Association between a polymorphic variant in the CDKN2B-AS1/ANRIL gene and pancreatic cancer risk.

Genes carrying high-penetrance germline mutations may also be associated with cancer susceptibility through common low-penetrance genetic variants. To increase the knowledge on genetic pancreatic ductal adenocarcinoma (PDAC) aetiology, the common genetic variability of PDAC familial genes was analysed in our study. We conducted a multiphase study analysing 7745 single nucleotide polymorphisms (SNPs) from 29 genes reported to harbour a high-penetrance PDAC-associated mutation in at least one published study. To assess the effect of the SNPs on PDAC risk, a total of 14 666 PDAC cases and 221 897 controls across five different studies were analysed. The T allele of the rs1412832 polymorphism, that is situated in the CDKN2B-AS1/ANRIL, showed a genome-wide significant association with increased risk of developing PDAC (OR = 1.11, 95% CI = 1.07-1.15, P = 5.25 × 10-9 ). CDKN2B-AS1/ANRIL is a long noncoding RNA, situated in 9p21.3, and regulates many target genes, among which CDKN2A (p16) that frequently shows deleterious somatic and germline mutations and deregulation in PDAC. Our results strongly support the role of the genetic variability of the 9p21.3 region in PDAC aetiopathogenesis and highlight the importance of secondary analysis as a tool for discovering new risk loci in complex human diseases.

Reliability of Transient Elastography-Based Liver Stiffness for Diagnosing Portal Hypertension in Patients with Alcoholic Liver Disease: A Diagnostic Meta-Analysis with Specific Cut-Off Values.

BACKGROUND: Transient elastography-based liver stiffness value (TE-LSV) has been studied for the diagnosis of portal hypertension. Liver stiffness is influenced by the disease etiology. We aimed to perform a meta-analysis to determine the performance of TE-LSV for diagnosing portal hypertension in patients with alcoholic liver disease (ALD). METHODS: We searched PubMed, Web of Science, Ovid and Cochrane library. A bivariate model was used to compute sensitivity and specificity. A random effects model was used to pool diagnostic odds ratios. RESULTS: 9 studies with 679 patients were included. The pooled sensitivity and specificity based on a cut-off value around 21.8 kPa for clinically significant portal hypertension (CSPH) were 0.89 (95 % confidence interval (CI), 0.83-0.93) and 0.71(95 % CI, 0.64-0.78), respectively. For severe portal hypertension (SPH), the pooled sensitivity and specificity for a cut-off value around 29.1 kPa were 0.88 (95 % CI, 0.83-0.92) and 0.74 (95 % CI, 0.67-0.81), respectively. CONCLUSION: TE-LSV showed good performance for diagnosing portal hypertension in patients with ALD. The optimal cut-off value for CSPH and SPH was around 21.8 kPa and 29.1 kPa, respectively, and these two cut-off values showed good sensitivity and modest specificity. The etiology should be clear before using TE-LSV for portal hypertension.

Comparison of three cut-offs to diagnose clinically significant portal hypertension by liver stiffness in chronic viral liver diseases: a meta-analysis.

BACKGROUND: Transient elastography-based liver stiffness value (TE-LSV) has been investigated for assessing clinically significant portal hypertension (CSPH). The aetiology of CSPH is an important factor determining TE-LSV. There is insufficient evidence for selecting cut-off values. AIMS: This study performed a meta-analysis to compare the three most widely used cut-off values (around 13.6 kPa, 18 kPa and 22kPa) of TE-LSV for the diagnosis of CSPH in patients with chronic viral liver disease. METHODS: The PubMed, Ovid, Web of Science and Cochrane Library databases were searched. Diagnostic data for cut-off values around 13.6 kPa, 18 kPa and 22 kPa in each included study were extracted. The bivariate model was performed to estimate pooled sensitivity, specificity, positive likelihood ratio (LR+) and negative likelihood ratio (LR-). RESULTS: Eleven studies assessing 910 patients were included in this meta-analysis. Pooled sensitivities of cut-off values around 13.6 kPa, 18 kPa and 22 kPa were 0.96 (95% CI 0.93-0.97), 0.85 (0.81-0.89) and 0.74 (0.66-0.80), respectively; pooled specificities were 0.60 (0.47-0.75), 0.80 (0.71-0.87) and 0.94 (0.86-0.97), respectively. Pooled LR+ values were 2.4 (1.6-3.7), 4.4 (2.9-6.8) and 11.5 (5.5-23.5) for cut-off values around 13.6 kPa, 18 kPa and 22 kPa, respectively, for pooled LR- values of 0.07 (0.04-0.13), 0.17 (0.12-0.25) and 0.28 (0.22-0.36), respectively. CONCLUSION: Cut-off values around 13.6 kPa (high sensitivity) and 22 kPa (high specificity) could be used as screening and confirmation tools, respectively, in the diagnosis of CSPH. Overall, the cut-off value around 22 kPa showed the best performance. KEY POINTS: Transient elastography-based liver stiffness could be used to diagnose portal hypertension. Comparison of certain cut-off values would provide more information for clinical decision-making. Cut-off around 13.6 kPa was able to exclude clinically significant portal hypertension (CSPH) effectively. Cut-off around 22 kPa was able to confirm CSPH effectively.

Liver and spleen transient elastography predicts portal hypertension in patients with chronic liver disease: a prospective cohort study.

BACKGROUND: To assess correlation between liver or spleen stiffness measurement by transient elastography (TE) and hepatic venous pressure gradient (HVPG) in patients with chronic liver disease as well find optimal and rule in/rule out cut-offs for prognosis of clinically significant (CSPH) and severe (SPH) portal hypertension. METHODS: In this prospective study patients with different chronic liver diseases were included. TE was performed at the same day prior to HVPG measurement. HVPG was measured using catheter tip occlusion technique. Based on HVPG, patients were categorized into groups of CSPH and SPH. Cut-off values were established by applying ROC curve analysis. RESULTS: The study included 107 consecutive patients referred for HVPG measurement or transjugular liver biopsy. Successful spleen TE was performed in 99 of the patients. Liver and spleen TE strongly correlated with HVPG, r = 0.75 and r = 0.62, respectively. Accuracy to detect CSPH was 88.7% for liver stiffness of 17.4 kPa and 77.7% for spleen stiffness of 47.6 kPa. Accuracy to detect SPH was 83.1% for liver stiffness of 20.6 kPa and 77.7 % for spleen stiffness of 50.7 kPa. Liver stiffness <11.4 kPa could rule out CSPH with 55.2% specificity and >21.9 kPa rule in CSPH with 74.4% sensitivity. Liver stiffness <12.1 kPa could rule out SPH with 50.0% specificity and >35 kPa rule in SPH with 58.2% sensitivity. CONCLUSIONS: Liver and spleen stiffness correlate with HVPG and could be used to predict CSPH or SPH. Spleen elastography was not superior to liver elastography in predicting portal hypertension.

Accuracy of spleen stiffness measurement for the diagnosis of clinically significant portal hypertension in patients with compensated advanced chronic liver disease: a systematic review and individual patient data meta-analysis.

BACKGROUND: The diagnosis of clinically significant portal hypertension is crucial for prognosis and treatment guidance in patients with compensated advanced chronic liver disease (ACLD). Spleen stiffness measurement (SSM) might improve the non-invasive diagnosis of clinically significant portal hypertension, but previous studies have reported heterogeneous SSM cutoffs. We aimed to evaluate the accuracy of SSM and SSM-based algorithms in this setting. METHODS: In this systematic review and individual patient data meta-analysis, we searched PubMed, Embase, Scopus, Web of Science, and the Cochrane Library from database inception to Dec 31, 2022, for articles, abstracts, and letters, with no restrictions on language. Cross-sectional studies reporting hepatic venous pressure gradient and SSM by different techniques (transient elastography; two-dimensional shear-wave elastography [2D-SWE]; point shear-wave elastography [p-SWE]) in adults (≥18 years) with compensated ACLD were eligible for inclusion. The main outcome was the diagnostic performance of two SSM-based algorithms, with the Baveno VII model as a reference, evaluating sensitivity and specificity, as well as summary negative predictive values (NPVs) and positive predictive values (PPVs). In the Baveno VII model, clinically significant portal hypertension was ruled out if patients had a liver stiffness measurement (LSM) of 15 kPa or less and a platelet count of 150 × 109 platelets per L or higher and ruled in if they had an LSM of greater than 25 kPa. The two SSM-based models combined these same cutoffs with additional criteria. In the Baveno VII-SSM single cutoff model, clinically significant portal hypertension was ruled out if at least two of the following were present: LSM of 15 kPa or less, platelet count of 150 × 109 platelets per L or higher, and SSM of 40 kPa or less; and ruled in if at least two were present: LSM of greater than 25 kPa, platelet count of less than 150 × 109 platelets per L, and SSM of greater than 40 kPa. The Baveno VII-SSM dual cutoff model used the same criteria, but with a cutoff of SSM of less than 21 kPa to rule out, and greater than 50 kPa to rule in, clinically significant portal hypertension. This study is registered with PROSPERO, CRD42019127164. FINDINGS: Of the 44 records assessed for eligibility, 17 studies (with 1245 patients) were included in the meta-analysis. In the transient elastography cohort (n=600), the Baveno VII algorithm was validated for both ruling out (NPV 100%, 95% CI 64-100; sensitivity 100%, 95% CI 70-100) and ruling in (PPV 95%, 85-98; specificity 94%, 95% CI 87-97) clinically significant portal hypertension, but the proportion of patients with indeterminate results (grey zone) was 48% (95% CI 44-52); 57% (95% CI 52-62) of patients with clinically significant portal hypertension were included in the rule-in zone. The Baveno VII-SSM dual cutoff model had adequate NPV (98%, 95% CI 58-100; sensitivity 100%, 95% CI 91-100) and PPV (93%, 95% CI 84-97; specificity 89%, 95% CI 84-93), with 32% (95% CI 28-36) of patients in the grey zone; 76% (95% CI 72-80) of the patients with clinically significant portal hypertension were in the rule-in zone. The Baveno VII-SSM single cutoff model had a sensitivity of 93% (95% CI 85-97) and a NPV of 85% (95% CI 60-96) for ruling out, and a specificity of 86% (95% CI 80-91) and a PPV of 92% (95% CI 83-95) for ruling in, clinically significant portal hypertension. 88% (95% CI 84-91) of patients with clinically significant portal hypertension were included in the rule-in zone and 9% (95% CI 7-12) of patients were in the grey zone. In the 2D-SWE cohort (n=225), all three algorithms could safely rule in clinically significant portal hypertension with adequate PPV (≥90%), but NPV was inadequate for ruling out clinically significant portal hypertension. Insufficient data were available to evaluate the performance of SSM assessed by p-SWE. Heterogeneity was low (I2<25%) for most estimates. INTERPRETATION: Algorithms combining Baveno VII criteria with SSM showed good performance and reduced the diagnostic grey zone for clinically significant portal hypertension compared with Baveno VII criteria alone. Future studies should evaluate whether SSM-based diagnosis allows for the identification of patients who would benefit from non-selective ß-blocker treatment. FUNDING: None.

Circulating microbiome in patients with portal hypertension.

Portal hypertension (PH) in liver cirrhosis leads to increased gut permeability and the translocation of bacteria across the gut-liver axis. Microbial DNA has recently been detected in different blood compartments; however, this phenomenon has not been thoroughly analyzed in PH. This study aimed to explore circulating bacterial DNA signatures, inflammatory cytokines, and gut permeability markers in different blood compartments (peripheral and hepatic veins) of patients with cirrhosis and PH. The 16S rRNA blood microbiome profiles were determined in 58 patients with liver cirrhosis and 46 control patients. Taxonomic differences were analyzed in relation to PH, liver function, inflammatory cytokines, and gut permeability markers. Circulating plasma microbiome profiles in patients with cirrhosis were distinct from those of the controls and were characterized by enrichment of Comamonas, Cnuella, Dialister, Escherichia/Shigella, and Prevotella and the depletion of Bradyrhizobium, Curvibacter, Diaphorobacter, Pseudarcicella, and Pseudomonas. Comparison of peripheral and hepatic vein blood compartments of patients with cirrhosis did not reveal differentially abundant taxa. Enrichment of the genera Bacteroides, Escherichia/Shigella, and Prevotella was associated with severe PH (SPH) in both blood compartments; however, circulating microbiome profiles could not predict PH severity. Escherichia/Shigella and Prevotella abundance was correlated with IL-8 levels in the hepatic vein. In conclusion, we demonstrated a distinct circulating blood microbiome profile in patients with cirrhosis, showing that specific bacterial genera in blood are marginally associated with SPH, Model for End-Stage Liver Disease score, and inflammation biomarkers; however, circulating microbial composition failed to predict PH severity.

Endogenous motion of liver correlates to the severity of portal hypertension.

BACKGROUND: Degree of portal hypertension (PH) is the most important prognostic factor for the decompensation of liver cirrhosis and death, therefore adequate care for patients with liver cirrhosis requires timely detection and evaluation of the presence of clinically significant PH (CSPH) and severe PH (SPH). As the most accurate method for the assessment of PH is an invasive direct measurement of hepatic venous pressure gradient (HVPG), the search for non-invasive methods to diagnose these conditions is actively ongoing. AIM: To evaluate the feasibility of parameters of endogenously induced displacements and strain of liver to assess degree of PH. METHODS: Of 36 patients with liver cirrhosis and measured HVPG were included in the case-control study. Endogenous motion of the liver was characterized by derived parameters of region average tissue displacement signal (d antero, dr etro, d RMS) and results of endogenous tissue strain imaging using specific radiofrequency signal processing algorithm. Average endogenous strain µ and standard deviation σ of strain were assessed in the regions of interest (ROI) (1 cm × 1 cm and 2 cm × 2 cm in size) and different frequency subbands of endogenous motion (0-10 Hz and 10-20 Hz). RESULTS: Four parameters showed statistically significant (P < 0.05) correlation with HVPG measurement. The strongest correlation was obtained for the standard deviation of strain (estimated at 0-10 Hz and 2 cm × 2 cm ROI size). Three parameters showed statistically significant differences between patient groups with CSPH, but only d retro showed significant results in SPH analysis. According to ROC analysis area under the curve (AUC) of the σ ROI[0…10Hz, 2 cm × 2 cm] parameter reached 0.71 (P = 0.036) for the diagnosis of CSPH; with a cut-off value of 1.28 µm/cm providing 73% sensitivity and 70% specificity. AUC for the diagnosis of CSPH for µ ROI[0…10Hz, 1 cm × 1 cm] was 0.78 (P = 0.0024); with a cut-off value of 3.92 µm/cm providing 73% sensitivity and 80% specificity. D retro parameter had an AUC of 0.86 (P = 0.0001) for the diagnosis of CSPH and 0.84 (P = 0.0001) for the diagnosis of SPH. A cut-off value of -132.34 µm yielded 100% sensitivity for both conditions, whereas specificity was 80% and 72% for CSPH and SPH respectively. CONCLUSION: The parameters of endogenously induced displacements and strain of the liver correlated with HVPG and might be used for non-invasive diagnosis of PH.

Plasma Nogo-A and placental growth factor levels are associated with portal hypertension in patients with liver cirrhosis.

BACKGROUND: Clinically significant portal hypertension (CSPH) and severe portal hypertension (SPH) increase the risk for decompensation and life-threatening complications in liver cirrhosis. Pathologic angiogenesis might contribute to the formation of these conditions. Placental growth factor (PlGF) and Nogo-A protein are biomarkers of pathological angiogenesis, but data on their role in liver cirrhosis and portal hypertension is scarce. AIM: To determine plasma levels of PlGF and Nogo-A in patients with liver cirrhosis, CSPH, SPH and potential to predict portal hypertension. METHODS: A cohort of 122 patients with hepatitis C virus and/or alcohol-induced liver cirrhosis with characterized hepatic venous pressure gradient (HVPG) were included in the study. Demographic data, medical history, Child-Turcotte-Pugh and Model of End Stage liver disease score, clinical chemistry, liver stiffness values were recorded on the day of the procedure prior HVPG measurement. The degree of portal hypertension was determined by the invasive HVPG measurement. Nogo-A and PlGF plasma levels were evaluated using enzyme linked immunosorbent assay. The control group consisted of 30 healthy age- and sex- matched individuals. RESULTS: Peripheral PlGF levels were higher and Nogo-A levels were lower in patients with liver cirrhosis (23.20 vs 9.85; P < 0.0001 and 2.19 vs 3.12; P = 0.004 respectively). There was a positive linear correlation between peripheral levels of PlGF and HVPG (r = 0.338, P = 0.001) and negative linear correlation between the peripheral Nogo-A levels and HVPG (r = -0.267, P = 0.007). PlGF levels were higher in CSPH and SPH (P = 0.006; P < 0.0001) whereas Nogo-A levels were lower (P = 0.01; P < 0.033). Area under the curve for the diagnosis of CSPH for PlGF was 0.68 (P = 0.003) and for Nogo-A - 0.67 (P = 0.01); for SPH 0.714 (P < 0.0001) and 0.65 (P = 0.014) respectively. PlGF levels were higher and Nogo-A levels were lower in patients with esophageal varices (P < 0.05). PlGF cut-off value of 25 pg/mL distinguished patients with CSPH at 55.7% sensitivity and 76.7% specificity; whereas Nogo-A cut-off value of 1.12 ng/mL was highly specific (93.1%) for the diagnosis of CSPH. CONCLUSION: Plasma PlGF levels were higher while Nogo-A levels were lower in patients with liver cirrhosis and portal hypertension. Biomarkers showed moderate predictive value in determining CSPH and SPH.

Noninvasive Evaluation of Portal Hypertension Using a Supervised Learning Technique.

Portal hypertension (PHT) is a key event in the evolution of different chronic liver diseases and leads to the morbidity and mortality of patients. The traditional reliable PHT evaluation method is a hepatic venous pressure gradient (HVPG) measurement, which is invasive and not always available or acceptable to patients. The HVPG measurement is relatively expensive and depends on the experience of the physician. There are many potential noninvasive methods to predict PHT, of which liver transient elastography is determined to be the most accurate; however, even transient elastography lacks the accuracy to be a perfect noninvasive diagnostic method of PHT. In this research, we are focusing on noninvasive PHT assessment methods that rely on selected best-supervised learning algorithms which use a wide set of noninvasively obtained data, including demographical, clinical, laboratory, instrumental, and transient elastography measurements. In order to build the best performing classification meta-algorithm, a set of 21 classification algorithms have been tested. The problem was expanded by selecting the best performing clinical attributes using algorithm-specific filtering methods that give the lowest error rate to predict clinically significant PHT. The suggested meta-algorithm objectively outperforms other methods found in literature and can be a good substitute for invasive PHT evaluation methods.