5-HIAA proved excellent markers of CHD while NT-proBNP lacked the required diagnostic accuracy to be used as a screening tool.

Alcohol use and hepatocellular carcinoma risk in patients with alcohol-related cirrhosis.

OBJECTIVES: Insights into risk factors for hepatocellular carcinoma (HCC) among patients with alcohol-related cirrhosis (ALD cirrhosis) are important for decisions about HCC surveillance. We studied the effects of continued hazardous alcohol use in ALD cirrhosis on HCC risk. METHODS: Within a nationwide registry-based cohort of patients with ALD cirrhosis, we compared HCC risk between patients with a continued hazardous alcohol use and matched comparators. We used Fine-Gray regression to compare the risk of HCC and Cox regression to compare all-cause mortality. We also included patients with ALD cirrhosis in a clinical case-control study. Cases had HCC, and controls did not. Alcohol use was quantified using the AUDIT-C-questionnaire. Logistic regression was used to analyze the association between hazardous alcohol use and HCC risk. RESULTS: In the registry-based study, we included 8,616 patients with continued hazardous alcohol use and 8,616 matched comparators. Patients with a continued hazardous alcohol use had a lower HCC risk (subdistribution hazard ratio: 0.64, 95% confidence interval [CI]: 0.57 - 0.72) and higher mortality (hazard ratio: 1.62, 95% CI: 1.56 - 1.67). In the clinical study, we included 146 patients with ALD cirrhosis of whom 53 had newly diagnosed HCC. Hazardous alcohol use was insignificantly associated with a lower HCC risk (odds ratio: 0.61, 95% CI: 0.25 - 1.46). CONCLUSIONS: Hazardous alcohol use in patients with ALD cirrhosis is associated with higher mortality and, consequently, a lower HCC risk. Even if alcohol is carcinogenic, HCC surveillance will therefore likely be more effective in patients with ALD cirrhosis without a hazardous alcohol use.

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

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

Effects of Curative-Intent Treatments on Hepatocellular Carcinoma Survival in Alcohol-Related Cirrhosis: A Nationwide Study.

Purpose: The aim of curative-intent treatment for hepatocellular carcinoma (HCC) is to restore the patients' survival to what it would have been, had they not developed HCC. We examined the chances of such 'statistical cure' from HCC in patients with cirrhosis due to alcohol-related liver disease (ALD cirrhosis). Patients and Methods: Using nationwide Danish healthcare registries, all patients with ALD cirrhosis who were treated for HCC in 2004-2018 were identified and included in cohorts based on initial HCC treatment. We used cure fraction analyses to estimate the chance of being statistically cured by each HCC treatment. Results: We included 1087 patients with HCC due to ALD cirrhosis, of whom 51 (4.7%) were treated with resection and 215 (19.8%) were treated with ablation. The cure fraction, ie the fraction of patients who experienced no excess mortality from HCC, was 31.8% (95% CI: 0.0-67.5) following resection and 22.9% (95% CI: 2.6-43.2) following ablation. In patients who were still alive five years after the initial HCC treatment, the likelihood of having been statistically cured at that time was 69.0% after resection and 60.2% after ablation. For both treatments, a 90% chance of having been statistically cured was reached after seven years. Conclusion: Based on cure fraction analyses, resection for HCC statistically cures 31.8% of patients with HCC and underlying ALD cirrhosis, while ablation statistically cures 22.9% of patients. Seven years after curative-intent treatments for HCC, surviving patients are 90% likely to be statistically cured of HCC. This information is valuable to patients and the clinicians caring for them.

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.

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

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

Incidental Finding of Pulmonary Embolism at Workup Before SIRT.

ABSTRACT: Selective internal radiation therapy (SIRT) is a catheter-guided treatment offered to selected patients with primary and secondary liver malignancies. SIRT is preceded by a workup procedure, where 99mTc-MAA (macroaggregated albumin) is injected in the tumor supplying artery/arteries followed by MAA scintigraphy. SIRT is frequently offered to patients with hepatocellular carcinoma (HCC), but large HCCs are known to be associated with a high risk of liver-to-lung shunting. We present a HCC patient case where a large lung-shunt enabled diagnosis of pulmonary embolism.

The altered serum lipidome and its diagnostic potential for Non-Alcoholic Fatty Liver (NAFL)-associated hepatocellular carcinoma.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is affecting more people globally. Indeed, NAFLD is a spectrum of metabolic dysfunctions that can progress to hepatocellular carcinoma (NAFLD-HCC). This development can occur in a non-cirrhotic liver and thus, often lack clinical surveillance. The aim of this study was to develop non-invasive surveillance method for NAFLD-HCC. METHODS: Using comprehensive ultra-high-performance liquid chromatography mass-spectrometry, we investigated 1,295 metabolites in serum from 249 patients. Area under the receiver operating characteristic curve was calculated for all detected metabolites and used to establish their diagnostic potential. Logistic regression analysis was used to establish the diagnostic score. FINDINGS: We show that NAFLD-HCC is characterised by a complete rearrangement of the serum lipidome, which distinguishes NAFLD-HCC from non-cancerous individuals and other HCC patients. We used machine learning to build a diagnostic model for NAFLD-HCC. We quantified predictive metabolites and developed the NAFLD-HCC Diagnostic Score (NHDS), presenting superior diagnostic potential compared to alpha-fetoprotein (AFP). Patients' metabolic landscapes show a progressive depletion in unsaturated fatty acids and acylcarnitines during transformation. Upregulation of fatty acid transporters in NAFLD-HCC tumours contribute to fatty acid depletion in the serum. INTERPRETATION: NAFLD-HCC patients can be efficiently distinguished by serum metabolic alterations from the healthy population and from HCC patients related to other aetiologies (alcohol and viral hepatitis). Our model can be used for non-invasive surveillance of individuals with metabolic syndrome(s), allowing for early detection of NAFLD-HCC. Therefore, serum metabolomics may provide valuable insight to monitor patients at risk, including morbidly obese, diabetics, and NAFLD patients. FUNDING: The funding sources for this study had no role in study design, data collection, data analyses, interpretation or writing of the report as it is presented herein.

First-generation somatostatin ligand receptor treatment in a pregnant patient with a neuroendocrine tumor with liver metastases.

SUMMARY: This rare case describes the course of a pregnancy in a patient with a disseminated small intestinal neuroendocrine tumor. The patient received treatment with first-generation somatostatin ligand receptor (SLR) every 4 weeks and had stable disease for several years before her pregnancy. First-generation SLR treatment was initially paused after detection of the pregnancy. During pregnancy, the patient experienced moderate gastro-intestinal discomfort and fatigue, which was considered predominantly pregnancy related. However, since symptoms could be linked to the patient's cancer, treatment was resumed after the first trimester. Chromogranin-A measurements remained stable throughout pregnancy and was paralleled by the absence of diarrhea and only minor flushing. She gave birth by elective caesarean section in week 37 to a healthy baby. Subsequent follow up imaging immediately after and 10 months postpartum showed no disease progression. The safety profile of SLR treatment during pregnancy in the context of disseminated neuroendocrine tumors (NET) is discussed. LEARNING POINTS: Neuroendocrine neoplasms (NEN) are rare cancers often occurring in the gastro-intestinal tract or lungs. Many patients with NEN live for several years with disseminated disease. SLR treatment has been given to pregnant patients before; often patients with acromegaly. Pregnancies are reported uneventful. This patient completed an uneventful pregnancy while receiving SLR treatment for disseminated neuroendocrine disease and gave birth to a healthy baby. More research regarding long term effects and safety signals of SLR treatment during pregnancy are much needed.

Regorafenib Efficacy After Sorafenib in Patients With Recurrent Hepatocellular Carcinoma After Liver Transplantation: A Retrospective Study.

Safety of regorafenib in hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) has been recently demonstrated. We aimed to assess the survival benefit of regorafenib compared with best supportive care (BSC) in LT patients after sorafenib discontinuation. This observational multicenter retrospective study included LT patients with HCC recurrence who discontinued first-line sorafenib. Group 1 comprised regorafenib-treated patients, whereas the control group was selected among patients treated with BSC due to unavailability of second-line options at the time of sorafenib discontinuation and who were sorafenib-tolerant progressors (group 2). Primary endpoint was overall survival (OS) of group 1 compared with group 2. Secondary endpoints were safety and OS of sequential treatment with sorafenib + regorafenib/BSC. Among 132 LT patients who discontinued sorafenib included in the study, 81 were sorafenib tolerant: 36 received regorafenib (group 1) and 45 (group 2) received BSC. Overall, 24 (67%) patients died in group 1 and 40 (89%) in group 2: the median OS was significantly longer in group 1 than in group 2 (13.1 versus 5.5 months; P < 0.01). Regorafenib treatment was an independent predictor of reduced mortality (hazard ratio, 0.37; 95% confidence interval [CI], 0.16-0.89; P = 0.02). Median treatment duration with regorafenib was 7.0 (95% CI, 5.5-8.5) months; regorafenib dose was reduced in 22 (61%) patients for adverse events and discontinued for tumor progression in 93% (n = 28). The median OS calculated from sorafenib start was 28.8 months (95% CI, 17.6-40.1) in group 1 versus 15.3 months (95% CI, 8.8-21.7) in group 2 (P < 0.01). Regorafenib is an effective second-line treatment after sorafenib in patients with HCC recurrence after LT.

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.

Randomised clinical study: acute effects of metformin versus placebo on portal pressure in patients with cirrhosis and portal hypertension.

BACKGROUND: Portal hypertension is the main determinant of clinical decompensation in patients with liver cirrhosis. In preclinical data metformin lowers portal pressure, but there are no clinical data for this beneficial effect. AIMS: To investigate the acute effects of metformin on hepatic venous pressure gradient (HVPG) and liver perfusion. METHODS: In a randomised, double-blinded study design, we investigated 32 patients with cirrhosis before and 90 minutes after ingestion of 1000-mg metformin (n = 16) or placebo (n = 16). Liver vein catherisation was performed to evaluate HVPG and indocyanine green (ICG) infusion for investigation of hepatic blood flow. RESULTS: The mean relative change in HVPG was -16% (95% CI: -28% to -4%) in the metformin group compared with 4% (95% CI: -6% to 14%) in the placebo group (time × group interaction, P = 0.008). In patients with baseline HVPG ≥12 mm Hg clinically significant improvements in HVPG (HVPG <12 mm Hg or a >20% reduction in HVPG) were observed in 46% (6/13) of metformin-treated and in 8% (1/13) of placebo-treated patients (P = 0.07). There were no changes or differences in systemic blood pressure, heart rate, hepatic plasma and blood flow, hepatic ICG clearance, hepatic O2 uptake or inflammation markers between groups. CONCLUSIONS: A single oral metformin dose acutely reduces HVPG in patients with portal hypertension without affecting systemic or liver hemodynamics or inflammatory biomarkers. This offers a promising perspective of a safe and inexpensive treatment option that should be investigated in larger-scale clinical studies with long-term outcomes in patients with cirrhosis and portal hypertension.

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.