Mechanism for reduced drug clearance in patients with cirrhosis.
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Biomedical subjects
Publications and source records attributed to D Lebrec.
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We report the case of a 66-year-old male patient with portal hypertension related to systemic mastocytosis. The liver was enlarged; microscopic examination showed portal mast cell infiltration and fibrosis. Portal hypertension was evidenced by splenomegaly, esophageal varices, and increased wedged-free hepatic venous pressure gradient. Arteriography showed that portal vein was patent. Portal hypertension could be the consequence of intrahepatic block due to mast cell infiltration and/or fibrosis of the liver.
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The authors report their experience of transjugular liver biopsy, a method which consists in taking a liver specimen with a needle placed in a hepatic vein. This method was used in 13 patients in whom conventional liver needle biopsy was contraindicated because of massive ascites or bleeding tendency. In 10 of these patients, a liver specimen was obtained; in patients with cirrhosis or chronic active hepatitis, the liver specimens were more or less divided into small fragments, which prevented correct assessment of liver architecture in three of them. The examination was well tolerated. The authors conclude that transjugular liver biopsy is not technically difficult in centers where hepatic vein catheterization is available and that this method is indicated in patients in whom conventional liver needle biopsy is contraindicated.
Portal hypertension has been regarded as an uncommon and late complication of primary biliary cirrhosis (PBC). 24 patients with PBC were investigated for portal hypertension. Esophageal varices were present in 20, 50, and 90% of the patients 1, 3, and 9 years, respectively, after the onset of pruritus and/or jaundice. Portal hypertension was responsible for gastrointestinal bleedings in 11 patients; bleeding was the first clinical manifestation of PBC in two of them. Wedged hepatic venous pressure was increased in all the patients with portal hypertension whether regenerative nodules were present or absent. Portacaval shunt was performed in five patients and was well tolerated in three of them. It is concluded that (a) portal hypertension is common in PBC; (b) the intrahepatic block is of the so-called postsinusoidal type, even in patients without regenerative nodules; (c) gastro-intestinal bleeding due to portal hypertension occurs in about half of the patients and may be the first manifestation of PBC; (d) portacaval shunt seems to be indicated when gastro-intestinal bleeding occurs in earlier stage of the disease.
Twenty cirrhotic patients with esophageal varices and an episode of gastrointestinal bleeding within the previous week underwent hemodynamic studies which used an indicator dilution technique based on selective catheterization of the splanchnic arteries and hepatic vein. Portasystemic shunting of splenic arterial flow averaged 95% (range 80 to 100%) in 17 patients with proved variceal bleeding, but only 8% in 3 who bled from another site. Superior mesenteric shunting averaged 70% (range 27 to 100%) in those who bled from varices, and no shunting was detectable in the nonvariceal bleeders. In at least 4 patients shunting was essentially complete from both beds. In 11 others, however, more than one-third of mesenteric flow still perfused the liver. The pressure gradient from the wedge to free position in the hepatic vein and the hepatic blood flow bore no relationship to the degree of shunting. These data indicated the variability of the splanchnic hemodynamic pattern that may exist in alcoholic patients with esophageal varices. If hemodynamic factors are important in determining the response to surgery, indicator dilution studies to quantitate portasystemic shunting may be a vital part of preoperative evaluation.
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The gradient between wedged and free hepatic venous pressures was measured in patients with alcoholic cirrhosis before and 1, 3, and 9 months after continuous oral administration of propranolol at doses reducing the heart rate by 25% or after administration of a placebo. The gradient between wedged and free hepatic venous pressures decreased throughout the duration of propranolol administration, and it did not significantly change in the patients receiving placebo. Since the gradient between wedged and free hepatic venous pressures closely reflects portal venous pressure in alcoholic cirrhosis, it is concluded that continuous oral administration of propranolol produced sustained reduction in portal venous pressure in these patients.
The effects on cardiac output and portal venous pressure of atenolol, a cardioselective beta-blocker, and propranolol, a nonselective beta-blocker, were compared in patients with portal hypertension due to cirrhosis. One hour after p.o. administration of 100 mg of atenolol, cardiac output decreased by 32%, and portal venous pressure by 16%; the decrease in cardiac output and the decrease in portal venous pressure were significantly correlated. One hour after p.o. administration of 40 mg of cardiac output and the decrease in portal venous pressure were not correlated. Whereas the decrease in cardiac output was similar after atenolol or propranolol, the decrease in portal venous pressure was significantly less marked after the former than after the latter beta-blocker. It is concluded that: (a) the decrease in portal venous pressure determined by atenolol results mainly from reduction in cardiac output; (b) the decrease in portal venous pressure determined by propranolol results not only from reduction in cardiac output, but also from extracardiac effects of this beta-blocker, and (c) atenolol might be less efficient in the prevention of recurrent gastrointestinal bleeding in cirrhosis, since the decrease in portal venous pressure is less marked than that which occurs with propranolol.
Splanchnic and systemic hemodynamics were evaluated in five adult patients with portal hypertension due to portal venous obstruction and were compared with those of patients with cirrhosis and those of a control group. In patients with portal venous obstruction, the gradient between wedged and free hepatic venous pressures ranged from 2 to 3 mm Hg, as in the control group, and was significantly lower than in patients with cirrhosis. Hepatic blood flow averaged 0.521 +/- 0.127 liter per min per m2 (mean +/- S.D.) and was significantly lower than that measured in cirrhotic and normal patients. Cardiac index averaged 3.788 +/- 0.629 liters per min per m2; this high value for cardiac index was not significantly different from that measured in cirrhotic patients, but was significantly higher than in patients of the control group. It is suggested that a hyperkinetic circulatory state may result from the development of portal-systemic venous collateral circulation in patients with portal venous obstruction having normal liver and hepatic venous pressures.
Hepatic artery and portal vein blood flows were assessed separately in anesthetized rats using radiolabeled taurocholate. The ratio of portal vein blood flow to total hepatic blood flow was calculated from measurements of taurocholate concentrations of portal vein, hepatic artery and hepatic vein, and of taurocholate hepatic extraction ratio. Animals were administered [14C]taurocholate intraperitoneally as a label of the taurocholate pool 24 hr before the experiments. In steady-state conditions, serum [14C]taurocholate activities were used as an index of taurocholate relative concentration and the hepatic extraction ratio of taurocholate was estimated using [3H]taurocholate infused into the systemic blood stream. Total hepatic blood flow was estimated by the Fick's principle using indocyanine green. The mean hepatic blood flow was 13.9 ml X min-1 (S.E. 1.9), and the mean ratio of portal blood flow to hepatic blood flow was 72.2% (S.E. 6.7). It is concluded that taurocholate may be used to assess separately portal venous and hepatic arterial blood flow in the rat.
We have previously reported the results of a controlled trial showing that continuous oral administration of propranolol reduced the risk of recurrent gastrointestinal bleeding in patients with cirrhosis; only part of our patients had been followed for 1 year. This controlled trial was continued for an additional year; accordingly, all of our patients have now been followed for at least 2 years. The purpose of the present study is to determine whether prolonged administration enhances the efficacy of this therapy. Seventy-four patients with cirrhosis, admitted for an episode of gastrointestinal bleeding, were included in this study; ascites, jaundice and encephalopathy were absent or mild and transient. The patients were randomly assigned to two groups; one group of 38 patients received propranolol twice daily at doses that reduced the resting heart rate by 25%, the other group of 36 patients received a placebo twice daily. The cumulative percentages of patients free of recurrent gastrointestinal bleeding 1 and 2 years after inclusion were 87 and 79% in the propranolol group, and 42 and 32% in the placebo group; both differences were highly significant (p less than 0.0001). Furthermore, the cumulative percentages of surviving patients 1 and 2 years after inclusion were 94 and 90% in the propranolol group, and 84 and 57% in the placebo group; the difference between the two groups was not significant at 1 year, but was statistically significant at 2 years (p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)
Fourteen patients with cirrhosis and bleeding esophageal varices were treated with propranolol. The dose of propranolol was determined by decreasing the resting heart rate by 25% 12 hr after an oral dose of propranolol which was given twice a day. Significant decreases in the hepatic venous pressure gradient and cardiac output after 1 month of propranolol administration was observed. To assess beta-adrenergic blockade, the isoproterenol test and plasma propranolol levels were evaluated. Increasing doses of isoproterenol were injected to increase the resting heart rate 25 beats per minute (chronotropic dose 25 or CD25 ). Plasma propranolol concentrations were measured in blood samples drawn 4 hr after the last oral dose. The mean CD25 was 5 +/- 2 micrograms before and 146 +/- 84 micrograms after 1 month of propranolol administration. The plasma propranolol level after 1 month of drug administration was 0.69 +/- 0.47 microM per liter i.e. 2.33 +/- 1.59 micrograms per ml. A significant correlation was found between the CD25 measured after continuous propranolol administration and plasma propranolol level. In conclusion, the efficacy of beta-adrenergic blockade was estimated by the isoproterenol test which correlates with the plasma propranolol level in patients with cirrhosis. This study suggests that the isoproterenol test is useful in assessing beta-adrenergic blockade with propranolol in patients with cirrhosis.