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We report a case of methotrexate (MTX) delaying the healing of an endoscopic submucosal dissection (ESD)-induced gastric ulcer. The patient, who had been taking MTX for rheumatoid arthritis, underwent ESD for early gastric carcinoma. Despite taking vonoprazan after ESD, abdominal pain and anorexia continued, and the gastric ulcer did not heal after the ESD. After discontinuing MTX, the patient's symptoms improved and the ulcer healed. Patients taking MTX require careful follow-up after ESD, considering that ulcers can be difficult to heal. Discontinuation of MTX should be considered if delayed healing of an ulcer is observed.

Activated liver macrophages are considered to play an important role in the development of liver injuries. Functional differences between activated and normal rat liver macrophages were investigated. In addition, from the therapeutic point of view, the effects of prostaglandin E1, prostaglandin I2 and E3330 ((2E)-3-[5-(2,3-dimethoxy-6-methyl-1,4- benzoquinoyl)]-2-nonyl-2-propenoic acid) on the functions of liver macrophages were also determined. Rat liver macrophages were primed by Propionibacterium acnes and activated by a small dose of lipopolysaccharide. Lipopolysaccharide uptake capacity was evaluated quantitatively by flow cytometric analysis. Tumor necrosis factor-alpha activities were measured by bioassay. There were no significant differences in lipopolysaccharide uptake capacity between activated and normal liver macrophages, while activated liver macrophages had a significantly (P < 0.01) higher capacity in the release of tumor necrosis factor-alpha. Prostaglandin E1 and E3330 inhibited tumor necrosis factor-alpha release without suppressing lipopolysaccharide uptake capacity. In this study we have clarified the functional differences between activated and normal liver macrophages. The beneficial effects of prostaglandin E1 and E3330 on the functions of liver macrophages were also demonstrated.

Recent studies have suggested an association between tumor necrosis factor-alpha (TNF-alpha) and the development and progression of acute liver failure. To investigate the role of TNF-alpha in the mechanism of massive hepatic necrosis, we studied a mouse model of TNF-alpha and D-galactosamine (GalN) -induced hepatic necrosis by ultrastructural analysis. Administration of GalN caused edema of hepatocellular microvilli and widening of sinusoidal endothelial fenestrae (SEF); administration of TNF-alpha caused only a widening of the SEF. Massive hepatic necrosis with hemorrhage was seen 6 hr after concomitant administration of TNF-alpha and GalN. In the ultrastructural analysis, edema of the hepatocellular microvilli, widening of the SEF, and transmigration of red blood cells (RBC) and platelets to the space of Disse without exfoliation and necrosis of the sinusoidal endothelial cells were observed. Fibrin deposits were seen in areas adjacent to injured hepatocytes. The diameter of the SEF was significantly greater than in the nontreated group and the groups treated with TNF-alpha or GalN alone. These results suggest that as a consequence of the increase in diameter of the SEF, transmigration of RBCs and platelets to the space of Disse may have resulted in massive hepatic necrosis due to occlusion of the microcirculation.

A 56-year-old man was admitted with obstructive jaundice. Abdominal computed tomography and endoscopic retrograde cholangiopancreatography showed circumferential stenosis with irregular wall in lower bile duct, but the cytology of biliary brushing was no malignancy. The patient was given a diagnosis of gastric carcinoma with bone and skin metastasis. He died 2 months after the first hospital admission and autopsy was performed. The histological findings of gastric and bile duct tumor revealed signet ring cell carcinoma. The immunohistological findings of both tumors were identical. We definitively diagnosed this case as metastasis of gastric carcinoma to the bile duct.

Microtubules, which are components of the cytoskeleton, are the organelles involved in vesicular transport. In the hepatocyte, the microtubular network is presumed to be concerned with bile acid secretion, and there may also be some structural changes in cholestatic conditions. The polymerized tubulin levels were determined as microtubules in the liver by the radiochemical assay in rats after the administration of taurocholic acid, colchicine, taurocholic acid following the treatment of colchicine, cytochalasin B and common bile duct ligation. The polymerized tubulin levels were increased after the high dose administration of taurocholic acid, but were decreased after the treatment with colchicine. In cholestasis models induced by cytochalasin B and common bile duct ligation, the polymerized tubulin levels were markedly increased. These findings suggest the microtubule system plays an important role in the excretion of a large amount of bile acids into the bile, and that growth of the microtubular network occurs in cholestasis in order to promote the vesicular transport and to maintain the cell shape.

Hepatocyte growth factor (HGF) and transforming growth factor alpha (TGF-alpha) stimulate liver regeneration, whereas transforming growth factor beta 1 (TGF-beta 1) inhibits it in rats. However their significance in human liver diseases, especially in severe acute liver injury, remains unclear. We studied HGF, TGF-alpha, and TGF-beta 1 messenger RNA (mRNA) expression in the livers of patients with live diseases using a competitive reverse transcriptase polymerase chain reaction. As little as a twofold difference in mRNA expression could be detected from minute liver biopsy samples. We then examined cell proliferation using proliferating cell nuclear antigen (PCNA) staining. HGF mRNA levels were significantly higher (approximately threefold) in acute hepatitis (AH) than in exacerbation of chronic liver disease (EX) (P < .05). TGF-alpha mRNA levels were significantly greater in AH (approximately twofold) than EX (P < .05), and the levels were significantly higher (approximately threefold) in chronic hepatitis (CH) than in EX (P < .05). The TGF-beta 1 mRNA levels in all the groups were not significantly different. In acute liver injury (AH and EX), there was a significant correlation between HGF mRNA expression and the PCNA labeling index (LI) in the liver (r = .87, P < .005). TGF-alpha mRNA expression also correlated with the PCNA LI (r = .92,P < .0001). There was no significant correlation between the serum HGF and the PCNA LI in the liver. In conclusion, HGF and TGF-alpha produced in the liver stimulate hepatocyte proliferation in response to acute liver injury in humans.

Lead nitrate induces liver cell proliferation in rats without accompanying liver cell necrosis. However, the mechanism of this proliferation and its effect on hepatocytes remain unknown. Therefore, we examined the liver and blood level of hepatocyte growth factor and tumor necrosis factor alpha (TNF-alpha) at various intervals to determine whether lead nitrate modifies hepatocyte proliferation by altering the production of these cytokines. We also administered several TNF-alpha inhibitors, dexamethasone, adenosine, (2E)-3-[5-(2,3- dimethoxy-6-methyl-1,4-benzoquinoyl)]-2-nonyl-2-propenoic acid (E 3330), and pentoxifylline, to rats to clarify whether pretreatment with these inhibitors suppresses the increase of TNF-alpha messenger RNA (mRNA) in the liver and prevents the hepatocyte proliferation induced by lead nitrate. Hepatocyte proliferation occurred by 24 hours and reached a peak 48 hours after a single intravenous injection of lead nitrate (100 mumol/kg). TNF-alpha mRNA expression in the liver was increased 1, 6, and 12 hours after the injection, whereas no alteration was observed in liver or blood level of hepatocyte growth factor. Pretreatment with dexamethasone (4.0 mg/kg), E3330 (100 mg/kg) adenosine (0.3 mmol/kg), and pentoxifylline (100 mg/kg), inhibited both TNF-alpha mRNA expression and hepatocyte proliferation 48 hours after the injection. These experimental results strongly support the hypothesis that TNF-alpha positively regulates the hepatocyte proliferation induced in rats by the mitogen, lead nitrate. (Hepatology 1996 Jan;23(1):104-14)

We investigated the safety and efficacy of percutaneous hot water injection therapy (PHoT) in six patients with hepatocellular carcinoma (HCC). PHoT produced the marked effect in five (62.5%) of eight lesions. No serious adverse effects have been encountered. We also compared the usefulness of percutaneous ethanol injection therapy (PEIT) (22 patients, 32 lesions) and PHoT (five patients, seven lesions) in patients with HCC with diameter of 3 cm or less. Patients in the PHoT group received significantly fewer treatments than in the PEIT group (P < 0.01), because the volume injected per treatment was greater. Residual cancer was found in five (15.6%) of 32 lesions after PEIT and in three (42.9%) of seven lesions after PHoT, but the difference was not statistically significant. Pain tended to be less frequent in patients treated with PHoT than in patients treated with PEIT. We could not determine whether PHoT was superior to PEIT, but our findings indicate that PHoT may be a safe and effective for treating HCC.

2.5 oligoadenylate synthetase (2.5AS) activity is induced during interferon (IFN) therapy of patients with chronic hepatitis C. It is assumed that the genotype and quantitative level of hepatitis C virus RNA (HCV-RNA) in serum preceding IFN therapy are closely associated with the response to IFN. However, it is not clear whether these viral factors may affect 2.5AS activity during IFN therapy. We analyzed 2.5AS activity during IFN therapy in patients with different genotypes or levels of serum HCV-RNA. However, there were no statistical differences es in 2.5AS activity among them. In the present study, those viral factors were not associated with the induction of 2.5AS activity during IFN therapy, and it is unlikely that differences in response to IFN among patients with different genotypes or quantitative levels of HCV-RNA depend on the 2.5AS pathway.

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.)

Secretin is known to stimulate bile flow from the bile duct epithelium. To investigate the effects of secretin in cholestasis, we studied the response of the bile flow and the excretion of biliary components to secretin using two cholestatic models with or without damage to the bile duct epithelium. The model without bile duct epithelial damage was a choledocho-caval (CC) fistula over a 24-hour period, and the model with bile duct damage was a bile duct ligation over a 48-hour period. Secretin was administered by intravenous infusion for 30 minutes and bile was collected for 120 minutes. Controls were given saline similarly. The bile flow and biliary bicarbonate excretion rate were significantly increased after secretin infusion in the CC fistula rats when compared with the control rats, but no stimulation by secretin was observed in the ligated rats. These data indicate that secretin-induced bile production was enhanced under cholestatic conditions with no bile duct epithelial disturbance.

To elucidate the differences in the progression of liver cirrhosis of chronic hepatitis B and C, the laparoscopic appearance of the liver surface and the histological findings were carefully assessed in 65 patients with chronic hepatitis B and 58 patients with chronic hepatitis C. There was a difference noted in the distribution of periportal reddish markings between the two types of chronic hepatitis. Localized and irregular markings were found to be common in hepatitis C. While the markings were seen to be diffusely distributed over the liver surface in hepatitis B. In addition, localized and longitudinal depressions on the liver surface were observbed more frequently in the hepatitis C patients than in those with hepatitis B. Biopsy specimens obtained from the hepatitis C patients with the above-mentioned laparoscopic findings showed more advanced histological activity. These laparoscopic changes developed in accordance with the progression of histological activity in chronic hepatitis C. Lymphoid follicles or aggregates within the portal areas were observed more frequently in the patients with chronic hepatitis C than in the chronic hepatitis B patients. Although it is not yet clear how the laparoscopic and histological differences between these two types of chronic hepatitis come about, it appears that the progression of hepatocellular necrosis in chronic hepatitis C is different from that of chronic hepatitis B.

Secretin is known to stimulate the flow of bicarbonate-rich bile from the bile-duct epithelium, but has no effect on hepatocytes. To investigate the effects of secretin on bile production during intrahepatic cholestasis, we infused secretin into rats with taurocholate-induced cholestasis. Secretin was given at 0.25 and 0.50 units·min −1 ·kg −1 to Wistar rats that simultaneously received a continuous infusion of taurocholic acid at above its maximum hepatic transport capacity to produce cholestasis. When taurocholic acid was infused at doses of 1.4 and 1.6 μ mol·min −1 ·100 g b.w. −1 , bile volume decreased in control rats. In contrast, the simultaneous infusion of secretin significantly increased bile flow and the biliary excretion of bile acids and bicarbonate. The serum taurocholic acid level at the end of the experiment was significantly lower in the secretin-treated groups than in the control group. These findings indicate that secretin prevents taurocholate-induced cholestasis and may enhance the biliary excretion of bile acids.

Using immunohistological methods, we studied the lymphoid follicles in liver biopsy specimens obtained from patients with chronic hepatitis C(CH-C) to determine whether they represented an autoimmune manifestation. In 84 specimens obtained by liver biopsy from 76 patients positive for C-100 antibody, we assessed the presence or absence of lymphoid follicles within the portal areas, and then compared the clinical and immunohistological profiles of the two groups defined on this basis. There were no significant differences in the serological and clinical profiles of the two groups, but the T4:T8 cell ratio within the portal areas differed significantly. A T4:T8 cell ratio > 1.0 was more common in the specimens containing lymphoid follicles. This finding resembled the distribution of T cell subpopulations in the portal areas of patients with autoimmune hepatitis, and suggested that lymphoid follicles may be worth investigating to elucidate the relationship between chronic hepatitis C and autoimmune hepatitis.

This study evaluated whether liver regeneration could take place after massive or submassive necrosis of liver cells in 25 patients with several kinds of hepatic failure by immunohistochemical staining for proliferating cell nuclear antigen (PCNA). PCNA positivity was significantly higher (P less than 0.01) in the patients who survived than in the patients who died. Furthermore, PCNA-positive hepatocytes were recognized diffusely in the lobule of the liver in survivors. There was positive correlation between PCNA positivity and plasma concentration of AFP (alpha-fetoprotein), (r = 0.77, P less than 0.01). These results show that liver regeneration could take place after massive necrosis of liver cells in survivors from acute hepatic failure and that immunohistochemical staining for PCNA is useful for prognostic evaluation.

われわれは自験肝細胞癌309例を対象とし内科的治療法の評価を行い,治療法の選択について検討した.309例に対する治療法の内訳は肝切除術(22例),肝動脈塞栓術(TAE)(35例),lipiodolization(32例),one-shot療法(140例),無治療あるいは抗癌剤全身投与(80例)である.また11例にインターフェロンγ療法を行った.症例はclinical stage (CS), tumor stage (TS), portal invasion (Vp)により3～4stageに分類した.TAE, lipiodolization, one-shot療法等activeな治療法はCS I～II, TS I～II, Vp 0～3で有効であり有効性もその順に認められたがCS III, TS III, Vp 4では延命効果はほとんど期待できなかった.またインターフェロンγ療法は投与後NK活性が上昇することから全身療法の一つとなる可能性が示唆された.

肝疾患以外に対してステロイド療法を施行し,その減量または中止後に肝炎を発症し,劇症化し死に至ったasymptomatic HBs Ag carrierの3症例を報告した.ステロイド投与による免疫能の抑制と,その後の中止または漸減による免疫能の過剰な賦活が,肝炎を劇症化させたと考えられた.B型慢性肝炎に対するステロイド離脱療法後の肝炎の重症化も報告されており,HBs抗原陽性者にステロイドを使用する際は充分な注意が必要である.ステロイド療法は各領域でしぼしば施行されており,このような症例の特徴を広く各領域の医療担当者に認識させることの重要性を指摘した.

アセトアミノフェンの大量服用により,急性肝障害の発症をみることは,よく知られた事実である.最近,教室では,少量のアセトアミノフェンの服用にもかかわらず,重症肝障害を生じた2例を経験したので報告した.患者は38歳の男性と31歳の女性である.アセトアミノフェン服用量は,それぞれ,3.7gと6.4gで,いずれも嘔吐,腹痛,全身倦怠感を訴えて入院した.本剤服用時,前者はアルコールを摂取し,後者は絶食状態であった.検査上,前者は著明な血清トランスアミナーゼの上昇,軽度の黄疸を認め,心内膜炎,腎障害,急性膵炎を併発し,肝組織では小葉内に巣状壊死が散在し,中心静脈周囲にも壊死が認められた.後者でも重篤な肝障害と血小板減少がみられ,肝組織像はbridging necrosisを示していた.アルコール摂取と絶食のために,少量のアセトアミノフェン服用にもかかわらず,予想以上に肝障害が重症化したと考えられ,本剤の使用にあたり,注意が必要である.

Many animal experiments have been studied on the choleretic effects of secretin. We intended to estimate secretin choleresis in human (15 patients) who had received PTCD or T-tube insertion into the common bile duct. Based upon these data of secretin and choleresis, secretin was administered to 11 patients with prolonged jaundice due to intrahepatic cholestasis in order to evaluate this as a new therapy for intrahepatic jaundice. As controls, eleven patients with intrahepatic cholestasis treated with steroid hormones and/or phenobarbital were used. In all cases with biliary drainage, secretin produced a remarkable choleretic effect with a high concentration of bicarbonate. In 9 out of 11 patients with intrahepatic cholestasis who were treated with secretin, levels of serum bilirubin decreased linearly and other liver function tests returned to the normal range. The mean values of T1/2 (number of days required for reduction by half) of serum bilirubin in 9 effective cases to secretin was 10.8 days. On the other hand, that in 11 effective cases treated with steroid hormones and/or phenobarbital was 23.2 days. These results suggest that secretin therapy may be an effective treatment for intrahepatic cholestasis.

Forty five patients were examined in order to evaluate the usefulness of glucagon and insulin as a therapy of fulminant hepatitis. Thirty patients were treated with simultaneous infusion of glucagon and insulin, whereas prednisolone was given at a daily dose of 60 to 90 mg in 15 cases. In the former group, 1 mg of glucagon and 10 units of regular insulin were infused over a period of 2 to 6 hours. Two such treatments were given per day in the early critical period of fulminant hepatitis. The therapeutic effect of glucagon and insulin was evaluated in comparison with that of prednisolone, and additionally, with a combination therapy of either blood exchange or plasmapheresis in both groups. The survival rate was superior in the group treated with glucagon and insulin (46%) and in the one with combined infusion of these hormones plus plasmapheresis (33%).