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Since the Asian Pacific Association for the Study of the Liver (APASL) published guidelines on non-cirrhotic portal fibrosis/idiopathic portal hypertension in 2007, there has been a surge in new information, especially with the introduction of the term porto-sinusoidal vascular disorder (PSVD). Non-cirrhotic intra-hepatic causes of portal hypertension include disorders with a clearly identifiable etiology, such as schistosomiasis, as well as disorders with an unclear etiology such as non-cirrhotic portal fibrosis (NCPF), also termed idiopathic portal hypertension (IPH). This entity is being increasingly recognized as being associated with systemic disease and drug therapy, especially cancer therapy. An international working group with extensive expertise in portal hypertension was assigned with formulating consensus guidelines to clarify the definition, diagnosis, histological features, natural history, and management of NCPF/IPH, especially in the context of PSVD. The guidelines were prepared based on evidence from existing published literature. Whenever there was paucity of evidence, expert opinion was included after detailed deliberation. The goal of this manuscript, therefore, is to enhance the current understanding and help create global consensus on the issues surrounding NCPF/IPH.

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.

Background Portal hypertension is secondary to either cirrhotic or non-cirrhotic causes, and complicating pregnancy poses a challenge to the treating team. A systematic review was performed to determine maternal and perinatal outcomes in women with portal hypertension. Outcomes were compared among those with cirrhotic (CPH) with non-cirrhotic portal hypertension (NCPH) as well as non-cirrhotic portal fibrosis (NCPF) with extra-hepatic portal vein obstruction (EHPVO). Methods Medline and EMBASE databases were searched for studies reporting outcomes among pregnant women with portal hypertension. Reference lists from relevant papers and reviews were hand-searched for appropriate citations. Data were extracted to describe maternal complications, obstetric and neonatal outcomes. A random-effects model was used to derive pooled estimates of various outcomes, and final estimates were reported as percentages with a 95% confidence interval (CI). Cumulative, sequential and sensitivity analysis was studied to assess the temporal trends of outcomes over the period. Results Information on 895 pregnancies among 581 patients with portal hypertension was included from 26 studies. Portal hypertension was diagnosed during pregnancy in 10% (95% CI 4–24%). There were 22 maternal deaths (0%, 95% CI 0–1%), mostly following complications from variceal bleeding or hepatic decompensation. Variceal bleeding complicated in 14% (95% CI 9–20%), and endoscopic interventions were performed in 12% (95% CI 8–17%) during pregnancy. Decompensation of liver function occurred in 7% (95% CI 3–12%). Thrombocytopenia was the most common complication (41%, 95% CI 23–60%). Miscarriages occurred in 14% (95% CI 8–20%), preterm birth in 27% (95% CI 19–37%), and low birth weights in 22% (95% CI 15–30%). Risk of postpartum hemorrhage was higher (RR 5.09, 95% CI 1.84–14.12), and variceal bleeding was lower (RR 0.51, 95% CI 0.30–0.86) among those with CPH compared to NCPH. Risk of various outcomes was comparable between NCPF and EHPVO. Conclusion One in ten pregnancies complicated with portal hypertension is diagnosed during pregnancy, and thrombocytopenia is the most common complication. Hepatic decompensation and variceal bleeding remain the most common cause of maternal deaths, with reduced rates of bleeding and its complications reported following the introduction of endoscopic procedures during pregnancy. CPH increases the risk of postpartum hemorrhage, whereas variceal bleeding is higher among NCPH.

Non-cirrhotic portal hypertension (NCPH), also known as idiopathic non-cirrhotic portal hypertension (INCPH) and porto-sinusoidal vascular disorder (PSVD), is a rare disease characterized by intrahepatic portal hypertension (IPH) in the absence of cirrhosis. The precise etiopathogenesis of IPH is an area of ongoing research. NCPH diagnosis is challenging, as there are no specific tests available to confirm the disease, and a high-quality liver biopsy, detailed clinical information, and an expert pathologist are necessary for diagnosis. Currently, the treatment of NCPH relies on the prevention of complications related to portal hypertension, following current guidelines of cirrhotic portal hypertension. No treatment has been studied that aimed to modify the natural history of the disease; however, transjugular intrahepatic porto-systemic shunt (TIPS) placement, shunt and liver transplantation are considerable symptomatic options. In this review, we discuss the heterogeneity of NCPH as well as its etiopathogenesis, clinical presentation and management issues. Starting from the assumption that portal hypertension does not always mean cirrhosis, cooperative studies are probably needed to clarify the issues of etiology and the possible genetic background of this rare disease. This knowledge might lead to better treatment and perhaps better prevention.

Background and Aim Obliterative portal venopathy (OPV) is one of the causes of non‐cirrhotic portal hypertension. However, many aspects of OPV remain unclear, including the etiology, pathogenesis, and natural history. The aim of this study was to describe the clinical features of OPV in a series of patients in Brazil in whom OPV was diagnosed through liver biopsy. Methods Forty‐three consecutive adult patients with OPV were retrospectively selected as a case series based on histologic criteria, defined by the presence of at least portal fibrosis, phlebosclerosis, disappearance and/or reduction of the caliber of portal vein branches, and exclusion of cirrhosis. Clinical and laboratory data were analyzed. Clinically significant portal hypertension was considered in the presence of esophageal varices and/or ascites. Results The mean age of patients at diagnosis was 44.5 ± 11 years, who were predominantly female (81%). Clinically significant portal hypertension was found in 28% of cases. The most frequent indication for liver biopsy was the elevation of liver enzymes, mostly γ‐glutamyl transferase (GGT) in 76% of patients, averaging 222 IU/L (upper limit of normality up to 40 IU/L) and alanine aminotransferase (ALT) in 64%, mean 84 IU/L (38 IU/L). One‐third of our patients had exposure to medications, especially herbal medicines, at the time of enzymatic changes. Other risk factors highlighted were features of autoimmunity in 25% of patients or thrombophilia in 20%. Conclusion OPV can be diagnosed even before the onset of portal hypertension, ALT elevation, and especially GGT elevation in most cases. Its etiology is not defined, but autoimmune diseases, thrombophilia, and the use of medications or herbal medicines may play a role. Classically described in the group of non‐cirrhotic portal hypertension, obliterative portal venopathy (OPV) causes are still unknown. Our aim is to describe the characteristics of 43 OPV patients and potential risk factors. Clinically significant portal hypertension was found in 28% of cases. The most frequent indication for liver biopsy was elevation of liver enzymes, mostly γ‐glutamyl transferase increase in 76% of patients. One third of our patients have exposure to medications, especially herbal medicines at the time of enzymatic changes.

In idiopathic portal hypertension (IPH) typical vascular lesions are present in the branches of the portal vein or in the perisinusoidal area of the liver. Similar histological alterations have been reported in the pulmonary vasculature of patients with idiopathic pulmonary artery hypertension (IPAH). As IPAH is associated with mutations of the bone morphogenetic protein receptor 2 (BMPR2) gene, the aim of this study was to investigate whether this association might also be found in patients with IPH. Twenty‐three samples belonging to 21 unrelated caucasian patients with IPH followed in the hepatic haemodynamic laboratory of the Hospital Clinic in Barcelona were included in the study. All patients were studied for the entire open reading frame and splice site of the BMPR2 gene by direct sequencing and multiple ligation probe amplification (MLPA) in order to detect large deletions/duplications. None of the 23 patients had pulmonary artery hypertension. Four patients presented one single nucleotide polymorphism (SNP) in intron 5, four patients had a SNP in exon 12 and a SNP in exon 1 was found in two cases. Two patients had both intron 5 and exon 12 polymorphisms. All SNPs were previously described. Except for these three SNPs, neither mutations nor rearrangements have been identified in the BMPR2 gene in this population. We did not detect mutations or rearrangements in the coding region of the BMPR2 gene in our patients with IPH. These findings suggest that, in contrast to IPAH, mutations in BMPR2 are not involved in the pathogenesis of IPH.

Idiopathic non-cirrhotic portal hypertension (INCPH) is a rare disease characterized of intrahepatic portal hypertension in the absence of cirrhosis or other causes of liver disease and splanchnic venous thrombosis. The etiology of INCPH can be classified in five categories: 1) immunological disorders (i.e. association with common variable immunodeficiency syndrome, connective tissue diseases, Crohn’s disease, etc.), 2) chronic infections, 3) exposure to medications or toxins (e.g. azathioprine, 6- thioguanine, arsenic), 4) genetic predisposition (i.e. familial aggregation and association with Adams-Oliver syndrome and Turner disease) and 5) prothrombotic conditions (e.g. inherited thrombophilias myeloproliferative neoplasm antiphospholipid syndrome). Roughly, INCPH diagnosis is based on clinical criteria and the formal exclusion of any other causes of portal hypertension. A formal diagnosis is based on the following criteria: 1) presence of unequivocal signs of portal hypertension, 2) absence of cirrhosis, advanced fibrosis or other causes of chronic liver diseases, and 3) absence of thrombosis of the hepatic veins or of the portal vein at imaging. Patients with INCPH usually present with signs or symptoms of portal hypertension such as gastro-esophageal varices, variceal bleeding or splenomegaly. Ascites and/or liver failure can occur in the context of precipitating factors. The development of portal vein thrombosis is common. Survival is manly limited by concomitant disorders. Currently, treatment of INCPH relies on the prevention of complications related to portal hypertension, following current guidelines of cirrhotic portal hypertension. No treatment has been studied aimed to modify the natural history of the disease. Anticoagulation therapy can be considered in patients who develop portal vein thrombosis.

BackgroundPorto-sinusoidal vascular disease (PSVD) is a novel nomenclature to describe non-cirrhotic portal hypertension and characteristic histology without portal vein thrombosis (PVT). It is a more inclusive definition than the previously well-recognized entity idiopathic non-cirrhotic portal hypertension. There is a paucity of data on PSVD patients.MethodsA total of 33 patients diagnosed with PSVD and portal hypertension (PH) between 2005 and 2021 were included. Data were retrieved from electronic medical record system and analyzed.ResultsOf the 33 patients, 6 (18%) occurred in post-transplant allograft liver. After a median follow-up of 96 months (interquartile range, IQR [52, 139]), 14 deaths occurred (42%), 4 directly related to decompensated liver disease. The Kaplan–Meier survival estimates at 1, 5, and 10 years were 94%, 87% and 58%. PVT occurred in 10 patients (30%). The Nelson–Aalen cumulative risk estimate for PVT at 1, 5 and 10 years were 16%, 25% and 48%. The median model for end-stage liver disease and Child–Pugh score at initial presentation were 8 (IQR [7–12]) and 5 [5–6], and increased to 13 [8, 18] and 7 [5, 8], respectively, at the end of follow-up. Of the 11 patients who presented with splenomegaly and no specific sign of PH, 7 (64%) developed varices and 3 (27%) ascites at a median follow-up of 100 months.ConclusionsPSVD with PH is not a benign entity. Mortality, PVT and hepatic decompensation are common. Patients with PSVD must be closely monitored, including those who only have non-specific clinical signs (e.g., splenomegaly) of PH.

Idiopathic non-cirrhotic portal hypertension is an under-recognized vascular liver disease of unknown etiology, characterized by clinical signs of portal hypertension in the absence of cirrhosis. By definition, any disorder known to cause portal hypertension in the absence of cirrhosis and any cause of chronic liver disease must be excluded to make a diagnosis of idiopathic non-cirrhotic portal hypertension. However, the diagnosis is often difficult because the disease resembles cirrhosis and there is no gold standard test. Liver biopsy is an essential tool: it is able to exclude cirrhosis and other causes of portal hypertension and it allows the identification of the characteristic lesions. Nonetheless, the histological diagnosis of idiopathic non-cirrhotic portal hypertension is not always straightforward, in particular by needle biopsy samples, because there is no pathognomonic lesion, but rather a variety of vascular changes which are unevenly distributed, very subtle, and not all necessarily identified in a single specimen. Pathologists should be able to recognize several patterns of injury, involving portal/periportal areas as well as parenchymal structures.The histological features of idiopathic non-cirrhotic portal hypertension are described in this review, focusing on their interpretation in needle biopsy specimens.

BackgroundIdiopathic portal hypertension (IPH) and extrahepatic portal venous obstruction (EHPVO) are non-cirrhotic vascular causes of portal hypertension (PHT). Variceal bleed and splenomegaly are the commonest presentations.AimThe present review is intended to provide the existing literature on etiopathogenesis, clinical profile, diagnosis, natural history and management of IPH and EHPVO.ResultsIPH and EHPVO are both characterized by normal hepatic venous pressure gradient, moderate to massive splenomegaly with preserved liver synthetic functions. While the level of block in IPH is presinusoidal, in EHPVO it is at prehepatic level. Infections, autoimmunity, drugs, immunodeficiency and prothrombotic states are possible etiological agents in IPH. Contrastingly in EHPVO, prothrombotic disorders and local factors around the portal vein are the incriminating factors. Diagnosis is often clinical, supported by simple radiological tools. Natural history is defined by episodes of variceal bleed and symptoms related to enlarged spleen. Growth failure, portal biliopathy and minimal hepatic encephalopathy are additional concerns in EHPVO. Long-term survival is reasonably good with endoscopic surveillance; however, parenchymal extinction leading to decompensation is seen in a minority of patients in both the disorders. Surgical shunts revert the complications secondary to PHT. Meso-Rex shunt has become the standard surgery in children with EHPVO.ConclusionThis review gives a detailed summary of these two vascular conditions of liver—IPH and EHPVO. Further research is needed to understand the pathogenesis and natural history of these disorders.