P.C. Hayes

The role of the transjugular intrahepatic portosystemic stent shunt (TIPSS) in the management of bleeding gastric varices: clinical and haemodynamic correlations

Background: The transjugular intrahepatic portosystemic stent shunt (TIPSS) is effective in the management of both oesophageal and gastric variceal bleeding. Although it has been reported that gastric varices can bleed at pressures of ≤12 mm Hg, this phenomenon has been little studied in the clinical setting. Aims: To assess the efficacy of TIPSS on rebleeding and mortality following gastric and oesophageal variceal bleeding, and the importance of portal pressure in both groups. Methods: Forty eligible patients who had bled from gastric varices and 232 from oesophageal varices were studied. Patients were also subdivided into those whose portal pressure gradients (PPG) prior to TIPSS were ≤12 mm Hg (group 1) and >12 mm Hg (group 2). Results: There was no difference in Child-Pugh score, age, sex, or alcohol related disease between patients bleeding from gastric or oesophageal varices. Patients who bled from gastric varices had a lower PPG pre-TIPSS (15.8 (0.8) v 21.44 (0.4) mm Hg; p<0.001). There was no difference in the rebleeding rate (20.0% v 14.7%; NS). There was a significant difference (p<0.05) in favour of the gastric varices group in the one year mortality (30.7% v 38.7%) and five year mortality (49.5% v 74.9%), particularly in those patients in group 2. Gastric variceal bleeding accounted for significantly more cases in group 1 than in group 2 (36.8% v 10.2%; p<0.001). Most patients in group 2 who rebled had a PPG post-TIPSS of >7 mm Hg. Conclusions: TIPSS is equally effective in the prevention of rebleeding following gastric and oesophageal variceal bleeding. A significant proportion of gastric varices bleed at a PPG ≤12 mm Hg. The improved mortality in patients with gastric variceal bleeding is seen only in those that bleed at a PPG >12 mm Hg, and warrants further study.

Reduction in renal blood flow following acute increase in the portal pressure: evidence for the existence of a hepatorenal reflex in man?

BACKGROUND: To investigate the relation between changes in portal haemodynamics and renal blood flow (RBF) in patients with cirrhosis. PATIENTS/METHODS: Twenty patients with cirrhosis and transjugular intrahepatic portosystemic stent-shunts were divided into two groups which were well matched. At routine portography, either changes in unilateral RBF (group I) or changes in cardiac output (group II) before and after shunt occlusion were studied. Blood was obtained from the renal and systemic circulations for the measurement of neurohumoral factors before and after shunt occlusion in group I patients. RESULTS: After shunt occlusion, there was a progressive reduction in unilateral RBF from a mean (SD) of 289 (32) to 155 (25) (-43.5%) (p < 0.001). These changes correlated significantly with the changes in the portal atrial gradient (p < 0.001). There was no significant change in heart rate, mean arterial pressure and right atrial pressure. No significant changes were found in the concentrations of the various neurohumoral factors measured. There was a less notable but significant reduction in the cardiac output (-10.9%) (p = 0.02) unaccompanied by significant reduction in the pulmonary capillary wedge pressure or mean arterial pressure. CONCLUSIONS: These results suggest the existence of hepatorenal reflex in man which is important in the regulation of RBF, although other mechanisms may also be contributory.

Clinical significance of intrahepatic hepatitis C virus levels in patients with chronic HCV infection

Background—The clinical significance of a single assessment of circulating hepatitis C virus (HCV) RNA and its relation to the level of intrahepatic HCV RNA remains unclear. Aims—To investigate the relation between intrahepatic HCV levels and clinicopathological characteristics of chronic HCV infection. Patients—Ninety eight consecutive patients with chronic HCV infection were studied; none had received α interferon therapy. Of these, 12 patients were repeatedly negative for HCV RNA in serum by reverse transcriptase polymerase chain reaction (RT-PCR). Methods—After diagnostic laparoscopy and liver biopsy, semiquantitative analysis of intrahepatic HCV RNA levels was carried out by limiting dilution of HCV cDNA. HCV genotypes were assessed in 96 patients by restriction fragment length polymorphism analysis of HCV cDNA. Results—Ten out of 12 patients who were RT-PCR negative for HCV RNA in serum were RT-PCR positive in liver; however, this group had a significantly lower intrahepatic HCV level and serum aminotransferase level than the remaining 86 patients. Histological severity (cirrhosis: n=10); histological activity index; HCV genotype (genotype 1: n=41; genotype 2: n=12; genotype 3: n=36; genotype 4: n=7); mode of infection (intravenous drug abuse: n=58; post-transfusion: n=10; haemophiliac: n=4; sporadic: n=26) and alcohol abuse did not affect the intrahepatic virus level. There was no correlation between patient age, duration of infection, and intrahepatic HCV level. Conclusions—Intrahepatic virus levels were not determined by host factors (age of patient, mode or duration of infection) or by virus factors (HCV genotype). Repeatedly negative RT-PCR for HCV RNA in serum does not indicate absence of HCV from the liver.

Cytosolic and microsomal glutathione S-transferase isoenzymes in normal human liver and intestinal epithelium.

Glutathione S-transferases are a group of drug metabolising and detoxification enzymes. We have studied the distribution of four isoenzymes, acidic, basic, neutral, and microsomal GST in human liver, gall bladder, and small and large intestinal epithelium by immunohistochemistry. Antibodies were raised in rabbits to purified GST subunits and several formalin fixed paraffin sections of each human tissue studied using the peroxidase-antiperoxidase method. Staining density was graded from very strong (+++) to negative (-). All four enzymes were identified within the liver, the acidic GST being found almost exclusively within the biliary epithelium. The gall bladder epithelium stained strongly for acidic and basic GST. In the small intestinal epithelium the acidic and neutral GST were readily identified in villi and crypts, whilst basic GST was found only in the villi and microsomal only in the crypts. In the colonic mucosa only acidic GST could consistently be identified. This histological heterogeneity may have functional implications for these enzymes in human hepatobiliary and intestinal tissue.

Association between chronic hepatitis C infection and hepatocellular carcinoma in a Scottish population.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. The geographical prevalence varies considerably in different countries and Scotland is regarded as an area of low risk for the disease. AIMS: To assess the association between chronic hepatitis C infection (HCV) and HCC in a population of patients presenting to a single hospital. PATIENTS: One hundred and fourteen cases of histologically confirmed liver cancer presenting to the Royal Infirmary of Edinburgh between 1985 and 1994 were examined. METHODS: Of 114 cases of HCC, 80 samples of stored sera were available. Samples positive for HCV Ab were genotyped by restriction fragment length polymorphism analysis of HCV c-DNA. A population of 29 cirrhotic patients (diagnosed between 1985 and 1994) with chronic HCV infection was also genotyped. RESULTS: Chronic HCV infection was a major risk factor (30% of tested HCC patients) identified. HCV genotype 1b was predominant (16 of 20 patients). The time from HCV transmission to development of cancer ranged from 10 to 50 years (median 30). In the cirrhotic patient population, a broader distribution of genotypes was present (genotype 1a: 7; genotype 1b: 8; genotype 2b: 3; genotype 3a: 8 and genotype 4: 2). However, this population was significantly younger. (Mean (SD) 52 (14.5) years) (p = 0.0002) and demonstrated a significantly shorter duration of infection: range 10-40 years (median: 19). CONCLUSION: There is a strong association between chronic HCV infection, cirrhosis, and hepatocarcinogenesis in this Scottish population. The study was unable to distinguish whether the high prevalence of genotype 1b in the HCC population reflected increased oncogenicity in itself, or whether 1b was simply the most prevalent genotype in Scotland when these patients were infected.

Transjugular intrahepatic portasystemic stent shunting for control of acute and recurrent upper gastrointestinal haemorrhage related to portal hypertension.

The insertion of a transjugular intrahepatic portasystemic stent shunt (TIPSS) was evaluated in 22 patients with recurrent upper gastrointestinal haemorrhage related to portal hypertension (bleeding from oesophageal varices 10, gastric varices six, portal hypertensive gastropathy six). TIPSS was successfully performed electively in 15 patients and as an emergency in three patients. Twelve patients have had no further admissions with bleeding after TIPSS. Single episodes of bleeding were noted in six patients after TIPSS associated with shunt thrombosis (two), intimal hyperplasia within the shunt (two), and shunt migration (one). Another patient presented with reaccumulated ascites suggesting poor shunt function but died from massive variceal haemorrhage before further assessment could be performed. There was one death related to the procedure. Two patients developed encephalopathy after TIPSS, in one patient this was controlled by the insertion of a smaller diameter stent within the existing TIPSS. Several complications arose in earlier patients that have not recurred after modification of the initial technique. TIPSS can be life saving and is effective in controlling variceal haemorrhage and rebleeding from oesophageal or gastric varices and portal hypertensive gastropathy. Larger and longer term studies are required, however, to define the role of TIPSS in the overall management of such patients.

The clinical significance of the detection of hepatitis GBV‐C RNA in the serum of patients with fulminant, presumed viral, hepatitis

In a significant number of cases of fulminant (presumed viral) hepatitis worldwide, no aetiological agent has been identified. Recently, it has been suggested that a newly described flavivirus, GBV‐C, is responsible for some of these cases. This study aimed to assess the clinical significance of GBV‐C RNA, demonstrated by reverse transcriptase–polymerase chain reaction (RT–PCR), in the serum of patients with fulminant non‐A to E hepatitis. Twenty‐three consecutive cases of non‐A to E fulminant hepatitis were included in the study. GBV‐C RNA was reverse transcribed and amplified using two RT–PCR based detection methods. Medical records were examined to assess clinical history, duration and mode of infection, transfusion history, liver histology and clinical outcome. Five (three female, two male; mean age 21.2 years) of 23 patients had GBV‐C RNA detected in their serum by RT–PCR; all five patients were RT–PCR positive following amplification by primers specific for the 5 non‐coding region (NCR), whilst four were positive by primers for the NS3 region. Prior to the onset of illness, two patients had risk factors for transmission of an infectious agent; however, all five patients had been transfused during their illness, prior to testing for GBV‐C. Of these, two (of two in whom serum was available) were negative for GBV‐C after the onset of fulminant hepatitis but before their first transfusion. This study does not support the hypothesis that the detection of hepatitis G virus (HGV)/GBV‐C RNA in the serum of patients with fulminant hepatitis indicates a causal association. However, it does demonstrate that a careful transfusion history and screening of blood products is vital before the importance of GBV‐C in the aetiology of fulminant hepatitis can be established.

Glutathione S-transferases in human liver cancer.

An immunohistochemical study of glutathione S-transferase (GST) expression in hepatocellular carcinoma and cholangiocarcinoma is described. Unlike most animal models of hepatic malignancy pi class GST was not consistently overexpressed in hepatocellular carcinoma. This tumour type either predominantly expressed alpha class GST or failed to express GST. By contrast, cholangiocarcinoma always expressed pi class GST, presumably reflecting the tissue of origin, since in human biliary epithelium pi class GST is the predominant GST. The variable expression of pi class GST which was observed in hepatocellular carcinoma may reflect transformation of hepatocytes damaged by toxins, since this GST can be induced after a chemical insult such as alcohol. As well as indicating the biochemical heterogeneity of hepatocellular carcinoma with respect to GST, this study indicates the need for further study of the nature of inherent drug resistance in these tumour types.

Prediction of cirrhosis in patients with chronic hepatitis C infection by artificial neural network analysis of virus and clinical factors

The diagnosis of cirrhosis in patients with hepatitis C virus (HCV) infection is currently made using a liver biopsy. In this study we have trained and validated artificial neural networks (ANN) with routine clinical host and viral parameters to predict the presence or absence of cirrhosis in patients with chronic HCV infection and assessed and interpreted the role of the different inputs on the ANN classification. Fifteen routine clinical and virological factors were collated from 112 patients who were HCV RNA positive by reverse transcriptase–polymerase chain reaction (RT–PCR). Standard and Ward‐type feed‐forward fully‐connected ANN analyses were carried out both by training the networks with data from 82 patients and subsequently testing with data from 30 patients plus performing leave‐one‐out tests for the whole patient data set. The ANN results were also compared with those from multiple logistic regression. The performance of both ANN methods was superior compared with the logistic regression. The best performance was obtained with the Ward‐type ANNs resulting in a sensitivity of 92% and a specificity of 98.9% together with a predictive value of a positive test of 95% and a predictive value of a negative test of 97% in the leave‐one‐out test. Hence, further validation of the ANN analysis is likely to provide a non‐invasive test for diagnosing cirrhosis in HCV‐infected patients.

Glutathione S-transferases in alcoholic liver disease.

There is already evidence in alcoholic liver disease, mostly from studies of morphology and cytokeratin distribution, that hepatocytes can undergo a variety of phenotypic changes. This study reports findings of immunohistochemistry using antibodies against members of the glutathione S-transferase supergene family of detoxification enzymes. Hepatocytes in severe alcoholic liver disease coexpressed both alpha and pi class glutathione S-transferase. This coexpression has been previously described only in human fetal liver and in chemically-induced preneoplastic foci in rat liver. The use of function associated markers should provide additional information in the investigation of liver disease.