Longitudinal evaluation of individuals with severe alpha-1 antitrypsin deficiency (Pi*ZZ genotype).

BACKGROUND AND AIMS: Homozygous Pi*Z mutation in alpha-1 antitrypsin (Pi*ZZ genotype) predisposes to pulmonary loss-of-function and hepatic gain-of-function injury. To facilitate selection into clinical trials typically targeting only one organ, we systematically evaluated an international, multicenter, longitudinal, Pi*ZZ cohort to uncover natural disease course and surrogates for future liver- and lung-related endpoints. METHODS: Cohort 1 recruited 737 Pi*ZZ individuals from 25 different centers without known liver comorbidities that received a baseline clinical and laboratory assessment as well as liver stiffness measurement (LSM). A follow-up interview was performed after at least six months. Cohort 2 consisted of 135 Pi*ZZ subjects without significant liver fibrosis, who received a standardized baseline and follow-up examination at least two years later, both including LSM. RESULTS: During 2634 patient-years of follow-up, 39 individuals died, with liver and lung being responsible for 46% and 36% of deaths, respectively. 41 Pi*ZZ subjects who developed a hepatic endpoint presented with significantly higher baseline liver fibrosis surrogates, i.e., LSM (24 vs. 5 kPa, p<.001) and AST-to-platelet ratio index (APRI, 1.1 vs. 0.3 units, p<.001). Liver-related endpoints within five years were most accurately predicted by LSM (area under the curve [AUC] 0.95) followed by APRI (0.92). Baseline lung parameters displayed only a moderate predictive utility for lung-related endpoints within five years (FEV1 AUC 0.76). Fibrosis progression in those with no/mild fibrosis at baseline was rare and primarily seen in those with preexisting risk factors. CONCLUSIONS: Non-invasive liver fibrosis surrogates accurately stratify liver-related risks in Pi*ZZ individuals. Our findings have direct implications for routine care and future clinical trials of Pi*ZZ patients.

Abdominal surgery in patients with chronic noncirrhotic extrahepatic portal vein obstruction: A multicenter retrospective study.

BACKGROUND AND AIMS: In patients with noncirrhotic chronic extrahepatic portal vein obstruction (EHPVO), data on the morbimortality of abdominal surgery are scarce. APPROACH AND RESULTS: We retrospectively analyzed the charts of 76 patients (78 interventions) with EHPVO undergoing abdominal surgery within the Vascular Disease Interest Group network. Fourteen percent of the patients had ≥1 major bleeding (unrelated to portal hypertension) and 21% had ≥1 Dindo-Clavien grade ≥3 postoperative complications within 1 month after surgery. Fifteen percent had ≥1 portal hypertension-related complication within 3 months after surgery. Three patients died within 12 months after surgery. An unfavorable outcome (ie, ≥1 abovementioned complication or death) occurred in 37% of the patients and was associated with a history of ascites and with nonwall, noncholecystectomy surgical intervention: 17% of the patients with none of these features had an unfavorable outcome, versus 48% and 100% when one or both features were present, respectively. We then compared 63/76 patients with EHPVO with 126 matched (2:1) control patients without EHPVO but with similar surgical interventions. As compared with control patients, the incidence of major bleeding ( p <0.001) and portal hypertension-related complication ( p <0.001) was significantly higher in patients with EHPVO, but not that of grade ≥3 postoperative complications nor of death. The incidence of unfavorable postoperative outcomes was significantly higher in patients with EHPVO than in those without (33% vs. 18%, p =0.01). CONCLUSIONS: Patients with EHPVO are at high risk of major perioperative or postoperative bleeding and postoperative complications, especially in those with ascites or undergoing surgery other than wall surgery or cholecystectomy.

Porto-sinusoidal vascular liver disorder with portal hypertension: Natural history and long-term outcome.

BACKGROUND & AIMS: Current knowledge of the natural history of patients with porto-sinusoidal vascular disorder (PSVD) is derived from small studies. The aim of the present study was to determine the natural history of PSVD and prognostic factors in a large multicenter cohort of patients. METHODS: We performed a retrospective study on patients with PSVD and signs of portal hypertension (PH) prospectively registered in 27 centers. RESULTS: A total of 587 patients were included, median age of 47 years and 38% were women. Four-hundred and one patients had an associated condition, which was graded as severe in 157. Median follow-up was 68 months. At diagnosis, 64% of patients were asymptomatic while 36% had a PH-related complication: PH-related bleeding in 112 patients, ascites in 117, and hepatic encephalopathy in 11. In those not presenting with bleeding, the incidence of first bleeding was 15% at 5 years, with a 5-year rebleeding rate of 18%. The 5-year cumulative incidence of new or worsening ascites was 18% and of developing PVT was 16%. Fifty (8.5%) patients received a liver transplantation and 109 (19%) died, including 55 non-liver-related deaths. Transplant-free survival was 97% and 83% at 1 and 5 years, respectively. Variables independently associated with transplant-free survival were age, ascites, serum bilirubin, albumin and creatinine levels at diagnosis and severe associated conditions. This allowed for the creation of a nomogram that accurately predicted prognosis. CONCLUSIONS: The prognosis of PSVD is strongly determined by the severity of the associated underlying conditions and parameters of liver and renal function. IMPACT AND IMPLICATIONS: Porto-sinusoidal vascular liver disorder (PSVD) is a rare entity that usually affects young people, frequently causes severe complications of portal hypertension, and may reduce life expectancy. To date, there is scarce information regarding its clinical manifestations, natural history and prognostic factors. The present study, including the largest number of patients with PSVD reported so far, shows that overall, when managed at centers of expertise, the prognosis of patients with PSVD is good, with LT-free survival rates of 83% and 72% at 5 and 10 years, respectively. Presence and severity of an underlying associated condition, presence of ascites, age and bilirubin, albumin and creatinine levels were associated with poor prognosis. These results are important to know for hepatologists. A final model combining these parameters enabled development of a nomogram that predicts prognosis with good discrimination and calibration capacity and can be easily applied in clinical practice.

Hepatic venous pressure gradient predicts risk of hepatic decompensation and liver-related mortality in patients with MASLD.

BACKGROUND & AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of advanced chronic liver disease (ACLD). Portal hypertension drives hepatic decompensation and is best diagnosed by hepatic venous pressure gradient (HVPG) measurement. Here, we investigate the prognostic value of HVPG in MASLD-related compensated ACLD (MASLD-cACLD). METHODS: This European multicentre study included patients with MASLD-cACLD characterised by HVPG at baseline. Hepatic decompensation (variceal bleeding/ascites/hepatic encephalopathy) and liver-related mortality were considered the primary events of interest. RESULTS: A total of 340 patients with MASLD-cACLD (56.2% male; median age 62 [55-68] years, median MELD 8 [7-9], 71.2% with diabetes) were included. Clinically significant portal hypertension (CSPH: i.e., HVPG ≥10 mmHg) was found in 209 patients (61.5%). During a median follow-up of 41.5 (27.5-65.8) months, 65 patients developed hepatic decompensation with a cumulative incidence of 10.0% after 2 years (2Y) and 30.7% after 5 years (5Y) in those with MASLD-cACLD with CSPH, compared to 2.4% after 2Y and 9.4% after 5Y in patients without CSPH. Variceal bleeding did not occur without CSPH. CSPH (subdistribution hazard ratio [SHR] 5.13; p <0.001) was associated with an increased decompensation risk and a higher HVPG remained an independent risk factor in the multivariable model (adjusted SHR per mmHg: 1.12, p <0.001). Liver-related mortality occurred in 37 patients at a cumulative incidence of 3.3% after 2Y and 21.4% after 5Y in CSPH. Without CSPH, the incidence after 5Y was 0.8%. Accordingly, a higher HVPG was also independently associated with a higher risk of liver-related death (adjusted SHR per mmHg: 1.20, p <0.001). CONCLUSION: HVPG measurement is of high prognostic value in MASLD-cACLD. In patients with MASLD-cACLD without CSPH, the short-term risk of decompensation is very low and liver-related mortality is rare, while the presence of CSPH substantially increases the risk of both. IMPACT AND IMPLICATIONS: While the incidence of compensated advanced chronic liver disease (cACLD) due to metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing worldwide, insights into the impact of clinically significant portal hypertension (CSPH) on the risk of liver-related events in MASLD-cACLD remain limited. Based on the findings of this European multicentre study including 340 MASLD-cACLD patients, we could show that increasing HVPG values and the presence of CSPH in particular were associated with a significantly higher risk of first hepatic decompensation and liver-related mortality. In contrast, the short-term incidence of decompensation in patients with MASLD-cACLD without CSPH was low and the risk of liver-mortality remained negligible. Thus, HVPG measurements can provide important prognostic information for individualised risk stratification in MASLD-cACLD and may help facilitate the study of novel and promising treatment possibilities for MASLD.

Targeted decrease of portal hepatic pressure gradient improves ascites control after TIPS.

BACKGROUND: Ascites is a definitive sign of decompensated liver cirrhosis driven by portal hypertension. Although transjugular intrahepatic portosystemic shunt insertion (TIPS) is indicated for therapy of recurrent and refractory ascites, there is no evidence-based recommendation for a specific target of portal hepatic pressure gradient (PPG) decrease. METHODS: In this single-center, retrospective trial, we investigated the decrease of PPG in 341 patients undergoing TIPS insertion for therapy of refractory or recurrent ascites until 2015. During each procedure, portal and inferior vena cava pressures were invasively measured and correlated with patients' outcome and ascites progression over time, according to the prespecified Noninvasive Evaluation Program for TIPS and Follow-Up Network protocol (NCT03628807). RESULTS: Patients without ascites at 6 weeks after TIPS had significantly greater PPG reduction immediately after TIPS, compared to the patients with refractory ascites (median reduction 65% vs. 55% of pre-TIPS PPG; p = 0.001). Survival was significantly better if ascites was controlled, compared to patients with need for paracentesis 6 weeks after TIPS (median survival: 185 vs. 41 weeks; HR 2.0 [1.3-2.9]; p < 0.001). Therefore, higher PPG reduction by TIPS ( p = 0.005) and lower PPG after TIPS ( p = 0.02) correlated with resolution of severe ascites 6 weeks after TIPS. Multivariable analyses demonstrated that higher Child-Pugh score before TIPS (OR 1.3 [1.0-1.7]; p = 0.03) and lower serum sodium levels (OR 0.9 [0.9-1.0]; p = 0.004) were independently associated with ascites persistence 6 weeks after TIPS, whereas PPG reduction (OR 0.98 [0.97-1.00]; p = 0.02) was associated with resolution of ascites 6 weeks after TIPS. CONCLUSION: Extent of PPG reduction and/or lowering of target PPG immediately after TIPS placement is associated with improved ascites control in the short term and with survival in the long term. A structured follow-up visit for patients should assess persistence of ascites at 6 weeks after TIPS.

Impaired HBsAg release and antiproliferative/antioxidant cell regulation by HBeAg-negative patient isolates reflects an evolutionary process.

BACKGROUND: The hepatitis B e antigen (HBeAg)-negative infection Phase 3 is characterized by no or minimal signs of hepatic inflammation and the absence of hepatic fibrosis. However, underlying molecular mechanisms leading to this benign phenotype are poorly understood. METHODS: Genotype A, B and D HBeAg-negative patient isolates with precore mutation G1896A from Phase 3 were analysed in comparison with respective HBeAg-positive rescue mutant and HBeAg-positive wild-type reference genomes regarding differences in viral replication, morphogenesis, infectivity and impact on NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE)-dependent gene expression and cellular kinome. RESULTS: In comparison with reference genomes, the patient isolates are characterized by a lower intra- and extracellular hepatitis B surface antigen (HBsAg)-amount, and HBsAg-retention in the endoplasmic reticulum. Rescue of HBeAg expression increased HBsAg-amount but not its release. Expression of the isolated genomes is associated with a higher Nrf2/ARE-dependent gene expression as compared to reference genomes independent of HBeAg expression. Kinome analyses revealed a decreased activity of receptors involved in regulation of proliferative pathways for all patient isolates compared to the reference genomes. No specific conserved mutations could be found between all genomes from Phase 3. CONCLUSIONS: HBeAg-negative genomes from Phase 3 exhibit distinct molecular characteristics leading to lower HBsAg synthesis and release, enhanced oxidative stress protection and decreased activity of key kinases, triggering an antiproliferative stage, which might contribute to the lower probability of hepatocellular carcinoma. The observed differences cannot be associated with loss of HBeAg or specific mutations common to all analysed isolates, indicating the phenotype of Phase 3 derived genomes to be the result of a multifactorial process likely reflecting a conserved natural selection process.

Imaging-based diagnosis of sarcopenia for transplant-free survival in primary sclerosing cholangitis.

BACKGROUND: Imaging-based assessment of sarcopenia is a well-validated prognostic tool for patients with chronic liver disease. However, little is known about its value in patients with primary sclerosing cholangitis (PSC). This cross-sectional study aimed to investigate the predictive value of the cross-sectional imaging-based skeletal muscle index (SMI) for transplant-free survival (TFS) in patients with PSC. METHODS: A total of 95 patients with PSC who underwent abdominal cross-sectional imaging between 2008 and 2022 were included in this retrospective study. SMI was measured at the third lumbar vertebra level (L3-SMI). The cut-off values to define sarcopenia were < 50 cm²/m² in male patients and < 39 cm²/m² in female patients. The primary outcome of this study was TFS, which was defined as survival without liver transplantation or death from any cause. RESULTS: Our study indicates that L3-SMI sarcopenia impairs TFS in patients with PSC (5-year TFS: 33.9% vs. 83.3%, p = 0.001, log-rank test). L3-SMI sarcopenia was independently associated with reduced TFS via multivariate Cox regression analysis (HR = 2.749; p = 0.028). Body mass index reduction > 10% at 12 months, which is used as MELD standard exception (SE) criterion in Eurotransplant (in Germany only until September 2023), was not significantly associated with TFS in the multivariate Cox regression analysis (HR = 1.417; p = 0.330). Substitution of BMI reduction with L3-SMI in the German SE criteria improved the predictive accuracy of TFS compared to the established SE criteria (multivariable Cox regression analysis: HR = 4.007, p < 0.001 vs. HR = 1.691, p = 0.141). CONCLUSION: Imaging-based diagnosis of sarcopenia via L3-SMI is associated with a low TFS in patients with PSC and may provide additional benefits as a prognostic factor in patient selection for liver transplantation.

To TIPS or Not to TIPS in High Risk of Variceal Rebleeding and Acute-on-Chronic Liver Failure.

Variceal bleeding is a consequence of severe portal hypertension in patients with liver cirrhosis. Although the rate of bleeding has decreased over time, variceal bleeding in the presence of acute-on-chronic liver failure (ACLF) carries a high risk of treatment failure and short-term mortality. Treatment and/or removal of precipitating events (mainly bacterial infection and alcoholic hepatitis) and decrease of portal pressure may improve outcome of patients with acute decompensation or ACLF. Transjugular intrahepatic portosystemic shunts (TIPSs), especially in the preemptive situation, have been found to efficiently control bleeding, prevent rebleeding, and reduce short-term mortality. Therefore, TIPS placement should be considered as an option in the management of ACLF patients with variceal bleeding.

Advances in Endohepatology.

Over the past decade, the number of endoscopic procedures relevant to patients with liver disease not only increased but also altered and expanded in terms of indications and applications. "Endohepatology" refers to the integration of advanced endoscopy within the practice of hepatology with endoscopic ultrasound as one of the main pillars. Current applications under the umbrella of endohepatology focus on advanced diagnostics and oncological, vascular, and metabolic interventions. These involve, among others, endoscopic ultrasound (EUS)-guided liver biopsy, EUS-guided portal pressure gradient measurement, and EUS-guided coil and glue embolization of gastric varices. In addition to its conceptually attractive technical and innovative characteristics, endohepatology is also an appealing practical option for daily practice because it can be offered as a "one-stop clinic" intervention where comprehensive endoscopic diagnostic and/or therapeutic testing is performed in a single outpatient visit. In this review, we will discuss current trends and future developments within endohepatology and the remaining hurdles to overcome.

Surgical site infections are independently associated with the development of postoperative acute-on-chronic liver failure in liver cirrhosis.

Acute-on-chronic liver failure (ACLF) is associated with organ failure and high short-term mortality. Bacterial infections and surgery have been reported as major precipitants for ACLF. However, detailed characterization of postoperative infections after elective surgery in patients with liver cirrhosis and their impact on the development of ACLF have not been investigated yet. A total of 235 patients with cirrhosis without ACLF and proven bacterial infections undergoing elective surgery were included. The primary end point was the development of ACLF within 28 days after surgery, and secondary end points were infection development within 28 days and 3-month ACLF-related mortality. Cox regression analysis was used for identification of risk factors associated with ACLF development, infection development, and mortality. A total of 86 patients (37%) developed ACLF within 28 days after surgery. Patients with new postoperative infections had significantly higher rates of associated ACLF episodes within 28 days (51% vs. 24%, p < 0.001) and higher 3-month mortality ( p < 0.05) than patients without postoperative infections. New infections after surgery [HR: 2.43 (1.59-3.71), p < 0.001] and organ/space surgical site infections [HR: 2.46 (1.26-4.80), p = 0.01] in particular were independent risk factors associated with ACLF development 28 days after surgery. Extensive procedures were associated with the development of new postoperative infection episodes within 28 days. Infections treated with initial appropriate empirical antibiotic strategies showed significantly improved survival. This study characterizes and identifies bacterial infections in general and organ/space surgical site infection in particular as precipitating events for the development of ACLF after elective surgery in patients with cirrhosis. Postoperative ACLF combined with infections leads to higher postoperative short-term mortality than each condition separately, especially in extensive procedures. Interdisciplinary care, early identification of postoperative ACLF and infections, and adequate, broad, and early treatment strategies are needed to improve postoperative outcome.

The clinical relevance of acute-on-chronic liver failure in medical procedures: Endoscopy, interventions and surgery.

Acute-on-chronic liver failure (ACLF) is a specific, but complex and multifactorial form of acute decompensation (AD) of cirrhosis and is characterized by an extraordinary dynamic natural course, rapidly evolving organ failure and high short-term mortality. In daily clinical practice, patients with liver cirrhosis and decompensation have indications for different medical procedures such as endoscopies, interventional treatments like transjugular intrahepatic portosystemic shunt (TIPS) or even surgical procedures. In these situations, clinicians often need to balance the expected benefits of such procedures with the risks of causing acute decompensation or ACLF. This review summarizes the evidence of medical procedures and their role in precipitating or preventing ACLF and highlights the aspects to consider during patient selection.

Circulating levels of endotrophin and cross-linked type III collagen reflect liver fibrosis in people with HIV.

BACKGROUND AND AIMS: Liver-associated complications still frequently lead to mortality in people with HIV (PWH), even though combined antiretroviral treatment (cART) has significantly improved overall survival. The quantification of circulating collagen fragments released during collagen formation and degradation correlate with the turnover of extracellular matrix (ECM) in liver disease. Here, we analysed the levels of ECM turnover markers PC3X, PRO-C5, and PRO-C6 in PWH and correlated these with hepatic fibrosis and steatosis. METHODS: This monocentre, retrospective study included 141 PWH. Liver stiffness and liver fat content were determined using transient elastography (Fibroscan) with integrated CAP function. Serum levels of formation of cross-linked type III collagen (PC3X), formation of type V collagen (PRO-C5) and formation type VI collagen (PRO-C6), also known as the hormone endotrophin, were measured with ELISA. RESULTS: Twenty-five (17.7%) of 141 PWH had clinical significant fibrosis with liver stiffness ≥ 7.1 kPa, and 62 PWH (44.0%) had steatosis with a CAP value > 238 dB/m. Study participants with fibrosis were older (p = 0.004) and had higher levels of AST (p = 0.037) and lower number of thrombocytes compared to individuals without fibrosis (p = 0.0001). PC3X and PRO-C6 were markedly elevated in PWH with fibrosis. Multivariable cox regression analysis confirmed PC3X as independently associated with hepatic fibrosis. PRO-C5 was significantly elevated in participants with presence of hepatic steatosis. CONCLUSION: Serological levels of cross-linked type III collagen formation and endotrophin were significantly associated with liver fibrosis in PWH receiving cART and thus may be suitable as a non-invasive evaluation of liver fibrosis in HIV disease.

Closing spontaneous portosystemic shunts in cirrhosis: Does it make sense? Does it work? What does it take?

Spontaneous portosystemic shunts (SPSS) are an often neglected cause of hepatic encephalopathy associated with cirrhosis. Nowadays, SPSS are considered as radiological biomarkers of clinically significant portal hypertension rather than the previous dogmatic perceived decompressive vessels. SPSS are not rare as they can be diagnosed in over 60% of the patients with cirrhosis by mere contrast-enhanced CT. Moreover, they are clinically relevant since they impact on all portal hypertensive related complications, in particular medically refractory HE, and represent an independent predictor of decompensation and mortality in cirrhosis, irrespective of the type of SPSS. Taken together, these elements warrant strategies to target these shunts directly which is currently is achieved via interventional radiology embolization. In this review, we discuss why it makes sense to tackle SPSS, how to do it and what it takes to do it right based on aggregated literature.

Fecal cytolysin does not predict disease severity in acutely decompensated cirrhosis and acute-on-chronic liver failure.

BACKGROUND: Cirrhosis with acute decompensation (AD) and acute-on-chronic liver failure (ACLF) are characterized by high morbidity and mortality. Cytolysin, a toxin from Enterococcus faecalis (E. faecalis), is associated with mortality in alcohol-associated hepatitis (AH). It is unclear whether cytolysin also contributes to disease severity in AD and ACLF. METHODS: We studied the role of fecal cytolysin in 78 cirrhotic patients with AD/ACLF. Bacterial DNA from fecal samples was extracted and real-time quantitative polymerase chain reaction (PCR) was performed. The association between fecal cytolysin and liver disease severity in cirrhosis with AD or ACLF was analyzed. RESULTS: Fecal cytolysin and E. faecalis abundance did not predict chronic liver failure (CLIF-C) AD and ACLF scores. Presence of fecal cytolysin was not associated with other liver disease markers, including Fibrosis-4 (FIB-4) index, 'Age, serum Bilirubin, INR, and serum Creatinine (ABIC)' score, Child-Pugh score, model for end-stage liver disease (MELD) nor MELD-Na scores in AD or ACLF patients. CONCLUSIONS: Fecal cytolysin does not predict disease severity in AD and ACLF patients. The predictive value of fecal cytolysin positivity for mortality appears to be restricted to AH.

Two-dimensional shear wave elastography predicts survival in advanced chronic liver disease.

OBJECTIVE: Liver stiffness measurement (LSM) is a tool used to screen for significant fibrosis and portal hypertension. The aim of this retrospective multicentre study was to develop an easy tool using LSM for clinical outcomes in advanced chronic liver disease (ACLD) patients. DESIGN: This international multicentre cohort study included a derivation ACLD patient cohort with valid two-dimensional shear wave elastography (2D-SWE) results. Clinical and laboratory parameters at baseline and during follow-up were recorded. LSM by transient elastography (TE) was also recorded if available. The primary outcome was overall mortality. The secondary outcome was the development of first/further decompensation. RESULTS: After screening 2148 patients (16 centres), 1827 patients (55 years, 62.4% men) were included in the 2D-SWE cohort, with median liver SWE (L-SWE) 11.8 kPa and a model for end stage liver disease (MELD) score of 8. Combination of MELD score and L-SWE predict independently of mortality (AUC 0.8). L-SWE cut-off at ≥20 kPa combined with MELD ≥10 could stratify the risk of mortality and first/further decompensation in ACLD patients. The 2-year mortality and decompensation rates were 36.9% and 61.8%, respectively, in the 305 (18.3%) high-risk patients (with L-SWE ≥20 kPa and MELD ≥10), while in the 944 (56.6%) low-risk patients, these were 1.1% and 3.5%, respectively. Importantly, this M10LS20 algorithm was validated by TE-based LSM and in an additional cohort of 119 patients with valid point shear SWE-LSM. CONCLUSION: The M10LS20 algorithm allows risk stratification of patients with ACLD. Patients with L-SWE ≥20 kPa and MELD ≥10 should be followed closely and receive intensified care, while patients with low risk may be managed at longer intervals.

Effect of sarcopenia on survival in patients with cirrhosis: A meta-analysis.

BACKGROUND & AIMS: The association between sarcopenia and prognosis in patients with cirrhosis remains to be determined. In this study, we aimed to quantify the association between sarcopenia and the risk of mortality in patients with cirrhosis, stratified by sex, underlying liver disease etiology, and severity of hepatic dysfunction. METHODS: PubMed, Web of Science, EMBASE, and major scientific conference sessions were searched without language restriction through 13 January 2021 with an additional manual search of bibliographies of relevant articles. Cohort studies of ≥100 patients with cirrhosis and ≥12 months of follow-up that evaluated the association between sarcopenia, muscle mass and the risk of mortality were included. RESULTS: Twenty-two studies involving 6,965 patients with cirrhosis were included. The pooled prevalence of sarcopenia in patients with cirrhosis was 37.5% overall (95% CI 32.4%-42.8%), and was higher in male patients, those with alcohol-associated liver disease, those with Child-Pugh grade C cirrhosis, and when sarcopenia was defined by L3-SMI (third lumbar-skeletal muscle index). Sarcopenia was associated with an increased risk of mortality in patients with cirrhosis (adjusted hazard ratio [aHR] 2.30, 95% CI 2.01-2.63), with similar findings in a sensitivity analysis of patients with cirrhosis without hepatocellular carcinoma (aHR 2.35, 95% CI 1.95-2.83) and in subgroups stratified by sex, liver disease etiology, and severity of hepatic dysfunction. The association between quantitative muscle mass index and mortality further supports the association between sarcopenia and poor prognosis (aHR 0.95, 95% CI 0.93-0.98). There was no significant heterogeneity in any of our analyses. CONCLUSIONS: Sarcopenia was highly and independently associated with higher risk of mortality in patients with cirrhosis. LAY SUMMARY: The prevalence of sarcopenia and its association with death in patients with cirrhosis remain unclear. This meta-analysis indicated that sarcopenia affected about one-third of patients with cirrhosis and up to 50% of patients with alcohol-related liver disease or Child-Pugh class C cirrhosis. Sarcopenia was independently associated with an ∼2-fold higher risk of mortality in patients with cirrhosis. The mortality rate increased with greater severity or longer durations of sarcopenia. Increasing awareness about the importance of sarcopenia in patients with cirrhosis among stakeholders must be prioritized.

TIPS for the management of stomal variceal bleeding due to cirrhotic and non-cirrhotic portal hypertension.

BACKGROUND: Portal hypertension (PH) is associated with the development of esophageal or gastric varices, which can cause bleedings with high mortality. Varices can also manifest at sites of stomata. These parastomal varices can cause recurrent variceal bleedings (VB) despite local therapies. We present a case series of parastomal VB due to PH that were managed with implantation of transjugular intrahepatic portosystemic shunt (TIPS). METHODS: We retrospectively included all patients (pt) from 2 tertiary medical centers with parastomal VB between January 2014 and February 2020 who underwent the TIPS procedure. RESULTS: Nine pt were included. Seven pt had liver cirrhosis, mostly alcohol-related. Two pt had non-cirrhotic PH due to porto-sinusoidal vascular disease (PSD). Four pt had a colostomy, 1 an ileostomy, and 4 an ileal conduit. Malignancy was the leading cause of stoma surgery. All 9 pt suffered from recurrent parastomal VB despite non-selective beta-blocker and/or local therapy (e.g., compression, coagulation, suture ligation, or surgical stoma revision). All pt received TIPS implantation. In 7 pt, TIPS implantation led to sustainable hemostasis. Two pt suffered a bleeding relapse that was attributable to TIPS dysfunction. TIPS revision with coil embolization of the varices terminated the VB sustainably in both pt. CONCLUSIONS: In pt presenting with recurrent stomal bleedings, parastomal varices as a rare complication of PH must be taken into consideration as an underlying cause. In our case series, we managed to sustainably cease parastomal VB by TIPS implantation with or without coil embolization of the ectopic varices.

Differential inflammasome activation predisposes to acute-on-chronic liver failure in human and experimental cirrhosis with and without previous decompensation.

OBJECTIVE: Systemic inflammation predisposes acutely decompensated (AD) cirrhosis to the development of acute-on-chronic liver failure (ACLF). Supportive treatment can improve AD patients, becoming recompensated. Little is known about the outcome of patients recompensated after AD. We hypothesise that different inflammasome activation is involved in ACLF development in compensated and recompensated patients. DESIGN: 249 patients with cirrhosis, divided into compensated and recompensated (previous AD), were followed prospectively for fatal ACLF development. Two external cohorts (n=327) (recompensation, AD and ACLF) were included. Inflammasome-driving interleukins (ILs), IL-1α (caspase-4/11-dependent) and IL-1ß (caspase-1-dependent), were measured. In rats, bile duct ligation-induced cirrhosis and lipopolysaccharide exposition were used to induce AD and subsequent recompensation. IL-1α and IL-1ß levels and upstream/downstream gene expression were measured. RESULTS: Patients developing ACLF showed higher baseline levels of ILs. Recompensated patients and patients with detectable ILs had higher rates of ACLF development than compensated patients. Baseline CLIF-C (European Foundation for the study of chronic liver failure consortium) AD, albumin and IL-1α were independent predictors of ACLF development in compensated and CLIF-C AD and IL-1ß in recompensated patients. Compensated rats showed higher IL-1α gene expression and recompensated rats higher IL-1ß levels with higher hepatic gene expression. Higher IL-1ß detection rates in recompensated patients developing ACLF and higher IL-1α and IL-1ß detection rates in patients with ACLF were confirmed in the two external cohorts. CONCLUSION: Previous AD is an important risk factor for fatal ACLF development and possibly linked with inflammasome activation. Animal models confirmed the results showing a link between ACLF development and IL-1α in compensated cirrhosis and IL-1ß in recompensated cirrhosis.

Refining prediction of survival after TIPS with the novel Freiburg index of post-TIPS survival.

BACKGROUND & AIMS: Transjugular intrahepatic portosystemic shunt (TIPS) implantation is an effective and safe treatment for complications of portal hypertension. Survival prediction is important in these patients as they constitute a high-risk population. Therefore, the aim of our study was to develop an alternative prognostic model for accurate survival prediction after planned TIPS implantation. METHODS: A total of 1,871 patients with de novo TIPS implantation for ascites or secondary prophylaxis of variceal bleeding were recruited retrospectively. The study cohort was divided into a training set (80% of study patients; n = 1,496) and a validation set (20% of study patients; n = 375). Further, patients with early (preemptive) TIPS implantation due to variceal bleeding were included as another validation cohort (n = 290). Medical data and overall survival (OS) were assessed. A Cox regression model was used to create an alternative prediction model, which includes significant prognostic factors. RESULTS: Age, bilirubin, albumin and creatinine were the most important prognostic factors. These parameters were included in a new score named the Freiburg index of post-TIPS survival (FIPS). The FIPS score was able to identify high-risk patients with a significantly reduced median survival of 5.0 (3.1-6.9) months after TIPS implantation in the training set. These results were confirmed in the validation set (median survival of 3.1 [0.9-5.3] months). The FIPS score showed better prognostic discrimination compared to the Child-Pugh, MELD, MELD-Na score and the bilirubin-platelet model. However, the FIPS score showed insufficient prognostic discrimination in patients with early TIPS implantation. CONCLUSIONS: The FIPS score is superior to established scoring systems for the identification of high-risk patients with a worse prognosis following elective TIPS implantation. LAY SUMMARY: Implantation of a transjugular intrahepatic portosystemic shunt (TIPS) is a safe and effective treatment for patients with cirrhosis and clinically significant portal hypertension. However, risk stratification is a major challenge in these patients as currently available scoring systems have major drawbacks. Age, bilirubin, albumin and creatinine were included in a new risk score which was named the Freiburg index of post-TIPS survival (FIPS). The FIPS score can identify patients at high risk and may guide clinical decision making.

Magnetic resonance parametric mapping of the spleen for non-invasive assessment of portal hypertension.

OBJECTIVES: In patients with advanced liver disease, portal hypertension is an important risk factor, leading to complications such as esophageal variceal bleeding, ascites, and hepatic encephalopathy. This study aimed to determine the diagnostic value of T1 and T2 mapping and extracellular volume fraction (ECV) for the non-invasive assessment of portal hypertension. METHODS: In this prospective study, 50 participants (33 patients with indication for trans-jugular intrahepatic portosystemic shunt (TIPS) and 17 healthy volunteers) underwent MRI. The derivation and validation cohorts included 40 and 10 participants, respectively. T1 and T2 relaxation times and ECV of the liver and the spleen were assessed using quantitative mapping techniques. Direct hepatic venous pressure gradient (HVPG) and portal pressure measurements were performed during TIPS procedure. ROC analysis was performed to compare diagnostic performance. RESULTS: Splenic ECV correlated with portal pressure (r = 0.72; p < 0.001) and direct HVPG (r = 0.50; p = 0.003). No significant correlations were found between native splenic T1 and T2 relaxation times with portal pressure measurements (p > 0.05, respectively). In the derivation cohort, splenic ECV revealed a perfect diagnostic performance with an AUC of 1.000 for the identification of clinically significant portal hypertension (direct HVPG ≥ 10 mmHg) and outperformed other parameters: hepatic T2 (AUC, 0.731), splenic T2 (AUC, 0.736), and splenic native T1 (AUC, 0.806) (p < 0.05, respectively). The diagnostic performance of mapping parameters was comparable in the validation cohort. CONCLUSION: Splenic ECV was associated with portal pressure measurements in patients with advanced liver disease. Future studies should explore the diagnostic value of parametric mapping accross a broader range of pressure values. KEY POINTS: • Non-invasive assessment and monitoring of portal hypertension is an area of unmet interest. • Splenic extracellular volume fraction is strongly associated with portal pressure in patients with end-stage liver disease. • Quantitative splenic and hepatic MRI-derived parameters have a potential to become a new non-invasive diagnostic parameter to assess and monitor portal pressure.