Katsuji Nakata

Endotoxin hepatotoxicity augmented by ethanol

To determine whether alcohol increases endotoxin hepatotoxicity, we administered ethanol (4.8 g/kg body wt in 4 ml of water) to rats through a gastric tube, then immediately injected endotoxin (2, 2.5, or 3 mg/kg body wt). In the rats pretreated with ethanol, the injection of 2 mg/kg body wt of endotoxin induced a slight rise of serum transaminase. However, when 2.5 mg/kg body wt of endotoxin was given, there were no significant histopathological or biochemical differences between the rats pretreated with ethanol and those pretreated with water. Moreover, there was no significant difference in mortality rates between the rats pretreated with ethanol and the controls when 3 mg/kg body wt (LD50) of endotoxin was injected. These results suggest that acute administration of alcohol enhances endotoxin hepatotoxicity when the dose of endotoxin is small, but that the effect of alcohol is masked when larger doses of endotoxin are given.

AN AUTOPSY CASE

A diagnosis of the heritable disorder Sipples syndrome was made in a Japanese male aged 28 years. The coexistence of bilateral pheochromocytomas, bilateral medullary thyroid carcinomas and secondary hyperplasia of parathyroid was confirmed at the time of autopsy. Pancreatic islets were hyperplastic with marked proliferation of A and D cells. Transition of the ductal cell to the islet, i.e. ‘nesidioblatosis’ was observed. There was no proliferation of B cells, but a retention of B cell granules, a manifestation of suppressed secretion of insulin attributed to the overproduction of catecholamines was evident. In the stomach, numerous petechial hemorrhages and proliferation of gastrin cells were found. The pathogenesis of changes in the pancreatic islets and stomach is discussed from the viewpoint of hormonal disorders induced by pheochromocytoma and medullary thyroid carcinoma such as are found in Sipples syndrome. ACTA PATH. JAP. 27: 739˜748,1977.

SINUSOIDAL STENOSIS AS THE CAUSE OF PORTAL HYPERTENSION IN CHOLINE DEFICIENT DIET INDUCED FATTY CIRRHOSIS OF THE RAT LIVER

The anatomical lesion of the liver is evaluated as being responsible for development of portal hypertension through measurement of portal vein pressures, hemodynamical analysis of Isolated perfused livers, diameter measurement of intrahepatic vascular trees, and histological as well as his‐tometrical examinations of the liver in rats fed with choline deficient diet. The mean portal vein pressure was elevated from the normal level, 132 mm H2O to 175 mm H2O In fatty liver, to 179 mm H2O In fatty liver with fibrosis, and to 218 mm H,0 in fatty cirrhosis of liver. The hepatic blood flow of the isolated perfused rat liver definitely decreased from the normal level, 3.0 ml/g/min to 1.2 ml/g/min in fatty liver, 0.4 ml/g/min in fatty liver with fibrosis and 0.7 ml/g/min in fatty cirrhosis of liver under the condition of Ht 33.5% and perfusion pressure 135 mm H2O. There was no abnormality in the pre‐and post sinusoidal vessel, but the space of sinusoid was markedly diminished, reciprocally, to the enlargement of the hepatic cells. An intimate correlationship existed between portal hypertension and reduction of sinusoidal space. Connective tissue proliferation did not have much to do with the increase in hepatic vascular resistance. The present experiment suggested that reduction of sinusoidal space was the anatomical lesion related to development of portal hypertension in choline deficient diet induced fatty liver as well as fatty cirrhosis of the liver (sinusoidal hypertension).

The role of sinusoidal stenoses in portal hypertension of liver cirrhosis

To investigate the significance of sinusoidal stenoses in portal hypertension, liver cirrhosis was produced by feeding a choline-deficient diet for 6 months in rats, and hepatic haemodynamics were examined in the cirrhotic rats before and after feeding ordinary rat pellets for another 2 months. Feeding ordinary rat pellets led to the disappearance of fat droplets accumulated in the hepatocytes, normalization of the size of the swollen hepatocytes, and recovery from sinusoidal stenoses. As a result, increased sinusoidal vascular resistance and elevated portal vein pressure were reduced markedly, and clinical signs of portal hypertension, ascites and collateral blood circulation around the liver improved prominently. These facts suggest that sinusoidal stenoses lead to an increase in hepatic vascular resistance and portal hypertension.

Relation of the reticuloendothelial function to endotoxin hepatotoxicity

The present study was undertaken in rats to clarify whether endotoxin hepatotoxicity can be modified by phagocytic activity of the reticuloendothelial system. Pretreatment with cortisone acetate, diethylstilbestrol, methyl palmitate, triolein or gadolinium chloride markedly improved the mortality rate from endotoxemia and prevented the development of focal random coagulative hepatocellular necrosis and the elevation of serum transaminase activities due to endotoxemia. Cortisone acetate, methyl palmitate and gadolinium chloride are the well-known depressors of reticuloendothelial phagocytic activity: Diethylstilbestrol and triolein are the stimulators. This suggests that phagocytic activity of the reticuloendothelial system does not relate to not only the mortality rate but also the degree of hepatic injury following endotoxemia.

Pathogenesis of centrilobular necrosis following congestion of the liver

The exact pathogenesis of centrilobular necrosis following congestion of the liver is still unknown. We reviewed the clinical data related to systemic circulatory disturbance and histopathology of the liver and the gut in 320 autopsy subjects. Congestion of the liver alone was associated only with atrophy and loss of hepatocytes in centrilobular areas, but not with hepatocellular coagulative necrosis. In many patients with coagulative necrosis of centrilobular hepatocytes and congestion of the liver, fibrin thrombi and neutrophil infiltration in the sinusoids, which are the characteristic histopathological features of the liver in endotoxaemia, were found in and around the necrotic area. Congestion, erosion or haemorrhage of the intestinal mucosa, which may allow entrance of endotoxin into the liver through the portal vein, was seen in such patients. Prolonged hypotension or shock, which may lead to portal endotoxaemia, was present in half the patients with centrilobular necrosis and congestion of the liver. These results suggest that not only congestion of the liver but also portal endotoxaemia may be involved in the pathogenesis of centrilobular necrosis in patients with congestion of the liver.

MICROCIRCULATION AND HEMODYNAMICAL ANALYSIS OF THE BLOOD CIRCULATION IN THE LIVER

1. The intrahepatic blood circulation in rat and mouse was observed microscopically in vivo by means of trans-illumination method. 2. The pattern of the terminal distribution of the hepatic artery in the human and other mammalian livers was investigated, and its role in nourishing the liver parenchyma was discussed. 3. The blood pressure in the minute intrahepatic vessels of the rat was measured directly in vivo by means of the micro-puncture technique, and a peculiar pressure gradient of the hepatic blood circulation was described. The hemodynamic analysis of the intrahepatic blood circulation under certain pathological conditions, such as passive congestion and toxic liver injury, was performed by means of perfusion of isolated rat livers, and the data were discussed in the light of the mechanism involved in the development of the histological lesions. 4.

Hepatic haemodynamics and microvascular architecture after portal venular embolization in the rat

To clarify the relationship between hepatic damage and alterations of hepatic microvascular architecture and haemodynamics following portal venule occlusion, the present study was performed in rats which had been injected into the portal vein with 700,000 plastic beads (30-35 microns in diameter). When the occluded segment of the portal venule was short, infarction did not occur because of the prompt development of vascular channels bypassing the obstructed venules. On the other hand, when the occluded segment was long, infarction usually occurred. In this case, formation of collateral vascular channels began as dilatation of the sinusoids in the vicinity of the occluded portal venules and increased in diameter and developed into new portal venules in 5 days. Increased portal vascular resistance after embolization was normalized after 5 days in parallel with the progression of reconstruction of vascular channels. Reduced bile production returned to a normal level 3 days after embolization. Necrotic tissue was resorbed completely and replaced by fibroblasts 5 days after embolization. These findings indicate that the development of infarct following portal venule occlusion depends on the length of the occluded segment, and that hepatic microvasculature has a great capacity for adaptation and rapid reconstruction of vascular channels which leads to speedy recovery from hepatic circulatory disturbances and resulting hepatic damage.

Focal veno-occlusive lesions following metastasis of cancer in the liver with special reference to obstruction of lymphatics in hepatic veins

Focal veno-occlusive lesions and congestion of the liver are found frequently at autopsy in patients with metastatic carcinoma in the liver. In 6 cases, intimal proliferation of loose connective tissue with dilatation of lymphatic capillaries was seen continuously from the terminal hepatic venule to the hepatic vein, and cancer cells were found only in lymphatic capillaries in the wall of the hepatic vein. In 7 cases, cancer cells infiltrated directly into the adventitia of the sublobular vein and intimai proliferation of loose connective tissue with or without formation of recent thrombi was observed. A main causative factor of hepatic veno-occlusive disease is thought to be leakage of plasma due to endothelial injury to the terminal hepatic venule and sublobular vein. Lymphatic obstruction, in addition to a direct reaction to invasion of cancer cells to the vessel wall, may also cause veno-occlusive lesions due to stasis and leakage of lymph fluid into the intima of the terminal hepatic venule, sublobular vein and hepatic vein.

The relation of periportal fibrosis to portal hypertension

To clarify the relation of periportal fibrosis to portal hypertension, the present study was undertaken in rats given lithocholate. Portal vascular resistance measured by an isolated liver perfusion method increased with the length of lithocholate administration. In vivo portal vein pressure elevation was closely correlated to the increase in portal vascular resistance. The blood pressure difference between the portal vein and the terminal portal venule increased compared to control rats. The blood pressure differences between the terminal portal venule and the terminal hepatic venule, and between the terminal hepatic venule and the inferior vena cava, were almost the same as those in control rats. Lithocholate administration induced narrowing and meandering of the portal vein branches due to periportal fibrosis with proliferation of bile ductules. There was no perceptible change in the sinusoids and the hepatic vein branches. These data suggest that periportal fibrosis causes deformation of the peripheral branches of the portal vein and leads to presinusoidal portal hypertension.