Remodeling of hepatic vascular changes after specific chemotherapy of schistosomal periportal fibrosis

Hepatosplenic schistosomiasis was the first human disease in which the possibility of extensive long standing hepatic fibrosis being degraded and removed has been demonstrated. When such changes occurred, the main signs of portal hypertension (splenomegaly, esophageal varices) progressively disappeared, implying that a profound vascular remodeling was concomitantly occurring. Hepatic vascular alterations associated with advanced schistosomiasis have already been investigated. Obstruction of the intrahepatic portal vein branches, plus marked angiogenesis and compensatory hyperplasia and hypertrophy of the arterial tree are the main changes present. However, there are no data revealing how these vascular changes behave during the process of fibrosis regression. Here the mouse model of pipestem fibrosis was used in an investigation about these vascular alterations during the course of the infection, and also after treatment and cure of the disease. Animals representing the two polar hepatic forms of the infection were included: (1) "isolated granulomas" characterized by isolated periovular granulomas sparsely distributed throughout the hepatica parenchyma; and (2) 'pipestem fibrosis' with periovular granulomas and fibrosis being concentrated within portal spaces, before and after treatment, were studied by means of histological and vascular injection-corrosion techniques. Instances of widespread portal vein obstruction of several types were commonly found in the livers of the untreated animals. These obstructive lesions were soon repaired, and completely disappeared four months following specific treatment of schistosomiasis. Treatment was accomplished by the simultaneous administration of praziquantel and oxamniquine. The most impressive results were revealed by the technique of injection of colored masses into the portal system, followed by corrosion in strong acid. The vascular lesions of non-treated pipestem fibrosis were represented...

Patogénesis de la hipertensión portal / Pathogenesis of portal hypertension

It is now well established that portal hypertension is not a purely mechanical phenomenon. Primary hemodynamic alterations develop in the hepatic and systemic circulatory systems; these alterations in combination with mechanical factors contribute to the development of portal hypertension. In the hepatic circulation, these hemodynamic alterations are characterized by vasoconstriction and impaired hepatic vasodilatory responses, whereas in the systemic circulation, particularly in the splanchnic bed, vessels are hyperemic with increased flow. Thus, an increase in intrahepatic resistance in conjunction with increased portal venous inflow, mediated through splanchnic dilation, contributes to the development of portal hypertension. The ensuing development of elevated flow and transmural pressure through collateral vessels from the hypertensive portal vasculature into the lower pressure systemic venous circulation accounts for many of the complications, such as bleeding esophageal varices, observed with portal hypertension. The importance of the primary vascular origin of portal hypertension is emphasized by the utility of current therapies aimed at reversing these hemodynamic alterations, such as nitrates, which reduce portal pressure through direct intrahepatic vasodilatation, and fi blockers and octreotide, which reduce splanchnic vasodilatation and portal venous inflow. New evidence concerning relevant molecular mechanisms of contractile signaling pathways in hepatic stellate cells and the complex regulatory pathways of vasoactive molecules in liver endothelial cells makes a better understanding of these processes essential for developing further experimental therapies for portal hypertension. This article examines the current concepts relating to cellular mechanism that underlie the hemodynamic alterations that characterize and account for the development of portal hypertension.

Actualmente está bien establecido que la hipertensión portal no es un fenómeno puramente mecánico. En esta entidad se presentan alteraciones hemodinámicas primarias en los sistemas circulatorios hepático y sistémico; estas alteraciones en combinación con factores mecánicos, contribuyen al desarrollo de la hipertensión portal. En la circulación hepática, las alteraciones hemodinámicas se caracterizan por vasoconstricción y una respuesta anómala a la vasodilatación, mientras que en la circulación sistémica, especialmente en el lecho esplácnico, los vasos están congestivos y con un flujo aumentado. Por lo tanto un incremento en las resistencias intrahepáticas asociado a un aumento del flujo venoso portal, mediado a través de la dilatación esplácnica, contribuyen al desarrollo de la hipertensión portal. La consecuencia del flujo y la presión transmural elevada a través de los vasos colaterales a partir de una vasculatura portal hipertensa hacia la circulación venosa sistémica con menor presión, conlleva a muchas de las complicaciones observadas en la hipertensión portal, como la hemorragia por várices esofágicas. La importancia del origen vascular primario de la hipertensión portal se basa en la utilidad de terapias actuales orientadas a revertir estas alteraciones hemodinámicas, como los nitratos que reducen la presión portal, a través de vasodilatación intrahepática directa y los P bloqueadores y octreótida, que reducen la vasodilatación esplácnica y el flujo venoso portal. Además, existen nuevas evidencias en relación con los mecanismos moleculares de vías de señalización contráctil de las células estelares hepáticas y complejas vías de regulación de sustancias vasoactivas en las células endoteliales hepáticas que han ayudado a entender mejor estos procesos esenciales para el desarrollo de terapias experimentales para la hipertensión portal. Este artículo revisa los conceptos actuales relacionados con los mecanismos celulares causales de las alteraciones hemodinámicas que caracterizan y condicionan el desarrollo de la hipertensión portal.

Portal hyperflow in patients with hepatosplenic mansonic schistosomiasis

OBJETIVOS: o objetivo do presente estudo é estudar a hemodinâmica portal em pacientes com hipertensão portal secundária a forma hepatoesplênica da esquistossomose e avaliar a contribuição do hiperfluxo esplênico na sua fisiopatologia CASUISTICA E MÉTODOS: Foram estudados prospectivamente 16 pacientes portadores de hipertensão portal secundária à forma hepatoesplênica da esquistossomose mansônica com indicação de tratamento cirúrgico. Todos foram submetidos a avaliação hemodinâmica portal com cateter de termodiluição 4F antes e após a realização de desvascularização esofago-gástrica com esplenectomia. RESULTADOS: Na avaliação intra-operatória inicial observou-se pressão (28,5 + 4,5 mmHg ) e fluxo (1750,59 ± 668,14 ml/min) portais iniciais bem acima dos valores considerados normais. Houve queda significante de 25 por cento na pressão (21,65 ± 5,55 mmHg ) e de 42 por cento no fluxo (1011,18 ± 332,73 ml/min) ao término da cirurgia. Quatorze pacientes (87.5 por cento) apresentavam fluxo portal superior a 1200 ml/min e, em 5 casos, valores superiores a 2000 ml/min foram observados. CONCLUSÕES: A pressão e o fluxo portais estão aumentados na hipertensão portal esquistossomótica. A desvascularização esofago-gástrica com esplenectomia reduz significativamente tanto a pressão quanto o fluxo portais. Estes dados favorecem a hipótese do hiperfluxo esplâncnico (esplênico e mesentérico) na fisiopatologia da hipertensão portal na esquistossomose forma hepatoesplênica.

Interplay of portal pressure, portal perfusion and hepatic arterial inflow in modulating expression of hepatic encephalopathy in patients with spontaneous or artificially created portosystemic shunts.

The major theme of this discussion is how portal pressure after portosystemic shunt procedures may modulate the expression of hepatic encephalopathy. Decades of emphasis on the paramount importance of maintaining portal venous perfusion after shunt procedures is now being re-examined. In countries where non-cirrhotic portal hypertension is common, physicians have long recognized that hepatic encephalopathy is rare even with total portosystemic shunting. However, once decompressive shunts are created, hepatic encephalopathy becomes a clinical problem. Why this occurs needs to be better understood. In the meantime, there has been virtual abandonment of surgical shunts in favor of endoscopic variceal ablation treatment. This is despite the fact that surgical shunts that only partially decompress the portal hypertension are associated with excellent long-term control of variceal bleeding and low rates of hepatic encephalopathy. The time has come to once again examine the key relationship between portal pressure, portal perfusion with hepatic arterial inflow in inducing hepatic encephalopathy after creation of portosystemic shunts.

Relationship of Propranolol Pharmacokinetic Parameters with Portosystemic Shunt in CCl4-induced cirrhotic Rats / 대한간학회지

BACKGROUND: This study was designed to determine the relationship of propranolol pharmacokinetic parameters with portosystemic shunt in CCl4-induced cirrhotic rats. METHODS: Cirrhotic rats(n=6) were induced by intramuscular injection of CCl4 in olive oil(two time per weeks) for 12 weeks. Controls (n=6) were injected intramuscularly with the same dose of olive oil for 12 weeks. We evaluated the amount of portosystemic shunt by thallium-201 per rectal scintigraphy. After intravenous bolus injection of propranolol (2mg/kg) to rats, the serum propranolol concentrations were analyzed by a HPLC-fluorimetric detector system. Pharmacokinetic parameters such as C0, AUC, t(1/2(beta)), and CLp were determined in each group. Then, a small amount of heptic tissue was obtained and subjected to determination of the hepatic collagen content by quantitating 4-hydroxyproline and were inspected by microscope after hematoxylin and eosin stain. RESULTS: In liver biopsy, liver fibrosis progressed in CCl4-induced cirrhotic rats. The serum concentrations of propranolol were significantly (p < 0.01) elevated in CCl4-induced cirrhotic rats. Mean amount of 4-hydroxyproline, mean H/L ratio, and mean AUC in CCl4-induced cirrhotic rats was significantly (p < 0.01) higher than that in control rats. There was a relationship between AUC, H/L ratio, and amount of 4-hydroxyproline. CONCLUSION: H/L ratio may help in the selection of drug dosage (especially blood flow dependent drug) in pre-clinical studies for chronic liver disease during the drug development process.

Reinfecçöes e desenvolvimento da fibrose periportal esquisomótica no modelo murino / Reinfections and the development of schistosomal periportal fibrosis in the murine model

A fibrose periportal esquistossomótica observada no modelo murino apareceu muito mais freqüentemente (69,2 por cento) em camundongos submetidos a múltiplas infecçöes pelo Schistosoma mansoni do que naqueles animais com infecçäo única (11,1 por cento). A contagem dos ovos depositados no fígado näo diferiu significativamente nos dois grupos ao término dos experimentos. Embora näo tenha ficado esclarecido o motivo pelo qual as infecçöes repetidas favorecem o desenvolvimento da fibrose periportal esquistossomótica, os dados observados fornecem apoio experimental às observaçöes clínico-epidemiológicas que sugerem ter as reinfecçöes um papel na patogenia da forma hepato-esplênica da esquistossomose

Portal hemodynamics in chronic liver disease.

Portal hypertension is a result of interplay of numerous static and dynamic forces. Portal hemodynamic characterization involves pressure and flow studies which in turn estimate portal pressure. Hepatic venous pressure gradient is the gold standard for determining portal pressure. Portal hemodynamic measurement has helped to understand the pathogenesis and prognosis of chronic liver disease and to define clinically important hepatic venous pressure gradients. Management strategies for ascites and prevention of variceal hemorrhage have been influenced by hemodynamic studies in animals and humans. The hemodynamics in non-cirrhotic portal fibrosis is ambiguous. The role of portal hemodynamic studies outside clinical trials needs further study.

Assessment of hemodynamic changes in portal circulation by doppler sonography after endoscopic sclerotherapy

To determine the effect of endoscopic variceal sclerotherapy [ES] on the hemodynamic of portal venous system, 40 patients with intrahepatic cause of portal hypertension and bleeding oesophageal varices [OV] were enrolled in this study. Assessment of main portal vein [MPV], its right and left branches [RPV], [LPV], splenic vein [SV] and superior mesenteric vein [SMV] by duplex [DU] and color coded Doppler sonography [CCDS] were done before and after complete obliteration of OV by ES to determine their diameters, patency, pattern and direction of flow, blood flow velocity, blood flow volume and congestion index. 28 patient were effectively treated by ES, 5 cases died after uncontrolled hemorrhage and 7 cases escaped before complete obliteration of OV. Coronary veins showed no flow in 65% of cases after ES. Incidence of reappearance of OV and recurrent attacks of bleeding were significantly lower in these cases than those with patent one. Child-Pugh's classification and hemodynamic parameters of studied vessels showed insignificant difference before and after complete obliteration of OV. We found that Duplex and CCDS are valuable, rapid, noninvasive screening procedure for monitoring hemodynamics of portal venous system. ES seems to be suitable method for patient with PH and bleeding OV. It preserves the relationship between the factors interacting in the portal venous system hemodynamic

Pulmonary function abnormality in patients with portal hypertension with or without chronic liver disease.

Pulmonary function (FVC, FEV1, PEFR, MMEF) and arterial blood gases (ABG) were analysed in 30 patients of portal hypertension. The aetiology of portal hypertension included cirrhosis of liver (n = 10), non cirrhotic portal fibrosis (NCPF, n = 10) and extrahepatic portal vein obstruction (EHPVO). Ten patients with chronic active hepatitis (CAH) without portal hypertension were also studied. Most pulmonary functions were abnormal (low) in portal hypertension and the most affected parameters, were FEV1, PEFR and MMEF (p < 0.05). The same was also observed in CAH, although in less number of patients. Hypoaxemia (26.7%) and wide alveolar--arterial oxygen gradient were observed most frequently in patients of portal hypertension. These patients also had a more alkaline blood pH. EHPVO patients had better lung function and arterial blood gas values. Patients with NCPF had greater impairment in pulmonary function.

Portal and systemic fibrinolysis in cirrhotic patients and their relation to oesophageal variceal bleeding

Disturbed hemostasis is well documented among patients with hepatic cirrhosis. In this work, plasma fibrinolytic activity was evaluated in both portal [variceal] and systemic [venous] blood in patients with cirrhosis, in a trial to investigate its possible relation to bleeding esophageal varices, as well as to the degree of liver cell failure, to find out whether it is locally enhanced in the varices or not. Sixty- three cirrhotic patients were the subjects of this work. Sixteen healthy individuals served as normal controls. BT, platelet count, PT, PTT and fibrinogen level were studied in all systemic blood samples. Plasminogen, t-PA, PAI-1, PAP, FDPs and D-dimers were evaluated in systemic and variceal samples. All parameters were considerably altered in diseased groups. With the exception of PAI-1 the impairment of hemostatic parameters tended to parallel the degree of liver cell failure. Unexpectedly, the hemostatic disturbance was more marked in patients with non bleeding esophageal varices than in those with bleeding varices. Furthermore, all fibrinolytic parameters studied showed insignificant differences between systemic and variceal samples, i.e. There is no evidence of locally enhanced fibrinolysis in the varices

Ultrasonic evaluation of portosystemic collateral circulation in portal hypertension.

The aim of the study was to evaluate portosystemic collateral circulation in relation to (1)individual etiological groups of portal hypertension., (2) Presence and size of esophageal varices, (3) esophageal sclerotherapy and (4) ascites. A prospective study of 101 patients of portal hypertension was carried out. Patients were divided into 4 etiological groups: Alcoholic cirrhosis (ALD) (38), Non-alcoholic cirrhosis (NALD) (35), non cirrhotic portal fibrosis (NCPF) (14) and extrahepatic portal vein obstruction (EHPVO) (14). Esophageal varices were assessed and graded endoscopically into 3 categories: no varix, small varices and large varices. Evaluation of portosystemic collateral circulation, other than esophageal varices was done ultrasonically. "Other" portosystemic collaterals (lienorenal, gastrorenal, dilated paraumbilical and umbilical veins, paraduodenal and gall bladdes varices) were seen in 26 out of 101 patients and more commonly in the non-cirrhotic groups (50%) [NCPF: 57.14%, EHPVO: 42.86%] than in the cirrhotic group (16.44%) [ALD: 13.5%, NALD: 20%]. Gall bladder varices were the only form of ectopic (extra esophagogastric) varices visualised with an overall incidence of 3.96%. Collateral shunts were seen more frequently in patients without varices (100%), than in patients with small varices (34.88%) or large varices (7.84%), and in patients having undergone esophageal sclerotherapy (57.14%). Collateral circulation did not contribute to the development of ascites. 37 patients with ascites did not have collateral shunts. We conclude portosystmic circulation plays a decompressive role in portal hypertension and prevents formation of esophageal varices or prevents them from increasing in size. It is seen more frequently in noncirrhotic patients and in those having undergone sclerotherapy and does not contribute to development of ascites.

Derivación portopulmonar mediante esplenoneumopexia en la hipertension portal del canino: modelo experimental / Portopulmonar derivation by means of splenoneumopexy in dog portal hypertension: an experimental model

En un modelo animal de hipertensión portal extrahepática, se intentó crear una derivación portopulmonar mediante la anastomosis parenquimatosa entre el bazo y pulmón (esplenoneumopexia), lo cual excluye a la cirugía vascular que fue el propósito fundamental del estudio. De ocho perros hipertensos en los que se efectuó esta técnica, modificando una de sus fases, misma que fue recientemente propuesta por autores japoneses se presentaron dos defunciones tempranas por causas infecciosas no atribuibles al procedimiento en sí y de los seis sobrevivientes, en cinco la presión portal disminuyó 13 cm de agua en promedio en relación a la cifra inicial (25.9 en promedio) dos meses después de la cirugía, angiográficamente se documentó a satisfacción el paso de material de contraste a través de la esplenoneumopexia, demostrando una reducción importante del calibre o diamétro de las principales venas del sistema, exceptuando la porta. Una vez sacrificados los animales, la anastomosis se mostró siempre bien integrada e histológicamente se observaron vasos de neoformación en su interfase. Se describe detalladamente la técnica empleada y se hacen inferencias de sus posibles indicaciones en niños menores de cuatro años (diámetro venoso menor de 0.8 cm), proponiéndose en el adulto como una alternativa en la cirugía de la hipertensión portal.