Total area of spontaneous portosystemic shunts independently predicts hepatic encephalopathy and mortality in liver cirrhosis

Background & Aims: Spontaneous portosystemic shunts (SPSS) frequently develop in liver cirrhosis. Recent data suggested that the presence of a single large SPSS is associated with complications, especially overt hepatic encephalopathy (oHE). However, the presence of >1 SPSS is common. This study evaluates the impact of total cross-sectional SPSS area (TSA) on outcomes in patients with liver cirrhosis. Methods: In this retrospective international multicentric study, CT scans of 908 cirrhotic patients with SPSS were evaluated for TSA. Clinical and laboratory data were recorded. Each detected SPSS radius was measured and TSA calculated. One-year survival was the primary endpoint and acute decompensation (oHE, variceal bleeding, ascites) was the secondary endpoint. Results: A total of 301 patients (169 male) were included in the training cohort. Thirty percent of all patients presented with >1 SPSS. A TSA cut-off of 83 mm2 was used to classify patients with small or large TSA (S-/L-TSA). Patients with L-TSA presented with higher model for end-stage liver disease score (11 vs. 14) and more commonly had a history of oHE (12% vs. 21%, p <0.05). During follow-up, patients with L-TSA experienced more oHE episodes (33% vs. 47%, p <0.05) and had lower 1-year survival than those with S-TSA (84% vs. 69%, p <0.001). Multivariate analysis identified L-TSA (hazard ratio 1.66; 95% CI 1.02–2.70, p <0.05) as an independent predictor of mortality. An independent multicentric validation cohort of 607 patients confirmed that patients with L-TSA had lower 1-year survival (77% vs. 64%, p <0.001) and more oHE development (35% vs. 49%, p <0.001) than those with S-TSA. Conclusion: This study suggests that TSA >83 mm2 increases the risk for oHE and mortality in patients with cirrhosis. Our results support the clinical use of TSA/SPSS for risk stratification and decision-making in the management of patients with cirrhosis. Lay summary: The prevalence of spontaneous portosystemic shunts (SPSS) is higher in patients with more advanced chronic liver disease. The presence of more than 1 SPSS is common in advanced chronic liver disease and is associated with the development of hepatic encephalopathy. This study shows that total cross-sectional SPSS area (rather than diameter of the single largest SPSS) predicts survival in patients with advanced chronic liver disease. Our results support the clinical use of total cross-sectional SPSS area for risk stratification and decision-making in the management of SPSS.Jonel Trebicka is supported by grants from the Deutsche Forschungsgemeinschaft (SFB TRR57, CRC1382), Cellex Foundation and European Union’s Horizon 2020 research and innovation program GALAXY study (No. 668031), LIVERHOPE (No. 731875) and MICROB-PREDICT (No. 825694) and the Cellex Foundation. Joan Genescà is a recipient of a Research Intensification grant from Instituto de Salud Carlos III, Spain. The study was partially funded by grants PI15/00066, and PI18/00947 from Instituto de Salud Carlos III and co-funded by European Union (ERDF/ESF, “Investing in your future”). Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivasis supported by Instituto de Salud Carlos III. Macarena Simón-Talero is a recipient of the grant JR 17/00029 from Instituto de Salud Carlos II

The story of HCC in NAFLD: from epidemiology, across pathogenesis, to prevention and treatment.

BACKGROUND & AIMS Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. An increasing number of reports describe HCC in the setting of obesity and diabetes, two major risk factors for non-alcoholic fatty liver disease (NAFLD). The increasing incidence of these conditions and the emerging evidence of HCC in non-cirrhotic NAFLD prioritize a better understanding of NAFLD-related HCC epidemiology and pathogenesis in order to target screening policies and develop preventive-therapeutic strategies. In this review, we focus on the epidemiological impact of this condition, suggesting a possible link between HCC in cryptogenic cirrhosis and NAFLD. Furthermore, we analyse the suggested pathogenic mechanisms and the possible preventive-therapeutic strategies

Portal vein thrombosis: The role of imaging in the clinical setting.

Portal vein thrombosis is an infrequent condition occurring in several different clinical scenarios. In the last years it has been increasingly recognised due to the broad use of radiological methods. In this review we underline the central role of imaging in diagnosing portal vein thrombosis, in clarifying its etiology, choosing the best therapeutic approach and screening possible complications. Special attention is given to the role of imaging to differentiate portal vein thrombosis from neoplastic invasion of the portal vein, and to new diagnostic methods available for clinical practice in this field

Fever of Unknown Origin, a Vascular Event, and Immunosuppression in Tick-Endemic Areas: Think About Neoehrlichiosis.

Three patients were referred to our hospital because of fever of unknown origin (FUO) and thrombosis or thrombophlebitis. All of them had been under immunosuppression (IS) with rituximab. Intensive diagnostics for FUO and blood cultures remained negative. Finally, the association of fever, immunosuppression, and a vascular event led to the suspicion of Candidatus Neoehrlichia mikurensis (CNM) infection. The diagnosis was confirmed by species-specific polymerase chain reaction (PCR) in the peripheral blood. Therapy with doxycycline or rifampicin led to the resolution of the disease. A liver biopsy was performed in one patient due to hepatomegaly and elevated liver enzymes demonstrating hemophagocytosis. To our knowledge, this is the first histopathological study of liver tissue in CNM infection. The evidence of hemophagocytosis raises the question of whether symptomatic CNM infection might be in part related to host inflammatory and immune responses

Noninvasive Markers of Portal Hypertension Detect Decompensation in Overweight or Obese Patients With Compensated Advanced Chronic Liver Disease.

BACKGROUND & AIMS Some patients with compensated advanced chronic liver disease (cACLD) require use of an extra-large probe for liver stiffness measurement (LSM), due to overweight or obesity. However, no one has fully assessed the ability of non-invasive markers of portal hypertension and the controlled attenuation parameter (CAP) to determine which of these patients are at risk for decompensation. METHODS We collected data from 272 patients with cACLD (LSM ≥10 kPa by XL probe; 57% with non-alcoholic steatohepatitis; mean body mass index, 33.8±6.5Kg/m2; median Child score, 5; median LSM, 16.8 kPa; mean CAP 318±66 dB/m) evaluated at 2 academic centers from 2015 through 2018. We collected clinical data on decompensation (ascites, portal hypertension bleeding, jaundice, hepatic encephalopathy) and severe bacterial infections; patients were followed for median 17 months (interquartile range, 11-24 months). We evaluated associations between these events and LSM, CAP, LSM*spleen size/platelet count (LSPS) and portal hypertension risk scores. RESULTS Decompensation occurred in 12 patients and severe bacterial infections developed in 5 patients. LSM, LSPS, and portal hypertension risk score identified patients with decompensation with area under the receiver operating characteristic curve values of 0.848 (95% CI, 0.720-0.976, P<.0001), 0.881 (95% CI, 0.798-0.954, P<.0001), and 0.890 (95% CI, 0.814-0.966, P<.0001) respectively. In multivariate Cox regression analysis, in patients with non-alcoholic steatohepatitis, LSM and CAP were independently associated with decompensation and severe bacterial infection; CAP≥220dB/m was associated with a reduced risk of decompensation (hazard ratio, 0.043, 95% CI, 0.004-0.476; P=.01). CONCLUSIONS LSM, LSPS, and portal hypertension risk score identify obese or overweight patients with cACLD who are at increased risk of decompensation and severe bacterial infection

Portal Hypertension and a Stiff Liver.

Portal hypertension (PH) is a common clinical syndrome leading to severe complications. In the western world, about 90% of cases of PH are due to liver cirrhosis, and thanks to the availability of ultrasound elastography methods, this diagnosis is usually confirmed at bedside. We report a case of a patient presenting with PH and ascites initially suspected of suffering from liver cirrhosis. The finding of large hepatomegaly and a massive increase in liver stiffness prompted us to perform a liver biopsy. This revealed no fibrosis, but diffuse primary amyloidosis (AL amyloidosis). We discuss the diagnostic and treatment of this case, with emphasis on non-invasive imaging methods available for diagnosis and follow up

Prognostic Significance of Controlled Attenuation Parameter in Patients With Compensated Advanced Chronic Liver Disease.

Obesity and steatosis have been associated with liver disease progression in patients with compensated advanced chronic liver disease (cACLD) (liver stiffness measurement [LSM] ≥ 10 kPa). The controlled attenuation parameter (CAP) estimates steatosis during LSM by transient elastography. We aimed to evaluate whether CAP is associated with the development of clinically relevant events in cACLD. Consecutive patients with cACLD and CAP measurements observed between September 2013 and September 2015 were retrospectively studied. Classical decompensation and severe bacterial infections on follow-up were recorded. A predefined CAP cut-off for steatosis was used (220 dB/m; 90% sensitivity). The association among LSM, CAP, and events was assessed by univariate and multivariate Cox regression. Among the 193 patients (viral etiology = 58%; median Child score = 5; LSM = 15.1 kPa; CAP = 255 ± 62 dB/m) who were followed up in median for 18 months, 18 developed clinically relevant events (11 liver decompensation, 7 severe bacterial infections). Patients developing events had higher LSM (median: 30.8 versus 14.3 kPa, < 0.001) and showed trends for higher CAP (275 ± 46 versus 252 ± 63 dB/m, = 0.07), lower platelet count (134 ± 74 versus 167 ± 74 G/L, = 0.07), and worse liver function versus patients remaining compensated. Body mass index was similar in the two groups. All events were more frequent in patients with CAP being greater than or equal to 220 dB/m (12.9% versus 1.6% in CAP < 220; = 0.013), and 10 of 11 episodes of liver decompensation occurred in patients with CAP being greater than or equal to 220 dB/m. Following multivariate analysis, LSM and CAP greater than or equal to 220 dB/m remained independently associated with clinical events in the whole population and in patients with clinically significant portal hypertension. The CAP being greater than or equal to 220 dB/m is associated with increased risk of clinical decompensation and bacterial infections independent of LSM in patients with cACLD and allows refining the noninvasive risk stratification in this population. ( 2018; 00:000-000)

Reinfusion of highly purified CD133+ bone marrow-derived stem/progenitor cells in patients with end-stage liver disease: A phase I clinical trial

Background: Bone marrow stem/progenitor cells seem to be effective in liver regeneration after tissueinjury. Aim: To evaluate the feasibility and safety of the mobilization and reinfusion of CD133+stem/progenitorcells in patients with end-stage liver disease.Methods: Autologous CD133+stem/progenitor cells, mobilized with granulocyte-colony stimulating fac-tor, were collected by leukapheresis and reinfused at increasing doses through the hepatic artery startingfrom 5 × 104/kg up to 1 × 106/kg.Results: 16 subjects with Model for End-stage Liver Disease (MELD) score between 17 and 25 wereenrolled, 14 mobilized an adequate number of CD133+stem/progenitor cells and 12 were reinfused.No severe adverse events related to the procedure were reported. MELD score significantly worsenedduring mobilization in Child Turcotte Pugh-C patients. A significant improvement of liver function wasobserved 2 months after reinfusion (MELD 19.5 vs 16; P = 0.045). Overall, 5 patients underwent livertransplantation within 12 months from reinfusion and 2 died because of progressive liver failure.Conclusions: CD133+stem/progenitor cells reinfusion in patients with end-stage liver disease is feasi-ble and safe. A worsening of liver function was observed during mobilization in Child Turcotte Pugh-Cpatients. The temporary improvement of MELD score after reinfusion suggests that stem cells therapymay be a “bridge to transplant” approach for these patients