Natural history of a randomized trial comparing distal spleno-renal shunt with endoscopic sclerotherapy in the prevention of variceal rebleeding： A lesson from the past

INTRODUCTION The selective distal splenorenal shunt (DSRS) proposed by Warren[1] in 1967 has been considered to be the best procedure available for surgical decompression of patients with portal hypertension[2-4]. DSRS has been compared with sclerotherapy…     

Results of distal splenorenal shunt with versus without splenopancreatic disconnection

From December 1973 to December 1987, we performed a distal splenorenal shunt (DSRS) in 112 cases of portal hypertension, including 107 with postnecrotic liver cirrhosis and 5 with idiopathic portal hypertension (IPH). They comprised about 50% of our surgical cases with esophageal varices. In 1981, we modified our operative procedure towards a more extended splenopancreatic disconnection (SPD) in order to prevent the "stealing" of the shunt through the pancreatic vein. In one group of 69 patients who underwent DSRS alone, the operative mortality was 2.9%; postoperative encephalopathy was seen in 17.4%, late hepatic failure in 40.6%, and recurrence of varices in 4.3%. In the other group, 43 patients who underwent DSRS with SPD, there were no operative deaths, no encephalopathy (better than DSRS alone at p less than 0.05), and late hepatic failure was seen in only 9.3% (better than DSRS alone at p less than 0.025), while the recurrence rate of 7% was the only statistical increase. These data show that DSRS + SPD can improve chances of survival.     

Non-cirrhotic portal hypertension versus idiopathic portal hypertension

Portal hypertension occurs in a number of disorders other than cirrhosis and they are collectively called non-cirrhotic portal hypertension (NCPH). The common causes of NCPH include idiopathic portal hypertension (IPH), non-cirrhotic portal fibrosis (NCPF) and extrahepatic portal venous thrombosis (EHPVT). Other causes include schistosomiasis, hepatic venous outflow tract obstruction, veno-occlusive disease and congenital hepatic fibrosis. Patients with IPH and EHPVT present with upper gastrointestinal bleeding, splenomegaly, ascites after gastrointestinal bleeding, features of hypersplenism, growth retardation and jaundice due to portal biliopathy. The diagnosis is usually made by abdominal ultrasound, upper gastrointestinal endoscopy, normal liver function tests and normal liver histology. Variceal bleeding in NCPH has lower mortality as compared with cirrhosis because of better liver functions in NCPH. Treatment for NCPH includes primary prophylaxis for variceal bleeding and prevention of repeat bleeding using drugs like beta-blockers, endoscopic sclerotherapy and endoscopic band ligation of varices. In patients with uncontrolled variceal bleeding or symptomatic hypersplenism, porto-systemic shunt surgery or splenectomy are required.     

Idiopathic portal hypertension and its pathology

Idiopathic portal hypertension (IPH) is a disorder of unknown etiology, clinically characterized by portal hypertension (varices and portosystemic collateral vessels), splenomegaly, and anemia (hypersplenism). A similar disorder is called noncirrhotic portal fibrosis in India, and hepatoportal sclerosis seems to be the counterpart in the United States. This disease is uncommon in developed countries. Middle-aged women are more prone to IPH in Japan. The liver has no cirrhosis or pseudonodule formation, and the principal pathologic changes are considerable portal fibrosis, devastation of intrahepatic terminal portal radicles, and parenchymal atrophy of the liver secondary to portal malperfusion. The characteristic portal hemodynamics include intrahepatic presinusoidal portal hypertension, increased splenic and portal vein blood flow, and increased intrahepatic portal resistance. The prognosis is generally good depending on the management of bleeding varices. Although the etiology is obscure, certain immunologic abnormalities seem to play an etiologic role in Japanese patients, and the incidence has markedly declined in recent years in Japan, indirectly suggesting a role of infection. The theory that IPH represents an undiagnosed intrahepatic portal vein thrombosis is refuted.     

Fundal varices: problem and management.

BACKGROUND/AIMS: The pathophysiology of gastric varices may be due to generalized or segmental portal hypertension. A considerable debate has arisen regarding the role of injection sclerotherapy in the pathogenesis of gastric varices. METHODOLOGY: During the period from 1987 to 1997, a total of 1686 cases with bleeding varices were presented to our center and 225 cases (13.3%) with bleeding gastric varices were diagnosed. There were 198 males and 27 females with a total mean age of 45.7 years (+/- 7.6). Primary fundal varices (FV) were found in 121 (54%) cases and secondary FV were found in 104 (46%) cases. All patients with isolated FV presented with repeated attacks of upper gastrointestinal bleeding. RESULTS: The pathological diagnosis was studied in 120 cases; it was schistosomal in 8.3% of cases, non-schistosomal in 33.3% of cases, and mixed (Schistosomal with post viral cirrhosis) in 58.3% of cases. Seventy-five cases were subjected to splenectomy and gastroesophageal decongestion (SGED), 64 cases were subjected to distal splenorenal shunt (DSRS), and 86 cases were subjected to sclerotherapy. Mortality after DSRS was 7.8%, after SGED it was 12%, and after sclerotherapy it was 21%. Rebleeding was the major complication and occurred in 3% after DSRS, in 13% after SGED, and in 18% of cases after sclerotherapy. CONCLUSIONS: Gastric varices are not an uncommon condition as a cause of upper gastrointestinal bleeding. Our findings support the hypothesis that gastric varices may be considered a late sequel of injection sclerotherapy, though they may also be considered as one of the pathophysiologies of generalized portal hypertension. Finally, DSRS was found to be the treatment of choice in the management of fundal varices.     

特发性门脉高压症凝血指标分析

研究特发性门脉高压症（IPH）和肝硬化患者的凝血酶原时间（PT）和凝血酶原标准化比率（INR）、活化部分凝血活酶时间（APTT）和纤维蛋白原（Fib）。分析其异常的原因及在IPH发病中的作用。收集IPH患者40例、肝硬化患者41例和正常对照组18例。结果IPH患者和肝硬化患者与正常组相比均存在明显的凝血异常,有轻度DIC发生。IPH凝血异常可能是感染引起的内毒素血症激活了凝血机制所致,凝血异常可引起肝内门脉微血栓形成,与其它原因所致的肝内门脉损伤,共同导致了IPH的发生。     

Long-term follow-up study of adult patients with non-cirrhotic obstruction of the portal system: comparison with cirrhotic patients.

Thirty-two patients with non-cirrhotic portal system obstruction and oesophageal varices of non-malignant etiology were recruited over 13 years. Diagnosis was based on the presence of oesophageal varices at endoscopy, minor alterations in liver function tests and liver histology, a low hepatic venous pressure gradient, and pertinent angiographic patterns. Twenty-three had portal vein thrombosis, nine had splenic vein thrombosis. Twenty-one had idiopathic portal vein obstruction, 11 had secondary obstruction. The outcome was compared with a group of 32 patients with cirrhosis and portal hypertension, matched for age, Child-Pugh class, previous history of gastrointestinal bleeding, and size of oesophageal varices. Patients with non-cirrhotic obstruction of the portal system were followed for up to 171 months (mean 94 months). During follow-up ten patients had gastrointestinal bleeding, and eight died (five of gastrointestinal bleeding). After 6 years of follow-up, the cumulative risk of gastrointestinal bleeding was 24%, the cumulative risk of death was 17%, and the cumulative risk of death from gastrointestinal bleeding was 14%. Cumulative probability of death by any cause and the probability of gastrointestinal bleeding were significantly lower in patients with non-cirrhotic obstruction of the portal system than in patients with cirrhosis comparable for liver function and portal hypertension (p = 0.04 for both). The cumulative probability of death by gastrointestinal bleeding was not significantly different. In conclusion, the prognosis for non-cirrhotic obstruction of the portal system is significantly better than for patients with cirrhosis with comparable levels of liver function impairment and severity of portal hypertension.     

Characteristics, prognosis and outcome of patients with oesophageal varices in a university hospital in Sweden 1994-1999

OBJECTIVE: Patients with liver cirrhosis, portal hypertension and oesophageal varices are known to have high morbidity and mortality. The knowledge of incidence, aetiology and outcome in Sweden in recent years is limited. MATERIAL AND METHODS: All patients with oesophageal varices diagnosed for the first time at Sahlgrenska University Hospital during the 6-year period 1994-1999 were retrospectively studied. Information about the aetiology of liver cirrhosis and oesophageal varices, as well as about the proportion of bleeding and non-bleeding varices, endoscopic and pharmacological treatment and outcome, was analyszed. RESULTS: 312 patients were retrieved, 297 with liver cirrhosis (197 diagnosed before first bleeding (P), 92 after bleeding (B) and 8 at autopsy) and 15 with portal vein thrombosis without cirrhosis. Fifty-four percent had alcoholic liver disease. Fifty-five percent in group B and 13% in group P had at least one bleeding episode during follow-up (p<0.001). There was no significant difference in survival between groups B and P. Twenty-six percent of the cirrhotics died of liver failure and 19% from variceal bleeding. In a multivariate analysis, variables predicting mortality were: Child-Pugh class, group B, age and bilirubin levels. CONCLUSIONS: Variceal bleeding is still a strong risk factor for recurrent bleeding, but few die from their first bleeding. This concurs with studies indicating declining mortality from variceal bleeding. However, this patient group still has a high mortality from other causes.     

Beneficial long term effect of a phosphodiesterase-5-inhibitor in cirrhotic portal hypertension: A case report with 8 years follow-up

Non-selective beta-blockers are the mainstay of medical therapy for portal hypertension in liver cirrhosis. Inhibitors of phosphodiesterase-5(PDE-5-inhibitors) reduce portal pressure in the acute setting by 10% which may suggest a long-term beneficial effect. Currently, there is no available data on long-term treatment of portal hypertension with PDE-5-inhibitors. This case of a patient with liver cirrhosis secondary to autoimmune liver disease with episodes of bleeding from esophageal varices is the first documented case in which a treatment with a PDE-5-inhibitor for eight years was monitored. In the acute setting, the PDE-5-inhibitor Vardenafil lowered portal pressure by 13%. The portal blood flow increased by 28% based onDoppler sonography and by 16% using MRI technique. As maintenance medication the PDE-5-inhibitor Tadalafil was used for eight consecutive years with comparable effects on portal pressure and portal blood flow. There were no recurrence of bleeding and no formation of new varices. Influencing the NO-pathway by the use of PDE-5 inhibitors may have long-term beneficial effects in compensated cirrhosis.     

Idiopathic portal hypertension associated with systemic lupus erythematosus

A case of idiopathic portal hypertension (IPH) associated with systemic lupus erythematosus (SLE) is reported in a 38-year-old man who had been diagnosed with SLE and treated for 18 years. Esophageal varices, found in 1994 on endoscopic examination, had been followed up for 2 years. On July 16, 1996, he was admitted to Nagoya University Hospital because there was a high risk of bleeding from the esophageal varices due to severe thrombocytopenia. As partial splenic embolization had temporarily controlled the thrombocytopenia, splenectomy and devascularization of the stomach vessels were performed after endoscopic ligation of the esophageal varices. Histological specimens of wedge biopsied liver showed chronic inactive hepatitis without cirrhosis. The presence of anticardiolipin antibody, indicated by positivity for lupus anticoagulant, was suggestive of the presence of a common immunological mechanism in the etiology of SLE and IPH. Received: January 20, 1999 / Accepted: July 23, 1999     

Splenic venous hemodynamics in portal hypertension]

The percentage of splenic blood in portal venous flow (SV%) was measured in 96 patients by using scintiphotosplenoportography and angiography. The patients were divided into two groups: Group 1, without collateral pathways from the splenic vein; Group 2, with collateral pathways from the splenic vein. SV% was significantly lower in patients without liver diseases or in patients of Group 1 with liver cirrhosis (LC). SV% was significantly higher in patients with idiopathic portal hypertension (IPH). A significant correlation was observed between SV% and splenic volume or ICGR15. No significant correlation of SV% was found with etiology of LC in patients of Group 1, esophagogastric varices, Child's criteria, portal venous pressure, cholinesterase, hepaplastin test or prothrombin time. Hence, the local hyperdynamic state of the splenic region was detected in patients with CH, LC and IPH.     

特发性门脉高压肝移植术后随访第3年再发1例报告及文献复习

目的 复习1例特发性门脉高压(IPH)患者接受肝移植(LT)后第3年出现病情“再发”,并进行了相关文献复习,以提高对该病的认识。方法 报道1例我们诊治的IPH患者的病例资料,并检索MEDLINE、EMBASE、万方等数据库经LT治疗的IPH患者的研究报道,分析其治疗和转归。结果 本文报道的病例为57岁女性,因消化道出血、腹水行LT术,组织病理学检查诊断为IPH;术后随访第3年病情复发,行经皮肝穿刺活检术,病理学检查提示结节性再生性增生(NRH)、轻度汇管区炎症及纤维化,提示IPH再发;文献检索到81例LT治疗的IPH患者,其中42例在LT前诊断为肝硬化;LT后最长随访时间为248个月,8例死亡,其中5例分别在首次LT后3.5月～14年进行肝活检,组织病理学检查提示NRH,3例分别于LT后第7月、第3年和第14年出现具有门脉高压表现的NRH。结论 具有严重的门脉高压或肝功能衰竭的IPH患者需要LT治疗。少数患者在LT后可能出现IPH“再发”。     

Mixed connective tissue disease associated with idiopathic portal hypertension and chronic thyroiditis

We report a patient with mixed connective tissue disease (MCTD) associated with idiopathic portal hypertension (IPH) and chronic thyroiditis. The patient was a 68-year-old Japanese woman who was admitted to our hospital for treatment of bleeding esophageal varices. She had previously exhibited Raynaud's phenomenon and had had arthritis for about 30 years. She also had had high titers anti-U1 of ribonucleoprotein (RNP) anti-single strand-DNA autoantibodies for 2 years, and had been diagnosed with MCTD 1 year previously. The bleeding from esophageal varices was successfully stopped by endoscopic injection sclerotherapy. Results of laboratory examinations, imaging examinations, and laparoscopy, including liver biopsy, indicated that the esophageal varices were caused by portal hypertension due to IPH. The patient also had a diffusely firm and enlarged goiter and hypothyroidism, and she exhibited anti-thyroid microsomal antibodies and anti-thyroglobulin antibodies, she was diagnosed as having a complication of chronic thyroiditis. This association of MCTD, IPH, and chronic thyroiditis is quite rare and provides a unique opportunity to observe immunological involvement in the pathogenesis of IPH.     

Outcome of cystic fibrosis-associated liver cirrhosis: management of portal hypertension.

BACKGROUND/AIM: Variceal bleeding is the most severe complication in patients with cystic fibrosis-associated liver cirrhosis, who often do not have severe respiratory failure. The advent of liver transplantation has broadened the treatment options. The purpose of this study was to report our experience with the management of portal hypertension. METHODS: Clinical and biochemical features, outcome of liver disease and management of portal hypertension were analyzed retrospectively in 44 children with cystic fibrosis-associated liver cirrhosis. RESULTS: The mean age at diagnosis of liver cirrhosis was 9 years. Eighty-six per cent of the children developed esophageal varices, 50% of whom bled early in their second decade. Injection sclerotherapy of esophageal varices did not prevent recurrence of bleeding in five of seven children. Elective surgical portosystemic shunting was successfully performed in nine of 11 patients considered being at high risk of bleeding or with recurrent bleeding episodes but without severe pulmonary failure and liver dysfunction, allowing prolonged post-operative survival up to 15 years. Two of three children who underwent isolated liver transplantation for severe portal hypertension died post-operatively. CONCLUSIONS: Management emphasis in cystic fibrosis patients with liver cirrhosis should be on control of bleeding and variceal decompression. These results suggest that surgical portosystemic shunting may be considered to relieve portal hypertension in patients without progressive liver failure and severe lung disease as an alternative to liver transplantation. With this policy, patients may be stabilized for many years until progression of liver or lung diseases indicates liver or lung-liver transplantation.     

Study of portal vein thrombosis in patients with idiopathic portal hypertension in Japan.

BACKGROUND/AIMS: The aim of this study was to elucidate the incidence and clinical manifestations of portal vein thrombosis (PVT) in patients with idiopathic portal hypertension (IPH) in Japan during long-term follow-up. PATIENTS AND METHODS: Twenty-two patients with IPH were examined for PVT by sonography during a follow-up of 12+/-6 years. Clinical manifestations and patient outcome related to PVT were studied. Seventy patients with liver cirrhosis were examined by sonography as an incidence control of thrombosis. RESULTS: Nine IPH patients had portal thrombosis (9/22, 41%), a higher incidence than in liver cirrhosis patients (7/70, 10%). Those with thrombosis showed ascites, marked hypersplenism, and low serum albumin. Four patients with thrombosis died. Patients without thrombosis showed less clinical problems after long-term follow-up. Plasma antithrombin III and protein C activity decreased in almost half of the patients. However, there were no differences in these parameters between patients with and without thrombosis. CONCLUSIONS: In Japan, IPH patients had a high incidence of portal thrombosis, a significant factor for poor prognosis. Whether the management of PVT contributes to an improvement of a clinical course of IPH or not should be clarified in further study.     

Case of idiopathic portal hypertension complicated with autoimmune hepatitis

We report a case of idiopathic portal hypertension (IPH) complicated with autoimmune hepatitis. A 60‐year‐old woman was admitted to our hospital with esophageal and gastric varices in February 2010. Abdominal ultrasonography and computed tomography showed splenomegaly and collateral veins without evidence of liver cirrhosis. Laboratory examinations and liver biopsy indicated that the esophageal and gastric varices were caused by IPH. She underwent endoscopic injection sclerotherapy and partial splenic embolization. Two years after these therapies, laboratory examinations showed liver dysfunction with elevated levels of aspartate aminotransferase (180 IU/L), alanine aminotransferase (190 IU/L), γ‐glutamyl transpeptidase (159 IU/L) and immunoglobulin G (2609 mg/dL). The titer of antinuclear antibodies was 1:320 and its pattern was homogeneous and speckled. Histological examination revealed plasma cell/lymphocyte infiltration and interface hepatitis in the portal tract. Based on these findings, a diagnosis of autoimmune hepatitis accompanied by IPH was made. After treatment with prednisolone (20 mg/day), liver functions were normalized immediately. Overlapping of IPH and AIH is extremely rare, but the present case is interesting considering the etiology of IPH because an autoimmune mechanism is thought to be involved in the pathogenesis of IPH.     

特发性门脉高压症的临床病理学特点

目的 探讨特发性门脉高压症(idiopathic portal hypertension,IPH)的临床病理学特点.方法 回顾性分析了9例IPH的临床及病理学资料,并对其肝脏标本进行常规病理学及免疫组化研究.结果 9例IPH中,5例首发症状为上消化道出血和黑便,3例体检发现脾大脾亢而无临床症状,1例以血管瘤入院.人院检查脾肿大7例,胃底食道静脉曲张6例,腹水征4例,贫血者6例,肝功能正常或接近正常9例.病理组织学显示9例肝小叶结构基本正常.均未见假小叶形成及肝细胞坏死;9例均有不同程度汇管区纤维化,3例汇管区纤细的不全纤维间隔形成并向肝实质延伸,6例有门脉末支管壁纤维化;9例中有6例小叶内肝细胞有不同程度的水肿变性,5例肝窦有不同程度的扩张,2例肝窦扩张较明显,肝细胞萎缩,呈血管瘤样结构,2例有轻-中度肝腺胞3区大泡脂变.脾脏组织学符合淤血性脾肿大病理表现.结论 IPH的临床表现与其他原因所致的肝硬化门脉高压相似,肝穿组织病理学可除外肝硬化,并有一定的特征.诊断时应与各种原因所致肝硬化门脉高压,肝窦阻塞综合征等相鉴别.     

Acute Deterioration of Idiopathic Portal Hypertension Requiring Living Donor Liver Transplantation: A Case Report

Case reports of severe idiopathic portal hypertension (IPH) requiring liver transplantation are very rare. We report the case of a 65-year-old woman who was diagnosed as having IPH. At the age of 60 years, her initial symptom was hematemesis, due to ruptured esophageal varices. Computed tomography of the abdomen showed splenomegaly and a small amount of ascites, without liver cirrhosis. She was diagnosed as having IPH and followed-up as an outpatient. Five years later, she developed symptoms of a common cold and rapidly progressive abdominal distension. She was found to have severe liver atrophy, liver dysfunction, and massive ascites. Living donor liver transplantation was then performed, and her postoperative course was uneventful. Histopathological findings of the explanted liver showed collapse and stenosis of the peripheral portal vein. The areas of liver parenchyma were narrow, while the portal tracts and central veins were approximate one another, leading to a diagnosis of IPH. There was no liver cirrhosis. The natural history of refractory IPH could be observed in this case. Patients with end-stage liver failure due to severe IPH can be treated by liver transplantation.     

Idiopathic portal hypertension in a systemic sclerosis patient heterozygous for factor V Leiden mutation

Here we present a rare case of systemic sclerosis (SSc) with idiopathic portal hypertension (IPH) having factor V Leiden mutation, a well-known genetic risk factor for various venous thromboses. A 53-year-old SSc patient showing huge esophageal varices and splenomegaly without liver cirrhosis was diagnosed with IPH. As heterozygous Leiden mutation was detected, some coagulation abnormality and resultant formation of microthrombi in the branches of portal vein were suggested as a cause of IPH in this case. This is the first report showing the possible association between Leiden mutation and one of the complications of SSc.