血清总胆汁酸在肝脏疾病诊治中的意义

目的 通过测定急、慢性病毒性肝炎、重型肝炎和肝硬化等不同肝病患者血清中总胆汁酸含量,探讨其在判定肝脏功能,指导临床治疗中的意义.方法 采集健康对照组(n=82)、急性病毒性肝炎(n=45)、慢性乙型病毒性肝炎(n=156)、重型肝炎(n=41)、肝硬化患者(n=104)清晨空腹静脉血,用自动生化分析仪测定.结果 急性病毒性肝炎组、慢性乙型病毒性肝炎组、重型肝炎组及肝硬化组血清TBA分别是健康对照组的42、15、66倍和9倍(P＜0.05);慢性乙型肝炎患者随着病情的加重,血清TBA水平也显著升高.结论 血清总胆汁酸含量的检测可了解肝细胞受损情况, 可作为肝功能检测的辅助指标, 对病毒性肝炎和肝硬化具有辅助诊断意义.     

Phytohemagglutinin-induced lymphocyte transformation in liver diseases and in asymptomatic HBsAg carriers.

Phytohemagglutin (PHA)-induced lymphocyte transformation was impaired in acute viral hepatitis. It was significantly correlated with grades of liver cell damage as shown by prothrombin time, GOT, or GPT. It was also lower in drug-induced hepatitis and in prolonged hepatitis than in controls. Of asymptomatic HBsAg carriers, only those with minimal hepatic change showed lower values in stimulation index as well as incorporated radioactivity.     

Optimized determination and properties of NADPH-dependent glutathione reductase in serum. Studies on serum glutathione reductase, I. (author's transl)]

Reaction conditions were optimized for the determination of serum glutathione reductase, which has not yet been investigated systematically. Imidazole was found to be the most suitable buffer material; the highest glutathione reductase activity in serum was always obtained with imidazole/HCl buffer, which, in contrast to all other tested buffers, also resulted in the maximal enzyme activity without preincubation. In imidazole buffer, the pH-activity curve of serum glutathione reductase shows a broad optimum between pH 6.5 and 6.9. A GSSG concentration of 2 mmol/l and a NADPH concentration of 0.43 mmol/l gave maximal enzyme activity and a linear reaction over 10 min up to 20 U/l test solution. An investigation of serum glutathione reductase activity from 100 clinically healthy probands gave values between 20 and 50 U/l. In the optimized assay system the glutathione reductase in the serum reacts specifically with GSSG and NADPH.     

临床各型病毒性肝炎血清肿瘤坏死因子检测及意义

目的 :探讨血清肿瘤坏死因子 (TNF α)在不同临床分型的病毒性肝炎患者血清中的含量及临床意义。方法 :采用双抗体夹心酶联免疫吸附试验检测 175例病毒性肝炎患者血清TNF α水平。结果 :175例肝炎病人中 ,急性重型肝炎 15例 ,TNF α平均含量 8.0 9± 1.85ng/ml;慢性肝炎 76例 ,其临床分型及TNF α平均含量分别是 :2 2例重度慢性肝炎 5 .94± 1.87ng/ml,2 4例中度慢性肝炎 5 .5 2± 1.6 7ng/ml,30例轻度慢性肝炎 3.0 3± 1.0 2ng/ml;肝炎肝硬化 14例 4.71± 1.2 7ng/ml;急性肝炎40例 1.0 2± 0 .35ng/ml;无症状乙肝病毒携带者 30例 0 .90± 0 .2 1ng/ml。结论 :除乙肝病毒携带者及急性肝炎的检测结果与对照组相比较无差异外 ,其余临床各型病毒性肝炎 (慢性肝炎、肝硬化、急性重型肝炎 )均有显著差异 ,在与其它检测指标配合下 ,血清TNF α活性检测对监测各型肝炎的进行性损害程度及预后可提供一个辅助性指标     

肝病患者血清Lp（a）检测的临床意义

测定急性肝炎、慢性肝炎、肝硬化和重症肝炎患者血清中脂蛋白（ａ）［ＰＬ（ａ）］的浓度，结果分别为１４１．３±９２．４、７２．４±４３．２、５４．７±３７．８和５０．９±４１．６ｍｇ／Ｌ，与正常对照组（１５５．６±９９．１ｍｇ／Ｌ）比较差异显著（Ｐ＜０．０５）．其含量随病情加重逐渐降低，与急性肝炎血清ＧＰＴ呈负相关（ｒ＝－０．２７８，Ｐ＜０．００１）．提示血清Ｌｐ（ａ）含量可作为反映肝脏合成功能和损害程度的指标之一。     

Acute hepatitis induced by cyproterone acetate

OBJECTIVE: To report a case of acute hepatitis resulting from the use of cyproterone acetate, an adjuvant treatment for prostate cancer. CASE SUMMARY: An 87 year-old white man, admitted to surgery for prostate cancer, received cyproterone acetate 300 mg/d orally and developed acute hepatitis, which initially was diagnosed clinically. A liver biopsy showed changes suggestive of acute cholestatic hepatitis. Cyprotorone was stopped immediately, and the patient was subsequently treated with corticosteroids. He then improved rapidly. DISCUSSION: Cyproterone acetate is thought to be well tolerated, but some authors have reported severe hepatic reactions, in particular acute hepatitis, fatal fulminant hepatic failure, and hepatocellular carcinoma. The above-mentioned hepatotoxicity represents an idiosyncratic drug reaction, probably due to the hepatomitogen action of cyproterone, causing an increase of hepatocytes expressing placental glutathione S-transferase, which are considered preneoplastic elements. CONCLUSION: This case suggests the possibility of hepatotoxicity from cyproterone.     

Living related liver transplantation for acute fulminant hepatitis B: experience from two possible hyper-acute cases

Fulminant hepatic failure, which is represented by fulminant hepatitis, is fatal in most cases unless prompt liver transplantation is performed. Even if liver transplantation is performed, irreversible neurological damage is often complicated. In this case report, we describe two cases of fulminant hepatitis induced by acute hepatitis B virus infection, both of which were successfully rescued by living related liver transplantation without significant complications. The case 1 was a 45-year-old Japanese male. He complained general malaise and anorexia. His local physician diagnosed him as acute hepatitis B, and referred to our hospital. Due to severe coagulopathy, plasma exchange was performed 3 times. However, his hepatic coma progressed rapidly along with rapid decrease of both his direct/indirect bilirubin (D/T) ratio and serum blood urea nitrogen (BUN) levels. Living related liver transplantation was performed under the diagnosis of acute fulminant hepatitis B. The case 2 was a 34-year-old Japanese male. His complaints were fever and skin rush. He was referred to our hospital under the diagnosis of acute hepatitis B. On the second day after admission, he developed grade II hepatic coma, which deteriorated into grade III in spite of intensive therapy including plasma exchange. He also demonstrated rapid decrease of both D/T ratio and serum BUN level. Living related liver transplantation was performed on the next day. Both cases recovered without any evidence of neurological sequelae. In general, it is extremely difficult to rescue fulminant hepatitis by conservative treatments, particularly in cases with rapid progression. Although emergency liver transplantation may be an only option to rescue in such a case, living related liver transplantation has an advantage in view of urgent organ donation over cadeveric transplantation.     

Clinical significance of serum glutathione reductase in various clinical conditions, especially in liver diseases.

Serum glutathione reductase activity was measured in various conditions including acute hepatitis, chronic hepatitis, liver cirrhosis, malignant neoplastic diseases, and obstructive jaundice. A statistically significant elevation of the enzyme activity was found in all of these clinical conditions above normal value, especially in patients with acute hepatitis, some liver cancer, and malignant biliary obstruction. Comparison with other liver function tests showed the existence of statistically significant correlations of serum glutathione reductase with SGOT, SGPT and alkaline phosphatase in acute hepatitis, and with alkaline phosphatase in cirrhosis. In parenchymatous liver disease, serial determination was found to be important. High values in obstructive jaundice suggest the malignant obstruction.     

Effects of acetaldehyde on human red cell metabolism: evidence for the formation of enzyme inhibitors

Since red cells transport and metabolize acetaldehyde in vivo, the effects of acetaldehyde on human red cell enzyme activities were studied. Incubation of intact red cells or undiluted red cell lysates at 37 degrees C for 4 h with 1-10 mmol/l acetaldehyde decreased only GOT, GPT and aldolase activities among the 26 enzymes tested. No inhibition occurred at 4 degrees C or when acetaldehyde was incubated with dilute hemolysates. Incubation of lysates with other reducing substrates or with acetate inhibited aldolase but not GOT or GPT. Preincubation of lysates with cyanate or fluoride markedly decreased acetaldehyde-mediated transaminase inhibition but not aldolase inhibition. Addition of pyridoxal phosphate, the vitamin B6 transaminase coenzyme, to GOT and GPT assay mixes did not reverse acetaldehyde-mediated transaminase inhibition. These findings suggest that acetaldehyde-mediated aldolase inhibition results from oxidation of acetaldehyde while transaminase inhibition results from nonoxidative acetaldehyde metabolism. When 100-200 mumol/l acetaldehyde is added to lysates at 2-h intervals and when lysates are incubated with ethanol, alcohol dehydrogenase and an NAD-regenerating system, enzyme inhibition occurs at acetaldehyde levels approaching those seen in vivo. Thus, the role of acetaldehyde-mediated enzyme inhibition in the toxicity of alcohol abuse warrants further study.     

Successful treatment of hepatic coma by a new artificial liver device in the pig

In this study, we tested a new artificial liver device using liver pieces in 8-h hemoperfusion of comatous porcine blood and compared two alternative tissue preparations. Acute hepatic coma in the pigs was induced by complete devascularization of the liver. The animals were killed in stage IV coma (15-25 h after the operation), and 1 l blood was perfused over 200 g fresh or DMSO-preserved liver cubes. After the devascularization GOT, GPT, GLDH, AP, LDH, SDH, bilirubin, free fatty acid, and bile acid levels in serum increased progressively. Ammonia concentrations underwent a rapid increase in the first 9 h of coma development from 126.0 +/- 9.9 to 321.9 +/- 62.2 mumol/l. Most of the amino acids in serum were elevated and molar ratio of BCAA/AAA declined from 3.87 +/- 0.79 to 0.92 +/- 0.24. In the course of hemoperfusion ammonia was removed from the perfusate to 71% of the initial values using fresh and to 39% using preserved tissue. Correspondingly, there was an increase in urea concentrations. Amino acid metabolism was ameliorated during the perfusion; Fischer's quotient increased from 0.91 +/- 0.15 to 1.38 +/- 0.14 (fresh liver) and from 0.89 +/- 0.14 to 2.11 +/- 0.44 (preserved liver); neuroexcitatory amino acids Asp and Glu were markedly elevated. Energy charge of the liver cells increased and reached levels exceeding 0.5 in both experimental groups, a balanced energy metabolism was maintained and suggests active metabolization by the liver pieces. In comparison with fresh tissue, preserved liver cubes proved effective. We consider our artificial liver device capable of temporary hepatic support in acute necrosis of the liver and suppose that its efficiency can be potentiated by combining this system with other procedures.     

GB virus C in patients with liver disease of unknown etiology

To assess the prevalence of GBV-C in patients suffering unknown liver disease we have investigated the GBV-C-RNA in serum of 54 patients: 10 with acute and 32 with chronic non-A-E hepatitis (16 active and 16 persistent), 10 with hepatocellular carcinoma, 2 diagnosed with hepatic fulminant failure, and 91 healthy blood donors (control). PCR with primers from NS3 helicase region was performed and the product was identified by a double strand DNA enzyme immunoassay. GBV appears to infect 40 and 31% of acute or chronic non-A-E hepatitis respectively. Also the GBV genome was found in 1 in 10 samples of hepatocarcinoma, in 2 cases of fulminant hepatitis, and in 1 in 91 of the control group. In spite of these results the role of GBV in the etiology of liver diseases has to be analyzed in more comprehensive studies.     

The current endeavors to understand the pathogenesis of intractable liver diseases

The death due to liver diseases accounts for more the 35,000 cases every year in Japan for decades. Among these liver diseases, the Ministry of Health, Labor, and Welfare of Japan has named both fulminant hepatitis and primary biliary cirrhosis (PBC) as intractable liver diseases, since the precise mechanism of these diseases are unclear. Accordingly, there are no effective medical treatments other than liver transplantation toward these diseases. However, still the number of the liver transplantation performed in Japan is small. Thus, we have focused on the pathogenesis of these two intractable conditions. The fulminant hepatitis is a distinct form of acute hepatitis, and hepatitis B virus infection accounts for 20~30% of this lethal condition. Only tiny proportions of patients with acute HBV infection develop fulminant hepatitis (less than 10%). It has been widely believed both viral and host factors contribute for fulminant hepatitis, although still unknown factors are expected to be involved. On the other hand, PBC is a chronic progressive cholestatic liver disease. Clinical features of PBC include female predominance (80 to 90%), the presence of antimitochondrial antibody (up to 95%), and elevated serum levels of immunoglobulin M. Eventually, patients with PBC will develop liver failure due to biliary cirrhosis in spite of medical interventions. Immune-mediated processes are believed to be responsible for the pathogenesis, although the precise mechanism is yet to be determined. In this review article, our endeavors to understand the mechanism of these intractable liver diseases are discussed.     

Clinical usefulness of serum tripeptide aminopeptidase activity in diagnosing liver diseases

We examined the clinical usefulness of serum tripeptide aminopeptidase (EC 3.4.11.4) activity in diagnosing liver diseases. We found that increased tripeptide aminopeptidase activity accompanied an elevation in alanine aminotransferase activity (ALT) in the sera of patients with non-cancerous liver diseases and that these enzyme activities were correlated (r = 0.826-0.972). In contrast, an increase in tripeptide aminopeptidase activity did not coincide with an elevation in ALT activity in the sera of patients with cancerous liver diseases. We also observed a correlation in acute hepatitis and in patients following transcatheter arterial embolization of hepatoma throughout their subsequent clinical courses. The difference in serum enzyme activities for cancerous and non-cancerous liver diseases seems to result from changes in enzyme activities in cancerous liver tissues. We found that the ratio of tripeptide aminopeptidase to ALT activity in hepatoma tissues (1.9) was 4 times higher than that in normal liver tissues (0.5).     

Determination of prolinase activity in plasma. Application to liver disease and its relation with prolidase activity

We describe prolinase (EC 3.4.13.8) activity in human plasma for the first time. Optimum activity was obtained with prolylvaline as substrate and 0.02 mmol/L manganese concentration at pH 9.0. Moreover, preincubation with manganese was not required, contrary to prolidase (EC 3.4.13.9) activity. The mean value observed in 106 subjects without liver and renal disorders was 16 U/L +/- 14 (2 SD). We determined this plasma enzyme activity in patients with acute hepatitis and chronic liver disease. Plasma prolinase activity was strongly dependent upon cytolysis because of the high activity in liver and the low activity in plasma. Of 24 patients with chronic liver disease (4 chronic hepatitis and 20 cirrhosis) and without cytolysis, prolinase activity was slightly increased in only three patients, whereas prolidase activity was increased in 13. This could be due to a difference in the activation of these two enzymes in liver during the fibrotic process.     

Decreased activity of carnosinase in serum of patients with chronic liver disorders

We measured the activity of carnosinase, a prominent hepatic peptidase, in sera from 69 patients with liver disorders. Mean values (and SDs) for those with liver cirrhosis (17 cases) and hepatoma (seven cases) were 0.51 (0.28) and 0.68 (0.21) mumol/mL per hour, respectively--clearly less than for normal adults: 4.19 (0.95) mumol/mL per hour. Samples from 17 cases of chronic hepatitis also showed moderately decreased activity, 1.41 (0.97) mumol/mL per hour. In contrast, 14 cases of acute hepatitis generally showed values falling within the normal limits: 3.41 (1.97) mumol/mL per hour. Our results for carnosinase correlated with those for cholinesterase (r = 0.70) and with the concentration of albumin in serum (r = 0.59), but not with the activity of either creatine kinase, aspartate aminotransferase, or alanine aminotransferase in serum. Carnosinase values differed more among groups of disorders than did the values for cholinesterase or albumin. Measurement of serum carnosinase activity may be of clinical value in assessing the severity of chronic liver-cell damage, but not in differentiating liver disease from nutritional, muscle, or endocrine disorders.     

Changes in serum enzyme activity after transcatheter arterial embolization for hepatic neoplasm

We assayed serum levels of certain enzymes and tumor markers in patients after transcatheter arterial embolization (TAE) to evaluate the effectiveness of this treatment. Twenty patients had hepatocellular carcinoma and two patients had metastases to the liver from colon cancer. Assays were first done immediately after TAE and were continued for the next 12 days. Glutamic oxaloacetic transminase (GOT; EC 2.6.1.1, -aspartate:2-oxoglutarate aminotransferase), glutamic pyruvic transaminase (GPT; EC 2.6.1.2, -alanine:2-oxoglutarate aminotransferase), and lactate dehydrogenase (EC 1.1.1.27; (S)-lactate:NAD⁺ oxidoreductase) peaked 24 to 48 h after TAE and returned to the base lines in 7 to 10 days. Mitochondrial GOT (mGOT) and glutamate dehydrogenase (GLDH; EC 1.4.1.2, -glutamate:NAD⁺ oxidoreductase) also peaked at the same time after TAE. -Fetoprotein peaked 2 h after TAE and decreased to half of the baseline on day 7. Carcinoembryonic antigen peaked at 24 h and fell at 48 h only in the patients with colon cancer. The total amount of cytosolic GOT, GPT, mGOT, and GLDH released was correlated to the volume of the necrotic mass estimated by computed tomography scans. The correlation coefficients for mGOT and GLDH were r = 0.919 and r = 0.939 (both p < 0.001), respectively. Assays of mGOT and GLDH may be useful to estimate the volume of the necrotic mass of a hepatoma or metastatic carcinoma in the liver.     

肝病患者的血清过氧化氢酶活性测定初探

采用比色法检测了３３７例不同肝病患者的血清ＣＡＴ活性水平。与正常对照组比较，有１２５例血清ＣＡＴ活性增高，占３７．１％（Ｐ＜０．０１）。试验结果表明，血清ＣＡＴ活性测定对不同肝病患者的检出阳性率依次为：肝癌５９．３％（１６／２７），急黄肝５１．７％（１５／２９），肝硬化４１．４％（１２／２９），甲肝３９．３％（２２／５６），慢活肝３９．１％（１８／４６）和乙肝２８．０％（４２／１５０）。     

Mutations in core nucleotide sequence of hepatitis B virus correlate with fulminant and severe hepatitis.

Infection with hepatitis B virus leads to a wide spectrum of liver injury, including self-limited acute hepatitis, fulminant hepatitis, and chronic hepatitis with progression to cirrhosis or acute exacerbation to liver failure, as well as an asymptomatic chronic carrier state. Several studies have suggested that the hepatitis B core antigen could be an immunological target of cytotoxic T lymphocytes. To investigate the reason why the extreme immunological attack occurred in fulminant hepatitis and severe exacerbation patients, the entire precore and core region of hepatitis B virus DNA was sequenced in 24 subjects (5 fulminant, 10 severe fatal exacerbation, and 9 self-limited acute hepatitis patients). No significant change in the nucleotide sequence and deduced amino acid residue was noted in the nine self-limited acute hepatitis patients. In contrast, clustering changes in a small segment of 16 amino acids (codon 84-99 from the start of the core gene) in all seven adr subtype infected fulminant and severe exacerbation patients was found. A different segment with clustering substitutions (codon 48-60) was also found in seven of eight adw subtype infected fulminant and severe exacerbation patients. Of the 15 patients, 2 lacked precore stop mutation which was previously reported to be associated with fulminant hepatitis. These data suggest that these core regions with mutations may play an important role in the pathogenesis of hepatitis B viral disease, and such mutations are related to severe liver damage.     

肝病患者和供血员血清中抗-HGV的检测及其意义

目的探讨肝病患者和供血员血清中抗 ＨＧＶ检测的意义。方法采用北京医科大学肝病研究所生产的试剂盒，对２２６例肝病患者和１８７例献血员血清中抗 ＨＧＶ进行检测。结果急性肝炎、慢性活动性肝炎、慢性迁延性肝炎、肝硬化、重型肝炎病人抗 ＨＧＶ阳性检出率分别为６．９％（３／４３），１７．９％（１９／１０６），１４．２％（５／３５），３３．３％（３／９）和９．１％（３．３３）。肝硬化患者血清中抗 ＨＧＶ的检出阳性率明显高于其它各型肝炎（Ｐ＜０．０５）。１８７例献血人员中检出抗 ＨＧＶ４例（２．１％）。结论作者认为在供血人员中对ＨＧＶ进行筛选，以避免和减少输血后肝炎的发生。     

Blood levels of glutamate oxaloacetate transaminase are more strongly associated with good outcome in acute ischaemic stroke than glutamate pyruvate transaminase levels

Ischaemic stroke is associated with an excessive release of glutamate in brain. GOT (glutamate-oxaloacetate transaminase) and GPT (glutamate-pyruvate transaminase) are two enzymes that are able to metabolize blood glutamate facilitating the lowering of extracellular levels of brain glutamate. Our aim was to study the association between blood levels of both enzymes and stroke outcome in patients with acute ischaemic stroke. We prospectively studied 365 patients with first ischaemic stroke<12 h. Glutamate, GOT and GPT levels were determined in blood samples obtained at admission. We considered functional outcome at 3 months [good outcome: mRS (modified Rankin Scale)≤2; poor outcome mRS >2], END (early neurological deterioration) in the first 72 h [increment ≥4 points in NIHSS (National Institutes of Health Stroke Scale)] and infarct volume [CT (computed tomography) at 36-72 h] as end points. We have found an inverse correlation between GOT and GPT levels and blood glutamate levels. Patients with poor outcome showed lower levels of GOT (11.9±8.2 compared with 22.7±10.2 m-units/ml, P<0.0001) and GPT (19.5±14.3 compared with 24.7±20.3 m-units/ml; P=0.004). A negative correlation has been found between GOT (Pearson coefficient=-0.477, P<0.0001) and GPT (Pearson coefficient=-0.116; P=0.027) levels and infarct volume. Patients with END showed higher levels of blood glutamate (381.7±97.9 compared with 237.6±114.0 μmol/l, P<0.0001) and lower levels of GOT (10.8±6.7 compared with 18.1±10.8 m-units/ml; P<0.0001). This clinical study shows an association between high blood GOT and GPT levels and good outcome in ischaemic stroke patients, this association being stronger for GOT than GPT levels.