Pathological abnormalities in splenic vasculature in non-cirrhotic portal hypertension:Its relevance in the management of portal hypertension

BACKGROUND Portal hypertension(PH)is associated with changes in vascular structure and function of the portosplenomesenteric system(PSMS).This is referred to as portal hypertensive vasculopathy.Pathological abnormalities of PSMS has been described in the literature for cirrhotic patients.Raised portal pressure and hyperdynamic circulation are thought to be the underlying cause of this vasculopathy.In view of this,it is expected that pathological changes in splenic and portal vein similar to those reported in cirrhotic patients with PH may also be present in patients with non-cirrhotic PH(NCPH).AIM To investigate pathological abnormalities of splenic vein in patients with NCPH,and suggest its possible implications in the management of PH.METHODS A prospective observational study was performed on 116 patients with NCPH[Extrahepatic portal vein obstruction(EHPVO):53 and non-cirrhotic portal fibrosis(NCPF):63]who underwent proximal splenorenal shunt(PSRS),interposition shunt or splenectomy with devascularization in JIPMER,Pondicherry,India,a tertiary level referral center,between 2011-2016.All patients were evaluated by Doppler study of PSMS,computed tomography portovenogram and upper gastrointestinal endoscopy.An acoustic resonance forced impulse(ARFI)scan and abdomen ultrasound were done for all cases to exclude cirrhosis.Intraoperative and histopathological assessment of the harvested splenic vein was performed in all.The study group was divided into delayed and early presentation based on the median duration of symptoms(i.e.108 mo).RESULTS The study group comprising of 116 patients[77(66%)females and 39(34%)males]with NCPH had a median age of 22 years.Median duration of symptoms was 108 mo.The most common presentation in both EHPVO and NCPF patients was upper gastrointestinal bleeding(hematemesis and melena).The ARFI scan revealed a median score of 1.2(1.0-1.8)m/s for EHPVO and 1.5(0.9-2.8)m/s for NCPF.PSRS was performed in 84 patients(two of whom underwent interposition PSRS using a 10 mm Dacron graft);splenoadrenal shunt in 9;interposition mesocaval shunt in 5;interposition 1st jejunal to caval shunt in 1 patient and devascularization with splenectomy in 17 patients.Median presplenectomy portal pressure was 25(range:15-51)mm Hg.In 77%cases,the splenic vein was abnormal upon intraoperative assessment.Under macroscopic examination,wall thickening was observed in 108(93%),venous thrombosis in 32(28%)and vein wall calcification in 27(23%)cases.Upon examination under a surgical magnification loupe,21(18%)patients had intimal defects in the splenic vein.Histopathological examination of veins was abnormal in all cases.Medial hypertrophy was noted in nearly all patients(107/116),while intimal fibrosis was seen in 30%.Ninety one percent of patients with intimal fibrosis also had venous thrombosis.Vein wall calcification was found in 22%,all of whom had intimal fibrosis and venous thrombosis.The proportion of patients with pathological abnormalities in the splenic vein were significantly greater in the delayed presentation group as compared to the early presentation group.CONCLUSION Pathological changes in the splenic vein similar to those in cirrhotic patients with PH are noted in NCPH.We recommend that PH in NCPH be treated as systemic and pulmonary hypertension equivalent in the gastrointestinal tract,and that early aggressive therapy be initiated to reduce portal pressure and hemodynamic stress to avoid potential lethal effects.

Non-cirrhotic portal hypertension with large regenerative nodules: A diagnostic challenge

Non-cirrhotic portal hypertension is a poorly understood condition characterized by portal hypertension in the absence of conventional hepatic cirrhosis and described in association with blood coagulation disorders, myeloproliferative and immunological diseases and with exposure to toxic drugs. Very recently, precise classification criteria have been proposed in order to define four distinct subcategories. The present case highlights how the clinical presentation, the confounding results from imaging studies, and the difficulties in the histological evaluation often render cases of non-cirrhotic portal hypertension a real diagnostic challenge. It also underscores the classification problems which can be faced once this diagnosis is performed. Indeed, the different subcategories proposed result from the prevalent subtypes in a spectrum of hepatic regenerative responses to a variety of injuries determining microcirculatory dis-turbances. More flexibility in classification should derive from this etiopathogenic background.

Isolated gastric variceal bleeding related to non-cirrhotic portal hypertension following oxaliplatin-based chemotherapy:A case report

BACKGROUND Sinusoidal obstruction syndrome has been reported after oxaliplatin-based chemotherapy,but liver fibrosis and non-cirrhotic portal hypertension(NCPH)are rarely reported.CASE SUMMARY Here,we describe the case of a 64-year-old woman who developed isolated gastric variceal bleeding 16 mo after completing eight cycles of oxaliplatin combined with capecitabine chemotherapy after colon cancer resection.Surprisingly,splenomegaly and thrombocytopenia were not accompanied by variceal bleeding,which has been reported to have predictive value for gastric variceal formation.However,a liver biopsy showed fibrosis in the portal area,suggesting NCPH.The patient underwent endoscopic treatment and experienced no further symptoms.CONCLUSION It is necessary to guard against long-term complications after oxaliplatin-based chemotherapy.Sometimes splenic size and platelet level may not always accurately predict the occurrence of portal hypertension.

Systemic mastocytosis: A rare cause of non-cirrhotic portal hypertension

Mastocytosis is a clonal neoplastic disorder of the mast cells(MC) that can be limited to the skin(cutaneous mastocytosis) or involve one or more extracutaneous organs(systemic mastocytosis). The clinical manifestations of mastocytosis are heterogeneous ranging from indolent disease with a long-term survival to a highly aggressive neoplasm with survival of about 6 mo. Although liver involvement in aggressive systemic mastocytosis(ASM) is relatively common, the development of portal hypertension with or without cirrhosis is rare. We report a case of ASM without skin involvement in a 72-year-old caucasian male who presented with non-cirrhotic portal hypertension based on clinical, analytical, imagiological and endoscopic findings. Given the hematological picture, the correct diagnosis was established based on ancillary tests for MC using bone marrow aspirates and biopsy. Extensive involvement of the liver and gastrointestinal tract was histologically documented. The disease progressed rapidly and severe pancytopenia and recurrent upper gastrointestinal bleeding became the dominant problem. This case illustrates the challenge in establishing a diagnosis of ASM especially when the clinical picture is atypical and without skin involvement. Gastroenterologists should consider infiltrative disease, particularly systemic mastocytosis, as a differential diagnosis in a clinical case of portal hypertension of unknown etiology.

Current concepts in the management of non-cirrhotic non-malignant portal vein thrombosis

Non-cirrhotic non-malignant portal vein thrombosis(NCPVT)is an uncommon condition characterised by thrombosis of the portal vein,with or without extension into other mesenteric veins,in the absence of cirrhosis or intra-abdominal malignancy.Complications can include intestinal infarction,variceal bleeding and portal biliopathy.In this article,we address current concepts in the management of NCPVT including identification of risk factors,classification and treatment,and review the latest evidence on medical and interventional management options.

A rabbit model of non- cirrhotic portal hypertension by repeated injections of E. coli through indwelling cannulation of the gastrosplenic vein

BACKGROUND: Non-cirrhotic portal hypertension is acommon cause of portal hypertension in developing coun-tries. To understand its etiopathogenesis we developed ananimal model by repeated portal endotoxemia inducedthrough the gastrosplenic vein.METHODS: Twenty-nine rabbits (1.5-2.0 kg) were divid-ed into control (group n = 13) and experimental ( groupn = 16) groups. Heat killed E. coli were injected throughan indwelling cannula into the gastrosplenic vein in pre-sensitized animals. The animals were sacriflced at 1, 3 and6 months.RESULTS: The mean portal pressure in group animalswas significantly (P < 0. 05) higher than in group at 1(17.5 ±3.4 vs 10.4±2.2 mmHg), 3 (17.8±1.3 vs7.2 +3.6mmHg), and 6 (19.8±3.1 vs 10.3±4.8 mmHg) months.Similarly, the mean splenic weight in group was signifi-cantly greater than in group (P <0.05). Histopathologi-cally, the spleen showed medullary congestion, hemosid-rin-laden macrophages and mild fibrosis. Histologically,the liver had normal parenchyma with mild portal lympho-cytic infiltrates and kupffer cell hyperplasia. No significantanomalies were detected by liver function tests.CONCLUSIONS: The rabbit model showed significantsplenomegaly with a persistent increase in portal pressureand mild fibrosis without hepatic parenchymal injury, quiteakin to non-cirrhotic portal fibrosis as seen in humans. Re-current intra-abdominal infection may play an importantrole in the pathogenesis of non-cirrhotic portal fibrosis.

Transjugular intrahepatic portosystemic shunt and splenectomy are more effective than endoscopic therapy for recurrent variceal bleeding in patients with idiopathic noncirrhotic portal hypertension

BACKGROUND Transjugular intrahepatic portosystemic shunt(TIPS),splenectomy plus esophagogastric devascularization(SED)and endoscopic therapy+non-selectiveβ-blockers(ET+NSBB)are widely applied in secondary prevention of recurrent gastroesophageal variceal bleeding in patients with liver cirrhosis.These different treatments,however,have not been compared in patients with idiopathic noncirrhotic portal hypertension(INCPH).AIM To compare the outcomes of TIPS,SED and ET+NSBB in the control of variceal rebleeding in patients with INCPH.METHODS This retrospective study recruited patients from six centers across China.Demographic characteristics,baseline profiles and follow-up clinical outcomes were collected.Post-procedural clinical outcomes,including incidence of rebleeding,hepatic encephalopathy(HE),portal vein thrombosis(PVT)and mortality rates,were compared in the different groups.RESULTS In total,81 patients were recruited,with 28 receiving TIPS,26 SED,and 27 ET+NSBB.No significant differences in demographic and baseline characteristics were found among these three groups before the procedures.After treatment,blood ammonia was significantly higher in the TIPS group;hemoglobin level and platelet count were significantly higher in the SED group(P<0.01).Rebleeding rate was significantly higher in the ET+NSBB group(P<0.01).Mortality was 3.6%,3.8%and 14.8%in the TIPS,SED and ET+NSBB groups,respectively,with no significant differences(P=0.082).Logistic regression analysis showed that mortality was significantly correlated with rebleeding,HE,portal thrombosis and superior mesenteric vein thrombosis(P<0.05).CONCLUSION In patients with INCPH,TIPS and SED were more effective in controlling rebleeding than ET+NSBB,but survival rates were not significantly different among the three groups.Mortality was significantly correlated with rebleeding,HE and PVT.

Successful treatment of noncirrhotic portal hypertension with eculizumab in paroxysmal nocturnal hemoglobinuria: A case report

BACKGROUND Idiopathic non-cirrhotic portal hypertension(INCPH)is mainly associated with thrombophilia in Western countries.Paroxysmal nocturnal hemoglobinuria(PNH)is a rare hematologic disease that manifests with hemolytic anemia,thrombosis,and peripheral blood cytopenias.Portal and hepatic venous thrombosis were reported in PNH.A rare case of INCPH complicating PNH is described.CASE SUMMARY A 63-year old woman with a 2-year past medical history of PNH without treatment was admitted because of jaundice and refractory ascites requiring large volume paracentesis.Liver histology revealed portal venopathy with portal fibrosis and sclerosis,nodular regenerative hyperplasia,parenchymal ischemic changes,and focal sinusoidal and perivenular fibrosis without bridging fibrosis or cirrhosis,all indicative of INCPH.The flow cytometry confirmed PNH diagnosis and eculizumab treatment was initiated.Her condition was improved gradually,bilirubin was normalized 6 months following initiation of eculizumab,and 1 year later diuretics were stopped.CONCLUSION Eculizumab improved intravascular hemolysis and reversed clinical manifestations of INCPH in a patient with paroxysmal nocturnal hemoglobinuria.

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.

Portal ductopathy:Clinical importance and nomenclature

Non-cirrhotic portal hypertension(PHT)accounts for about 20%of all PHT cases,portal vein thrombosis(PVT) resulting in cavernous transformation being the most common cause.All known complications of PHT may be encountered in patients with chronic PVT.However,the effect of this entity on the biliary tree and pancreatic duct has not yet been fully established.Additionally,a dispute remains regarding the nomenclature of common bile duct abnormalities which occur as a result of chronic PVT.Although many clinical reports have focused on biliary abnormalities,only a few have evaluated both the biliary and pancreatic ductal systems.In this review the relevant literature evaluating the effect of PVT on both ductal systems is discussed,and findings are considered with reference to results of a prominent center in Turkey,from which the term"portal ductopathy"has been put forth to replace"portal biliopathy".

重视非肝硬化门脉高压症的早期诊断

非肝硬化门脉高压症(NCPH)是指在没有肝硬化或不完全间隔性肝硬化(ISC)患者,门静脉压力梯度明显升高,而肝静脉压力梯度正常或轻度升高,以肝脏血管病变为特征,临床表现为门脉高压症、病因复杂的一组异质性疾病。其命名尚未完全统一。相同病因所致的NCPH,在不同阶段其肝脏病理及临床表现不同。食管胃静脉曲张出血是NCPH最常见的并发症,容易漏诊或误诊为肝硬化。NCPH病因治疗是关键,内镜及药物是治疗NCPH并发食管胃静脉曲张出血的有效方法。

Gastroesophageal varices in a patient presenting with essential thrombocythemia:A case report

BACKGROUND Gastroesophageal varices are a rare complication of essential thrombocythemia(ET).ET is a chronic myeloproliferative neoplasm(MPN)characterized by an increased number of blood platelets.CASE SUMMARY A 46-year-old woman,who denied a history of liver disease,was admitted to our hospital on presentation of hematemesis.Laboratory examination revealed a hemoglobin level of 83 g/L,and a platelet count of 397×109/L.The appearance of gastric and esophageal varices with red colored signs as displayed by an urgent endoscopy was followed by endoscopic variceal ligation and endoscopic tissue adhesive.Abdominal computed tomography revealed cirrhosis,marked splenomegaly,portal vein thrombosis and portal hypertension.In addition,bone marrow biopsy and evidence of mutated Janus kinase 2,substantiated the onset of ET.The patient was asymptomatic with regular routine blood testing during the 6-mo follow-up period.Therefore,in this case,gastroesophageal varices were induced by ET.CONCLUSION MPN should be given considerable attention when performing differential diagnoses in patients with gastroesophageal varices.An integrated approach such as laboratory tests,radiological examination,and pathological biopsy,should be included to allow optimal decisions and management.

Prevalence of significant liver disease in human immunodeficiency virus-infected patients exposed to Didanosine: A cross sectional study

AIM To identify significant liver disease [including nodular regenerative hyperplasia(NRH)] in asymptomatic Didanosine(DDI) exposed human immunodeficiency virus(HIV) positive patients.METHODS Patients without known liver disease and with > 6 mo previous DDI use had liver stiffness assessed by transient elastography(TE). Those with alanine transaminase(ALT) above upper limit normal and/or TE > 7.65 k Pa underwent ultrasound scan(U/S). Patients with:(1) abnormal U/S; or(2) elevated ALT plus TE > 7.65 k Pa;or(3) TE > 9.4 k Pa were offered trans-jugular liver biopsy(TJLB) with hepatic venous pressure gradient(HVPG) assessment.RESULTS Ninety-nine patients were recruited, median age 50 years(range 31-70), 81% male and 70% men who have sex with men. Ninety-five percent with VL < 50 copies on antiretroviral therapy with median CD4 count 639 IU/L. Median DDI exposure was 3.4 years(range 0.5-14.6). Eighty-one had a valid TE readings(interquartile range/score ratio < 0.3): 71(88%) < 7.65 k Pa, 6(7%) 7.65-9.4 k Pa and 4(6%) > 9.4 k Pa. Seventeen(17%) met criteria for TJLB, of whom 12 accepted. All had HVPG < 6 mm Hg. Commonest histological findings were steatosis(n = 6), normal architecture(n = 4) and NRH(n = 2), giving a prevalence of previously undiagnosed NRH of 2%(95%CI: 0.55%, 7.0%).CONCLUSION A screening strategy based on TE, liver enzymes and U/S scan found a low prevalence of previously undiagnosed NRH in DDI exposed, asymptomatic HIV positive patients. Patients were more likely to have steatosis highlighting the increased risk of multifactorial liver disease in this population.

New guidelines for screening,evaluation and management of hepatobiliary disease in cystic fibrosis

The recently published guidelines on screening,monitoring and treatment update previous guidelines published 25 years ago(1,2).This update is timely as much has happened in the interim.Cystic fibrosis(CF)modulator therapy has dramatically improved prognosis for patients with CF,although it is not yet clear whether liver disease is improved.Our understanding of the pathophysiology of CF liver disease has also changed with the recognition of the importance of non-cirrhotic portal hypertension(3,4).Non-invasive tests for fibrosis and elastography have changed the practice of hepatology and reduced the need for liver biopsy.The guideline committee was made up of experts from North America and Europe and included adult and paediatric hepatologists and pulmonologists together with allied health practitioners and representatives of the CF community.A systematic literature search was performed and a vote of 80%was required to adopt a recommendation.The guidelines contain 7 recommendations for screening,13 for disease monitoring and 14 for treatment.