Scanning electron microscopic studies on morphological abnormalities of erythrocytes in alcoholic liver diseases.

BACKGROUND: We previously reported that morphological abnormalities and the altered deformability of erythrocytes play important roles in disturbances of hepatic microcirculation associated with alcoholic liver disease. METHODS: The subjects of this study were five patients with alcoholic liver cirrhosis, two patients with alcoholic fatty liver, and two healthy volunteers. Concentrating on erythrocyte morphology in the presence of alcoholic liver disease, we observed erythrocytes under a scanning electron microscope and examined their morphological changes in relation to the disease. RESULTS: Among the five patients with alcoholic liver cirrhosis, stomatocytes accounted for about 14% and acanthocytes for about 10% of all erythrocytes. In the fatty liver group (n = 2), acanthocytes were absent, and stomatocytes accounted for 23% in one subject and 56% in the other, of the total. When the two patients with liver cirrhosis were examined over time, one of them was found to have 12% stomatocytes, 21% acanthocytes, and a filtration time of 14.7 sec at admission. Following 1 month of abstinence, this patient had 1% stomatocytes, 6% acanthocytes, and a filtration time of 10.4 sec, which were accompanied by improvements in peripheral blood parameters and liver function. In another patient with liver cirrhosis, there were no acanthocytes, 8% stomatocytes, and a filtration time of 5 sec at admission; this patient had 1% stomatocytes and a filtration time of 7.7 sec after 1 month of abstinence. In one patient with fatty liver who was examined over time, the percentage of stomatocytes was 56%, and the filtration time was 7.7 sec at admission; these parameters were 1% and 5.1 sec, respectively, after 1 month of abstinence. CONCLUSIONS: The present study revealed that stomatocytes and acanthocytes are morphologically abnormal erythrocytes observed in the presence of alcoholic liver disease. These abnormal forms of erythrocytes tended to normalize as peripheral blood parameters and liver function were improved by abstinence, which suggests that erythrocyte morphology is related to the pathophysiology of alcoholic liver disease.

Mechanisms of hepatic microcirculatory disturbances induced by acute ethanol administration in rats, with special reference to alterations of sinusoidal endothelial fenestrae.

Elucidation of the hepatic hemodynamics in acute ethanol administration is an issue of clinical importance for better understanding of alcoholic liver diseases. The purpose of this study is to clarify the mechanism of hepatic microcirculatory disturbances after acute ethanol administration, especially regarding the effects of ethanol on alterations of sinusoidal endothelial fenestrae (SEF) and the involvement of endothelin-1 (ET-1) in the mechanism of portal hypertension induced by ethanol. Ethanol was administrated into the portal vein via the mesenteric vein branch of rats as a continuous infusion (4 and 8 mg/min of ethanol) for 60 min. Hepatic tissue blood flow measured with a laser Doppler blood flowmeter was found to be remarkably decreased with time, whereas portal pressure began to increase at 10 min and showed a significant increase by approximately 1.5 cm H2O at 60 min. Ethanol concentrations in blood at 60 min after 4 and 8 mg/min of ethanol infusion were 0.75 mg/ml and 1.77 mg/ml, respectively. At this point, scanning electron microscopy revealed significant decreases in number and diameter of SEF both in zone 1 and zone 3, with the increase in ethanol level. These findings suggested that decreases in number and diameter of SEF, whether primary or secondary, may lead to the impairment of the transport of plasma substances from sinusoids to hepatocytes in acute ethanol administration. Furthermore, the pretreatment of BQ-123 inhibited a decrease in hepatic tissue blood flow and an increase in portal pressure caused by ethanol, indicating that ET-1 may be involved in the mechanism of hepatic circulatory disturbances in acute ethanol administration.

Differential expression of multidrug resistance (mdr) and canalicular multispecific organic anion transporter (cMOAT) genes following extrahepatic biliary obstruction in rats.

The hepatic canalicular membrane has transporters that play an important role as efflux pumps in the excretion of endogenous bile constituents or xenobiotics into bile canaliculi. To elucidate functional significance of canalicular transporters in the mechanism of cholestasis, mRNA expression levels of multidrug resistance (mdr) 1b, mdr2 and canalicular multispecific organic anion transporter (cMOAT) genes were analyzed by Southern blotting of reverse-transcribed PCR products of liver mRNA obtained from cholestatic rats that had been subjected to bile duct ligation. Both mdr1b and mdr2 mRNA expression increased after ligation. Immunohistochemical study revealed that the products of both mdr1b and mdr2 were present on the canaliculi, and that their levels increased after ligation. In contrast, cMOAT mRNA expression was not increased, but rather attenuated by ligation. The expression of canalicular transporters was differentially regulated in extrahepatic biliary obstruction, indicating the different roles are played by mdr and cMOAT in the pathogenesis of cholestasis.

Comparison of two interferon alfa treatment regimens characterized by an early virological response in patients with chronic hepatitis C.

OBJECTIVE: We investigated the efficacy of an interferon regimen characterized by an early virological response in patients with chronic hepatitis C and evaluated whether the patient's virological status during therapy would be useful for predicting a complete response. METHODS: We treated 62 patients with chronic hepatitis C with 6 million units (MU) of human lymphoblastoid interferon daily for 4 wk. The serum HCV RNA was assayed at week 2 by the reverse transcription-polymerase chain reaction. HCV RNA-negative patients (group A) received 6 MU of interferon three times weekly for an additional 22 wk (total dose, 564 MU). HCV RNA-positive patients were randomly assigned to group B-1, which received the same regimen as group A, or to group B-2, which received 6 MU of interferon daily for 4 wk followed by 6 MU three times weekly for 18 wk (total dose, 660 MU). RESULTS: Complete responses were achieved by 19 (63.3%) of 30 group A patients, compared with one (6.3%) of 16 group B-1 patients and none of 16 group B-2 patients. The virological response at week 2 and the pretreatment serum HCV RNA level were independent significant predictors of a complete response. CONCLUSION: Patients who were still HCV RNA-positive at week 2 were unlikely to achieve a complete response after interferon therapy. An increase in the total dose of interferon failed to yield further benefit in these patients.