Chronic Active Liver Disease Research Articles

Localization of hepatitis C virus antigens in liver and skin tissues of chronic hepatitis C virus-infected patients with mixed cryoglobulinemia

Skin and/or liver biopsy specimens were obtained from the following patients: 15 anti-hepatitis C virus (HCV), HCV RNA-positive patients and 3 anti-HCV, HCV RNA-negative patients with type II mixed cryoglobulinemia (MC); 7 anti-HCV, HCV RNA-positive patients with chronic active liver disease (CALD); 5 anti-HCV, HCV RNA-negative patients with noncryoglobulinemic vasculitis; and 7 anti-HCV, HCV RNA-negative patients with lichen ruber planus. A pool of murine monoclonal antibodies (MAbs) developed against c22-3, c33c, and c100-3 proteins was used to detect HCV-related antigens (Ags) by indirect immunohistochemistry. Acid electroelution (AEE) of tissue sections was performed to enhance the sensitivity of the immunohistochemical method. In anti-HCV-positive MC patients, specific HCV-related Ags were detected in the small vessels of the skin and in the cytoplasm of hepatocytes. Prior AEE of biopsy sections allowed detection of HCV Ags in 6 of 15 (40%) skin biopsy and in 9 of 14 (64.3%) liver biopsy specimens. HCV immunoreactive deposits in the skin displayed two immunohistochemical patterns: (1) coarse intraluminal material associated with dermal inflammatory infiltrates and intravascular deposition of eosinophilic hyaline material; and (2) reactivity confined to the vessel wall in the context of an apparently normal tissue. Immunoglobulin (Ig) G and IgM deposition in the skin showed immunohistochemical features comparable with those found for HCV Ag deposits.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence of non-A, non-B, non-C infection in chronic hepatitis by polymerase chain raction testing for hepatitis B and C viruses

Background/Aims: Although hepatitis C virus is clearly the major cause of non-A, non-B acute and chronic hepatitis, there is a group of patients with histologically documented chronic hepatitis with no serological marker of hepatitis B and C, nor any other risk factors for liver disease. Methods: We have investigated 17 well-characterized patients and chronic active hepatitis. HBV-DNA and HCV-RNA were tested by polymerase chain reaction in 17 serum samples and in six liver biopsies. Results: Four of the 17 patients had serum HCV-RNA detectable by polymerase chain reaction, while non had HBV-DNA detectable by polymerase chain reaction. Three of the six liver samples gave a positive signal by cyclin A and HLA, and only these were considered for the study. One of the three was HCV-RNA positive, while none was HBV-DNA positive. Conclusions: Our results, obtained through careful elimination of all known risk factors for liver disease, strongly suggest that non-A, non-B, non-C hepatotropic virus(es) could be involved in some cases of chronic active liver disease.

Genomic instability involved in virus-related hepatocarcinogenesis.

In spite of the epidemiological link between the hepatitis C virus (HCV) infection and the incidence of hepatocellular carcinoma (HCC), there is currently no data to prove the direct oncogenicity of HCV. In this situation, we must consider not only the viral but also the nonviral factor which may accelerate hepatocarcinogenesis. Previously, we showed that a 60-bp subgenomic HBV DNA (15AB, nt 1555-1914 of HBV DNA) is a hot spot for the genomic recombination, and the cellular protein binding to 15AB may be the putative recombinogenic protein. In this paper, we show that the 15AB-like sequence exists in the human chromosomal DNA. The 15AB-binding proteins, candidates for the cellular recombinogenic protein, are now isolated and being characterized. We showed the possibility that, in HCV- as well as HBV-associated chronic active liver diseases, the recombinogenic proteins are expressed more abundantly than in the normal liver, and their functions are triggered by the binding to the recombinational hot spot in the chromosomal DNA.

Hepatic expression of interferon-α in chronic hepatitis B virus infection

Hepatic expression of interferon-alpha (IFN-alpha) was examined by immunohistochemistry in 90 Chinese patients (M/F 67:23, age: 14-69) with a spectrum of hepatitis B virus (HBV)-related chronic liver diseases. Immunoreactive IFN-alpha was detected in sinusoidal cells in 79 patients (88%) and in mononuclear cells in 59 patients (65.6%). Patients with active liver diseases (chronic active hepatitis, active cirrhosis, N = 55) had a higher level of IFN-alpha expression compared to patients with inactive histology (N = 35; sinusoidal cells, P < 0.01; mononuclear cells, P < 0.01). Cytoplasmic HBsAg, nuclear HBcAg, and cytoplasmic HBcAg were detected in 79 (88%), 42 (47%), and 23 (27%) patients respectively. Expression of IFN-alpha in mononuclear cells correlated with the expression of cytoplasmic HBcAg (P < 0.05) but not with nuclear HBcAg or cytoplasmic HBsAg. When the patients were divided into four different phases according to the natural history of chronic HBV infection, patients in the active liver disease phase had higher IFN-alpha expression compared to the immunotolerant and late phase patients (P < 0.01). Using double immunohistochemical staining, both IFN-alpha and cytoplasmic HBcAg were frequently detected near inflammatory infiltrates but no correlation existed between the hepatic expression of HBsAg and IFN-alpha. These data indicate that IFN-alpha is expressed in the liver in HBV-related active liver diseases and that the reported suboptimal production of IFN-alpha by PBMC in HBV-related chronic active liver diseases may be due to a redistribution of the IFN-alpha-producing mononuclear cells into the liver, the site of inflammation.

CD3- and CD28-activating pathways in HCV infection.

We investigated the proliferative response and IL-2 receptor (IL-2R) expression in peripheral blood mononuclear cells (PBMC) activated with anti-CD3 mAb alone or in combination with anti-CD28 mAb in a group of hepatitis C virus (HCV)-infected patients with detectable viremia demonstrated by "nested" PCR. PBMC from HCV patients and controls showed similar proliferative responses either to anti-CD3 mAb, 64.1, and/or to anti-CD28 mAb, 9.3. No differences were found in anti-CD3 or anti-CD3 plus anti-CD28-induced proliferative responses between patients who demonstrated circulating PBMC bearing HCV-RNA when compared to those with negative HCV-RNA PBMC. Moreover, flow cytometry studies confirmed that anti-CD3 alone or in combination with anti-CD28 were able to induce a significant increase of IL-2R expression in patients or controls PBMC. Both groups showed similar basal CD28 expression. These results indicate that both CD3- and CD28-activating pathways are preserved in HCV-infected patients with chronic active liver disease.

Interferon related neuropsychiatric manifestation in chronic active liver disease (CALD)

Interferon related neuropsychiatric manifestation in chronic active liver disease (CALD)

Hepatic fibrosis—Current concepts of pathogenesis and therapy

Chronic active liver diseases are characterized by the extensive substitution of liver parenchyma by connective tissue. An increased propagation of extracellular matrix components (collagens, structural glycoproteins, proteoglycans) finally leads to the dreaded complications of decompensated liver cirrhosis as well as to liver cell failure or oesophageal variceal bleeding. In Germany, about 14,000 individuals die annually from liver cirrhosis and its complications 1. The number of patients suffering from fibrotic liver diseases is estimated to exceed one million in this country. Needless to say that the disentanglement of basic pathogenetic mechanisms which lead to an increased deposition of connective tissue constituents is gaining high priority in basic science and practical gastroenterology. Essential pathogenetic concepts include pathobiochemical and cellular reactions as follows2: 1. Parenchymal cell injury 2. Inflammation 3. Cell proliferation (regeneration) 4. Extracellular matrix (ECM) production and remodelling.

Phenotypic and functional characteristics of lymphocytes isolated from liver biopsy specimens from patients with active liver disease.

Liver-derived lymphocytes were isolated from 73 liver biopsy specimens obtained from patients with chronic active liver disease and from six samples of normal liver. Mean absolute numbers (+/- S.E.M) of liver-derived lymphocytes recovered from needle biopsy specimens by mild enzymatic digestion of the liver tissue varied from 0.7 +/- 0.3 x 10(3)/mm3 in allografts being rejected to 8.9 +/- 0.9 X 10(3)/mm3 in chronic non-A, non-B hepatitis. By two-color flow cytometry, T lymphocytes (CD3+) were the major liver-derived lymphocyte population in all biopsy specimens. The mean CD4/CD8 ratio (0.6 +/- 0.2) was similar for liver-derived lymphocytes obtained from samples of normal or diseased liver. However, activated (human leukocyte antigen DR+) T cells were significantly (p less than 0.05) increased in liver-derived lymphocytes obtained from liver disease specimens than they were in samples from normal livers. Natural killer cells were less numerous than T cells in specimens obtained from diseased livers, with the mean natural killer/T cell ratio ranging from a low of 0.1 in allograft rejection to a high of 0.8 +/- 0.3 in primary sclerosing cholangitis. Liver-derived lymphocytes isolated from diseased liver contained significantly fewer (p less than 0.05) CD3-CD56+ or CD56+CD16-natural killer cells than did those obtained from normal liver samples. Natural killer activity was consistently detectable in liver-derived lymphocytes obtained from specimens of normal or diseased livers. Moreover, natural killer activity in the liver did not differ significantly from that in either normal or patient peripheral blood.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic ethanol abuse and membrane fluidity changes in liver disease

The long-term effect of ethanol on human red cell membrane fluidity was studied, by fluorescence polarization with 1,6-diphenyl-1,3,5-hexatriene as a probe, in 11 healthy subjects, 9 chronic alcoholics without evidence of liver disease, 12 chronic alcoholics with biopsy-proven alcoholic liver disease and 9 abstemious patients with chronic active liver disease, most of them cirrhosis of the liver. Fluorescence polarization values were not significantly different in the two groups without liver disease. Patients with alcoholic and non-alcoholic liver disease showed higher fluorescence polarization values than patients without liver disease. These changes correlated with the severity of liver dysfunction and were not related to alcohol consumption. In conclusion, the decrease in fluidity of the erythrocyte membrane in alcoholic patients with chronic liver disease, is related to liver dysfunction but not to chronic ethanol ingestion. Changes in membrane fluidity in chronic alcoholics are found only in the presence of liver disease.

DISEASE RECURRENCE AND REJECTION FOLLOWING LIVER TRANSPLANTATION FOR AUTOIMMUNE CHRONIC ACTIVE LIVER DISEASE

Autoimmune chronic active liver disease (ACALD), a major indication for liver transplantation, is associated strongly with antigenic determinants HLA-B8 and DR3. A retrospective analysis of 43 patients who underwent OLTx for putative ACALD and who, as well as their tissue organ donors, were typed, was performed. Disease recurrence and graft rejection episodes were determined by chart review and histopathological review of all material available. Disease recurrence was histologically documented in 11 (25.6%) of these 43 cases. Graft rejection episodes occurred in 24 (55.8%). All recurrences were in recipients of HLA-DR3-negative grafts. Nine of the recurrences were in HLA-DR3-positive recipients (odds ratio: 6.14, P less than 0.03). Two of 11 cases of disease recurrence were in recipients who were HLA-DR3-negative. Nine of these 11 had received HLA-DR3-negative grafts. Rejection occurred in 13 HLA-B8-positive recipients, 12 of whom received HLA-B8-negative grafts. Eleven HLA-B8-negative recipients experienced at least one rejection episode and 9 of these had received HLA-B8-negative grafts. Based upon these data we conclude: 1) that recurrence of putative ACALD is more likely to occur in HLA-DR3-positive recipients of HLA-DR3-negative grafts; (2) that recurrences were not seen in recipients of HLA-DR3-positive grafts; (3) that HLA-B8 status does not affect disease recurrence; and (4) that neither the HLA-B8 nor the DR3 status of the graft or recipient has an effect on the observed frequency of rejection.

Plasma free amino acid pattern in chronic hepatitis as a sensitive and prognostic index

To evaluate the diagnostic and prognostic significance of plasma amino acid imbalance in chronic hepatitis (CH), plasma-free neutral amino acid levels were examined in 47 patients with CH, consisting of 8 chronic persistent hepatitis (CPH), 26 chronic aggressive hepatitis (CAH) 2A and 13 CAH 2B, compared with those of 58 patients with liver cirrhosis (LC) and of 12 healthy controls. Fischer's ratio (a molar ratio of branched chain amino acids to aromatic amino acids) was found to be reduced in the order of normal subjects (3.5 +/- 0.4), CPH (3.0 +/- 0.2), CAH2A (2.7 +/- 0.3), CAH2B (2.1 +/- 0.3), compensated LC (LC-C, 1.5 +/- 0.4) and decompensated LC (LC-D, 1.1 +/- 0.2). Patients with CPH showed a significant decrease of the ratio compared with normal subjects (P less than 0.05). The ratio was significantly higher in patients with CAH 2B in comparison with LC-C (P less than 0.001). Especially, the ratio could be used to discriminate the three distinct stages of CH. Discriminant analysis, carried out using six amino acids, Fischer's ratio and conventional liver function tests indicated that Fischer's ratio was the most reliable parameter for differentiation of the three stages of CH. Furthermore, serial examinations of Fischer's ratio in patients with CH remained unchanged in CPH, whereas was significantly reduced in CAH during 2-3 years follow-up. These results strongly suggest that Fischer's ratio is a useful indicator for differential diagnosis and for prediction of the subsequent clinical course of CH as well as being a sensitive index for functional hepatic reserve in chronic active liver diseases.

Omeprazole in the management of intractable esophageal ulceration following injection sclerotherapy

Transient esophageal ulceration is a common finding after sclerotherapy of varices. A small proportion of these ulcers become chronic and resistant to conventional therapy. Such chronic ulcers have been associated with pain, stricture formation, and recurrent hemorrhage. The use of omeprazole, a proton pump inhibitor, was examined in the current study in the treatment of 10 patients (6 women, 4 men; age range, 27–86 years) with cirrhosis (PBC, 4; sclerosing cholangitis, 2; chronic active liver disease, 2; alcohol, 1; and cryptogenic, 1) who developed an esophageal ulcer after a mean of 13 (range, 8–21) sessions of sclerotherapy. The ulcers had been present for 3–54 months despite prolonged treatment with high-dose H2-receptor antagonists and sucralfate. In each case one or more complications had occurred: severe pain in 3, stricture formation in 4, and recurrent hemorrhage in 7 cases. After an 8-week course of omeprazole, 40 mg daily, endoscopy confirmed complete healing of the ulceration in all 10 cases with symptom resolution. In 2 cases the ulcer recurred, with associated bleeding within 6 weeks of discontinuing the treatment in 1 patient. Both cases responded to repeat therapy. These results confirm the efficacy of omeprazole for postsclerotherapy ulceration and imply that acid-pepsin has a role in perpetuating such ulcers.

Cryptogenic chronic active liver disease. Evaluation of serum aminoterminal peptide of type III procollagen as a marker of histological activity

Sera from 64 patients with HBsAg-negative chronic liver disease with or without cirrhosis were investigated for aminoterminal peptide of type III procollagen (sP-III-P) as a suitable marker of hepatic fibrosis; 244 healthy control subjects were included in the study. A close correlation (p less than 0.01) between sP-III-P levels and histological activity was observed; on the contrary, no correlation was found between the same serum marker of liver fibroplasia and biochemical activity or clinical severity of the disease. We conclude that sP-III-P as a suitable marker of liver overload of collagen fibers is strongly correlated with the histological activity of the disease. Local immune reactions produce soluble substances that might stimulate fibroblastic activity. The test has a significant sensitivity and a very high specificity as a marker of chronic liver disease with histological activity.

Intrahepatic expression of HBcAg and delta antigen in anti‐HBe positive HBsAg carriers with acute exacerbation or chronic active liver disease

Intrahepatic expression of HBcAg and hepatitis delta antigen (HDAg) was studied in 43 patients with acute exacerbation AE and 37 with chronic active liver disease CALD, in order to evaluate the role of hepatitis B virus (HBV) replication and hepatitis delta virus (HDV) superinfection in development of AE or CALD in anti-HBe positive HBsAg carriers in Taiwan, and the results were compared with 37 patients with only minor hepatitic activity. Only 8.1% of patients with minor hepatitic activity were HBcAg positive, and none were HDAg positive. In contrast, 41.8% and 32.6% of patients with AE were positive for HBcAg and HDAg, respectively, and the other 25.6% were negative for both. The clinical features of AE showed no difference in relation to HBcAg and HDAg activity in the liver except that patients without HBcAg and HDAg were predominantly older adults. These patients might be supposed to have non-A, non-B hepatitis (NANB) virus superinfection, as many reports have shown a predominance of older patients in acute NANB hepatitis. Of the patients with CALD, 40.5% were HBcAg positive, 27.0% were HDAg positive, and 32.5% were positive for neither. Histological features of CALD were identified in 83.3% and 100% of patients with HBcAg and HDAg activity, respectively, but only in 26.1% of those without HBcAg and HDAg. The etiology of CALD in the latter group remains unclear. Furthermore, some of the anti-delta seropositive patients with AE or CALD expressed HBcAg rather than HDAg in the liver.(ABSTRACT TRUNCATED AT 250 WORDS)

Detection of hepatitis B viral DNA by polymerase chain reaction in patients with hepatitis B surface antigen

Hepatitis B virus (HBV) DNA was assayed using the polymerase chain reaction in serum samples of 116 hepatitis B surface antigen (HBsAg) carriers, including 30 positive for hepatitis B e antigen (HBeAg) and 86 negative for HBeAg. In the HBeAg-positive group, all were positive for HBV DNA. In the HBeAg-negative group, 80.2% were positive for HBV DNA (80.0% in the healthy carrier group, 90.0% in the chronic active liver disease group, and 69.2% in patients with cirrhosis). This study indicated that every HBeAg-positive carrier as well as the majority of HBeAg-negative carriers were infectious and, in the latter group, that viral replication is most active in patients with chronic active liver disease.

Etiopathogenetic consideration of chronic active liver diseases in tattooed patients

Etiopathogenetic consideration of chronic active liver diseases in tattooed patients

Serum levels of soluble tac peptide in acute and chronic hepatitis B virus infection

Serum-soluble Tac peptide was measured by an enzyme-linked immunosorbent assay in 12 patients with acute type B hepatitis, 33 patients with chronic type B hepatitis, and 15 age- and sex-matched controls. All 12 patients with acute type B hepatitis had elevated levels of soluble Tac peptide with a mean (±SD) of 1527 ± 432 U/ml, significantly higher than that of normal controls (264 ± 74 U/ml) or patients with chronic type B hepatitis (646 ± 399 U/ml). Serial follow-up showed that serum levels of soluble Tac peptide tended to return to normal 2–4 months after onset of acute hepatitis along with the normalization of alanine aminotransferase and seroconversion of hepatitis B surface antigen (HBsAg) to anti-HBs. Patients with chronic type B hepatitis also had significantly higher levels of soluble Tac peptide than normal controls, although only 63.6% ( 21 33 ) of them had a level greater than the upper limit of normal. Serum levels of soluble Tac peptide in patients with chronic type B hepatitis varied considerably with the inflammatity in liver. The hepatitis B e antigen (HBeAg)-positive patients with chronic active liver disease had significantly higher levels of soluble Tac peptide (928 ± 424 U/ml) than HBeAg-positive (412 ± 146 U/ml) or anti-HBe-positive (424 ± 175 U/ml) patients with chronic persistent hepatitis or minimal histological change. In addition, there was a significant positive correlation between serum levels of soluble Tac peptide and alanine aminotransferase. These findings suggested that activation of T cells might play an important role in the pathogenesis of acute and chronic type B hepatitis. Assay of serum-soluble Tac peptide might provide a simple and useful means to better understand the immune mechanisms of acute and chronic hepatitis B virus infection.

In defence of the anecdotal.

In defence of the anecdotal.

Proline-incorporating cells in chronic active liver diseases.

The incorporation of 3H-proline in cells of liver biopsy specimens from patients with chronic active liver diseases has been studied by light and electron microscopic autoradiography. The labeled proline is incorporated by hepatocytes of the external rows of the residual liver lobule, by the cells of the proliferating bile ductule and very actively by the plasma cells localized at the boundary between the inflammatory infiltrate and the liver lobule. These plasma cells, which are often in close contact with the hepatocytes at the edge of the liver lobule, appear to be either negative or positive after the immunohistochemical tests for the k and lambda chains of immunoglobulins. Results are discussed in relation to both the synthesis of collagen and the role of the immunocompetent cells during the process of the piecemeal necrosis.

Interferon in HBV+ chronic active liver disease: Low or high doses?

Interferon in HBV+ chronic active liver disease: Low or high doses?