Hepatic First-Pass Clearance of Oral Galactose and its Potential Use in the Assessment of Portasystemic Shunting in Portal Hypertension

Smith, Sheelah (1990) Hepatic First-Pass Clearance of Oral Galactose and its Potential Use in the Assessment of Portasystemic Shunting in Portal Hypertension. PhD thesis, University of Glasgow.

Abstract

Portasystemic shunting is an important consequence of all diseases that lead to portal hypertension. The clinical-pathological problems associated with portasystemic shunting, such as hepatic encephalopathy and oesophageal varices, remain a potent cause of much morbidity and mortality. The aetiology of hepatic encephalopathy remains poorly understood, but it is thought that the more subtle sequallae of portasystemic shunting, such as hormonal (Fischer et al, 1974), and nutritional (Phear et al, 1955; Fischer and Baldessarini, 1971) changes contribute in varying degrees to the onset and progression of the condition. Quantitation of the magnitude of portasystemic shunting is thus potentially most useful in the study of hepatic encephalopathy. Up to now it has not been practical to measure on a routine basis the fraction of portal blood that bypasses functioning hepatocytes to reach the systemic circulation. The available methods are either highly invasive (Okuda et al, 1977), time consuming (McLean et al, 1979), or suffer from known measurement inaccuracies (Porchet and Bircher, 1982; Cavanna et al, 1987), and their applications have been limited to a few studies. The purpose of this thesis is to describe and assess a novel, non-invasive procedure that approaches quantitative assessement of portasystemic shunting. The principle of the method consists of a comparison of the systemic availability of an oral and intravenous dose of galactose. The ability of galactose to quantitate the magnitude of portasystemic shunting associated with portal hypertension has been examined in patients with documented oesophageal varices and in a rat model of prehepatic portal hypertension using partial portal vein ligation. The rat model had been established and characterised previously in the University Department of Surgery, Glasgow Royal Infirmary (Geraghty et al, 1989). Data from the studies described in this thesis has shown a marked difference in the systemic availability of galactose between control patients and patients with liver disease and/or portal hypertension. In the former group only 14 percent of the oral dose appeared in the systemic circulation, whereas in portal hypertensive patients an average of 72 percent (range 38% to 108%) was detected systemically. The absence of a gold standard for portasystemic shunting measurements, and ambiguity in the definition of portasystemic shunting itself, preclude direct validation of the measurements in man. However, the key assumptions about galactose elimination kinetics underlying the measurement technique were tested independently and found to be satisfied. The initial application of the technique in the rat model of prehepatic portal hypertension, in which independent measurements of portasystemic shunting could be performed using a radioactive microsphere technique, failed to show a difference in the systemic availability of oral galactose between control and portal hypertensive rats. Further studies showed this was largely due to erratic and incomplete absorption of galactose from the gastrointestinal tract. A more comprehensive investigation was carried out and the kinetics of hepatic galactose elimination in the rat was studied by direct infusion of galactose into the portal vein. From this it was shown that, in contrast to man, hepatic extraction efficiency in this animal model had a high dependence on circulating blood galactose concentrations. This compromised the accuracy of the technique for quantitation of portasystemic shunting in individual animals because of the variability in kinetic parameters. However, there was a highly significant correlation between the systemic availability of intraportally administered galactose in rats and portasystemic shunting as measured with radioactive microspheres. The galactose technique described in this thesis may thus be regarded as a tool to assess the magitude of portasystemic shunting, and may have a role in the study of the associated complications of hypertension and liver disease.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Medicine, Surgery
• Date of Award: 1990
• Depositing User: Enlighten Team
• Unique ID: glathesis:1990-78132
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 28 Feb 2020 12:09
• Last Modified: 28 Feb 2020 12:09
• URI: https://theses.gla.ac.uk/id/eprint/78132