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BACKGROUND Neuropathic pain (NeP) medications have several side effects that affect NeP patients' quality of life. Betanin, the most common betacyanin pigment, has been shown to have potent antioxidant and anti-inflammatory properties in vivo; thus, it has potential as a healthcare treatment. In this study, we focused on betanin (red beetroot extract) as a potential therapy for NeP. METHODS Mice model of NeP were made by chronic constriction injury (CCI), and the development of mechanical hypersensitivity was confirmed using the von Frey test. Motor coordination and locomotor activity were assessed using open field tests and rotarod tests, respectively. The expression level of glial markers in the spinal cords was analyzed by immunostaining. The direct effects of betanin on microglial cells were investigated using primary cultured microglial cells. RESULTS In CCI model mice, repeated betanin treatment, both intraperitoneally and orally, attenuated developing mechanical hypersensitivity in a dose-dependent manner without impairing motor coordination. Betanin treatment also attenuated mechanical hypersensitivity that had developed and prevented the onset of mechanical hypersensitivity in CCI mice. Microglial activation in the spinal cord is known to play a key role in the development of NeP; betanin treatment reduced CCI-induced microglial activation in the spinal cord of model mice. Moreover, in primary microglia cultured cells, the activation of microglia by lipopolysaccharide application was suppressed by betanin treatment. CONCLUSION Betanin treatment appears to ameliorate mechanical hypersensitivity related to CCI-induced NeP in mice by inhibiting microglial activation. SIGNIFICANCE This article supports findings of the effect of betanin on NeP and provides a potential therapeutic candidate for NeP. Furthermore, elucidating the underlying mechanism of the effect of betanin on microglial activation could assist the development of new treatments for chronic pain.

Background Functional dyspepsia (FD) is a common gastrointestinal disorder associated with persistent or recurrent upper gastrointestinal tract symptoms such as pain without any obvious pathological changes. Psychological and psychiatric factors might have a pathogenic role in FD. Changes in the sensation of stomach pain were determined after application of stress to adult rats. The involvement of corticotropin-releasing factor (CRF), Type 2 CRF receptor (CRF2) and inflammatory cytokine interleukin-6 (IL-6) was also investigated in the gastric hyperalgesia observed in this model. Results Repeated water avoidance stress (WA-S) produced gastric hyperalgesia, with no obvious lesions in the gastric mucosa. Gastric hyperalgesia was inhibited by CRF and CRF2 antagonists, suggesting their involvement in gastric hyperalgesia observed after application of stress. Gastric hyperalgesia was inhibited by IL-6 neutralizing antibody. Immunofluorescence staining demonstrated CRF, CRF2, urocortin (Ucn)1, and Ucn2-positive cells in the gastric mucosa. CRF2-positive cells increased after WA-S, compared to sham stress. CRF2 and Ucn2 were expressed in the mast cells in the gastric mucosa. Conclusions CRF2 plays an important role in gastric hyperalgesia produced by stress. CRF2 signaling may be a useful therapeutic target for functional dyspepsia.

Background Diabetic gastropathy is a complex neuromuscular dysfunction of the stomach that commonly occurs in diabetes mellitus. Diabetic patients often present with upper gastrointestinal symptoms, such as epigastric discomfort or pain. The aim of this study was to assess gastric sensation in streptozocin-induced diabetes mellitus (DM) rats and to determine the contribution of C-C motif chemokine receptor 2 (CCR2) signaling to gastric hyperalgesia. Results DM rats showed signs of neuropathy (cutaneous mechanical hyperalgesia) from two weeks after streptozocin administration until the end of the experiment. Accelerated solid gastric emptying was observed at two weeks after streptozocin administration compared to the controls. Intense gastric hyperalgesia also developed in DM rats at two weeks after streptozocin administration, which was significantly reduced after intrathecal administration of the CCR2 antagonist INCB3344. Immunochemical analysis indicated that CCR2 expression was substantially upregulated in small and medium-sized dorsal root ganglia neurons of DM rats, although the protein level of monocyte chemoattractant protein-1, the preferred ligand for CCR2, was not significantly different between the control and DM groups. Conclusions These data suggest that CCR2 activation in nociceptive dorsal root ganglia neurons plays a role in the pathogenesis of gastric hyperalgesia associated with diabetic gastropathy and that CCR2 antagonist may be a promising treatment for therapeutic intervention.

Objective A late evening snack improves the catabolic state in patients with advanced liver cirrhosis. We tested whether long-term (3 mo) late evening snacking that included a branched-chain amino acid (BCAA)–enriched nutrient mixture produces a better nutritional state and better quality of life than ordinary food in patients with hepatitis C virus–positive liver cirrhosis. Methods In a multicenter, randomized study, 48 patients with liver cirrhosis received late-evening supplementation with the BCAA-enriched nutrient mixture or ordinary food, such as a rice ball or bread, for 3 mo. During the study period, each patient was instructed on energy and protein intake. Blood biochemical data, nitrogen balance, respiratory quotient, and health-related quality of life (Short Form 36 questionnaire) were evaluated at baseline and at the end of the study. Results Total and late-evening energy intakes were similar in the two groups at 3 mo. Serum albumin level, nitrogen balance, and respiratory quotient were significantly improved by the BCAA mixture but not by ordinary food. The parameters of the Short Form 36 did not statistically significantly improve over 3 mo in either group. Conclusion Long-term oral supplementation with a BCAA mixture is better than ordinary food in a late evening snack at improving the serum albumin level and the energy metabolism in patients with cirrhosis.

The development of hepatocellular carcinoma (HCC), the mechanisms of hepatocarcinogenesis, the prevention of HCC, and screening for HCC will be discussed. Cirrhosis has been considered as a pre-neoplastic condition for the development of HCC. The worldwide incidence of HCC differs according to different hepatitis viruses, and information is lacking. Hepatocarcinogenesis is a multistep process involving a number of different genetic alterations and is poorly understood. Interferon should help prevent the development of HCC in patients with chronic hepatitis C. Screening is the only practical approach for improving the management of HCC patients, as early detection increases the application of curative treatments. However, the cost-effectiveness of various screening strategies needs to be analysed.

Background: Some patients who are seropositive for lectin-reactive α-fetoprotein (AFP-L3) have intrahepatic cholangiocarcinoma (ICC). There have been no studies regarding the features of ICC patients seropositive for AFP-L3. Thus, the purpose of the present paper was to compare the features of ICC patients from the viewpoint of two different tumor markers, AFP-L3 and carbohydrate antigen (CA) 19-9. Methods: The ICC patients who underwent hepatectomy (n = 51) were divided into three groups, and their clinicopathologic features were compared: (i) group A, seropositive for AFP-L3 ≥ 15%; (ii) group B, seropositive for CA 19-9 ≥ 37 U/mL; and (iii) group C, seronegative for both AFP-L3 and CA 19-9. The features of combined hepatocellular and cholangiocarcinoma (n = 11) were also studied. Results: Group A had a higher positivity rate for hepatitis viruses than group B (60%vs 20%, P

Background: There has been no comparative study of the clinicopathological features of HCC patients who are seropositive for α-fetoprotein (AFP) alone and those who are seropositive for des-γ-carboxy prothrombin (DCP) alone. The authors, thus, performed this comparative study. Methods: The clinicopathological features of patients with solitary hepatocellular carcinoma (HCC), who underwent a hepatectomy were compared among the four below groups according to the seropositivity of AFP and DCP: group A, seronegative for both AFP below 20 ng/mL and DCP below 40 mAU/mL; group B, seropositive for AFP above 100 ng/mL and seronegative for DCP; group C, seronegative for AFP and seropositive for DCP above 100 mAU/mL; and group D, seropositive for both AFP and DCP. Results: Group B patients showed a higher incidence of HCC with an indistinct margin, and a somewhat higher incidence of small HCC less than 2 cm in greatest dimension compared with group C patients. By contrast, group C patients had a higher frequency of HCC with a distinct margin compared with that of an indistinct margin, large tumors more than 3 cm compared with that of small tumors less than 2 cm, and a somewhat higher frequency of moderately to poorly differentiated HCC compared with that of well-differentiated HCC. Our HCC cases showed advanced clinicopathological features in the order of group C, group B and group A. Groups C and D patients showed similar characteristics. Conclusions: Hepatocellular carcinoma patients who were seropositive for AFP alone demonstrated clinicopathological features of less advanced HCC compared with those who were seropositive for DCP alone.

BACKGROUND Des-γ-carboxy prothrombin (DCP) is an established marker for hepatocellular carcinoma (HCC), but the conventional enzyme immunoassay (EIA) kit lacks adequate sensitivity. Thus, a revised EIA kit with increased sensitivity has been developed. In this kit, the sensitivity has increased while high specificity to HCC has been maintained. The authors have already reported the clinical usefulness of this revised EIA kit. In this study, they examined the serum levels of DCP measured by this revised EIA kit in relation to the clinicopathologic features of solitary HCC. METHODS Fifty-six patients with solitary HCC who underwent hepatectomy were studied. The relation between the greatest dimension and the histologic differentiation of HCC was investigated in these 56 patients, as were the serum levels of DCP measured by the revised EIA kit (Sensitive DCP), α-fetoprotein (AFP), and DCP measured by the conventional EIA kit (DCP). The cutoff value for Sensitive DCP was set at 40 mAU/mL, and the values for AFP and DCP were 20 ng/mL and 100 mAU/mL (0.1 AU/mL), respectively. RESULTS The positivity rates for Sensitive DCP, AFP, and DCP (n = 56) were 53.6%, 53.6%, and 35.7%, respectively, and the rate was 73.2% when Sensitive DCP was used in combination with AFP (Sensitive DCP + AFP). The positivity rates for these markers were as follows: 1) When the greatest dimension of HCC was more than 3 cm (n = 16) and less than 2 cm (n = 23), the rates were 81.3% and 30.4% for Sensitive DCP, 68.8% and 39.1% for AFP, 56.3% and 13.0% for DCP, and 93.8% and 56.5% for Sensitive DCP + AFP. 2) When HCC was moderately to poorly differentiated (n = 41) and well differentiated (n = 15), the rates were 68.3% and 13.3% for Sensitive DCP, 61.0% and 33.3% for AFP, 48.8% and 0% for DCP, and 85.4% and 40% for Sensitive DCP + AFP. 3) When HCC was either more than 3 cm or moderately to poorly differentiated (n = 42) and either less than 2 cm or well differentiated (n = 27), the rates were 69.0% and 29.6% for Sensitive DCP, 61.9% and 37.0% for AFP, 47.6% and 11.1% for DCP, and 85.7% and 51.9% for Sensitive DCP + AFP. CONCLUSIONS DCP measured by the revised EIA kit with increased sensitivity has a stronger correlation than AFP with size and histologic differentiation of HCC. This Sensitive DCP is a very useful marker for HCC and should be used in combination with AFP. Cancer 2000;88:544–9. © 2000 American Cancer Society.

BACKGROUND Des-γ-carboxy prothrombin (DCP) is a useful tumor marker for hepatocellular carcinoma (HCC). The conventional enzyme immunoassay (EIA) kit for DCP lacks adequate sensitivity to detect small HCC. Thus, a revised EIA kit for DCP has been developed. In this revised DCP kit, the blank value has been reduced, making it now possible to obtain a normal value. The authors used this revised EIA kit for DCP with increased sensitivity and evaluated its usefulness as a tumor marker for HCC. METHODS Serum DCP and α-fetoprotein (AFP) levels were determined in 60 patients with HCC, 60 with cirrhosis, 57 with chronic hepatitis, and 273 normal subjects. The cutoff value for the revised DCP kit was determined to be 40 mAU/mL, and the values for the conventional DCP kit and AFP were 100 mAU/mL (0.1 AU/mL) and 20 ng/mL, respectively. RESULTS The mean DCP value was 17.5 mAU/mL in the normal subjects, and the detection limit was 10 mAU/mL for this revised DCP kit. The positivity rate for DCP in patients with HCC was 60% by the revised DCP kit, in contrast to 40% by the conventional DCP kit. The sensitivity, specificity, and accuracy of the revised kit were 60%, 92.3%, and 81.4%, respectively, whereas those of the conventional kit were 40%, 98.3%, and 78.5%. Thirty-five percent of HCC tumors smaller than 2 cm and 78.1% of those larger than 3 cm were positive for DCP by the revised kit. The corresponding figures were 20% and 56.3% with the conventional kit. Twelve (33.3%) of the 36 HCC patients who were negative for DCP by the conventional kit were positive by the revised kit. When the revised DCP kit was used in combination with AFP, 86.7% of the HCC patients and 78.3% of the patients with solitary HCC were positive for at least 1 of these markers. CONCLUSIONS The revised DCP kit is more useful than the conventional DCP kit as a tumor marker for HCC and should be used in combination with AFP. Cancer 1999;85:812–8. © 1999 American Cancer Society.

14歳時に自己免疫性肝炎様所見を呈しautoimmune hepatitis (AIH) と診断され22歳時にPrimary sclerosing cholangitis (PSC) と診断された症例を経験した. 発症時の検査成績は, T-Bil 2.1mg/dl, GPT 323KU, ALP 2, 051IU, γ-GTP 398mU/ml, γ-glob. 4.5g/dl, 抗核抗体640倍陽性 (homogeneous pattern), 抗ミトコンドリア抗体陰性, 肝生検ではpiecemeal necrosis及びbridging necrosis, 形質細胞とリンパ球の浸潤を認めAIHと診断された. プレドニン40mgより治療開始され胆管系酵素以外の生化学dataは改善した. 18歳時より通院を中止, 21歳時に食道静脈瘤破裂にて近医受診した.22歳で肝移植目的に当院へ転院, T-Bil 18.2mg/dl, GPT 39KU, ALP 897IU, γ-GTP 141 mU/ml, γ-glob. 3.1g/dl, 抗核抗体320倍陽性 (homogeneous pattern), 抗ミトコンドリア抗体陰性, perinuclear antineutrophil cytoplasmic antibody (PANCA) 陰性で, 肝組織では, 胆汁性肝硬変, fibrous obliterative cholangitis, ductopeniaを認め, ERCにてPSCの確定診断が得られた. 若年発症のPSCは, 自己免疫的要因が強く, 留意すべき病態と考え報告する.

The traditional Chinese herbal medicine yi-gan san has been used to cure neuropsychological disorders. Schizophrenia can be one of the target diseases of yi-gan san. We aimed at evaluating the possible use of yi-gan san in improving the schizophrenic symptoms of an animal model. Yi-gan san or distilled water was administered to mice born from pregnant mice injected with polyinosinic-polycytidilic acid or phosphate buffered saline. The former is a model of schizophrenia based on the epidemiological data that maternal infection leads to psychotic disorders including schizophrenia in the offspring. Prepulse inhibition and sensitivity to methamphetamine in open field tests were analyzed and the total glutathione content of whole brains was measured. Yi-gan san reversed the decrease in prepulse inhibition, hypersensitivity to methamphetamine and cognitive deficits found in the model mice to the level of control mice. Total glutathione content in whole brains was reduced in the model mice but was restored to normal levels by yi-gan san treatment. These results suggest that yi-gan san may have ameliorating effects on the pathological symptoms of schizophrenia.

The Japanese Ministry of Health and Welfare Research Committee on Aberrant Portal Blood Flow carried out an epidemiological survey and clinical study on Budd-Chiari syndrome in 1990. In the primary survey for determining the prevalence of the disease, a questionnaire was sent to all major hospitals throughout Japan and 160 cases seen in 1989 were compiled. More epidemiological details were obtained in 87 of these 160 cases. The number of patients with Budd-Chiari syndrome in this country was estimated to be about 300 (prevalence of 2.4/million) with about 20 new cases occurring every year. In the clinical study, 157 authentic cases of Budd-Chiari syndrome studied in 15 years (1975-89) were analyzed. There were 87 males (average age, 36.4 years) and 70 females (46.5 years), and the average period from the likely onset to the first medical consultation was 6.6 years, suggesting that these patients were mostly chronic cases. The main clinical features were hepatomegaly, leg edema, ascites and venous dilatation over the trunk. Abdominal pain was recorded in only four (2.5%). There were 16 (10.2%) with known identifiable etiologies. Of the patients 93% showed an obstructing lesion of various thickness in the hepatic portion of the inferior vena cava. Only nine (5.7%) had hepatic vein obstruction without caval lesions. Thus, the majority of Budd-Chiari syndrome patients in Japan are idiopathic, having an obstructing lesion in the inferior vena cava. The main causes of 33 deaths (21%) were liver failure, variceal bleeding and hepatocellular carcinoma. Hepatocellular carcinoma occurred in 10 (6.4%) in the 15-year period. However, the incidence of Budd-Chiari syndrome among all cases of hepatocellular carcinoma was less than 1% in the survey made by the Liver Cancer Study Group of Japan.

アーチダムの地震時の安全性をより合理的に評価するには, ダムの動的挙動を解析により正確に把握する必要がある. しかし, 解析はダム―岩盤―貯水の大規模な三次元連成問題であり, 解析条件はかなり複雑である. 十分な信頼度を有する解析を行うためには, 解析モデル, 解析条件についての検討が必要であり, 実測値に基づく実証的な研究が望まれる. 本研究は, このような考えに基づき, 起振実験のシミュレーションを試みたもので良好なシミュレーションを行うことができた. シミュレーション結果を示すとともに, 用いるべき解析モデル, 物性値の評価, 解析の手順等について明らかにする.

コンクリートの円柱形割裂試験供試体の, 割裂引張強度に到る破壊メカニズムについて, コンクリートを粗骨材とモルタルの複合体ととらえ, 割裂試験を行って得られた応力-ひずみ曲線や, 破壊性状等の観察結果と, はく離やクラックの破壊力学における応力特異性値の数理弾性解析結果により, 粗骨材に関わる個々の内部破壊現象の理論的裏付けを示しながら, 破壊力学的考察を行う.

Background. In hepatocellular carcinoma (HCC), a high prevalence of hepatitis C virus antibody (anti-HCV) has been reported, indicating that it may be an important etiologic factor in the pathogenesis of HCC. In this study, the authors investigated the prevalence of anti-HCV in HCC patients, as well as the same prevalence in patients with cholangiocarcinoma (CC) and combined hepatocellular–cholangiocarcinoma (combined HCC-CC), to study the clinicopathologic features of anti-HCV–positive cases. Methods. The authors examined 141 patients with primary liver cancer who were pathologically diagnosed as having HCC (121 cases), CC (13 cases), or combined HCC-CC (7 cases). Hepatitis B surface antigen (HBsAg) and anti-HCV were measured in these patients. Results. Of 121 HCC cases, 85 (70.3%) were found to be anti-HCV positive, 16 (13.2%) were HBsAg positive, and 5 (4.1%) were both anti-HCV and HBsAg positive. In 13 cases with CC and in 7 with combined HCC-CC examined, 4 (30.8%) and 5 (71.4%), respectively, were anti-HCV positive. Conclusions. The anti-HCV–positive rate was high in combined HCC-CC as well as in HCC. These three types of primary liver cancer, which were anti-HCV positive, shared two common features: male dominance and high incidences of complication with liver cirrhosis.

An association between primary sclerosing cholangitis (PSC) and chronic ulcerative colitis (CUC) is well known in Western countries, but there have been no reports on this association in Japan. We reviewed 163 consecutive CUC patients (91 males and 72 females) diagnosed from 1984 to 1990 at Tokyo Women's Medical College. Abnormal liver function tests were found in 42 patients with CUC (25.8%), but chronic liver disease was only diagnosed in seven patients (4.3%). Among these seven patients, there were four with PSC, one with small-duct PSC, one with transfusion-associated chronic hepatitis and one with Type B liver cirrhosis. No relationship was found between the documented colonic manifestations of CUC and the presence of PSC. The four PSC patients did not have a longer history of CUC at the time of diagnosis of PSC than CUC patients without PSC. At the time of PSC diagnosis, two patients were asymptomatic, one presented with right upper quadrant pain, and the other had fatigue. Three patients were diagnosed as having CUC before the onset of PSC (range 2-13 years), and the other patient had both diseases simultaneously. All four had a good prognosis. Thus PSC was the most common chronic liver disease associated with CUC in our series, and it was present in all our CUC patients with alkaline phosphatase levels exceeding twice the upper limit of normal and mild transaminase elevation.

To clarify the factors relating to the prognosis of patients with idiopathic portal hypertension (IPH), we followed 171 patients with IPH until the end of 1990, who were registered in the database among those with abnormal portal circulation as of 1985 in hospitals of Japan. During the follow-up period, twenty patients died; 6 from gastro-intestinal tract bleeding, 5 from hepatic insufficiency and 9 from other causes. Cox's proportional hazard model suggested that male patients (hazard ratio 4.85, 95% confidence interval 1.82-12.94), with a disease onset at less than 40 years of age (H.R.3.94, 95% C.I. 1.31-11.57), and/or with varices (H.R.2.86, 95% C.I. 1.05-7.77) generally had poorer prognoses.

症例は59歳男性.職業は溶接業.トロトラスト,塩化ビニールモノマー(VCM),素などの直接の汚染歴なし.昭和56年より肝障害と食道静脈瘤を指摘され,昭和59年,腹部超音波検査にて,肝内に占拠性病変を認めた為,精査目的で入院.入院時,肝脾腫,及び食道,胃静脈瘤,血小板減少を認め,各種画像診断上,肝には左葉内側区域と右葉にそれぞれ約7×10cm, 5×7cm程度の塊状の腫瘍が認められた.入院3ヵ月後に肝不全,呼吸不全にて死亡.剖検所見では,腫瘍は肉眼的には血管腫様で,総織学的には紡錘形の腫瘍細胞の充実性増生と,部分的には血管腫様の管腔形成を認め,肝血管肉鍾と診断.他臓器(肺及び骨髄)の転移巣も同様の所見であった.また,非腫瘍部の一部には,Edmondson III型の肝細胞癌も顕微鏡的に観察された.非腫瘍部には肝硬変はなく,門脈枝の硬化,異常血行路を認め,特発性門脈圧亢進症(IPH)に類似した組織像であった.

In recent years, a better understanding of the biology of renal cell carcinoma has allowed a more aggresive approach to resection of the tumor and a coexisting tumor thrombus. The suprahepatic extension of tumor thrombus, however, has difficulties in the surgical treatment. We report a 58-year-old man who had left renal cell carcinoma with tumor thrombus extending into suprahepatic vena cava inferior and received the curative operation using cardiopulmonary bypass. The disease accompaning tumor thrombus in vena cava inferior was also reviewed and discussed.

The effect of menaquinone-4 (MK-4, vitamin K2) was studied on des-gamma-carboxy prothrombin (DCP or PIVKA-II) levels in three subjects with vitamin K deficiency and five patients with hepatocellular carcinoma (HCC) with positive DCP. The half-life of DCP in HCC patients after intravenous MK-4 administration (50 mg daily for 14 days) was determined to be 60 hours, identical to that found in vitamin K-deficient subjects who received MK-4. When a single dose of MK-4 (10 mg) was given intravenously to three patients with HCC and elevated DCP, the levels decreased with a reduction rate identical to that in vitamin K-deficient subjects for the first 1 to 3 days, followed by an increase reaching the previous level in 7 to 10 days. Changes in plasma coagulant activity were compared between subjects with vitamin K deficiency and those with HCC before and after a single dose of MK-4 (10 mg). The activity increased in DCP-positive patients with HCC as in vitamin K-deficient subjects who received the same single dose of MK-4. The increase was greater in HCC patients with higher DCP levels. These results suggest that the level of plasma DCP in patients with HCC responded to vitamin K with the same sensitivity as that in vitamin K-deficient subjects. When patients with HCC underwent effective tumor therapy (resection or arterial embolization), the reduction rate (slope of DCP decline) was found to be identical to that in vitamin K-deficient subjects given with MK-4. In patients with less effective therapy, the reduction rate was smaller, or there was an increase in DCP. These observations strongly suggest that sequential measurements of the DCP reduction rate after treatment for HCC are useful for assessing therapeutic effects.

特発性門脈圧亢進症(IPH)として経過を観察されていたが,再度の肝生検で先天性肝線維症(CHF)と診断された48歳女性の1例を経験したので報告する.1990年全身倦怠感を主訴に受診.CHFを疑わせる家族歴はなく,脾腫軽度,貧血はないが,血小板は8.6万と減少していた.門脈圧亢進症としては,巨大脾腎シャントを認めた.原因となるべき肝疾患を認めず,腹腔鏡,腹部エコー,CTにて肝硬変は否定された.肝生検組織は細断されており診断は困難であったが,炎症性変化のない門脈域の線維化を認めた.以上より,IPHと診断した.1991年シャント閉鎖術施行目的で再度肝精査し,この時の肝組織で,胆管増生,門脈の低形成を認め,CHFと診断した.CHFは,本邦において今日までに約70例の報告があり,20歳以下では吐下血で発症することが多く,30歳以上では,健診などで偶然に発見されることが多く,CHFによる死亡は認めなかった.中高年に至ったCHFの中には本例のように診断の困難な例もあり,腹腔鏡・肝生検による慎重な診断が必要である.

Background: Patients with hepatocellular carcinoma (HCC) seropositive for lectin-reactive α-fetoprotein (AFP-L3) have a poor prognosis. However, there have been no studies of the clinicopathologic features of patients seronegative for both AFP and des-γ-carboxy prothrombin (DCP), and seropositive for AFP-L3 alone in comparison with other patients seropositive for AFP-L3. Methods: Patients with primary malignant hepatic tumors seropositive for AFP-L3 who underwent hepatectomy (n = 84) were divided into four groups, and their clinicopathologic features were compared: (i) group A, seronegative for AFP

Background : There has been no study of the clinicopathologic features of patients with hepatocellular carcinoma (HCC) who are seropositive for lectin-reactive α-fetoprotein (AFP-L3) alone, or seropositive for AFP-L3 and seronegative for des-γ-carboxy prothrombin (DCP) in comparison with those who are seropositive for DCP alone. Thus, the present comparative study was performed. Methods : The clinicopathologic features of HCC patients with either one or two tumors who underwent a hepatectomy (n = 88) were compared among the following five groups according to the seropositivity of AFP, AFP-L3 and DCP: (i) group A, seropositive for AFP above 100 ng/mL, AFP-L3 above 15% and DCP above 100 mAU/mL; (ii) group B, seropositive for AFP-L3 and seronegative for DCP below 40 mAU/mL; (iii) group C, seronegative for AFP below 20 ng/mL, AFP-L3 below 15% and seropositive for DCP; (iv) group D, seropositive for AFP and seronegative for AFP-L3 and DCP; and (v) group E, seronegative for AFP, AFP-L3 and DCP. Results : Group B patients showed a higher incidence of infiltrative-type HCC with an irregular margin (P

We describe six patients with non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). From 1990 to 2001, we treated 82 patients with NASH and observed six patients (three men and three women, aged 56-72 years) in this group who were referred with HCC or developed the complication during follow-up. In five of these six patients, NASH was associated with obesity (cases 3, 4 and 5), hyperlipidemia (case 5), or diabetes mellitus (cases 1, 3 and 6). We confirmed the presence of HCC by ultrasonography-guided tumor biopsy or surgery except in case 3 where we diagnosed the tumor by ultrasonography, computed tomography and selective hepatic arteriography. The carcinomas measured 1.5-6.0 cm in diameter and three were well differentiated. When HCC was diagnosed, cirrhosis was present in all instances. Four of the six tumor patients also had esophageal varices but only one patient had a history of variceal bleeding and ascites. Treatment of HCC consisted of surgery (cases 1 and 5), transcatheter arterial embolization or infusion and/or percutaneous ethanol injection (cases 2, 3, 4, and 6). In patients with NASH cirrhosis, the development of treatable HCC is sufficiently common to warrant regular screening for this grave complication.

To clarify the mechanism of production of des-gamma-carboxy (abnormal) prothrombin (DCP) by hepatocellular carcinoma (HCC), we measured the levels of vitamin K, DCP, immunoreactive prothrombin and the activity of gamma-glutamyl carboxylase in liver tissues from HCC patients and in the medium of cultured human hepatoma cells. There was no significant difference in vitamin K (K1, MK-4) contents between HCC and non-HCC cirrhotic liver tissues. The activity of gamma-glutamyl carboxylase per unit amount of endogenous microsomal prothrombin precursor was decreased in HCC tissue compared with non-HCC liver tissue (positive plasma DCP: 335 +/- 72 vs 372 +/- 67, negative plasma DCP: 370 +/- 84 vs 393 +/- 56 nmol/min per mg prothrombin precursor, P > 0.05), although the total incorporation of 14COOH into microsomal precursor protein was higher in the former. By contrast, levels of DCP and immunoreactive prothrombin in HCC tissue were greater (P < 0.05) than those in non-HCC cirrhotic liver tissue. Furthermore, production of large amounts of immunoreactive prothrombin was observed in human hepatoma cells huH-1 and huH-2, which produced large amounts of DCP. These results suggest that there was excessive synthesis of prothrombin precursors by human HCC tissue and hepatoma cell lines huH-1 and huH-2. Thus, excessive synthesis of prothrombin precursors seems to be the main mechanism of DCP production by HCC.

We measured plasma abnormal prothrombin (des-gamma-carboxy prothrombin; DCP) levels in normal subjects and in patients with hepatocellular carcinoma and other various diseases using the enzyme-linked immunosorbent assay developed by Motohara et al. (Pediatr Res 1985; 19: 354-357). Fifty-eight percent of 52 patients with hepatocellular carcinoma had elevated DCP levels; 24 of 28 patients with advanced or moderately advanced hepatocellular carcinoma were positive. By contrast, 50 normal controls, 13 pregnant women and 10 patients with acute hepatitis had normal levels. Three of 55 patients with chronic liver disease, and 6 of 32 patients with other malignancies, showed a slight increase. Thus, increased plasma DCP appears useful for the diagnosis of hepatocellular carcinoma. To elucidate the mechanism for the increase of DCP in hepatocellular carcinoma, we cultured a human hepatoma cell line, huH-2, and measured the levels of this abnormal prothrombin in the medium. The huH-2 cells produced large amounts of DCP in the medium without added vitamin K. It increased in a cell concentration- and time-dependent fashion. These cells produced no detectable amount of DCP in the medium with added vitamin K. Thus, human hepatoma cell line huH-2 produces DCP, and its production is dependent on the amount of vitamin K available in the medium. Des-gamma-carboxy prothrombin may be a useful tumor marker for the diagnosis of hepatocellular carcinoma.

健常者及び肝細胞癌(HCC)を含む各種疾患例において血漿中の異常プロトロンビンPIVKA-II (P-II)をEIA法を用いて測定し,HCC例の57.7%が高値を示した.他の肝疾患,悪性腫瘍疾患例では陽性率は極めて低く,そのうち肝硬変例では全例低値であり,HCCに高い特異性が認められた.HCCにおけるP-IIの上昇機序を検索する目的でAFP産生株であるヒト肝癌由来細胞株(huH-2)を用いて培養上清中のP-IIを測定した結果,細胞濃度に比例してP-II量は増加し,vitamin K添加によりP-IIは検出されなかった.以上からヒト肝癌培養細胞huH-2はP-IIを産生し,それはvitamin Kの存在に左右される事が示唆され,P-IIは臨床的に有意義な腫瘍マーカーとみなされる.

HBワクチン接種例の長期観察と,follow-up後にHBs抗体の力価(PHA法)が23以下の例にHBワクチンのBooster injectionを施行し,そのHBs抗体responseを検討した.HBsAg, anti-HBs陰性の116例に1981年8月から82年11月の期間にHBワクチン(HBsAg 20μg)を,初回,4週,24週後に接種した.そして,84年5月,85年8月にfollow-up後の検査を施行した.HBs抗体(PHA法)陽性率は,ワクチン接種終了時の28週では,79.8%で,経過とともに(平均156週)25例陰性化し,57.7%と低下し,力価も28週をピークとして低下した.又,力価上昇の1例はHBウイルスの感染と考えられた. Booster injectionでは,Responderでは全例,すみやかに十分なHBs抗体responseがみられ,HBs抗体産生メモリは保たれていると考えられ,Low responderでは70%, No responderでは23.1%であった.経過とともに,HBワクチンによって得られたHBs抗体の力価は低下し,力価が感染予防に不十分な例には,Booster injection(1回)が必要であるので,少なくとも1年毎の定期的なfollow-upを要すると思われた.

A sero-epidemiological study was made of 6863 apparently healthy randomly selected volunteers from various parts of Taiwan. It revealed an 18% incidence of hepatitis B surface antigen (HBsAg) carriers amongst the general population, the prevalence being significantly higher in males than females (21.7% vs 14.1%). The Takasago natives showed the highest HBsAg carrier rate (27.0%). Those who are primarily derived from Ming Nan had a significantly higher prevalence (19.0%) than those from Hakka (14.7%) and recent immigrants from Mainland China (14.6%). About one-third of female carriers of child-bearing age in southern Taiwan were positive for e antigen (HBeAg) in a limited study; they may be an important source of HB virus (HBV) infection. The positivity rate for HBeAg was significantly higher in subjects below 40 years of age (36.7%) than those above 40 years (7.5%). There was a significant association between HBsAg positivity and elevated serum transaminase levels, especially in males; 20.3% of carriers had elevated transaminase in comparison with 11.1% of female carriers. Among HBsAg seronegative individuals, the frequency of abnormal transaminase increased with age with an overall abnormality rate of 10.6% in males and 5.0% in females, suggesting that factors other than HBV may also contribute to liver disease in Taiwan. Altogether, 9.3% had elevated transaminase. Out of 82 randomly selected HBsAg carriers who were evenly distributed in geography, serum antidelta antibody was positive in only five men (6.1%), of whom four had a mild elevation of transaminase levels (< 100 KU). The overall positivity rate for anti-hepatitis A (HA) antibody was 93.0% in southern Taiwan, indicating poor sanitation. These findings indicate that HB and HA virus infections are highly endemic in Taiwan and that delta infection is infrequent despite a high prevalence of HB virus infection.

Hepatocellular carcinoma (HCC) associated with cirrhosis and HCC developing in a noncirrhotic liver may have differing pathogeneses. To study this possibility, 425 autopsied cases of HCC were investigated. Of these, 45 livers were not cirrhotic, 50 were highly cirrhotic (liver weight less than 99 g), and the remaining 331 were cirrhotic but not so highly. The average age was significantly older in the highly cirrhotic group, suggesting a longer premalignant period of chronic liver disease. The liver weight in the noncirrhotic group was about 3.5 times that in the highly cirrhotic group. Hepatitis B surface antigen was positive in serum in only 9.3% and in liver tissue in 10% in the noncirrhotic cases, the positivity rate being much lower compared with other groups (P less than 0.005--0.01), yet antibody to HB core was positive in 90%. The antibody titers were low, however, indicating that these noncirrhotic patients had in the past had HB virus (HBV) infection with no residual chronic B hepatitis. Analysis of the grades of anaplasia of cancer tissue demonstrated an inverse correlation between the degree of fibrosis and grade of anaplasia, i.e., the more advanced the fibrosis, the less anaplastic the cancer. These data suggest that HCC arising in highly cirrhotic liver and in noncirrhotic livers have different pathogenetic backgrounds, and that HBV infection, even though transient, has a certain role in hepatocarcinogenesis. The generally held conjecture that HCC in a noncirrhotic liver is caused by nonviral carcinogens and HCC arising on the ground of cirrhosis is due to HBV seems untenable in such a simple concept.

Clinicopathological features were studied in 41 patients with histology-proven hepatocellular carcinoma without cirrhosis. Of these, 13 (31.7%) were positive for hepatitis B virus surface antigen (HBsAg) and 28 were negative. Twenty-six of 28 (92.9%) HBsAg negative cases had anticore antibody (anti-HBc) of low titres. The age of patients at the time of diagnosis of hepatocellular carcinoma was significantly younger in the HBsAg positive cases compared with the negative. The initial diagnostic clue was either abdominal mass or abdominal pain in 18 (43.9%) patients. However, the number of patients in whom hepatocellular carcinoma was detected by imaging in the absence of such clinical signs has increased recently. The tumour was encapsulated in 31 cases (75.6%) and most solitary encapsulated tumours were growing expansively. Tumours were resectable in 29 (70.7%) cases, and the prognosis of resected cases was much better than that of 12 non-operated cases. Twenty-one out of 29 (72.4%) resected tumours were solitary and encapsulated. However, recurrence of tumour occurred in 12 out of 28 (42.9%) cases, and it was within 2 years of resection in 11 cases. These observations and data seem to indicate that early detection and resection of tumour is very important in management, but tumour recurrence is inevitable in a considerable proportion of the patients with non-cirrhotic hepatocellular carcinoma.

A survey of 2985 apparently healthy Taiwanese in southern Taiwan revealed a high prevalence (18.2%) of hepatitis B surface antigen (HBsAg). It was significantly higher in males (22.3%) than in females (13.6%), but no correlation with family origin, socioeconomic status or residence was established. About one-third of the breeding female HBsAg carriers were HBeAg-positive, and these may be an important source in the spread of HBV. Subtyping of HBsAg in 63 subjects showed adw to be dominant in this area, and 8 subjects with suspicious results had overlapping heterotypic HBV’s (7 adwr and 1 adyw) in addition to 2 subjects in which coexistence of HBsAg and anti-HBs was recognized. The association between HBsAg positivity and serum transaminase elevation was significant, especially in the older groups who had a higher abnormal rate. Hepatitis A virus infection was serious too, with nearly 100% of people above 20 years of age being anti-HA antibody positive.