Primary biliary cirrhosis (PBC) is a slowly progressing autoimmune disease of the liver that is characterized by portal inflammation and immune-mediated destruction of the intrahepatic bile ducts. Serum total bilirubin is one of the various prognostic factors that have been proposed. A recent study found that PBC with accompanying autoimmune hepatitis (AIH) carries a negative prognosis. This study examined the clinical characteristics of PBC and analyzed the factors that affect its prognosis.
Patients diagnosed with PBC between January 1998 and December 2010 based on clinical and histopathological findings were compiled and analyzed retrospectively.
Among 27 patients, 24 (1 male and 23 females, ages 50.0±9.3 years) were followed up. The follow-up period was 8.6±0.9 years. Of the 24 patients, 9 patients progressed to liver cirrhosis (LC). Comparison between patients who did and did not progress to LC revealed statistically significant differences in the patients' serum total bilirubin (2.7±1.8 vs. 0.8±0.4,
We propose that serum total bilirubin, the Mayo risk score, and the revised IAHG score at the time of diagnosis are helpful for predicting PBC prognosis. In particular, since all of the patients with accompanying AIH progressed to LC, the presence of overlap syndrome at the time of diagnosis is helpful for predicting PBC prognosis and providing an adequate treatment.
Primary biliary cirrhosis (PBC) is a slowly progressive autoimmune disease of the liver that primarily affects women. In terms of pathology, PBC is characterized by portal inflammation and immune-mediated destruction of the intrahepatic bile ducts. Fifty to 60 percent of patients are asymptomatic at diagnosis.
A study conducted in 1979 claimed that when total bilirubin, a prognostic factor of PBC, is 10 mg/dL or greater, the average survival period is 1.4 years.
The aim of this study was to analyze the factors that affect the clinical characteristics and the prognosis of patients diagnosed with PBC at a single center.
The subjects of this study were 27 patients diagnosed with PBC at Soonchunhyang University Hospital, Seoul, from January 1998 to December 2010. PBC was diagnosed based on liver function tests, presence of serum antimitochondrial antibody (AMA), and histopathological findings. The diagnosis of PBC was defined as having chronic cholestatic liver disease for greater than 6 months, possessing a positive AMA titer ≥1:40, having liver histology with features consistent with, or diagnostic of PBC, and the exclusion of other etiologies for chronic liver disease, including viral hepatitis, biliary obstruction, drug-induced cholestatic disease, nonalcoholic fatty liver disease, hemochromatosis, Wilson's disease, and α1-antitrypsin deficiency. Patients having viral hepatitis B and C were excluded. Among 27 patients, 24 have had follow-up monitoring to the present day. Finally, 24 patients were enrolled in this study.
Subject patients' data were retrospectively collected for analysis, including age, gender, AMA, ANA (antinuclear antibody), SMA (smooth muscle antibody), IgM (immunoglobulin M), IgG (immunoglobulin G), AST (aspartate transaminase), ALT (alanine transaminase), ALP (alkaline phosphatase), r-GT (gamma glutamyl transpeptidase), total bilirubin, PT (prothrombin time), HBsAg (hepatitis B surface antigen), anti-HCV (antihepatitis C virus) and histopathological findings. ANA and AMA titers of 1:40 or greater were deemed positive. All patients had liver biopsy at the time of first evaluation.
The histological stages were determined according to Ludwig's classiflcation.
Based on the test results at the time of diagnosis, the Mayo risk score and the revised IAHG score were calculated. The Mayo risk score is designed to overcome the limitations of liver biopsy by taking into account only clinical and biochemical variables. The score is calculated using age, total bilirubin, albumin, PT and existence of peripheral edema. The revised IAHG score highlights the importance of the ALP/AST ratio and histological findings. The score is calculated by evaluating 15 items, including ANA, AMA, IgG level, hepatitis viral marker, drug history, alcohol intake and gender (specifically, female). The identification of definite AIH overlap is based on an aggregate score of >15 points. A score between 10 and 15 denotes the presence of probable AIH overlap.
Patients were evaluated laboratory study per three months, abdominal ultrasonography (USG) per six months and esophagogastroduodenoscopy (EGD) per 1 year during follow-up. All patients were treated with Ursodeoxycholic acid (UDCA) in doses of 13-15 mg/kg per day and seven patients also were treated with prednisolon once daily with or without azathioprine 50 mg once daily.
Presence of cirrhosis was established by clinical criteria (ascites, esophageal varices, hepatic encephalopathy, prolonged PT, thrombocytopenia, and hypoalbuminemia) and morphologic criteria (computed tomography or USG). The USG findings for cirrhosis are nodularity and irregular surface of the liver. There is also coarse echo-texture of the liver with increased echogenicity.
SPSS 18.0 version was used for statistical analysis, and quantitative variables were expressed in terms of average and standard deviation. Results were elicited using technical statistics and cross tabulation. Group comparisons for continuous and non-continuous variables were performed using the Mann-Whitney
Of the 27 patients who participated in this study, 24 (1 male and 23 female with mean age of 50.0±9.3) have been followed and monitored thus far. The average follow-up period is 8.6±0.9 years. At the time of diagnosis, 13 (56%) were asymptomatic, 7 (29%) suffered from pruritus, 6 (25%) showed signs of jaundice, and 6 (25%) complained of fatigue among 24 patients. The levels of AST, ALT, ALP, and r-GT were 104.5±72.4 IU/L, 100.5±70.0 IU/L, 513.8±242.1 IU/L, and 586±427.7 IU/L, respectively. The levels of albumin, PT, INR (international normalized ratio), and total bilirubin were 4.1±0.4 g/dL, 11.2±1.0 sec, 1.0±0.1 unit, and 1.5±1.5 mg/dL, respectively. Average IgG and IgM were 1488.8±330.3 mg/dL (normal range 870-1700) and 432.4±200.6 mg/dL (35-220), respectively. AMA and ANA positivity was 88% and 83%, respectively (
Among 24 patients, nine progressed to LC. There were no differences in clinical traits, such as gender, age, AST, ALT, ALP, r-GT, albumin, PT, IgG, and IgM, between the progressed and non-progressed groups (
In this study, there was one case of liver transplantation because the patient showed progress to LC and hepatic failure after being diagnosed with PBC. The case involved a 38-year-old female patient who visited our hospital because of jaundice. At the time of the initial visit, the total bilirubin, Mayo score, and AIH scores were 4.0 mg/dL, 6.5, and 12, respectively. The results of the liver biopsy performed in November 2004 revealed stage 3 PBC. As the patient was administered UDCA 900 mg daily and was being followed up as outpatient, symptoms of jaundice became increasingly more severe. A follow-up liver biopsy was performed in May 2007, and the findings showed that the disease had progressed to stage 4 PBC. On multiple occasions, the patient suffered from hepatic encephalopathy, a complication of LC, and received liver transplantation in May 2010.
Owing to easy administration of biochemical tests such as quantification of AST, ALT, total bilirubin, ALP, and r-GT, as well as other forms of tests, including AMA, IgM, and IgG, PBC is often diagnosed in its early stages. Common symptoms of PBC include fatigue and pruritus; however, more than 50% of cases are asymptomatic, and frequently occur in middle-aged women.
The importance of this study is that total bilirubin, the Mayo risk score, and the revised IAHG score were significantly important as prognostic factors of PBC.
In terms of prognostic indicators, the level of serum bilirubin concentration is the best indicator for prognostic purposes. Pretreatment levels of serum bilirubin, bilirubin levels during follow-up, and the occurrence of normal levels of serum bilirubin were significantly associated with prognosis.
A number of studies have reported that the Mayo risk score is an effective means of predicting prognoses of PBC patients. Some have claimed that cases with Mayo risk scores of 4.5 or lower reacted favorably to treatment,
The simultaneous coexistence of PBC and AIH in the same patient has been described as overlap syndrome.
UDCA is a safe and life-extending therapye for most patients with PBC,
All 24 patients in our study received UDCA treatment, and seven also received immunosuppressive therapy. Despite immunosuppressive therapy, the seven patients progressed to LC. We attribute this to the fact that immunosuppressive therapy did not begin immediately upon diagnosis of PBC-AIH overlap syndrome, but after its progression. However, prospective research is necessary to investigate this issue.
Thanks to advances in testing methodology, many cases of PBC are diagnosed early in the asymptomatic phase, and early diagnosis of PBC provides a much better prognosis. UDCA is effective in reducing total bilirubin, ALP, AST, ALT, IgM, and cholesterol, and in delaying the progress of the disease. In addition, early diagnosis and treatment of PBC is important because early administration of UDCA is effective in delaying development of hepatic fibrosis and esophageal varix.
Hirshfield et al recently reported that PBC is associated with the mutation of genes such as HLA, IL12A, IL12RB2 and IRF5-TNPO3.
This research had limitations in terms of data compilation and evaluating long-term prognosis and prognostic factors because it was a retrospective small-scale study conducted with 24 patients, over an average follow-up period of 8.6±0.9 years. Therefore, prospective research involving multiple facilities is necessary in the future.
In our study, total bilirubin, the Mayo risk score, and the revised IAHG score were significantly important as prognostic factors of PBC. In particular, since all cases that accompanied AIH progressed to LC, existence of the overlap syndrome at the time of diagnosis is believed to be significantly helpful for predicting the prognosis of, and providing treatment for, PBC.
The authors have no conflicts to disclose.
autoimmune hepatitis
alkaline phosphatase
alanine transaminase
antimitochondrial antibody
antinuclear antibody
antihepatitis C virus
aspartate transaminase
hepatitis B surface antigen
International Autoimmune Hepatitis Group
immunoglobulin G
immunoglobulin M
international normalized ratio
liver cirrhosis
primary biliary cirrhosis
prothrombin time
gamma glutamyl transpeptidase
smooth muscle antibody
Ursodeoxycholic acid
Serum bilirubin relative to the progression of PBC. Serum total bilirubin was significantly higher in the progressed group (2.7±1.8) than in the unprogressed group (0.8±0.4;
The risk score of the Mayo clinic model relative to the progression of PBC. The Mayo score was significantly lower in the unprogressed group (3.9±0.6) than in the progressed group (5.1±0.7;
AIH score relative to the progression of PBC. The revised IAHG score was significantly lower in the unprogressed group (5.4±3.0) than in the progressed group (9.2±2.3;
Frequency of overlapping AIH relative to the progression of PBC. Among nine PBC patients whose case progressed to LC, five exhibited overlap with AIH, and the prevalence of AIH was significantly higher among these progressed patients than among the unprogressed group, in which no patients had accompanying AIH (
Clinical characteristics of the patients
Total (n=24) | |
---|---|
Gender (M/F) | 1/23 |
Age (yrs) | 50.0±9.3 |
F/U period (yrs) | 8.6±0.9 |
Clinical features (n, %) | |
Asymptomatic | 13 (56) |
Pruritus | 7 (29) |
Jaundice | 6 (25) |
Fatigue | 6 (25) |
AST (IU/L) | 104.5±72.4 |
ALT (IU/L) | 100.5±70.0 |
ALP (IU/L) | 513.8±242.1 |
r-GT (IU/L) | 586±427.7 |
Albumin (g/dL) | 3.9±0.4 |
PT (sec) | 11.3±1.3 |
PT (INR) | 1.0±0.1 |
Bilirubin (mg/dL) | 1.5±1.5 |
IgG (mg/dL) | 1488.8±330.3 |
IgM (mg/dL) | 432.4±200.6 |
AMA positivity (%) | 88% (21/24) |
ANA positivity (%) | 83% (20/24) |
Liver histology (n, %) | |
Grade I | 2 (8) |
Grade II | 12 (50) |
Grade III | 10 (42) |
Grade IV | 0 |
Mayo risk score (n, %) | |
<4 | 9 (38) |
4 - 5 | 9 (38) |
5< | 6 (24) |
Revised IAHG score (n, %) | |
<10 | 19 (79) |
10-15 | 5 (21) |
15< | 0 |
Data are presented as n (%) or mean±SD.
AST, aspartate transaminase; ALT, alanine transaminase; ALP, alkalaine phosphatase; r-GT, gamma glutamyl transpeptidase; PT, prothrombin time; INR, international normalized ratio; IgG, immunoglobulin G; IgM, immunoglobulin M; AMA, antimitochondrial antibody; ANA, antinuclear antibody; IAHG, International Autoimmune Hepatitis Group.
Clinical characteristics of the patients relative to the progression of PBC
No progression (n=15) | Progression to LC (n=9) | ||
---|---|---|---|
Gender (M/F) | 1/14 | 0/9 | 0.43 |
Age (yrs) | 50.9±9.6 | 48.3±9.0 | 0.52 |
F/U period | 8.3±4.3 | 9.0±4.8 | 0.73 |
AST (IU/L) | 80.7±42.5 | 144.1±95.3 | 0.09 |
ALT (IU/L) | 78.4±49.0 | 137.2±85.6 | 0.09 |
ALP (IU/L) | 468.1±241.0 | 589.9±240.6 | 0.24 |
r-GT (IU/L) | 478.5±326.9 | 766.3±529.8 | 0.11 |
Albumin (g/dL) | 4.1±0.4 | 3.7±0.4 | 0.06 |
PT (sec) | 11.2±1.0 | 11.4±1.7 | 0.72 |
PT (INR) | 1.0±0.1 | 1.0±0.1 | 0.76 |
IgG (mg/dL) | 1421.1±356.6 | 1595.1±274.8 | 0.29 |
IgM (mg/dL) | 408.1±172.7 | 470.6±248.0 | 0.54 |
AMA positivity (%) | 93% (14/15) | 78% (7/9) | 0.26 |
ANA positivity (%) | 80% (12/15) | 89% (8/9) | 0.57 |
Data are presented as n (%) or mean±SD.
Statistical significance was calculated by the Fisher’s exact test.
Statistical significance was calculated by the Mann-Whitney
AST, aspartate transaminase; ALT, alanine transaminase; ALP, alkalaine phosphatase; r-GT, gamma glutamyl transpeptidase; PT, prothrombin time; INR, international normalized ratio; IgG, immunoglobulin G; IgM, immunoglobulin M; AMA, antimitochondrial antibody; ANA, antinuclear antibody.
Multivariate analysis of the prognostic factors
Factor | Odds ratio | 95% confidence interval | |
---|---|---|---|
Total bilirubin (mg/dL) | 11.340 | 1.110-115.792 | 0.041 |
Mayo risk score | 10.637 | 1.017-111.291 | 0.048 |
Revised IAHG score | 9.667 | 1.874-49.859 | 0.007 |
Statistical significance was calculated by the Cox proportional hazards regression.
IAHG, International Autoimmune Hepatitis Group.