Reduced bone mineral density is associated to post-TIPS survival of female patients with decompensated cirrhosis.

BACKGROUND: Malnutrition is common in patients with cirrhosis, eventually leading to sarcopenia and loss of bone mass. AIMS: The aims of this study was the assessment of body composition (BC) and bone mineral density (BMD) in patients with decompensated cirrhosis and the prognostic impact on survival after transjugular intrahepatic portosystemic shunt (TIPS) implantation. METHODS: BMD and BC of 107 patients with cirrhosis undergoing TIPS implantation were prospectively analyzed by dual-energy X-ray absorptiometry. The prevalence and predisposing risk factors for reduced BMD and sarcopenia were assessed. Impact on 12-month survival after TIPS implantation was evaluated. RESULTS: Sarcopenia was diagnosed in 48.6 % of the patients with a predominance of male patients (58.7% vs. 25.0 %, p = 0.001). 67.2 % had reduced BMD. Low BMI was independently associated with sarcopenia (OR 0.751 (95 % CI: 0.662;0.852), p < 0.001) and reduced BMD (OR 0.851 (0.773;0.937), p = 0.001). Patients with reduced BMD, but not sarcopenia, had impaired 12-month survival after TIPS-implantation (61.2% vs. 82.9 %, p = 0.030). Subgroup analysis showed that this was especially valid for female patients. CONCLUSIONS: Sarcopenia and reduced BMD are frequently observed in patients with decompensated cirrhosis. Reduced BMD negatively affects post-TIPS survival. Since malnutrition is a leading cause, assessment of nutritional status and specific treatment should be included in clinical practice.

Fibrosis Progression in Patients with Budd-Chiari Syndrome and Transjugular Intrahepatic Portosystemic Shunt (TIPS): A Long-Term Study Using Transient Elastography.

Hepatic vein outflow obstruction causes congestion of the liver, leading to necrosis, fibrosis, and portal hypertension (PH). A transjugular intrahepatic portosystemic shunt (TIPS) reduces congestion and PH by providing artificial outflow. The aim of the study was to investigate fibrosis progression in patients with Budd-Chiari syndrome (BCS) and TIPS using transient elastography (TE). From 2010 to 2022, 25 patients received 80 TEs using FibroScan®, Echosens, Paris, France (3.2 ± 2.1 per patient). TIPS function was assessed via Doppler ultrasound or radiological intervention. At the time of TE examination, 21 patients had patent shunts. Four patients had occluded shunts but normal pressure gradients during the intervention. The first TE measurement performed 9.8 ± 6.8 years after the BCS diagnosis showed stiffness values of 24.6 ± 11.5 kPa. A second or last measurement performed 7.0 ± 2.9 years after the first measurement showed similar stiffness values of 24.1 ± 15.7 kPa (p = 0.943). Except for three patients, the liver stiffness was always >12 kPa, indicating advanced fibrosis. Stiffness values obtained <5 years (n = 8, 23.8 ± 9.2 kPa) or >5 years after the BCS diagnosis (24.9 ± 12.7 kPa) did not differ (p = 0.907). In addition, stiffness was not related to the interval between BCS and TIPS implantation (p = 0.999). One patient received liver transplantation, and two patients died from non-hepatic causes. Most patients developed mild to moderate cirrhosis, possibly during the early phase of the disease. Timing of TIPS did not influence fibrosis progression. This and the release of portal hypertension may argue in favor of a generous TIPS implantation practice in patients with BCS.

Diastolic dysfunction is associated with cardiac decompensation after transjugular intrahepatic portosystemic shunt in patients with liver cirrhosis.

BACKGROUND AND AIMS: About 20% of patients develop cardiac decompensation within the first year after transjugular intrahepatic portosystemic shunt (TIPS) insertion. However, risk factors for cardiac decompensation remain poorly defined. We aimed to evaluate predictors of cardiac decompensation after TIPS insertion in a large, well-defined cohort of patients with liver cirrhosis. METHODS: 234 cirrhotic patients who received a TIPS at Hannover Medical School were retrospectively followed up for one year to assess the incidence of cardiac decompensation. Echocardiographic parameters and established diagnostic criteria for cardiac impairment (e.g. by the American Society of Echocardiography/ European Association of Cardiovascular Imaging (ASE/EACVI)) were investigated for an association with cardiac decompensation in a competing risk analysis. Survival was analyzed using a multivariable cox regression analysis adjusting for Freiburg index of post-TIPS survival. RESULTS: Predominant TIPS indication was ascites (83%). Median age was 59 years, median MELD-score 12% and 58% were male. Overall, 41 patients (18%) developed cardiac decompensation within one year after TIPS insertion. Diastolic dysfunction according to the ASE/EACVI was diagnosed in 26% of patients at baseline and was linked to a significantly higher risk for cardiac decompensation (p = 0.025) after TIPS. When investigating individual echocardiographic baseline parameters, only pathological E/A (<0.8 or >2) was identified as a risk factor for cardiac decompensation (p = 0.015). Mortality and liver transplantation (n = 50) were significantly higher among patients who developed cardiac decompensation (HR = 5.29, p < 0.001) as well as in patients with a pathological E/A (HR = 2.34, p = 0.006). Cardiac high-risk status (44% of patients) was strongly linked to cardiac decompensation (HR = 2.93, p = 0.002) and mortality (HR = 2.24, p = 0.012). CONCLUSION: Cardiac decompensation after TIPS is a frequent and important complication and is associated with reduced survival. American Society of Echocardiography/EACVI criteria and E/A seem to be the best parameters to predict the cardiac risk in cirrhotic patients undergoing TIPS insertion.

[Complications of liver cirrhosis]. / Komplikationen der Leberzirrhose.

Liver cirrhosis is a chronic disease, progressing from a compensated and asymptomatic state to decompensated cirrhosis with the occurrence of multiple organ complications. This progression is accompanied by a significant increase of morbidity and mortality. Main complications include clinical manifestations of portal hypertension (ascites and varices) as well as consequences of liver insufficiency as hepatic encephalopathy. Besides, many other organ systems can be affected, as liver cirrhosis is today more and more seen as a multisystemic disease. Unfortunately, most therapy options of these complications are purely symptomatic, and the only curative treatment of advanced chronic liver disease is liver transplantation.

Prediction of postembolization syndrome after transarterial chemoembolization of hepatocellular carcinoma and its impact on prognosis.

BACKGROUND: Postembolization syndrome (PES) represents the most frequent complication after transarterial chemoembolization (TACE) in patients with HCC. Given the vague definition as a symptom complex comprising abdominal pain, fever, and nausea, PES is diagnosed in heterogeneous patient cohorts with symptoms ranging from mild pain to severe deterioration of their general condition. This study aimed to evaluate predictive factors and the prognostic impact of PES with regard to different severity grades. METHODS: A total of 954 patients treated with TACE for HCC at the University Medical Centres Mainz and Freiburg were included in this study. PES disease severity was graded as mild, moderate, or severe according to a predefined combination of symptoms. Logistic regression models were used to identify independent predictors of PES. The prognostic impact of PES was evaluated by competing risk analyses considering liver transplantation as a competing risk. RESULTS: PES occurred in 616 patients (64.5%), but only 56 patients (5.9%) had severe PES, defined as moderate to severe abdominal pain requiring opioids in combination with fever and nausea. The largest tumor diameter was the strongest independent predictor of PES (OR = 1.21, 95% CI = 1.13-1.28), and severe PES (OR = 1.23, 95% CI = 1.14-1.33, p < 0.0001). Presence of liver cirrhosis was protective against PES (OR = 0.48, 95% CI = 0.27-0.84, p = 0.01). Furthermore, PES was independently associated with an impaired disease control rate (OR = 0.33, 95% CI = 0.16-0.69, p = 0.003) and severe PES with poor overall survival (subdistribution HR = 1.53, 95% CI = 0.99-2.36, p = 0.04). CONCLUSIONS: Tumor size and absence of liver cirrhosis are predictors of severe PES and associated with impaired prognosis in HCC patients after TACE.

Proton pump inhibitor treatment aggravates bacterial translocation in patients with advanced cirrhosis and portal hypertension.

IMPORTANCE: Long-term prescription of proton pump inhibitors (PPIs) in patients with cirrhosis is common practice. However, in recent years, several observational studies have reported increased complications and negative prognostic effects of PPI treatment in these patients. Judging the significance of these associations is complicated by the fact that a plausible underlying pathomechanism has not been identified so far. In the present study, we address this important issue by investigating the impact of PPI treatment on subclinical bacterial translocation from the gut into the blood stream in patients with advanced cirrhosis and portal hypertension. Indeed, we report significantly aggravated bacterial translocation in cirrhosis patients receiving PPI treatment. This finding is highly relevant, as bacterial translocation is known to promote the development of complications and impair prognosis in patients with cirrhosis. Hence, the present study could establish a plausible link between PPI treatment and adverse effects in cirrhosis.

Predictive Value of [99mTc]-MAA-Based Dosimetry in Hepatocellular Carcinoma Patients Treated with [90Y]-TARE: A Single-Center Experience.

Transarterial radioembolization is a well-established method for the treatment of hepatocellular carcinoma. The tolerability and incidence of hepatic decompensation are related to the doses delivered to the tumor and healthy liver. This retrospective study was performed at our center to evaluate whether tumor- and healthy-liver-absorbed dose levels in TARE are predictive of tumor response according to the mRECIST 1.1 criteria and overall survival. One hundred and six patients with hepatocellular carcinoma were treated with [90Y]-loaded resin microspheres and completed the follow-up. The dose delivered to each compartment was calculated using a compartmental model. The model was based on [99mTc]-labelled albumin aggregate images obtained before the start of therapy. Tumor response was assessed after three months of treatment. Kaplan-Meier analysis was used to assess survival. The mean age of our population was 66 ± 13 years with a majority being BCLC B tumors. Forty-two patients presented with portal vein thrombosis. The response rate was 57% in the overall population and 59% in patients with thrombosis. Target-to-background (TBR) values measured on initial [99mTc]MAA-SPECT-imaging and tumor model dosimetric values were associated with tumor response (p < 0.001 and p = 0.009, respectively). A dosimetric threshold of 136.5 Gy was predictive of tumor response with a sensitivity of 84.2% and specificity of 89.4%. Overall survival was 24.1 months [IQR 13.1-36.4] for patients who responded to treatment compared to 10.4 months [IQR 6.3-15.9] for the remaining patients (p = 0.022). In this cohort, the initial [99mTc]MAA imaging is predictive of response and survival. The dosimetry prior to the application of TARE can be used for treatment planning and our results also suggest that the therapy is well-tolerated. In particular, hepatic decompensation can be predicted even in the presence of PVT.

Proton pump inhibitor treatment is associated with acute-on-chronic liver failure in patients with advanced cirrhosis.

BACKGROUND: Acute-on-chronic liver failure (ACLF) is a fatal complication of cirrhosis. Hence, identification of risk factors for ACLF is crucial. Previous studies have linked proton pump inhibitor (PPI) treatment to complications of cirrhosis, however, a possible effect of PPI treatment on the risk of ACLF has not been investigated yet. Therefore, the present study aimed to characterize the impact of PPI treatment on ACLF development. METHODS: A total of 642 patients hospitalized due to complications of cirrhosis were retrospectively identified, and PPI treatment during an observation period of 3 years following the hospitalization was reviewed. Subsequently, 74 patients with newly initiated PPI treatment at the time of hospitalization (PPI group) were 1:1 propensity score matched to 74 patients who received no PPI treatment (no-PPI group). Primary end point was the development of ACLF during the observation period, and secondary endpoints were mortality and upper gastrointestinal bleeding. RESULTS: PPI and no-PPI groups had comparably severe chronic liver disease at baseline. Nevertheless, the cumulative incidence of ACLF in the presence of death as competing risk was markedly higher in the PPI group compared with the no-PPI group. ACLF-related deaths contributed significantly to a higher 3-year mortality in the PPI group. Uni and multivariable competing risk regression models confirmed that PPI treatment was an independent predictor of ACLF in the study collective (subdistribution HR: 1.892, 95% CI: 1.092-3.281, p = 0.023). The impact of PPI treatment on ACLF development was particularly strong in patients with a model for end-stage liver disease score >12. Upper gastrointestinal bleeding was slightly less frequent in the PPI group. CONCLUSIONS: The present results indicate that PPI treatment could be a risk factor for ACLF in patients with advanced cirrhosis.

[Elevated liver enzymes: A diagnostic challenge]. / Erhöhte Leberwerte: eine differenzialdiagnostische Herausforderung.

The differential diagnosis of elevated liver enzymes is a key aspect of hepatology and a diagnostic challenge for many. Elevated liver enzymes may mostly indicate liver damage but also physiologic elevations or extrahepatic causes are possible. A rational approach to the differential diagnosis of elevated liver enzymes is necessary to avoid overdiagnosis while not missing rare causes of liver disease.

Outcomes of beta blocker use in advanced hepatocellular carcinoma treated with immune checkpoint inhibitors.

Background: In patients with cirrhosis, portal hypertension increases intestinal permeability, dysbiosis, and bacterial translocation, promoting an inflammatory state that can lead to the progression of liver disease and development of hepatocellular carcinoma (HCC). We aimed to investigate whether beta blockers (BBs), which can mediate portal hypertension, conferred survival benefits in patients treated with immune checkpoint inhibitors (ICIs). Methods: We conducted a retrospective, observational study of 578 patients with unresectable HCC treated with ICI from 2017 to 2019 at 13 institutions across three continents. BB use was defined as exposure to BBs at any time during ICI therapy. The primary objective was to assess the association of BB exposure with overall survival (OS). Secondary objectives were to evaluate the association of BB use with progression-free survival (PFS) and objective response rate (ORR) according to RECIST 1.1 criteria. Results: In our study cohort, 203 (35%) patients used BBs at any point during ICI therapy. Of these, 51% were taking a nonselective BB. BB use was not significantly correlated with OS (hazard ratio [HR] 1.12, 95% CI 0.9-1.39, P = 0.298), PFS (HR 1.02, 95% CI 0.83-1.26, P = 0.844) or ORR (odds ratio [OR] 0.84, 95% CI 0.54-1.31, P = 0.451) in univariate or multivariate analyses. BB use was also not associated with incidence of adverse events (OR 1.38, 95% CI 0.96-1.97, P = 0.079). Specifically, nonselective BB use was not correlated with OS (HR 0.94, 95% CI 0.66-1.33, P = 0.721), PFS (HR 0.92, 0.66-1.29, P = 0.629), ORR (OR 1.20, 95% CI 0.58-2.49, P = 0.623), or rate of adverse events (OR 0.82, 95% CI 0.46-1.47, P = 0.510). Conclusion: In this real-world population of patients with unresectable HCC treated with immunotherapy, BB use was not associated with OS, PFS or ORR.

Hepatic decompensation after transarterial radioembolization: A retrospective analysis of risk factors and outcome in patients with hepatocellular carcinoma.

Transarterial radioembolization (TARE) is a well-established therapy for intermediate and advanced tumor stages of hepatocellular carcinoma (HCC). Treatment-associated toxicities are rare. Previous studies have outlined that the prognosis after TARE is determined primarily by tumor stage and liver function. The subset of patients benefiting from TARE remains to be defined. Sixty-one patients with HCC treated with TARE between 2015 and 2020 were retrospectively included in the study. Hepatic decompensation was defined as an increase of bilirubin or newly developed ascites that was not explained by tumor progression within 3 months after TARE. Predictive factors of hepatic decompensation and prognostic factors were assessed. Hepatic decompensation was observed in 27.9% (n = 17) of TARE-treated patients during follow-up. Albumin-bilirubin (ALBI) score at baseline and radiation dose on nontumor liver proved to be independent risk factors for the development of hepatic decompensation in multivariable regression models (ALBI score: odds ratio [OR] 6.425 [1.735;23.797], p < 0.005; radiation dose: OR 1.072 [1.016;1.131], p < 0.011). The occurrence of hepatic decompensation markedly impaired the prognosis of the patients. Survival was significantly worsened. Hepatic decompensation has shown to be an independent negative prognostic factor for death, adjusted for Barcelona Clinic Liver Cancer stage, age and ALBI grade (hazard ratio 5.694 [2.713;11.952], p < 0.001). Conclusion: Hepatic decompensation after TARE for HCC treatment is a highly relevant complication with major effects on the prognosis of patients. Main risk factors are the pretreatment ALBI score and radiation dose. There is an urgent need to define safe cutoff values and exclusion criteria for TARE to limit complications and improve patient outcomes.

[Current pathophysiological concepts of acute decompensation in patients with liver cirrhosis and prognostic scores in different stages of disease]. / Pathophysiologie der Dekompensation bei Leberzirrhose ­ Prognose-Scores.

Acute decompensation and acute-on chronic liver failure (ACLF) are associated with a significant reduced prognosis. Previously, the pathophysiological concept of acute decompensation was mainly based on the peripheral vasodilatation hypothesis. However, during the last years, systemic inflammation was recognized as a major driver for decompensation of liver cirrhosis and ACLF. Further, it has been shown that systemic inflammation is associated with the clinical course and the prognosis of the patients. Inflammation also affects the function of extrahepatic organs and therefore leads to the development of an inflammatory cirrhotic multi-organ syndrome. The importance of systemic inflammation in the context of decompensated liver cirrhosis is also transferred to new clinical scores such as the CLIF-C AD and CLIF-C ACLF score. In this article, we provide an overview of the new systemic inflammation hypothesis of decompensated cirrhosis and also discuss current clinical scores for prognostication in different stages of liver cirrhosis.

Survival prediction using the Freiburg index of post-TIPS survival (FIPS) in critically ill patients with acute- on chronic liver failure: A retrospective observational study.

Background and aim: Liver cirrhosis in patients treated in the intensive care unit (ICU) is associated with high mortality. Well established scores are useful to allow for assessment of prognosis and support ICU treatment guidance. However, currently used scoring systems often do not reflect the complexity of critically ill patients. Therefore, we tested the newly developed Freiburg index-of post-TIPS survival (FIPS) score in order to assess its potential role for prognostication of cirrhotic patients in the ICU. Methods: A total of 310 patients with liver cirrhosis treated in the ICU between 2010 and 2021 were enrolled in this retrospective observational study. Prognostic factors for mortality and 28-day mortality were assessed. Moreover, using c indices the prognostic discrimination of different prognostic scores was analyzed. Results: The FIPS score allowed to discriminate patients with high ICU mortality and within 28-days after ICU treatment (ICU mortality: 42.2 vs. 59.9%, p = 0.008 and 28-day mortality: 43.3 vs. 74.1%, p < 0.001). However, the FIPS score in its current composition showed no superior prognostic discrimination compared to other established scores. Multivariable analyses identified the FIPS score (HR 1.25 [1.04-1.49], p = 0.015) and lactate at admission (HR 1.07 [1.04-1.09], p < 0.001) as significant predictors of ICU mortality. Lactate at admission substantially improved patient risk stratification within each FIPS risk groups. Conclusion: Similar to other commonly used scores, the FIPS score in its current composition does not allow a sufficiently reliable prognostication of critically ill patients treated in the ICU. However, adding lactate as additional factor to the FIPS score may improve its prognostic ability.

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.

Plasma Cyclic Guanosine Monophosphate Is a Promising Biomarker of Clinically Significant Portal Hypertension in Patients With Liver Cirrhosis.

Introduction: Despite intensive research, reliable blood-derived parameters to detect clinically significant portal hypertension (CSPH) in patients with cirrhosis are lacking. As altered homeostasis of cyclic guanosine monophosphate (cGMP), the central mediator of vasodilatation, is an essential factor in the pathogenesis of portal hypertension, the aim of our study was to evaluate plasma cGMP as potential biomarker of cirrhotic portal hypertension. Methods: Plasma cGMP was analyzed in cirrhotic patients with CSPH (ascites, n = 39; esophageal varices, n = 31), cirrhotic patients without CSPH (n = 21), patients with chronic liver disease without cirrhosis (n = 11) and healthy controls (n = 8). cGMP was evaluated as predictor of CSPH using logistic regression models. Further, the effect of transjugular intrahepatic portosystemic shunt (TIPS) placement on plasma cGMP was investigated in a subgroup of cirrhotic patients (n = 13). Results: Plasma cGMP was significantly elevated in cirrhotic patients with CSPH compared to cirrhotic patients without CSPH [78.1 (67.6-89.2) pmol/ml vs. 39.1 (35.0-45.3) pmol/l, p < 0.001]. Of note, this effect was consistent in the subgroup of patients with esophageal varices detected at screening endoscopy who had no prior manifestations of portal hypertension (p < 0.001). Cirrhotic patients without CSPH displayed no significant elevation of plasma cGMP compared to patients without cirrhosis (p = 0.347) and healthy controls (p = 0.200). Regression analyses confirmed that cGMP was an independent predictor of CSPH (OR 1.042, 95% CI 1.008-1.078, p = 0.016). Interestingly, portal decompression by TIPS implantation did not lead to normalization of plasma cGMP levels (p = 0.101). Conclusions: Plasma cGMP is a promising biomarker of CSPH in patients with cirrhosis, especially with respect to screening for esophageal varices. The lacking normalization of plasma cGMP after portal decompression suggests that elevated plasma cGMP in cirrhotic portal hypertension is mainly a correlate of systemic and splanchnic vasodilatation, as these alterations have been shown to persist after TIPS implantation.

The Antigen Presenting Potential of CD21low B Cells.

Human CD21low B cells are expanded in autoimmune (AI) diseases and display a unique phenotype with high expression of co-stimulatory molecules, compatible with a potential role as antigen-presenting cells (APCs). Thus, we addressed the co-stimulatory capacity of naïve-like, IgM-memory, switched memory and CD27negIgDneg memory CD21low B cells in allogenic co-cultures with CD4 T cells. CD21low B cells of patients with AI disorders expressed high levels of not only CD86, CD80, and HLA-DR (memory B cells) but also PD-L1 ex vivo and efficiently co-stimulated CD4 T cells of healthy donors (HD), as measured by upregulation of CD25, CD69, inducible co-stimulator (ICOS), and programmed cell death protein 1 (PD-1) and induction of cytokines. While the co-stimulatory capacity of the different CD21low B-cell populations was over all comparable to CD21pos counterparts of patients and HD, especially switched memory CD21low B cells lacked the increased capacity of CD21pos switched memory B-cells to induce high expression of ICOS, IL-2, IL-10, and IFN-γ. Acknowledging the limitation of the in vitro setting, CD21low B cells do not seem to preferentially support a specific Th effector response. In summary, our data implies that CD21low B cells of patients with AI diseases can become competent APCs and may, when enriched for autoreactive B-cell receptors (BCR), potentially contribute to AI reactions as cognate interaction partners of autoreactive T cells at sites of inflammation.