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.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Hepatic encephalopathy (HE) is a peculiar kind of brain dysfunction typical of liver cirrhosis characterized by nonspecific neurological and psychiatric manifestations. HE ranges from minimal hepatic ...encephalopathy (MHE) to the most severe form characterized by alteration of consciousness or coma (overt HE, OHE). Once the diagnosis of OHE is made, every effort to identify and correct the precipitating cause is essential for the resolution of symptoms. Clinical studies that assessed the prevalence and incidence of any type of HE (MHE and OHE) in patients affected by cirrhosis were included in this review. No language, publication date, or publication status restrictions were imposed. The studies were identified by searching electronic databases (PubMed and SCOPUS).
The most widely empirical pharmacological approach consists of non-absorbable antibiotics (rifaximin) and non-absorbable disaccharides (lactulose, lactitol per os and per enemas). Other agents (including branched-chain amino acids, probiotics, other antibiotics, or intravenous L-ornithine L-aspartate) are available, but the evidence supporting their efficacy remains under debate.
Gray areas and future needs remain the therapeutic approach to MHE and issues in the design of therapeutic studies for HE which have been extensively discussed in this review.
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.
To investigate the effect of directly acting antivirals (DAAs) treatment on HRQoL and neuropsychological symptoms.
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).
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.
Neuropsychological symptoms strongly influenced HRQoL in HCV patients and there was a significant improvement of neuropsychological tests and HRQoL after DAAs treatment.
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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Evidence is scarce on the efficacy of long-term human albumin (HA) administration in patients with decompensated cirrhosis. The human Albumin for the treatmeNt of aScites in patients With hEpatic ...ciRrhosis (ANSWER) study was designed to clarify this issue.
We did an investigator-initiated multicentre randomised, parallel, open-label, pragmatic trial in 33 academic and non-academic Italian hospitals. We randomly assigned patients with cirrhosis and uncomplicated ascites who were treated with anti-aldosteronic drugs (≥200 mg/day) and furosemide (≥25 mg/day) to receive either standard medical treatment (SMT) or SMT plus HA (40 g twice weekly for 2 weeks, and then 40 g weekly) for up to 18 months. The primary endpoint was 18-month mortality, evaluated as difference of events and analysis of survival time in patients included in the modified intention-to-treat and per-protocol populations. This study is registered with EudraCT, number 2008–000625–19, and ClinicalTrials.gov, number NCT01288794.
From April 2, 2011, to May 27, 2015, 440 patients were randomly assigned and 431 were included in the modified intention-to-treat analysis. 38 of 218 patients died in the SMT plus HA group and 46 of 213 in the SMT group. Overall 18-month survival was significantly higher in the SMT plus HA than in the SMT group (Kaplan-Meier estimates 77% vs 66%; p=0·028), resulting in a 38% reduction in the mortality hazard ratio (0·62 95% CI 0·40–0·95). 46 (22%) patients in the SMT group and 49 (22%) in the SMT plus HA group had grade 3–4 non-liver related adverse events.
In this trial, long-term HA administration prolongs overall survival and might act as a disease modifying treatment in patients with decompensated cirrhosis.
Italian Medicine Agency.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Overt hepatic encephalopathy (OHE) is a major complication of transjugular intrahepatic portosystemic shunt (TIPS) placement, given its high incidence and possibility of refractoriness to medical ...treatment. Nevertheless, the impact of post-TIPS OHE on mortality has not been investigated in a large population.
We designed a multicenter, non-inferiority, observational study to evaluate the mortality rate at 30 months in patients with and without OHE after TIPS. We analyzed a database of 614 patients who underwent TIPS in three Italian centers and estimated the cumulative incidence of OHE and mortality with competitive risk analyses, setting the non-inferiority limit at 0.12.
During a median follow-up of 30 months (IQR 12-30), 293 patients developed at least one episode of OHE. Twenty-seven (9.2%) of them experienced recurrent/persistent OHE. Patients with OHE were older (64 57-71 vs. 59 50-67 years, p <0.001), had lower albumin (3.1 2.8-3.5 vs. 3.25 2.9-3.6 g/dl, p = 0.023), and had a higher prevalence of pre-TIPS OHE (15.4% vs. 9.0%, p = 0.023). Child-Pugh and MELD scores were similar. The 30-month difference in mortality between patients with and without post-TIPS OHE was 0.03 (95% CI -0.042 to 0.102). Multivariable analysis showed that age (subdistribution hazard ratio 1.04, 95% CI 1.02–1.05, p <0.001) and MELD score (subdistribution hazard ratio 1.09, 95% CI 1.05–1.13, p <0.001), but not post-TIPS OHE, were associated with a higher mortality rate. Similar results were obtained when patients undergoing TIPS for variceal re-bleeding prophylaxis (n = 356) or refractory ascites (n = 258) were analyzed separately. The proportion of patients with persistent OHE after TIPS was significantly higher in the group of patients who died. The robustness of these results was increased following propensity score matching.
Episodic OHE after TIPS is not associated with mortality in patients undergoing TIPS, regardless of the indication.
Overt hepatic encephalopathy (OHE) is a common complication in patients with advanced liver disease and it is particularly frequent following transjugular intrahepatic portosystemic shunt (TIPS) placement. In patients with cirrhosis outside the setting of TIPS, the development of OHE negatively impacts survival, regardless of the severity of cirrhosis or the presence of acute-on-chronic liver failure. In this multicenter, non-inferiority, observational study we demonstrated that post-TIPS OHE does not increase the risk of mortality in patients undergoing TIPS, irrespective of the indication. This finding alleviates concerns regarding the weight of this complication after TIPS. Intensive research to improve patient selection and risk stratification remains crucial to enhance the quality of life of patients and caregivers and to avoid undermining the positive effects of TIPS on survival.
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•In patients with cirrhosis outside the setting of TIPS, the development of OHE negatively impacts survival.•OHE is considered a major complication in patients treated with TIPS.•We show that post-TIPS episodic OHE does not increase the risk of death in patients undergoing TIPS, irrespective of the indication.•This finding alleviates concerns regarding the impact of this complication on survival after TIPS.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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.
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