Giovanni Marasco

Spleen stiffness measurement can predict clinical complications in compensated HCV-related cirrhosis: A prospective study

BACKGROUND & AIMS Hepatic venous pressure gradient (HVPG) measurement represents the best predictor of clinical decompensation (CD) in cirrhotic patients. Recently data show that measurement of spleen stiffness (SS) has an excellent correlation with HVPG levels. Aim of the present prospective study was to assess SS predictive value for CD compared to HVPG, liver stiffness (LS), and other non-invasive tests for portal hypertension in a cohort of patients with HCV-related compensated cirrhosis. METHODS From an initial cohort of 124 patients, 92 underwent baseline LS, SS, HVPG measurements and upper gastrointestinal endoscopy at enrolment and then followed-up for 2 years or until the occurrence of the first CD. Univariate and multivariate logistic regression models were used for determining judgement criteria associated parameters. Accuracy of predictive factors was evaluated using c statistic. The final model was internally validated using the bootstrap method. RESULTS During follow-up, 30 out 92 (32.6%) patients developed CD. At univariate analysis varices at enrolment, all non-invasive parameters, HVPG, and model for end-stage liver disease (MELD) resulted clinical predictors of CD. At multivariate analysis only SS (p=0.0001) and MELD (p=0.014) resulted as predictive factors. A decision algorithm based on the results of a predictive model was proposed to detect patients with low risk of decompensation. CONCLUSIONS This study shows that in compensated cirrhotic patients a SS and MELD predictive model represents an accurate predictor of CD with accuracy at least equivalent to that of HVPG. If confirmed by further studies, SS and MELD could represent valid alternatives to HVPG as prognostic indicator of CD in HCV-related cirrhosis.

Gut microbiota, metabolome and immune signatures in patients with uncomplicated diverticular disease

Objective The engagement of the gut microbiota in the development of symptoms and complications of diverticular disease has been frequently hypothesised. Our aim was to explore colonic immunocytes, gut microbiota and the metabolome in patients with diverticular disease in a descriptive, cross-sectional, pilot study. Design Following colonoscopy with biopsy and questionnaire phenotyping, patients were classified into diverticulosis or symptomatic uncomplicated diverticular disease; asymptomatic subjects served as controls. Mucosal immunocytes, in the diverticular region and in unaffected sites, were quantified with immunohistochemistry. Mucosa and faecal microbiota were analysed by the phylogenetic platform high taxonomic fingerprint (HTF)-Microbi.Array, while the metabolome was assessed by 1H nuclear magnetic resonance. Results Compared with controls, patients with diverticula, regardless of symptoms, had a >70% increase in colonic macrophages. Their faecal microbiota showed depletion of Clostridium cluster IV. Clostridium cluster IX, Fusobacterium and Lactobacillaceae were reduced in symptomatic versus asymptomatic patients. A negative correlation was found between macrophages and mucosal Clostridium cluster IV and Akkermansia. Urinary and faecal metabolome changes in diverticular disease involved the hippurate and kynurenine pathways. Six urinary molecules allowed to discriminate diverticular disease and control groups with >95% accuracy. Conclusions Patients with colonic diverticular disease show depletion of microbiota members with anti-inflammatory activity associated with mucosal macrophage infiltration. Metabolome profiles were linked to inflammatory pathways and gut neuromotor dysfunction and showed the ability to discriminate diverticular subgroups and controls. These data pave the way for further large-scale studies specifically aimed at identifying microbiota signatures with a potential diagnostic value in patients with diverticular disease.

Prognostic factors for hepatocellular carcinoma recurrence

The recurrence of hepatocellular carcinoma, the sixth most common neoplasm and the third leading cause of cancer-related mortality worldwide, represents an important clinical problem, since it may occur after both surgical and medical treatment. The recurrence rate involves 2 phases: an early phase and a late phase. The early phase usually occurs within 2 years after resection; it is mainly related to local invasion and intrahepatic metastases and, therefore, to the intrinsic biology of the tumor. On the other hand, the late phase occurs more than 2 years after surgery and is mainly related to de novo tumor formation as a consequence of the carcinogenic cirrhotic environment. Since recent studies have reported that early and late recurrences may have different risk factors, it is clinically important to recognize these factors in the individual patient as soon as possible. The aim of this review was, therefore, to identify predicting factors for the recurrence of hepatocellular carcinoma, by means of invasive and non-invasive methods, according to the different therapeutic strategies available. In particular the role of emerging techniques (e.g., transient elastography) and biological features of hepatocellular carcinoma in predicting recurrence have been discussed. In particular, invasive methods were differentiated from non-invasive ones for research purposes, taking into consideration the emerging role of the genetic signature of hepatocellular carcinoma in order to better allocate treatment strategies and surveillance follow-up in patients with this type of tumor.

Gut Microbiota and Celiac Disease

Recent evidence regarding celiac disease has increasingly shown the role of innate immunity in triggering the immune response by stimulating the adaptive immune response and by mucosal damage. The interaction between the gut microbiota and the mucosal wall is mediated by the same receptors which can activate innate immunity. Thus, changes in gut microbiota may lead to activation of this inflammatory pathway. This paper is a review of the current knowledge regarding the relationship between celiac disease and gut microbiota. In fact, patients with celiac disease have a reduction in beneficial species and an increase in those potentially pathogenic as compared to healthy subjects. This dysbiosis is reduced, but might still remain, after a gluten-free diet. Thus, gut microbiota could play a significant role in the pathogenesis of celiac disease, as described by studies which link dysbiosis with the inflammatory milieu in celiac patients. The use of probiotics seems to reduce the inflammatory response and restore a normal proportion of beneficial bacteria in the gastrointestinal tract. Additional evidence is needed in order to better understand the role of gut microbiota in the pathogenesis of celiac disease, and the clinical impact and therapeutic use of probiotics in this setting.

Differences in liver stiffness values obtained with new ultrasound elastography machines and Fibroscan: A comparative study

BACKGROUND AND AIMS Whether Fibroscan thresholds can be immediately adopted for none, some or all other shear wave elastography techniques has not been tested. The aim of the present study was to test the concordance of the findings obtained from 7 of the most recent ultrasound elastography machines with respect to Fibroscan. METHODS Sixteen hepatitis C virus-related patients with fibrosis ≥2 and having reliable results at Fibroscan were investigated in two intercostal spaces using 7 different elastography machines. Coefficients of both precision (an index of data dispersion) and accuracy (an index of bias correction factors expressing different magnitudes of changes in comparison to the reference) were calculated. RESULTS Median stiffness values differed among the different machines as did coefficients of both precision (range 0.54-0.72) and accuracy (range 0.28-0.87). When the average of the measurements of two intercostal spaces was considered, coefficients of precision significantly increased with all machines (range 0.72-0.90) whereas of accuracy improved more scatteredly and by a smaller degree (range 0.40-0.99). CONCLUSIONS The present results showed only moderate concordance of the majority of elastography machines with the Fibroscan results, preventing the possibility of the immediate universal adoption of Fibroscan thresholds for defining liver fibrosis staging for all new machines.

Liver and spleen stiffness and other noninvasive methods to assess portal hypertension in cirrhotic patients: a review of the literature.

Portal hypertension (PH) is one of the most important causes of morbidity and mortality in patients with chronic liver disease. PH measurement is crucial to stage and predict the clinical outcome of liver cirrhosis. Measurement of hepatic vein pressure gradient is considered the gold standard for assessment of the degree of PH; however, it is an invasive method and has not been used widely. Thus, noninvasive methods have been proposed recently. We critically evaluated serum markers, abdominal ultrasonography, and particularly liver and spleen stiffness measurement, which represent the more promising methods to stage PH degree and to assess the presence/absence of esophageal varices (EV). A literature search was carried out on MEDLINE, EMBASE, Web of Science, and Scopus for articles and abstracts. The search terms used included ‘liver cirrhosis’, ‘portal hypertension’, ‘liver stiffness’, ‘spleen stiffness’, ‘ultrasonography’, and ‘portal hypertension serum biomarker’. The articles cited were selected on the basis of their relevance to the objective of the review. The results of available studies indicate that individually, these methods have a mild accuracy in predicting the presence of EV, and thus they cannot substitute endoscopy to predict EV. When these tests were used in combination, their accuracy increased. In addition to the PH staging, several serum markers and spleen stiffness measurement can predict the clinical outcome of liver cirrhosis with a good accuracy, comparable to that of hepatic vein pressure gradient. In the future, noninvasive methods could be used to select patients requiring further investigations to identify the best tailored clinical management.

A combined model based on spleen stiffness measurement and Baveno VI criteria to rule out high-risk varices in advanced chronic liver disease

BACKGROUND & AIMS Recently, Baveno VI guidelines suggested that esophagogastroduodenoscopy (EGD) can be avoided in patients with compensated advanced chronic liver disease (cACLD) who have a liver stiffness measurement (LSM) <20 kPa and platelet count >150,000/mm3. We aimed to: assess the performance of spleen stiffness measurement (SSM) in ruling out patients with high-risk varices (HRV); validate Baveno VI criteria in a large population and assess how the sequential use of Baveno VI criteria and SSM could safely avoid the need for endoscopy. METHODS We retrospectively analyzed 498 patients with cACLD who had undergone LSM/SSM by transient elastography (TE) (FibroScan®), platelet count and EGDs from 2012 to 2016 referred to our tertiary centre. The new combined model was validated internally by a split-validation method, and externally in a prospective multicentre cohort of 115 patients. RESULTS SSM, LSM, platelet count and Child-Pugh-B were independent predictors of HRV. Applying the newly identified SSM cut-off (≤46 kPa) or Baveno VI criteria, 35.8% and 21.7% of patients in the internal validation cohort could have avoided EGD, with only 2% of HRVs being missed with either model. The combination of SSM with Baveno VI criteria would have avoided an additional 22.5% of EGDs, reaching a final value of 43.8% spared EGDs, with <5% missed HRVs. Results were confirmed in the prospective external validation cohort, as the combined Baveno VI/SSM ≤46 model would have safely spared (0 HRV missed) 37.4% of EGDs, compared to 16.5% when using the Baveno VI criteria alone. CONCLUSIONS A non-invasive prediction model combining SSM with Baveno VI criteria may be useful to rule out HRV and could make it possible to avoid a significantly larger number of unnecessary EGDs compared to Baveno VI criteria only. LAY SUMMARY Spleen stiffness measurement assessed by transient elastography, the most widely used elastography technique, is a non-invasive technique that can help the physician to better stratify the degree of portal hypertension and the risk of esophageal varices in patients with compensated advanced chronic liver disease. Performing spleen stiffness measurement together with liver stiffness measurement during the same examination is simple and fast and this sequential model can identify a greater number of patients that can safely avoid endoscopy, which is an invasive and expensive examination.

Usefulness of liver stiffness measurement in predicting hepatic veno-occlusive disease development in patients who undergo HSCT.

Hepatic veno-occlusive disease (VOD), or sinusoidal obstructive syndrome (SOS), is a clinical syndrome characterized by hepatomegaly, ascites, weight gain and jaundice, which can develop more frequently in the first 30 days after hematopoietic stem cell transplantation (HSCT).1, 2 Its incidence, although influenced by diagnostic criteria, has been estimated to be 13.7% (range 0–62.3%) and, in untreated hepatic severe VOD/SOS, it is associated with >80% mortality.3 In this syndrome, sinusoidal endothelial cells and hepatocytes in zone 3 of the hepatic acinus are damaged by toxic metabolites generated during the conditioning regimen.4 The classic VOD pathway develops by the narrowing of the sinusoids, embolization of endothelial cells and increased clot formation, leading to obstruction of the sinusoids, subendothelial and centro-acinar fibrosis and then to portal-central fibrosis resulting in post-sinusoidal portal hypertension, which dominates the clinical picture.5

Non-invasive diagnostic approach to non-alcoholic fatty liver disease: current evidence and future perspectives

Non-alcoholic fatty liver disease is a new epidemic liver disease, thus, its early diagnosis and the identification of those patients with the worst prognosis is mandatory. Liver biopsy is still the diagnostic gold standard, even if it is associated to a significant rate of complications; moreover, the interpretation of histological samples is not always univocal. Several non-invasive alternative scores have been proposed for the diagnostic approach to non-alcoholic fatty liver disease. This article evaluates the performance of the currently available non-invasive diagnostic strategies. The authors also suggest a potential diagnostic algorithm, with two or more non-invasive techniques, to increase the overall accuracy for identifying patients with worst prognosis, and to minimize the recourse to liver biopsy.

Dysbiosis in Celiac Disease Patients With Persistent Symptoms on Gluten-Free Diet: A Condition Similar to that Present in Irritable Bowel Syndrome Patients?

Dysbiosis in Celiac Disease Patients With Persistent Symptoms on Gluten-Free Diet: A Condition Similar to that Present in Irritable Bowel Syndrome Patients?