ABSTRACT
BACKGROUND: Genetic testing can be used to evaluate disease risk. We evaluated if the use of three Single Nucleotide Polymorphisms (SNPs), alone or combined into a genetic risk score (GRS), can aid identify significant fibrosis in subjects with metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: We assessed three known risk variants: PNPLA3 rs738409, TM6SF2 rs58542926, and HSD17B13 rs72613567. The study included 414 adult individuals invited from the Danish population, who were defined as at-risk of MASLD due to elevated ALT and body mass index (BMI) >25 kg/m2. Participants were assessed clinically and by the Fibrosis-4 (FIB-4) index and Fibroscan. RESULTS: In total, 17 participants (4.1 %) had alcohol-related liver disease, 79 (19.1 %) had no evidence of liver disease, and four (1.0 %) were diagnosed with other liver diseases, including malignant disease. The remaining 314 participants (75.8 %) were diagnosed with MASLD. Of the 27 who underwent a liver biopsy for suspected fibrosis, 15 had significant fibrosis (≥F2) and 12 had no/mild fibrosis (F0/F1). The GRS was not associated with significant fibrosis (p = 0.09) but PNPLA3 was with an odds ratio of 6.75 (95 % CI 1.29 - 50.7; p = 0.039) risk allele CG/GG versus CC. The diagnostic accuracy of PNPLA3 combined with an increased Fib-4 (>1.3) was excellent for detecting significant fibrosis with a sensitivity of 1.00 (95 % CI 0.72-1.00), but the specificity was no better than for FIB-4 alone. CONCLUSIONS: This study found no evidence to support the use of GRS for diagnosing significant fibrosis in MASLD. However, the combination of PNPLA3 and Fib-4 increased sensitivity considerably. In addition, ALT remains a useful tool for screening diagnosing other liver diseases than MASLD.
Subject(s)
17-Hydroxysteroid Dehydrogenases , Lipase , Liver Cirrhosis , Membrane Proteins , Polymorphism, Single Nucleotide , Humans , Lipase/genetics , Membrane Proteins/genetics , Male , Female , Middle Aged , 17-Hydroxysteroid Dehydrogenases/genetics , Liver Cirrhosis/genetics , Adult , Fatty Liver/genetics , Fatty Liver/diagnosis , Aged , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/complications , Acyltransferases , Phospholipases A2, Calcium-IndependentABSTRACT
Accurate non-invasive biomarkers to diagnose metabolic dysfunction-associated steatotic liver disease (MASLD)-related fibrosis are urgently needed. This study applies a translational approach to develop a blood-based biomarker panel for fibrosis detection in MASLD. A molecular gene expression signature identified from a diet-induced MASLD mouse model (LDLr-/-.Leiden) is translated into human blood-based biomarkers based on liver biopsy transcriptomic profiles and protein levels in MASLD patient serum samples. The resulting biomarker panel consists of IGFBP7, SSc5D and Sema4D. LightGBM modeling using this panel demonstrates high accuracy in predicting MASLD fibrosis stage (F0/F1: AUC = 0.82; F2: AUC = 0.89; F3/F4: AUC = 0.87), which is replicated in an independent validation cohort. The overall accuracy of the model outperforms predictions by the existing markers Fib-4, APRI and FibroScan. In conclusion, here we show a disease mechanism-related blood-based biomarker panel with three biomarkers which is able to identify MASLD patients with mild or advanced hepatic fibrosis with high accuracy.
Subject(s)
Biomarkers , Liver Cirrhosis , Semaphorins , Humans , Liver Cirrhosis/blood , Liver Cirrhosis/diagnosis , Liver Cirrhosis/pathology , Biomarkers/blood , Animals , Male , Mice , Female , Semaphorins/blood , Semaphorins/genetics , Semaphorins/metabolism , Middle Aged , Fatty Liver/blood , Fatty Liver/diagnosis , Fatty Liver/pathology , Liver/pathology , Liver/metabolism , Disease Models, Animal , Receptors, LDL/genetics , Receptors, LDL/metabolism , Transcriptome , Mice, Knockout , Adult , Mice, Inbred C57BL , Insulin-Like Growth Factor Binding ProteinsABSTRACT
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.
Subject(s)
Blood Glucose , Hepatitis, Autoimmune , Insulin Resistance , Insulin , Humans , Female , Male , Middle Aged , Blood Glucose/metabolism , Cross-Sectional Studies , Adult , Insulin/blood , Hepatitis, Autoimmune/blood , Hepatitis, Autoimmune/metabolism , Hepatitis, Autoimmune/complications , Glucagon-Like Peptide 1/blood , Glucagon-Like Peptide 1/metabolism , Fatty Liver/metabolism , Fatty Liver/blood , Gastric Inhibitory Polypeptide/blood , Gastric Inhibitory Polypeptide/metabolism , Aged , Glucose Tolerance Test , Cholangitis, Sclerosing/blood , Cholangitis, Sclerosing/metabolism , Cholangitis, Sclerosing/complications , Glucagon/blood , Glucagon/metabolism , Liver Cirrhosis, Biliary/blood , Liver Cirrhosis, Biliary/metabolism , Liver Cirrhosis, Biliary/complications , C-Peptide/bloodABSTRACT
BACKGROUND: Alterations in the production of short-chain fatty acids (SCFAs) may reflect disturbances in the gut microbiota and have been linked to metabolic dysfunction-associated steatotic liver disease (MASLD). We assessed plasma SCFAs in patients with MASLD and healthy controls. METHODS: Fasting venous blood samples were collected and eight SCFAs were measured using gas chromatography-tandem mass spectrometry (GC-MS/MS). Relative between-group differences in circulating SCFA concentrations were estimated by linear regression, and the relation between SCFA concentrations, MASLD, and fibrosis severity was investigated using logistic regression. RESULTS: The study includes 100 patients with MASLD (51% with mild/no fibrosis and 49% with significant fibrosis) and 50 healthy controls. Compared with healthy controls, MASLD patients had higher plasma concentrations of propionate (21.8%, 95% CI 3.33 to 43.6, p = 0.02), formate (21.9%, 95% CI 6.99 to 38.9, p = 0.003), valerate (35.7%, 95% CI 4.53 to 76.2, p = 0.02), and α-methylbutyrate (16.2%, 95% CI 3.66 to 30.3, p = 0.01) but lower plasma acetate concentrations (- 30.0%, 95% CI - 40.4 to - 17.9, p < 0.001). Among patients with MASLD, significant fibrosis was positively associated with propionate (p = 0.02), butyrate (p = 0.03), valerate (p = 0.03), and α-methylbutyrate (p = 0.02). Six of eight SCFAs were significantly increased in F4 fibrosis. CONCLUSIONS: In the present study, SCFAs were associated with MASLD and fibrosis severity, but further research is needed to elucidate the potential mechanisms underlying our observations and to assess the possible benefit of therapies modulating gut microbiota.
Subject(s)
Butyrates , Fatty Liver , Metabolic Diseases , Humans , Propionates , Tandem Mass Spectrometry , Fatty Acids, Volatile , Valerates , FibrosisABSTRACT
BACKGROUND: Non-selective beta-blockers (NSBB) are widely used in the treatment of patients with cirrhosis. Only about 50% respond with a sufficient reduction in their hepatic venous pressure gradient (HVPG) and NSBB may induce detrimental cardiac and renal effects in the presence of severe decompensation. We aimed to assess the effects of NSBB on haemodynamics using magnetic resonance imaging (MRI) and to assess if these haemodynamic changes were related to the disease severity and HVPG response. METHOD: A prospective cross-over study of 39 patients with cirrhosis. Patients underwent hepatic vein catheterization and MRI with assessments of HVPG, cardiac function, systemic and splanchnic haemodynamics before and after propranolol infusion. RESULTS: Propranolol induced significant decreases in cardiac output (-12%) and blood flow of all vascular compartments, with the largest reductions seen in the azygos venous (-28%), portal venous (-21%), splenic (-19%) and superior mesenteric artery (-16%) blood flow. Renal artery blood flow fell by -5% in the total cohort, with a more pronounced reduction in patients without ascites than in those with ascites (-8% vs. -3%, p = .01). Twenty-four patients were NSBB responders. Their changes in HVPG after NSBB were not significantly associated with other haemodynamic changes. CONCLUSION: The changes in cardiac, systemic and splanchnic haemodynamics did not differ between NSBB responders and non-responders. The effects of acute NSBB blockade on renal flow seem to depend on the severity of the hyperdynamic state, with the largest reduction in renal blood flow in compensated patients compared to decompensated patients with cirrhosis. However, future studies are needed to assess the effects of NSBB on haemodynamics and renal blood flow in patients with diuretic-resistant ascites.
Subject(s)
Hypertension, Portal , Propranolol , Humans , Propranolol/pharmacology , Propranolol/therapeutic use , Cross-Over Studies , Hepatic Veins/diagnostic imaging , Ascites/diagnostic imaging , Ascites/drug therapy , Ascites/etiology , Prospective Studies , Hypertension, Portal/etiology , Hypertension, Portal/complications , Adrenergic beta-Antagonists/pharmacology , Adrenergic beta-Antagonists/therapeutic use , Liver Cirrhosis/diagnostic imaging , Liver Cirrhosis/drug therapy , Liver Cirrhosis/complications , Hemodynamics , Magnetic Resonance Imaging , CatheterizationABSTRACT
INTRODUCTION: Portal hypertension exacerbates the disease course of cirrhosis and is responsible for major complications, including bleeding from esophageal varices, ascites, and encephalopathy. More than 40 years ago, Lebrec and colleagues introduced beta-blockers to prevent esophageal bleeding. However, evidence now suggests that beta-blockers may cause adverse reactions in patients with advanced cirrhosis. AREAS COVERED: This review addresses current evidence for the pathophysiology of portal hypertension, focusing on the pharmacological effects of treatment with beta-blockers, indications for preventing variceal bleeding, their effects on decompensated cirrhosis, and the risk of treating patients suffering from decompensated ascites and renal dysfunction with beta-blockers. EXPERT OPINION: The diagnosis of portal hypertension should be based on direct measurements of portal pressure. Carvedilol or nonselective beta-blockers are the first-line treatment for patients with medium-to-large varices as primary or secondary prophylaxis, in Child C patients with small varices, and sometimes for patients with clinically significant portal hypertension (HVPG ≥ 10 mm Hg, irrespective of the presence of varices) to prevent decompensation. Caution should be used when treating decompensated patients who are suspected of imminent cardiac and renal dysfunction. Future strategies for managing patients with portal hypertension should aim for more personalized treatment that takes into account the disease stage.
Subject(s)
Esophageal and Gastric Varices , Hypertension, Portal , Kidney Diseases , Varicose Veins , Child , Humans , Esophageal and Gastric Varices/drug therapy , Esophageal and Gastric Varices/etiology , Propranolol/therapeutic use , Ascites/drug therapy , Ascites/etiology , Gastrointestinal Hemorrhage/chemically induced , Gastrointestinal Hemorrhage/prevention & control , Adrenergic beta-Antagonists/adverse effects , Liver Cirrhosis/complications , Liver Cirrhosis/diagnosis , Liver Cirrhosis/drug therapy , Fibrosis , Hypertension, Portal/drug therapy , Hypertension, Portal/etiology , Varicose Veins/chemically induced , Varicose Veins/complications , Varicose Veins/drug therapyABSTRACT
INTRODUCTION: Arterial vasodilation and hyperdynamic circulation are considered hallmarks of the pathophysiological mechanisms of decompensation in cirrhosis. However, detailed characterization of peripheral, splanchnic, renal, and cardiac hemodynamic have not previously been published in a spectrum from healthy stage to advanced decompensated liver disease with hepatorenal syndrome-acute kidney injury (HRS-AKI). METHODS: We included 87 patients with cirrhosis and 27 healthy controls in this prospective cohort study. The population comprised patients with compensated cirrhosis (n = 27) and decompensated cirrhosis (n = 60); patients with decompensated cirrhosis were further separated into subsets of responsive ascites (33), refractory ascites (n = 16), and HRS-AKI (n = 11). We measured portal pressure and assessed regional blood flow by magnetic resonance imaging. RESULTS: Patients with compensated cirrhosis experienced higher azygos venous flow and higher hepatic artery flow fraction of cardiac index than controls ( P < 0.01), but other flow parameters were not significantly different. Patients with decompensated cirrhosis experienced significantly higher cardiac index ( P < 0.01), higher superior mesenteric artery flow ( P = 0.01), and lower systemic vascular resistance ( P < 0.001) compared with patients with compensated cirrhosis. Patients with HRS-AKI had the highest cardiac output and lowest renal flow of all groups ( P < 0.01 and P = 0.02, respectively). Associations of single hemodynamic parameters were stronger with model for end-stage liver disease than with portal pressure. DISCUSSION: The regional cardiocirculatory changes seem closely linked to clinical symptoms with 3 distinguished hemodynamic stages from compensated to decompensated cirrhosis and, finally, to HRS-AKI. The attenuated renal perfusion despite high cardiac output in patients with HRS-AKI challenges the prevailing pathophysiological hypothesis of cardiac dysfunction as a causal factor in HRS-AKI. Finally, magnetic resonance imaging seems an accurate and reliable noninvasive method to assess hemodynamics and has potential as a diagnostic tool in patients with cirrhosis.
Subject(s)
Acute Kidney Injury , End Stage Liver Disease , Hepatorenal Syndrome , Acute Kidney Injury/complications , Acute Kidney Injury/etiology , Ascites , End Stage Liver Disease/complications , Hepatorenal Syndrome/diagnostic imaging , Hepatorenal Syndrome/etiology , Humans , Liver Cirrhosis/complications , Liver Cirrhosis/diagnostic imaging , Magnetic Resonance Imaging , Magnetic Resonance Spectroscopy/adverse effects , Prospective Studies , Severity of Illness IndexABSTRACT
AIMS: Patients with cirrhosis and portal hypertension are at high risk of developing complications such as variceal hemorrhage, ascites, and cardiac dysfunction, the latter of which is known as cirrhotic cardiomyopathy. Since non-selective beta-blockers (NSBB) may aggravate hemodynamic complications we investigated the effect of real-time propranolol infusion on cardiac function in patients with varying degrees of cirrhosis. METHODS: Thirty-eight patients with Child-Pugh A (n = 17), B (n = 17) and C (n = 4) underwent liver vein catheterization and cardiac magnetic resonance imaging. We assessed the effect of real-time propranolol infusion on the hepatic venous pressure gradient, cardiac index, stroke volume, ejection fraction, heart rate, and contractility. RESULTS: Nineteen patients were classified as responders to beta-blocker therapy. In pooling Child-Pugh B and C patients, the reduction in cardiac index by beta-blockade was weaker than in Child-Pugh A patients (-8.5% vs. -20.5%, p = 0.043). The effect of NSBB on portal pressure was inversely correlated to changes in the left atrium where the left atrial volume changed by 4 mL±18 in responders compared to 15 mL±11 in non-responders (p = 0.03). Finally, the baseline ejection fraction correlated inversely with the reduction in portal pressure (r = -0.39, p = 0.02). CONCLUSION: We found the effect of beta-blockade on cardiac index in patients with advanced cirrhosis to be less potent than in patients with early cirrhosis, indicating that underlying cirrhotic cardiomyopathy increases, and the cardiac compensatory reserve becomes more compromised, with disease progression. The differential effects of beta-blockade in the left atrium may be used to predict the effect of beta-blockers on portal pressure, but further studies are needed to investigate this possibility.
Subject(s)
Esophageal and Gastric Varices , Propranolol , Adrenergic beta-Antagonists/pharmacology , Adrenergic beta-Antagonists/therapeutic use , Esophageal and Gastric Varices/complications , Gastrointestinal Hemorrhage/complications , Humans , Liver Cirrhosis/complications , Liver Cirrhosis/drug therapy , Propranolol/pharmacology , Propranolol/therapeutic useABSTRACT
Yersinia pseudotuberculosis is a Gram-negative bacterium causing infection in humans through contaminated water and/or food. The infection commonly occurs as gastroenteritis and fever, abdominal pain due to mesenteric lymphadenitis and diarrhoea. Bacteraemia is rare and is typically seen in immunocompromised patients and occurs with different clinical presentations like Far East scarlet-like fever, splenic abscess, or mimic appendicitis. This is a case report of Y. pseudotuberculosis bacteraemia and splenic abscess in a Caucasian male.
Subject(s)
Bacteremia , Mesenteric Lymphadenitis , Splenic Diseases , Yersinia pseudotuberculosis Infections , Yersinia pseudotuberculosis , Humans , Male , Yersinia pseudotuberculosis Infections/diagnosis , Yersinia pseudotuberculosis Infections/drug therapyABSTRACT
BACKGROUND: MR elastography can determine organ-related stiffness, which reflects the degree of fibrosis. Liver stiffness increases in cirrhosis, and stiffness increases further post-prandially due to increased portal blood in-flow. Non-selective beta-blockers (NSBB) reduce the portal venous inflow, but their effect on liver and spleen stiffness are disputed. AIMS: To assess whether MR elastography of the liver or spleen reflects the severity of cirrhosis, whether treatment with NSBB changes liver and spleen stiffness and whether changes in stiffness can predict the effect of NSBB on portal pressure. METHODS: Fifty-two patients with cirrhosis underwent liver vein catheterization and two-dimensional (2D) MR elastography on separate days. Thirty-six of the patients had a hepatic venous pressure gradient (HVPG) of ≥12 mmHg and were tested prior to, and after, intravenous infusion of NSBB using HVPG measurement and MR elastography. RESULTS: HVPG showed a strong, positive, linear relationship with liver stiffness (r2 = 0.92; P < .001) and spleen stiffness (r2 = 0.94; P < .001). The cut-off points for identifying patients with a HVPG ≥ 12 mmHg were 7.7 kPa for liver stiffness (sensitivity 0.78, specificity 0.64) and 10.5 kPa for spleen stiffness (sensitivity 0.8, specificity 0.79). Intravenous administration of NSBB significantly decreased spleen stiffness by 6.9% (CI: 3.5-10.4, P < .001), but NSBB had no consistent effect on liver stiffness. However, changes in spleen stiffness were not related to the HVPG response (P = .75). CONCLUSIONS: Two-dimensional MR elastographic estimation of liver or spleen stiffness reflects the degree of portal hypertension in patients with liver cirrhosis, but changes in stiffness after NSBB do not predict the effect on HVPG.