Rabbit model of non-cirrhotic portal fibrosis with repeated immunosensitization by rabbit splenic extract

BACKGROUND: Non-cirrhotic portal fibrosis (NCPF) or idiopathic portal hypertension, a disease of unknown etiology, is a common cause of portal hypertension in developing countries. Attempts to understand the etiopathogenesis of NCPF by developing animal models have been made. We describe a novel approach using repeated injections of rabbit splenic extract that were obtained from a previously primed rabbit, to develop a model of NCPF. METHODS: Twenty-eight rabbits (1.5-2.0 kg) were divided into the control (group I, n = 13) and the experimental (group II, n = 15) groups. The supernatant obtained after centrifugation of a 20% splenic homogenate, containing 6 mg protein/mL, was mixed with Freund's complete adjuvant (1:1 ratio) and injected intramuscularly to the recipient rabbits every 2 weeks for 3 months. Portal pressure was measured by inserting a cannula into the gastrosplenic vein. RESULTS: The mean portal pressure in group II was significantly (P < 0.05) higher than group I at 1 (19.4 +/- 2.9 vs 10.4 +/- 2.2 mmHg), 3 (16.7 +/- 1.1 vs 7.2 +/- 3.6 mmHg), and 6 (20.3 +/- 5.4 vs 10.3 +/- 4.8 mmHg) months. The mean splenic weight in group II was significantly (P < 0.05) greater than group I at 1, 3 and 6 months. Histopathology of spleen showed medullary congestion, hemosidrin laden macrophages and mild fibrosis. Liver showed normal hepatocytes with mild portal lymphocytic infiltrates and Kupffer cell hyperplasia. No significant anomalies were observed in the tests of liver function at 1 and 6 months. CONCLUSIONS: This animal model showed significant splenomegaly, with persistent rise in portal pressure without hepatic parenchymal injury, quite akin to NCPF seen in humans. This study also proposes that repeated immunostimulation may have an important role in the pathogenesis of NCPF.     

Natural/spontaneous shunts in non-cirrhotic portal fibrosis

Large natural/spontaneous shunts on splenoportovenography were demonstrated in 10 of 93 patients with non-cirrhotic portal fibrosis. There was significantly less bleeding in patients with spontaneous shunt than in those having no shunt. Large oesophageal varices (grade III-IV) were seen more frequently in patients without spontaneous shunt.     

Biliary lipid composition in patients with non-cirrhotic portal fibrosis – a comparison with compensated cirrhosis of the liver

ABSTRACT— Patients with non-cirrhotic portal fibrosis (NCPF) are known to have mild hepatic functional abnormalities. To study the biliary lipid composition in these patients, duodenal bile was collected from 18 patients with NCPF, 15 patients with non-alcoholic compensated cirrhosis of the liver and 18 matched, non-obese, healthy control subjects. There were no significant differences in the mean (± SD) concentrations of cholesterol, phospholipids and bile acids in patients with NCPF and healthy controls. On the other hand, patients with cirrhosis had significantly lower concentrations of all the three biliary lipids as compared with the NCPF patients and controls (p<0.05). The cholesterol solubilizing capacity of the bile was the same in NCPF patients, cirrhotics and controls. It is concluded that the relative proportions of the three biliary lipids remain unchanged in patients with NCPF despite mild hepatic derangement.     

Coagulation profile and platelet function in patients with extrahepatic portal vein obstruction and non-cirrhotic portal fibrosis

BACKGROUND AND AIMS: Coagulation disorders commonly develop in patients with cirrhosis of the liver. They have also been reported in patients with non-cirrhotic portal fibrosis (NCPF) and extra-hepatic portal venous obstruction (EHPVO); the two conditions with portal hypertension and near-normal liver functions. The spectrum and prevalence of coagulation abnormalities and their association with the pathogenesis of these diseases and with hypersplenism was prospectively studied. METHODS: Eighteen EHPVO patients that included an equal number of NCPF patients and 20 healthy controls were prospectively studied. The coagulation parameters assessed included: international normalized ratio, partial thromboplastin time, and fibrinogen and fibrinogen degradation products. Platelet aggregation and malondialdehyde levels were measured. RESULTS: Both EHPVO (83%) and NCPF (78%) patients had a significantly prolonged international normalized ratio and a decrease in fibrinogen and platelet aggregation. The EHPVO patients had a significant prolongation in partial thromboplastin time (67% patients), with increased levels of fibrinogen degradation product levels occurring in all patients; these were normal in NCPF patients. Platelet malondialdehyde levels were normal in both groups. Hypersplenism was present in four EHPVO and seven NCPF patients. It did not significantly influence the coagulation profile in either NCPF or EHPVO patients. CONCLUSIONS: Coagulation anomalies are common and significant in both NCPF and EHPVO patients, suggestive of a mild disseminated intravascular coagulation disorder. These imbalances could be caused by chronic subclinical endotoxemia and cytokine activation after the initial portal thromboembolic event. The persistence of these abnormalities in adolescent patients indicates an ongoing coagulation derangement.     

非肝硬化性门静脉高压症的研究现状

肝硬化是门静脉高压的最常见原因,但仍有约20%的门静脉高压继发于非肝硬化因素,称为非肝硬化性门静脉高压症(NCPH),在发展中国家发病率较高。NCPH是一组异源性的肝脏血管疾病,临床上多见的是特发性门静脉高压(IPH)、肝外门静脉血管阻塞(EHPVO),以及布加综合征、先天性肝纤维化和结节再生性增生等少见病。此类患者常常具有门静脉高压的证据,如反复发生的静脉曲张出血和脾脏肿大,但肝功能保存尚好。目前尚无诊断NCPH的统一标准,对其诊断仍是一个挑战。临床上往往采用排除性诊断,必要时可行肝穿刺活组织检查来确诊。介绍了IPH和EHPVO的发病机制、病理表现、诊断方法及治疗策略的选择,若能有效控制上消化道出血,NCPH被认为是预后相对良好的一类疾病。     

Cerebral function in unoperated patients with non-cirrhotic portal fibrosis: A comparison with compensated non-alcoholic cirrhotics

Cerebral functions were studied in 22 unoperated patients with non-cirrhotic portal fibrosis (NCPF), 23 patients with compensated non-alcoholic cirrhosis of the liver and 45 healthy controls. In each patient electroencephalography (EEG) and psychometric tests were performed. Neither EEG nor any psychometric test was abnormal in patients with NCPF, whereas in patients with cirrhosis of the liver, EEG was abnormal in 9%, the number connection in 35%, five point star construction in 13% and reverse counting test in 39%. These results suggest that subclinical hepatic encephalopathy is not common in non-cirrhotic portal fibrosis seen in India.     

Effect of shunt surgery on spleen size, portal pressure and oesophageal varices in patients with non-cirrhotic portal hypertension

Shunt surgery is considered to be the treatment of choice in patients with non-cirrhotic portal hypertension. There is little data on the effect of side-to-side lieno-renal (SSLR) shunt on oesophageal variceal size, splenic size and splenic pulp pressure (SPP) in patients with non-cirrhotic portal hypertension. We evaluated pre- and postoperatively endoscopic grading of varices, splenic size and SPP for predicting shunt patency in 86 patients with non-cirrhotic portal hypertension: 56 with extrahepatic portal venous obstruction (EHPVO) and 30 with non-cirrhotic portal fibrosis (NCPF). The EHPVO patients with patent shunts (n= 47) showed significant reduction in SPP (pre-operative 43.56±7.9 vs postoperative 29.96±7.7 cm of saline), splenic size (6.5±2.8 vs 4.00±2.6 cm below costal margin) and varices grades (2.96±0.5 vs 0.92±0.8). Patients with blocked shunt (n= 9) did not show significant reduction in SPP and varices grades. However, there was reduction in spleen size (8.6±3.0 vs 6.3±4.3). In the NCPF group, 28 had patent shunts and showed significant reduction in SPP (46.3±13.5 vs 33.8±7.6 cm of saline), splenic size (9.1±3.3 vs 6.8±4.6 cm below costal margin) and varices grades (2.8±0.7 vs 1.05±0.96). As only two patients with NCPF had blocked shunts, no statistical comparison between patients with patent and patients with blocked shunts could be done. In conclusion, following SSLR, there is a significant reduction in SPP and varices grades in patients with patent shunts. Endoscopic grading of varices can be used to predict shunt patency. However, spleen size is not a good criteria for predicting shunt patency.     

Altered alpha adrenergic vasoresponsiveness in a non-cirrhotic portal hypertension model of E. coli injection

BACKGROUND AND AIM: Portal hypertension is associated with decreased vascular responsiveness to vasoconstrictors, which may contribute to the hyperdynamic circulation in cirrhosis. Animal models of cirrhosis and portal vein ligation have helped in our understanding of portal hypertension. The etiopathogenesis of non-cirrhotic portal fibrosis (NCPF), a common cause of portal hypertension, is still poorly understood. The aim of this study was to investigate the pathophysiology of NCPF in a rabbit model. METHODS: An indwelling cannula was inserted into the gastrosplenic vein of rabbits. Animals were randomly injected with saline (Group I, n = 13) or lipopolysaccharide (Group II, n = 13) from heat killed Escherichia coli at 0, 1, 2, 7, 14 and 28 days. Portal pressure was measured at 3 months and vasoresponsiveness studied in isolated aortic rings in intact and in endothelium-denuded tissues from both groups. RESULTS: In all group II compared with group I animals, the splenic weight (0.89 +/- 0.16 vs 0.62 +/- 0.1 g, P < 0.05) and the portal pressure (14.99 +/- 0.56 vs 7.04 +/- 0.42 mmHg, P < 0.05) were higher at 3 months. The group II animals showed reduced responsiveness to phenylephrine showing maximal contraction of 1.25 +/- 0.08 at 10(-4) mol/L as compared to 2.85 +/- 0.33 g tension in Group I (P < 0.05). Endothelium denudation of aortic rings had no effect on reduced reactivity in Group II animals. Acetylcholine induced an increase in vasorelaxation at lower concentrations in preconstricted aortic rings in Group II compared to Group I animals, but this decreased in higher concentrations. Nifedipine produced comparable vasodilatation in preconstricted rings in both the groups of animals. CONCLUSIONS: Repeated injection of lipopolysaccharide into the gastrosplenic vein leads to the development of portal hypertension. This non-cirrhotic model of portal hypertension is characterized by generalized arterial hyporeactivity to vasoconstrictors akin to other models of portal hypertension.     

Variceal pressure is a strong predictor of variceal haemorrhage in patients with cirrhosis as well as in patients with non-cirrhotic portal hypertension

BACKGROUND: Variceal pressure is a strong predictor for a first variceal bleed in patients with cirrhosis. AIMS: To evaluate whether variceal pressure is also a determinant of the risk of a first variceal bleed in patients with non-cirrhotic portal hypertension. METHODS: Variceal pressure was measured non-invasively in 25 patients with non-cirrhotic portal hypertension and large varices while receiving a stable therapeutic regimen. Factors predictive of bleeding were compared with those observed in 87 cirrhotics. RESULTS: The one year incidence of variceal bleeding was 32% (n=28) for the cirrhotic and 20% (n=5) for the non-cirrhotic patients. There was no difference in factors predicting the risk of bleeding between the groups, except for variceal pressure. For the same level of variceal pressure, the risk of variceal bleeding was lower in patients with non-cirrhotic portal hypertension. Multiple logistic regression analysis revealed the following variables as having a significant predictive power: variceal pressure (p=0.0001), red spots (p=0.004), and the time interval between the first observation of the varices and the moment of variceal pressure measurement (p=0. 0046). For the non-cirrhotics the risk of bleeding increased with higher Child-Pugh score (p=0.0024); this was not the case for the cirrhotic patients (p=0.9521). CONCLUSION: Variceal pressure is a major predictor of variceal bleeding in patients with cirrhosis as well as in patients with non-cirrhotic portal hypertension. The risk of bleeding in non-cirrhotics is less than in cirrhotics for the same level of variceal pressure. In patients with non-cirrhotic portal hypertension the risk of variceal bleeding increases more with advancing disease.     

Liver pathology of idiopathic portal hypertension. Comparison with non-cirrhotic portal fibrosis of India The Japan idiopathic portal hypertension study*,+

ABSTRACT— Morphological changes of the liver were studied in 24 autopsy cases of noncirrhotic portal hypertension of unknown etiology (idiopathic portal hypertension, IPH), and in 123 surgical biopsies from such patients. For comparison, 15 whole-cut liver slices from autopsy cases of noncirrhotic portal fibrosis (NCPF) from India were also studied. Liver pathology was very similar in IPH and NCPF, characterized by phlebosclerotic changes and perivascular fibrosis of the portal vein system, and parenchymal atrophy perhaps secondary to portal circulatory insufficiency. The distribution of lesions was uneven, and despite marked fibrosis and occasional surface nodularity, there was no diffuse pseudonodule formation in the parenchyma. Surgical specimens showed similar changes except for more frequent portal cellular infiltrates, but the changes seen in one biopsy specimen were limited and not always diagnostic. It seems that IPH of Japan and NCPF of India are the same disease, and perhaps hepatoportal sclerosis elsewhere is also the same disease.     

特发性非肝硬化门静脉高压症诊治进展

特发性非肝硬化门静脉高压症(idiopathic non-cirrhotic portal hypertension,INCPH)是一种罕见疾病,特点是在无肝硬化、无其他导致肝脏疾病的病因以及无内脏静脉血栓病因存在的情况下,出现的门静脉高压.该病的发病机制尚不清楚,但其病理学特征明显有别于肝硬化.在临床实践中,INCP...     

重视非肝硬化性门静脉高压的诊断和治疗

非肝硬化性门静脉高压(NCPH)是指除肝硬化外多种疾病导致的门静脉高压症。NCPH常见的原因有门静脉血栓形成、先天性肝纤维化和特发性门静脉高压等。这组疾病的主要特点是门静脉高压相关的表现突出,而肝功能储备相对较好,鉴别该类疾病需要临床,影像学和病理学的深入检查。通过适当的内外科治疗,多数患者预后较好。     

Non-cirrhotic portal fibrosis (idiopathic portal hypertension): experience with 151 patients and a review of the literature

BACKGROUND: Non-cirrhotic portal fibrosis (NCPF), the equivalent of idiopathic portal hypertension in Japan and hepatoportal sclerosis in the United States of America, is a common cause of portal hypertension in India. The clinical features, portographic and histological findings, and management of 151 patients with non-cirrhotic portal fibrosis are presented. METHODS: The disease is diagnosed by the presence of unequivocal evidence of portal hypertension in the definite absence of liver cirrhosis and extrahepatic portal vein obstruction (EHPVO). Retrospective analysis of records of 151 patients with NCPF was analyzed for the clinical presentation, physical findings, laboratory tests, radiological and histological findings, and for the outcome of treatment. RESULTS: The disease is characterized by massive splenomegaly with anemia, preserved liver function and benign prognosis in a majority of patients. Splenoportovenography (SPV) showed massive dilatation of the portal and splenic veins, and the presence of collaterals. Twenty-four (15.9%) patients showed evidence of natural/spontaneous shunts (splenorenal 15, umbilical nine) on SPV; these patients had a lower incidence of variceal bleeding. Liver histology demonstrated maintained lobular architecture, portal fibrosis of variable degree, sclerosis and obliteration of small-sized portal vein radicles, and subcapsular scarring with the collapse of the underlying parenchyma. Piecemeal or hepatocytic necrosis was absent in all histology specimens. Three patients showed nodular transformation along with abnormal liver functions, and may represent late manifestation of NCPF where features are similar to those seen in patients with incomplete septal cirrhosis. In the initial part of the study, surgery (side-to-side lieno-renal shunt) was the preferred modality of treatment, however, endoscopic sclerotherapy or variceal ligation has now become the preferred first line of management of variceal bleeding. CONCLUSIONS: The epidemiological and clinical features of NCPF have more similarity to IPH than has previously been documented. The development of spontaneous shunts tends to protect these patients from variceal bleeding.     

特发性非肝硬化性门脉高压1例并文献复习

<正>特发性非肝硬化性门脉高压(idiopathic non-cirrhotic portal hypertension,INCPH)是一种血管性疾病,临床表现为门脉高压的一系列症候,但缺乏肝硬化的病理学表现,约占门脉高压症患者的10%。因缺乏相对特异的诊断标准,易误诊。现报道1例我科诊治的以脾功能亢进症为首发症状的、经13年就医路终确诊的INCPH患者,以期提高临床医师对该病的诊治水平。1病例摘要患者女,68岁。主因“发现脾肿大13年,间断腹泻8月”于2020年9月9日入院。患者于13年前因“急性胆囊炎、胆囊结石”于我院普外科行手术治疗,     

Repeated endoscopic sclerotherapy of oesophageal varices due to non-cirrhotic portal fibrosis using intravariceal polidocanol

Forty patients with variceal bleeding due to non-cirrhotic portal fibrosis have been treated by repeated endoscopic injection sclerotherapy using intravariceal polidocanol (1%). This has decreased re-bleeding as evidenced by a decrease in mean bleeding risk factor (BRF) and transfusion requirement; difference between presclerotherapy and postsclerotherapy parameters were significant ( P < 0.001). Low doses of polidocanol (mean 13.2 ml per session) were effective in the obliteration of varices. The mean sclerotherapy sessions required for obliteration were 8.04 (s.d. = 2.24). Complications were infrequent. Cumulative survival for 4 years was 92.5%. Based on these results endoscopic sclerotherapy is recommended for managing variceal bleeding due to non-cirrhotic portal fibrosis and is a reasonable alternative to surgery.     

Natural history of patients with non cirrhotic portal hypertension: Comparison with patients with compensated cirrhosis

BackgroundThe knowledge of natural history of patients with portal hypertension (PH) not due to cirrhosis is less well known than that of cirrhotic patients.AimTo 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.MethodsThe 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.ResultsAt 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).ConclusionsIn 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.     

特发性非肝硬化门静脉高压症患者肝脏影像学和病理学特征分析

目的 分析特发性非肝硬化门静脉高压症(INCPH)患者肝脏影像学和病理学特征,并与肝硬化的鉴别要点。方法 2016年1月～2021年7月我院收治的INCPH患者16例和乙型肝炎肝硬化患者28例,常规进行超声、CT和MRI及肝穿刺活检检查。结果 INCPH与肝硬化患者在影像学检查发现的弥漫性结节样改变(0.0%对35.7%)、门静脉直径【9.7(7.2,11.6)mm对13.6(9.2,15.7)mm】、门静脉壁厚【2.6(1.4,4.0)mm对1.4(1.1,1.6)mm】方面比较,差异具有统计学意义(P<0.05);肝组织学检查发现,INCPH与肝硬化患者在门静脉区域纤维化、肝膈膜纤维化、肝小叶间静脉闭塞、肝细胞坏死和肝细胞水肿或脂肪变性方面【分别为100.0%对0.0%、18.7%对92.8%、56.2%对10.7%、0.0%对75.0%和12.5%对89.3%】,差异具有统计学意义(P<0.05)。结论 INCPH仍是一种病因不明的疾病,注意分析影像学和组织病理学特征可以作出与肝硬化的鉴别诊断。     

Comparative efficacy of emergency endoscopic sclerotherapy for active variceal bleeding due to cirrhosis of the liver, non-cirrhotic portal fibrosis and extrahepatic portal venous obstruction

Patients with continued variceal bleeding due to portal hypertension (n = 202) were treated by endoscopic injection sclerotherapy after resuscitation. Portal hypertension was due to hepatic cirrhosis in 123, non-cirrhotic portal fibrosis (NCPF) in 49 and extrahepatic portal venous obstruction (EHO) in 30 patients. Polidocanol 1% was injected intravariceally. An adequate sclerotherapy was carried out in 97% of patients. Immediate haemostasis was achieved in 177 (88%) patients. Rebleeding occurred in 31 (17.5%) of 177 patients. By reinjection of varices, definitive control of bleeding occurred in 160 (79%) patients. There was no significant difference in terms of immediate control of bleeding in patients with different aetiologies of portal hypertension and hepatic functional status (Child's grade). Rebleeding episodes were lower in patients with EHO than cirrhosis of the liver and NCPF. Similarly, the Child's status significantly influenced the recurrence of bleeding which was lower in Child's A than B and B than C. The in-hospital mortality was 18.6%. This was also significantly related to Child's status and aetiology of portal hypertension. Minor complications occurred in 10.4% of patients. It is concluded that endoscopic sclerotherapy as the first line of treatment is an effective and technically feasible procedure for the control of active variceal bleeding, regardless of the cause of portal hypertension. Furthermore, the results were influenced by the aetiology of portal hypertension and hepatic functional status.     

Characterization of peripheral blood lymphocytes in patients with non-cirrhotic portal fibrosis: A comparison with cirrhotics and healthy controls

Non-cirrhotic portal fibrosis (NCPF) is a common cause of portal hypertension in India. Its aetiopathogenesis is not well understood. To investigate the possibility of an immune mediated injury, phenotypes of peripheral blood lymphocytes were studied in 15 NCPF patients and were compared with an equal number of compensated cirrhotics and matched healthy controls. The population of total peripheral T lymphocytes (T1) and suppressor/cytotoxic phenotype (T8) was significantly (P less than 0.01) decreased in NCPF patients compared with controls. The sub-populations of helper/inducer lymphocytes (T4) and total B lymphocytes, however, were comparable with controls. The ratio of T4 to T8 lymphocytes was significantly (P less than 0.01) increased in NCPF patients in comparison with controls. Similar changes in the lymphocyte population were also observed in cirrhotic patients. Further investigations are required to identify whether the cellular alterations seen in NCPF have a pathogenetic basis or are secondary to the disease process itself.     

Non-cirrhotic portal fibrosis: current concepts and management

Non-cirrhotic portal hypertension (NCPH) comprises diseases having an increase in portal pressure (PP) due to intraheptic or prehepatic lesions, in the absence of cirrhosis. The lesions are generally vascular, either in the portal vein, its branches or in the perisinusoidal area. Because the wedged hepatic venous pressure is near normal, measurement of intravariceal or intrasplenic pressure is needed to assess PP. The majority of diseases included in the category of NCPH are well-characterized disease entities where portal hypertension (PHT) is a late manifestation and, hence, these are not discussed. Two diseases that present only with features of PHT and are common in developing countries are non-cirrhotic portal fibrosis (NCPF) and extrahepatic portal vein obstruction (EHPVO). Non-cirrhotic portal fibrosis is a syndrome of obscure etiology, characterized by 'obliterative portovenopathy' leading to PHT, massive splenomegaly and well-tolerated episodes of variceal bleeding in young adults from low socioeconomic backgrounds, having near normal hepatic functions. In some parts of the world, NCPF is called idiopathic portal hypertension (IPH) or 'hepatoportal sclerosis'. Because 85-95% of patients with NCPF and EHPVO present with variceal bleeding, treatment involves management with endoscopic sclerotherapy (EST) or variceal ligation (EVL). These therapies are effective in approximately 90-95% of patients. Gastric varices are another common cause of upper gastrointestinal bleeding in these patients and these can be managed with cyanoacrylate glue injection or surgery. Other indications for surgery include failure of EST/EVL, and symptomatic hypersplenism. The prognosis of patients with NCPF is good and 5 years survival in patients in whom variceal bleeding can be controlled has been reported to be approximately 95-100%.