Withdrawal of immunosuppressive therapy in allogeneic bone marrow transplantation reactivates chronic viral hepatitis C.

A 28-year-old female patient with acute myelogenous leukemia and post-transfusion chronic viral hepatitis C received an allogeneic bone marrow transplantation (BMT) in first complete remission. The inflammatory activity of chronic hepatitis C decreased dramatically with the start of BMT and during the whole course of cyclosporin A treatment. After the immunosuppressive therapy was stopped, however, the chronic hepatitis C activity increased and the serum alanine amino-transferase levels thereafter remained as high as before BMT. Hepatitis C virus RNA was detected by polymerase chain reaction in serum drawn 60 days and 52 months after BMT. Since fulminant viral hepatitis B may take place after tapering of immunosuppressive therapy following BMT due to an excessive response of recovering immunity to the actively replicating virus during immune suppression, careful monitoring of liver function for patients with chronic viral hepatitis C in BMT is suggested.     

Detection of serum inhibitory factor for lymphocyte stimulation in chronic viral hepatitis: relationship with the replication level

Sera from 111 patients with chronic viral hepatitis and from 55 cases with other liver disorders were assayed for serum inhibitory factor. The prevalence of this immunosuppressive factor was very similar between chronic hepatitis B (61%), chronic hepatitis delta (57%) and chronic hepatitis C (68%). At the same time, serum inhibitory factor was never detected in the other disorders studied. The presence of this inhibitory factor was detected in a significantly higher percentage (p less than 0.05) of HBeAg, HBV-DNA positive cases (75%) than in anti-HBe positive, HBV-DNA negative cases (44.4%). In chronic hepatitis delta, this immunosuppressive factor was also related to HDV-RNA positivity. The detection of this serum immunosuppressive factor in chronic viral hepatitis and its association with a high viral replication level implies a possible role of this factor in the immune pathogenic mechanism in infectious viral hepatitis.     

血清前白蛋白在肝病中的临床意义

了解病毒性肝炎患者血清前白蛋白 (PA)的变化 ,探讨测定血清前白蛋白对病毒性肝炎患者的诊断价值。采用免疫比浊法检测 2 76例病毒性肝炎患者血清前白蛋白 ,比较不同临床类型的血清PA的水平及同一临床类型间PA与A的异常率。血清PA的水平在急性肝炎与轻度慢性肝炎之间、慢性肝炎轻度与中度、中度与重度之间、肝硬化与慢性重型肝炎之间均有显著性差异 (P <0 0 5 ) ;急性肝炎组PA与白蛋白 (A)两者相比有高度显著性差异 (P <0 0 0 1) ;PA值比A值更灵敏地反映肝功能损害。血清PA的水平持续 <10 0mg/L作为重症肝炎早期诊断指标之一。检测血清PA对病毒性肝炎临床诊断、病情判断和预后估计有一定参考价值     

Changes of serum angiotensin I converting enzyme in patients with viral hepatitis and liver cirrhosis.

Serum angiotensin I converting enzyme, identical with kininase II, was measured fluorometrically in patients with acute viral hepatitis (n=18), liver cirrhosis without (n=44) and with (n=19) ascites. In all groups of patients the enzyme was significantly elevated as compared to 44 healthy controls (p less than 0.001). No correlation could be found between angiotensin I converting enzyme activity and liver function tests (serum glutamic oxalacetic transaminase, serum glutamic pyruvic transaminase, total protein, albumin, bilirubin) or other parameters (serum potassium, serum sodium). High serum converting enzyme activity in chronic liver diseases might originate primarily from an altered pulmonary circulation and indicates higher conversion rate of angiotensin I by passage through the lungs as well as increased bradykinin degradation. The reason for the enzyme liberation in acute viral hepatitis is as yet uncertain.     

Immunosuppressive serum factors in viral hepatitis. I. Characterization of serum inhibition factor(s) as lymphocyte antiactivator(s)

Sera from patients with acute viral hepatitis B were found to inhibit the in vitro proliferation of normal lymphocytes induced by different mitogens and antigens. In addition, an effect on concanavalin A-induced T suppressor cell activity and pokeweed mitogen-stimulated IgG and IgM synthesis was demonstrated. Studies concerning the kinetics of serum immunosuppressive effects indicated that serum immunosuppressive factor (SIF) interfered with the intermediate phase of mitogen-induced lymphocyte activation which was defined by protein and RNA synthesis. Thus, when SIF-positive sera were added to lymphocytes, which were already activated by phytohemagglutinin, for 8, 12, or 18 hr, the inhibitory effect decreased in relation to the duration of lymphocyte activation. No inhibition could be demonstrated when SIF-positive sera were added 24 hr after initiation of mitogen stimulation. Furthermore, similar inhibitory effects were found measuring either uptake of [3H]uridine (RNA synthesis) or [3H]leucine (protein synthesis) in a 24 hr culture of phytohemagglutinin-stimulated lymphocytes or [3H]thymidine uptake (DNA synthesis) after 48 hr. These results indicate that SIF act(s) like an antiactivator and may belong to immunoregulatory physiologic serum factors.     

SIF和RIF在5种慢性肝病伴HBV感染患者中的平行检测

经平行检测125例伴有HBV感染的慢性肝病患者、16例无HBV感染的其它感染性疾病患者及20例健康献血员血清中血清抑制因子(SIF)的玫瑰花结抑制因子(RIF)。并对SIF和RIF以及两者与HBsAg及ALT之间的关系作相关性分析,发现:①SIF和RIF在不同类型的慢性肝病中阳性检出率不同;②SIF不足病毒性肝炎所特有的。它与HBsAg滴度有显著的相关性,与ALT不相关。③RIF主要见于伴有ALT异常的慢性肝病患者。     

Occurrence and significance of antibody to liver-specific membrane lipoprotein by double-antibody immunoprecipitation method in sera of patients with acute and chronic liver diseases.

A double-antibody immunoprecipitation method was developed for detecting antibody to liver-specific membrane lipoprotein (anti-LSP) in sera of patients with various liver diseases and primary nonhepatic autoimmune diseases. Liver-specific membrane lipoprotein prepared from normal rat livers was labeled with 125I (chloramine-T) and monospecific antibody raised in rabbits. Cross-reactivity and absorption studies demonstrated that the assay used was highly specific. The frequency and titer of anti-LSP were similar for HBsAg-positive and -negative patients with both acute and chronic liver diseases. Patients with chronic active hepatitis had the highest frequenzy (25 of 44 cases, 57%) when compared with those with chronic persistent hepatitis (5 of 23 cases, 22%) and nonalcoholic cirrhosis (8 of 21 cases, 38%). Of the anti-LSP positive cases, the mean titer in patients with chronic active hepatitis tended to be the highest. In patients recovered from acute viral hepatitis, anti-LSP was transiently positive (7 of 20 cases, 35%) in the acute phase. In those who progressed to chronic hepatitis, a late rise as well as an early rise occurred in 6 of 10 patients before the diagnosis was made. Two of 6 patients with primary biliary cirrhosis had anti-LSP, but none of 41 patients with other nonviral liver diseases and none of 60 patients with primary nonhepatic autoimmune diseases. These data indicate that an autoimmune reaction directed against LSP can be initiated during the acute phase of viral hepatitis and it may persist in chronic hepatitis in both HBsAg-positive and -negative cases.     

Absence of detectable serum interferon in acute and chronic viral hepatitis

Amounts of interferon were measured in sera from 59 patients with acute viral hepatitis and 49 patients with chronic hepatitis B and compared to those from patients with nonviral liver disease or influenza, and from healthy controls. In all patients with acute and chronic viral hepatitis, no serum interferon could be detected, confirming data from earlier studies of acute viral hepatitis in which no circulating interferon was found. Our results disprove the view that the amounts of serum interferon, detected at the time of the acute clinical illness, may be a determinant of outcome.     

Immunosuppressive serum factors in viral hepatitis. II. Further characterization of serum inhibition factor as an albumin-associated molecule

Immunosuppressive factor(s) in sera from patients with acute viral hepatitis B [serum inhibition factor(s) (SIF)] which functioned like an antiactivator of lymphocytes were further characterized and purified. The active moiety could be separated from immunoglobulins and other serum proteins by means of gel filtration, anion exchange, and affinity chromatography. The major SIF activity always copurified with albumin. Affinity chromatography with Cibacron blue agarose matrix followed by elution with 2 M NaCl proved an optimal procedure to obtain SIF-positive albumin fractions. The SIF moiety could be dissociated from albumin by use of 5 M NaCl or 6 M urea and was separated from protein by sequential molecular filtration and G-10 gel filtration indicating a low molecular weight substance. SIF activity of lower degree could also be detected in albumin-containing fractions derived from normal sera and exhibited similar biochemical properties as the factor which was isolated from patients' sera. The purified SIF fractions could not be stained with various protein dyes after sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The active moiety was partially extractable with chloroform:methanol indicating a lipophilic nature. Common fatty acids or bile acids were excluded as causative factors by gas chromatographic-mass spectrometric and radioimmunologic analyses. These data suggest that the SIF effect is caused by an albumin-associated low molecular weight lipid or lipophilic peptide. SIF may be physiological immunoregulatory products of the immune system which are probably produced in response to a viral antigenic stimulus.     

血清氨基酸指标在病毒性肝炎及肝炎肝硬化诊断中的意义

通过临床研究，探讨急慢性病毒性肝炎、肝炎肝硬化患者氨基酸分析指标中可作为对诊断有独立项报作用的指标，并对其意义进行分析。123例患者分为急性病毒性肝炎组22例，慢性病毒性肝炎组59例，肝炎肝硬化组42例，用比色法测定各自血清氨基酸分析指标，行对数校正后的逐步判别分析。经逐步判别分析确定血清牛磺酸、亮氨酸、酪氨酸、尿素、甘氨酸是三组间的独立判别因素，另外急肝与慢肝之间天冬氨酸、慢肝与肝硬化之间苏氨酸也有重要意义。氨基酸分析指标中，牛磺酸、亮氨酸、酪氨酸、尿素、甘氨酸等在嗜肝病毒感染引起的肝病中对诊断及明确肝功储备情况有重要的临床意义。     

Persistence of serum hepatitis B virus deoxyribonucleic acid in hepatitis B surface antigen-positive patients with chronic persistent hepatitis treated with prednisone

The effect of a short course of prednisone therapy was evaluated in 8 patients with liver biopsy-verified chronic persistent hepatitis B. In 6 of the 8 (75%) patients, an abrupt fall in serum alanine aminotransferase levels after the initiation of prednisone was noted, and in 4 patients, there was an increase in serum alanine aminotransferase values after prednisone was discontinued. However, the serum levels of hepatitis B virus deoxyribonucleic acid were consistently greater than or equal to 200 pg before, during, and after the course of treatment in 7 of the 8 (87.5%) patients. All patients were initially hepatitis B e antigen-positive and remained so during the study period. These findings indicate that, unlike some patients with chronic active hepatitis B, immunosuppression with prednisone had no effect in altering hepatitis B viral replication in patients with chronic persistent hepatitis.     

Liver pathology of hepatitis C,beyond grading and staging of the disease

Liver biopsy evaluation plays a critical role in management of patients with viral hepatitis C. In patients with acute viral hepatitis, a liver biopsy, though uncommonly performed, helps to rule out other nonviral causes of deranged liver function. In chronic viral hepatitis C, it is considered the gold standard in assessment of the degree of necroinflammation and the stage of fibrosis, to help guide treatment and determine prognosis. It also helps rule out any concomitant diseases such as steatohepatitis, hemochromatosis or others. In patients with chronic progressive liver disease with cirrhosis and dominant nodules, a targeted liver biopsy is helpful in differentiating a regenerative nodule from dysplastic nodule or hepatocellular carcinoma. In the setting of transplantation, the liver biopsy helps distinguish recurrent hepatitis C from acute rejection and also is invaluable in the diagnosis of fibrosing cholestatic hepatitis, a rare variant of recurrent hepatitis C. This comprehensive review discusses the entire spectrum of pathologic findings in the course of hepatitis C infection.     

Chronic persistent hepatitis. A clinical, serological, and prognostic study.

The diagnosis of chronic persistent hepatitis is based on a combination of clinical and morphological data. During a 7-year period 26 cases were diagnosed in 3 medical departments in Copenhagen. In 22 patients the disease was considered to be a sequela to acute viral hepatitis, and 12 had Australia antigen in serum. Only few patients had circulating auto-antibodies. The clinical and biochemical activity at the time of diagnosis was usually slight. A morphological and clinical follow-up study revealed that the course of the disease was generally benign. However, in 3 patients the last repeat biopsy showed progression to cirrhosis, severe portal fibrosis, and chronic aggressive hepatitis. Such exceptions may represent a sampling error in the interpretation of the first needle biopsy, or the correct diagnosis may have been chronic aggressive (active) hepatitis at a stage with slight activity. Clinical and biochemical observation is recommended in chronic persistent hepatitis, and in some patients serial needle biopsies are necessary to reveal the few exceptional cases which progress to an active chronic liver disease.     

Macrophage colony stimulating factor and hepatitis

We investigated the serum level of macrophage colony stimulating factor (M-CSF) in patients with hepatitis using a newly developed radioimmunoassay (RIA). The mean level of M-CSF in patients with chronic active hepatitis was significantly higher than that of the healthy controls (P < 0.01). The mean level of M-CSF in patients with acute hepatitis in the acute phase was prominently higher than that of the patients with chronic active hepatitis (P < 0.001). However, in the convalescence phase of acute hepatitis, the mean level of M-CSF decreased to the lower level comparable to the mean level of the patients with chronic active hepatitis. These data suggest that the serum level of M-CSF is one of the factors which represents the inflammatory activity of liver diseases.     

Cryptogenic chronic liver disease and serum or liver hepatitis B virus markers. Their possible correlations and etiologic significance

In an attempt to evaluate a possible correlation between cryptogenic chronic liver disease and a present or past hepatitis B virus (HBV) infection, we studied 17 patients with hepatitis B surface antigen (HBsAg)-negative, nonalcoholic chronic liver disease; 9 of them were positive for serum HBsAg detected by a solid-phase enzyme immunoassay with monoclonal antibody (M-EIA) and 8 were negative for the same marker. Liver hepatitis B core antigen (HBcAg), studied by an indirect immunofluorescence technique, was present in 55.5% of the patients positive for serum HBsAg by M-EIA. In the same group of patients, liver HBV-DNA was found in 66.6% of the patients. On the other hand, only 1 patient without serum positivity for HBsAg by M-EIA was positive for liver HBcAg and HBV-DNA. None of our patients showed serum positivity for HBV-DNA sequences. We conclude that HBV infection may be a possible cause of cryptogenic chronic liver disease; this HBV-related, HBsAg-negative chronic liver disease seems to have no viral replication or undetectable levels of HBV-DNA in serum. HBsAg, detected by a monoclonal assay, seems to be a suitable marker to identify this subgroup of patients with HBsAg-negative chronic liver disease.     

Serum levels of alpha-interferon and gamma-interferon in patients with acute and chronic viral hepatitis

We measured activities of alpha- and gamma-interferon simultaneously in 198 sera of 70 patients with acute and chronic viral hepatitis using specific and sensitive enzyme immunoassay and immunoradiometric assay. The results were compared with those in patients with influenza and in healthy controls. Twelve out of 28 patients with acute viral hepatitis showed positive alpha-IFN and/or gamma-IFN activities. alpha-IFN was detectable throughout the clinical course while gamma-IFN levels rose in the convalescent phase regardless of etiology. Conversely, in patients with influenza, both alpha-IFN and gamma-IFN levels of initial samples tended to be higher than those of late samples. Six out of 12 patients with chronic active type B hepatitis showed increased alpha-IFN and/or gamma-IFN values during acute deterioration with marked elevation of serum alanine aminotransferase. However, the two interferons did not always appear simultaneously, although either was detectable in both acute and chronic hepatitis. Enhanced alpha-IFN or gamma-IFN activity was not found in asymptomatic chronic hepatitis B carriers or in patients with chronic persistent hepatitis and liver cirrhosis with chronic hepatitis B virus infection, with the exception of 2 cases. Our results indicated that circulating multiple IFN species were present during the clinical course in some patients with acute and chronic viral hepatitis.     

Relationship of serum alpha-fetoprotein to the severity and duration of illness in patients with viral hepatitis.

Using a radioimmunoassay which detect concentrations of alpha-fetoprotein as low as 5 ng per ml, 38% of 176 patients with viral hepatitis compared with health volunteers and patients with chronic diseases not affecting the liver. When separated into two groups based on histological classification of liver biopsy specimens, differences in the degree and frequency of increased serum alpha-fetoprotein were related to the severity of the hepatic lesion. Of 75 patients with the lesion of viral subacute hepatic necrosis, in which zones of necrosis bridge adjacent portal triads or central veins, 52% had increased values, and 12% had levels ranging from 500 to 3300 ng per ml. In contrast, only 28% of the 101 patients without bridging necrosis had increased values, and none had levels that exceeded 500 ng per ml. In the patients with subacute hepatic necrosis, comparison of alpha-fetoprotein concentrations with the duration of illness indicated that the protein rose to peak levels in serum as the SGOT was declining. This was confirmed by serial observations in 10 patients. Thus, the increase of alpha-fetoprotein in the sera of patients with severe hepatitis occurs as liver necrosis is subsiding. Due to other known features of alpha-fetoprotein, it is intriguing to speculate that the increase in serum levels of this protein in viral hepatitis reflects hepatic regeneration after parenchymal damage.     

The epidemiology and clinical outcome of hepatitis D virus (delta) infection in Jordan

The epidemiology and clinical outcome of hepatitis D viral infection in HBsAg-positive acute hepatitis, chronic liver disease, primary hepatocellular carcinoma and the symptomless carrier state was studied in Jordan. The prevalence of hepatitis D viral infection was significantly higher in patients with chronic liver disease (18/79, 23%) and acute hepatitis (17/108, 16%) than in symptomless HBsAg carriers (2/136, 2%). The highest prevalence of hepatitis D viral infection was found in patients with primary hepatocellular carcinoma (10/15, 67%) who were also significantly older than such patients without hepatitis D viral infection. Antihepatitis D virus IgM was detected persistently in 83% of patients with antihepatitis D virus-positive chronic liver disease and transiently in 41% of patients with acute hepatitis. A trend to increased mortality was observed in acute hepatitis D viral superinfection (25%) compared to hepatitis D viral coinfection (0%) and to antihepatitis D virus-negative HBsAg-positive acute hepatitis (4%). In patients with established chronic liver disease, however, neither survival nor histological parameters of disease activity were significantly different in the antihepatitis D virus-positive and antihepatitis D virus-negative groups. While the early stage of hepatitis D viral superinfection is associated with increased mortality, it appears that in patients with late-stage chronic liver disease, severe histological activity subsides, and survival is no longer influenced by the factor of hepatitis D viral infection. However, primary hepatocellular carcinoma appears to complicate the course of those antihepatitis D virus-positive patients surviving beyond this stage.     

肝病患者血清肉碱水平的临床研究

目的观察肝病患者血清肉碱水平,探讨其临床意义,为肉碱治疗肝病提供依据。方法用酶循环法检测25例急性病毒性肝炎,34例慢性病毒性肝炎,22例肾功能正常及9例肾功能异常的肝炎后肝硬化患者血清游离肉碱水平,并分别与40名正常人的检测值比较。结果血清游离肉碱:正常人为(48．3±10．2)μmol／L;急性病毒性肝炎患者为(35．2±13．2)μmol／L,明显低于正常对照组,P=0．000。慢性病毒性肝炎患者为(36．5±9．9) μmol／L,明显低于正常对照组,P=0．000。肾功能正常的肝炎后肝硬化患者为(45．0±11．0)μmol／L,比正常对照组略有下降,但差异无统计学意义,P=0．232。肾功能异常的肝炎后肝硬化患者为(83．6±50.4)μmol／L,比正常对照组升高,但差异无统计学意义,P=0．069。结论肝病患者可发生肉碱代谢异常,肝脏疾病是导致继发性肉碱缺乏的原因之一。     

Serum alpha 1-antitrypsin levels in alcoholic hepatitis.

Serum alpha 1-antitrypsin concentrations have been measured in 68 patients with liver disease. High mean values (359 +/- 18.0) were found in patients with alcoholic hepatitis whereas patients with acute viral hepatitis and chronic active hepatitis did not show any significant differences from the controls. In a group of patients with both alcoholic hepatitis and acute pancreatitis the mean value (218 +/- 5.8) was significantly lower than in the control group. The mechanism for the reduction of serum alpha 1-antitrypsin levels in this group remains to be clarified but low serum alpha 1-antitrypsin may be due to increased proteolytic enzyme concentrations in acute pancreatitis.