Inhibition by colchicine of fibrinogen translocation in hepatocytes.

In the rat, 8 h after intraperitoneal administration of colchicine, fibrinogen (detected by antirat fibrinogen antibodies labeled with peroxidase) accumulated in the lumina of the rough endoplasmic reticulum of the hepatocytes; 16 and 24 h after colchicine administration, fibrinogen was detected, respectively, in the lumina of the smooth endoplasmic reticulum and in the Golgi apparatus. The effect of colchicine on the cytoplasmic translocation of fibrinogen could be due to a direct action of the drug on the membranes of the endoplasmic reticulum or could be the indirect result of the disruptive action of the drug on the microtubules.

Hypoglycemia. A common complication of septicemia in cirrhosis.

Asymptomatic hypoglycemia was demonstrated in 15 of 30 cirrhotic patients with septicemia. Blood glucose levels were measured daily in these patients. Severe circulatory failure was present in the 15 patients with hypoglycemia and was absent in the 15 patients with normal blood glucose levels. Hypoglycemia is a common complication of septic shock in patients with cirrhosis, and blood glucose levels should be systematically measured in cirrhotic patients with septicemia or shock. Septicemia should be considered in any cirrhosis patient with a low blood glucose level.

Right-sided endocarditis complicating peritoneovenous shunting for ascites.

We describe two patients with alcoholic cirrhosis in whom staphylococcal right-sided endocarditis developed after insertion of a peritoneovenous shunt (PVS). Massive pulmonary embolism caused early death in one patient. In the other patient, staphylococcal septicemia was cured after shunt removal and antibiotic treatment; recurrent endocarditis due to Corynebacterium xerosis ultimately caused the patient's death. No clinical manifestation of tricuspid valve dysfunction was noted in either patient, and right-sided endocarditis was recognized only at autopsy. The protracted contact of the tip of the venous line of PVS with the atrial wall is likely to be a major factor in the development of right-sided endocarditis in these patients.

Pharmacokinetics of lomefloxacin in patients with cirrhosis.

The effect of liver failure on the pharmacokinetics of lomefloxacin was studied in 12 patients with cirrhosis. Patients received a single oral dose of 400 mg lomefloxacin, and blood and urine samples were collected at intervals over the next 48 hours. The concentrations of lomefloxacin in all samples were measured using high-pressure liquid chromatography (HPLC). The mean (+/- standard deviation) maximum plasma concentration (Cmax) in these patients was 3.9 +/- 1.20 micrograms/mL. The mean time to maximum serum concentration (Tmax) was 2.1 +/- 2.6 hours, and the mean elimination half-life (t1/2) was 9.16 +/- 1.93 hours. Mean renal clearance was 88.9 +/- 38.0 mL/min/1.73 m2, and the mean nonrenal clearance was 61.6 +/- 19.0 mL/min/1.73 m2, which corresponded to 41% of the total body clearance. No correlations were observed between nonrenal clearance and hepatic insufficiency (Pugh score) or nonrenal clearance and plasma bilirubin. These results show that liver failure does not per se affect lomefloxacin kinetics. Thus, no adjustments in lomefloxacin dosages appear to be necessary for patients with impaired liver function tests.

Is renal transplantation involved in post-transplantation liver disease? A prospective study.

Various lesions of the liver commonly observed in renal transplant recipients are usually considered as a consequence of the transplantation procedures (immunosuppression, drug toxicity, alteration of immune responses to various viruses). A group of 64 patients all treated with corticosteroids and azathioprine was studied prospectively, and serial liver biopsies were performed on the day of transplantation and at 1 and 3 years after transplantation. Chronic hepatitis was already present in 40% of the patients on the day of transplantation and an increase of only 15% in the frequency of this condition was observed 3 years later. The presence of HBsAg in 45% of the patients at the time of transplantation was significantly associated with liver lesions. In about 3% of the cases, transplantation was directly responsible for a liver disease (peliosis hepatitis). During the followup period an evolution from chronic persistent hepatitis to chronic active hepatitis was observed with an abnormally high frequency (25%). We conclude that most of the liver diseases observed in transplant recipients are the consequence of events before transplantation and probably related to hemodialysis.

Orthotopic liver transplantation with hepatic artery anastomoses. Hemodynamics and response to hemorrhage in conscious rats.

Orthotopic liver isotransplantation was performed in one group of Lewis rats using cuffs for the portal vein and the infrahepatic vena cava, stents for the hepatic artery and the bile duct. Three other groups were also investigated: group A, normal rats; group B, sham-transplanted rats (clamping of the vessels, washing of the liver, placing cuffs around the portal vein); and group C, sham-transplanted rats with ligature section of the hepatic artery. Blood-flow measurements were performed, 1 week after the surgical procedure, with the radioactive microsphere method in conscious animals. Transplanted rats exhibited significant (ANOVA, P less than 0.05) increase in cardiac index and decrease in mean arterial pressure and systemic vascular resistance. Blood flows of the portal territory and to the kidneys were not significantly modified. Arterial liver blood flow and arterial liver vascular resistance in rats with liver transplantation were not significantly different between normal and sham-transplanted rats but were significantly different from rats with ligature of the hepatic artery. These results confirm the validity of the method used for vascular anastomoses. Hypotensive hemorrhage (2 ml/100 g bw) induced marked hemodynamic changes, but rats with liver transplantation when compared with normal and sham-transplanted rats exhibited the following: (a) significantly lower percentage of decrease in cardiac index and in mean arterial pressure; and (b) significantly higher renal and portal tributary blood flows. Plasma catecholamine concentrations and plasma volume were higher in rats with liver transplantation than in normal rats but were not significantly different from sham-operated rats. Histologic examination of the liver revealed slight portal edema in sham-operated rats and small necrotic areas in the liver, probably corresponding to the reperfusion injury, in rats with liver transplantation. In conclusion, the method described for the four vascular anastomoses allows functional perfusion of the transplanted liver. Rats with liver transplantation exhibited a hyperkinetic circulatory syndrome and an improved tolerance to hemorrhage. Changes in plasma catecholamine concentrations and in plasma volume did not account for the hemodynamic changes.

Pharmacokinetics of ketanserin in patients with cirrhosis.

The pharmacokinetics of ketanserin, a new serotonin S2 (5HT2) antagonist, were studied in 26 patients with cirrhosis. Patients were randomised to receive either a single oral dose of ketanserin 20mg (n = 14) or 40mg (n = 8) or an intravenous dose of ketanserin 5mg (n = 4). The plasma kinetics of ketanserin and its metabolite ketanserinol were determined over 48 hours, by high pressure liquid chromatography with a fluorometric detector. Pharmacokinetic parameters were calculated using noncompartmental analysis based on a statistical moment theory. The first-pass effect of ketanserin was markedly decreased after oral administration compared with results previously obtained in healthy subjects. The peak concentration was not higher in cirrhotic patients than in controls. This result could be due to an increase in the initial volume of distribution. The production of ketanserinol was reduced in cirrhotics. A decreased mean ketanserin elimination half-life (t1/2 = 12 +/- 4 and 10 +/- 3h vs 16 +/- 3 and 18 +/- 4h in healthy controls after oral ketanserin 40mg and intravenous ketanserin 5mg, respectively) contrasted with a substantial increase in t1/2 for ketanserinol (33 +/- 13 vs 19 +/- 4h). The volumes of distribution were also markedly reduced in patients with cirrhosis. These results suggest either a reduction in the oral dosage of ketanserin or an increase in the interval between doses in patients with cirrhosis.

Hepatic granulomas and hepatic sarcoidosis.

The causes of hepatic granulomas are numerous and their identification can be difficult. Sarcoidosis is a main cause of hepatic granulomas. The mechanisms that initiate the formation of sarcoid granulomas are unknown. This article discusses the pathology of hepatic sarcoidosis and hepatic granulomas.

A randomised controlled study of propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis.

74 cirrhotic patients with a history of variceal or gastric bleeding were randomly assigned to treatment with propranolol (40 to 360 mg/day) or placebo. The patients were all in good condition and doses of propranolol were titrated until a 25% reduction in heart rate was achieved. After 2 years, the cumulative percentage of patients free from rebleeding was significantly greater among the patients receiving propranolol (79%) than in the placebo group (32%; p less than 0.0001). Similarly, the percentage of surviving patients was significantly greater with propranolol (90%) than with placebo (57%; p less than 0.02) after 2 years. It was concluded that in cirrhotic patients in good condition, propranolol reduced both the risk of recurrent gastrointestinal haemorrhage and the mortality rate during a 2-year period of continuous administration of the drug.

Formation of an inactive cytochrome P-450 Fe(II)-metabolite complex after administration of troleandomycin in humans.

In rats, it has been shown that troleandomycin induces its own transformation into a metabolite forming an inactive complex with reduced cytochrome P-450. To determine whether similar effects occur in humans, we studied hepatic microsomes from 6 untreated patients and 6 patients treated with troleandomycin, 2 g per os daily for 7 days. In the treated patients, NADPH-cytochrome c reductase activity was increased by 48%; total cytochrome P-450 concentration was also increased, but 33% of total cytochrome P-450 was complexed by a troleandomycin metabolite. The cytochrome P-450 Fe(II)-metabolite complex exhibited properties identical to those of the inactive complex formed in rats: it exhibited a Soret peak at 456 nm, was unable to bind CO, and was destroyed by addition of 50 microM potassium ferricyanide. We also measured the clearance of antipyrine in 6 other subjects. This clearance was decreased by 45% when measured again on te seventh day of the troleandomycin treatment. We conclude that repeated administration of troleandomycin induces microsomal enzymes, produces an inactive cytochrome P-450 Fe(II)-metabolite complex, and decreases the clearance of antipyrine in humans.

Epithelioid hemangioendothelioma of the liver: an ultrastructural study.

Epithelioid hemangioendotheliomas are uncommon vascular tumors, mainly observed in lung and soft tissues. Liver involvement is infrequent and, in contrast to the extrahepatic localizations of the tumor, has not been subjected to detailed ultrastructural analysis. This prompted us to report the results of the ultrastructural study of three cases of epithelioid hemangioendothelioma of the liver. Neoplastic proliferation was heterogeneous. Most of neoplastic cells presented features suggestive of endothelial differentiation, including presence of Weibel-Palade bodies and evidence of vasoformative properties demonstrated by formation of both intra- and extracellular vascular channels resembling the normal structures successively observed during embryogenesis and tissue regeneration. A minor cell population, unreported so far, exhibited ultrastructural characters resembling those of pericytes and presented organoid relationship to neoplastic endothelial cells. Tumor spreading along sinusoids induced pseudopeliotic dilatations and led to a progressive disruption of normal liver architecture. In conclusion, the three cases of hepatic epithelioid hemangioendothelioma examined in this work assume many organoid features mimicking the successive steps of normal angioformation and indicative of a high degree of morphological differentiation.

The hepatic sinusoid in hairy cell leukemia: an ultrastructural study of 12 cases.

Ultrastructural lesions of the liver were studied in 12 cases of hairy cell leukemia, with the alterations of the sinusoidal barrier receiving special emphasis. Portal and sinusoidal tumoral infiltration was observed in all cases. It was associated with angiomatous lesions of the sinusoids in eight cases; these lesions consisted of randomly distributed cavities lined by hairy cells and containing hairy cells and erythrocytes. In addition to the attachment of hairy cells to the sinusoidal wall, other striking electron microscopic abnormalities of the sinusoids included 1) wide areas of communication between the sinusoidal lumen and Disse's space, allowing extravasation of blood cells; 2) focal disruption of the sinusoidal wall; and 3) replacement of the sinusoidal cell lining by tumor cells in close contact with hepatocytes. Most of these changes closely resembled those observed in peliosis hepatis. As in peliosis, sinusoidal alterations in hairy cell leukemia might be due to the destruction of the sinusoidal wall, and tumor cells could play a role in the pathogenesis of the lesions. The pattern of liver involvement in hairy cell leukemia, which is peculiar among hepatic localizations of blood malignancies, might reflect the unique phenotype of the tumor cells.

Hepatocytic PAS-positive diastase-resistance inclusions in the absence of alpha-1-antitrypsin deficiency--high prevalence in alcoholic cirrhosis.

The presence of PAS-positive, diastase-resistant inclusions in the cytoplasm of the hepatocytes is characteristic of alpha-1-antitrypsin deficiency. The purpose of this investigation was to determine whether the presence of these inclusions is a specific feature, permitting the recognition of alpha-1-antitrypsin deficiency in patients with liver disease. We examined the liver specimens from 20 patients suffering from alcoholic cirrhosis with the Pi M phenotype, i.e., in whom alpha-1-antitrypsin deficiency was excluded. In seven of these patients, PAS-positive, diastase-resistant inclusions were seen in the hepatocytes; in two patients, these inclusions contained a material antigenically similar to alpha-1-antitrypsin. These inclusions might represent deposits of glycoproteins poorly excreted by the diseased hepatocytes. It is concluded that, in patients with liver disease, the presence of PAS-positive, diastase-resistant inclusions--even containing alpha-1-antitrypsin--in the cytoplasm of the hepatocytes does not permit the hepatic lesions to be ascribed to alpha-1-antitrypsin deficiency.

Portosystemic shunt in Budd-Chiari syndrome: long-term survival and factors affecting shunt patency in 25 patients in Western countries.

BACKGROUND: In Budd-Chiari syndrome (BCS) treated by portosystemic shunt, postoperative shunt thrombosis is associated with high morbidity and mortality rates. The aim of this study was to determine factors associated with shunt thrombosis. METHODS: From 1985 to 1991, 25 patients underwent portosystemic shunt for BCS. According to the patency of the shunt during the postoperative period and follow-up, patients were divided into two groups including 17 patients with patent shunt and 8 (32%) with shunt thrombosis. RESULTS: In patients with patent shunt, actuarial survival rate at 5 years was 87% versus 38% in patients with shunt thrombosis (p < 0.05). Duration of symptoms before operation was higher in patients with shunt thrombosis than in patients with patent shunt (315 +/- 483 vs 109 +/- 168 days, p < 0.05). In patients with patent shunt, extensive fibrosis or cirrhosis was observed in 3 of 17 (18%) versus in 5 of 8 (63%) of patients with shunt thrombosis (p < 0.05). Shunt thrombosis was observed in 3 of 3 patients (100%) with the combination of myeloproliferative disorder, duration of symptoms more than 100 days, and cirrhosis versus 0 of 6 (0%) patients without this combination (p < 0.05). CONCLUSIONS: In acute form of BCS (with short history of the disease and absence of extensive fibrosis or cirrhosis), early portal decompression is mandatory, with low risk of shunt thrombosis and good long-term results. In chronic form of BCS, the risk of shunt thrombosis is high and long-term results are bad; in these patients, orthotopic liver transplantation must be considered.

Caustic sclerosing cholangitis. A complication of the surgical treatment of hydatid disease of the liver.

In five patients, sclerosing cholangitis developed after the surgical treatment of hydatid cyst of the liver. The cyst communicated with the biliary tree, and a scolicidal solution (2% formaldehyde in two patients and 20% sodium chloride in three) was injected into the cyst. Cholangiography showed strictures affecting the intrahepatic biliary tree in two and both the intrahepatic and extrahepatic biliary tree in three. Sclerosing cholangitis in these patients was likely to result from the caustic effect of the scolicidal solution having diffused from the cyst into the biliary tree. We propose to designate this entity "caustic sclerosing cholangitis". Because of the risk of this complication, and the unproved efficacy of intracystic injection of a scolicidal solution in preventing the dissemination of the parasite, we recommend that this maneuver be abandoned in the surgical treatment of hydatid disease of the liver.

Sclerosing cholangitis induced by formaldehyde solution injected into the biliary tree of rats.

Sclerosing cholangitis has been reported after surgical treatment of hydatid disease of the liver and has been hypothetically attributed to the caustic effect of the parasiticide solution injected into the cyst and diffusing into the biliary tree through a cystic-biliary fistula. In this experimental study, we showed that, in rats, injection into the biliary tract of 20% hypertonic saline solution or 2% formaldehyde solution, the most commonly used scolicidal solutions, was followed by lesions of the biliary epithelium. As compared with 20% hypertonic saline solution, the 2% formaldehyde solution caused more severe lesions of the biliary epithelium and, in addition, induced the development of sclerosis. This experimental study confirms the deleterious effect of scolicidal solutions to the biliary epithelium, shows that their effect is mainly related to the causticity of the scolicidal solution, and indicates that intracystic injection of 2% formaldehyde solution should be abandoned.

Predictors of sustained response to alpha interferon therapy in chronic hepatitis C.

OBJECTIVES: To utilize cytokine levels to predict sustained response (SR) to alpha interferon (IFN alpha) therapy in chronic hepatitis C patients, and to determine the relationship between serum tumor necrosis factor alpha (TNF alpha), interleukin (IL) IL 6, IL 8, IL 12, transforming growth factor beta (TGF beta 1) and the degree of liver damage as reflected by traditional markers. DESIGN AND METHODS: Serum cytokine levels were assessed using ELISA in 18 patients included in a controlled clinical trial of IFN alpha. RESULTS: Of the 18 patients, 27% were sustained responders (SR), 27% were response and relapse responders (RR), and 46% were non-responders (NR). Multivariate analysis showed that a low serum TNF alpha level and high serum IL 8 levels were independent factors associated with SR to IFN alpha therapy. Serum TNF alpha level highly correlated with viral load and genotype predictive values (p < 0.001). Therapy lowered the IL 6 and IL 12 profile. TGF beta 1 levels in serum are positively correlated with fibrinogenesis. CONCLUSIONS: IFN alpha therapy modulates immune response to hepatitis C virus, contributing to sustained response.

Cytokines as predictors for sustained response and as markers for immunomodulation in patients with chronic hepatitis C.

OBJECTIVES: (i) To characterize serum cytokine levels of tumor necrosis factor alpha (TNF alpha), interleukin 6 (IL 6), IL 8 and IL 12 in non-cirrhotic patients with chronic hepatitis C, (ii) to correlate the levels of these cytokines with the degree of the disease at the basal level, (iii) to correlate these levels with the response to therapy, (iv) to compare profiles of cytokines in monotherapy (MT) versus combination therapy (CT), and (v) to compare the immunomodulatory effects of MT versus CT. DESIGN AND METHODS: 47 patients were enrolled in the study. The controls were 120 volunteers (recruited from students and staff) that did not present HCV RNA positive and were not known to suffer any other metabolic disease. Thirty patients formed the other group of controls, with alcoholic liver disease (ALD). Serum cytokine levels were assessed using enzyme-linked immunosorbent assay (ELISA). RESULTS: The sustained responders (SRs) have basal values much lower than relapsed responders (RRs) and non-responders (NRs) regardless of the therapy. CONCLUSIONS: Cytokines can be used as non-invasive markers for sustained response and as monitors for the outcome of therapy.

Latent hepatitis B virus (HBV) infection in systemic necrotizing vasculitis.

We have investigated hepatitis B virus (HBV) infection in systemic necrotizing vasculitis (SNV). Our approach included the detection of the viral surface antigen (HBsAg) with a radioimmunoassay employing monoclonal anti-HBs (m-RIA); in addition, HBV DNA was looked for in serum and peripheral mononuclear blood cells. Among 28 subjects with SNV, 12 were found to be positive for HBsAg with the conventional test (p-RIA) and 7 additional subjects had anti-HBc and/or anti-HBs. From the 16 HBsAg negative individuals, 9 had HBsAg epitopes identified in serum with the m-RIA test and 1 had a low amount of circulating viral DNA. In contrast, only 1 among 6 subjects with other systemic vasculitis showed a positive test for m-RIA and HBV DNA assays; this individual had acquired HIV infection through transfusions which were also probably the source of his HBV infection. HBV DNA sequences were identified in peripheral mononuclear blood cells of 9 from the 37 tested, including 2 individuals who were HBsAg positive only with m-RIA. Therefore, our study indicates a much higher rate of HBV infection in patients with polyarteritis nodosa than previously suspected.

What should the clinician know about the cytochrome P450 system?

The cytochromes P450 are a superfamily of enzymes which catalyse mono-oxidation, thus transforming fat-soluble toxins into water-soluble metabolites which are excreted in urine. Cytochromes P450 are mainly located in the liver, they play a major role in hepatotoxicity. The toxins (or the drugs) can be in part transformed into reactive metabolites which destroy intrahepatocytic proteins (metabolite-related hepatotoxicity) or form an immune complex that induces immune reactions (immune-related hepatotoxicity).