Studies related to portal hypertension

Cirrhosis of the liver is a chronic disorder resulting from a variety of known and unknown aetiological factors, which lead to hepatocyte damage and death, regeneration of remaining hepatocytes and progressive fibrosis in a sequential manner. This ultimately leads to distortion of the architecture of the liver lobules. The net result is liver cell dysfunction and an increase in the intrahepatic resistance to blood flow. The latter, combined with alteration of portal blood flow and of extrahepatic splanchnic vascular responsiveness characterizes portal hypertension.Systemic and splanchnic vasodilatation seem to be prominent features of decompensated hepatic cirrhosis and lead to a fall in the effective circulating blood volume. This results in the activation of a cascade of compensatory events, which include the RAS, release of AVP and heightened sympathetic nervous system activity. Neuronal and humoral mechanisms, therefore, seem to be central to the sodium and water retention, which occurs in cirrhosis of the liver. These pathophysiological changes contribute to fluid retention and ascites.The regulation of arterial tone in cirrhosis of the liver is complex and a multitude of factors seem to be playing a part. The areas which have been explored in the past include the role of endothelial-derived vasodilator agents, circulating vasodilator agents which act on the vascular smooth muscle, and lack of response of the vascular smooth muscle to vasoconstrictor agents.The last could in fact be a result of the first two factors. There is a paucity of data on human tissues in the literature because of difficulty in acquiring larger distributory arteries from cirrhotic patients for experimentation. Blood vessels acquired at OLT offer the opportunity to study donor (normal) and recipient (cirrhotic) blood vessels invitro under controlled standardized conditions (organ bath experiments).The development of portal hypertension itself is followed by clinically important sequelae. Enlargement of the spleen is an early and cardinal sign of portal hypertension and it is difficult to make a diagnosis of portal hypertension without the demonstration of splenomegaly. Factors which participate in the development of splenomegaly include increase in portal pressure and splanchnic blood flow, and RE cell hyperplasia. However, the correlation of spleen size to these factors is not entirely clear. The difficulty in interpreting the results of different studies in this area of medicine is partly due to the lack of information about the accuracy of methods used for determining spleen size and partly due to the paucity of data comparing the different methods of measuring spleen size including ultrasonography, CT scanning, MRI and radionuclide studies. Radionuclides have also been used to quantify splanchnic blood flows as well as liver function in the normal and patients with chronic liver disease but there is again a scarcity of data in this regardThe development of portal hypertension is associated with the opening up of portasystemic collateral shunts at different sites in order to decompress the portal circulation. Clinically important shunt vessels develop in the oesophagus, stomach and the duodenum. These assume varicose proportions and can rupture when the intravascular pressures rise above a threshold value. This can lead to potentially life threatening haemorrhage. Shunting of blood to the systemic circulation is also a contributory factor in hepatic encephalopathyImpairment of glucose tolerance and even the development of diabetes mellitus are also consequences of cirrhosis and portal hypertension occurring in 10-40% of patients. The prevalence of these abnormalities of glycaemic control increases as the duration and severity of liver disease increases. Although, it is generally believed to be a result of insulin resistance at the peripheral receptor sites, the pattern of insulin secretion from the P cells of the pancreas is also believed to be altered in this form of diabetes, particularly in the later stages. However, there are obvious problems in quantifying insulin secretion from the endocrine pancreas as it undergoes significant extraction during first pass through the normal liver and the pulse mass is lost to a large extent. Measurements done at the peripheral vein site are therefore not an accurate reflection of the quantum of insulin secretion over a period of time. TIPSS used to treat complications of portal hypertension are reviewed at portographic examinations and can be used to study the pattern of insulin secretion directly from the portal vein. Although this complex investigation could only be done in a few patients with relatively stable liver function, this human model can be used to study the pattern of insulin secretion in the patients with different grades of severity of liver disease and normal as well as abnormal glucose tolerance in hepatic cirrhosisA number of treatment strategies have been devised for prevention of bleeding and control active bleeding from varices in the gastro-intestinal tract. These include endoscopic sclerotherapy, endoscopic variceal ligation, pharmacological measures including ß adrenoreceptor blocking agents and nitrates, surgical decompressive shunts and TIPSS.TIPSS is the most recent addition to the armamentarium of treatment modalities. Although it is a highly effective of treatment, there are obvious problems in that procedure related and short and long-term complications limit its acceptability. Procedure related complications include intraperitoneal bleeding and subcapsular haematoma in the liver. The main longer-term problems relate to sepsis, precipitation of hepatic encephalopathy and SI and occlusion. A number of shunt and patient related factors have been assessed as predictors of SI and these include, age and sex of patients, the liver functions, pre- and post-stent insertion portal pressures and the diameter of the stent. The role of diabetes mellitus, which has been shown to encourage stenosis in vascular stents placed elsewhere in the body, has not been assessed in TIPSS.Accordingly, the aim of this thesis was to explore the following aspects of hepatic cirrhosis and portal hypertension.1.1 TO STUDY THE PATHOPHYSIOLOGIC MECHANISM OF VASCULAR HYPORESPONSIVENESS IN HEPATIC CIRRHOSIS. • The aim in these experiments was to investigate the role of NO release in modulating a-adrenoceptor mediated contraction in hepatic cirrhosis.1.2 TO STUDY CLINICAL SEQUELAE OF PORTAL HYPERTENSION DUE TO HEPATIC CIRRHOSIS. These were the areas of study in relation to clinical sequelae: • The clinical aspects of splenomegaly and its relation to portal haemodynamic factors in portal hypertension due to hepatic cirrhosis. • The role of radionuclides in measuring spleen size and assessing liver function in hepatic cirrosis and portal hypertension.1.3 TO STUDY THE PATTERN OF INSULIN SECRETION IN CIRRHOTIC PATIENTS WITH TIPSS AND THE IMPACT OF DIABETES MELLITUS ON TIPSS FUNCTION. • The pattern of pulsatile insulin secretion in portal vein in patients suffering from hepatic cirrhosis using a TIPSS inserted model was studied. This model should help study pattern of insulin secretion in different stages of hepatogenous diabetes mellitus, ie., impaired glucose tolerance and frank diabetes mellitus. • The effect of diabetes mellitus on the efficacy of TIPSS in the treatment of patients suffering from portal hypertension has been studie