α₁-antitrypsin phenotypes were detcrmined by polyacrylamide gel slab isoelectric focusing in the samples of 648 normal subjects and 761 patients with liver diseases. Three common PiM subtypes (M1M1, M1M2, M2M2) were classified and the allele frequencies estimated fbr Pi^M1 and Pi^M2 were 0.82 and 0.18, respectively. α₁-antitrypsin in serum was on the lowest level in M2M2 (M1M1>M1M2>M2M2).
In 761 patients with liver diseases we found 416 M1M1 (54.7%), 256 M1M2 (33.6%), 79 M2M2 (10.4%) and 10 rare variants (1.3%)-2 Etokyo M1, 1 Etokyo M2, 1 IM1, 1 M1N, 1 M1P, 3M2P, 1M1S.
Of 648 normal subjects, there were found 447 M1M1 (69.0%), 164 M1M2 (25.3%), 32 M2M2 (4.9%) and 5 rare variants (0.8%)-2 Etokyo M1, 1 IM1, 2M1N.
1) Frequencies of rare variants were quite low as compared with those in the European populations, and none of Z gene Was detected.
2) Four heterozygotes fbr Pi^P were detected in a group of liver diseases.
3) A significant difference in M2M2 frequency was found between patients with liver diseases and controls (p<0.001).
P and M2M2 might be predisposing factors to the developing of liver diseases.

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Since alanine induced glycemic response can be interpreted as an exellent index of hepatic gluconeogenesis, functional capacity of the liver was tested by means of the 30 minutes' intravenous infusion of 300ml of 10% L-alanine solution in fasted state to 17 patients with cirrhosis of the liver (8 compensated and 9 decompensated cirrhotics) and 6 controls.
In compensated cirrhotics, maximum glycemic response to alanine was not significantly different from that of controls at the end of the infusion. By contrast, there was no glycemic response to alanine in decompensated cirrhosis. In fact, blood glucose level was even decreased from the pre-infusion level. Blood lactate level after alanine infusion was significantly higher in decompensated cirrhosis when compared to the controls. Furthermore, in decompensated cirrhosis, blood alanine levels remained elevated even at 120 minutes after the end of the infusion. Moreover the degree of alanine-induced glycemic response was closely related with that of the dye (ICG) retention.
In conclusion, alanine-induced glycemic response provides a sensitive tool for evaluating the fuctional capacity of the cirrhotic liver.

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ICG Rmax was measured in 207 patients with various liver diseases to quantitate the total functioning hepatic cell mass. Simplification of the method for measurement of ICG Rmax was also studied for routine clinical use. The most reliable value of ICG Rmax was obtained by the method loaded with three dose (0.5, 2.0 and 5.0mg/kg B.W.). However, two dose loading (0.5 and 5.0mg/kg B.W.) also revealed a reliable result suggesting usefulness as a routine test.
ICG Rmax decreased significantly in various liver diseases. Especially in liver cirrhosis, the decrease was prominent. The differences of ICG Rmax between acute and convalescent stage of acute hepatitis, and between compensated and decompensated liver cirrhosis were statistically significant, respectively. In liver cirrhosis, fatal cases by hepatic failure showed significantly lower ICG Rmax than survived cases, or dead cases by the other causes. ICG Rmax showed significantly higher incidence of abnormal value than the other ICG clearance tests in acute and chronic hepatitis but not in cirrhosis and primary hepatoma.
These results suggested that ICG Rmax well reflects the changes in the total functioning hepatic cell mass, and is a useful parameter for analysis of pathophysiology of liver diseases, which can not be evaluated by the other liver function tests.

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In order to evaluate the effect of insulin-glucagon (I-G) therapy on acute hepatitis, the present study was carried out on 2 cases of fulminant hepatitis (FH), 3 cases of subacute hepatitis (SH) and 8 cases of acute hepatitis (AH). These cases were treated with 10% glucose fluid (500ml) containing regular insulin (10 units) and glucagon (1mg). Normotest (NT), prothrombin time (PT), α₂-HS-glycoprotein and prealbumin were measured. In FH and SH, the mean values of NT remained less than 10%. In AH the mean values of NT increased after I-G therapy, but these values were decreased when I-G therapy was stopped. In FH and SH, PT remained prolonged and in AH, it was slightly shortened during I-G therapy. In FH and SH, the mean values of α₂-HS-glycoprotein remained less than 20mg/dl. In AH, the mean values were increased after I-G therapy. In FH and SH, the mean values of prealbumin were less than 5mg/dl. In AH, they increased, but these values were decreased when I-G therapy was stopped. From these results we suggest that I-G therapy may enhance the reserve of liver in acute hepatitis.

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The clinical effect of the treatment of hepatic encephalopathy with intravenous glucagon and insulin (G-I) was studied. Both of 2 cases with acute hepatic insufficiency survived, whereas the survival in chronic hepatic insufficiency was 2 out of 6 cases, so that the over-all survival rate was 50%. Improvement of the conciousness state, including temporary arousal, was observed in 7 of 8 cases, and the average period required before arousal was 4 days. The improvements of the consciousness states were accompanied by decreases of blood ammonia levels within 3 hours after the start of the infusion, whereas this could not be observed in cases where the G-I treatment was ineffective. Cases with acute hepatic insufficiency showed improvements of GOT and GPT levels, while no appreciable improvement was observed in chronic cases. It is concluded that the G-I treatment is a very effective method, at least no less effective than any of the conventional methods, of treatment for the control of hepatic insufficiency. The mechanism of action of this treatment was discussed.

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It was reported that horse anti-AFP serum had a suppressive effect on 3'-Me-DAB rat hepatoma.
In order to clarify the mechanism of the effect, the correlation between tissue AFP and administered anti-AFP was immunohistochemically investigated.
The result was characterized by a decrease in the number of AFP positive cells, and the proven localization of horse immunoglobulin in the liver of rats treated with anti-AFP specific antibody.
This fact indicates the possibility of AFP-anti AFP immunoreaction at the site of AFP producing cells, and it is suggested that this Ag-Ab reaction may cause the suppressive effect on 3'-Me-DAB rat hepatoma.

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To study the effects of habitual alcohol intake on the time of the development of liver cirrhosis and hepatocellular carcinoma (HCC), 158 patients with cirrhosis and 79 with HCC were classified into the following four groups based on the presence (+) or absence (-) of HBsAg in serum, and history of intake of more than 25.2ml of ethanol per day (EtOH): group I-HBsAg (+), EtOH (-); group II-HBsAg (+), EtOH (+); group III-HBsAg (-), EtOH (-); group IV-HBsAg (-), EtOH (+). The ages of cirrhotics and HCC cases of each group were compared at the time of diagnosis. The average age of cirrhotics of group II (n=10) were 38.8 years, 8 years younger than that of group I (n=15). The average of cirrhotics of group IV (n=97) was 47.9 years, 8 years younger than that of group III (n=36). The average laboratory data in each group of cirrhotics were almost the same. The average age of HCC cases of group II (n=20) was 48.9 years, and was 9 years younger than that of group I (n=12). Although there was no significant difference in average age of HCC cases between group IV (n=31) and III (n=16), the average age of male HCC cases with history of intake of more than 126ml of ethanol per day, of group III was 51.0 years (n=8), 10 years younger than that of male HCC cases of group IV (n=11). The average laboratory data in each group of HCC patients were almost the same. These data suggest that habitual alcohol intake may promote the development of liver cirrhosis and HCC, especially in HBsAg carriers.

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Minute hepatocellular carcinoma (MHCC) revealed expansive growth, and was largely composed of trabecular pattern with narrow blood space or fine fibrous stroma and revealed well-differentiated HCC, but huge HCC (HHCC) was frequently composed of trabecular pattern with widened blood space and poorly-differentiated HCC. The difference in points examined, was not marked. In non-neoplastic liver tissue of MHCC, mostly postnecrotic liver cirrhosis, intracellular hepatitis B surface antigen was detected in a half cases, the incidence being not different significantly from that (36.4%) of HHCC.

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A 27 year-old male with mild obesity was admitted for evaluation of slight abnormality in serum total bilirubin and serum transaminase activity. There was marked discrepancy between ICG clearance and bromsulphthalein (BSP) clearance rate: ICG R₁₅ was 79.5%, KICG was 0.026 and BSP R₁₅ was 3%. The transfer rate constants of ICG showed decreases in all of three components (a: the rate of leaving the plasma to enter the liver, b: the rate of passing back from the liver to the plasma, h: the rate of passing back from the liver to the bile), especially in a component. In this patient, a component was not changed but b component was clearly increased following the increase in ICG loading dose, while both components were clearly decreased in normal controls. The maximal removal rate of ICG (ICG R max) showed a marked decrease. Ultrastructural study of his hepatic biopsy showed that the smooth and rough endoplasmic reticulum of the hepatocytes was vesiculated, and in the enlarged cisterna of these organelles slight electron dense particles were observed, suggesting disturbance in intraccllular transport of ICG carring substances. By his familiar study, one of sisters showed prominent ICG clearance abnormality and the other sister showed slightly abnormal clearance of ICG. These findings suggested that the defect of ICG excretory mechanism could be due to, at least in part, a decrease in saturating index of receptor-carrier protein for ICG of hepatocytes and disturbance in intracellular transport of ICG.

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An interesting case of liver cirrhosis with chronic type of hepatic encephalopathy (63year-old male) was presented here fbr considering the pathogenesis and treatment of hepatic coma. Various therapies for encephalopathy were carried out in this case, and clinical improvements were obtained with correction of altered amino acid levels in serum and cerebrospinal fluid after those treatments. In addition to close correlation between hepatic encephalopathy and blood ammonia levels, marked derangements of serum aminogram with increased aromatic amino acids (AAA) and decreased branched-chain amino acids (BCAA) and lower ratios of BCAA/AAA were also observed possibly as one of factors iducing encephalopathy. Free tryptophan concentrations in serum were not correlated with consciousness levels of this patient. Three hours' drip infusion of Hep-OU, Fischer or BCAA solution improved hepatic encephalopathy and abnormal electroencephalogram of this patient with normalization of serum amino acid pattern. Abnormal aminogram in cerebrospinal fluid probably due to the increased transport of aromatic amino acids into the brain was also much improved by Hep-OU infusion. Although marked elevation in molar ratio of BCAA/AAA was seen both immediately and 3 hours after the end of infusion of valine alone hepatic encephalopathy was not recovered clinically. Arginine-Glutamate solution was effective for arousing encephalopathy during the early course of this patient, but thereafter this became to be not effective in the advanced stage. Simultaneous administrations of glucagon and insulin were not effective for hepatic coma, but deterioration of amino acid imbalance in serum were not observed with hormone administration.
These observations suggest that both decreased levels of branched-chain amino acids and impaired metabolisms of ammonia may be related each other to the pathogenesis of hepatic encephalopathy observed in this case.

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A 48-year-old man who showed a regular diurnal fluctuation of blood ammonia level was diagnosed as adult-type citrullinemia with quantitative estimation of plasma amino acids and urea cycle enzymes in the liver. The restriction of daily protein intake less than 50g and oral administration of lactulose had no effect on blood ammonia level. The efficacy of four amino acid solutions which had been used in order to improve the hepatic encephalopathy was compared each other in this case. Glutamate-arginine mixture had the same effect as glutamate solution in lowering blood ammonia level, and glutamate was thought to be essential. Also, oral administration of citrate showed a remarkable effect almost comparable to intravenous administration of glutamate. Analysis of plasma amino acids three hours later after citrate ingestion demonstrated an increase in glutamate and a decrease in citrulline. These observation may suggest that a metabolic pathway of citrate-α-ketoglutarateglutamate-glutamine, takes part in disposing free ammonia in the blood.

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We reported a case of 29 year-old male with nonhemolytic unconjugated hyperbilirubinemia (continued since 15 year old) and with marked retention of BSP test without retention of ICG test.
The plasma disappearance rate of BSP showed 0.030 and plasma retention rate at 45 minutes was 25.6%, whereas ICG plasma disappearance rate revealed 0.154 and plasma retention rate at 15 minutes was 9.8%.
The serum bilirubin concentration was ranges between 2.1mg/dl to 3.0mg/dl, and unconjugated bilirubin was dominant. The bilirubin levels were elevated after the intake of low calorie diet (400Cal/day) for 3 days, and lowered after the administration of phenobarbital (100mg/day) for 7 days.
Bilirubin composition in bile showed decrease of molar ratio of glucuronic acid to ester form of bilirubin. This result suggested the decreased activity of UDP glucuronyl transferase in liver cells.
The hepatic uptake of ^99mTc-HIDA was retarded and the excretion rate was within normal. Hepatic uptake and excretion of ^99mTc-PI were almost normal. The secondary rise was observed at 180 minutes on the plasma disappearance curve of UDCA following an oral administration of UDCA (300mg).
The elution pattern of serum protein conjugated with ICG or BSP using column chromatography (Sephadex G-200) showed the same result as of healthy subjects.
From above mentioned results it was concluded that this case was a new type of constitutional hyperbilirubinemia with marked retention of BSP.

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Two cases of hepatoma with secondary erythrocytosis were presented. These patients were diagnosed as having hepatoma by an increase of α-fetoprotein level in plasma, the findings of hepatic scintigram and an abnormality of selective arteriography on liver (in the second case, it was confirmed by an autopsy). Hematological examination showed erythrocytosis (red blood cell: 778×10⁴ and 682×10⁴, and hematocrit: 65.4% and 57.7%, respectively). The increase of erythropoietin concentration in urine was observed in these two patients, and additionally, the elevation of its plasma concentration and circulating red cell blood volume were noted in the second case.
Based on these findings, it was considered that the erythrocytosis observed in this study was caused by the development of hepatoma.

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