Pathology and pathogenesis of portal venopathy in idiopathic portal hypertension: Hints from systemic sclerosis

Idiopathic portal hypertension (IPH) is a non-cirrhotic presinuosidal portal hypertension of unknown etiology. Stenosis of smaller portal veins with portal fibrosis is a pathologic hallmark of IPH. Association of systemic sclerosis (SSc) with IPH is recognized, and similar pathologic features are reported in small portal tracts and skin of IPH and SSc, respectively. In addition, levels of transforming growth factor-β (TGF-β) and connective tissue growth factor are elevated in serum and in affected skin and portal tracts of these two diseases, suggesting that IPH share fibrogenetic mechanisms with SSc. Endothelial to mesenchymal transition (EndMT) of microvasculatures of skin could be responsible for dermal fibrosis in SSc. In IPH, EndMT of portal vein endothelium via TGF-β/Smad activation may also be involved in small portal venpathy. In IPH, enhanced expression of pSmad2 in venous endothelium of smaller portal veins was associated with reduced CD34 expression. CD34 and S100A4, and CD34 and type I collagen were colocalized to portal vein endothelium in IPH. Such myofibroblastic phenotypes may be responsible for periportal-venous deposition of collagen and compressive portal venous obliteration. These small portal venous lesions may in turn lead to portal venous insufficiency followed by subcapsular atrophy in IPH.     

Portal and pulmonary hypertension in a patient with MCTD]

A 42-year-old woman with mixed connective tissue disease (MCTD) died due to the rupture of esophageal varices. The autopsy revealed fresh thrombi in the main trunk of the portal vein. Microscopic examination disclosed wide-spread periportal fibrosis and stenosis of peripheral portal veins without remodeling of hepatic lobular architecture, which was compatible to idiopathic portal hypertension (IPH). Anti-phospholipid antibody was negative. Accordingly it is likely that portal vein thrombosis developed secondary to IPH. In the literature 6 (37.5%) of 16 collagen vascular disease patients with IPH died, and three of them were due to rupture of esophageal varices. Therefore IPH should be considered to be one of the most important complications affecting its grave prognosis in patients with collagen vascular disease. The patient also had had pulmonary hypertension (PH) when the diagnosis of portal hypertension was made. In the literature we found 5 collagen vascular disease patients with both PH and IPH like this case. The most outstanding common clinical feature among these 6 patients was Raynaud's phenomenon associated with positive anti-RNP antibody. Moreover 5 of 6 cases including this case simultaneously developed both PH and IPH. The clinical course of these patients suggests there may be a common pathogenetic factor for these two lesions. A possible candidate involved in the pathogenesis of PH and IPH may be endothelin, one of the vasoactive substances, since its receptor is said to be expressed abundantly in pulmonary and portal vasculatures. However, further investigation is necessary to elucidate the mechanism of PH and IPH in collagen vascular diseases.     

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.     

Fibulin-5 is involved in phlebosclerosis of major portal vein branches associated with elastic fiber deposition in idiopathic portal hypertension.

Aim: In cases of idiopathic portal hypertension (IPH), the deposition of elastic fibers in the major portal vein branches and peripheral portal tracts is a common and characteristic histological finding, which may be related to the disease's pathogenesis. This study aimed to clarify the mechanism of this portal fibroelastosis. Methods: The expression of fibulin-5 and fibrillin-1, proteins essential for elastogenesis, was examined in IPH livers (n = 15) using immunohistochemistry. Liver specimens obtained from patients with chronic viral hepatitis (CVH)/liver cirrhosis (LC) (n = 12) and normal/subnormal livers (n = 10) were used as controls. Results: In IPH livers, immunohistochemical labeling of fibulin-5 was observed in the major portal vein branches in eight cases (53%), and the distribution corresponded to that of elastic fibers in the vessel walls, while the peripheral portaltracts totally lacked fibulin-5 in spite of the presence of dense elastic fibers. In CVH/LC and normal livers, fibulin-5 expression was absent or faint throughout the sections. Fibrillin-1 was detected in the connective tissue of the hilar region and peripheral portal tracts in IPH, CVH/LC and normal livers, with the expression varying greatly among cases. Conclusions: These results suggest that fibulin-5, rather than fibrillin-1, expressed in the major portal vein branches of IPH livers is related to phlebosclerosis, leading to an increase in presinusoidal vascular resistance and portal hypertension. In addition, the mechanism of fibroelastosis may differ between the major portal vein branches and peripheral portal tracts of IPH livers.     

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。     

Connective tissue diseases and the liver

Connective tissue diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis, Sj?gren's syndrome, and scleroderma are systemic disorders that may have an autoimmune basis. The system manifestations vary, and there is frequent overlap among the syndromes. Liver involvement in patients with connective tissue diseases has been well documented but is generally considered rare. Although advanced liver disease with cirrhosis and liver failure is rare in patients with connective tissue diseases, clinical and biochemical evidence of associated liver abnormalities is common. Previous treatment with potentially hepatotoxic drugs or coincident viral hepatitis has usually been implicated as the main causes of liver disease in patients with connective tissue diseases. However, even after careful exclusion of these etiologies, the question remains whether to classify the patient as having a primary liver disease with associated autoimmune, clinical, and laboratory features or as having liver disease as a manifestation of generalized connective tissue disease. The main example of this pathogenetic dilemma is autoimmune hepatitis and SLE-associated hepatitis, which have been regarded as two different entities, although they have features in common of autoimmune syndromes. Several clinical and histopathologic features have been used to discriminate autoimmune hepatitis from SLE, a relevant diagnostic exercise because complications and therapy are quite different. Although hepatic steatosis and abnormal results on biochemical liver function tests are the most common hepatic abnormalities associated with connective tissue diseases, other less frequent abnormalities have been noted, such as nodular regenerative hyperplasia, portal vein obliteration and portal hypertension, features of primary biliary cirrhosis, and rarely portal fibrosis with abnormal lobular architecture. Vascular disorders of the liver also have been described, such as Budd-Chiari syndrome. Histologic assessment may reveal a variety of subclinical liver diseases. The aim of this contribution is to review the current published data regarding liver involvement in connective tissue diseases.     

Histological changes in the liver and portal hypertension subsequent to repeated intraportal injections of killed E. coli in the dog

The etiology of idiopathic portal hypertension (IPH) is not known. To obtain clues to the pathogenesis, an attempt was made to produce a hepatic lesion similar to that in IPH by repeated injections of aggregated killed non-pathogenic E. coli directly into the portal vein. In the treated dogs, histology of the liver showed dense fibrosis in the portal tract and an aberrant vasculature around the portal area after 1 month. Portal pressure was elevated and middle-to-small-sized portal branches were decreased in number as studied by portography. These changes closely mimic those seen in human IPH. The possibility is discussed that chronic entrance of an antigen such as bacteria from the intestine to the portal venous system plays an etiologic role in IPH.     

特发性门静脉高压的肝脏病理学分析

耳的观察特发性门静脉高压的肝脏病理改变,明确病理诊断标准,并探讨临床病理联系。方法收集中日友好医院2005年1月-2007年3月病理确诊的特发性门静脉高压病例29例,对其肝组织行HE、网织纤维加Masson三色染色,以及α-平滑肌肌动蛋白、细胞角蛋白7、细胞角蛋白19免疫组织化学染色,并分析病变特点。结果29例中男9例,女20例。临床有门静脉高压、脾大等症状、体征。23例临床误诊为肝硬化。主要病理改变有：明显的汇管区纤维化,伴终末门静脉细小分支闭锁（缺乏）及不完全细纤维隔形成。部分门静脉支扩张并疝入小叶内。肝细胞萎缩及结节状再生相伴。结论特发性门静脉高压的肝脏病变具有一定的形态学特征,汇管区纤维化、门静脉小支闭锁,部分门静脉分支疝入肝实质,肝细胞萎缩及结节状再生相伴,较具诊断价值。     

Intrahepatic portal venopathy and related disorders of the liver

Intrahepatic portal venopathy leads to various entities that are important causes of portal hypertension. Noncirrhotic portal fibrosis (NCPF) occurs in the Indian subcontinent, whereas idiopathic portal hypertension (IPH) occurs in Japan although the pathogenesis and presentation of both are similar. NCPF presents mainly with upper gastrointestinal bleeding; IPH presents with massive splenomegaly. The liver functions are preserved. Wedged hepatic venous pressure is normal, but portal venous pressure is high indicating a presinusoidal block. Patients are best managed with endoscopic therapy or surgery, with better results than in patients with cirrhosis. Nodular regenerative hyperplasia is a histological diagnosis characterized by development of nodules in the liver due to uneven perfusion of the portal venous blood. These patients may develop portal hypertension and if they bleed would require treatment as in NCPF/IPH. Schistosomiasis produces portal hypertension by the development of fibrous tissue around the portal veins as a response to schistosome eggs. Gratifying results have been reported with praziquantel therapy. Rarely sarcoidosis and chronic biliary obstruction may also produce portal venopathy.     

A case of idiopathic portal hypertension after renal transplantation

A case of idiopathic portal hypertension (IPH) developing after renal transplantation is reported. A 33-year-old Japanese male who had undergone renal transplantation 8 years previously was transferred to our hospital because of hematemesis from ruptured esophageal varices. He had no history of any liver disease before the renal transplantation, but had a history of receiving blood transfusion. Abdominal computed tomography (CT) and ultrasonography revealed marked splenomegaly and collateral channels, but no obliteration which might cause portal hypertension in the hepatic or portal vein. No findings suggestive of hepatitis or liver cirrhosis were found either macroscopically on laparoscopy or by liver biopsy. Light microscopic study of the liver biopsy specimen showed mild periportal fibrosis, inconspicuous portal branches in the most peripheral tracts, but no pseudolobule formation or piecemeal necrosis. However collagen deposition was found in the perisinusoidal space and partly in intercellular space on electron microscopy. We consider that the development of portal hypertension in this case is responsible for the collagen deposition, which may be related to the administration of azathioprine after renal transplantation. There are few reports on IPH after renal transplantation, and it is stressed that a lower amount of azathioprine than previously reported may induce IPH under such conditions.     

21例特发性门脉高压临床及病理特点分析

目的分析特发性门脉高压(idiopathic portal hypertension,IPH)的临床及病理特点。方法回顾性分析2012年1月—2016年12月在解放军第三〇二医院住院治疗(资料完整)的21例IPH患者的临床及病理特点。结果 21例IPH患者中,男女比例6∶15,平均发病年龄(38.1±12.7)岁,临床以门脉高压症表现为主,肝功能无明显减退,主要并发症为上消化道出血及腹水。21例肝组织病理主要表现为肝细胞板排列基本正常,无假小叶形成,汇管区扩大,门静脉周围纤维化,门脉周围有不同程度的细胞浸润,血管紊乱,中央静脉及小叶间静脉扩张,肝窦扩张,窦周纤维化。结论 IPH患者门脉高压和肝功能损害不平行,门脉高压表现较重,确诊仍须病理学检查,治疗以防治并发症为主。     

A case of idiopathic portal hypertension after renal transplantation

A case of idiopathic portal hypertension (IPH) developing after renal transplantation is reported. A 33-year-old Japanese male who had undergone renal transplantation 8 years previously was transferred to our hospital because of hematemesis from ruptured esophageal varices. He had no history of any liver disease before the renal transplantation, but had a history of receiving blood transfusion. Abdominal computed tomography (CT) and ultrasonography revealed marked splenomegaly and collateral channels, but no obliteration which might cause portal hypertension in the hepatic or portal vein. No findings suggestive of hepatitis or liver cirrhosis were found either macroscopically on laparoscopy or by liver biopsy. Light microscopic study of the liver biopsy specimen showed mild periportal fibrosis, inconspicuous portal branches in the most peripheral tracts, but no pseudolobule formation or piecemeal necrosis. However collagen deposition was found in the perisinusoidal space and partly in intercellular space on electron microscopy. We consider that the development of portal hypertension in this case is responsible for the collagen deposition, which may be related to the administration of azathioprine after renal transplantation. There are few reports on IPH after renal transplantation, and it is stressed that a lower amount of azathioprine than previously reported may induce IPH under such conditions.     

Association of celiac disease with non-cirrhotic portal fibrosis

Both celiac disease and non‐cirrhotic portal fibrosis are known to be associated with various autoimmune diseases and have numerous immunological abnormalities. Herein two patients with celiac disease having associated non‐cirrhotic portal fibrosis are reported. An autoimmune link between the two conditions is likely to explain coexistence in the same patient.     

Three-dimensional reconstruction of hepatic bridging fibrosis in chronic hepatitis C viral infection

BACKGROUND/AIMS: Fibrosis in chronic hepatitis C infection begins in portal tracts, and can progress to 'bridging fibrosis' and eventually lead to cirrhosis. All current fibrosis staging systems are based on these three conceptual fibrosis stages (portal fibrosis, bridging fibrosis, cirrhosis) and vary only in how these stages are further subdivided. Despite the importance of bridging fibrosis, little is known about its three-dimensional characteristics. METHODS: Foci of bridging fibrosis were digitally reconstructed in three dimensions on two separate liver specimens with chronic hepatitis C viral infection. The amount of portal fibrosis was then correlated with bile duct diameter on trichrome-stained sections. RESULTS: After three-dimensional reconstruction, the bridges were seen to represent webs or membranes of fibrosis located at branch points of the portal tracts that extended between two portal branches, much like the webbing between the thumb and forefinger in a baseball-mitt. Direct measurements indicated that early portal fibrosis was associated with portal tracts containing bile ducts of approximately 18-19 mum diameter. CONCLUSIONS: Fibrosis bridges are located at branch points of portal tracts and are composed of three-dimensional webs or membranes that extend between portal tracts; when viewed as two dimensions on a glass slide, a 'bridge' of fibrosis is seen.     

Coexistence of systemic sclerosis with other autoimmune diseases

To evaluate the coexistence of additional autoimmune disease in a population of patients suffering from systemic sclerosis. The record-charts of 118 Italian patients affected by systemic sclerosis (12 men, 106 women, mean age of 57.2 years, mean duration of disease 8.7 years) followed by a single centre were reviewed; any other diagnose of autoimmune disease the patient was given was recorded. Thirty-eight scleroderma patients (32.2%) were affected by one or two concomitant autoimmune diseases, for a total of 42 diagnoses. The most represented associated autoimmune diseases were autoimmune thyroiditis (17 cases) and primary Sjögren’s syndrome (10 cases). Both pulmonary fibrosis as diagnosed by chest X-ray and the extension of skin involvement evaluated by Rodnan total skin score were not correlated with an increased incidence of an additional autoimmune disorder. Our study shows that approximately one third of patients affected by systemic sclerosis developed one or more additional autoimmune diseases. Therefore patients with systemic sclerosis should be carefully evaluated both at onset and during the follow-up for the possible coexistence of other autoimmune disorders.     

Scleroderma overlap syndromes

Scleroderma is a connective tissue disease that causes fibrosis and vascular abnormalities, but that also has an autoimmune component. Many patients with scleroderma have a positive antinuclear antibody, and there can be family histories of other connective tissue diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis. Some patients have features of scleroderma and other autoimmune conditions. This article will review recent literature to help in the understanding of scleroderma with overlap features. Recent reports of scleroderma overlap with rheumatoid arthritis suggest distinct features of diffuse scleroderma with positive Scl-70, pulmonary fibrosis, and later seropositive erosive rheumatoid arthritis. SLE rarely occurs with scleroderma. Sj?gren syndrome symptoms are common in scleroderma. In primary Sj?gren syndrome, anticentromere antibody positive patients have more Raynaud phenomenon. Antibodies that occur in scleroderma that are thought to be specific are present in other connective tissue diseases. For instance, Scl-70 antibody is reported in as many as 35% of patients with scleroderma but can be present in 25% of patients with SLE. Myositis or myopathy can be features of scleroderma. Scleroderma overlap with polymyositis is frequently anti-PM Scl antibody positive, whereas anti-Jo-1 does not normally occur in the overlap of scleroderma and polymyositis but is usually exclusively positive in polymyositis with arthritis and alveolitis. A better prognosis is found with PM Scl antibody in myositis. Vasculitis is not a typical feature of scleroderma, but has been reported. Eosinophilic fasciitis is rare, and the onset could be associated with simvastatin.     

Obliterative portal venopathy: A comparative study of 184 cases of extrahepatic portal obstruction and 469 cases of idiopathic portal hypertension

Abstract A total of 184 cases of extrahepatic portal obstruction (EHPO), mostly demonstrated by intraoperative portography and studied at 17 institutes during the period 1957–1983, were compared with 469 cases of idiopathic portal hypertension (IPH) similarly studied. Of the cases of EHPO, there were 101 males and 83 females; 93 were under 20 years of age and the average age was 25.9 years (i.e. much younger than that of IPH cases). There were two age peaks, one before age 19 years and the other at age 40–49 years. One out of three adult cases had a history of abdominal surgery, but otherwise the aetiologic factor was difficult to elicit. Bleeding was the initial symptom in the majority, and splenectomy and haematological findings of hypersplenism were less pronounced compared with IPH. Liver function tests were almost always normal. The liver appeared normal macroscopically in 69% and histologically in 35%. The changes seen in the remainder were similar to those in IPH; they were less frequent in young patients than in cases above age 20 years. Compared with IPH, the wedged hepatic venous pressure in patients with EHPO was lower and the gradient from the portal venous pressure was greater. It is concluded that extrahepatic portal obstruction is less common compared with IPH in Japan, and that there are cases particularly among adults that present clinicopathological features very similar to those of IPH. It is unclear at present whether these two disorders represent two different disease entities, or whether they represent one disorder with differences in the site of involvement along the portal vein system.     

胰源性与特发性门脉高压症的临床特点分析

目的探讨PPH与IPH的临床特点,加深对二者的认识,提高临床医师的诊治水平。方法对18例PPH与36例IPH患者的临床资料作一回顾分析。结果二者的肝脏形态、功能正常,病毒学指标阴性,超声检查脾静脉迂曲扩张,脾肿大;PPH患者超声检查门静脉正常,胰腺可见炎症、肿瘤、囊肿等表现;IPH患者门静脉及肠系膜上静脉迂曲扩张,但胰腺方面无异常。IPH患者汇管区纤维组织增生和炎性细胞浸润但无肝硬化改变而PPH患者肝脏组织学正常。结论临床中发现肝脏形态、功能正常,病毒学指标阴性,以门脉高压为主要表现而无肝硬化改变的患者,应考虑IPH与PPH的可能。进一步行超声检查门脉系统及胰腺情况,可进一步区分二者。     

Histopathology of portal tracts in livers after transcatheter arterial chemo-embolization therapy for hepatocellular carcinoma

Abstract To study the influence of transcatheter arterial embolization therapy (TAE) on the portal tracts, 32 cases of hepatocellular carcinoma (HCC) with a history of TAE were examined. Portal tract elements are said to be mainly supplied by hepatic arterial blood, as is HCC. The following changes were found: peribile duct fibrosis; biliary epithelial injuries; bile duct necrosis; fibrous thickening of the intima and adventitia of arteries; thrombosis or stenosis of portal vein branches; and fibrosis of portal tract itself. We failed to correlate these histopathologic changes with the frequency of TAE or the interval between TAE therapy and surgery or autopsy. Semi-quantitative assessment disclosed that vessels of the peribiliary vascular plexus (PVP) which are known to be derived from hepatic arterial branches, were considerably decreased. There was little correlation between the degree of reduction of PVP and the observed histopathologic changes of portal tracts. It is suggested that TAE causes adverse effects on the elements of portal tracts and a reduction in the PVP in the vicinity of HCC, but the relationship between them is unclear.