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To clarify the nature of nitrogen metabolism between branched chain amino acid (BCAA) and glutamine (Gln) in liver failure, we measured arterial plasma concentrations of Gln and 15N uptake to amino-N and amide-N of Gln in normal and D-galactosamine-induced fulminant hepatic failure (FHF) rats after 15N-leucine (Leu) injection. Fifteen, 30 and 60 min after Leu injection, the arterial plasma concentrations of Gln were significantly higher in FHF rats than in controls. The concentrations of amino-15N Gln were also significantly higher in FHF rats than in controls at 5, 15, 30 and 60 min after injection. The concentrations of amide-15N Gln did not significantly differ between FHF and controls at 5, 15 and 30 min. However, at 60 min, the concentration was significantly higher in the FHF rats. The higher uptake of 15N to amino-N of Gln in FHF rats suggests the presence of an enhanced ability to synthesize Gln from Leu in FHF rats. The higher uptake of 15N to amide-N of Gln in FHF rats at 60 min after injection suggests that excessive administration of BCAA to patients with severely impaired urea-cycle capacity suffering with hepatic failure may lead to greater levels of hyperammonemia.

To clarify the role of cytosolic Ca2+ in hepatocellular death, we exposed cultured hepatocytes to human serum and a monoclonal antibody directed against rat liver plasma membranes to produce complement-mediated cell injury. The change in cytosolic Ca2+ concentration was measured by fura2 and fluo3 fluorescence. With the addition of monoclonal antibody, an increase in cytosolic Ca2+ was observed, followed by cell death. Both the increase in intracellular Ca2+ and cell death were prevented by intracellular Ca2+ chelation or removal of extracellular Ca2+. We conclude that an increase in cytosolic Ca2+ plays a major role in hepatocellular injury induced by exposure of the cell membrane to monoclonal antibody.

Of the eight patients with fulminant hepatitis placed under total parenteral nutrition with an amino acid solution rich in branched chain amino acids and treated by plasma exchange, four survived and four died from hepatic failure. Serum uric acid levels in the non-survived group were significantly lower on days 1-6 compared with the survived group. The concentration ratios of uric acid to creatinine and prothrombin time were significantly lower on days 5-8 and days 3-8, respectively, in a similar comparison. Thus, the uric acid to creatinine ratio, which corrects for the possible renal dysfunction associated with acute hepatic failure, may serve as a clinically useful prognostic indicator for patients with fulminant hepatitis.

To determine the risk of death at an early stage of fulminant viral hepatitis, we created severity indexes drawn from clinical data on the day of development of encephalopathy in 128 patients with fulminant hepatitis B and 103 with fulminant hepatitis non-A, non-B. In fulminant hepatitis B, the risk score was 2.75 x BL + 2.75 x BR + 2.7 x AG + 2.3 x WB + 1.67 x CD + 1.56 x AL - 0.098 x PR - 0.88, where BL is 1 if total bilirubin is higher than 20 mg/dl, BR is 1 if the ratio of total to direct bilirubin exceeds 2.2, AG is 1 if age is above 40 yr, WB is 1 if white blood cell count is less than 4,000 cells/mm3 or more than 18,000 cells/mm3, CD is 1 if a hazardous disease coexists and AL is 1 if ALT is less than 100 times the upper limit of normal (otherwise all are 0), and PR is prothrombin time (percentage of normal value). Using a cutoff score of 0, we found the positive predictive value, negative predictive value and predictive accuracy to be 0.90, 0.86 and 0.89, respectively. Sensitivity and specificity were 0.94 and 0.77, respectively. In fulminant non-A, non-B hepatitis, the risk score was 2.66 x BR + 2.25 x BL + 2.24 x DI + 2.05 x AL +/- 1.38 x AG + 0.00021 x WB - 6.33.(ABSTRACT TRUNCATED AT 250 WORDS)

We administered a branched-chain amino acid (BCAA) infusion to 16 patients with hepatic failure and two healthy subjects, and then evaluated its effects on ammonia metabolism and amino acid metabolic pool. Immediately after the BCAA infusion, the venous blood ammonia concentration increased in 12 of 15 patients with hepatic failure and in both two healthy subjects. Glutamine (Gln) also rose in all cases following the BCAA infusion, and this rise was particularly marked in the hepatic failure group. The increase in Gln due to the BCAA infusion and the arteriovenous difference in the pre-administration ammonia concentration showed a good correlation. These results suggest an increase in glutamine cycle capacity in patients with hepatic failure.

We evaluated serum anti-hepatitis C virus (HCV) using a synthetic peptide (AR142) which includes an epitope in the core region of HCV. The incidence of anti-AR142 in 98 patients with type non-A, non-B chronic liver diseases (NANB-CLD) was 89.8%, while all the 28 patients with non-type C chronic liver diseases were negative for anti-AR142. Among 98 NANB-CLD patients, 74 were positive for both anti-AR142 and anti-C100-3, 23 showed discordant results, and one was positive for neither. Eighty-one NANB-CLD patients underwent reverse transcription-polymerase chain reaction assay to detect viremia and 76 (93.8%) had a detectable level of HCV-RNA. Titers of anti-AR142 were not different among groups of different disease activities, genotypes of HCV, nor amount of serum HCV-RNA. These observations suggest that anti-AR142 could be a useful marker for chronic HCV infection.

To investigate the role of Kupffer cells in complement activation, we used a rat model of acute hepatic injury induced by D-Galactosamine (GalN) and lipopolysaccharide (LPS). In in vivo study, minimal histological changes were observed after i.p. GalN (200 mg/kg) single administration. Complement hemolytic activity (CH 50) decreased to 70% of its initial value 2-3 h after i.p. LPS (1.5 mg/kg) single administration. Massive hepatic necrosis was induced by simultaneous administration of GalN and LPS. After 2-3 h, CH 50 decreased to 70% of its initial value, and deposition of C3 fluorescence (C3) was observed in Kupffer cells. After 4 h, GPT was greatly increased (1286 +/- 240 IU/l), CH 50 was further reduced, and C3 was observed on hepatocyte membranes and in the cytosol. In in vitro study, we used hepatocyte cultures and co-cultures of hepatocytes and Kupffer cells to investigate the participation of GalN, LPS, complement, and Kupffer cells in hepatic cell necrosis. We found no increase of LDH (% leakage) when LPS and complement were added to the medium (22.7 +/- 5.7%). A moderate increase was observed with the addition of GalN (33.2 +/- 2.6%). A remarkable increase was observed only with the addition of GalN, LPS, and complement to the co-culture (50.0 +/- 8.8%). These results suggest that Kupffer cells activated by LPS are very important in promoting acute hepatic injury by complement.

In patients with liver cirrhosis the fasting plasma alpha-amino nitrogen concentration is high as the rule, due to reduced clearance of total alpha-amino nitrogen. The urea cycle is diminished of its capacity in cirrhotic patients than in the control subject, and to compensate for this, the extrahepatic glutamine cycle capacity is enlarged in the patients. The following important topics were taken up in this mini review: some problems concerning Fischer ratio, amino acids metabolism and pH regulation in the liver, and the supplementation therapy with branched chain amino acids under the condition of organ relationship.

Liver function tests were ranked in the order useful to differentiate 8 liver parenchymal diseases in combination of tests by forward selection and backward elimination procedures in the likelihood method using a microcomputer. The orders were almost same in both procedures: indocyanine green plasma disappearance rate, glutamic pyruvic transaminase (GPT), zinc turbidity test, alkaline phosphatase, age, HBsAg, RA test, glutamic oxaloacetic transaminase (GOT)/GPT ratio, GOT, cholesterol, total protein, total bilirubin, albumin/globulin ratio and gamma-globulin. The first 9 tests had almost all informations of all tests. The first likelihood diagnosis using the 9 tests was correct in 53% and the first or the second diagnosis was correct in 71% of 444 cases of 8 liver parenchymal diseases. A score table of likelihood diagnosis using the 9 tests was presented for manual application to new cases.

A new immunotherapy for hepatocellular carcinoma (HCC) using Freund's adjuvant and recombinant interleukin-2 (IL-2) combined with conventional transarterial chemoembolization therapy was performed. In 16 patients with HCC and one patient with metastatic liver cancer receiving this therapy, decrease and suppression of reelevation of alpha-fetoprotein after therapy was observed. Disappearance of tumor thrombi of HCC in the main portal vein was observed in a patient, and decrease of carcinoembryonic antigen was also observed in a patient with metastatic liver cancer. The present therapy using Freund's adjuvant and IL-2 is likely to open a new avenue for the treatment of patients with advanced liver cancer.

Rat liver hyperplastic foci (HF) and hyperplastic nodules (HN) induced by diethylnitrosamine (DEN) according to the method of Solt and Farber were observed by light microscopy (LM) and scanning electron microscopy (SEM). Liver cirrhosis was not observed. HF, which were composed of basophilic hepatocytes arranged usually in two-cell-thick plates and occasionally one-cell-thick plates, were followed by early HN, which were composed of eosinophilic hepatocytes with enlarged nuclei and prominent nucleoli, at 4 weeks after DEN administration. SEM revealed that hepatocytes in HF had smooth surfaces and dilated bile canaliculi with a few short microvilli. Early HN (4 and 6 weeks) were composed of two-cell-thick plates of hepatocytes, whose intercellular surfaces were covered with numerous microvillous projections. Bile canaliculi were dilated and had numerous short microvilli. Late HN (6 and 8 months) were composed of eosinophilic hepatocytes, which were irregular in shape and size. Their nuclei were enlarged and nucleoli were prominent. Hepatocytes were arranged in two-cell-thick plates, but never in many-cell-thick plates. Bile canaliculi were larger than sinusoids. The bile canaliculi had numerous diverticula, but the zona occludens was present. Microvillous projections of intercellular surfaces of hepatocytes were more numerous than those of early HN. Fenestrae of the sinusoidal endothelium were lost in most parts. Kupffer cells were not seen in any stage of HN. HN progressed gradually toward hepatocellular carcinoma.

8 patients with liver cirrhosis and chronic hepatic encephalopathy (CHE) stage I and II on a protein restricted diet and partly on lactulose therapy received in alternate periods of 4 to 8 weeks a) 45 g/day of a protein mixture enriched in branched chain amino acids (BCAA-protein), b) the same amount of milk protein and c) an isocaloric carbohydrate mixture. The additional amount of protein in form of BCAA-protein was well tolerated by all the patients. Patients with and without additional lactulose therapy showed a tendency to improvement in the performance of the number connection test while on BCAA-protein, but this improvement did not reach statistical significance. The patients did not tolerate milk protein given in the same amount as BCAA-protein.

Amino acids were determined in whole and deproteinized plasma from six subjects, before and after storage at -20 degrees C over a period of four weeks. When the native plasma was stored the following changes were observed after four weeks (fractions, mean +/- SEM): increase of glutamic acid (to 1.30 +/- 0.11), decrease of glutamine (to 0.91 +/- 0.03), half-cystine (to 0.24 +/- 0.09) and arginine (to 0.94 +/- 0.02). In stored deproteinized plasma, only glutamine decreased slightly (to 0.96 +/- 0.02) in four weeks. The concentration of 22 other amino acids remained unchanged irrespective of the type of storage.

Three men (aged 29 to 36 years) were admitted after swallowing 20-40 ml of carbon tetrachloride-containing liquid. On admission the Quick values were between 15 and 45%, maximal transaminase values 1900-5500 U/1. Acute renal failure occurred, requiring dialysis in two. In addition to the usual biochemical values, daily plasma concentrations of 18 amino acids were determined. The concentrations of phenylalanine, tyrosine, methionine, valine, leucine, ornithine and lysine were definitely elevated in the first 2-12 days. Except for glycine, tryptophan and arginine, the other aminoacids were slightly or definitely elevated for two to six days in two of the patients. Arginine concentrations were extremely low in the first two days. This shift in the pattern of plasma aminoacids in patients with carbon tetrachloride poisoning largely corresponds to those with severe acute liver necrosis of other aetiology and in part differ from the aminoacid pattern observed in animal experiments.

The whole body including extended processes of Ito's fat-storing cells was observed by scanning electron microscopy in rat liver injured with lithocholic acid (LCA). Necrotic foci developed in the midlobular zone 48 h after LCA administration. Demonstration of Ito cell bodies around the foci was probably facilitated by easy detachment of hepatocytes from Ito cells. The body and the processes were located mainly between the sinusoidal endothelium and hepatocytes; sometimes they were between hepatocytes. Ito cells often were proximate to collagen fiber bundles and sometimes were attached to them. The cell body was flatly round or elliptic, 7 to 12 micron in diameter. Its surface was finely undulated with microvillous projections about 0.1 micron in length. Branching patterns of the processes resembled a fern-leaf mantling the sinusoidal endothelium. The trunks of the processes were about 2 micron in diameter and 20-30 micron in length. These processes tapered, branching into thinner processes, with the most peripheral being 0.1 micron in diameter. Ito cells and their branching processes likely strengthen sinusoidal walls and control blood flow in the sinusoids.

Liver parenchymal diseases were statistically diagnosed by likelihood method using 12 routine liver function tests and age. 444 cases of liver diseases were classified into 8 groups by histological diagnosis. A score diagnosis table was made from the data of these cases. For the likelihood diagnosis, data of each case were adapted to the score table and the probable diagnosis was calculated. Correct diagnosis rate of the first probable diagnosis was 50% in all cases and that of the first and the second was 71%. Descending order of the correct diagnosis rate of the first diagnosis was fatty liver (76%), liver cirrhosis (67%), slight histological changes (61%), acute hepatitis (51%), alcoholic liver injury (48%), chronic aggressive hepatitis 2A (43%), chronic persistent hepatitis (40%) and chronic aggressive hepatitis 2B (26%). In conclusion, differential diagnosis of liver parenchymal diseases was made easily with the score table of 13 informations with a considerable success.

Computed tomographic arteriography (CTA) was performed in 30 patients with hepatocellular carcinoma (HCC). Detection of HCC by CTA was compared with that of conventional celiac or hepatic arteriography. CT scanning was performed immediately, 30 seconds and 1 min after an injection of 5 to 10 ml of contrast medium into the common or proper hepatic artery. Repeated infusions allowed whole liver sections to be visualized. HCC was localized in 28 of the 30 patients by conventional arteriography, with CTA detecting the masses in 27 of the 28 patients. CTA imaging presented the tumor mass in 1 of the 2 patients missed by arteriography. Conventional arteriography delineated the boundaries of HCC in 15 (50%) of the 30 patients. CTA clearly delineated the masses in 26 (87%) of the 30 patients including 11 patients in which the tumor borders were obscure by conventional arteriography. HCC lesions smaller than 1 cm in diameter were detected only by CTA in 6 (20%) of the patients. It was concluded that CTA is both useful and necessary in the demarcation of small HCC masses.

The incidence of intraperitoneal adhesion after abdominal surgery was studied. Peritoneoscopy was performed in 933 patients with liver diseases over the 6 year 5 month period from March 1974 to July 1980. Of the patients, 352 (37.7%) had undergone an abdominal operation, and intraperitoneal adhesion was detected in 205 (58.2%) of these patients. The liver was not observable in 5 out of 61 patients with adhesions after upper abdominal operations. Whereas, the liver was clearly observable in patients with lower abdominal operations in spite of adhesions. Out of the 581 patients without any abdominal operations, 30 patients (5.2%) had adhesions in the abdominal cavity, and 6 of them had extensive adhesions that partially obscured the observation of liver surface. In all patients, peritoneoscopy was performed without complications by avoiding the surgical scar for puncture sites and ensuring a free air lumen before trocar puncture.

Liver surface patterns were observed by peritoneoscopy after intravenous injection of indocyanine green (ICG). The normal rat liver was diffusely stained dark greenish-brown 5 minutes after the injection of ICG 25 mg/kg body weight into the tail vein. Green spots persisted longer in the centrolobular area, clearly revealing lobular markings. This regional difference in hepatocyte staining suggested differing abilities of hepatocytes to take up or excrete ICG. This dyeing technique was applied to liver disease patients. The liver was diffusely stained light greenish-brown 5 minutes after the injection of ICG 5 mg/kg body weight. In patients, especially those with obscure lobular markings before ICG injection, lobules were clearly demarcated by reddish terminal portal veins against a green background. This simplified detection of lobular distortions. Prenodular patches (Kalk's Bunteflecke) on the liver surface were stained green more intensely than surrounding areas, which supports the hypothesis that patches are composed of active hepatocytes.

Sex, age and 21 routine liver function assays were analyzed by stepwise selection and the best-of-all-possible-combinations method to identify a small group of assays valuable in establishing which liver cirrhosis (LC) patients have a high risk of hepatocellular carcinoma (HCC), when alpha-fetoprotein (AFP) is not elevated. Data was obtained from 115 HCC and 122 LC patients on admission. Tumor size correlated with AFP (0.73), alkaline phosphatase (ALP, 0.47), leucine aminopeptidase (LAP, 0.42), lactic dehydrogenase (LDH, 0.42), and the glutamic oxaloacetic transaminase (GOT)/glutamic pyruvic transaminase (GPT) ratio (GOT/GPT, 0.41). The mean of the correct diagnosis rates (CDR) of HCC and LC utilizing AFP as the sole parameter (89%) was markedly higher than those of the other parameters. The best-of-all-possible-combinations method presented a more powerful combination than stepwise selection. The best combination of 7 parameters (LAP, GOT/GPT, choline esterase, one-hour erythrocyte sedimentation rate, age, albumin/globulin ratio, and total bilirubin) presented a mean CDR of 80%, HCC CDR of 77%, and false positive rate of 18%. LC patients statistically diagnosed as having HCC by these 7 parameters are proposed as high risk patients. Fourteen (78%) of 18 HCC patients who were AFP-negative were statistically diagnosed. This analysis can be applied to LC patients to distinguish those that should be followed closely by imaging diagnostic techniques.

Scanning electron microscopy of a liver biopsy specimen from a patient 6 months after the onset of acute hepatitis revealed a normal appearing bile ductule. The bile ductule was 13 micron in outer diameter and 1.5-2.7 micron in inner diameter. The ductular lumen was surrounded by two ductular cells and ampullary dilated at the canalicular side. In the lumen, intracytoplasmic diverticles were observed with an orifice diameter of 0.9 micron. About 15 microvilli 0.4-0.6 micron in length and 0.1 micron in thickness were observed on 1 micron2 of luminal surface. The number of microvilli was calculated to be approximately 1,500 per ductular cell. A single cilium 0.15 micron in diameter at the base and 0.10 micron at the trunk, and 7-15 micron in length was found on each ductular cell. The cilium arose from a recess at the canalicular side of the ductular cell, and the free-end was on the bile-duct side. The cilia seemed to play an important role in bile flow to the duct. Sometimes between the ductular cells at the edge of the basal portion a cell was intercalated with thin processes. Such thin processes were not observed on ductular cells.

Hepatocellular carcinomas (HCC) induced in rats by diethylnitrosamine were observed by light microscopy (LM) and scanning electron microscopy (SEM). Liver cirrhosis did not develop. The tumors were of 4 types; trabecular, glandular, adenoid and hyperplastic nodular (HN). SEM demonstrated that trabecular lesions were packed with many layers of HCC cells which had in some places bile canaliculi on the intercellular surfaces with sparse microvilli. Glandular lesions were composed of gland-like structures having columnar or cuboidal cells with numerous microvilli on the hemispherical apex. Glandular lumens were bordered from intercellular spaces by the zona occludens. The glandular structures were derived from the exterior of the trabecular lesions and were closed at both ends, as confirmed by reconstruction of serial sections. Adenoid lesions, which had gland-like structures in the trabecula, were often observed between purely trabecular and purely glandular lesions. HN-type lesions composed of two-cell-thick plates were mostly located at the peripheral parts of the HCC tumor and were continuous with other lesions. HN-type lesions had markedly dilated bile canaliculi and well-developed microvillous projections on the intercellular surfaces. The HN-type lesions had structures similar to those of late HN. The existence of lesions indistinguishable from late HN in the periphery of HCC tumors indicates the HCC develop from HN. In summary, the rat HCC were of 4 types of lesions which had characteristic histological and cytological structures, but which were connected with each other, changing gradually from one to the other.

The portal vein system was clearly visualized in superior mesenteric arterial portography using prostaglandin E1. Angiographic examination was performed in 68 patients with various liver diseases during the 2 year period from 1980 to 1981. Twenty microgram of prostaglandin E1 was injected into the superior mesenteric artery 30 seconds before injection of 60 ml of contrast medium. The main portal vein was visualized in all of 68 cases. A high rate of success for visualization of the intrahepatic portal vein system by prostaglandin E1 was achieved. The first branches of the intrahepatic portal vein were visualized in 100% of the cases, the second branches in 82%, the third branches in 44%, and the fourth branches in 4% in the right portal vein system. In the left portal vein system, the first branches were visualized in 87%, the second branches in 41%, and the third branches in 3% of the cases. The intrahepatic portal vein system was more clearly visualized in females than in males (P less than 0.05). This procedure is simple, safe and useful for clear visualization of the portal vein system.

Three linear plots by which the liver's maximum removal rate (Rmax) of indocyanine green (ICG) and the Michaelis constant (Km) can be calculated were compared in a microcomputer simulation study. The widely-used Lineweaver-Burk plot (1/V vs. 1/S; V, ICG initial removal rate (mg/kg/min); S, ICG loading dose (mg/kg] presented the greatest bias and variance. There was no remarkable difference in bias between the S/V vs. S plot and the V vs. V/S plot, but the latter possessed a smaller variance. Therefore, the V vs. V/S plot was considered the best for estimating Rmax. The best combination of three ICG loading doses was 0.5, 2, and 5 mg/kg. This combination was selected by comparison of the Rmax estimated from three points with that estimated from six points (0.5, 1, 2, 3, 4 and 5 mg/kg).

The amino-terminal peptides of type III procollagen (PIIIP) in the urine of 40 patients with various liver diseases were determined with a commercial radioimmunoassay kit. The level of urinary PIIIP (uPIIIP) was correlated well with serum PIIIP (sPIIIP) in 9 patients, the coefficient of correlation being r = 0.836 (p less than 0.01) and the regression line being y = 1.42x + 24. Urinary PIIIP consisted of at least 4 different molecular species with molecular weights of 49 k, 18 k, 10 k and 4.6 k as estimated by column chromatography on Sephadex G-100. Furthermore. uPIIIP was found to be significantly elevated in acute hepatitis, chronic hepatitis, liver cirrhosis, hepatocellular carcinoma and other liver diseases, in which the elevation of sPIIIP has been reported by others. The mean values +/- standard deviations of uPIIIP were 44.0 +/- 32.0, 60.4 +/- 32.0, 62.0 +/- 46.5, 53.0 +/- 27.1 and 48.1 +/- 22.8 ng/ml for the respective liver diseases, and 13.2 +/- 4.5 for the non-hepatic disease group.

Peritoneoscopic findings of 39 patients with alcoholic liver cirrhosis (ALC) were compared with those of 95 patients with non-alcoholic liver cirrhosis (NALC). They were selected from 245 patients with liver cirrhosis subjected to peritoneoscopy in the 7 year period from 1975 to 1981. Out of the 95 NALC patients, 24 had hepatitis B surface antigen. The ALC patients had nodules which varied in size (61%), large depressions (69%), and a markedly rounded edge of the liver (33%) more often than NALC patients (18, 43 and 3%, respectively). Nodularity differed between the right and left lobes in ALC (41%) more often than in NALC (16%). Interstitial reddish markings and patchy nodules were, however, more frequent in NALC (51 and 28%, respectively) than in ALC (8 and 5%, respectively). Lymphatic vesicles were observed both in ALC (85%) and NALC (78%). In conclusion, the peritoneoscopic features which suggested ALC were the coexistence of nodules of various sizes, large depressions and a markedly dull edge of the liver. Interstitial reddish markings and patchy nodules were more indicative of NALC than ALC.

Fulminant hepatic failure (FHF) was produced in rats with intraperitoneal injection of D-galactosamine. 15NH4Cl (50 mg/kg of body weight) was injected into the rats via the tail vein. Arterial blood was drawn before and 5, 15, 30, 60 min after the injection of 15NH4Cl. 15N-ammonia, -urea, and -glutamine (amide and amino) were determined by gas chromatography and mass spectrometry. The plasma 15N-ammonia level was higher but decreased more rapidly in the FHF rats than in the control rats. This suggests that in FHF rats, the systemic vascular pool of ammonia is enlarged and ammonia clearance from blood is increased. The incorporation of 15N into urea was significantly different between the two groups. In FHF rats, the plasma urea-15N level rose 5 min after the injection, decreased at 15 min and was elevated again up to 60 min after injection. This biphasic change suggests that in FHF rats the incorporation of 15N into the extrahepatic glutamine pool is accelerated up to 15 min and that after 30 min a larger volume of glutamine-amide-15N is transferred to the urea cycle.

A new peritoneoscopic classification of liver surface using a three digit code was developed. The first digit represents the lobular change from normal structure to nodules. The second digit represents the size of the nodule and the internodular distance. The third digit represents the pathological findings, such as inflammation, degeneration, necrosis or regeneration. Furthermore, peritoneoscopic findings of necrosis of lobular size around the portal vein and patchy markings of the liver were presented. These findings were the most prominent in the course of hepatitis progression to cirrhosis.

A 39-year-old female with a large cavernous hemangioma of the liver was successfully treated by ligation of the left hepatic artery. A wedge biopsy specimen of the hemangioma was obtained after the ligation and was examined by scanning electron microscopy. The hemangioma was demarcated from the surrounding normal liver parenchyma and had a labyrinth of caves 50-150 microns in diameter. The caves were separated by fibrous septa 20-40 microns in width. Endothelial cells of the caves were spindle-shaped and arranged in parallel. The surface property of the caves resembled that of the hepatic artery and differed from that of the portal vein or hepatic vein. These findings support that the cavernous hemangioma of the liver was supplied by the hepatic artery. The labyrinthine structure of the cavernous hemangioma may explain the long standing contrast enhancement of the hemangioma after hepatic arteriography.

Sixty-seven cases of alcoholic liver disease were histologically classified into 4 groups: alcoholic liver cirrhosis (ALC), alcoholic hepatitis (AH), alcoholic liver fibrosis (ALF) and alcoholic fatty liver (AFL). They were statistically reclassified by the likelihood method using age, total alcohol intake, hepatomegaly and 12 liver function tests. A score table for likely diagnosis was constructed from the incidences of each range. The cases were re-evaluated using the score table, with an overall correct diagnosis rate of 73%. The best combination of 5 parameters included the indocyanine green plasma disappearance rate, total alcohol intake, cholesterol, choline esterase and glutamic oxaloacetic transaminase/glutamic pyruvic transaminase ratio. A correct diagnosis rate of 75% was attained using these 5 parameters, and 94% of patients were correctly diagnosed by the first or the second likelihood diagnosis. Differential diagnosis of alcoholic liver diseases was easily and confidently obtained with the likelihood score table.

Sake or bourbon (8g ethanol/kg body weight) was intragastrically administered to rats for 12 days. An equal dose of ethanol in water or an isocaloric glucose solution was administered to control groups. Food was withheld, but water freely provided. Neither mortality nor liver and body weights were different between the alcohol-treated groups. Glutamic oxaloacetic transaminase and glutamic pyruvic transaminase were more elevated in the sake group than in the other groups. Additionally, liver fibrosis was more pronounced, and vacuole formation or steatosis was less in this group. These results suggest that sake is more fibrogenic. Some components other than ethanol, such as long-alkyl chain alcohols, may have been responsible for the differential histopathology.

The application of photodynamic therapy (PDT) to hepatocellular carcinoma (HCC) has been difficult because hematoporphyrin derivatives (HpD) accumulate not only in cancer cells but also in normal hepatocytes and, hence, laser irradiation causes injuries in both tissues. Protection of the normal liver tissue from laser phototoxicity was demonstrated using indocyanine green (ICG) as a protective agent. In vitro, argon laser irradiation decolored the green tint of ICG much faster in solutions containing HpD than those without, suggesting that ICG captured singlet oxygen from HpD. Degeneration of Change hepatocytes induced by HpD and laser irradiation was prevented by an addition of ICG into the medium. In vivo, laser irradiation of the rat liver surface caused hyperemia when HpD was injected two days before, while the hyperemia was much milder in rats additionally receiving ICG injection 10 minutes before the irradiation. ICG injected into rat HCC accumulated only in the normal liver tissue. Laser irradiation of rat HCC preinjected with both HpD and ICG destroyed only the cancer tissue, while the surrounding liver tissue was preserved. Both in vitro and in vivo results suggest that ICG has a scavenger effect against excited oxygen and it might be used as a protective agent in PDT of HCC.

The tracing of ammonium nitrogen is important in hepatic diseases, especially in liver cirrhosis with hyperammonemia. In this paper, a new convenient method is described for determining stable isotope 15N-labeled ammonia using the Conway apparatus and chemical ionization mass spectrometry. The minimum quantity of ammonia necessary for reliable measure of 15N content was 0.1 muMol. The average error was 5.3%. In clinical application, 4 ml of blood after oral administration of 1 g of 15NH4Cl was sufficient for measurement.

Absence of Kupffer cells in rat liver hyperplastic nodules induced by a chemical carcinogen was demonstrated by intravenous injection of indian ink. Hyperplastic nodules appeared 4 weeks after diethylnitrosamine (DEN) was administered, and the nodules continued growing and became eosinophilic hyperplastic nodules after 5 to 6 weeks. After intravenous injection of indian ink, hyperplastic nodules were observed as carbon-free white nodules, which were macroscopically distinguishable from the black surrounding tissue. As observed by light microscopy, Kupffer cells were absent in hyperplastic nodules in contrast to being present in the surrounding tissue. Scanning electron microscopy confirmed these findings and furthermore revealed that the sinusoidal endothelium of hyperplastic nodules had no fenestrae. Injection of indian ink is a useful method for delineation and enucleation of hyperplastic nodules in the study of morphological and chemical changes of nodules.

Fulminant hepatic failure (FHF) was produced in rats with intraperitoneal injection of D-galactosamine. Control rats received only physiological saline. 15N-leucine (200 mg/kg of body weight) was injected into the rats via the tail vein. Arterial blood was drawn before and 5, 15, 30 and 60 min after the injection of 15N-leucine. 15N-amino acids were determined quantitatively by gas chromatography and mass spectrometry. The plasma 15N-leucine level decreased logarithmically in the same manner in both groups. This result suggests that leucine is mainly metabolized in extrahepatic tissues. The incorporation of 15N into plasma isoleucine and valine was not significantly different between the groups. Plasma alanine and glutamine concentrations increased in controls and decreased in FHF rates after the injection. The incorporation of 15N into plasma alanine in rats with FHF was significantly later than in controls. This result may suggest that undergoing hyperammonemia causes to form more glutamine from glutamate in extrahepatic sites as the same manner as for chronic hepatic failure. Additionally, insulin levels increased temporarily after the injection of leucine in both groups. This increase may play a role in the decrease in plasma isoleucine and valine concentrations after injection of leucine.

Experimental hepatocellular carcinoma (HCC) in rats did not take up intravenously administered indocyanine green (ICG) and trypan blue, while surrounding tissue did. The lack of ICG uptake was also observed by peritoneoscopy in patients with HCC. The contrast between ICG-stained cirrhotic nodules and HCC tumors was intensified with infrared photography. Non-uptake of dyes by HCC cells may enable discrimination between tumors and normal cells.