Evaluation of postprandial serum bile acid response as a test of hepatic function

Commercial assays for serum bile acids (SBA) have made this measurement practical. The purpose of this study was to examine the utility of SBA measured every 30 min after a standardized meal in controls and in patients with acute viral hepatitis, cholestasis, and anicteric cirrhosis. In five controls, repeated examination of the area under the bile acid curve (AUC) was not statistically different, whereas the fasting and 2-hr postprandial levels were significantly different. In the group of patients with anicteric cirrhosis, AUC identified disease in 18/20 using total serum bile acids (TSBAs) and in 15/20 using cholylglycine (CG). AUC can be calculated from three samples obtained at 0, 60, and 120 min without losing the sensitivity achieved with seven serial samples. SGOT, alkaline phosphatase, and serum albumin were compared for sensitivity to the total SBA response curve in 20 patients with anicteric cirrhosis. SGOT and alkaline phosphatase identified only 50% and 55% as abnormal and serum albumin was less sensitive. Using total SBA, combining the fasting level and AUC identified 100% as abnormal; using CG, 85% of these patients were detected. As a stepwise cost-effective approach, the fasting level of SBAs can identify most patients with anicteric liver disease. In cases with normal fasting levels where liver disease is suspected, the three-point AUC determination may identify additional patients.Supported in part by a grant from the Diagnostic Division, Abbott Laboratories, North Chicago, Illinois.     

Persistent elevation of the aminoterminal peptide of procollagen type III in serum of patients with acute viral hepatitis distinguishes chronic active hepatitis from resolving or chronic persistent hepatitis

We measured the serum concentration of the aminoterminal propeptide of collagen type III (PIIIP) in 22 patients with acute viral hepatitis (19 hepatitis B, 3 hepatitis non-A, non-B). Nine patients showed persistent biochemical remission, 13 patients developed chronic active hepatitis (CAH); 6 of those underwent therapy with methylprednisolone and azathioprine. Thirteen patients with chronic persistent viral hepatitis (CPH) and 38 healthy individuals were also investigated. In the control group, PIIIP values were 9.5 +/- 2.25 ng/ml (chi +/- SD; range 4-14 ng/ml). All patients with acute hepatitis showed elevated PIIIP values (range 20-125 ng/ml). In the 9 patients with biochemical resolution, PIIIP normalized after a maximum of 6.5 months (range 7.5-14 ng/ml). In CAH, PIIIP was persistently elevated on the day of the diagnostic biopsy (range 15.6-35.7 ng/ml). In comparison, the patients with chronic persistent hepatitis showed a range of 5.0-15.4 ng/ml. Differences between controls and CAH and CPH/CAH were statistically highly significant (P less than 0.001). Treatment of patients with CAH by immunosuppression resulted in normal PIIIP values in 3 and persistently elevated values in 3. One additional patient had normal PIIIP after treatment with an increased dose of methylprednisolone of 16 mg p.d. Serum concentrations of PIIIP offer a non-invasive index for the development of chronic active hepatitis from acute viral hepatitis. This blood test may also be useful for monitoring immunosuppressive treatment in CAH.     

Chronic non-A, non-B hepatitis. A long-term follow-up study in 49 patients

Forty-nine patients with biopsy-verified chronic non-A, non-B hepatitis (NANBH) of both percutaneously transmitted and sporadic types were followed up for up to 20 years (mean, 62 months +/- 44 months). Drug addicts were not included. Twenty-four patients had chronic persistent hepatitis (CPH), and 25 had chronic active hepatitis (CAH) or cirrhosis on the basis of the first biopsy. Patients with CPH were significantly younger than patients with CAH (mean age, 31 and 51 years, respectively; p less than 0.001). Standard laboratory data (means) correlated with histology, but great variations made liver biopsy essential for the diagnosis. Twenty-one patients were rebiopsied, and 24% had more severe lesions. In total, 16 patients (33%) had signs of cirrhosis. The disease seemed to resolve in eight patients (16%), whereas two patients died of it. Some patients with CPH might progress to CAH, and the frequent finding of cirrhosis in CAH implies the possibility of hepatic failure and fatality in chronic NANBH.     

Influence of HDV infection on clinical, biochemical and histological presentation of HBsAg positive chronic hepatitis

In an attempt to identify some characteristics of HDV infection in the different forms of HBsAg positive chronic hepatitis (CH), we evaluated numerous clinical, biochemical and histological aspects in 203 consecutive HBsAg positive CH patients. The presence of hepatitis delta antigen (HD-Ag) in the liver tissue was the criterion used to identify HDV infection. HD-Ag was observed in none of the 7 patients with non-specific reactive hepatitis, in 14.6% of the 48 with chronic persistent hepatitis (CPH), in 36.4% of the 44 with chronic lobular hepatitis (CLH), in 36% of the 25 with mild chronic active hepatitis (CAH), in 52% of the 36 with severe CAH and in 30.2% of the 43 with inactive or moderately active cirrhosis. Compared with the 139 HD-Ag negative patients in this study, the 64 HD-Ag positive patients more frequently had severe CAH (29.7 vs. 12.2%, p less than 0.01) and less frequently CPH (10.9 vs. 29.5%, p less than 0.01). Of the 139 HD-Ag negative patients, 80 were anti-HD positive and 59 anti-HD negative. The 59 patients with no HD-Ag or anti-HD showed severe CAH less frequently than the 64 HD-Ag positive patients (6.8 vs. 29.7, p less than 0.01) and CPH more frequently (44.1 vs. 10.9, p less than 0.001). Both in CPH and CLH the presence of HD-Ag in the hepatocytes identified subgroups of patients who frequently showed high serum levels of aminotransferases and gammaglobulins and more extended areas of circumscribed lobular necrosis. HD-Ag positive CAH was characterized by a more frequent occurrence of eosinophilic degeneration of hepatocytes without peripolesis (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Circulating HCV-RNA,HCV genotype,and liver histology in asymptomatic individuals reactive for anti-HCV antibody and their follow-up study

Abstract: The present study was aimed to clarify the virologic status, liver histologies, and the results of follow-up liver tests in symptom-free individuals with anti-HCV antibodies and normal liver tests. Forty-nine individuals with normal liver tests and positive second generation anti-HCV antibody assay were entered into this study. Cases with hepatitis C viremia were evaluated for HCV genotype, amount of circulating HCV-RNA, and liver histology and were followed-up for more than one year. Of the forty-nine individuals, 36 had hepatitis C viremia, indicated by polymerase chain reaction (PCR) assay. Liver histology was as follows: 3 had non-specific changes, 25 had chronic persistent hepatitis (CPH), and 8 had chronic active hepatitis (CAH). Twenty-four cases with CPH and CAH developed an elevated AST and/or ALT concentration (> 30IU/1) between 12 and 32 months of follow-up. The amount of circulating HCV-RNA ranged from 10² to 10⁷ copies/50 μl serum. The distribution of HCV genotypes was nearly the same as that for symptomatic CAH. These data suggest that the histological examination and follow-up examination are very important for following symptom-free individuals with hepatitis C viremia because there are some candidates for interferon therapy among them. There are few individuals who will remain healthy among asymptomatic HCV carriers.     

Active E rosette-forming cells in the peripheral blood of patients with chronic active hepatitis

E rosette-forming cells (E-RFC) and active E-RFC were studied in the peripheral blood in patients with chronic active hepatitis (CAH), chronic persistent hepatitis (CPH), and in control subjects. A significant reduction in active E-RFC (a subpopulation of T lymphocytes considered actively involved in cell-mediated immune reactions) was found in patients with untreated CAH, both HB_sAg positive or negative. In contrast, patients with immunosuppressive-treated CAH showed an increased relative number of active E-RFC. A significant increase in active E-RFC was demonstrable in other immunosuppressivetreated chronic inflammatory disorders. In CPH active E-RFC were not different from normal controls. The number of E-RFC showed a relative and absolute decrease in both CPH and untreated CAH. These studies demonstrate an increase in active E-RFC in immunosuppressive-treated CAH and suggest that prednisone and azathioprine may have a differential effect on T lymphocyte subpopulations.This study was supported in part by a grant from the Instituto Nacional de Investigaçào Cientifica.     

A study of the relationship between tryptophan metabolism and hepatic pathologic changes in chronic viral hepatitis]

The results of intravenous tryptophan tolerance test and its relationship with hepatic pathologic changes were studied in 47 patients with chronic viral hepatitis (CVH). It is shown that patients with CVH whether chronic persistent hepatitis (CPH) or chronic active hepatitis (CAH), the average value of total tryptophan were above 97 mumol/L (normal less than or equal to 85 mumol/L). There was no significant difference between the CPH and CAH groups (P greater than 0.05). In CPH, the value of free tryptophan (F) was all normal (normal less than or equal to 7.5 mumol/L), but in CAH, the average value of F was above 8 mumol/L. There was much difference (P less than 0.01) between the two groups. Moreover, there was also significant difference between the mild and severe CAH groups (P less than 0.05). It is found that retention of intravenous F is closely related to the degree of hepatic tissue necrosis the presence of balloon cells and acidophilic bodies as well as the severity of intralobular and portal inflammatory reaction.     

IL-1β and TNF-α produced by peripheral blood mononuclear cells before and during interferon therapy in patients with chronic hepatitis C

We investigated the spontaneous and phytohemagglutinin-stimulated production of interleukin-1 (IL-1) and tumor necrosis factor- (TNF-) by peripheral blood mononuclear cells in patients with chronic hepatitis C during treatment with interferon- (IFN-). Spontaneous productions of these were significantly higher in patients with chronic hepatitis C than in healthy subjects. For patients prescribed interferon, stimulated production of TNF- was significantly higher in complete responders than in partial responders, but the differences were small between the other cytokine levels and outcome of IFN treatment. Spontaneous production of these cytokines was higher in patients with genotype III with complete response than in genotype III patients with a partial response, but this was not the case in patients with genotype II. There was a negative correlation between these cytokines and histological activity index. Spontaneous production of cytokines was decreased only in complete responders after the administration of interferon. These data suggest that the elevated production of cytokines in patients with chronic hepatitis C may be due to host response to the virus, and monitoring cytokines along with alanine aminotransferase and hepatitis C virus RNA during treatment may provide more precise information of the effectiveness of therapy.     

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<0.05). The ratio was significantly higher in patients with CAH 2B in comparison with LC-C (P<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.     

Serum HCV-RNA and Liver Histologic Findings in Patients with Long-Term Normal Transaminases

In this study we aimed to correlate liverhistology and the presence of hepatitis C virus (HCV)viremia, genotype, and quantity of HCV genome in 19positive and 11 RIBA II indeterminate patientspresenting persistently normal ALT values over 24 monthsbefore biopsy. In addition, after biopsy serum ALTvalues were monitored monthly for a mean follow-upperiod of 24.8 months, after which patients werereevaluated for RIBA II and the presence of viremia.Sixteen patients (53%) were serum HCV-RNA-positive; 13of them (68%) were confirmed positive and 3 (27%)indeterminate on RIBA II. Histology of the HCV-RNA-positive patients showed eight cases of CPH (one case ofgenotype 1a; four cases type 1b; three cases type 2),six cases of CAH (three cases type 1b, three cases type2), one case of CLH (type not determined), and one case of normal liver (NL) (type 1b).Histology of the HCV-RNA-negative patients showed fourcases of CPH, one case of CAH, two cases of CLH, andseven cases of NL. During the follow-up period ninepatients (30%) presented slight increases in ALT values(<2 × N), and in particular, flares of ALT wereobserved four times in the CAH and five times in the CPHpatients, who were all viremic, but never in the NL subjects. These results indicate that subjectspositive on RIBA II, but with persistently normal ALTvalues, had a high probability of being serumHCV-RNA-positive and that almost all these viremicsubjects presented histologic signs of liver disease. Incontrast, RIBA II indeterminate subjects had a moderateprobability of being HCV-RNA-positive, but a number ofthese may present signs of liver disease. In both cases there was no association withgenotype or HCV-RNA serum levels. The other nonviremiccases included subjects with hepatic changes goingtoward resolution or with normal liver in whom hepatic biopsy can be avoided. Only one case was a truecarrier since he was viremic with normal liver andpersistently normal ALT values.     

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.     

Detection and clinical significance of acetone-insoluble liver cell membrane antigen in sera of patients with chronic active liver diseases

An enzyme-linked immunosorbent assay was developed to detect insoluble liver cell membrane antigen (LMAg) which gives rise to serum LMA (anti-LM) in HBsAg-negative patients. The optical density (OD) ratio of the average LMAg level of normal subjects was less than 1.2. In HBsAg-positive cases, high LMAg levels (OD ratio greater than 2.4) were noted in 8 of 8 patients with acute hepatitis (AH), 3 of 8 with chronic persistent hepatitis (CPH), 5 of 10 with moderate chronic aggressive hepatitis (CAH), 7 of 10 severe CAH and 4 of 8 with liver cirrhosis (LC). In HBsAg-negative cases, however, high LMAg levels were noted in only 6 of 8 patients with AH, 1 of 10 with CPH, 1 of 10 with moderate CAH, 1 of of 10 with severe CAH, 0 of 8 with LC, 0 of 8 with fatty liver and 5 of 10 with alcoholic hepatitis. In micro-immunodiffusion experiments, intensively absorbed rabbit anti-rat LM precipitated two organ-specific components of rat liver homogenate, one of which was identical to liver specific protein (LSP). In immunohistochemical demonstrations of LMAg and LSP, anti-LM, prepared from the serum of a HBsAg-negative CAH patient, bound to both human and rat acetone-fixed liver cell membranes, but not to those of human or rat kidneys. Absorbed rabbit anti-rat LM also bound to liver cell membranes, but absorbed anti-rat LSP lacked organ-specificity when assayed with the immunofluorescence technique using acetone-fixed liver sections. In conclusion, the appearance of serum LMAg was associated with high-SGPT patients and HBsAg-positive CAH patients.     

Thyroxine-binding globulin in patients with chronic hepatitis B virus infection: different implications in hepatitis and hepatocellular carcinoma.

To determine serum thyroxine-binding globulin (TBG) levels, we used radioimmunoassay, and compared the results obtained with other tests in 231 patients with chronic hepatitis B virus infection to evaluate its clinical implications. All of these patients were hepatitis B surface antigen (HBsAg)-positive. Among them, 38 patients had hepatocellular carcinoma (HCC), 18 had chronic persistent hepatitis, 70 had chronic lobular or active hepatitis (grouped as CAH), 31 had active cirrhosis (AC), 25 had inactive cirrhosis, 20 had decompensated cirrhosis, and 29 were "healthy" HBsAg carriers. Twenty-seven patients with acute hepatitis, 12 with cancer metastasis to the liver, and 81 normal adults served as disease or normal controls. The results showed that serum TBG level increased significantly in patients with CAH, AC, or HCC. Serum TBG did not correlate with albumin or bilirubin level, but correlated with alanine aminotransferase (ALT) positively in patients with CAH (p less than 0.001) and negatively in patients with HCC (p less than 0.01) (slope difference p less than 0.05). Serial determination of serum TBG and ALT also showed parallel changes in 15 patients with CAH, but not in nine patients with HCC. In contrast, the fall and rise of serum TBG levels in patients with HCC coincided with tumor resection and recurrence. The data suggest that serum TBG elevation in patients with hepatitis activity is the result of hepatocellular damage, whereas that in patients with HCC is due to increased synthesis. Whether serum TBG elevation without concomitant rise of ALT could be used as a marker of HCC awaits further study.     

Prevalence of HBcAg and delta-Ag in liver tissue of patients with HBsAg positive chronic hepatitis

One hundred and twenty HBsAg positive patients with chronic liver disease, 94 with CAH and 26 with CPH, were studied in order to characterize chronic HBsAg positive hepatitis virologically. All patients came from a geographical area (Campania, Italy) with a high prevalence of HBV and HDV infection. Each patient was tested for the presence of HBsAg, HBeAg, anti-HBe and anti-delta in serum (by RIA techniques), and of HDV (by direct immunofluorescence) and HBcAg (by indirect immunofluorescence and PAP-immunoperoxidase) in liver biopsy specimens. Anti-delta serum positivity was remarkably more frequent in patients with CAH (40%) than in those with CPH (19%). Delta-Ag was found in 94.7% of the anti-delta positive patients with CAH, but in none of the five anti-delta positive patients with CPH. In contrast, the frequency of HBcAg tissue positivity was similar in CAH and CPH. Positivity for HBcAg was less frequent in CAH with cirrhosis than in CAH without cirrhosis, while there was no difference in the prevalence of delta-Ag.     

Hepatocellular carcinoma in 13 patients with hepatitis C virus-associated chronic hepatitis

Abstract Thirteen of 81 patients with chronic hepatitis and positive hepatitis C virus (HCV) antibody developed hepatocellular carcinoma (HCC) during a follow-up period of 54 ± 38 months. The histopathological findings in HCC-bearing liver in these patients included six cases of chronic persistent hepatitis [CPH; mean hepatitis activity index (HAI) score: 5.8] and seven cases of chronic aggressive hepatitis (CAH) 2A, or 2B (HAI) score: 13.6). Multiple biopsies of the liver in six cases revealed that five cases, including four with CPH at the time of HCC diagnosis, previously had histopathological findings identical to CAH 2A, and another case constantly had CPH during the 8-year follow-up. These findings suggest that HCV-associated HCC can occur even in patients with HCV antibody positivity and inactive or mild chronic hepatitis. This is of interest in the pathogenetic mechanisms of HCV-associated HCC.     

Fasting and postprandial serum bile acids as a screening test for hepatocellular disease

Postprandial serum bile acid estimation was recently proposed as the most sensitive test of liver function. In our study, the fasting and postprandial serum bile acid measurements were performed on 19 normal subjects, 20 patients with cirrhosis, 10 with acute hepatitis, 4 with resolving viral hepatitis, and 6 with chronic active hepatitis. A gas-chromatographic method was used. One healthy subject had postprandial serum bile acid levels above the normal range, while 7 patients with liver disease had postprandial levels within normal limits. Of the latter group, 2 had chronic active hepatitis in remission and 3 had resolving viral hepatitis. Significant correlations were seen between serum bile acid levels and most of the conventional liver function tests. Our data indicate that the postprandial serum bile acid determination is better than any of the other conventional tests taken separately, but no better than their combined use. No significant modification of the cholic acid/chenodeoxycholic acid ratio was observed between the fasting and the postprandial determinations.     

Detection of two forms of HBeAg (free-and IgG-bound HBeAg) in patients with HBe antigenemia using staphylococcus bearing protein A

Protein A-bearing Staphylococcus aureus organisms (STA) were used to separate free HBeAg from IgG-bound HBeAg. Free HBeAg was detected in the supernate while IgG-bound HBeAg could be liberated from the pellets using MgCl2 or a glycine buffer. HBeAg was determined by radioimmunoassay and the results expressed as patient's cpm/normal control's cpm ratio (S/N ratio). This ratio was demonstrated to be proportionate to the antigen concentration and used as a titer of HBeAg. Sera of 40 HBsAg-negative healthy volunteers and 82 HBeAg-positive patients who were either asymptomatic HBsAg carriers or had various diseases including chronic persistent hepatitis (CPH), chronic active hepatitis (CAH), and renal disease undergoing hemodialysis, were tested for free HBeAg and IgG-bound HBeAg. Patients with CAH from two different countries were compared. Free HBeAg was detected in all patients but one, IgG-bound HBeAg was detected with similar prevalences (from 56% to 67%) in HBsAg asymptomatic carriers, hemodialysis patients, CPH and Italian CAH patients. In contrast, all CAH patients from New York, who had frequently been exposed to HBV infection, had detectable levels of IgG-bound HBeAg, with the highest S/N ratios observed in the study, and frequently showed an unfavorable outcome. In AVH due to HBV and delta agent co-infection, IgG-bound HBeAg was detected in two of four patients only in the initial stage of the disease. The data reported indicate that a separate determination of free- and IgG-bound HBeAg may have clinical value.     

Long-term follow-up of posttransfusion and sporadic chronic hepatitis non-A, non-B and frequency of circulating antibodies to hepatitis C virus (HCV)

The natural course of chronic hepatitis non-A, non-B (HNANB) was documented for 3-20 yr (mean 8 yr) in 86 patients, who attended our special ambulance between 1981 and 1988. Sixty five of the 86 patients (75%) were positive for circulating antibodies against hepatitis C virus (HCV) (anti-HCV). Twenty four patients had chronic posttransfusion (PT)-HNANB (18 anti-HCV-positive; 75%), and 62 patients had sporadic (S)-HNANB (47 anti-HCV-positive; 75%). Twenty nine per cent of patients with chronic PT-HNANB had sustained normalization of aminotransferases after a period up to 5 yr, 55% demonstrated chronic persistent hepatitis (CPH) and 16% progressed to chronic active hepatitis (CAH) with transition to cirrhosis. In the group with chronic S-HNANB, 2% of patients showed remission, 43% had stable CPH and 55% progressed to CAH or cirrhosis. However, development of cirrhotic complications required many years. Transition from CAH to CPH or remission was not observed. The results indicate that 75% of both patients groups with chronic PT- and S-HNANB are infected with the same agent, of which antibodies are detected by the new anti-HCV assay. There was no statistical association between the severity of the disease and the presence of anti-HCV. The different proportions of progressive courses in chronic PT- and S-HNANB might be explained by the patient recruitment.     

Natural Course of Chronic Hepatitis C

We studied 333 chronic hepatitis C patients to evaluate the natural course of this disease. Among 57 patients undergoing serial biopsies, 20 had chronic persistent hepatitis (CPH) at the first biopsy, and 10 of them progressed to chronic active hepatitis (CAH) or liver cirrhosis (LC) after 11 yr. Sixteen patients had CAH 2A, and this progressed to CAH 2B or LC in 10 cases over 9 yr. Among the 21 patients with CAH 2B, progression to LC was noted in 15 after 7 yr. Among the 100 patients observed for over 5 yr, the normalization of liver function for at least 3 yr was seen in only four patients. In two of these four patients, serum HCVRNA was tested serially. Despite the sustained normalization of alanine aminotransferase levels, HCVRNA continued to be detectable in one patient. We conclude that many patients with chronic hepatitis C eventually show progression of their disease after a long and symptomless course.     

A cell kinetic study of liver cells in various liver diseases by the detection of DNA polymerase alpha

DNA polymerase alpha (DNA-P alpha) in the nuclei of hepatocytes was visualized by the immunoperoxidase method to study the number of liver cells which were at the stage of G1, S, and G2 stage in the cell cycle. Seven liver specimens from patients with acute hepatitis (AH), 17 with chronic persistent hepatitis (CPH), 32 with chronic active hepatitis (CAH), 6 with liver cirrhosis (LC), 4 with hepatocellular carcinoma (HCC) and 4 with hospital controls were studied. The number of DNA-P alpha-positive hepatocytes in 1000 hepatocytes were as follows: 19.1 +/- 18.0 in AH, 8.8 +/- 6.1 in CPH, 27.3 +/- 23.8 in CAH, 21.8 +/- 14.3 in LC, 545.3 +/- 184.0 in HCC and 1.1 +/- 1.1 in hospital controls. The number of DNA-P alpha-positive hepatocytes in HCC were significantly increased compared with other liver diseases. Likewise, those in CAH and LC were higher than those in CPH and hospital controls. The liver cell necrosis was thought to be one of the secondary stimulators for cell division of hepatocytes.