Histocompatibility antigens in primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is characterized by marked perturbation of the immune system. In addition, there are familial associations which suggest genetic background to the disease. We have studied HLA-A, B, and D loci in 15 Japanese women with PBC, and compared them to controls. Although HLA-A and B loci in PBC patients showed similar prevalence to the control population, HLA-DHO was significantly more common, occurring in 69% of patients with PBC and 21% of controls. This suggests a genetic predisposition to PBC, and the HLA-DHO locus association may reflect a genetic abnormality of the immune responses.     

Serum type III procollagen and basement membrane proteins as noninvasive markers of hepatic pathology in Indian childhood cirrhosis

While serum concentrations of antigens of the aminopropeptide of type III procollagen have been considered as indicators of hepatic pathology in adults, the high concentrations normally found in children during growth may preclude their use in pediatric liver disease. To clarify this and to determine the role of other circulating connective tissue-related substances in children, we have measured serum concentrations of antigens related to aminopropeptide of type III procollagen, the 7S domain of type IV collagen and the P1 fragment of laminin in healthy subjects aged 1 month to 4 years and in children with Indian childhood cirrhosis, a particularly aggressive form of liver disease. In healthy subjects, there was a considerable age variation in serum aminopropeptide of type III procollagen but not in 7S collagen or laminin P1. In Indian childhood cirrhosis, all three serum antigens were increased (p less than 0.001) above the upper limit of normal for age. Both the serum 7S collagen and laminin P1 concentrations showed a significant correlation with the degree of intralobular fibrosis and also with the severity of necrosis and cellular infiltration, suggesting that these serum antigens may be a noninvasive means of assessing and monitoring events associated with hepatic fibrosis in Indian childhood cirrhosis. The raised serum aminopropeptide of type III procollagen in Indian childhood cirrhosis did not correlate with any histological parameter assessed. Gel filtration of serum showed that, in healthy subjects, the predominant antigenic form of aminopropeptide of type III procollagen was a degradation peptide smaller than authentic aminopropeptide of type III procollagen; while in Indian childhood cirrhosis the authentic peptide and a larger degradation peptide predominated.(ABSTRACT TRUNCATED AT 250 WORDS)     

Serum bile acids in primary biliary cirrhosis

Serum bile acid classes have been studied in 15 patients with primary biliary cirrhosis in five patients with cholestasis, and in five patients who had cirrhosis without cholestatic features. Conjugated monohydroxy bile acids (12-35% serum total bile acids) were found in eight of 11 sera from patients with primary biliary cirrhosis, in sera from four patients with cholestasis but not in any of the five patients with cirrhosis. The glycine conjugates/taurine conjugates (G/T) ratio in eight of 11 patients with primary biliary cirrhosis and two of four patients with cholestasis was <1.0.Bile acid concentrations in seven patients with primary biliary cirrhosis were measured before and during cholestyramine therapy. Decreases in serum total bile acid concentrations were observed which were accompanied by small increases in the trihydroxy/dihydroxy ratio and also in the G/T ratio in six of the seven patients. No association was found between the concentration of any particular conjugated or free bile acid and the presence or absence of pruritus.     

Aminoterminal propeptide of type III procollagen and hyaluronan in patients with primary biliary cirrhosis: Markers of fibrosis in primary biliary cirrhosis

The aminoterminal propeptide of type III procollagen (PIIINP) and hyaluronan have previously been studied in different liver diseases. The results of these studies are controversial. The aim of the present study was to examine the relationship between PIIINP and hyaluronan levels and the clinical, biochemical and histological features of primary biliary cirrhosis (PBC) and its prognosis. Fifty-five PBC patients were studied at the time of diagnosis of PBC and were followed up for a mean of 58 months. During the follow-up period 21 patients died. In addition, 30 healthy subjects were examined in the present study. Hyaluronan and PIIINP were measured by radioimmunoassay and the levels of both PIIINP and hyaluronan were higher in PBC patients than in healthy volunteers (P< 1.8 times 10^-6 and 1.6 times 10^-9, respectively). Hyaluronan and PIIINP levels were above normal values in 82 and 84% of PBC patients, respectively. There were correlations between PIIINP and hyaluronan and the histological stage of PBC (r=0.44, P< 0.004 and r=0.56, P< 0.00001, respectively). The correlation between PIIINP and hyaluronan was 0.46 (P< 0.0035). In symptomatic patients, both PIIINP and hyaluronan values were higher than in controls (P< 0.002 and P< 0.006, respectively). The levels of PIIINP correlated significantly with bilirubin (r=0.43, P< 0.006), while hyaluronan was correlated with age (r=0.33, P< 0.015), pruritus (r=0.32, P< 0.02), fatigue (r=0.41, P< 0.003), hepatomegaly (r=-0.46, P< 0.0008), the presence of oesophageal varices (r=0.34, P< 0.002), weight loss (r=0.29, P< 0.05), bilirubin (r=0.54, P< 0.0001), albumin (r=-0.30, P< 0.04), extent of fat excretion (r=0.53, P< 0.009) and length of symptomatic period before diagnosis of PBC (r=0.43, P< 0.002). Using Cox's logistic regression analysis, survival was found to be influenced by bilirubin concentration but not by hyaluronan, PIIINP, age, albumin or histological stage. Therefore, hyaluronan is a more sensitive marker for predicting advanced PBC than is PIIINP. However, neither hyaluronan nor PIIINP gave any indication of prognostic outcome.     

Hepatobiliary membrane transporters in primary biliary cirrhosis

The secretion of bile normally depends on the function of a number of membrane transport systems in hepatocytes and cholangiocytes. The transport of solutes from the blood to the bile is driven by transport systems in the plasma membrane of the basolateral and canalicular surfaces of the hepatocytes. In cholestatic animal models, the expression of hepatobiliary transporters changes in response to functional impairment of the efflux of bile salts and various organic anions. In recent years, several studies have led to an improved understanding of the function and regulation of hepatobiliary transport systems in patients with primary biliary cirrhosis (PBC). This review focuses on the adaptations in hepatobiliary transporters in PBC patients.     

Serum bile acids in primary biliary cirrhosis.

Fasting serum bile acid levels were measured by gas-liquid chromatography in 56 patients with primary biliary cirrhosis. Of these, 52 (93%) had increased levels (greater than 2mug/ml), including 14 of the 18 with normal serum bilirubin concentrations. The four patients with normal bile acid levels had early lesions as judged by histological and clinical criteria. With progression of the disease, as indicated by the histological features of the lesions, total bile acid levels increased, and the ratio of serum cholic-to-chenodeoxycholic acid decreased. Ratios of serum cholic-to-chenodeoxycholic acid below 1 occurred predominantly in patients with advanced or terminal disease. These studies suggest that serial measurement of serum bile acids may aid in the evaluation of primary biliary cirrhosis.     

Is measurement of type III procollagen amino propeptide useful in primary biliary cirrhosis?

We have examined the value of serum type III procollagen amino propeptide (PIIINP) measurement both in evaluation of disease activity and in estimation of prognosis in primary biliary cirrhosis (PBC). 55 paired sera from 32 PBC patients not receiving treatment known to affect PIIINP levels not with non-hepatic inflammatory conditions were used to estimate serum PIIINP by radioimmunoassay. Significant correlations were found between serum PIIINP and serum albumin (P less than 0.001), bilirubin (P less than 0.002) and aspartate transaminase (P = 0.01). The mean serum PIIINP level rose with advancing histological stage (P less than 0.001). In 18 patients in whom more than 1 serum was assayed (mean follow-up 42 months) PIIINP often fell, particularly in patients with established cirrhosis and advanced disease. The independent prognostic value of PIIINP was examined using Cox's proportional hazards model with three other prognostic co-variables (bilirubin, albumin, patient age). Stepwise regression analysis selected albumin (P less than 0.001) and bilirubin (P = 0.002) as the most important prognostic factors. PIIINP did not give independent prognostic information. We conclude that PIIINP is another marker of disease activity in PBC which confers no benefit over existing conventional measurements in routine management of this disease.     

Serum surrogate markers of liver fibrosis in primary biliary cirrhosis

Background

Hyaluronan, leptin, laminin and collagen IV have been used extensively for the assessment of liver fibrosis. The aim of this study was to assay these markers in the peripheral and hepatic vein blood of primary biliary cirrhosis (PBC) patients and to study their ability to discriminate early from advanced disease.

Methods

Sera from 62 PBC patients were compared to 60 controls, 44 chronic Hepatitis C, 38 hepatocellular carcinoma and 34 viral cirrhosis patients. Serum from the hepatic vein of 15 cirrhotic PBC patients and 17 patients with viral cirrhosis was also assayed.

Results

All disease groups had significantly increased levels of hyaluronan and collagen IV, compared to controls, while laminin was significantly increased only in viral cirrhosis. Hyaluronan levels were statistically different between early (54.5 ng/ml; 95%CI 27.3-426.9) and late PBC (154.5 ng/ml; 95%CI 55.3-764.4, p < 0.05). The area under the curve (AUC) for the identification of late PBC was 0.74 for hyaluronan, 0.63 for leptin, 0.59 for laminin and 0.70 for collagen IV. Hyaluronan had high sensitivity and NPV in identifying late stages of PBC (96% and 90%, respectively). Short term UDCA had no effect on these markers.

Conclusion

No single measurement can differentiate between advanced and early fibrosis in PBC. However serum hyaluronan is a promising single serum marker for longitudinal studies in PBC.     

HLA-DR antigens in primary biliary cirrhosis: lack of association.

A study of HLA-DR antigen in 75 patients with primary biliary cirrhosis has been carried out in order to test the hypothesis that genetic factors related to genes controlling immune responses might be important in the pathogenesis of primary biliary cirrhosis. The frequencies of HLA-DR locus antigens was not significantly different from those in 200 normal controls, nor were those of tissue antigens on the A and B loci. No HLA-DR antigen was significantly associated with the appearance of granulomata on liver biopsy (possibly good prognosis) or with raised serum bilirubin (possibly bad prognosis); nor was there any association between any HLA-DR antigen and adverse reactions to D-penicillamine treatment in 17 patients with such adverse reactions. It is concluded that genetic traits related to HLA antigens studied are probably not important in the aetiology of the disease.     

Serum hyaluronan and aminoterminal propeptide of type III procollagen in primary biliary cirrhosis: relation to clinical symptoms, liver histopathology and outcome.

Hyaluronan (HA) and aminoterminal propeptide of type III procollagen (PIIINP), two biochemical connective tissue markers, were determined in 76 patients with primary biliary cirrhosis (PBC). The HA and PIIINP concentrations were significantly increased compared with controls (P less than 0.001). Both HA and PIIINP levels correlated significantly with conventional liver-function tests. All patients with stage IV PBC showed increased concentrations of both these variables. However, HA was a better marker with regard to prediction of development of cirrhosis as well as prediction of symptoms. Furthermore, HA also showed a negative correlation with time of survival (P less than 0.05). The present data indicate that HA is a more sensitive marker of liver damage in PBC than PIIINP.     

Serum bilirubin: a prognostic factor in primary biliary cirrhosis.

We followed up 55 patients with proven primary biliary cirrhosis for several years or until death. A graph of the level of serum bilirubin versus time that was constructed for each patient shows an initial period of variable length in which the serum bilirubin level remained constant. This was followed by a period of rapid rise in serum bilirubin which culminated in the patient's death. Whenever two successive serum bilirubin values taken six months apart exceeded 34 mumol/l (2.0 mg/dl) the patient had entered a late phase of disease and lived an average of 49 months. Ninety-five per cent confidence limits on survival time were 32-74 months. If two successive six month bilirubin values exceeded 102 mumol/l (6.0 mg/dl), calculated survival time was 25 months, and if two successive six month bilirubin values exceeded 170 mumol/l (10.0 mg/dl), survival time was 17 months. Fifteen of the 41 living patients had two consecutive serum bilirubin levels greater than 34 mumol/l (2.0 mg/dl). However, the slope of the rising bilirubin in the living patients is only 35 mumol/l/yr (1.5 mg/dl/yr) compared with 42 mumol/l/yr (2.5 mg/dl/yr) in the dead patients. This means that patients with this disease not may be living considerably longer.     

Differential in vitro immune responses to biliary tract antigens in primary biliary cirrhosis and chronic active hepatitis

ABSTRACT— Cellular immune reactions against normal biliary tract antigens have been investigated in 21 patients with primary biliary cirrhosis (PBC) and 18 with chronic active hepatitis (CAH) using the leucocyte migration inhibition test with partially purified antigens from normal human gall-bladder bile. Four antigen fractions, containing (either separately or together) three previously-described biliary antigens, were employed: (1) Antigen I; (2) Canalicular antigen; (3) Canalicular and Ductular antigens; (4) All three antigens. Seventeen (81%) of the PBC patients showed migration inhibition with all four fractions. Five (28%) of the CAH patients showed inhibition with three fractions but none exhibited sensitization to the fraction containing only the antigen derived from the bile canalicular portion of the hepatocyte membrane. In experiments with purified lymphocyte sub-populations from PBC patients, leucocyte migration inhibitory factor production was shown to be a function of T-lymphocytes. The antigenic selectivity with respect to the responses in CAH patients suggests that sensitization to biliary tract antigens is probably not a secondary phenomenon resulting from »unmasking« of antigens after bile duct damage has occurred but may be more directly related to the disease process.     

The N-terminal propeptide of collagen type III in serum as a prognostic indicator in primary biliary cirrhosis

The serum level of N-terminal propeptide of collagen III (Col 1-3) has received increasing attention as a possible marker of liver fibrosis. Elevated levels have been reported in patients with primary biliary cirrhosis (PBC). We measured Col 1-3 levels in 24 patients with PBC (mean age 56 +/- 8 years) and compared their value as a prognostic marker with serum bilirubin and IgM levels, the aminopyrine demethylating capacity (ABT) and presence of clinical symptoms. Mean observation time was 5.1 +/- 2.7 years. When these parameters and age were evaluated as predictive factors for survival, only bilirubin, Col 1-3 levels and symptom status variables were found to be significant. When tested as explanatory variables for survival in a stepwise linear logistic regression model Col 1-3 was identified as the strongest significant (P less than 0.001) explanatory variable followed by bilirubin (P less than 0.01) whereas the symptom status emerged as a non-significant variable. The results suggest that the serum level of Col 1-3 may be a useful prognostic indicator in PBC, which is independent of the bilirubin level.     

Fatigue in primary biliary cirrhosis

The autoimmune liver disease, primary biliary cirrhosis (PBC), is associated with debilitating fatigue in a significant proportion of patients. The pathogenesis of fatigue in PBC is unclear, but preliminary studies suggest it has central mechanisms and may have peripheral manifestations. Studies are beginning to elucidate the biological associates of fatigue in PBC, particularly sleep disturbance and autonomic dysfunction. Comprehensive studies investigating the pathogenesis of fatigue in PBC are urgently needed as are large-scale prospective outcome studies.