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Interleukin‐6 receptors (IL‐6R) and interleukin‐1 receptors (IL‐1R) on lymphocyte surfaces were analyzed, using flow cytometry and dye‐labeled IL‐6 and IL‐1β, to examine the clinical and immunological significance of these receptors. Incubation of peripheral blood mononuclear cells in the presence of mitogen resulted in a remarkable increase of lymphocytes expressing the IL‐6 and IL‐1β receptors on the cell surface. The increase in lymphocytes bearing these cytokine receptors may reflect an increase in stimulated lymphocytes. When peripheral blood from patients with primary biliary cirrhosis (PBC) was examined for these receptors, the percentage of IL‐6R positive cells was significantly higher in the patients than in healthy controls (P

Small dose intradermal (i.d.) inoculation methods of hepatitis B vaccine have been reported to be effective and economical. We determined the best method to obtain high antibody levels within a short period of time and for the long-term maintenance of these levels. A total of 173 female students were randomly allocated to seven groups: six i.d. inoculation groups, to which 6-12 micrograms was administered in three or four divided doses (Groups A-F), and a control group (Group G) which received three 10 micrograms intramuscular (i.m.) inoculations. Serum hepatitis B antibody levels were quantified in weeks 4 and 8, and months 4, 7, and 12. Positivities in all groups were not significantly different at each measurement time. In month 4, geometric mean antibody levels in the three i.d. groups (10-12 micrograms in three divided doses; 79.1-107.0 IU l-1) were significantly higher than in Group G, which had received two of three i.m. injections (17.6 IU l-1; P0.01, P0.05). In the group which received four 2 micrograms i.d. inoculations, the level was higher than in Group G in month 7, but lower in month 12. It was concluded that three i.d. inoculations, each of 4 micrograms, may be used to obtain high antibody levels within a short period of time. However, it is recommended that a 10 micrograms i.m. injection in month 6 is applied as a booster. Consequently, we could not present an economic and effective low-dose intradermal inoculation method.

During the past 2 years, drug-induced interstitial pneumonia was reported in 66 Japanese patients, mainly among chronic hepatitis C patients, undergoing treatment with the Japanese herbal medicine "Sho-saiko-to" (TJ-9). As interstitial pneumonia is also induced by granulocyte colony-stimulating factor (G-CSF), we examined the effects of TJ-9 on G-CSF production in peripheral blood mononuclear cells. In patients with hepatitis B or C, G-CSF production in the absence of any stimulation was significantly lower than healthy controls (p0.01). G-CSF production increased along with the increase of TJ-9 levels, and this could induce excessive production of G-CSF in hepatitis C patients, and this may be a cause of interstitial pneumonia.

"Sho-saiko-to" (TJ-9) consists of 7 herbal components. In Japan, it is widely prescribed to patients with chronic viral liver disease. TJ-9 is known to suppress liver cancer development and possess macrobiotic effects, but its mode of action is not fully understood. This study investigated the following: 1) cytokine production levels, mainly interleukin (IL)-10, in peripheral blood mononuclear cells of chronic active hepatitis B and C patients, and healthy volunteers; 2) effects of TJ-9 on these productions; and 3) effects of each of its herb components on cytokine production in cell fractions. Results showed that without stimulants, IL-10 production in mononuclear cells of hepatitis B and C patients was significantly lower than that of healthy subjects (P < .01). IL-10 production induced by either phytohemagglutinin (PHA) or pokeweed mitogen (PWM) in mononuclear cells of hepatitis C patients were significantly lower than in patients with hepatitis B (P < .01) and healthy subjects (P < .05). IL-10 production induced by anti-CD3 or lipopolysaccharide (LPS) was significantly lower than in healthy subjects (P < .05). The addition of TJ-9 to the cultures strongly induced IL-10, and this induction was mainly attributable to the effects of 2 components (scutellaria root and glycyrrhiza root) on the monocyte/macrophage fraction. The production of IL-4 and IL-5 in cultures with concanavalin A (conA) was significantly higher in patients with hepatitis C than in the healthy subjects (P < .01; P < .05), but the addition of TJ-9 suppressed these increases by 25% to 33% (P < .01). Therefore, TJ-9 could adjust the decreased IL-10 production and the increased IL-4 and IL-5 production of mononuclear cells from patients with hepatitis C. Moderate regulation of the cytokine production system in patients with hepatitis C by using TJ-9 may be useful in the prevention of disease progression.

There appear to be hepatitis viruses other than hepatitis A, B, C, D and E. One of these has been proposed with a designation of GB virus C. Sera from 44 patients with fulminant hepatitis were tested for RNA of GB virus C by reverse-transcription polymerase chain reaction with nested primers deduced from the putative non-structural 3 (helicase) region.RNA of GB virus C was detected in three (20%) of 15 patients with hepatitis B virus infection and three (12%) of 25 patients without markers of hepatitis A-E virus infection. Overall, GB virus C RNA was detected in six (14%) of the 44 patients with fulminant hepatitis, at a frequency significantly higher (p0.001) than that in three (0.9%) of 326 blood donors matched for age with the patients.These results indicate a role of GB virus C in inducing fulminant hepatitis either by itself or in concert with the other hepatitis viruses.

To evaluate the usefulness of proliferating cell nuclear antigen (PCNA) immunostaining in the assessment of the efficacy of interferon (IFN) therapy in chronic hepatitis C, we investigated the proliferative activity of hepatocytes in 67 patients with chronic hepatitis C, using this immunostaining method. The percentage of PCNA-positive hepatocytes was 2.4% in patients with chronic persistent hepatitis, 2.5% in those with chronic aggressive hepatitis 2A, and 3.9% in those with chronic aggressive hepatitis 2B. The PCNA count increased with the progression of the liver disease. Patients were classified as complete, partial, and non-responders to IFN; the percentage of PCNA-positive hepatocytes before IFN therapy was 1.6% in the complete responders, 3.9% in the partial responders, and 4.9% in the non-responders. There was a significant negative correlation between the percentage of PCNA-positive hepatocytes and the response to IFN treatment. Thirty-two of 53 cases (60.4%) in which the PCNA labeling index (LI) was less than 5.0 were complete responders compared with 13 of 14 cases (92.9%) in which the PCNA LI was higher than 5.0, representing partial responders or non-responders (P

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×BL+2.75×BR+2.7×AG+2.3×WB+1.67×CD+1.56×AL−0.098×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×BR+2.25×BL+2.24×DI+2.05×AL ± 1.38×AG+0.00021×WB−6.33. BR is 1 if the ratio of total to direct bilirubin is more than 1.5, BL is 1 if total bilirubin is higher than 15 mg/dl, DI is 1 if the duration of illness before encephalopathy is less than 4 days or more than 12 days, AL is 1 if the ALT level exceeds 40 times the upper limit of normal and AG is 1 if age exceeds 50; otherwise all variables are 0. WB is WBC count per cubic millimeter. Positive predictive value, negative predictive value and predictive accuracy were 0.92, 0.80 and 0.89, respectively. Sensitivity and specificity were 0.95 and 0.70, respectively. These prediction equations were validated prospectively on a population of testing samples comprising 52 patients with fulminant hepatitis B and 47 with fulminant non-A, non-B hepatitis. Positive predictive values were 0.92 and 0.92, negative predictive values were 0.71 and 0.78 and predictive accuracies were 0.87 and 0.89 for patients with fulminant hepatitis B and fulminant non-A, non-B hepatitis, respectively. They may be used for selecting candidates for liver transplantation and for evaluating efficacy of a new therapy. (HEPATOLOGY 1994;19:1065–1071.)

“Xiao-Chai-Hu-Tang” is a herbal medicine that has been used for the treatment of pyretic diseases in China for several thousand years. In Japan, this medicine was modified into “Sho-saiko-to,” a prescription drug with standard quality and volume of ingredients. It is widely used as a biological response modifier in the treatment of chronic viral liver diseases. Several researchers have reported improvement of general physical conditions and the drug's usefulness in preventing liver cancer development. In this in vitro study, peripheral blood mononuclear cells (PBMC) were obtained from 12 healthy volunteers, and Sho-saiko-to (TJ-9) was added to the cultures of the PBMC. Dose-dependent increases in the levels of tumor necrosis factor-α (TNF-α) were observed in the cultures. Similar but smaller increases in the TNF-α levels were also observed when other Japanese herbal medicines, Dai-saiko-to (TJ-8) or Saiko-keishi-to (TJ-10), were added to the cultures. These results demonstrated that the increases of TNF-α levels are specifically due to Sho-saiko-to and other drugs with similar ingredients. TNF-α is believed to have anti-tumor effects and also to have an important role as IL-1 in the defense mechanism of the body. Therefore, the induction of TNF-α could also be useful in clinical treatment, and this effect could be one of the mechanisms by which Sho-saiko-to demonstrates efficacy in the treatment of patients with chronic viral liver diseases. © 1994 Wiley-Liss, Inc.

We studied 134 “healthy persons” with no past history of any serious or latent diseases, and observed differences in their 25 lymphocyte subsets by conducting two-color analyses using 12 useful combinations of dye-labeled monoclonal antibodies. CD4+Leu8+ cells and CD25+CD3+ cells were significantly higher in males than in females, whereas CD4+ Leu8− cells and CD23+ CD19+ cells were significantly higher in females. In comparison of the 25 lymphocyte subsets among four age groups, CD45RA− CD4+ cells and CDw29+ CD4+ cells significantly increased with age, and CD8+ CD11b− cells and CD57− CD8+ cells significantly decreased with age. In females, helper T cells significantly increased and helper inducer T cells increased, while cytotoxic T cells decreased with age. These are important findings that should be considered in studies of immune function and autoimmune disorders. © 1994 Wiley-Liss, Inc.

Herbal medicine “Sai-rei-to” (TJ-114) has been used for the treatment of swelling and edema for about 3000 years in China. Recently, this drug has been used by Japan's western medicine physicians as an adjunct therapy in the treatment of rheumatoid arthritis (RA). This drug is believed to exhibit immunoregulatory effects, but its mode of action has not yet been fully described. In this in vitro study, the Japanese herbal medicine Sai-rei-to was used. Results demonstrated that TJ-114 induced the interleukin-1 receptor antagonist (IL-1ra) dose-dependently in cultures of peripheral blood mononuclear cells (PBMC) collected from healthy persons. Another herbal medicine “Sho-saiko-to” (TJ-9), consisting of several common ingredients as in TJ-114, also showed similar, but smaller increases in production levels. However, other herbal medicines used in this study did not significantly increase IL-1ra production. Therefore, this effect was evaluated as being specific to TJ-114 and those herbal medicines containing similar ingredients. Interleukin-1 (IL-1) is regarded as the most important cytokine affecting the pathology of RA and IL-1ra inhibits the immunopathological functions of IL-1. TJ-114, which increases IL-1ra production, has a rather low incidence of adverse effects and can be administered orally for a long period. It is expected that this medicine will show a high degree of clinical usefulness for the treatment of RA.

The herbal medicine Sho-saiko-to has been widely used in Japan as an oral medication in the treatment of viral liver cirrhosis and its clinical efficacy is well established. Sho-saiko-to is believed to generally strengthen the biophylactic functions of the body and improve immunological functions. However, its mode of action has not been fully described. General practitioners in Japan most frequently administer Sho-saiko-to to patients with liver cirrhosis. Physicians empirically know that this drug is useful in improving the general condition of patients with this disorder. Yet, it is not known how Sho-saiko-to works to improve the immunological disorders in liver cirrhosis patients and how it achieves such good clinical results. This study examined in vitro cytokine production capability of the peripheral mononuclear cells obtained from 25 patients with viral liver cirrhosis utilizing pokeweed mitogen stimulation. The in vitro capability of these cells to produce cytokines such as interleukin-β, interleukin-6, and granulocyte-macrophage, colony-stimulating factor, was specifically investigated. To obtain cultures, peripheral blood was collected from patients with viral liver cirrhosis, as well as from healthy volunteers as controls. Cytokine levels with or without pokeweed mitogen were examined via incubation of each sample for 1 to 5 days. To the samples in which pokeweed mitogen was not added, Sho-saiko-to or Sho-seiryu-to solutions were added and incubated. After this culture period, each sample was centrifuged and a supernatant was collected for measurement. As a result, there was no difference in the cultures without pokeweed mitogen: production of interleukin-1β, interleukin-6, and granulocyte-macrophage colony-stimulating factor of patients' cells and cultures of healthy subjects remained the same. However, production of all three cytokines was significantly lower in the patient group than the control in the cultures with pokeweed mitogen. The production of interleukin-1β, interleukin-6, and granulocyte-macrophage colony-stimulating factor, in the cultures containing the control drug Sho-seiryu-to was the same as those in the cultures with only the control medium. However, cytokine production levels in cultures with Sho-saiko-to concentrations 6 μg/ml or higher significantly increased. The findings of this study suggest that Sho-saiko-to's clinical efficacy could be the result of improvement in the immunological mechanism in patients with liver cirrhosis.

We present two patients with multiple microhamartomas of the biliary tract (von Meyenburg complexes) with multiple liver cysts with special reference to their diagnostic imaging and laparoscopic findings. Case 1 was a 76-year-old male and case 2 was 51-year-old male, who was later found to have adenocarcinoma of the common bile duct as a complication. The characteristic findings of ultrasonography (US) were markedly heterogeneous and there was a severe hyperechoic pattern in the liver with small cystic lesions. Computed tomography (CT) demonstrated multiple low attenuation focal defects scattered throughout both lobes which showed no enhancement following the application of intravenous contrast medium. Laparoscopically, multiple whitish nodular or stellate-shaped lesions, which were slightly depressed, and multiple small dark greenish cystic lesions of various sizes were scattered on the smooth surface of both lobes. Some dark greenish cystic lesions and whitish lesions were adjoining. A histological study of the whitish nodular lesions revealed a collection of proliferated and irregularly dilated bile ducts and ductules in a dense fibrous stroma. These findings are compatible with microhamartomas. These features are characteristic of this disease, and support the close association between liver cysts and microhamartomas. Our hypothesis is that a polycystic liver may result from cystic dilatation of microhamartomas.

A method for determining levels of serum HBs antigen has been developed, applying the principles of the integrating sphere turbidimetric assay (ISTA). Using this method, the minimum detectable level of HBs antigen is 15 ng/ml, i.e., it is three times more sensitive than the reversed passive hemagglutination (RPHA) method. Reproducibility and specificity are also excellent with ISTA. With a cut-off level of 20 ng/ml, the highest reading possible with this method is 1000 ng/ml. Serum HBs antigen can readily be measured by this method if a fully automated EL-1000 analyzer is used. This rapid and simple method of measurement should be clinically useful.

A method for determining serum HBs antibody applying the principle of integrating sphere turbidimetric assay (ISTA) by latex agglutination was developed. The minimum detectable level of HBs antibody by this method is 12.5 IU/L, indicating that this method is 3 times or more sensitive with better reproducibility and specificity than the passive hemagglutination (PHA) method. With a cut-off level of 25 IU/L, the possible highest simultaneous reading by this method was 1,000 IU/L Serum HBs antibody can be readily measured in 10 or so minutes by this method if a fully automated EL-1000 analyzer is used. This rapid and simple method for determining serum HBs antibody will be useful not only clinically, but also in preventive medicine. © 1993 Wiley-Liss, Inc.

急性心筋梗塞を発症した82歳女性でCK-Mサブユニット変異 (fast type) を経験した. そしてこの変異が, LDHのHおよびMサブユニット変異と同様に遺伝的変異であることを明白にした. fast type の変異Mサブユニットが存在する結果, CKアイソザイムのMMはブロードで, しかも通常のMMより陽極寄りに泳動された. そしてCK-MMアイソフォームは電気泳動法により7本のハンドに分離され, 陰極から3本目までのバンドは通常のMM1～MM3と移動度が一致した. 変異サブユニットの存在下では, 理論上, 通常のMM1, MM2, MM3が三つのアイソフォームから構成されるために九つのCK-MMアイソフォームが存在するはずであるが, 実際には2カ所で二つのアイソフォームが重なるために, 7本のバンドとなると思われた.

Rubella was accompanied by hepatic dysfunction in a 28-year-old male. Serum aminotransferase levels were moderately elevated and LDH markedly increased, especially LDH isoenzyme 5, whereas total bilirubin and ALP remained almost normal. GOT, GPT and LDH levels were completely normalized by the 21st hospital day. Paired antibody titers of viruses which may cause hepatitis, other than rubella, were of no significance. Laparoscopy showed enlarged, red liver. Histologic and electron microscopic findings of the liver were consistent with acute hepatitis. Hepatic damage with rubella is rare, and it is possible that the hepatic dysfunction seen in adult rubella may be mediated by an immunopathologic mechanism.

Clones of hepatitis B virus were propagated from 10 cases of fulminant hepatitis B after amplification by polymerase chain reaction and their nucleotide sequences of the precore region were determined. All 113 clones from 9 cases had a point mutation from guanine to adenine at nucleotide 83 in the precore region, which converted codon 28 for tryptophan (TGG) to a stop codon (TAG) and prohibited the synthesis and secretion of hepatitis B e antigen. Precore-region defects were not detected in any of 23 clones from the remaining 1 case. By contrast, precore-region defects were not found in any of 180 clones from 8 cases of acute hepatitis B without hepatic failure serving as controls. The source of infection was traceable in 3 cases. The same precore-region defect, along with the sequence identity of 435 nucleotides, was observed in clones from the case of a baby and his grandmother, who carried the virus and was implicated in the transmission, and also in clones from two pediatricians and the carrier patients they attended. These findings support the hypothesis that precore-defective mutants have stronger activity to induce fulminant hepatitis than nondefective viruses.

A case of acute pancreatitis in a 29-year-old female associated with an attack of acute intermittent porphyria (AIP) is reported. Following the attack of AIP, serum pancreatic amylase originating from the pancreas increased transiently, and mild swelling of the pancreas was detected by ultrasonography. On this basis acute pancreatitis was diagnosed. Additionally, this patient had mild hepatic dysfunction. Laparoscopy disclosed diffuse slightly dark bluish pigmentation on the irregular surface of the liver. Mild fibrous dilatation of the portal area with lymphocytic infiltration was seen histologically. Acute pancreatitis and hepatic damage with AIP is extremely rare, however it is possible that these findings are etiologically connected in this patient.

A型急性肝炎に急性赤芽球癆を合併した1例を経験した.症例は70歳男性.尿の濃染を自覚し,近医で黄疸を指摘されて当科に入院した.IgM型HA抗体陽性よりA型急性肝炎と診断,保存的治療が施行され,GOT, GPTは改善傾向にあった.しかし高度の黄疸が持続,入院第15日より急速な貧血の進行を認め,入院第23日にHb 4.3g/dlと低下した.網状赤血球は0.1%と著減,骨髄は赤芽球系のみが著しい低形成を示した.またT. Bil, LDH (1型優位)の上昇,Haptoglobinの著明な低下が見られた.以上の検査結果より溶血を合併した急性赤芽球癆と診断した.洗浄赤血球輸血とPrednisolone 60mg/dayの投与により網状赤血球,Hbは上昇し,骨髄像は赤芽球系の過形成を呈した.T. Bil, LDHは低下傾向を示し,ステロイドの減量後も経過は良好であった.入院第77日に施行した腹腔鏡所見は胆汁うっ滞像を呈し,組織学的には肝内胆汁うっ滞を伴う急性肝炎回復期の像であった.

ICG, BSP試験とも高度異常を呈した色素排泄異常症の2症例とその家族調査の結果を報告した.両例とも,ICG試験において血中消失率K (ICG)は0.0173, 15分停滞率は,93.2%, 80.7%と高度異常を示した.また,BSP試験でも,それぞれK (BSP)は0.0356, 0.0385, 45分停滞率は29.6%, 28.0%と高度異常を示した.ICG, BSP試験の移行率においては,特に血漿から肝への移行率(a)が低下しており色素の肝への取り込みの障害が主であると考えられた.肝組織所見では,両例とも慢性活動性肝炎であった.さらに,両症例の家族調査を行ったところ,症例1の二女,四女と症例2の妹に色素排泄異常が認められた.したがって,両例とも色素排泄異常の素因を持っていたと思われるが,後天的な肝炎の関与も否定できなかった.3このような色素排泄異常のパターン(ICG, BSP試験高度異常,ビリルビン値正常)は極めて稀で,新しい病態である可能性が示唆された.

The prognostic value of peritoneoscopy was examined in 372 patients with liver cirrhosis according to the degree of development and size of regenerating nodules, the development of reddish markings, the development of small lymphatic vesicles, the presence or absence of patchy markings, the size of the right and left hepatic lobes, and the degree of splenomegaly. The cumulative survival rate was compared with these peritoneoscopic parameters. The usefulness of peritoneoscopic and histological findings in the prognosis of liver cirrhosis was evaluated using the proportional hazard model of Cox. Significant differences were observed in the cumulative survival rate with respect to the degree of development of regenerating nodules, the size of the right hepatic lobe, the formation of small lymphatic vesicles, and the degree of splenomegaly. Analysis using Cox's proportional hazard model indicated that peritoneoscopic findings are of greater clinical use than histological findings in determining the prognosis of liver cirrhosis.

AIM: To determine the complex of AST and immunoglobulin and to investigate its clinical significance in patients with liver disease. METHODS: The complex of AST and immunoglobulin was determined by encounter immunoelectrophoresis and its clinical significance was investigated in 128 patients with liver disease. RESULTS: AST was bound to immunoglobulin of anti-immunoglobulin A (IgA) class, but any binding to anti-immunoglobulin G and anti-immunoglobulin M classes was not observed. Although the incidence of AST–immunoglobulin complex was 41.8% in chronic hepatitis (CH), the incidences in liver cirrhosis and hepatocellular carcinoma were 62.2 and 90.0%, respectively. In alcoholic liver disease with high level of serum IgA, the incidence of the complex was 66.7%, which was higher than that in CH. The ratio of binding to lambda-chain of IgA was higher than that to kappa-chain of IgA. The serum level of IgA and the ratio of AST/alanine aminotransferase (ALT) were significantly higher in patients with AST–IgA complex than in those without complex. CONCLUSION: These results suggest that AST–IgA complex in patients with progressive liver diseases and alcoholic liver injury can lead to elevation of the ratio of AST/ALT.

By using commercially available ELISA kits, serum IL‐6 and TNF‐α levels in healthy adults, and the levels of various cytokines in patients with primary biliary cirrhosis or chronic viral liver diseases, were investigated. IL‐6 levels of healthy subjects were distributed in a wide range, and the distribution pattern was similar to those of the patients. TNF‐α levels tended to be low in females in their 30s, but there were no abnormalities in the patients. Characteristic findings, in the primary biliary cirrhosis patients, were an increase of IFN‐γ and IL‐2 levels, and a decrease of GM‐CSF levels (P

The herbal medicine, Sho-saiko-to (TJ-9), has been widely prescribed to chronic viral liver disease patients in Japan. This study examined the inductions of such sytokines as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and granulocyte-colony stimulating factor (G-CSF), on some fractions of peripheral blood mononuclear cells (PBMC) by TJ-9 and each of its seven components. IL-1β, TNF-α, and G-CSF were highly induced by scutellaria root and glycyrrhiza root on monocytes/macrophages. By repeating the same experiments using taxol (an LPS antagonist)-treated substances, authors confirmed that these inductions were not attributable to the presence of quite low LPS in TJ-9 solution, and the cytokine inductions are the specific effect of TJ-9. Because TJ-9's macrobiotic effect in liver cirrhosis patients has been proven statistically in an etiological study, TJ-9 could be a new important therapy in chronic liver diseases.

'Sho-saiko-to' (TJ-9) is a Japanese herbal medicine that is commonly administered to patients with chronic viral liver disease in order to improve their overall physical condition and to prevent the development of liver cancer, The present in vitro study demonstrated that, by adding TJ-9 to cell cultures, there were dose-dependent increases in production levels of tumour necrosis factor-alpha (TNF-alpha) and granulocyte colony-stimulating factor (G-CSF) in peripheral mononuclear cells of patients with hepatocellular carcinoma accompanied by liver cirrhosis. Increases in the production of TNF-alpha and G-CSF in control cell cultures exposed to different herbal medicines were low, and this indicates the specificity of the response increases in production of these cytokines to TJ-9. TNF-alpha and G-CSF are known to play important roles in the biological defence mechanism. Administration of TJ-9 may, therefore, be beneficial for patients afflicted with intractable liver diseases because it could mildly induce these cytokines.

Levels of two types of lectin-reactive alpha-fetoprotein (AFP), designated AFP-L3 and AFP-P4+P5, were analyzed with Lens culinaris agglutinin A and AFP-P4+P5 with erythroagglutinating phytohemagglutinin, respectively, in an attempt to determine the utility and significance of these macromolecules as early indicators of hepatocellular carcinoma during the periodic follow-up of cirrhotic patients. The subjects were 51 of 190 consecutive cirrhotic patients in whom hepatocellular carcinoma developed during a 6-year follow-up period and 21 cirrhotic patients without hepatocellular carcinoma. Serum AFP levels were of limited value to diagnose and predict hepatocellular carcinoma. The relative levels of AFP-L3 and AFP-P4+P5 in patients with hepatocellular carcinoma at the time of tumor detection were significantly higher than those in patients with cirrhosis. The sensitivity was 61%, and the specificity was 90%. Fourteen patients (48%) of 29 patients with small hepatocellular carcinomas less than 2 cm in diameter showed elevated percentage of lectin-reactive AFP. Retrospective examination of 21 patients who were positive for lectin-reactive AFP at diagnosis of hepatocellular carcinoma showed that 41% of them had already expressed lectin-reactive AFP 12 months before the direct detection of hepatocellular carcinoma by diagnostic imaging. These results lead us to conclude that the level of lectin-reactive AFP is a suitable predictive marker for the early recognition of hepatocellular carcinoma in the follow-up of patients with cirrhosis, and that measurements of the level of lectin-reactive AFP should be added to the screening methods that are now in use.

We measured des-gamma-carboxyglutamic acid prothrombin (protein induced by vitamin K absence or antagonist-Factor II: [PIVKA-II]) in plasmas of normal subjects, patients with thrombotic disease, those with hepatic disease including hepatocellular carcinoma, and those with carcinoma of other tissues, and compared the results with results of blood coagulation tests used for the examination of hepatic function. In addition, in the patients with hepatic disease, PIVKA-II and alpha-fetoprotein (AFP) levels were compared. The PIVKA-II level was frequently high in patients with thrombotic disease given warfarin therapy and those with hepatocellular carcinoma. However, in patients with thrombotic disease who were not given warfarin therapy, no significant correlation was seen between the PIVKA-II value and the results of the thrombotest or hepaplastin test, suggesting no association between the PIVKA-II level and the degree of impairment of hepatic function. In 70 patients with hepatocellular carcinoma, the percentage of patients positive for PIVKA-II (greater than or equal to 0.1 micrograms/ml) and those positive for AFP (greater than or equal to 20 ng/ml) were similar (77% and 74%, respectively). Pearson's correlation of coefficient between the PIVKA-II value and the AFP value in the 70 patients was 0.463. However, false-positive rates in patients with hepatic disease other than hepatocellular carcinoma were lower for PIVKA-II. Combined assessment of PIVKA-II and AFP increased positive rates and allowed exclusion of false-positive patients. The plasma PIVKA-II level is suggested to be useful as an indicator of warfarin control in patients with thrombotic disease, as a marker of hepatocellular carcinoma, and is particularly of value when assessed in combination with AFP.

In a double-blind clinical trial, 24 patients with advanced chronic liver disease received 1.2 g of nicotinohydroxamic acid daily and 23 patients received 1.5 g of neomycin. Patients receiving nicotin

warfarin potassiumによる肝障害は極めて稀であり,内外で数例の報告をみるにすぎない.著者らはwarfarin potassiumによる薬剤性肝炎を経験したので報告する.症例は55歳の男性でaorto-coronary bypass術後の抗凝固療法としてwarfarin potassiumが投与され,約50日後黄疸とトランスアミナーゼおよび胆道系酵素の著明な上昇を示した.HBウイルスマーカー,IgM HA抗体は陰性で薬剤性肝障害が示唆されたため同薬剤の投与を中止したところ速やかに肝機能検査は正常となった.肝生検所見では急性肝炎回復期と診断された.warfarin potassiumによるリンパ球培養試験は陰性を示し臨床上抗凝固療法を必要としたため再度warfarin potassiumを投与したところ3日後全身倦怠感とともに肝機能検査に異常を来した.再度同剤によるリンパ球培養試験を行ったところstimulation indexは320%と陽性でwarfarin potassiumによる薬剤性肝障害と診断された.

カロリー病の1例を報告する.症例は22歳,男性で腹痛を主訴に来院した.腹部エコー,腹部CTにて多発性嚢状性肝内胆管拡張を末梢性優位に認めたことからカロリー病と診断し,確認のため胆道シンチグラフィー,ERCPを施行した.胆道シンチグラフィーでは拡張胆管に一致する不均一な取りこみ像および十二指腸,小腸への排泄遅延を認めた.またERCPでは総胆管,2次肝管に異常なく,末梢性優位の多発性嚢状性肝内胆管拡張を両葉にび漫性に認め,典型的なカロリー病と思われた.腎病変としては腹部エコー,腹部CTより嚢胞腎の合併が考えられた.入院中施行しえた腹腔鏡検査では,肝は硬度が増強し,肝表面に幅広い白色紋理が肝小葉構造を規則正しく取り囲んでいたため,肝はしもふり様を呈していた.組織学的には門脈周囲に著明な線維化を認めるも,肝実質細胞,肝小葉構造に異常を認めず,先天性肝線維症の合併を認めた.

The effects of ranitidine on plasma clearance of ICG were investigated in 68 cirrhotic patients (9 were positive for HBsAg, 33 were alcoholics and 26 had cryptogenic cirrhosis). The ICG clearance test was performed before and after ranitidine administration. In 31 patients treated with ranitidine (150 mg perorally), the plasma ICG clearance were 233.6 +/- 20.4 ml/min (mean +/- S.E.) and 239.2 +/- 20.5 ml/min before and after ranitidine, respectively. In the 37 treated with intravenous ranitidine 50 mg, the corresponding values were 205.4 +/- 17.7 ml/min and 206.4 +/- 17.9 ml/min. There was no significant change in the plasma clearance of ICG or the elimination rate constant after ranitidine administration. Even in patients with decompensated liver cirrhosis, no significant change was demonstrated in the plasma ICG clearance after ranitidine. These results led to the conclusions that ranitidine does not reduce the hepatic blood flow and that it is a safe and useful drug for the treatment of gastrointestinal tract bleeding in patients with liver cirrhosis.

In an attempt to evaluate the clinical significance of “Hepaplastintest”, comparative studies have been undertaken by simultaneous observation on Hepaplastintest, Owren's Thrombotest and Quick's one step prothrombintest respectively.159 cases with liver diseases, including acute, chronic hepatitis, cirrohsis of the liver, hepatoma and fatty liver.Significantly lower hepaplastintest values were obtained in acute stage of acute hepatitis, chronic hepatitis active form and cirrohsis as compared with other types of liver diseases.Earlier recovery of hepaplastintest value as within two weeks was impressed in acute hepatitis, contrasting to definite delay of recovery in subacute hepatitis as long as more than one month.In chronic hepatitis active form with sublobular zonal necrosis, concomitant lower values both in choline esterase arid hepaplastintest were impressive.In cirrohsis, preceeding depression of hepaplastintest value was noted shortly before the onset of hepatic failure.

42歳の男性でKasabach-Merritt症候群を呈した巨大肝海綿状血管腫の一例を経験した.主な症候は腹部膨満感と肝腫大であり,肝機能検査では著明な異常は認めず,腹腔鏡ならびに肝の血管造影で肝左葉全体及び中葉の一部に血管腫を確認した.また,凝血学的検査で血小板,fibrinogenの減少,第V因子の低下,FDPの上昇などを認め消耗性凝固障害の存在が考えられ,131I-fibrinogenによるシンチグラムで腫瘍に一致するactivityを認めたことより局所的な血管内凝固を確認した.本凝固障害に対してヘパリン,抗プラスミン剤投与が施行されたが効を奏せず,肝左半切除術で腫瘍を摘出することにより,速やかに凝血学的所見の改善が得られた.摘出標本は2,500g,組織学的には海綿状血管腫で,一部の血管内にfibrinの沈着を認め,典型的なKasabach-Merritt症候群を呈した肝海綿状血管腫であつた.

We found functionally active thrombomodulin in human platelets (60 +/- 18 molecules per platelet). Protein C appeared not to be activated by thrombin with gel-filtered platelets. However, the activation of protein C by thrombin was accelerated by thrombin-stimulated and washed platelets. This cofactor activity of the platelets was neutralized by the anti-lung thrombomodulin-F(ab')2. From the Triton X-extract of platelets, thrombomodulin was partially purified by diisopropylphosphoryl-thrombin-agarose affinity chromatography. The Mr of the predominant platelet thrombomodulin was 78,000 before and 109,000 after reduction on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, values identical to those of placental thrombomodulin. The specific activity of the cofactor activity, apparent Kd (0.4 nM) for thrombin and Km (0.67 microM) for protein C of platelet thrombomodulin were also identical to those of placenta thrombomodulin. Thrombomodulin may play a role in activation of protein C on the surface of platelets.

肝障害診断時の一般的な臨床所見から薬剤性肝障害と輸血後非A非B型肝炎との鑑別予測を判別分析と数量化理論II類を用いて行なった.判別分析では変数増減法により選択されたGOT, T-ch,年齢,好酸球,TTT, ALPの6項目を用いて判別式を作成した結果,薬剤性肝障害群は35例中31例(88.6%),輸血後非A非B型肝炎群は37例中33例(89.2%)が正しく判別された.数量化理論II類では質的データと量的データの16項目を用いて判別式を作成した結果,薬剤性肝障害群は34例中31例(91.2%),輸血後非A非B型肝炎群は35例中34例(97.8%)が正しく判別され,疾患判別に寄与する項目を偏相関係数により検討すると,GOT,好酸球,黄疸,γ-globulin, T-ch,発熱の順に高値を示した.本判別式作成以降の13症例を用いて外部検定を行なうと,正診率は判別分析で84.6%,数量化理論II類で92.8%といずれの解析方法においても内部検定とほぼ同様の判別率を得た.

Forty-two arterial blood pH and gas determinations were carried out on 11 patients with fulminant hepatic failure. The most common type of acid-base disturbance was that of respiratory alkalosis in 22 cases (52.4%). This was partially compensated in 13 subjects (31.0%) while an accompanying metabolic alkalosis was present in 9 (21.5%). Partially compensated metabolic acidosis was observed on 15 occasions (35.7%), all of which were in patients with laboratory evidence of impaired renal failure. The mental status of the patients was evaluated in each of the categories of acid-base disturbances. Some degree of correlation was evident between the PCO2 and the magnitude of base excess and that of the severity of the encephalopathy. The lower PCO2 and greater negative base excess values tended to be nearly always present in totally comatose subjects. By contrast, there was no clear cut relationship between blood pH and mental state.