Hepatic vascular disease and portal hypertension in polycythemia vera and agnogenic myeloid metaplasia: a clinicopathological study of 145 patients examined at autopsy

The pathogenesis of portal hypertension arising in patients with myeloproliferative disorders has been difficult to understand because liver biopsy findings often show minimal changes. It has been suggested that increased splenic blood flow, hepatic infiltration with hematopoietic cells or sinusoidal fibrosis may be important. We have reviewed the autopsy findings and clinical histories of 97 patients with polycythemia vera and 48 patients with agnogenic myeloid metaplasia collected from three institutions and from the Polycythemia Vera Study Group. Cirrhosis was present in seven patients, one of whom had bleeding varices. Esophageal varices were present clinically in 10 patients without cirrhosis (seven polycythemia and three agnogenic myeloid metaplasia). All of these patients had lesions in small or medium-sized portal veins and four had stenosis of the extrahepatic portal vein with histology compatible with organized thrombi. Nodular regenerative hyperplasia occurred in 14.6% and correlated closely with the presence of portal vein lesions. Thirty patients had greater than 500 ml of ascites, seven of these patients also had varices and six of them had hepatic vein thrombosis. Ascites also correlated with hepatic vein disease confined to small intrahepatic branches. No correlation was seen between hepatic hematopoietic infiltration and signs of portal hypertension. We conclude that esophageal varices are common and are almost always associated with portal vein lesions visible by light microscopy. These portal vein lesions, and the secondary effects of nodular regenerative hyperplasia and portal hypertension, are most likely a result of portal vein thrombosis in patients with myeloproliferative disorders.     

Portal hypertension and primary biliary cirrhosis.

Portal hypertension has been regarded as an uncommon and late complication of primary biliary cirrhosis (PBC). 24 patients with PBC were investigated for portal hypertension. Esophageal varices were present in 20, 50, and 90% of the patients 1, 3, and 9 years, respectively, after the onset of pruritus and/or jaundice. Portal hypertension was responsible for gastrointestinal bleedings in 11 patients; bleeding was the first clinical manifestation of PBC in two of them. Wedged hepatic venous pressure was increased in all the patients with portal hypertension whether regenerative nodules were present or absent. Portacaval shunt was performed in five patients and was well tolerated in three of them. It is concluded that (a) portal hypertension is common in PBC; (b) the intrahepatic block is of the so-called postsinusoidal type, even in patients without regenerative nodules; (c) gastro-intestinal bleeding due to portal hypertension occurs in about half of the patients and may be the first manifestation of PBC; (d) portacaval shunt seems to be indicated when gastro-intestinal bleeding occurs in earlier stage of the disease.     

Nodular regenerative hyperplasia of the liver and primary biliary cirrhosis. A fortuitous association?

We report here in a case of primary biliary cirrhosis associated with nodular regenerative hyperplasia of the liver in a white woman revealed by digestive hemorrhage due to ruptured esophageal varices. The diagnosis of primary biliary cirrhosis was based on the following: elevated serum IgM, high titer of antimitochondrial antibody (anti M2), typical histopathological picture of stage I/II disease. The diagnosis of nodular regenerative hyperplasia was supported by the demonstration of disseminated small hepatic nodules without perinodular fibrosis. This association may be a supplementary argument in favor of a possible autoimmune origin of nodular regenerative hyperplasia of the liver.     

Portal hypertension in primary biliary cirrhosis

Evidence of portal hypertension was found in 50 out of 109 patients (47%) with primary biliary cirrhosis, and of these 32 bled from oesophageal varices. In four patients portal hypertension was the initial manifestation of the disease and this complication was recognized in a further 17 within two years of the first symptom of primary biliary cirrhosis. The development of portal hypertension was associated with a poor prognosis and death could frequently be attributed to variceal bleeding; the mean duration of survival from the time that portal hypertension was recognized was 14.9 months. Portal decompression operations may have improved the immediate prognosis in some patients but did not otherwise influence the progression of the disease. In 47 patients the histological findings in wedge biopsy or necropsy material were correlated with the presence or absence of varices. An association between nodular regeneration of the liver and varices was confirmed, but, in the absence of nodules, no other histological cause for portal venous obstruction could be found.     

Endoscopic ultrasonographic evaluation of hemodynamics related to variceal relapse in esophageal variceal patients

Aim:  To evaluate retrospectively the hemodynamics of esophageal varices before and after endoscopic injection sclerotherapy (EIS) using endoscopic color Doppler ultrasonography (ECDUS).
Methods:  The study included 306 patients whose esophageal varices had been treated with EIS. The underlying pathologies of portal hypertension in these 306 patients included liver cirrhosis (193), cirrhosis associated with hepatocellular carcinoma (102), primary biliary cirrhosis (6), idiopathic portal hypertension (4) and extrahepatic portal vein obstruction (1). ECDUS was used for the examination of all 306 cases before EIS and 3–5 months after EIS. ECDUS was performed to evaluate flow in the left gastric vein, paraesophageal veins, perforating veins and cardiac intramural veins.
Results:  The patients were divided into three groups according to time of esophageal variceal recurrence: early recurrence within one year (Group A, n  = 16), no recurrence over three years (Group B, n  = 12), and recurrence between one and three years (Group C, n  = 278). Before EIS, the frequency of detection of perforating veins and the inflowing type of perforating veins using ECDUS was significantly higher for Group A than Groups B or C. After EIS, the frequency of detection of cardiac intramural veins, perforating veins and the inflowing type of perforating veins using ECDUS was significantly higher in Group A than Groups B or C.
Conclusion:  Endoscopic ultrasonographic evaluation of the hemodynamics in esophageal varices before and after EIS enables prediction of early variceal recurrence.     

HEMODYNAMIC MECHANISM OF ESOPHAGEAL VARICES

We investigated the correlation between the collaterals around the esophagus and recurrence of esophageal varices in patients with portal hypertension who had undergone endoscopic injection sclerotherapy (EIS). In patients with portal hypertension, many types of collaterals around the esophagus were visualized by endoscopic ultrasonography (EUS). The collaterals outside the esophageal wall detected by EUS were divided into two groups according to the location of the veins: peri‐esophageal collateral veins (peri‐ECV) and para‐esophageal collateral veins (para‐ECV) Perforating veins are those that have penetrated the esophageal wall and have connected with either peri‐ECV or para‐ECV. We demonstrated that severe peri‐ECV and large perforating veins play an important role in the development of esophageal varices in untreated patients with portal hypertension. The results of our investigation have shown that detection of peri‐ECV and perforating veins by EUS and treatment of them by EIS appears to be important for the treatment of esophageal varices. The disappearance of peri‐ECV by EIS is essential for reducing the recurrence rate of esophageal varices. To prevent variceal recurrence, a mucosal fibrosing method using argon plasma coagulation has been widely performed in Japan. If EUS abnormalities are associated with variceal recurrence, we recommend the use of the mucosal fibrosing method. In conclusion, the presence of severe peri‐ECV and large perforating veins in the esophageal wall strongly correlate with the recurrence of esophageal varices in patients with portal hypertension. An understanding of these EUS abnormalities on the basis of hemodynamics around the esophagus is important for the management of esophageal varices in patients with portal hypertension.     

Molecular and structural basis of portal hypertension

Portal hypertension is a complication of diseases that obstruct portal blood flow, such as cirrhosis or portal vein thrombosis. In these diseases, increased vascular resistance to portal blood flow is the primary mechanism that increases portal pressure. In cirrhosis, increased intrahepatic vascular resistance is a result of both intrahepatic vasoconstriction and surrounding mechanical factors including collagen deposition and regenerative nodules. This article summarizes recent progress in the understanding of molecular mechanisms underlying the portal hypertension-associated arterial alterations in splanchnic systemic territories and those involved in the development of portal-systemic collateral circulation.     

Hepatosplenic schistosomiasis. Pathophysiology and treatment.

HSS represents a special model of intrahepatic portal hypertension characterized by a presinusoidal portal block and a well-preserved liver parenchyma. Symmers' fibrosis appears in a small but significant proportion of patients with a high worm load. Its pathogenesis is not well established, although experimental and clinical studies point to egg granulomata as the main pathogenetic factor. The eggs carried continuously through the portal circulation produce inflammation and gross amputation of the intrahepatic veins, portal and periportal granulomas, and, eventually, a coarse perilobular fibrosis ("pipe-stem"). Portal hypertension, esophageal varices, and hepatosplenomegaly are the main consequences of these morphologic changes. Gastrointestinal bleeding is the most frequent cause of death. Unlike in cirrhosis, advanced liver failure is not seen except when HSS is associated with liver lesions from other causes such as virus and alcoholism. Helminthiasis treatment is based on chemotherapy with praziquantel or oxamniquine. Bleeding esophageal varices are managed by sclerotherapy or surgical procedures. Splenectomy with gastroesophageal devascularization seems to be the best choice.     

Nodules in antrum after variceal eradication a new finding in patients with portal hypertension

Portal hypertension is known to cause esophageal varices, gastric varices and portal hypertensive gastropathy (PHG). The prevalence of gastric varices and PHG is known to increase after eradication of esophageal varices. PHG includes the presence of a mucosal mosaic pattern, cherry red spots, and/or black-brown spots and gastric vascular ectasia (GAVE). Patients with portal hypertension in whom esophageal varices were eradicated were on follow up endoscopy for detection of recurrence of esophageal varices. Their status of PHG was assessed and patients antral nodules were enrolled. Twenty patients with antral nodules were identified over one year. Fifteen out of 20 patients had cirrhosis as etiology of portal hypertension, three had non-cirrhotic portal hypertension and two had extra-hepatic portal vein thrombosis. GAVE was seen more commonly (n=8, 40%) in patients with PHG with nodules. PHG with antral nodules is a novel endoscopic finding present both in cirrhotic and non-cirrhotic portal hypertension with unknown pathogenesis, and is seen more commonly in patients with eradicated varices who are on long-term follow up.     

Utility of endoscopic ultrasound in patients with portal hypertension

Endoscopic ultrasound(EUS) has revolutionized the diagnostic and therapeutic approach to patients with gastrointestinal disorders. Its application in patients with liver disease and portal hypertension is increasing. Patients with chronic liver disease are at risk for development of portal hypertension sequale such as ascites, spontaneous bacterial peritonitis and gastroesophageal varices. Bleeding esophageal and gastric varices are among the most common causes of mortality in patients with cirrhosis. Thus, early detection and treatment improve the outcome in this population. EUS can improve the detection and diagnosis of gastroesophageal varices and collateral veins and can provide endoscopic therapy of gastroesophageal varices such as EUS-guided sclerotherapy of esophageal collateral vessels and EUS-guided cynoacrylate(Glue) injection of gastric varices. EUS can also provide knowledge on the efficacy of pharmacotherapy of portal hypertension. Furthermore, EUS can provide assessment and prediction of variceal recurrence after endoscopic therapy and assessment of portal hemodynamics such as E-Flow and Doppler study of the azygous and portal veins. Moreover, EUS-guided fine needle aspiration may provide cytologic diagnosis of focal hepatic tumors andanalysis of free abdominal fluid.Using specialized EUSguided needle biopsy,a sample of liver tissue can be obtained to diagnose and evaluate for chronic liver disease.EUS-guided fine needle injection can be used to study portal vein pressure and hemodynamics,and potentially could be used to assist in exact measurement of portal vein pressure and placement of intrahepatic portosystemic shunt.     

Nodular Hyperplasia of the Liver in Primary Biliary Cirrhosis of Early Histological Stages

Twenty-six patients with the clinical and histologic diagnosis of primary biliary cirrhosis were reviewed. Nodular hyperplasia of the liver without fibrous rims, not reported hitherto in patients with primary biliary cirrhosis, was found in several patients with early histological stages. These changes resembled "nodular regenerative hyperplasia of the liver" and were usually present as multicellular thickness in zones 1 and 2 of the hepatic lobules. Such lesions were preferentially found in patients with esophageal varices, suggesting that the nodular hyperplasia may occur in relation to a disturbance of portal venous blood flow within the liver in primary biliary cirrhosis in early histological stages.     

USEFULNESS OF EUS IN PORTAL HYPERTENSION WITH ESOPHAGEAL VARICES

We investigated the relationship between esophageal varices and the collaterals by endoscopy and endoscopic ultrasound (20 MHz ultrasonic miniprobe; UMP). Moreover, we investigated the correlation between the collaterals around the esophagus and recurrence of esophageal varices in patients with portal hypertension who had undergone EIS. The collaterals were divided into two groups: peri‐esophageal collateral veins (peri‐ECVs) and para‐esophageal collateral veins (para‐ECVs). These were scored as mild or severe according to the stage of development. According to endoscopy, the varix form was significantly larger in severe the peri‐ECVs group than in mild the peri‐ECVs group. The prevalence of perforating veins increased according to the varix form. With regard to variceal recurrence, in patients with variceal recurrences, UMP findings included a significantly higher incidence of severe peri‐ECVs, a significantly larger diameter of perforating veins compared with patients without recurrence. In conclusion, the presence of severe peri‐ECVs and large perforating veins in the esophageal wall strongly correlates with occurrence and recurrence of esophageal varices in patients with portal hypertension. An understanding of these UMP abnormalities on the basis of hemodynamics around the esophagus is thought to be important for management of esophageal varices in patients with portal hypertension.     

原发性胆汁性肝硬化患者食管静脉曲张程度与肝功能评价的相关性研究

目的 探讨原发性胆汁性肝硬化食管静脉曲张程度与门脾静脉内径、肝功能Child-Pugh分级,Meld评分间的关系.方法 对2008年9月至2011年5月间选择92例原发性胆汁性肝硬化患者行增强CT,测量门静脉主干及脾门部脾静脉直径,行胃镜了解食管静脉曲张的程度,并对其中44例出现过静脉曲张破裂出血患者采用Child-Pugh分级,Meld评分标准进行肝功能分级.结果 食管静脉曲张程度与门静脉内径（P =0.018）、脾静脉内径（P=O.O02）呈正相关,而Child-Pugh分级（P＞0.05）,Meld评分（P＞0.05）则与食管静脉曲张程度无相关性.结论 根据门、脾静脉内径可预测原发性胆汁性肝硬化的食管静脉曲张程度;而Child-Pugh分级,Meld评分对患者的食管静脉曲张程度及出血风险不能进行有效评估.     

Noncirrhotic portal fibrosis

In India noncirrhotic portal fibrosis (portal hypertension without demonstrable intrahepatic or extrahepatic obstruction) accounted for seventy-five (25 per cent) of 300 cases of portal hypertension studied by us. The majority of patients presented with marked splenomegaly of long duration and recurrent hemorrhage from esophageal varices (usually well tolerated), with minimal features of hepatocellular failure. There was an increase of alpha₂ globulin, beta globulins and immunoglobulin G (IgG). Hemodynamically, two significant findings were a marked gradient between the splenic pressure and wedged hepatic vein pressure, and a normal hepatic blood flow; in some patients wedged hepatic vein pressure was high. Roentgenologically, there was dilatation and tortuosity of the portal and splenic veins, with massive varices and hepatofugal collaterals. The intrahepatic vascular pattern was not much distorted, in contrast to cirrhosis. At shunt surgery the gross appearance of the liver varied from near normal to irregular nodularity resembling cirrhosis. There was at times shrinkage of the left lobe and hypertrophy of the right lobe. A needle biopsy specimen of the liver showed nonspecific changes, I.e., small focal areas of necrosis and regeneration, focal infiltrates, Kupffer cell hyperplasia and portal scars of varying size. Wedge biopsy and autopsy specimens revealed focal occlusive changes in the medium-sized radicals of the portal vein, changes considered specific for this disease. Electron microscopy revealed widening and collagenization of the space of Disse, with laying down of large collagen bundles in and around the sinusoids.     

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.     

Sonographic Patent Umbilical Vein: Lack of Specificity for Portal Hypertension

The sonographically patent umbilical vein is commonly considered a sign of portal hypertension and is held to be specific by some authors. We found sonoagraphically patent umbilical veins in 11 patients with hepatic cirrhosis and esophageal varices, and in three subjects without liver disease and without esophageal varices. All subjects were submitted to Doppler flowmetry, which, with the investigation of the direction of venous flow, proved to be a simple discriminatory test.     

Portal hemodynamics in primary biliary cirrhosis as evaluated by per-rectal portal scintigraphy with Tc-99m pertechnetate

BACKGROUND/AIMS: Portal circulation can be evaluated in a relatively noninvasive manner by per-rectal portal scintigraphy. We used this method to evaluate portal hemodynamics in patients with primary biliary cirrhosis and idiopathic portal hypertension. We did the procedures simultaneously in some patients to examine the relation between portal circulation and hepatic functional reserve in these diseases. METHODOLOGY: Per-rectal portal scintigraphy with Tc-99m pertechnetate was done in 17 healthy subjects, 154 patients with chronic hepatitis, 447 patients with cirrhosis, 40 patients with primary biliary cirrhosis, and 20 patients with idiopathic portal hypertension. Eighty-three patients (14 with hepatitis, 48 with cirrhosis, 16 with primary biliary cirrhosis, and 5 with idiopathic portal hypertension) also underwent scintigraphy with Tc-99m galactosyl human serum albumin with 2 weeks. A solution containing Tc-99m pertechnetate was instilled into the rectum, and serial scintigrams were taken while radioactivity curves for the liver and heart were recorded sequentially. The per-rectal portal shunt index was calculated from the curves. A receptor index was calculated by dividing the radioactivity of the liver region of interest by that of the liver-plus-heart region of interest 15 min after the injection of Tc-99m galactosyl human serum albumin. The index of blood clearance was calculated by dividing the radioactivity of the heart region of interest at 15 min by that of the heart region of interest at 3 min. RESULTS: The shunt index was higher for more severe disorders, increasing in the order of chronic hepatitis, cirrhosis without varices, and cirrhosis with varices. The shunt indices in patients with primary biliary cirrhosis and idiopathic portal hypertension were higher than that in patients with chronic hepatitis. In terms of receptor index, the standard residuals were more than 0 in 10 of 16 patients with primary biliary cirrhosis and 4 of 5 patients with idiopathic portal hypertension. In terms of index of blood clearance, the standard residuals were more than 0 in 10 of 16 patients with primary biliary cirrhosis and 4 of 5 patients with idiopathic portal hypertension CONCLUSIONS: Abnormalities of portal hemodynamics in patients with primary biliary cirrhosis or idiopathic portal hypertension occur while hepatic functional reserve is still satisfactory as compared with patients who have chronic hepatitis or cirrhosis.     

Mechanisms of adaptation of the hepatic vasculature to the deteriorating conditions of blood circulation in liver cirrhosis

Pub Med, EMBASE, Orphanet, MIDLINE, Google Scholar and Cochrane Library were searched for articles published between 1983 and 2015. Relevant articles were selected by using the following terms: "Liver cirrhosis", "Endothelial dysfunction", "Sinusoidal remodeling", "Intrahepatic angiogenesis" and "Pathogenesis of portal hypertension". Then the reference lists of identified articles were searched for other relevant publications as well. Besides gross hepatic structural disorders related to diffuse fibrosis and formation of regenerative nodules, the complex morphofunctional rearrangement of the hepatic microvascular bed and intrahepatic angiogenesis also play important roles in hemodynamic disturbances in liver cirrhosis. It is characterized by endothelial dysfunction and impaired paracrine interaction between activated stellate hepatocytes and sinusoidal endotheliocytes, sinusoidal remodeling and capillarization, as well as development of the collateral microcirculation. In spite of the fact that complex morphofunctional rearrangement of the hepatic microvascular bed and intrahepatic angiogenesis in liver cirrhosis are the compensatory-adaptive reaction to the deteriorating conditions of blood circulation, they contribute to progression of disease and development of serious complications, in particular, related to portal hypertension.Pub Med,EMBASE,Orphanet,MIDLINE,Google Scholar and Cochrane Library were searched for articles published between 1983 and 2015.Relevant articles were selected by using the following terms:"Liver cirrhosis","Endothelial dysfunction","Sinusoidal remodeling","Intrahepatic angiogenesis"and"Pathogenesis of portal hypertension".Then the reference lists of identified articles were searched for other relevant publications as well.Besides gross hepatic structural disorders related to diffuse fibrosis and formation of regenerative nodules,the complex morphofunctional rearrangement of the hepatic microvascular bed and intrahepatic angiogenesis also play important roles in hemodynamic disturbances in liver cirrhosis.It is characterized by endothelial dysfunction and impaired paracrine interaction between activated stellate hepatocytes and sinusoidal endotheliocytes,sinusoidal remodeling and capillarization,as well as development of the collateral microcirculation.In spite of the fact that complex morphofunctional rearrangement of the hepatic microvascular bed and intrahepatic angiogenesis in liver cirrhosis are the compensatory-adaptive reaction to the deteriorating conditions of blood circulation,they contribute to progression of disease and development of serious complications,in particular,related to portal hypertension.     

Giant Hepatic Regenerative Nodule in a Patient With Hepatitis B Virus-related Cirrhosis

Hepatic regenerative nodules are reactive hepatocellular proliferations that develop in response to liver injury. Giant hepatic regenerative nodules of 10 cm or more are extremely rare and have only been reported in patients with biliary atresia or Alagille syndrome. A 50-year-old man presented with a pathologically confirmed giant 11.3×9.4×11.2 cm hepatic regenerative nodule and hepatitis B virus-related cirrhosis. Imaging of intrahepatic nodule included mild hyperenhancement in the portal phase of contrast-enhanced CT and the hepatobiliary phase in the gadoxetic acid-enhanced MRI scan, as well as the portal vein crossing through sign in the setting of liver cirrhosis. This case highlights the imaging characteristics of giant hepatic regenerative nodules in hepatitis cirrhosis.     

Cruveilhier-Baumgarten syndrome without esophageal varices: ultrasonographic diagnosis and echo-Doppler study

Two cases of Cruveilhier-Baumgarten syndrome not clinically evident and without esophageal varices in patients with liver cirrhosis and portal hypertension are presented. The diagnosis was made by real-time ultrasonography, which showed echographic caput medusae with large afferent umbilical veins and efferent inferior superficial epigastric veins. Doppler flowmetry documented high blood flow rates in these collateral portal-systemic circulations, and this explained the absence of large varices at endoscopy. The role of massive spontaneous portal-systemic shunts in preventing the formation of other shunts and particularly esophageal variceal bleeding is discussed.