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BACKGROUND AND AIMS Porto-sinusoidal vascular liver disorder (PSVD) is a rare disease that occasionally requires liver transplantation (LT), despite usually presenting preserved liver function. There remains a paucity of data pertaining to LT in PSVD. The aim was to identify features associated with post-LT outcomes in PSVD. METHODS Retrospective multicentre study of 79 patients who received LT for PSVD. RESULTS Median post-LT follow-up was 37 (range 1-261) mo. Refractory ascites 24 (30%), hepatic encephalopathy 16 (20%), and hepatopulmonary syndrome 13 (16.3%) were the most frequent indications for LT. Hepatocellular carcinoma was the indication in only 2 patients. Twenty-four patients died, 7 due to liver and 17 to non-liver related causes. Post-LT survival was 82.2%, 80.7%, and 68.6% at 1, 2, and 5 y, respectively. Post-LT survival was significantly better in patients without (n = 58) than in those with a persistent severe PSVD-associated condition (n = 21). Pre-LT hyperbilirubinemia levels and creatinine >100 µmol/L were also independently associated with poor survival. Six patients (7.6%) required a second LT. Recurrence of PSVD was confirmed by liver biopsy in only 1 patient and in 3 further patients it was likely. CONCLUSIONS LT in PSVD is associated with an acceptable outcome in the absence of associated severe conditions. However, persistence of a severe associated condition, pre-LT high bilirubin levels, or creatinine >100 µmol/L impact outcome, and these are features that should be considered when evaluating PSVD patients for LT. PSVD recurrence is possible after LT and needs to be explored, at least, in cases of posttransplant portal hypertension.

Minimal hepatic encephalopathy (MHE) is considered a risk factor for falls in patients with liver cirrhosis. However, MHE is prevalent in patients with muscle alterations (sarcopenia and myosteatosis) probably due to the role of muscle in ammonia handling.To assess the respective role of muscle alterations and MHE on the risk of falls in cirrhotic patients.Fifty cirrhotics were studied for MHE detection by using Psychometric Hepatic Encephalopathy Score (PHES) and Animal Naming Test (ANT). CT scan was used to quantify the skeletal muscle index (SMI) and muscle attenuation, as a measure of myosteatosis. The risk of falls was evaluated by the Timed UpGo test (TUG). The occurrence of falls during follow up was also detected.32 patients (64%) had an abnormal TUG (14 s). In the group with TUG ≥ 14 s, MHE (72vs31%, p0.005) and myosteatosis (94vs50%, p = 0.002) were significantly more frequent than in patients with TUG14 s. At multivariate the variables independently associated to TUG ≥ 14 s were myosteatosis, MHE and chronic beta-blockers use. During a mean follow-up of 25±16.9 months, 12 patients fell; the percentage of falls was significantly higher in patients with TUG ≥ 14 s (50%vs9%, p = 0.001) as well as in patients with myosteatosis (33%vs6%, p = 0.03), but similar in patients with or without MHE (35%vs15%, NS).In cirrhotic patients both muscle alterations and cognitive impairment, as well as chronic beta-blockers use, are associated to the risk of falls.

A total of 2%-10% of patients with vascular liver disease (VLD) have paroxysmal nocturnal hemoglobinuria (PNH). Eculizumab reduces complement-mediated haemolytic activity in PNH. This study was aimed at assessing the impact of eculizumab on VLD outcome. Retrospective cohort of PNH patients, in Valdig registry, who had VLD diagnosed between 1997 and 2019 is considered. Eculizumab was the exposure of interest. Studied outcomes were death, venous thrombosis, bleeding, arterial ischemic event, infection, and liver-related complications. We compared survival and new thrombotic events from PNH/VLD cohort to Envie2 non-PNH cohort. Sixty-two patients (33 women), median age 35 years (28-48) and median follow-up VLD diagnosis 4.7 years (1.2-9.5), were included. Clone size was 80% (70-90), median hemoglobin concentration was 10.0 g/dl (8-11), and lactate dehydrogenase (LDH) was 736 IU (482-1744). Forty-two patients (68%) had eculizumab; median exposure time was 40.1 [9.3-72.6] months. Mortality was significantly lower in exposed versus nonexposed period: 2.6 versus 8.7 per 100 (PY), incidence rate ratio (IRR) was 0.29, 95% CI (0.1-0.9), p = .035. Thrombosis recurrence occurred less frequently during the exposure to eculizumab: 0.5 versus 2.8 per 100 PY, IRR 0.22 (0.07-0.64). Other secondary end points (i.e., bleeding, arterial ischemic lesions, infection, and liver complications) were less common during the exposure to eculizumab, although not reaching statistical significance. Six-year thrombosis-free survival was 70%, 95% CI [0.60-0.83] for PNH cohort and 83%, 95% CI [0.70-1.00] for non-PNH Envie 2 patients, (p .001). In conclusion, patients with PNH and VLD are at higher risk of recurrent thrombosis than non-PNH patients. Eculizumab is significantly associated with a lower mortality and less thrombotic recurrence in patients with PNH and VLD.

Transjugular intrahepatic portosystemic shunt (TIPS) has been used since more than 25 years to treat some of the complications of portal hypertension, especially variceal bleeding and ascites refractory to conventional therapy. TIPS establishes a communication between the portal and hepatic veins, inducing the blood to shift from the splanchnic circulation into the systemic vascular bed with the aim of decompressing the portal venous system, and avoids the major complications of portal hypertension. However, the shunt of the portal blood into the systemic circulation is the cause of one of the major complications of the procedure: the post-TIPS hepatic encephalopathy (HE). To date, few pharmacological treatment has been proven effective to prevent this complication and thus, the identification of patients at high risk of post-TIPS hepatic encephalopathy and the patients' carefully selection is the only way to prevent this frequent complication.

Hepatic encephalopathy (HE) is a common complication in patients with advanced liver disease. It is a brain dysfunction characterized by neurological and psychiatric symptoms that significantly affects quality of life, morbidity and mortality of patients. HE has various precipitants that can potentially promote its onset, alone or in combination. Among the historically well-known precipitants, such as infections, gastrointestinal bleeding, dehydration, electrolyte disorders and constipation, recent studies have highlighted the role of malnutrition and portosystemic shunts as new precipitating factors of HE. The identification, management and correction of these factors are fundamental for effective HE treatment, in addition to pharmacological therapy with non-absorbable disaccharides and/or antibiotics.

In the last years the link between the presence of muscular alterations and hepatic encephalopathy (HE), both minimal and overt, has been deeply studied. The pathophysiological background supporting the relationship between muscle depletion, and HE is characterized by an imbalance between the capacity of muscle in ammonia metabolism and trafficking and the inability of the liver in removing ammonia through urea synthesis due to liver failure and/or the presence of porto-systemic shunts. This review will focus on the clinical burden, the physio pathological mechanisms understanding the liver muscle axis and principles of management of muscular alterations in cirrhosis.

Hepatic encephalopathy (HE) is one of the most frequent complications of cirrhosis. Several studies and case reports have shown that cognitive impairment may also be a tangible complication of portal hypertension secondary to chronic portal vein thrombosis and to porto-sinusoidal vascular disease (PSVD). In these conditions, representing the main causes of non-cirrhotic portal hypertension (NCPH) in the Western world, both overt and minimal/covert HE occurs in a non-neglectable proportion of patients, even lower than in cirrhosis, and it is mainly sustained by the presence of large porto-systemic shunt. In these patients, the liver function is usually preserved or only mildly altered, and the development of porto-systemic shunt is either spontaneous or iatrogenically frequent; HE is an example of type-B HE. To date, in the absence of strong evidence and large cooperative studies, for the diagnosis and the management of HE in NCPH, the same approach used for HE occurring in cirrhosis is applied. The aim of this paper is to provide an overview of type B hepatic encephalopathy, focusing on its pathophysiology, diagnostic tools and management in patients affected by porto-sinusoidal vascular disease and chronic portal vein thrombosis.

Background Alterations in health-related quality of life (HRQoL) and neuropsychological disorders were described in the hepatitis C virus (HCV) patients. Although several studies investigated the modifications of HRQoL after HCV eradication, no data exists on the modifications of neuropsychological symptoms. Aim To investigate the effect of directly acting antivirals (DAAs) treatment on HRQoL and neuropsychological symptoms. Methods Thirty nine patients with HCV infection underwent a neuropsychological assessment, including Zung-Self Depression-Rating-Scale, Spielberg State-Trait Anxiety Inventory Y1-Y2 and the Toronto-Alexithymia Scale-20 items before and after DAAs treatment. HRQoL was detected by Short-Form-36 (SF-36). Results All HRQoL domains, but role limitation physical and bodily pain, significantly improved after treatment. Interestingly, after DAAs treatment, all domains of HRQoL returned similar to those of controls. Each neuropsychological test significantly improved after HCV eradication. A significant correlation was observed among each psychological test and the summary components of SF-36. At multiple linear regression analysis including each psychological test as possible covariates, Zung-Self Depression Rating Scale (Zung-SDS) score was independently and significantly related to summary components of the SF-36 in the basal state and the difference between Zung-SDS score before and after treatment was the only variable significantly and independently related to the modification of HRQoL induced by the treatment. Conclusion Neuropsychological symptoms strongly influenced HRQoL in HCV patients and there was a significant improvement of neuropsychological tests and HRQoL after DAAs treatment.

Muscle alterations, portosystemic shunts (SPSS) and minimal hepatic encephalopathy (MHE) are related to hepatic encephalopathy (HE), however no studies have investigated the relative role of all these risk factors detected in the same patients. The aim of the study was to assess the prognostic impact of muscle alterations, MHE and SPSS on hepatic encephalopathy and transplant free survival.114 cirrhotics were submitted to Psychometric Hepatic Encephalopathy Score (PHES) and Animal Naming Test (ANT) to detect MHE. CT scan was used to analyze the skeletal muscle index (SMI), muscle attenuation and SPSS. The incidence of the first episode of HE and survival were estimated.Previous HE was present in 47 patients (41%). The variables independently associated to previous HE were: sarcopenia, MHE and SPSS. 44 patients (39%) developed overt HE during 14±11 months; MHE and SPSS were the only variables significantly asociated to overt HE. During the same follow-up, 42 patients died (37%); MELD and sarcopenia were the only variables significantly asociated to transplant free survival.MHE, sarcopenia and SPSS are clinically relevant and should be sought for in cirrhotics. In particular, MHE and SPSS are the only risk factors significantly associated to the development of HE while MELD and sarcopenia are independently associated to overall mortality.

Minimal hepatic encephalopathy (MHE) is a frequent complication of hepatic encephalopathy (HE) and can affect up to 80% of patients with liver cirrhosis. It is characterized by the lack of obvious clinical signs and the presence of alterations detectable using psychometric or electrophysiological testing focused on attention, working memory, psychomotor speed and visuospatial ability. Ideally, each patient should be tested for this condition because, despite the absence of symptoms, it has severe repercussions on daily life activities. It may be responsible for an inability to drive, sleep disturbances, risk of falls and inability to work. Some studies have highlighted its prognostically unfavorable role on mortality and risk of “overt” HE (OHE). Finally, MHE severely affects the lives of patients and caregivers, altering their quality of life and their socioeconomic status. Several treatments have been proposed for MHE treatment, including non-absorbable disaccharides, poorly absorbable antibiotics, such as rifaximin, probiotics and branched-chain amino acids, with promising results. For this reason, early diagnosis and intervention with appropriate measures is essential, with the aim of improving both performance on psychometric tests, as well as clinical aspects related to this condition.

Summary Small hepatic veins Budd-Chiari syndrome is a rare disorder characterized by hepatic venous outflow obstruction limited to the small intrahepatic veins, with normal appearance of the large hepatic veins at imaging. In this case only a liver biopsy can demonstrate the presence of a small vessels outflow block. Paroxysmal nocturnal haemoglobinuria (PNH) is one of the most severe acquired thrombophilic state and represents one of the main aetiological factors of Budd-Chiari syndrome. In patient affected by PNH with liver impairment and/or ascites, Budd-Chiari syndrome must be always taken into consideration and, if necessary, a liver biopsy performed to exclude the small hepatic veins involvement. We report a case of small hepatic veins Budd–Chiari syndrome secondary to paroxysmal nocturnal haemoglobinuria.

Minimal hepatic encephalopathy (MHE) represents the mildest type of hepatic encephalopathy (HE). MHE is considered as a preclinical stage of HE and is part of a wide spectrum of typical neurocognitive alterations characteristic of patients with liver cirrhosis, particularly involving the areas of attention, alertness, response inhibition, and executive functions. MHE can be detected by testing the patients’ psychometric performance, attention, working memory, psychomotor speed, and visuospatial ability, as well as by means of electrophysiological and other functional brain measures. MHE is very frequent, affecting from 20% up to 80% of patients tested, depending of the diagnostic tools used. Although subclinical, MHE is considered to be clinically relevant. In fact, MHE has been related to the patients’ falls, fitness to drive, and working ability. As a consequence, MHE affects the patients and caregivers lives by altering their quality of life and even their socioeconomic status. Recently sarcopenia, a very common condition in patients with advanced liver disease, has been shown to be strictly related to both minimal and overt HE. Aim of this review is to summarize the most recently published evidences about the emerging relationship between sarcopenia and cognitive impairment in cirrhotic patients and provide suggestions for future research.

Porto sinusoidal vascular liver disease (PSVD) and portal vein thrombosis (PVT) are distinct vascular liver diseases characterized, respectively, by an intrahepatic and a prehepatic obstacle to the flow in the liver portal system. PVT may also occur as a complication of the natural history of PSVD, especially if a prothrombotic condition coexists. In other cases, it is associated to local and systemic pro-thrombotic conditions, even if its cause remains unknown in up to 25% despite an active search. In our opinion, the presence of PSVD should be suspected in patients with PVT especially in those with PVT “sine causa” and the active search of this condition should be included in their diagnostic work-out. However, sometimes the diagnosis of pre-existing PSVD is very hard. Biopsy cannot be fully discriminant as similar histological data have been described in both conditions. Liver stiffness may help as it has been shown to be higher in PSVD than in “pure” PVT, due to the presence of sclerosis in the portal venous radicles observable in PSVD patients. Nevertheless, comparing liver stiffness between PVT and PSVD has until now been restricted to very limited series of patients. In conclusion, even if it is still totally hypothetical, our point of view may have clinical consequences, especially when deciding to perform a liver biopsy in patients with a higher liver stiffness and suspending the anticoagulation in patients with PVT and no detectable prothrombotic factors.

Muscle alterations (myosteatosis and sarcopenia) are frequent in cirrhosis and related to some complications including overt hepatic encephalopathy (HE). The aim of our study was to investigate the relationship between muscle alterations and minimal HE (MHE) and their role in the risk of overt HE. Sixty-four patients with cirrhosis were administered the Psychometric Hepatic Encephalopathy Score and animal naming test to detect MHE. Computed tomography was used to analyze the skeletal muscle index and attenuation. The incidence of the first episode of HE, taking into account the competing risk nature of the data, was estimated. Myosteatosis was observed in 24 patients (37.5%), sarcopenia in 37 (58%), and MHE in 32 (50%). Both myosteatosis (62.5% versus 12.5%, P < 0.001) and sarcopenia (84% versus 31%, P < 0.001) were more frequent in patients with MHE. The variables independently associated with the presence of MHE were sarcopenia, previous overt HE, and myosteatosis. Thirty-one (48%) patients developed overt HE over 16.1 ± 13 months; myosteatosis was detected in 68% and sarcopenia in 84% of them. Sarcopenia and myosteatosis were also independently associated with the development of overt HE. Venous ammonia was significantly higher in patients with sarcopenia (62.6 ± 17.7 versus 41.4 ± 16.1 μg/dL, P < 0.001) and in patients with myosteatosis (65.2 ± 19.2 versus 46.7 ± 17.1 μg/dL, P < 0.001) and inversely correlated to both parameters. Survival was significantly lower in malnourished patients compared to patients without myosteatosis or sarcopenia (P < 0.001). Conclusion: Myosteatosis and sarcopenia, probably by reducing the handling of ammonia in the muscle, are independently associated with MHE and the risk of overt HE in patients with cirrhosis; in malnourished patients, the amelioration of nutritional status may be a goal to decrease both the prevalence of MHE and the incidence of overt HE.

Hepatic encephalopathy (HE) represents a common complication of liver cirrhosis. Protein-calorie malnutrition is frequently encountered in the cirrhotic patient and its most obvious clinical manifestation is sarcopenia. This condition represents a risk factor for HE occurrence because skeletal muscle acts as an alternative site for ammonium detoxification. Preventive intervention through an adequate assessment of nutritional status should be carried out at early stages of the disease and in a multidisciplinary team using both non-instrumental methods (food diary, anthropometric measurements, blood chemistry tests) and instrumental methods (bioimpedance testing, DEXA, CT, indirect calorimetry, dynamometry). Dietary recommendations for patients with HE do not differ from those for cirrhotic patient without HE. Daily caloric intake in the non-obese patient should be 30–40 Kcal/Kg/day with a protein intake of 1–1.5 g/Kg/day, especially of vegetable origin, through 4–6 meals daily. In patients with HE, it is also essential to monitor electrolyte balance, supplementing any micronutrient deficiencies such as sodium and zinc, as well as vitamin deficiencies because they can cause neurological symptoms similar to those of HE. In light of the critical role of nutritional status, this aspect should not be underestimated and should be included in the diagnostic–therapeutic algorithm of patients with HE.

Background Cirrhosis leads to portal hypertension and to the consequent formation of spontaneous portosystemic shunts (SPSSs), leading to complications related to the diversion of portal blood into the systemic circulation, which is called portosystemic shunt syndrome. Purpose To investigate the characteristics of patients with cirrhosis and an SPSS and secondarily to assess the prognostic impact of SPSSs on portal hypertension-related complications and transplant-free survival. Materials and Methods A retrospective database review of patients with cirrhosis (observed from March 2015 to July 2019) was performed to identify patients with CT imaging and outcomes data. For each patient, clinical and biochemical data were collected, and the presence, types, and sizes of SPSSs were investigated with CT. Patients were followed for a mean of 27.5 months ± 22.8. Multivariable logistic analysis was used to identify the clinical characteristics associated with the presence of SPSSs (any size) and presence of SPSSs 1 cm or larger. Competitive risk analysis (Fine and Gray model) was used to identify the association between SPSSs and complications and mortality. Results Two hundred twenty-two patients with cirrhosis (157 male, 65 female; mean age, 62 years ± 12 [standard deviation]) were evaluated. An SPSS was found in 141 of 222 patients (63.5%), and 40 of 222 (18%) had a shunt diameter of at least 1 cm. At presentation, variables independently associated with the presence of SPSSs (any size) were portal vein thrombosis (odds ratio, 5.5

Hepatitis C virus (HCV) infection is widespread and affects 71 million people worldwide. Although hepatic manifestations are the most frequent, ranging from chronic hepatitis to cirrhosis and hepatocellular carcinoma, it is also associated with several extrahepatic manifestations. Infected patients may present non-specific neurological symptoms, regardless of the presence of liver cirrhosis. Several pathogenetic mechanisms underlying neurological symptoms have been hypothesized: neuroinvasion, immune-mediated damage, neurotransmitter alterations and cryoglobulinemia. Alterations of the central nervous system include cerebral vasculopathy, acute or subacute encephalopathy and inflammatory disorders. HCV infection may be responsible for neuropathies, of which the most frequent form is symmetrical axonal sensory or sensory-motor polyneuropathy which causes loss of leg sensitivity and weakness. Up to 50% of patients with HCV infection may experience cognitive decline and psychological disorders, such as depression and fatigue. HCV associated neurocognitive disorder is independent of the presence of liver cirrhosis and affects different domains than in patients with hepatic encephalopathy. It can be studied using specific tests that mainly explore executive functions, verbal learning and verbal recall. These disorders significantly reduce the quality of life. The new antiviral therapies improve the extrahepatic symptoms of HCV infection and their success depends on the achievement of sustained virological response. However, the effect of therapy may differ depending on the type of organ involved; neurological symptoms can be irreversible if there is organic liver damage. The aim of this review is to provide a critical overview of physiopathological mechanisms, diagnostic and therapeutic strategies of the neurological and psychiatric effects of HCV infection.

Type C hepatic encephalopathy (HE) is a brain dysfunction caused by severe hepatocellular failure or presence of portal-systemic shunts in patients with liver cirrhosis. In its subclinical form, called “minimal hepatic encephalopathy (MHE), only psychometric tests or electrophysiological evaluation can reveal alterations in attention, working memory, psychomotor speed and visuospatial ability, while clinical neurological signs are lacking. The term “covert” (CHE) has been recently used to unify MHE and Grade I HE in order to refer to a condition that is not unapparent but also non overt. “Overt” HE (OHE) is characterized by personality changes, progressive disorientation in time and space, acute confusional state, stupor and coma. Based on its time course, OHE can be divided in Episodic, Recurrent or Persistent. Episodic HE is generally triggered by one or more precipitant factors that should be found and treated. Unlike MHE, clinical examination and clinical decision are crucial for OHE diagnosis and West Haven criteria are widely used to assess the severity of neurological dysfunction. Primary prophylaxis of OHE is indicated only in the patient with gastrointestinal bleeding using non-absorbable antibiotics (Rifaximin) or non-absorbable disaccharides (Lactulose). Treatment of OHE is based on the identification and correction of precipitating factors and starting empirical ammonia-lowering treatment with Rifaximin and Lactulose (per os and enemas). The latter should be used for secondary prophylaxis, adding Rifaximin if HE becomes recurrent. In recurrent/persistent HE, the treatment options include fecal transplantation, TIPS revision and closure of eventual splenorenal shunts. Treatment of MHE should be individualized on a case-by-case basis.

Background Sarcopenia and myosteatosis have been associated to a poor prognosis of cirrhosis and to a higher incidence of hepatic encephalopathy (HE). The prognostic implications of visceral and subcutaneous adiposity are less known. Aim to evaluate the modifications of visceral and subcutaneous adipose tissue after TIPS and to investigate their relationships with the modification of muscle mass and with the incidence of post-TIPS HE. Patients and methods 35 cirrhotic patients submitted to TIPS were retrospectively studied. The modification of skeletal muscle index (SMI), muscle attenuation (myosteatosis), subcutaneous adipose tissue index (SATI), visceral adipose tissue index (VATI), assessed by CT-scan and plasma ammonia were evaluated before and after a mean follow-up of 19 ± 15 months after TIPS. The number of episodes of overt HE was also recorded. Results During the follow-up, the mean SMI and muscle attenuation increased significantly; SATI significantly increased while VATI significantly decreased, although not uniformly in all patients. By comparing the patients with or without improvement in their nutritional status after TIPS, MELD remained stable while the number of episodes of overt HE was significantly lower in the patients with improved SMI and in the patients with improved SATI. Finally, inverse correlation was observed between the variation of ammonia and SATI (r= -0.40; p Conclusion In addition to muscle mass, adipose tissue is modified after TIPS. The improvement of subcutaneous adipose tissue as well as of sarcopenia and myosteatosis is associated to the amelioration of cognitive impairment independently of liver function. The correlation between adipose tissue and ammonia modification may suggest an active role of the adipose tissue in the inter-organ ammonia trafficking.

Purpose of the Review Non-cirrhotic portal hypertension (NCPH) includes a heterogeneous group of conditions. The aim of this paper is to make an overview on the denominations, diagnostical features and management of porto-sinusoidal vascular disease (PSVD) and chronic portal vein thrombosis (PVT) being the main causes of NCPH in the Western world. Recent Findings The management of NCPH consists in the treatment of associated diseases and of portal hypertension (PH). PH due to PSVD or PVT is managed similarly to PH due to cirrhosis. TIPS placement and liver transplantation are considerable options in patients with refractory variceal bleeding/ascites and with progressive liver failure. Anticoagulation is a cornerstone both in the treatment of thrombosis in PSVD and in the prevention of thrombosis recurrence in patients with portal cavernoma. Summary Physicians should be aware of the existence of PSVD and chronic PVT and actively search them in particular settings. To now, the management of portal hypertension-related complications in NCPH is the same of those of cirrhosis. Large cooperative studies on the natural history of NCPH are necessary to better define its management.

Background Splanchnic vein thrombosis (SVT) is an uncommon but potentially life-threatening disease usually related to different underlying clinical conditions. The risk of SVT recurrences is high over time in patients with an underlying permanent prothrombotic condition. Vitamin K antagonists (VKA) represent the mainstay of treatment for SVT. Data about the efficacy and safety of direct oral anticoagulants (DOACs) are reported in the literature for the treatment of acute SVT, but less is known about their application for the secondary prophylaxis of venous thromboembolism (VTE). The aim of this study was to assess the efficacy and safety of long-term DOACs therapy in patients at high-risk of thrombosis, compared to VKA. Methods This is a retrospective single-centre study including 70 patients with SVT on long-term anticoagulant treatment with VKA followed-up at our Units between January 2017 and December 2019. All the patients were at high thrombotic risk defined as the presence of a permanent prothrombotic condition requiring long-term anticoagulation. During follow-up, 28 patients were shifted to DOACs and their clinical outcomes were compared to those of the patients who continued VKA therapy. All the arterial and venous thrombotic events of the splanchnic and extra-splanchnic districts as well as the haemorrhagic adverse events occurring during follow-up were recorded. Results Of the seventy patients enrolled in the study, 36 patients (51.4%) had a single-segment involvement thrombosis (28.5% of portal vein, 7.1% of superior mesenteric vein, 4.3% of splenic vein, 11.5% of hepatic veins) and 34 patients (48.6%) had multi-segment involvement at the time of diagnosis. 42 patients (60%) continued VKA therapy and 28 (40%) were switched to DOACs. Median follow-up was 6 years (range 2-8) during VKA and 1.9 years (range 1-5.2) during DOACs. The incidence of thrombotic events was similar between patients on VKA and those on DOACs. Patients on VKA developed deep vein thrombosis (DVT), and of the patients on DOACs 1 developed NSTEMI and 1 DVT. No major haemorrhagic events occurred. Minor bleedings occurred in 26% of patients on VKA and in none of the DOACs patients (P: 0.09). Conclusions Our results highlight that DOACs could represent an effective and safe alternative to the VKA for secondary prophylaxis in SVT patients at high risk of thrombosis.

Spontaneous porto-systemic shunts (SPSS) are frequent in liver cirrhosis and their prevalence increases as liver function deteriorates, probably as a consequence of worsening portal hypertension, but without achieving an effective protection against cirrhosis' complications. Several types of SPSS have been described in the literature, each one associated with different clinical manifestations. In particular, recurrent or persistent hepatic encephalopathy is more frequent in patients with splenorenal shunt, while the presence of gastric varices and consequently the incidence of variceal bleeding is more common in gastrorenal shunt. In the advanced stage, the presence of large SPSS can lead to the so called "portosystemic shunt syndrome", characterized by a progressive deterioration of hepatic function, hepatic encephalopathy and, sometimes, portal vein thrombosis. The detection of SPSS in patients with liver cirrhosis is recommended in order to prevent or treat recurrent hepatic encephalopathy or variceal bleeding.

Type-C hepatic encephalopathy is a complex neurological syndrome, characteristic of patients with liver disease, causing a wide and complex spectrum of nonspecific neurological and psychiatric manifestations, ranging from a subclinical entity, minimal hepatic encephalopathy, to a deep form in which a complete alteration of consciousness can be observed: overt hepatic encephalopathy. Overt hepatic encephalopathy occurs in 30-40% of patients. According to the time course, hepatic encephalopathy is subdivided into episodic, recurrent and persistent. Diagnostic strategies range from simple clinical scales to more complex psychometric and neurophysiological tools. Therapeutic options may vary between episodic hepatic encephalopathy, in which it is important to define and treat the precipitating factor and hepatic encephalopathy and secondary prophylaxis, where the standard of care is non-absorbable disaccharides and rifaximin. Grey areas and future needs remain the therapeutic approach to minimal hepatic encephalopathy and issues in the design of therapeutic studies for hepatic encephalopathy.

Background & Aims: The ANSWER study reported that long-term albumin administration in patients with cirrhosis and uncomplicated ascites improves survival. During treatment, serum albumin increased within a month and remained stable thereafter. In this post hoc analysis, we aimed to determine whether on-treatment serum albumin levels could guide therapy. Methods: Logistic regression was used to assess the association between baseline serum albumin and mortality, as well as to determine on-treatment factors associated with mortality and to predict the achievement of a given on-treatment serum albumin level. Survival was assessed by Kaplan-Meier estimates and second-order polynomial regression. Patients whose on-treatment serum albumin remained below normal were compared with a subset of patients from the control arm matched by principal score. Results: Baseline serum albumin was closely associated with 18-month mortality in untreated patients; albumin treatment almost effaced this relationship. On-treatment serum albumin and MELD-Na at month 1 were the sole independent variables associated with mortality. Second-order polynomial regression revealed that survival improved in parallel with increased 1-month on-treatment serum albumin. Kaplan-Meier estimations showed that any value of 1-month on-treatment serum albumin (0.1 g/dl intervals) in the range 2.5–4.5 g/dl discriminated patient survival. In the normal range of serum albumin, the best discriminant value was 4.0 g/dl. Compared to untreated patients, survival even improved in patients whose on-treatment serum albumin remained below normal. Conclusion: Baseline serum albumin per se should not guide the decision to start albumin therapy. Conversely, 1-month on-treatment serum albumin levels are strongly associated with outcomes and could guide the use of albumin – 4.0 g/dl being the target threshold. However, even patients whose serum albumin remains below normal benefit from long-term albumin administration. Lay summary: The ANSWER study has shown that long-term albumin administration improves survival and prevents the occurrence of major complications in patients with cirrhosis and ascites. This study shows that the achievement of these beneficial effects is related to a significant increase in serum albumin concentration. Even though the best results follow the achievement of a serum albumin concentration of 4 g/dl, a survival benefit is also achieved in patients who fail to normalise serum albumin.

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that occurs in up to 30% of patients with cirrhosis. HE may be a consequence of pure liver failure, as in patients with fulminant hepatitis, or of the combination of liver failure and portal-systemic shunting, as in patients with liver cirrhosis. Episodes of HE are usually related to precipitating events, such as infections or gastrointestinal bleeding; a minority of cirrhotic patients experienced a chronic HE, refractory to standard medical treatment. The prevention of HE recurrence, after the first episode of HE, could be obtained by the administration of prophylactic therapy with lactulose, rifaximin or a combination of both. The aim of this review is to clarify some key points in the management of cirrhotic patients with HE, not responsive to first line treatment. Recent studies investigated the role of fecal microbiota transplantation in the treatment of HE with promising results, but further investigations are needed. In a cirrhotic patient with acute cognitive impairment, the correct diagnosis of HE, after excluding other causes of neurological diseases, is mandatory for the correct management of the precipitating factors and for the treatment. In patients not responsive to standard treatment, the probable precipitating factors have not been correctly identified, multiple precipitating events are coexisting or a new precipitating event is superimposed. In some patients with recurrent HE, characterized by persistent alterations in neurological symptoms, without specific precipitants events, the presence of spontaneous or iatrogenic shunts should be investigated.

Hepatic encephalopathy (HE) is considered reversible regarding mental status but may not be cognitively in single-center studies. To evaluate persistence of learning impairment in prior HE compared to those who never experienced HE (no-HE) in a multicenter study. A total of 174 outpatient cirrhotics from three centers (94 Virginia, 30 Ohio, and 50 Rome; 36 prior HE) underwent psychometric hepatic encephalopathy score (PHES) and inhibitory control (ICT) testing at baseline and then at least 7 days apart. ICT learning (change in 2nd half lures compared to 1st half) was compared between patient groups at both visits. Change in the PHES individual sub-tests and total score between visits was compared in both groups. US versus Italian trends were also analyzed. HE patients had worse PHES and ICT results compared to no-HE patients at baseline. Significant improvement (1st half 7.1 vs. 2nd half 6.2, p

Background & aims Little is known on nutritional parameters in patients with chronic portal vein thrombosis (PVT) and idiopathic non-cirrhotic portal hypertension (INCPH). The study aims to assess the prevalence and the clinical impact of sarcopenia in patients with non-cirrhotic portal hypertension (NCPH). A control group of cirrhotic patients was also studied. Both groups were followed up to establish the relationship between sarcopenia and clinical outcomes. Methods Sixty-seven patients with NCPH (51 PVT and 16 INCPH) were included in the study group and 104 patients with liver cirrhosis in the control group. The axial plane passing through the intersomatic disk between L3 and L4 was evaluated for the quantitative analysis of muscle mass and the skeletal muscle index (SMI) was calculated. The presence of sarcopenia was established according to SMI validated cut off. Results Sarcopenia was present in the 38% of patients with INCPH, 35% of patients with chronic PVT, 32% of patients with compensated cirrhosis and 54% of decompensated cirrhotics. During a mean follow-up of 51 ± 62 months, there was no difference in sarcopenic and non-sarcopenic patients with NCPH for incidence of ascites, hepatic encephalopathy, esophageal varices, variceal bleeding and death. However, the incidence of refractory variceal bleeding requiring TIPS placement was significantly higher in comparison with the non-sarcopenic ones (29% vs 7%, P = 0.01 at log-rank test). Conclusions In patients with NCPH sarcopenia is similar to that observed in cirrhotic patients. Moreover, the rate of refractory variceal bleeding was higher in sarcopenic patients suggesting a clinical negative impact of muscle depletion.

Background Since the use of the Model for End-Stage Liver Disease (MELD) score for establishing the prognosis of cirrhotic patients has been introduced, questions have been raised whether complications of liver cirrhosis would provide additional information. Myosteatosis, sarcopenia and hepatic encephalopathy (HE) are frequent in cirrhosis and may affect prognosis. Aim of the study was analyzing if these factors are independently related to survival and may improve the accuracy of MELD. Methods 249 cirrhotics that underwent abdominal CT-scan were enrolled. For each patient, information about previous episodes of HE and muscle alterations were obtained. Patients were followed until transplantation or death. Results History of HE, MELD, sarcopenia and myosteatosis were independently associated with mortality. The MELD-Sarco-Myo-HE score added accuracy to the MELD score alone for 6- and 3-months mortality. By removing HE, as the only not quantifiable parameter of the model, no relevant decrease in accuracy for 6- and 3-months mortality detection was observed. Conclusions The accuracy of MELD in predicting 3- and 6-months mortality may be improved by considering the muscle alterations. A model considering the above parameters may classify more accurately over 30% of the patients.

Minimal hepatic encephalopathy (MHE) is a subclinical cognitive impairment frequently observable in patients with cirrhosis. Proton pump inhibitors (PPIs) can contribute to small-bowel bacterial overgrowth, but no study has investigated the link between PPIs and MHE. We investigated the relationship between MHE and PPI use as well as the role of PPI use in the development of overt HE and survival. Consecutive patients with cirrhosis (n = 310) were included in the study and followed up for 14.1 ± 12.3 months. At entry, MHE was diagnosed when the Psychometric Hepatic Encephalopathy Score was ≤-4. Data were analyzed by logistic regression for the factors associated with MHE and by time-related models for overt HE development and survival. At inclusion, 131 out of 310 patients with cirrhosis (42%) were affected by MHE. One hundred and twenty-five patients (40%) were using PPIs. The variables independently associated with the presence of MHE were PPI use, previous overt HE, low albumin, low sodium, and age. During follow-up, the development of overt HE was higher (64% versus 25%, P < 0.001) and overall survival lower (41% versus 81%, P < 0.001) in PPI users than in nonusers. Variables independently associated with the development of overt HE were PPIs, history of overt HE, low albumin, MHE, and age, while variables independently associated with mortality were PPIs, development of overt HE, Model for End-Stage Liver Disease score, low sodium, and age. Conclusion: The study identifies a potentially removable factor associated with the presence of MHE and related to the development of overt HE and survival in patients with liver cirrhosis.

Hepatic encephalopathy (HE) is a major problem in patients treated with TIPS. The aim of the study was to establish whether pre-TIPS covert HE is an independent risk factor for the development of HE after TIPS.Eighty-two consecutive cirrhotic patients submitted to TIPS were included. All patients underwent the PHES to identify those affected by covert HE before a TIPS. The incidence of the first episode of HE was estimated, taking into account the nature of the competing risks in the data (death or liver transplantation).Thirty-five (43%) patients developed overt HE. The difference of post-TIPS HE was highly significant (P=0.0003) among patients with or without covert HE before a TIPS. Seventy-seven percent of patients with post-TIPS HE were classified as affected by covert HE before TIPS. Age: (sHR 1.05, CI 1.02-1.08, P=0.002); Child-Pugh score: (sHR 1.29, CI 1.06-1.56, P=0.01); and covert HE: (sHR 3.16, CI: 1.43-6.99 P=0.004) were associated with post-TIPS HE. Taking into consideration only the results of PHES evaluation, the negative predicting value was 0.80 for all patients and 0.88 for the patients submitted to TIPS because of refractory ascites. Thus, a patient with refractory ascites, without covert HE before a TIPS, has almost 90% probability of being free of HE after TIPS.Psychometric evaluation before TIPS is able to identify most of the patients who will develop HE after a TIPS and can be used to select patients in order to have the lowest incidence of this important complication.

Background Hepatic encephalopathy (HE) is the major complication of transjugular intrahepatic portosystemic shunt (TIPS). In cirrhotic patients, a correlation between sarcopenia and HE has been suggested. Aim To evaluate the evolution of the skeletal muscle quantity and quality at CT scan and of the patients' cognitive impairment (both overt and minimal HE) before and after TIPS. Patients and methods Twenty-seven cirrhotic patients submitted to TIPS were studied. The modification of Skeletal Muscle Index (SMI), muscle attenuation, HE and plasma ammonia were evaluated before and after a mean follow-up of 9.8 ± 4 months after TIPS. Results During the follow-up, the mean SMI and muscle attenuation increased significantly, although not uniformly in all patients. Psychometric Hepatic Encephalopathy Score (PHES) and ammonia improved significantly in the patients with amelioration in SMI >10% (n = 16) and not in those without (n = 11) (PHES: -1.6 ± 2 vs -4.8 ± 2.1; P = 0.0005; ammonia: 48.5 ± 28.7 vs 96 ± 31.5 μg/dL; P = 0.0004). Moreover, the prevalence of minimal HE (12.5% vs 73%, P = 0.001) as well as the number of episodes of overt HE during the follow-up were significantly reduced in the patients with improved SMI. Model for end-stage liver disease remained stable or worsened after TIPS and was not significantly different between the groups with or without SMI improvement. Conclusion The amelioration of muscle wasting and HE independent of liver function observed after TIPS supports the causal relationship between muscle wasting and HE.

The design of clinical trials on Hepatic Encephalopathy (HE) is not an easy task, in fact there are several issues related to the performance of clinical trials in HE that have impeded progress in the field, mainly because most of the studies on HE therapy were performed before the era of rigorous Randomized Controlled Trials (RCTs). In this review we discuss the major problems affecting previously published trials on HE treatments aiming to provide evidences, suggestions and indications to prepare well designed RCTs in three different settings: (1) management of hospitalized patients with episodic HE; (2) secondary prophylaxis in patients following an episode of HE; and (3) management of minimal/covert HE.

The knowledge of natural history of patients with portal hypertension (PH) not due to cirrhosis is less well known than that of cirrhotic patients.To describe the clinical presentation and the outcomes of 89 patients with non-cirrhotic PH (25 with non-cirrhotic portal hypertension, INCPH, and 64 with chronic portal vein thrombosis, PVT) in comparison with 77 patients with Child A cirrhosis.The patients were submitted to a standardized clinical, laboratory, ultrasonographic and endoscopic follow-up. Variceal progression, incidence of variceal bleeding, portal vein thrombosis, ascites and survival were recorded.At presentation, the prevalence of varices, variceal bleeding and ascites was similar in the 3 groups. During follow-up, the rate of progression to varices at risk of bleeding (p 0.0001) and the incidence of first variceal bleeding (p = 0.02) were significantly higher in non-cirrhotic then in cirrhotic patients. A PVT developed in 32% of INCPH patients and in 18% of cirrhotics (p = 0.02).In the patients with non-cirrhotic PH variceal progression is more rapid and bleeding more frequent than in cirrhotics. Patients with INCPH are particularly prompt to develop PVT. This observational study suggests that the management of patients with non-cirrhotic PH should take into consideration the natural history of portal hypertension in these patients and cannot be simply derived by the observation of cirrhotic patients.

Hepatic Encephalopathy (HE) is a neuropsychiatric syndrome that occurs in up to 30% of patients with cirrhosis. HE may be a consequence of pure liver failure, as in patients with fulminant hepatitis, or of the combination of liver failure and portal-systemic shunting, as in patients with liver cirrhosis. Several clinical and pathophysiologic observations suggest the importance of portal-systemic shunts in the development of HE. Episodes of HE are usually related to precipitating events, such as infections or gastrointestinal bleeding; a minority of cirrhotic patients experienced a chronic HE, refractory to standard medical treatment. This latter type of HE should be related to spontaneous or radiological (such as Transjugular Intrahepatic Portosystemic Shunt (TIPS)) portal systemic shunts, that could be restricted or occluded in patients with chronic HE. Both TIPS reduction and shunt occlusion are radiological procedures, safe and effective to ameliorate neurological symptoms in patients with refractory HE.