Collagen biosynthesis enzymes in serum and hepatic tissue in liver disease

Abstract. Serum immunoreactive prolyl hydroxylase protein was measured in sixty-five patients with liver disease, and liver prolyl hydroxylase activity, immunoreactive prolyl hydroxylase protein and collagen hydroxyproline in forty of these patients. Serum immunoreactive prolyl hydroxylase protein was above the 95% confidence limit of the controls in most patients with primary biliary cirrhosis, portal cirrhosis, acute hepatitis and cancer with liver metastases, but below this in most patients with fatty liver, chronic active hepatitis, extrahepatic cholestasis, cholangitis, cancer without liver metastases and other malignant diseases. Elevated serum immunoreactive prolyl hydroxylase protein decreased rapidly with time in acute hepatitis but not in primary biliary cirrhosis. Liver prolyl hydroxylase activity and immunoreactive prolyl hydroxylase protein were elevated in the same diseases as serum immunoreactive prolyl hydroxylase protein, and correlated significantly with the latter whereas no correlation was found between serum immunoreactive prolyl hydroxylase protein and collagen hydroxyproline. Serum immunoreactive prolyl hydroxylase protein correlated highly significantly with serum alkaline phosphatase and weakly with serum aspartate aminotransferase in primary biliary cirrhosis, but not in any other disease. No correlation was found between serum immunoreactive prolyl hydroxylase protein and other tests of liver function. The results suggest that changes in serum immunoreactive prolyl hydroxylase protein in liver disease primarily reflect changes in this enzyme in the hepatic tissue, and that assays of serum immunoreactive prolyl hydroxylase in liver disease may give useful information on the actual hepatic collagen synthesis.     

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.     

Assessment of nutritional status of patients with end-stage liver disease undergoing liver transplantation

Nutritional assessment factors (including dietary history, anthropometric and biochemical measurements, and evaluation of immunocompetence) were retrospectively reviewed in 74 patients undergoing an initial liver transplantation procedure. The patients were subdivided into four categories on the basis of type of liver disease: chronic active hepatitis (N = 24), primary sclerosing cholangitis (N = 22), primary biliary cirrhosis (N = 20), and acute or subacute hepatitis (N = 8). Our nutritional assessment data indicated that malnutrition was present preoperatively in all liver transplantation groups but that each group had distinct characteristics. The group with primary biliary cirrhosis seemed to have the best hepatic synthetic function despite extreme wasting of muscle and fat. On the basis of all criteria, the group with acute hepatitis was the most malnourished of the various disease groups. Aggressive nutritional support, which includes adequate intake of nutrients and supplementation of vitamins and trace minerals, should be encouraged for all potential liver transplant patients.     

gamma-Glutamyl transpeptidase activity in liver disease: serum elevation is independent of hepatic GGTP activity

gamma-Glutamyl transpeptidase activity was measured in liver and serum from 110 patients undergoing diagnostic liver biopsy, including patients with alcoholic liver disease, fatty liver not due to alcohol, primary biliary cirrhosis, persistent hepatic disease, chronic active hepatitis and normal livers. Serum gamma-glutamyl transpeptidase was markedly elevated in patients with alcoholic liver disease and primary biliary cirrhosis while mean hepatic gamma-glutamyl transpeptidase activity was significantly increased only in the alcoholic liver disease group. There was considerable overlap of individual enzyme values among the different disease groups. There was no inhibitors or activators of liver gamma-glutamyl transpeptidase in any of these disorders. The increased liver activity was not related to the degree of hepatic fibrosis or cirrhosis. There was no correlation between hepatic and serum gamma-glutamyl transpeptidase activity. Hepatic and serum gamma activities were equally increased in individuals with alcoholic liver disease whether or not they were drinking at the time of the study. The data suggest that increased hepatic gamma-glutamyl transpeptidase activity is neither specific for alcoholic liver disease nor essential for serum GGTP to be elevated.     

Concanavalin A induced suppression of lymphocyte proliferation in chronic liver disease. A study of suppressor and responder populations in autologous and allogeneic systems

Abnormal T-cell regulation of lymphocyte proliferation may contribute towards tissue damaging mechanisms in chronic liver disease. We therefore studied Concanavalin A induced suppressor cell activity in T-T interaction in 47 patients with chronic liver disease, using both an autologous and an allogeneic system. In the autologous system, no differences were found between those with auto-immune chronic active hepatitis, HBsAg positive chronic active hepatitis, primary biliary cirrhosis, alcoholic liver disease and normal controls. However, several abnormalities were identified in allogeneic cultures with normal lymphocytes which allowed separate analysis of the influence of suppressor and responder cells from patients with chronic liver disease. An abnormality of the suppressor population was found in those with autoimmune chronic active hepatitis, primary biliary cirrhosis and alcoholic liver disease, while the responder population was abnormal in those with autoimmune or HBsAg positive CAH. Failure to demonstrate an abnormality in an autologous system may reflect a combined defect of suppressor and responder populations, and in this study the allogeneic system was a more sensitive index of abnormal cellular T-T interaction.     

Chronic liver disease. The scope of causes and treatments.

Evaluation of chronic liver disease begins with a carefully taken history, thorough physical examination, and standard laboratory tests. Often, however, other studies are required, such as a viral hepatitis panel, serologic tests for autoimmune markers, tests for antimitochondrial antibodies, measurement of serum iron and ceruloplasmin levels, liver biopsy, and imaging studies of the extra-hepatic bile ducts. Medical treatment of chronic active hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis remains unsatisfactory. Early treatment of hemochromatosis and Wilson's disease can prevent cirrhosis and liver failure. Liver transplantation is now a viable procedure for patients with end-stage chronic liver disease.     

自身免疫性肝病患者肝纤维化血清标志物检测的意义

目的 探讨血清透明质酸(HA)、Ⅲ型前胶原(PCⅢ)、Ⅳ型胶原(CⅣ)和层粘连蛋白(LN)对自身免疫性肝病(ALD)患者肝纤维化诊断及鉴别的意义.方法 采用增强化学发光免疫分析法对37例原发性胆汁性肝硬化(PBC)患者、25例自身免疫性肝炎(AIH)患者、33例肝硬化患者、37例病毒性肝炎患者及20例健康体检者血清HA、PCⅢ、CⅣ、LN进行检测,并对部分患者在治疗6个月后再次检测上述指标,同时和部分肝功能指标进行相关性分析.结果 ALD患者4项肝纤维化指标均高于健康对照组(均P<0.05);AIH组4项指标均高于病毒性肝炎组(均P<0.01),ROC曲线下面积分别为0.823、0.849、0.824和0.830; PBC组CⅣ和LN低于肝硬化组(P<0.05);两组ALD患者在经治疗6个月后,上述指标均明显下降(均P<0.05).结论 肝纤维化血清标志物HA、PCⅢ、CⅣ和LN对于ALD患者肝纤维化的诊断及和病毒性肝炎的鉴别具有一定价值,并能间接反映肝脏炎症的情况.     

Lecithin.cholesterol acyl-transferase and lipoprotein-X in liver disease

Determinations of serum lecithin : cholesterol acyl transferase (LCAT) and the “abnormal serum lipoprotein of cholestasis” (LP-X) have been carried out in 52 patients with different liver disorders and in 20 normal subjects.In acute hepatitis reduced LCAT activity was demonstrated in both LP-X positive and LP-X negative patients. In primary biliary cirrhosis and large bile duct obstruction the presence of LP-X was associated with reduced, normal or increased LCAT activity. Thus this study could reveal no specific LCAT/LP-X pattern in liver diseases, nor were we able to differentiate between intra- and extrahepatic cholestasis on the basis of these two tests.Possible relationships between LP-X and LCAT are discussed and mechanisms for the formation of LP-X in liver- and bile duct diseases are considered.     

Treatment of chronic diseases of the liver with catergen

Fifty-seven patients with chronic liver diseases of different etiology were treated with catergen ((+)-cyanidanol 3) given in a dose of 1.5 g (3 tablets) a day throughout 3 months. The findings were compared with those derived in the control groups of patients (82) who received vitamins or essentiale. It was shown that catergen significantly improved some biochemical characteristics of the blood and indicators of the antipyrine test in patients with compensated liver cirrhosis of the viral and alcoholic etiology. In patients with alcoholic cirrhosis, catergen, like essentiale, exerted an inhibitory effect on lipid peroxidation in the liver. There were no significant differences in the biochemical characteristics of the blood in patients with chronic alcoholic hepatitis treated with catergen and control group patients. In patients with primary biliary cirrhosis, catergen exerted an insignificant symptomatic effect but in single cases. The side dyspeptic effects which demanded the drug withdrawal were only recorded in 2 patients. It is concluded that catergen may be used in the treatment of virus- and alcohol-induced chronic liver diseases of moderate activity.     

Asymptomatic primary biliary cirrhosis. Presentation, histology, and results with D-penicillamine.

Of 103 patients with the syndrome of primary biliary cirrhosis (chronic, nonsuppurative destructive cholangitis) who entered a double-blind, randomized, controlled treatment trial with either D-penicillamine or placebo, 21 (20%) were asymptomatic with respect to their liver disease. Study of these 21 patients revealed that (1) 43% of patients with asymptomatic primary biliary cirrhosis had advanced histologic lesions (fibrosis or cirrhosis); (2) asymptomatic patients with advanced histologic lesions likely have had their disease for 10 years or more; (3) stage of primary biliary cirrhosis may remain unchanged for years; and (4) most asymptomatic patients receiving D-penicillamine, when compared with patients given placebo, had improved liver function tests at 1-year follow-up. However, the incidence of major toxicity with D-penicillamine for primary biliary cirrhosis in a maintenance dose of 1 g approximates 20%. Furthermore, one of our patients who was asymptomatic but who had advanced histologic changes died recently from D-penicillamine-associated bone marrow suppression. It remains to be determined whether the benefit-to-risk ratio of D-penicillamine in primary biliary cirrhosis justifies its use.     

Fibro Scan 与超声检查诊断肝纤维化的异同性及关联性

【目的】探讨FibroScan检查（FS检查）与超声检查（US检查）在诊断慢性肝病患者肝纤维化的异同性和相关性。【方法】选取2014年1月至2015年5月在院诊治的慢性肝病患者382例作为研究对象,其中慢性乙型肝炎（HBV ）感染260例,慢性丙型肝炎82例,原发性胆汁性肝硬化40例。分别采用FS检查和U S检查两种方法对肝脏、脾脏等器官及其血管分布等进行测定,并采用Spearman相关性分析、多重线性回归分析对各项检测指标,特别是FS检查的肝硬度值（FS值）,进行相关性分析。【结果】US检查结果显示,慢性乙型肝炎患者、慢性丙型肝炎患者、原发性胆汁性肝硬化患者的肝左叶厚度、肝右叶厚度、门静脉内径、肝脏血管走形、胆囊疾病及脂肪肝发病率等差异无统计学意义（ P ＞00．5）;三组患者的FS值分别为（95．74±94．91）kPa、（163．38±113．58）kPa、（276．87±186．77）kPa ,三组患者间差异无统计学意义（ P ＞00．5）,各组间两两比较差异均有统计学意义（ P ＜00．5）;原发性胆汁性肝硬化患者肝脏表面光滑度、肝脏回声状况差于慢性乙型肝炎患者和慢性丙型肝炎患者,肝硬化发生率明显高于后两组患者（ P ＜00．5）;FS值与肝左叶厚度、门静脉内径、肝脏表面光滑度、肝脏回声、肝脏血管走形、肝硬化等成正相关（ P ＜00．1）,与胆囊疾病发生率呈负相关（ P ＜00．1）;FS值与超声检测结果的回归性分析显示,肝脏表面光滑度、肝左叶厚径和门静脉内径,各个偏回归系数差异均有统计学意义（ P ＜00．5）。【结论】FS检查与US检查具有较好的相关性,在临床工作中结合US和Fibroscan检查结果进行综合分析,能更好对肝病患者肝纤维化程度做出准确评估,更好的指导临床治疗。     

Diagnostic efficiency in discriminating liver malignancies from cirrhosis by serum gamma-glutamyltransferase isoforms

Total GGT and GGT complexed with low-density-lipoprotein plus very low-density lipoprotein (LDL + VLDL) have been evaluated in sera from 53 healthy subjects, 23 patients with chronic hepatitis, 87 with liver cirrhosis and 50 with liver tumors (primary and metastatic). A cut-off of 20 U/l of GGT complexed with LDL + VLDL results in a diagnostic sensitivity of 84% for liver tumor patients, and a diagnostic specificity of about 80% towards the two groups of patients affected by cirrhosis or chronic hepatitis. This test, because of its high diagnostic efficiency, is a useful addition to the battery of laboratory tests that serve to discriminate cirrhosis and chronic hepatitis from liver malignancies.     

核不均一核糖核蛋白K(hnRNP K)在慢性肝病不同病理阶段的表达水平

目的:观察核不均一核糖核蛋白K(heterogeneous ribonucleoprotein K,hnRNP K)在健康体检者、慢性乙型病毒性肝炎、肝炎后肝硬化及乙肝相关性原发性肝癌患者血液和尿液中的表达差异,探讨hnRNP K在慢性肝病不同病理阶段表达水平及与乙肝相关性原发性肝癌的相关性。方法:选取2018年8月至2018年10月我院收治的健康体检者50例、慢性乙型病毒性肝炎患者43例、肝炎后肝硬化患者35例及乙肝相关性原发性肝癌患者53例,采集其空腹外周静脉血5 mL及清洁中段晨尿标本,利用ELISA分别检测hnRNP K在慢性肝病不同病理阶段血液和尿液中表达的含量,绘制ROC曲线评价hnRNP K在原发性肝癌诊断中的意义。结果:hnRNP K在慢性乙型病毒性肝炎、肝炎后肝硬化及乙肝相关性原发性肝癌患者血液、尿液中表达水平均高于健康体检者,差异有统计学意义(P<0.05)。乙型肝炎相关性原发性肝癌患者血清hnRNP K的ROC曲线AUC为0.775,敏感度和特异度分别为76.9%和64.3%;尿液hnRNP K的ROC曲线AUC为0.652,诊断乙肝相关性原发性肝癌的敏感度和特异度分别为100%和28.6%。结论:相较于健康体检者,慢性乙型病毒性肝炎、肝炎后肝硬化及乙肝相关性原发性肝癌患者的血清、尿液中hnRNP K表达水平上调,与乙肝相关性原发性肝癌具有相关性,提示hnRNP K可能是乙肝相关性原发性肝癌的潜在标志物,对原发性肝癌的诊断具有一定参考价值。     

Determination of the superoxide dismutase activity in puncture biopsy specimens of the liver in chronic liver diseases]

Analysis of liver biopsy specimens from patients with chronic active hepatitis has shown reduced superoxide dismutase (SOD) and catalase activities. More profound changes were revealed in the patients with fibrosis, cirrhosis, and primary biliary cirrhosis. Suppressed activities of antioxidative enzymes and dissociation of their systemic interaction were found to be related to the pathologic process severity. Measurement of SOD activity in a biopsy specimen appears to be clinically valuable and may be used for the assessment of liver antioxidative defense in patients with liver conditions.     

In vitro cell-mediated cytotoxicity in primary biliary cirrhosis and chronic hepatitis. Dysfunction of spontaneous cell-mediated cytotoxicity in primary biliary cirrhosis.

The in vitro cytotoxic function and target cell specificity of peripheral blood lymphocytes from selected patients with primary biliary cirrhosis and hepatitis B surface antigen-negative chronic hepatitis were investigated using 51Cr-labeled human Chang and EL-4 mouse sarcoma cell targets in assays of spontaneous cell-mediated cytotoxicity (SCMC) and mitogen-induced cellular cytotoxicity (MICC). In addition, antibody-dependent cellular cytotoxicity (ADCC) against Chang cells was assessed. At an effector-to-target cell ration of 100:1, the mean SCMC against Chang cells was much less in patients with primary biliary cirrhosis than that in either the controls (P less than 0.001) or the patients with chronic hepatitis (P less than 0.005) whereas the value for patients with chronic hepatitis did not differ significantly from that of the controls. The mean SCMC against EL-4 mouse sarcoma cells was also less in patients with primary biliary cirrhosis than in controls (P less than 0.005) whereas the value for chronic hepatitis was not significantly different from that of the controls or patients with primary biliary cirrhosis. In contrast, MICC against both targets and ADCC against Chang cells were similar for each group. Comparison of SCMC and MICC against both target cells, measured simultaneously, showed similar cytotoxic potenital against both target cells for each group. Effector cells capable of mediating cytotoxicity in each assay were defined by testing the cytotoxic function of lymphocyte subpopulations isolated from two representative patients with each disease using techniques of immunoabsorbent affinity chromatography and Fc receptor binding to antigen-antibody complexes. In both primary biliary cirrhosis and chronic hepatitis SCMC and ADCC were mediated by a subpopulation of lymphocytes which lack surface immunoglobulin (sIg-) and bear Fc receptors (Fc+). In contrast, MICC was mediated by sIg- cells which lack Fc receptors. Lymphocytes bearing sIg- were not cytotoxic in any assay. These results establish a difference in cytotoxic function in primary biliary cirrhosis and chronic hepatitis by defining the presence of a defect in spontaneous cytotoxic function of sIg-, Fc+ lymphocytes against Chang cells in primary biliary cirrhosis.     

Biliary alkaline phosphatase measured by mini-column chromatography on DEAE-cellulose: application to detection of hepatobiliary diseases

Using chromatography on diethylaminoethyl (DEAE) cellulose, we measured biliary alkaline phosphatase (BALP; EC 3.1.3.1) activities in sera from 182 patients, most with hepatobiliary disorders but some with non-hepatobiliary diseases. Relative BALP activities were extremely low in otherwise healthy carriers of hepatitis B virus (mean: 5.4 U/L) and in patients with non-hepatobiliary diseases (mean: 5.3 U/L). Although BALP activities were detectable in some cases of liver cirrhosis and chronic hepatitis, these values were generally low (respective means: 12.6 and 12.0 U/L). High BALP activities were detected in patients with primary hepatocellular carcinoma, secondary metastatic liver tumors, and obstructive jaundice: mean values were 27.2, 37.2, and 73.6 U/L, respectively. There was no correlation between BALP activity and bilirubin concentration in patients with obstructive jaundice, nor between BALP activities in obstructive jaundice caused by stones and in those caused by extrahepatic tumor. Some patients with primary hepatocellular carcinoma had high BALP but low alpha-fetoprotein (AFP) values, some others the reverse. Based on AFP alone, the sensitivity for detecting hepatocellular carcinoma was 79%; adding BALP in parallel improved the sensitivity to 97%. We found minicolumn chromatography on DEAE-cellulose useful for determining BALP activity in hepatobiliary diseases.     

Increased plasma cathepsin D concentration in hepatic carcinoma and cirrhosis but not in breast cancer

Using a sandwich enzyme-linked immunoassay, plasma total cathepsin D concentration was assayed in 40 breast cancer patients and 84 patients with various liver diseases and compared to that of 52 normal subjects. There were no significant variations found in breast cancer patients related to tumor size, node invasiveness or metastases. In normal women, cathepsin D levels were slightly but not significantly increased in the luteal phase and in pregnancy. By contrast, plasma cathepsin D concentration was significantly increased in 70-75% of patients with liver disease (cirrhosis, hepatocarcinoma, hepatitis), but not in those with liver steatosis. Cathepsin D was independent of most of the plasma hepatic function tests and was correlated with alpha-fetoprotein in cirrhosis and with alpha-fucosidase in primary hepatocellular carcinoma. We conclude that plasma cathepsin D is not a useful marker in breast cancer. However, since the cellular level of this protease is associated with risk of metastasis in breast cancer, clinical follow-up will be required to test whether high cathepsin D plasma concentration has any prognostic value in liver cirrhosis and primary hepatocarcinoma.     

肝移植后的并发症

背景：原位肝移植因其移植过程复杂,易产生各种并发症,制约着肝移植手术的成功率。目的：分析肝移植后并发症发生的常见原因及预防处理措施。方法：回顾性分析176例肝移植患者中出现并发症的59例患者的临床资料,男53例,女6例,年龄25—74岁,平均（46．41±12．02）岁。原发病中乙型肝炎后肝硬化10例（合并肾衰1例）,肝硬化合并肝细胞性癌7例,胆汁性肝硬化4例,酒精性肝硬化1例,肝细胞性癌13例,胆管细胞癌1例,肝豆状核变性3例,肝功能衰竭13例,重型乙型病毒性肝炎7例（合并肾衰1例）。所有病例供、受者均符合血型相符原则。结果与结论：肝移植后发生并发症102例次,其中腹腔内出血15例,上消化道出血5例,肺部感染21例,腹腔感染5例,胆道并发症21例,慢性排斥3例,急性排斥10例,急性肾功能衰竭7例,乙肝复发3例,神经精神并发症6例,移植肝无功能4例,下腔静脉血栓形成、移植物抗宿主反应各1例。围手术期死亡24人,直接死亡原因腹腔出血6例,肺部感染6例,移植肝无功能4例,多器官功能衰竭3例,腹腔感染、移植物抗宿主、心脏骤停、胆管坏死、蛛网膜下腔出血各1例。提示重视肝移植患者围移植期的处理,改善肝功能、纠正凝血障碍、改善营养、控制感染,重视移植技术的完善和并发症的及时诊断处理,是提高肝移植成功率的关键。     

Alpha-fetoprotein-like activity in sera from patients with malignant and non-malignant disease and healthy individuals.

A new method, radio-crossed immunoelectrophoresis, demonstrates alpha-fetoprotein (AFP) in sera with a sensitivity of 1 mug/1. By this method AFP with alpha mobility was not found in sera from healthy individuals, patients with chronic active hepatitis and cirrhosis, primary biliary cirrhosis, secondary liver cancer and cystic fibrosis. In some of the sera, AFP was elevated when measured by conventional radioimmunoassay method and the sera contained an AFP-like substance with gamma mobility when analyzed by radio-crossed immunoelectrophoresis. The nature of this gamma substance is still obscure and needs further investigation.     

The calcium content in the bile of patients with cholelithiasis, chronic hepatitis, liver cirrhosis and in healthy subjects]

Measurements of calcium levels in the blood of normal subjects and patients with cholelithiasis, chronic hepatitis, and liver cirrhosis have revealed that biliary calcium levels during the physicochemical stage of cholelithiasis are much higher than during the calculi formation stage and that in chronic hepatitis and liver cirrhosis C bile calcium content is much higher than B bile calcium content.