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.

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.

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 extralarge probe for liver stiffness measurement (LSM), owing to overweight or obesity. However, the ability of noninvasive markers of portal hypertension and the controlled attenuation parameter (CAP) to determine which of these patients are at risk for decompensation has not been fully assessed. METHODS: We collected data from 272 patients with cACLD (LSM ≥10 kPa by XL probe; 57% with nonalcoholic steatohepatitis; mean body mass index, 33.8 ± 6.5 kg/m2; median Child-Pugh 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 up for a median of 17 months (interquartile range, 11-24 mo). 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 the 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 nonalcoholic steatohepatitis, LSM and CAP were associated independently with decompensation and severe bacterial infection; CAP ≥ 220 dB/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 the portal hypertension risk score identify obese or overweight patients with cACLD who are at increased risk of decompensation and severe bacterial infection.

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, P < 0.001) and showed trends for higher CAP (275 ± 46 versus 252 ± 63 dB/m, P = 0.07), lower platelet count (134 ± 74 versus 167 ± 74 G/L, P = 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; P = 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. Conclusion: 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. (Hepatology Communications 2018; 00:000-000).

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.

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.

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.

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 tissue injury. AIM: To evaluate the feasibility and safety of the mobilization and reinfusion of CD133+ stem/progenitor cells in patients with end-stage liver disease. METHODS: Autologous CD133+ stem/progenitor cells, mobilized with granulocyte-colony stimulating factor, were collected by leukapheresis and reinfused at increasing doses through the hepatic artery starting from 5×10(4)/kg up to 1×10(6)/kg. RESULTS: 16 subjects with Model for End-stage Liver Disease (MELD) score between 17 and 25 were enrolled, 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 worsened during mobilization in Child Turcotte Pugh-C patients. A significant improvement of liver function was observed 2 months after reinfusion (MELD 19.5 vs. 16; P=0.045). Overall, 5 patients underwent liver transplantation 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 feasible and safe. A worsening of liver function was observed during mobilization in Child Turcotte Pugh-C patients. The temporary improvement of MELD score after reinfusion suggests that stem cells therapy may be a "bridge to transplant" approach for these patients.

Bone marrow derived stem cells for the treatment of end-stage liver disease.

End-stage disease due to liver cirrhosis is an important cause of death worldwide. Cirrhosis results from progressive, extensive fibrosis and impaired hepatocyte regeneration. The only curative treatment is liver transplantation, but due to the several limitations of this procedure, the interest in alternative therapeutic strategies is increasing. In particular, the potential of bone marrow stem cell (BMSC) therapy in cirrhosis has been explored in different trials. In this article, we evaluate the results of 18 prospective clinical trials, and we provide a descriptive overview of recent advances in the research on hepatic regenerative medicine. The main message from the currently available data in the literature is that BMSC therapy is extremely promising in the context of liver cirrhosis. However, its application should be further explored in randomized, controlled trials with large cohorts and long follow-ups.