Complication Of Cirrhosis Research Articles

S3122 Portal Vein Thrombosis Post Laparoscopic Sleeve Gastrectomy

Introduction: Portal vein thrombosis (PVT) is a clot formation in one of the branches of the portal vein. It is a well-known complication in patients with cirrhosis or post-abdominal surgery. Data on PVT post laparoscopic bariatric surgeries are scarce. Here we present a case of PVT post laparoscopic sleeve gastrectomy. Case Description/Methods: A 43- years-old female with a known past medical history of hypertension, Asthma, and obesity underwent a robotic-assisted laparoscopic sleeve gastrectomy. She presented to the Emergency Department (ED) complaining of Abdominal pain 2 days after the sleeve gastrectomy operation. The patient reported doing well postoperatively till 2 days when she developed sudden epigastric abdominal pain and generalized abdominal discomfort, associated with nausea and anorexia. On arrival at the ED, her vital signs were stable and liver enzymes were normal. She had RUQ tenderness on the physical exam without guarding or rebound. The patient then had a Computed tomography (CT) of the abdomen and pelvis with IV contrast which showed occlusive left portal vein thrombosis extending to branches. She was started on oral direct Anticoagulant (DOAC) with Rivaroxaban. She had complete hypercoagulable work up with hematology which was unremarkable (Figure 1). Discussion: PVT is a well-described complication of cirrhosis. in non-cirrhotic patients, the etiology of PVT can be due to systemic or local factors. A hypercoagulable state such as Factor V Leiden, antithrombin III deficiency, protein C and S deficiency, or Methylenetetrahydrofolate reductase (MTHFR) mutation is associated with higher thrombosis risk. Local factors include direct manipulation of portosystemic vessels such as during splenectomy with resultant endothelial damage and increase vascular thrombogenicity. A gastric sleeve is less likely to cause PVT since it only involves the short gastric vein. However, with the use of laparoscopic surgical techniques, there has been an increase in reported PVT. It is suspected that an increase in intra-abdominal pressure during carbon dioxide insufflation causes a pro-thrombotic state by decreasing venous and portal blood flow. The diagnosis of PVT post-operatively requires a high level of suspicion and can be made with abdominal imaging such as Ultrasound with color doppler or CT with IV contrast. The treatment is usually anticoagulation with the goal of recanalization of the portal vein on repeat imaging to prevent the development of non-cirrhotic portal hypertension in these patients.Figure 1.: Color doppler showing left portal vein thrombosis.

S1375 Role of Rifaximin in the Prevention of Acute Variceal Bleeding in Cirrhosis: A Systematic Review and Meta-Analysis

Introduction: Acute variceal bleeding is one of the most severe complications of cirrhosis and is associated with high mortality. Rifaximin has been shown to be efficacious in the treatment of hepatic encephalopathy (HE). Some studies have also shown rifaximin to be beneficial in decreasing the risk of initial episode of variceal bleeding and to decrease the risk of re-bleeding in those with prior variceal hemorrhage. We performed a systematic review and meta-analysis to evaluate the efficacy of rifaximin in prevention of acute variceal bleeding. Methods: A systematic literature search was performed at PubMed, Embase, Web of Science and Cochrane library database until March 2022. All studies that evaluated the role of rifaximin in prevention of initial episode of variceal bleeding or risk of re-bleeding in cirrhotic patients were included in the meta-analysis. The analysis was performed using Revman 5.4 software. Results: Seven studies including 1999 patients were included in the final meta-analysis. Of these, 3 studies were randomized controlled trials (RCTs) and 4 studies were observational studies. Out of 1999 included patients, 769 patients received rifaximin along with standard care management and 1230 patients received standard of care management only. Patients in the rifaximin group had significantly lower odds of acute variceal bleeding with OR= 0.43 (95% CI: 0.31, 0.58), I2=0. We also performed a subgroup analysis including only RCTs, which although showed trend toward lower risk of variceal bleeding in rifaximin group but did not reach statistically significance OR=0.58 (0.27, 1.28). In a second subgroup analysis, patients who received rifaximin also had significantly lower odds of spontaneous bacterial peritonitis (SBP) OR= 0.15 (0.10, 0.22), risk of acute kidney injury/hepatorenal syndrome (AKI/HRS) OR=0.39 (0.22, 0.68) and HE OR=0.37 (0.21, 0.68). Publication bias was deferred as number of studies were less than 10. (Figure) Conclusion: Rifaximin is associated with lower odds of variceal bleeding, SBP, AKI/HRS and HE in patients with cirrhosis. Although the overall analysis demonstrates rifxamin can decrease the risk of variceal bleeding this loses statistical significance when only RCTs were included in the analysis. Therefore, additional RCTs are needed to further evaluate if there is any benefit of rifaximin in reducing the risk of variceal bleeding and to justify its use aside from the treatment HE.Figure 1.: Forest plot for variceal bleeding.

S3269 A Rare Case of HCC Recurrence as a Bleeding Gastric Ulcer

Introduction: Hepatocellular Carcinoma (HCC) is a potential complication of cirrhosis. Liver transplantation is often viewed as curative of HCC when fulfilling the Milan criteria prior to surgery. However, recurrence rates of HCC post-transplant remain high. Here, we present a case of post-transplant HCC recurrence presenting as a bleeding gastric ulcer. Case Description/Methods: A 72-year-old Caucasian female presented with coffee-ground emesis. Three years prior, she had orthotopic liver transplantation due to hepatitis C virus (HCV) related cirrhosis, previously treated with Vosevi/ribavarin with sustained virologic response and HCC with evidence of moderate differentiation and focus of vascular invasion on explanted liver. Upper endoscopy revealed a cratered gastric ulcer with heaped edges. Biopsies from the ulcer edges showed poorly differentiated adenocarcinoma with signet ring features. Immunohistochemical testing showed tumor cells positive for CK8/18, Glutamine Synthetase, and polyclonal CEA with canalicular pattern; features consistent with high grade HCC. CT scan revealed a necrotic mass replacing most of the pancreatic body and tail, a lung mass and multiple vertebral compression fractures. Fine needle biopsy of pancreatic mass was consistent with metastatic carcinoma compatible with HCC. (Figure) Discussion: Tumor recurrence post-liver transplantation is noted in 15-20% of cases after 5 years. There is no clear consensus for Standard post-transplantation monitoring. A multi-center study has proposed a protocol using the RETREAT (Risk Estimation of Tumor Recurrence Post-Transplantation) scoring system for determining screening of HCC recurrence. This includes: AFP levels prior to transplant (max score of 3 for AFP >1000), vascular invasion (max score of 2 for any evidence of invasion), and sum of the diameters of HCC lesions (max score of 3 for sum >10). In our patient, with microvascular invasion, a score of 2 would standardize her to screening every 6 months for 2 years which was consistent with the monitoring she had. The median time to HCC tumor recurrence is within 12-16 months post-transplantation, with over 75% occurring in first 2 years. Initial presentation of HCC recurrence as a direct gastrointestinal invasion is exceeding rare. There have been few case reports describing similar presentations as in our case, however, none have occurred after liver transplantation. Given its rarity, differential diagnosis of gastric ulcers in patients with history of HCC should include metastatic disease.Figure 1.: A. Gastric Ulcer B. Pancreatic Mass C. Lung Mass.

S3237 Pneumocystis jirovecii Infection in Cirrhosis: A Case Report and Review of the Literature

Introduction: Pneumocystis jirovecii is a fungus that causes serious pneumonia in immunocompromised individuals most classically associated with AIDS or prolonged steroid use. Immune dysfunction is a well- nown complication of cirrhosis; however, Pneumocystis pneumonia (PCP) is not typically associated with cirrhosis as a common risk factor. We present a case of PCP in a patient with cirrhosis and review the existing cases in the literature. Case Description/Methods: A 59-year-old male with past medical history of alcoholic cirrhosis (MELD 30, Child Pugh Class C) presented with sepsis secondary to spontaneous bacterial peritonitis. He reported he was 6 months sober. He initially improved on ceftriaxone alone; he did not receive steroids. On hospital day five he developed dyspnea and hypoxia. CT-angiogram revealed extensive ground glass opacities. Despite broad spectrum antimicrobials, his condition deteriorated resulting in invasive ventilation. Bronchoalveolar lavage was significant for Pneumocystis jiroveci by polymerase chain reaction. HIV testing was negative. Due to renal impairment, therapy was initiated with clindamycin and primaquine before he expired (Figure). Discussion: This case was unique in that cirrhosis was the only identified risk factor for immunosuppression which predisposed to PCP. PCP is rare outside of risk factors including AIDS, prolonged systemic steroids and other immunosuppressive therapies, organ transplantation, hematologic malignancy, and solid tumors. There were 14 similar cases in the literature. Of the 15 total cases, 66% were male; the median age was 54. Eleven were in the setting of alcoholic hepatitis, and 9 of these received steroids. However, none of the steroid exposures were significant enough to be a classic risk factor for PCP. Common comorbidities included COPD and lymphopenia. CMV pneumonia was seen in 33% of cases. Esophageal candidiasis and Histoplasma capsulatum pneumonia were also recorded. Fatality in 87% of cases suggests that PCP in cirrhosis is associated with a poor prognosis. There are multiple possible mechanisms why these patients developed PCP. Systemic inflammation related to cirrhosis may dysregulate key inflammatory mediators required for immune response to Pneumocystis. Also, Low CD4 counts related to portal hypertension and splenic sequestration may play a role, although an effective immune response also requires interplay of B cells and natural killer cells. This case and review are important reminders of the severity of immunocompromise in cirrhosis.Figure 1.: CT-Angiogram with diffuse ground glass opacities. Table 1. - Author Date Age/sex Prior steroid exposure (duration if applicable) Etiology of cirrhosis Additional conditions Treatment for PCP Death (y/n) Ikawa 2001 40M Y (10 days and 22 days with a 7 day interim in between) alcohol abuse cytomegalovirus pneumonia, esophageal candidiasis, lymphopenia none Y Faria 2007 44F present in 6 of 7 cases (median duration: 16 days)* alcohol abuse cytomegalovirus isolated in 3 of 7 cases* trimethoprim/ sulfamethoxazole (TMP/SMX) Y 49M alcohol abuse TMP/SMX Y 50M alcohol abuse TMP/SMX Y 53M alcohol abuse TMP/SMX Y 56F alcohol abuse TMP/SMX Y 58F alcohol abuse TMP/SMX Y 61M alcohol abuse TMP/SMX Y Dodi 2010 54F Y (9 days) alcohol abuse cytomegalovirus pneumonia, hepatorenal syndrome TMP/SMX Y Yee 2017 52M N hepatitis c hepatitis c, lymphopenia primaquine, clindamycin, corticosteroids, TMP/SMX N Hadfield 2019 63M N alcohol abuse COPD TMP/SMX Y Akhter 2020 67F N hepatitis c COPD steroids, antibiotics (unspecified) N Dugan 2020 64M N NASH COPD, lymphopenia, histoplasma capsulatum pneumonia TMP/SMX Y Chung 2020 43M Y (26 days) alcohol abuse n/a TMP/SMX Y Meyers 2022 59M N alcohol abuse COPD, lymphopenia clindamycin, primaquine Y *Not specified which cases had the exposures and/or conditions.

S1235 Endoscopic Ultrasound-Guided Shear Wave Elastography of the Liver and Spleen to Predict Complications of Cirrhosis and Correlation With EUS-Guided Portal Pressure Gradient

Introduction: Endo-hepatology (EH) is an emerging field which utilizes endoscopic ultrasound (EUS) to evaluate patients with chronic liver disease (CLD). This workup includes EUS-guided liver biopsies, EUS-guided portal pressure gradients (EUS-PPG), EUS-shear wave elastography of the liver (EUS-SWE-L) and spleen (EUS-SWE-S). Our study aimed to determine a correlation between EUS-SWE of the liver , spleen, and EUS-PPG and complications of CLD. Methods: Retrospective analysis of 28 patients from 2021-22. Pearson correlation (PC) coefficients were used to compare EUS-SWE-L and EUS-SWE-S to EUS-PPG. T tests were used to compare EUS-SWE-L and EUS-SWE-S to complications of CLD such as ascites, presence of esophageal varices, and thrombocytopenia. Receiver Operating Characteristics Curve (ROCC) analysis was done to evaluate the utility of shear wave/liver stiffness and shear wave/spleen stiffness to predict the presence of esophageal varices or ascites. Results: 23 patients underwent EUS-SWE-S and 20 had EUS-PPG. Significant correlation noted between platelet count and EUS-SWE-L measurement (PC= -0.496, p=0.01). There was a significant difference in EUS-SWE-L measurement in patients with and without thrombocytopenia (28.90 kPa vs. 17.66 kPa, p=0.002) and in those with and without ascites (29.67 kPa vs. 18.64 kPa, p=0.003). There was also a significant difference in EUS-SWE-S measurements in patients with and without ascites (39.44 kPa vs. 30.06 kPa, p= 0.029). There was a weak correlation between EUS-PPG and EUS-SWE-S (PC = -0.45, p=0.05). ROCC analysis determined the best cut-off for EUS-SWE-L to predict the presence of esophageal varices or ascites was > 22.7 kPa with sensitivity of 78.6% and specificity of 55.6%. Best cut-off for EUS-SWE-S to predict the presence of esophageal varices or ascites was > 31.12 kPa with sensitivity of 85.7% and specificity of 55.6%. (Figure) Conclusion: EUS-SWE of Liver and Spleen showed utility in predicting complications of liver disease such as varices, ascites and thrombocytopenia. There was also a weak, but statistically insignificant correlation between EUS-SWE-S and EUS-PPG. The limitations of our study include small sample size and, therefore, decreased power of the study. Further evaluation with a larger sample size is needed to better elucidate the findings determined in our study regarding EUS-PPG, EUS-SWE-S, and EUS-SWE-L. Our data suggests that these techniques have significant potential in determining those at greatest risk of complications of clinically significant CLD (Table).Figure 1.: Descriptive Statistical Analysis Table 1. - Patient characteristics Total number of patients, n 28 Age, mean in years (std. dev.) 50.25 (+/- 12.02) Male, n (%) 16 (57%) Race- white, n (%) 28 (100%) BMI, mean (std. dev) 31.53 (+/- 9.85) Liver biopsy performed, n (%) 22 (78.6%) Stage > F3 on biopsy, n (%) 16 (72.7%) Esophageal varices, n (%) 9 (32.1%) Ascites, n (%) 12 (42.9%) Plt count < 150, n (%) 16 (57.1%) MELD-Na, mean (std. dev.) 12.67 (+/- 4.97) Child score, mean (std. dev.) 6.81 (+/- 1.82)

Alcohol-associated Liver Disease Is Now the Most Common Indication for Liver Transplant Waitlisting Among Young American Adults.

Mortality from cirrhosis is increasing and is the highest among young adults with alcohol-associated liver disease (ALD). The aim of this study was to describe rates of liver transplant (LT) waitlisting stratified by age, sex, and cirrhosis etiology. Retrospective population-based study from 2003 to 2018 using the Scientific Registry of Transplant Recipients database. Adults newly registered on the LT waitlist were included, and age at listing was dichotomized to ±40 y. Annual standardized incidence proportions of LT waitlisting by age group, sex, and etiology were calculated using census data. Changes in annual rates were described with Poisson regression. A total of 209 399 unique individuals were included, 10 326 (5%) <40 y at listing. In those <40 y of age, listing increased most for ALD (4-fold increase) followed by nonalcoholic fatty liver disease (NAFLD; 2-fold increase). Compared to young adult males, young females were more likely to be listed for ALD and less likely to be listed for NAFLD. In those ≥40 y of age, listings increased most for ALD (2-fold increase) and NAFLD (2-fold increase). Hepatitis C virus increased from 2003 to 2013 and declined post-2014 in the ≥40-y age group. LT waitlisting is increasing substantially in young Americans, driven primarily by ALD. These data support ongoing efforts to identify adolescents and young adults with early stages of ALD where interventions can be implemented to prevent the development of cirrhosis and liver-related complications.

Toll-like receptor 4 signaling pathway mediates both liver and kidney injuries in mice with hepatorenal syndrome.

Hepatorenal syndrome (HRS) is a complication of cirrhosis with high morbidity and mortality. Nevertheless, the underlying mechanism involving how kidney injury aggravates the progression of cirrhosis remains unclear. This study aims to explore the role of the Toll-like receptor 4 (TLR4) signaling pathway in mediating liver and kidney injuries in HRS mice induced by unilateral ureteral obstruction (UUO) and/or bile duct ligation (BDL). Two weeks after UUO, there were no obvious pathological changes in mouse liver and the unligated side of kidney. Nevertheless, impaired liver and kidney functions, inflammatory response, and fibrosis were examined in mice after 2 wk of BDL. Compared with those of other groups, mice in the BDL + UUO group presented severer liver and kidney injuries, higher levels of inflammatory factors, and faster deposition of collagens, suggesting that kidney injuries accelerated the aggravation of HRS. Correlation analysis identified a positive correlation between expression levels of inflammatory factors and fibrotic levels. Meanwhile, TLR4 and its ligand MyD88 were upregulated during the process of liver and kidney injuries in HRS mice. Further animal experiments in transgenic TLR4-/- mice or in those treated with TAK242, a small molecule inhibitor of TLR4, showed that blocking the TLR4 signaling pathway significantly improved survival quality and survival rate in HRS mice by alleviating liver fibrosis and kidney injury. It is concluded that kidney dysfunction plays an important role in the aggravation of cirrhosis, which may be attributed to the TLR4 signaling pathway. Targeting TLR4 could be a promising therapeutic strategy for protecting both liver and kidneys in patients with HRS.NEW & NOTEWORTHY Our study established BDL, UUO, and BDL + UUO models, providing a novel idea for analyzing liver and kidney diseases. It is highlighted that the kidney injury accelerated the aggravation of HRS via inflammatory response, which could be protected by inhibiting the TLR4 signaling pathway. We believed that targeting TLR4 was a promising therapeutic strategy for protecting both liver and kidney functions in patients with HRS.

Nutritional assessment in patients with liver cirrhosis.

Malnutrition is a liver cirrhosis complication affecting more than 20%-50% of patients. Although the term can refer to either nutrient deficiency or excess, it usually relates to undernutrition in cirrhosis settings. Frailty is defined as limited physical function due to muscle weakness, whereas sarcopenia is defined as muscle mass loss and an advanced malnutrition stage. The pathogenesis of malnutrition in liver cirrhosis is multifactorial, including decreased oral intake, maldigestion/malabsorption, physical inactivity, hyperammonemia, hypermetabolism, altered macronutrient metabolism and gut microbiome dysbiosis. Patients with chronic liver disease with a Body Mass Index of < 18.5 kg/m2 and/or decompensated cirrhosis or Child-Pugh class C are at the highest risk of malnutrition. For patients at risk of malnutrition, a detailed nutritional assessment is required, typically including a history and physical examination, laboratory testing, global assessment tools and body composition testing. The latter can be done using anthropometry, cross-sectional imaging including computed tomography or magnetic resonance, bioelectrical impedance analysis and dual-energy X-ray absorptiometry. A multidisciplinary team should screen for and treat malnutrition in patients with cirrhosis. Malnutrition and sarcopenia are associated with an increased risk of complications and a poor prognosis in patients with liver cirrhosis; thus, it is critical to diagnose these conditions early and initiate the appropriate nutritional therapy. In this review, we describe the prevalence and pathogenesis of malnutrition in liver cirrhosis patients and discuss the best diagnostic approach to nutritional assessment for them.

Hereditary hemochromatosis: Temporal trends, sociodemographic characteristics, and independent risk factor of hepatocellular cancer - nationwide population-based study.

BACKGROUNDHereditary hemochromatosis (HH) has an increased risk of hepatocellular cancer (HCC) both due to genetic risks and iron overload as iron overload can be carcinogenic; HH impacts the increasing risk of HCC, not only through the development of cirrhosis but concerning hepatic iron deposition, which has been studied further recently. AIMTo evaluate HH yearly trends, patient demographics, symptoms, comorbidities, and hospital outcomes. The secondary aim sheds light on the risk of iron overload for developing HCC in HH patients, independent of liver cirrhosis complications. The study investigated HH (without cirrhosis) as an independent risk factor for HCC.METHODSWe analyzed data from National Inpatient Sample (NIS) Database, the largest national inpatient data collection in the United States, and selected HH and HCC cohorts. HH was first defined in 2011 International Classification of Disease - 9th edition (ICD-9) as a separate diagnosis; the HH cohort is extracted from January 2011 to December 2019 using 275.01 (ICD-9) and E83.110 (ICD-10) diagnosis codes of HH. Patients were excluded from the HH cohort if they had a primary or secondary diagnostic code of cirrhosis (alcoholic, non-alcoholic, and biliary), viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH). We removed these patients from the HH cohort to rule out bias or ICD-10 diagnostic errors. The HCC cohort is selected from January 2011 to December 2019 using the ICD-9 and ICD-10 codes of HCC. We selected a non-HCC cohort with the 1:1 fixed ratio nearest neighbor (greedy) propensity score method using the patients' age, gender, and race. We performed multivariate analysis for the risk factors of HCC in the HCC and non-HCC matched cohort. We further analyzed HH without cirrhosis (removing HH patients with a diagnosis of cirrhosis) as an independent risk factor of HCC after adjusting all known risk factors of HCC in the multivariate model. RESULTSDuring the 2011-2019 period, a total of 18031 hospitalizations with a primary or secondary diagnosis of HH (excluding liver diseases) were recorded in the NIS database. We analyzed different patients’ characteristics, and we found increments in inpatient population trend with a Ptrend < 0.001 and total hospital cost of care trend from $42957 in 2011 to $66152 in 2019 with a Ptrend < 0.001 despite no change in Length of Stay over the last decade. The multivariate analyses showed that HH without cirrhosis (aOR, 28.8; 95%CI, 10.4–80.1; P < 0.0001), biliary cirrhosis (aOR, 19.3; 95%CI, 13.4–27.6; P < 0.0001), non-alcoholic cirrhosis (aOR, 17.4; 95%CI, 16.5–18.4; P < 0.0001), alcoholic cirrhosis (aOR, 16.9; 95%CI, 15.9–17.9; P < 0.0001), hepatitis B (aOR, 12.1; 95%CI, 10.85–13.60; P < 0.0001), hepatitis C (aOR, 8.58; 95%CI, 8.20–8.98; P < 0.0001), Wilson disease (aOR, 4.27; 95%CI, 1.18–15.41; P < 0.0001), NAFLD or NASH (aOR, 2.96; 95%CI, 2.73–3.20; P < 0.0001), alpha1-antitrypsin deficiency (aOR, 2.10; 95%CI, 1.21–3.64; P < 0.0001), diabetes mellitus without chronic complications (aOR, 1.17; 95%CI, 1.13–1.21; P < 0.0001), and blood transfusion (aOR, 1.80; 95%CI, 1.69–1.92; P < 0.0001) are independent risk factor for liver cancer.CONCLUSIONOur study showed an increasing trend of in-hospital admissions of HH patients in the last decade. These trends were likely related to advances in diagnostic approach, which can lead to increased hospital utilization and cost increments. Still, the length of stay remained the same, likely due to a big part of management being done in outpatient settings. Another vital part of our study is the significant result that HH without cirrhosis is an independent risk factor for HCC with adjusting all known risk factors. More prospective and retrospective large studies are needed to re-evaluate the HH independent risk in developing HCC.

Platelet-derived TGF-β1 is related to portal vein thrombosis in cirrhosis by promoting hypercoagulability and endothelial dysfunction.

BackgroundPortal vein thrombosis (PVT) is a serious complication of cirrhosis accompanied by unclear pathogenesis. Transforming growth factor-beta (TGF-β) has been implicated in atherosclerosis and venous thrombosis whereas study regarding its part in PVT is lacking. The aim of this study was to explore the role of cytokine TGF-β1 in PVT and the potential mechanism.Materials and methodsWe included patients with cirrhotic gastroesophageal varices and divided them into two groups according to the presence of PVT. Serum levels of TGF-β1 were detected using Cytometric Bead Array kit and compared between two groups. Coagulation status was assessed using thromboelastography (TEG). Primary liver sinusoidal endothelial cells were treated with TGF-β1 and evaluated for endothelial dysfunction by RT-PCR.ResultsOur results uncovered that TGF-β1 (6,866.55 vs. 3,840.60 pg/ml, P = 0.015) significantly increased in the PVT group. Splenectomy might promote PVT by increasing platelet-derived TGF-β1 levels. Other cytokines showed no difference between PVT and non-PVT groups. Besides, TGF-β1 was correlated with platelet, fibrinogen, TEG-CI, TEG-MA, and TEG-α (coef = 0.733, 0.494, 0.604, 0.608, and 0.511; P < 0.001, 0.027, 0.004, 0.004, and 0.021, respectively), which indicated a hypercoagulable state in PVT patients. RT-PCR of liver sinusoidal endothelial cells showed a markable increment of von Willebrand Factor (vWF), thrombomodulin(TM), intercellular adhesion moleclar-1(ICAM-1), and vascular endothelial growth factor(VEGF) after TGF-β1 treatment, suggesting the involvement of endothelial dysfunction.ConclusionElevated platelet-derived TGF-β1 exhibited association with hypercoagulability and promoting effect on endothelial dysfunction, closely related with PVT in cirrhotic patients.

Dysnatremia in patients with chronic liver disease: a cross-sectional observational study

Background: The clinical significance of serum sodium levels and its association with a higher rate of complications in cirrhosis is debatable. This study was done to study the serum sodium levels in chronic liver disease (CLD) patients and establish its association with the severity of disease in such patients.Methods: In this cross-sectional study, we included adult patients diagnosed with CLD and assessed their serum electrolytes. The severity of liver disease was assessed using Child Pugh score (CPS) and model for end stage liver disease (MELD). Those with serum sodium levels less than 130 mEq/l were classified as group A, 131 to 135 mEq/l as normal group B and greater or equal to 136 mEq/l as Group C.Results: In the present study, hepatic encephalopathy (p&lt;0.01), hepatorenal syndrome (p&lt;0.01) and coagulopathy (p&lt;0.01) were found to occur significantly more common among patients from Group A, as compared to those in patients from group B or C. Mean MELD, CPS score and mortality was significantly higher among group A patients.Conclusions: Patients with lower serum salt levels had a substantially higher MELD score and CPS. Low blood sodium levels were linked to more severe liver disease, greater complications, and increased death. As a result, we urge that serum salt levels be checked on a frequent basis in patients with chronic liver disease.

Natural history and outcomes of patients with liver cirrhosis complicated by hepatic hydrothorax.

BACKGROUNDHepatic hydrothorax (HH) is an uncommon and difficult-to-manage complication of cirrhosis with limited treatment options.AIMTo define the clinical outcomes of patients presenting with HH managed with current standards-of-care and to identify factors associated with mortality.METHODSCirrhotic patients with HH presenting to 3 tertiary centres from 2010 to 2018 were retrospectively identified. HH was defined as pleural effusion in the absence of cardiopulmonary disease. The primary outcomes were overall and transplant-free survival at 12-mo after the index admission. Cox proportional hazards analysis was used to determine factors associated with the primary outcomes.RESULTSOverall, 84 patients were included (mean age, 58 years) with a mean model for end-stage liver disease score of 29. Management with diuretics alone achieved long-term resolution of HH in only 12% patients. At least one thoracocentesis was performed in 73.8% patients, transjugular intrahepatic portosystemic shunt insertion in 11.9% patients and 33% patients received liver transplantation within 12-mo of index admission. Overall patient survival and transplant-free survival at 12 mo were 68% and 41% respectively. At multivariable analysis, current smoking [hazard ratio (HR) = 8.65, 95% confidence interval (CI): 3.43-21.9, P < 0.001) and acute kidney injury (AKI) (HR = 2.91, 95%CI: 1.21-6.97, P = 0.017) were associated with a significantly increased risk of mortality.CONCLUSIONCirrhotic patients with HH are a challenging population with a poor 12-mo survival despite current treatments. Current smoking and episodes of AKI are potential modifiable factors affecting survival. HH is often refractory of diuretic therapy and transplant assessment should be considered in all cases.

Recommendations of EASL clinical practice guidelines on haemochromatosis

Haemochromatosis is characterised by elevated transferrin saturation (TSAT) and progressive iron loading that mainly affects the liver. Early diagnosis and treatment by phlebotomy can prevent cirrhosis, hepatocellular carcinoma, diabetes, arthropathy and other complications. In patients homozygous for p.Cys282Tyr in HFE, provisional iron overload based on serum iron parameters (TSAT >45% and ferritin >200 μg/L in females and TSAT >50% and ferritin >300 μg/L in males and postmenopausal women) is sufficient to diagnose haemochromatosis. In patients with high TSAT and elevated ferritin but other HFE genotypes, diagnosis requires the presence of hepatic iron overload on MRI or liver biopsy. The stage of liver fibrosis and other end-organ damage should be carefully assessed at diagnosis because they determine disease management. Patients with advanced fibrosis should be included in a screening programme for hepatocellular carcinoma. Treatment targets for phlebotomy are ferritin <50 μg/L during the induction phase and <100 μg/L during the maintenance phase.

Impacts of muscle mass dynamics on prognosis of outpatients with cirrhosis.

Sarcopenia negatively affects the prognosis of cirrhotic patients, but clinical implications of changes in muscle mass remain unclear. We aimed to elucidate its role in the prognosis of outpatients with cirrhosis. Patients with cirrhosis who underwent annual abdominal computed tomography (CT) for hepatocellular carcinoma surveillance were included in the prospective cohort. The L3 skeletal muscle index (SMI) was adopted as a proxy for the amount of skeletal muscle, and the rate of SMI change between inclusion and after 1 year (ΔSMI/yr%) was calculated. In total, 595 patients underwent a second CT after 1 year. Among them, 109 and 64 patients had sarcopenia and Child-Pugh class B/C decompensation at inclusion, which changed to 103 and 45 at the 1-year follow-up, respectively. During a median follow-up of 30.1 months after 1 year, 86 patients had at least one cirrhosis complication, and 18 died or received liver transplantation. In the development of cirrhosis complications, ΔSMI/yr% was independently associated, even after adjusting for the Child-Pugh and model for end stage liver disease (MELD)-Na scores. In addition, ΔSMI/yr% showed a good predictive performance for the development of cirrhosis complications within 6 months after 1-year follow-up in all subgroups, with a cut-off of -2.62 (sensitivity, 83.9%; specificity, 74.5%) in the overall population. SMI at 1-year and Child-Pugh score were independent factors associated with survival. In addition, changes in sarcopenia status significantly stratified survival. ΔSMI/yr% was a good predictor of the development of cirrhosis complications in outpatients with cirrhosis, independent of Child-Pugh and MELD scores.

Differences in the pattern and cost of hospital care between Indigenous and non-Indigenous Australians with cirrhosis: an exploratory study.

Liver diseases are important contributors to the mortality gap between Indigenous and non-Indigenous Australians. This cohort study examined factors associated with hospital admissions and healthcare outcomes among Indigenous Australians with cirrhosis. Patient-reported outcomes were obtained by face-to-face interview (Chronic Liver Disease Questionnaire and Short Form 36 (SF-36)). Clinical data were extracted from medical records and through data linkage for 534 patients (25 indigenous). Cumulative overall survival (Kaplan-Meier), rates of hospital admissions and emergency presentations, and costs were assessed by indigenous status. Incidence rate ratios (IRR; Poisson regression) were reported. Indigenous Australians admitted to hospital with cirrhosis had lower educational status compared with non-indigenous patients (79.2% vs 43.4%; P< 0.001). The two groups had, in general, similar clinical characteristics including disease severity (P= 0.78), presence of cirrhosis complications (P= 0.67), comorbidities (P= 0.62), rates of cirrhosis-related admissions (P= 0.86) and 5-year survival (P= 0.30). However, indigenous patients had a lower score in the SF-36 domain related to bodily pain (P= 0.037), more cirrhosis admissions via the emergency department (IRR=1.42, 95% confidence interval (CI) 1.10-1.83) and fewer planned cirrhosis admissions (IRR=0.32, 95% CI 0.14-0.72). The total cost for cirrhosis-related hospital admissions for 534 patients over 6 years (July 2012 to June 2018) was A$13.7 million. The cost of cirrhosis-related hospital admissions was double for indigenous patients (cost ratio=2.04, 95% CI 2.04-2.05). Our data highlight the disparities in health service use and patient-reported outcomes, despite having similar clinical profiles. Integration between primary care, Aboriginal Community Controlled Health Organisations and liver specialists is critical for appropriate health service delivery and effective use of resources. Chronic liver disease costs the community dearly.

Role of erosive and ulcerative gastric lesions in the development of hemorrhagic complications in liver cirrhosis

We present the results of the treatment of 135 patients with a hepatic form of portal hypertension (liver cirrhosis) that have been hospitalized in the clinic of the Department of Surgery No. 2 in Bogomolets National Medical University within the period from 2011 to 2020. The aim of our study was to reveal the factors of the development of erosive and ulcerative gastric lesions in liver cirrhosis and their role in the occurrence of hemorrhagic complications. Based on studies of the rheological properties of gastric mucus, it was found that one of the leading factors in the development of erosive and ulcerative stomach lesions in portal hypertension is increased transcapillary filtration in the edematous-ascitic stage of liver cirrhosis. As a result, portal stagnation and reduced colloid mucus-bicarbonate barrier of the stomach led to the development of actual gastric ulcers. Erosive and ulcerative lesions on a part of the gastric mucosa were found in 66 (48.9%) of patients with cirrhosis of the liver, and in 45.2% of cases (28 persons) they were complicated by gastric bleeding development. Pathogenetic treatment of gastric ulcer-erosive bleeding in portal hypertension, against the background of the use of endoscopic hemostasis, should be aimed at strengthening the protective properties of the mucous-bicarbonate barrier of the stomach. Successful results of surgical treatment were achieved in 64.3% of patients. The overall mortality in liver cirrhosis complicated by gastric bleeding from ulcerative lesions of the stomach was 21.4% (6 patients died), and postoperative mortality was 25% (2 patients died).

Molecular docking and in vitro experiments verified that kaempferol induced apoptosis and inhibited human HepG2 cell proliferation by targeting BAX, CDK1, and JUN.

Hepatocellular carcinoma, as a common liver cirrhosis complication, has become the sixth most common cancer worldwide, and its increasing incidence has resulted in considerable medical and economic burdens. As a natural polyphenolic compound, kaempferol has exhibits a wide range of antitumor activities against multiple cancer targets. In this study, the Autodock software was used for molecular docking to simulate the interaction process between kaempferol and HCC targets and the PyMOL software was used for visualization. Proliferation of kaempferol HepG2 cells under the effect of kaempferol was detected using Cell Counting Kit-8 (CCK-8) assay, and the apoptosis rate of HepG2 cells was detected using flow cytometry. The expressions of proteins BAX, CDK1, and JUN protein expressions were detected by Western blot. Molecular docking found that the kaempferol ligand has 3 rotatable bonds, 6 nonpolar hydrogen atoms, and 12 aromatic carbon atoms, and can form complexes with the kaempferol targets P53, BAX, AR, CDK1, and JUN through electrostatic energy. GO (Gene Ontology) enrichment analysis suggests that kaempferol regulates the biological function of hepatocellular carcinoma cells and is related to apoptosis. Cell Counting Kit-8 assay suggested that Kaempferol can significantly inhibited HepG2 cell proliferation, and the inhibition rate increased with the increase in drug concentration and incubation time. Moreover, kaempferol can promoted HepG2 cell apoptosis in a dose-dependent manner. This compound upregulated BAX and JUN expression and downregulated CDK1 expression. Thus, Kaempferol can promote HepG2 cell apoptosis, and the regulatory mechanism may be related to the regulation of the expression levels of the apoptosis-related proteins BAX, CDK1, and JUN.

Albumin administration in patients with cirrhosis: Current role and novel perspectives.

Mortality in cirrhosis is mostly associated with the development of clinical decompensation, characterized by ascites, hepatic encephalopathy, variceal bleeding, or jaundice. Therefore, it is important to prevent and manage such complications. Traditionally, the pathophysiology of decompensated cirrhosis was explained by the peripheral arterial vasodilation hypothesis, but it is currently understood that decompensation might also be driven by a systemic inflammatory state (the systemic inflammation hypothesis). Considering its oncotic and nononcotic properties, albumin has been thoroughly evaluated in the prevention and management of several of these decompensating events. There are formal evidence-based recommendations from international medical societies proposing that albumin be administered in individuals with cirrhosis undergoing large-volume paracentesis, patients with spontaneous bacterial peritonitis, those with acute kidney injury (even before the etiological diagnosis), and those with hepatorenal syndrome. Moreover, there are a few randomized controlled trials and meta-analyses suggesting a possible role for albumin infusion in patients with cirrhosis and ascites (long-term albumin administration), individuals with hepatic encephalopathy, and those with acute-on-chronic liver failure undergoing modest-volume paracentesis. Further studies are necessary to elucidate whether albumin administration also benefits patients with cirrhosis and other complications, such as individuals with extraperitoneal infections, those hospitalized with decompensated cirrhosis and hypoalbuminemia, and patients with hyponatremia.

The natural history of patients with compensated cirrhosis and elevated hepatic venous pressure gradient.

Portal hypertension is a major complication of liver cirrhosis. Hepatic venous pressure gradient (HVPG) appears to be one of the best surrogates of clinical outcomes. However, the utility of elevated HVPG in predicting subsequent clinical decompensation is unclear. We analyzed 410 patients who underwent HVPG assessment between 2014 and 2018. Of these, we identified and analyzed 20 patients with HVPG >12 mmHg without evidence of clinical decompensation (defined as ascites, non-bleeding esophageal varices or bleeding esophageal varices, hepatic encephalopathy, hepato-pulmonary syndrome, or hepatic hydrothorax). Additionally, we compared this group to 40 randomly selected cirrhotic patients with HVPG >12 mmHg with signs of clinical decompensation. Clinical events were subsequently assessed (mean = 33 months) after HVPG measurement. Patients with high HVPG without evidence of clinical decompensation had significantly lower model for end stage liver disease (MELD) scores (8 ± 4) compared to decompensated patients (13 ± 8, P = 0.05). HVPG measurements were similar in compensated (17 ± 6 mmHg) and decompensated (18 ± 4 mmHg) patients. Over follow-up for 33 months, 8/20 compensated patients had a decompensating event and neither MELD (8 and 8, respectively) nor HVPG (17 mmHg and 18 mmHg, respectively) differentiated patients who remained compensated vs. those that decompensated. Serum albumin at the time of HVPG measurement was significantly higher in patients who remained compensated than those with a decompensating event (3.5 g/dL vs. 2.6 g/dL, respectively, P = 0.05). A small, unique, population of cirrhotic patients with substantially elevated HVPG appear to remain free of complications over long term follow-up.

Increased platelet aggregation in patients with decompensated cirrhosis indicates higher risk of further decompensation and death.

Studies on platelet aggregation in cirrhosis are controversial because interpretation of platelet function is challenged by thrombocytopenia. We conducted a prospective study to investigate whole blood platelet aggregation in cirrhosis and its association with liver-related outcomes. Platelet aggregation was assessed by whole blood aggregometry (Multiplate®). To overcome the influence of platelet count and compare cirrhosis with thrombocytopenia vs. controls with normal platelet count, we calculated a ratio between platelet aggregation and platelet count (PLT ratio). Then, we prospectively followed patients with cirrhosis and ascertained predictors of decompensation, transplantation, and death. Two-hundred and three patients with cirrhosis were prospectively recruited (77% decompensated). PLT ratio was significantly higher in cirrhosis than in those with chronic hepatitis and healthy individuals (0.44 vs. 0.25 and 0.26, respectively; p <0.0001). In cirrhosis, the ratio increased with disease severity (Child-Pugh class C>B>A) and was particularly elevated in decompensated patients with severe thrombocytopenia. Among decompensated patients, 65 had further decompensation, underwent transplantation, or died during a 6-month follow-up. On multivariate analysis, PLT ratio (odds ratio 1.87; 95% CI 1.23-2.84; p= 0.003) and MELD score (odds ratio 1.05; 95% CI 1.01-1.08; p= 0.01) were independently associated with outcome. The relative risk of events was 7.5-fold higher in patients with PLT ratio >0.75 vs. patients with PLT ratio <0.25 (95% CI 2.5-21.9; p= 0.003). The increased PLT ratio, its discriminative ability for composite outcome, and the prognostic value of PLT ratio >0.75 were confirmed in an independent cohort of hospitalized patients with decompensated cirrhosis (n= 41). Patients with cirrhosis, particularly when decompensated, exhibit significantly increased whole blood platelet aggregation. Decompensated patients with a PLT ratio >0.75 have a >80% probability of further decompensation, transplantation, or liver-related death within 6 months. In patients with cirrhosis, previous studies have suggested that platelets (i.e. circulating blood cells that help form clots to stop bleeding) are dysfunctional. In particular, these studies suggested that platelet aggregation (the process by which platelets adhere to each other to form clots) is reduced. Since platelet aggregation is important for clot formation, it has been hypothesized that alterations of platelet aggregation may be responsible for the increased risk of bleeding observed in patients with cirrhosis. Our study demonstrates: i) that platelet aggregation in patients with cirrhosis is higher than in healthy individuals; ii) that platelet aggregation in patients with decompensated cirrhosis (i.e. those who have already experienced some complications of cirrhosis) is particularly elevated and associated with risk of further complications and death.