Single-cell RNA sequencing of cystic fibrosis liver disease explants reveals endothelial complement activation.

BACKGROUND & AIMS: Cystic fibrosis (CF) is considered a multisystemic disorder in which CF-associated liver disease (CFLD) is the third most common cause of mortality. Currently, no effective treatment is available for CFLD because its pathophysiology is still unclear. Interestingly, CFLD exhibits identical vascular characteristics as non-cirrhotic portal hypertension, recently classified as porto-sinusoidal vascular disorders (PSVD). METHODS: Since endothelial cells (ECs) are an important component in PSVD, we performed single-cell RNA sequencing (scRNA-seq) on four explant livers from CFLD patients to identify differential endothelial characteristics which could contribute to the disease. We comprehensively characterized the endothelial compartment and compared it with publicly available scRNA-seq datasets from cirrhotic and healthy livers. Key gene signatures were validated ex vivo on patient tissues. RESULTS: We found that ECs from CF liver explants are more closely related to healthy than cirrhotic patients. In CF patients we also discovered a distinct population of liver sinusoidal ECs-coined CF LSECs-upregulating genes involved in the complement cascade and coagulation. Finally, our immunostainings further validated the predominant periportal location of CF LSECs. CONCLUSIONS: Our work showed novel aspects of human liver ECs at the single-cell level thereby supporting endothelial involvement in CFLD, and reinforcing the hypothesis that ECs could be a driver of PSVD. Therefore, considering the vascular compartment in CF and CFLD may help developing new therapeutic approaches for these diseases.

Application of ultrasonography-elastography score to suspect porto-sinusoidal vascular disease in patients with portal vein thrombosis.

BACKGROUND: Porto-sinusoidal vascular disease (PSVD) and portal vein thrombosis (PVT) are causes of portal hypertension characterized respectively by an intrahepatic and a pre-hepatic obstacle to the flow in the portal system. As PVT may be a consequence of PSVD, in PVT patients at presentation, a pre-existing PSVD should be suspected. In these patients the identification of an underlying PSVD would have relevant implication regarding follow-up and therapeutic management, but it could be challenging. In this setting ultrasonography may be valuable in differential diagnosis. The aim of the study was to use ultrasonography to identify parameters to discriminate between PSVD and "pure" PVT and then to suspect PVT secondary to a pre-existing PSVD. METHODS: Fifty-three patients with histologically proven PSVD and forty-eight patients affected by chronic PVT were enrolled and submitted to abdominal ultrasonography with elastography by acoustic radiation force impulse (ARFI). RESULTS: ARFI was higher and superior mesenteric vein (SMV) diameter was wider in PSVD patients than in PVT patients. Thus, a prognostic score was obtained as linear combinations of the two parameters with a good discrimination capacity between PSVD and PVT (the area under the curve = 0.780; 95% confidence interval: 0.690-0.869). CONCLUSIONS: A score based on ARFI and SMV diameter may be useful to suspect an underlying PSVD in patients with PVT and to identify a subgroup of patients to be submitted to liver biopsy.

Partial splenic embolization as a rescue and emergency treatment for portal hypertension and gastroesophageal variceal hemorrhage.

BACKGROUND: Partial splenic embolization (PSE) is a non-surgical procedure which was initially used to treat hypersplenism. Furthermore, partial splenic embolization can be used for the treatment of different conditions, including gastroesophageal variceal hemorrhage. Here, we evaluated the safety and efficacy of emergency and non-emergency PSE in patients with gastroesophageal variceal hemorrhage and recurrent portal hypertensive gastropathy bleeding due to cirrhotic (CPH) and non-cirrhotic portal hypertension (NCPH). METHODS: From December 2014 to July 2022, twenty-five patients with persistent esophageal variceal hemorrhage (EVH) and gastric variceal hemorrhage (GVH), recurrent EVH and GVH, controlled EVH with a high risk of recurrent bleeding, controlled GVH with a high risk of rebleeding, and portal hypertensive gastropathy due to CPH and NCPH underwent emergency and non-emergency PSE. PSE for treatment of persistent EVH and GVH was defined as emergency PSE. In all patients pharmacological and endoscopic treatment alone had not been sufficient to control variceal bleeding, and the placement of a transjugular intrahepatic portosystemic shunt (TIPS) was contraindicated, not reasonable due to portal hemodynamics, or TIPS failure with recurrent esophageal bleeding had occurred. The patients were followed-up for six months. RESULTS: All twenty-five patients, 12 with CPH and 13 with NCPH were successfully treated with PSE. In 13 out of 25 (52%) patients, PSE was performed under emergency conditions due to persistent EVH and GVH, clearly stopping the bleeding. Follow-up gastroscopy showed a significant regression of esophageal and gastric varices, classified as grade II or lower according to Paquet's classification after PSE in comparison to grade III to IV before PSE. During the follow-up period, no variceal re-bleeding occurred, neither in patients who were treated under emergency conditions nor in patients with non-emergency PSE. Furthermore, platelet count increased starting from day one after PSE, and after one week, thrombocyte levels had improved significantly. After six months, there was a sustained increase in the thrombocyte count at significantly higher levels. Fever, abdominal pain, and an increase in leucocyte count were transient side effects of the procedure. Severe complications were not observed. CONCLUSION: This is the first study analyzing the efficacy of emergency and non-emergency PSE for the treatment of gastroesophageal hemorrhage and recurrent portal hypertensive gastropathy bleeding in patients with CPH and NCPH. We show that PSE is a successful rescue therapy for patients in whom pharmacological and endoscopic treatment options fail and the placement of a TIPS is contraindicated. In critically ill CPH and NCPH patients with fulminant gastroesophageal variceal bleeding, PSE showed good results and is therefore an effective tool for the rescue and emergency management of gastroesophageal hemorrhage.

Idiopathic non-cirrhotic portal hypertension in a patient with Talaromyces marneffei infection: a case report.

BACKGROUND: The etiopathogenesis of idiopathic non-cirrhotic portal hypertension (INCPH) is so far poorly understood. Altered immunity, blood diseases, infections, congenital defects and drug exposure have been documented in a part of patients with INCPH owing to increased recognition of the disorder in patients with HIV, or various haematological disorders or autoimmune diseases. We aim to discuss the possible etiopathogenesis of INCPH. CASE PRESENTATION: We reported that a patient with intestinal infection of T. Marneffei and hyper-IgE syndrome, a group of rare primary immunodeficiency disorders, was finally diagnosed with INCPH for gastroesophageal variceal bleeding. The diagnosis was mainly based on histopathological features. Transjugular intrahepatic portosystemic shunt was performed and there was no recurrence of melena during the six-month follow-up. CONCLUSION: In the context of immunodeficiency, INCPH may associated with intestinal infections. Thus, screening for enterogenic infection and immunological disorders in patients with unexplained portal hypertension is necessary.

Clinical Course of Porto-Sinusoidal Vascular Disease Is Distinct From Idiopathic Noncirrhotic Portal Hypertension.

BACKGROUND & AIMS: Porto-sinusoidal vascular disease (PSVD) was recently proposed as novel clinical entity characterized by typical histological changes with or without portal hypertension (PH) in the absence of cirrhosis. Thus, we aimed to describe clinical characteristics and the outcome of PSVD patients and to compare these to patients meeting traditional idiopathic non-cirrhotic portal hypertension (INCPH) criteria. METHODS: Patients undergoing liver biopsy (baseline) ±hepatic venous pressure gradient (HVPG) measurement at the Vienna General Hospital between 2000-2019 were screened for PSVD and INCPH criteria. RESULTS: 91 patients were diagnosed with PSVD of which 28 (30.8%) also fulfilled INCPH criteria (INCPH+/PSVD+). Specific histological and specific clinical PH signs were found in 72 (79.1%) and 54 (59.3%) patients, respectively. INCPH+/PSVD+ showed higher Child-Pugh-scores (7±2 vs 6±1 points; P = .002) and a higher prevalence of decompensation (57.1% vs 28.6%; P = .009) than INCPH-/PSVD+ patients. Importantly, hepatic decompensation after three years (3Y) occurred in 11.2% of PSVD patients with specific clinical signs of PH, while no decompensation occurred in patients with only specific histological or with unspecific clinical/histological signs (P = .002). When categorizing by INCPH definition, 3Y decompensation was 13.4% in INCPH+/PSVD+ and 3.8% in INCPH-/PSVD+ (P = .120). While overall mortality was similar in INCPH+/PSVD+ (n = 6; 21.4%) and INCPH-/PSVD+ (n = 10; 15.9%) patients (P = .558), liver-related mortality tended to be higher in INCPH+/PSVD+ (6.9%) than in INCPH-/PSVD+ (0%; P = .078). CONCLUSION: Novel PSVD criteria facilitate diagnosis. Compared to INCPH, clinical course of PSVD patients is more favorable. Importantly, specific signs of PH including varices and collaterals are associated with hepatic decompensation and mortality.

Outcomes of idiopathic versus secondary nodular regenerative hyperplasia of the liver: A longitudinal study of 167 cases.

BACKGROUND: Nodular regenerative hyperplasia (NRH) is a rare condition characterized clinically by the development of non-cirrhotic portal hypertension. NRH is the histopathological result in the liver of various systemic disease processes including autoimmune disorders, haematological malignancies and medications. However, natural history of this condition has been limited to small case series while patient outcomes pertaining to different aetiologies of NRH are largely unknown. METHODS: A retrospective cohort of consecutive patients diagnosed with pathology-confirmed NRH at Mayo Clinic between 2002 and 2017 was identified. The histological diagnosis of NRH was determined by expert liver pathologists. Patients with metastatic liver disease, history of liver transplantation or younger than 18 were excluded. Potential aetiologies of NRH were classified as haematological, rheumatological, drug-associated, miscellaneous or idiopathic. Long-term mortality was analysed using Kaplan-Meier estimation and Cox regression models. RESULTS: One hundred and sixty-seven consecutive patients with pathology-confirmed NRH were analysed over a 15-year period and followed for a median time of 50 months (1-306 months). The mean age at diagnosis was 53 years. No aetiology or risk factor for NRH was identified in the majority of patients (94, 56.3%), whereas an associated, possibly causal, condition was found in 73 patients (secondary NRH). The most common presenting feature was elevated liver tests (80%), but no significant differences in laboratory tests were seen based on aetiology of NRH. Compared to idiopathic NRH, those with an identified cause had a higher rate of splenomegaly at presentation (54% vs. 27%, p = 0.002). Portal hypertension-related complications at diagnosis were common, with ascites present in one-third of patients. Overall transplant-free survival was 63% at 5 years. Median survival in idiopathic NRH was 9.4 years compared to 7.3 years in secondary NRH. Age, renal function and volume status at presentation were significantly associated with survival; however, MELD score was not. CONCLUSIONS: The rates of liver-related complications and mortality in NRH are low, and only a small number of patients ultimately require liver transplantation. Most patients do not have an identified risk factor or aetiology for NRH, and liver-related outcomes do not appear to differ based on associated, possibly causal, conditions.

Interventional Management of Portal Hypertension in Cancer Patients.

PURPOSE OF REVIEW: To provide an overview of the classifications and clinical hallmarks of common cancer-related conditions that contribute to the high incidence of portal hypertension in this population and provide an update on currently available interventional radiology therapeutic approaches. RECENT FINDINGS: In the last few decades, there have been significant advancements in understanding the pathophysiology of portal hypertension. This knowledge has led to the development of safer and more effective minimally invasive approaches. The main objective is to provide alternatives to prevent life-threatening complications from clinically significant portal hypertension and to allow the continuation of cancer treatment interventions that would otherwise be stopped. Clinicians involved in cancer care should be aware of risk factors, associated complications, and management of portal hypertension in cancer patients. Interventional radiology offers minimally invasive alternatives that play a central role in improving clinical outcomes and survival of these patients, allowing the continuation of cancer treatments.

A POEMS syndrome patient with idiopathic non-cirrhotic portal hypertension received the transjugular intrahepatic portosystemic shunt: a case report and literature review.

Polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes (POEMS) syndrome is a rare plasma cell dyscrasia disease involving multiple organs combined with idiopathic non-cirrhotic portal hypertension. It has been reported only four times in the English literature. Here, we present the first case of a 62-year-old male POEMS syndrome patient with portal hypertension treated with the transjugular intrahepatic portosystemic shunt (TIPS), after he presented with a 10-day history of melena. The diagnosis of POEMS syndrome was given because the patient presented with polyneuropathy, monoclonal plasma cell proliferative disorder, sclerotic bone lesions, splenomegaly, lymphadenopathy, ascites, hypothyroidism, and hyperpigmentation. The presence of portal hypertension was confirmed by esophageal varices, congested and edematous stomach body, splenomegaly, and transudate ascites in which the serum-ascites albumin gradient of ascites fluid was over 11 g/L (a concentration considered to be associated with POEMS syndrome), as no other causes were found. The patient fasted and received conservative drug treatments on admission, but symptoms of melena soon recurred within 1 week after resuming his diet. After TIPS and venous embolization were performed, symptoms of bleeding were effectively controlled, while the patient subsequently developed hepatic encephalopathy, which ultimately led to death. The presence of gastrointestinal bleeding in POEMS syndrome with idiopathic non-cirrhotic portal hypertension indicates a poor prognosis. Given that this was the first patient to receive TIPS, and although the incidence of hepatic encephalopathy has increased, TIPS is still acceptable for refractory variceal bleeding.

Co-expression gene network analysis reveals novel regulatory pathways involved in porto-sinusoidal vascular disease.

BACKGROUND & AIMS: Porto-sinusoidal vascular disease (PSVD) is a rare vascular liver disease of unknown etiology that causes portal hypertension. It usually affects young individuals and shortens live expectancy. The deregulated pathways involved in PSVD development are unknown and therefore we lack curative treatments. The purpose of this study was to integrate transcriptomic and clinical data by comprehensive network-based modeling in order to uncover altered biological processes in patients with PSVD. METHODS: We obtained liver tissue samples from 20 consecutive patients with PSVD and 21 sex- and age-matched patients with cirrhosis and 13 histologically normal livers (HNL) (initial cohort) and performed transcriptomic analysis. Microarray data were analyzed using weighted gene correlation network analysis to identify clusters of highly correlated genes differently expressed in patients with PSVD. We next evaluated the molecular pathways enriched in patients with PSVD and the core-related genes from the most significantly enriched pathways in patients with PSVD. Our main findings were validated using RNA sequencing in a different cohort of PSVD, cirrhosis and HNL (n = 8 for each group). RESULTS: Patients with PSVD have a distinctive genetic profile enriched mainly in canonical pathways involving hemostasis and coagulation but also lipid metabolism and oxidative phosphorylation. Serpin family (SERPINC1), the apolipoproteins (APOA, APOB, APOC), ATP synthases (ATP5G1, ATP5B), fibrinogen genes (FGB, FGA) and alpha-2-macroglobulin were identified as highly connective genes that may have an important role in PSVD pathogenesis. CONCLUSION: PSVD has a unique transcriptomic profile and we have identified deregulation of pathways involved in vascular homeostasis as the main pathogenic event of disease development. LAY SUMMARY: Porto-sinusoidal vascular disease is a rare but life-shortening disease that affects mainly young people. Knowledge of the disrupted pathways involved in its development will help to identify novel therapeutic targets and new treatments. Using a systems biology approach, we identify that pathways regulating endothelial function and tone may act as drivers of porto-sinusoidal vascular disease.

Autoimmune biomarkers in porto-sinusoidal vascular disease: Potential role in its diagnosis and pathophysiology.

BACKGROUND AND AIMS: Porto-sinusoidal vascular disease (PSVD) is a rare disease that requires excluding cirrhosis and other causes of portal hypertension for its diagnosis because it lacks a specific diagnostical test. Although it has been occasionally associated with autoimmune diseases, the pathophysiology of PSVD remains unknown. The aim of this study was to evaluate the potential role of autoimmunity in the pathophysiology and diagnosis of PSVD. METHODS: Thirty-seven consecutive patients with PSVD and 39 with cirrhosis matched by gender, signs of portal hypertension and liver function were included (training set). By using Indirect Immunofluorescence, ELISA and slot-blot methods data 22 autoantibodies were identified in patients with PSVD and cirrhosis. Presence of anti-endothelial cells antibodies (AECA) was assayed by a cell-based ELISA. Thirty-one PSVD, 40 cirrhosis patients, 15 patients with splenomegaly associated with haematological disease and 14 healthy donors were included in a validation set. FINDINGS: The proportion of patients with at least one positive antibody was statistically significantly higher in patients with PSVD compared with cirrhosis (92% vs 56%; P < .01). Specifically, AECA were significantly more frequent in PSVD than in cirrhosis (38% vs 15%; P = .013). Results were confirmed in the validation set. In the overall population, presence of AECA had a 63% positive predictive value for diagnosing PSVD and a 71% negative predictive value, with a specificity of 94% when the 1/16 level is used as cut-off. AECA positive serum samples react with a 68-72 kDa protein of human liver endothelial sinusoidal cells.

A Rare Quadruple Association: Fibromuscular Dysplasia, Giant Splenic Artery Aneurysm, Extrahepatic Portal Hypertension, and Hypersplenism.

Fibromuscular dysplasia (FMD) is a non-atherosclerotic, non-inflammatory vascular lesion. It is a very rare cause of splenic artery aneurysm (SAA). An 18-year-old girl presented with hematemesis, melena, pancytopenia, and splenomegaly. Endoscopy showed esophageal varices. Computed tomography angiography showed splenic infarct and a giant splenic artery aneurysm. Portal vein showed cavernous transformation with enlarged periportal and lienorenal collaterals. The liver and pancreas were unremarkable. Microscopy of the SAA revealed intimal fibroplasia and medial dysplasia. Symptoms of extrahepatic portal hypertension were relieved by aneurysmectomy, thus proving SAA as the underlying cause. Pancytopenia was reversed post-splenectomy, thus proving hypersplenism. This is the first-ever report showing a quadruple association of FMD, splenic artery aneurysm, extrahepatic portal hypertension, and hypersplenism. KEY MESSAGES: Fibromuscular dysplasia can present as a giant aneurysm of the splenic artery. The resultant extrahepatic portal hypertension and splenomegaly can result in hypersplenism. Splenectomy and aneurysmectomy can reverse pancytopenia and portal hypertension. HOW TO CITE THIS ARTICLE: Shinde S. A Rare Quadruple Association: Fibromuscular Dysplasia, Giant Splenic Artery Aneurysm, Extrahepatic Portal Hypertension, and Hypersplenism. Indian J Crit Care Med 2021;25(1):100-103.

Aberrant von Willebrand factor expression of sinusoidal endothelial cells and quiescence of hepatic stellate cells in nodular regenerative hyperplasia and obliterative portal venopathy.

AIMS: Nodular regenerative hyperplasia (NRH) and obliterative portal venopathy (OPV), entities that comprise idiopathic non-cirrhotic portal hypertension (INCPH), are under-recognised diseases of uncertain aetiology and the diagnosis can be easily missed on liver biopsy. The expression of CD34 and von Willebrand factor (vWF) in liver sinusoidal endothelial cells (LSEC) and alpha-smooth muscle actin (ASMA) in hepatic stellate cells (HSCs) is unknown in NRH and OPV. We sought to investigate the pathogenesis and potential immunomarkers that might aid in making the diagnosis of NRH and OPV. METHODS AND RESULTS: Immunohistochemical (IHC) staining for CD34, vWF and ASMA was performed in clinically and histologically well-characterised NRH (n = 15) and OPV (n = 47) liver specimens. Among the 47 OPV cases, 37 (78.7%) had concurrent features of NRH. CD34 positive staining was mainly confined to small vessels in the portal tracts and LSECs in periportal areas, a finding similar to that in non-NRH/OPV livers. However, expression of vWF in LSECs was positive in the compressed sinusoids of NRH and in a patchy or geographic pattern, particularly prominent in the perivenular areas and dilated sinusoids of OPV cases. HSCs were negative for ASMA in all NRH and OPV cases. CONCLUSION: Our findings indicate that NRH may be a subtle but common concurrent morphological feature in OPV. The aberrant expression of vWF in LSECs suggests that endothelial injury may play a role in the pathogenesis, which may thus aid in the recognition and diagnosis of NRH and OPV, particularly when confronted with otherwise apparent normal liver histology on needle biopsy.

Histology of portal vascular changes associated with idiopathic non-cirrhotic portal hypertension: nomenclature and definition.

Idiopathic non-cirrhotic portal hypertension (INCPH) is a rare vascular liver disease that has attracted new interest in recent years. It is characterised by clinical signs of portal hypertension in the absence of cirrhosis or severe fibrosis and any known cause of portal hypertension. As much uncertainty exists about INCPH pathophysiology, and no definite diagnostic tests are available, liver biopsy is an essential tool for achieving a definite diagnosis. Unfortunately, the histological diagnosis of INCPH is not always straightforward, as the characteristic lesions are unevenly distributed, vary greatly in their severity, are often very subtle, and are not all necessarily present in a single case. Furthermore, specifically for the characteristic portal vessel changes observed in INCPH, the terminology and definition are ambiguous, which adds complexity to the already complex clinicopathological scenario. An international study group of liver pathologists and hepatologists pursued a consensus on nomenclature for the portal vascular lesions of INCPH. Such standardisation may assist pathologists in the recognition of such lesions, and will possibly facilitate further advancement in this field.

Prevalence and impact of sarcopenia in non-cirrhotic portal hypertension.

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.

Limited relevance and progression of histological alterations in the liver during thioguanine therapy in inflammatory bowel disease patients.

Background: Thioguanine is associated with liver toxicity, especially nodular regenerative hyperplasia (NRH). We assessed if liver histology alters during long-term maintenance treatment with thioguanine in patients with inflammatory bowel disease (IBD). Methods: Liver specimens of thioguanine treated IBD patients with at least two liver biopsies were revised by two independent liver pathologists, blinded to clinical characteristics. Alterations in histopathological findings between first and sequential liver specimen were evaluated and associated clinical data, including laboratory parameters and abdominal imaging reports, were collected. Results: Twenty-five IBD patients underwent sequential liver biopsies prior to, at time of, or after cessation of thioguanine treatment. The median time between the first and second biopsy was 25 months (range: 14-54). Except for one normal liver specimen, any degree of irregularities including inflammation, steatosis, fibrosis and some vascular disturbances were observed in the biopsies. The rates of perisinusoidal fibrosis (91%), sinusoidal dilatation (68%) and nodularity (18%) were the same in the first and second liver biopsies. A trend towards statistical significance was observed for phlebosclerosis (36% of the first vs. 68% of the second biopsies, p = .092). Presence of histopathological liver abnormalities was not associated with clinical outcomes. Furthermore, two patients in this cohort had portal hypertension in presence of phlebosclerosis. In another two patients, nodularity of the liver resolved upon thioguanine withdrawal. Conclusion: Vascular abnormalities of the liver were commonly observed in thioguanine treated IBD patients, although these were not progressive and remained of limited clinical relevance over time.

An 18-Year-Old Man with Idiopathic Non-cirrhotic Portal Hypertension.

Non-Cirrhotic Portal Hypertension (NCPH) is a rare cause of hematemesis and melena. Like in cirrhotic patient, hematemesis in NCPH patient was caused by rupture of esophageal varices. But unlike in cirrhotic patient, in NCPH there are no sign of liver failure, because liver physiology is still normal. We reported case of male patient with NCPH that had hematemesis because of rupture of esophageal varices.

[Analysis of influencing factors on hepatic encephalopathy in patients with non-cirrhotic portal hypertension].

Objective: To investigate the incidence of hepatic encephalopathy (HE) in patients with non-cirrhotic portal hypertension (NCPH) and to explore its risk factors. Methods: The incidence rate of HE in 150 cases with NCPH was evaluated in two hospitals, and 188 cases of compensated cirrhosis patients were taken as control. Logistic regression was used to screen for independent risk factors for HE in patients with NCPH. Results: The incidence of overt hepatic encephalopathy (OHE) in patients with NCPH was not statistically significantly different from that in patients with cirrhosis (4.7% vs. 6.9%, P = 0.682). The incidence of mild hepatic encephalopathy (MHE) was significantly lower than that of cirrhosis patients (32.7% vs. 46.3%, P < 0.05). The presence of upper gastrointestinal bleeding, infection and portosystemic venous shunt were the main independent factors for HE in NCPH patients (OR > 1, P < 0.05). Conclusion: HE is one of the important complications of NCP, and may be influenced by factors such as upper gastrointestinal bleeding, infection and portosystemic venous shunt.

Mutations in the novel gene FOPV are associated with familial autosomal dominant and non-familial obliterative portal venopathy.

BACKGROUND & AIMS: Obliterative portal venopathy (OPV) is characterized by lesions of portal vein intrahepatic branches and is thought to be responsible for many cases of portal hypertension in the absence of cirrhosis or obstruction of large portal or hepatic veins. In most cases the cause of OPV remains unknown. The aim was to identify a candidate gene of OPV. METHODS: Whole exome sequencing was performed in two families, including 6 patients with OPV. Identified mutations were confirmed by Sanger sequencing and expression of candidate gene transcript was studied by real time qPCR in human tissues. RESULTS: In both families, no mutations were identified in genes previously reported to be associated with OPV. In each family, we identified a heterozygous mutation (c.1783G>A, p.Gly595Arg and c.4895C>T, p.Thr1632Ile) in a novel gene located on chromosome 4, that we called FOPV (Familial Obliterative Portal Venopathy), and having a cDNA coding for 1793 amino acids. The FOPV mutations segregated with the disease in families and the pattern of inheritance was suggestive of autosomal dominant inherited OPV, with incomplete penetrance and variable expressivity. In silico analysis predicted a deleterious effect of each mutant and mutations concerned highly conserved amino acids in mammals. A deleterious heterozygous FOPV missense mutation (c.4244T>C, p.Phe1415Ser) was also identified in a patient with non-familial OPV. Expression study in liver veins showed that FOPV transcript was mainly expressed in intrahepatic portal vein. CONCLUSIONS: This report suggests that FOPV mutations may have a pathogenic role in some cases of familial and non-familial OPV.

ß-Blockers Improve Presinusoidal Portal Hypertension.

BACKGROUND: Presinusoidal portal hypertension is a clinically important cause of gastric and gastroesophageal varices. Whereas ß-blockers have an established prophylactic role against bleeding from esophageal and gastric varices in portal hypertension due to cirrhosis, the effect on presinusoidal portal hypertension is unknown. AIMS: To evaluate the hemodynamic effect of ß-blockers in non-cirrhotic patients with presinusoidal portal hypertension. METHODS: We measured the blood pressure gradient from spleen pulp to free hepatic vein in 12 patients with presinusoidal portal hypertension by combined hepatic vein catheterization and spleen pulp puncture while on and off ß-blocker treatment (random sequence). RESULTS: The ß-blockers reduced the gradient from a mean off-treatment value of 32 mm Hg to a on-treatment value of 26 mm Hg (P < 0.05) with a reduction of at least 20% in five patients (42%). CONCLUSIONS: ß-blocker treatment caused a clinically significant reduction in the pressure gradient from spleen pulp to the free hepatic vein. This finding supports the recommendation for prophylactic ß-blockage in patients with presinusoidal portal hypertension.