Pathophysiology of portal hypertension and implications for its pharmacological control.
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Biomedical subjects
Publications and source records attributed to F J Dudley.
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To be maximally effective, antiulcer medications should relieve ulcer symptoms rapidly and promote rapid healing of an ulcer crater; after the cessation of a course of treatment the ulcer should not recur. A wide variety of agents is available. These are of similar efficiency in the control of ulcer symptoms and in the acceleration of the healing of the ulcer crater. However, evidence exists of differences in the rate of the recurrence of duodenal ulcers on the cessation of these drugs. Surface-active agents (bismuth complexes, sucralfate, prostaglandins and carbenoxolone) are consistently superior to H2-histamine receptor antagonist drugs (cimetidine and ranitidine). A high relapse rate produces more patients with active disease at any one time, hence more patients will be exposed to the complications of the disease, and will require active investigation and therapy. Because of the increased rate of relapse, the use of H2-receptor antagonist drugs as first-line intermittent healing therapy can be shown to be associated with an eight-fold (800%) increase in cost of pharmaceutical agents as compared with first-line treatment with bismuth salts; a four-fold increase compared with the cost of using antacid drugs; and a two-fold increase compared with the cost of using sucralfate. When maintenance therapy with H2-receptor antagonist agents is given instead of intermittent therapy with bismuth complexes, a 14-fold increase in pharmaceutical costs is incurred, with inferior results that have already been demonstrated under the conditions of a controlled clinical trial. These considerations of efficacy and cost suggest that H2-receptor antagonist drugs ought not to be first-line therapy for duodenal ulcers; rather, surface-active agents such as colloidal bismuth or sucralfate should be prescribed initially.
A case is presented where a patient's cirrhotic ascites was refractory to conventional treatment and where the usual factors which precipitate refractory ascites were excluded. We believe that this patient's apparently refractory ascites was precipitated by an obstructive uropathy, as evidenced by dramatic diuresis, natriuresis, and return to diuretic sensitivity following relief of the obstruction.
Sixteen alcoholic cirrhotic patients with portal hypertension were studied before and after 2.5 micrograms/kg intravenous clonidine. In six patients portal venous pressure was assessed simultaneously by wedged hepatic vein and transhepatic portal vein cannulation. Wedged hepatic vein pressure accurately reflected portal venous pressure both before and after clonidine (r = 0.912 and 0.940; p less than 0.01). In all the other ten patients, sympathetic tone, measured by total plasma noradrenaline spillover, was high (755 +/- 123 ng/min; normal 296 +/- 29 ng/min). It fell significantly after clonidine (378 +/- 95 ng/min; p less than 0.01). This fall was associated with a decrease in corrected wedged hepatic vein pressure (18.6 +/- 1.1 to 13.4 +/- 0.5 mm Hg; p less than 0.01) but no change in estimated hepatic blood flow (934 +/- 94 to 976 +/- 102 ml/min), indicating a fall in postsinusoidal hepatic vascular outflow resistance. Clonidine-induced changes in mean arterial pressure and cardiac output were independent of the change in portal venous pressure. The results suggest that in alcoholic cirrhosis there is a labile component of hepatic vascular resistance which is partly under sympathetic nervous control and is thus potentially sensitive to pharmacological control.
To assess whether portal venous pressure remains elevated following distal lienorenal shunt surgery, 11 patients with alcoholic cirrhosis were assessed from 0.5 to 59 months following the creation of a distal lienorenal shunt. These were compared with five patients following mesocaval shunt surgery and nine with cirrhosis alone. Portal pressure was measured by direct transhepatic catheterization of the portal vein or by determining intrahepatic pulp pressure. Splenic pulp pressure was also measured in the shunt groups at the time of assessment of shunt patency by scintisplenoportography. All shunts were patent. Four of five patients studied within 10 months of distal lienorenal shunt surgery had persisting portal hypertension (comparable with that in the cirrhosis alone group) and persisting portasplenic gradient. In contrast, five of six patients studied more than 10 months following surgery had portal pressures similar to that following mesocaval shunt surgery and no portasplenic gradient. Thus, with time, selective decompression tends to become total decompression. Whether this correlates with deterioration of hepatic function requires further study.
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The case of a 67-year-old woman who had a long history of recurrent cholangitis after repeated biliary tract surgery, and whose clinical course was complicated by the development of multiple biliary strictures and secondary biliary cirrhosis, is reported. Nasobiliary drainage was used to successfully decompress the biliary system and to control infection during an acute episode of cholangitis. Subsequent endoscopic, hydrostatic balloon dilatation of the major bile-duct strictures resulted in an improvement in her clinical condition which was supported by the results of biochemical tests.
Healing of duodenal ulcers was assessed in 66 patients who received omeprazole either 10 mg or 30 mg daily for four weeks in a double blind study. Healing was rapid in both groups. At two weeks the ulcers in 15 of the 30 patients taking 10 mg daily had healed compared with 28 of the 36 (78%) taking 30 mg daily (p less than 0.03). At four weeks the respective proportions had risen to 83% (25/30) and 94% (33/35) (p greater than 0.05). In non-smokers the proportion of ulcers healed did not differ significantly with the two doses, although there was a trend for less healing at two weeks with 10 mg daily; in smokers significantly fewer ulcers (p less than 0.05) were healed with 10 mg than 30 mg daily at two weeks (7/16 (44%) v 17/21 (81%] and at four weeks (12/16 (75%) v all 21 (100%]. Adverse reactions were few and transient and were considered unlikely to be due to omeprazole.
This study establishes that real differences between relapse rates exist, and confirmed previous observations by Pounder et al. that relapse rates influence clinical outcomes in ulcer populations. The results make it clear that the way in which a drug influences relapse is an important determinant of therapeutic efficiency, additional to the requirement for healing efficiency. Cytoprotective agents as a group appear to be associated with lower relapse rates than cimetidine. It is not known whether the differences are peculiar to cimetidine, specific to the blockade of H2-histamine receptors, or whether they relate to the process of inhibition of secretory processes generally. Clearly, further comparisons are needed; however, conventional clinical trials are not designed to provide the necessary information. For the healing of peptic ulcers, lower relapse rates appear to provide therapeutic advantage to members of the cytoprotective group when compared with agents acting via anti-secretory mechanisms, in addition to that associated with the local (non-systemic) mode of action where applicable.
The clinical features of 77 patients with primary liver cell carcinoma seen over a nine-year period were examined. Eighty per cent of the patients had underlying cirrhosis, of alcoholic origin in most cases. In nine of the patients hepatitis B surface antigen was found in the serum; all nine patients were born in areas where hepatitis B virus infection is endemic. Abdominal pain and ascites were the most common presenting symptoms; they are due mainly to the locally invasive nature of the tumour. A confirmatory laboratory finding in the diagnosis is the observation of raised alkaline phosphatase levels and the presence of alpha-fetoprotein in the serum. The diagnosis should be established without performing a laparotomy and should seriously be considered in a previously stable patient with cirrhosis who deteriorates clinically without obvious cause.
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Two cases of right hepatic hydrothorax occurring in the absence of clinical ascites are reported. Diagnosis was confirmed by the intraperitoneal and intrapleural injection of radioisotope 99mTc-sulfur colloid that demonstrated the one-way transdiaphragmatic flow of fluid from the peritoneal to pleural cavities. In contrast, radioisotope injected into the peritoneal cavity of 5 patients with pleural effusions secondary to pulmonary or cardiac disease failed to traverse the diaphragm and localize in the pleural space. Medical therapy with salt and water restriction and diuretics resulted in both of the patients with hepatic hydrothorax developing signs of intravascular volume depletion without significant mobilization of the pleural fluid. Thoracotomy allowed identification of the diaphragmatic defects that were repaired by chemical and traumatic pleurodesis followed by postoperative peritoneal and pleural drainage. This therapy resulted in complete resolution of the pleural effusions, which have not recurred despite the subsequent development of clinical ascites in both patients.
The long term morbidity and mortality of two consecutive groups of patients undergoing successful shunt surgery for bleeding oesophageal varices has been studied. Twenty-seven patients with a non-selective shunt in the form of a mesocaval Dacron 'H' graft and 21 patients with selective variceal decompression via a distal lienorenal shunt, all of whom had a patent shunt on discharge from hospital, were included in the study. Shunt associated encephalopathy was documented in 77% of the patients following mesocaval shunts and only 19% of patients following distal lienorenal surgery. Other postoperative morbidity was largely related to problems with the synthetic Dacron graft. Late shunt blockage, often resulting in recurrent variceal bleeding, was documented in 25% of these patients and shunt infection was responsible for complicating fatal disseminated sepsis in 18.5%. Long term survival, as assessed by life table analysis, following distal lienorenal shunt surgery was consistently better than that following mesocaval shunts. This was largely due to specific problems which could be directly related to the synthetic nature of the Dacron graft. It is concluded that the mesocaval Dacron interposition graft carries the potentially lethal long term complications of shunt blockage and infection rendering it unsuitable as a portasystemic shunt. Provided that successful surgery can be performed the distal lienorenal shunt may be a more appropriate alternative due to its reduced shunt related morbidity and, possibly, mortality.
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In conclusion, an understanding of the pathophysiology of ascitic fluid formation and clearance in patients with liver disease has resulted in the development of new approaches to the treatment of refractory ascites. Although these techniques have been very successful in controlling ascites they have been associated with a number of complications which can contribute to both short and long term morbidity and mortality. An approach to the individual patient must be based on detailed evaluation of the associated liver disease, its potential reversibility, and documentation that the ascites is truly refractory. If ascites reaccumulates rapidly following ultrafiltration and reinfusion of ascitic fluid then careful consideration may be given to insertion of a peritoneovenous shunt. Careful pre- and postoperative monitoring is necessary if significant complications are to be avoided.
The mode of pharmacological healing influences subsequent ulcer relapse. Duodenal ulcer relapse following healing and withdrawal of active therapy has been studied in 18 prospectively randomised comparative studies involving cimetidine and alternative healing agents. Most studies (eleven of the 18) showed comparative agents with a lower (greater than 10%) incidence of relapse than cimetidine while a minority (seven of the 18) showed equal (+/- 10%) relapse. The probability of this distribution occurring by chance is less than 1:1000 (p = 0.0005, sign test). In three of the 11 published comparative studies the relapse rate was significantly higher in those who had previously received cimetidine (p less than 0.05, two-sided significance test). This was despite the fact that most of the individual studies were small and required a substantial difference in results for the 5% significance level to be reached. Paired comparative incidences of relapse at six months were converted to relapse rates (percentage of healed population relapsing monthly), average rates for comparative agents were 8.05 +/- 2.7% while those for cimetidine were 16.9 +/- 4.4% (means +/- SEM, n = 5); cimetidine relapse rates derived from non-comparative trials were 17.0 +/- 1.9% (means +/- SEM, n = 7). Higher relapse rates translate into larger numbers of patients at risk and in need of active therapy. These results are of biological and clinical significance. Differences in relapse must reflect beneficial effects of one group of agents on the ulcer diathesis or adverse effects of the comparator, cimetidine. Each alternative reflects negatively on cimetidine as an antiulcer medication; however, confirmation of adverse effects would force radical review of most current therapy of ulcer disease. Research into ulcer therapeutics must emphasise both the relapse and the healing potential of pharmacologic agents.