INTRODUCTION
Primary biliary cholangitis (PBC) is a progressive autoimmune cholestatic liver disease characterized by the destruction of the small intralobular bile ducts, leading to a chronic non-suppurative destructive cholangitis, with eventual bile duct loss, fibrosis, and cirrhosis.[ 1-3 ]
PBC is a rare disease that affects women 10 times more than men, with a peak incidence in the fifth decade. The prevalence is estimated to be between 19 and 151 cases per million population.[ 4 ] A marked geographic variation exists in the prevalence of PBC due to differences in health care access, detection of the cases, existing environmental triggers, and genetic susceptibilities. For example, PBC prevalence is much higher in the US and Northern Europe when compared to Africa, Asia, and Australia.[ 1 , 5 ]
In Saudi Arabia, data on the prevalence and incidence of PBC are scarce and mainly originate from sporadic case reports.[ 6 , 7 ]
Up to 60% of the patients with PBC are asymptomatic at diagnosis, and are usually unmasked because of abnormal liver biochemical tests.[ 8 ] The PBC patients often have fatigue as their initial symptom, with the second common complaint being pruritus. The patients may develop jaundice after many months to years from the onset of the disease. Metabolic bone diseases, osteopenia and osteoporosis, hyperlipidemia, and manifestations from many other autoimmune diseases are also possible.[ 1 , 9 , 10 ]
The diagnosis of PBC is established when two of the following criteria are met: elevated alkaline phosphate (ALP) >1.5 times the upper limit of normal (ULN) for >24 weeks; antimitochondrial antibodies (AMA) titer >1.40; and histologic evidence of non-suppurative destructive cholangitis and interlobular bile duct destruction.[ 3 , 11 ] For the patients with an elevated ALP and positive AMA, liver biopsy is not needed for diagnosis but might be helpful for staging purposes. When AMA is negative, liver biopsy is needed to differentiate AMA-negative PBC from other conditions.[ 12 ]
Ursodeoxycholic acid (UDCA) is the first-line treatment for PBC; it improves the histological findings and patient survival, hence, it also reduces the need for liver transplantation. However, about 40% of the patients with PBC will have an inadequate or no response to UDCA.[ 13 ]
Obeticholic acid, a farnesoid X receptor agonist (FXR), was approved for the treatment of PBC. It improves biochemical changes in PBC.[ 14 , 15 ] Besides the above treatments, fibrates in combination with UDCA were found beneficial in treating PBC patients with inadequate response to UDCA.[ 14-16 ]
Currently, no publications related to the treatments in PBC patients from Saudi Arabia have been reported. To fill this knowledge gap, we conducted this study to determine the baseline characteristics of patients with PBC, and track the treatment response to UDCA in these patients within the first 2 years of the first visit to a center in Saudi Arabia.
PATIENTS AND METHODS
The study was conducted at King Faisal Specialist Hospital & Research Centre (KFSH&RC) in Riyadh, Saudi Arabia. This retrospective and non-interventional study enrolled patients with PBC from January 1, 2008, to December 31, 2017. The patients with a diagnosis of PBC were identified from our records.
Inclusion and exclusion criteria
The patients were included if they were above 18 years and met the diagnostic criteria for PBC.[ 11 ]
We excluded patients with a diagnosis of overlap syndrome (PBC plus autoimmune hepatitis, PBC plus primary sclerosing cholangitis [PSC]). We also excluded patients if they had a different diagnosis other than PBC as well as viral hepatitis.
Diagnosis of PBC
The diagnosis of PBC was established when two of the following criteria were met: elevated ALP >1.5 times the ULN for >24 weeks; AMA titer >1.40; and/or histologic evidence of non-suppurative destructive cholangitis and interlobular bile duct destruction.
In patients who had an elevated ALP and positive AMA, liver biopsy was not needed for the diagnosis, although some patients may have undergone histopathological examination for staging and to rule out an overlapping disease with autoimmune hepatitis (AIH) or PSC. When AMA was negative, liver biopsy was performed to differentiate AMA-negative PBC from other conditions.
Treatment response assessment
The response to UDCA treatment was analyzed according to the following criteria: The Barcelona criteria are the decrease of ALP greater than 40% of the baseline values or normal values after 1 year of treatment. The Paris I criteria are the decrease of ALP <3 times the ULN, aspartate aminotransferase (AST) <2 ULN, and bilirubin <1 mg/dL after 1 year of UDCA treatment. The Paris II criteria include a decrease of ALP <1.5 times the ULN, AST <1.5 ULN, and normal bilirubin after 1 year of UDCA treatment. The Toronto criterion requires a reduction of ALP to < 1.67 times the ULN after 2 years of treatment.[ 17 ] In addition, the treatment response to UDCA in PBC was assessed by finding the difference in the mean alkaline phosphatase from the baseline values to the first year and 2 years of UDCA treatment.
Data management and collection methods
The medical records of the patients with PBC were reviewed. Computerized data entry was performed using the Redcap website to store data. The variables included demographic data, date of diagnosis, clinical presentation, biochemical markers including liver enzymes and AMA titers, liver biopsy findings, treatment, and outcomes. The pathological descriptions and diagnosis of liver biopsies were collected from the pathology records.
Statistical analysis
Statistical analysis was done using the Statistical Package for the Social Sciences (SPSS) version 20 (IBM, USA). Relevant statistical tools were used for the proposed research. Descriptive statistics were used to summarize the continuous variables. The categorical variables were expressed as proportions, while continuous variables were expressed as medians and/or means. The Pearson’s Chi-square test was used to compare categorical variables and the paired t -test, Wilcoxon signed-ranked tests, and the repeated measures of Analysis of Variance (ANOVA) for comparing continuous variables. A two-tailed P value of < 0.05 was considered statistically significant.
Ethical considerations
All the required data and information obtained in the study already existed in the subjects’ medical records and were obtained through routine clinical practice. The subjects were not contacted for missing information or follow-up.
The study was conducted according to the principles of Good Clinical Practice, the Declaration of Helsinki, and the rules and regulations of the ethical committee of KFSHRC, Riyadh. The investigators in the study took all the precautions to protect the confidentiality of the collected data.
RESULTS
A total of 30 patients were identified with PBC in the KFSH&RC in the period between January 1, 2008, and December 31, 2017. The demographic data and clinical characteristics of the patients at baseline are displayed in Table 1 . The mean age of the study population was 46 (± 11.75) years, of which, 28 (93.3%) of them were females. Five (16.7%) of the patients had associated autoimmune diseases including type I diabetes mellitus, hypothyroidism, and systemic lupus erythematous.
Table 1: Baseline characteristics of 30 patients with PBC
Pruritus was the most common clinical presentation reported in 27 (90%) patients and 4 (13.3%) patients had icterus with a bilirubin >51 μmol/L, while fatigue was reported only in 5 (17%) patients. The median cholesterol was 5.8 mmol/L; albumin was 39 g/L, and the mean platelet count was 281,000 per mm3 . The AMA was positive in 26 (86.7%) patients.
Ursodeoxycholic acid treatment
Twenty-two patients received 1,000 mg of UDCA per day in divided doses. Two patients were treated with 600 mg of UDCA per day. The UDCA dose was 15 mg/kg/day and was given in divided doses. The mean weight of the patients was 69 kgs. Supplementary Figure 1
Liver enzymes
From the analysis of the laboratory data, the following results were detected at the time of their first-time presentation to the KFSH&RC: The median total bilirubin was 17.4 umol/L (high normal 21 umol/L); ALP was 310 U/L (2.6 times above the ULN); alanine aminotransferase (ALT) was 60.8 U/L (1.3 times above the ULN), and AST was 66.5 U/L (1.4 times above the ULN). The blood test results of liver enzymes and bilirubin at the time of presentation, at 1 year, and at 2 years are given in Supplementary Table 1
Biochemical changes with UDCA treatment
There was a statistically significant reduction in mean alkaline phosphatase, ALT, and AST from the baseline values to the values obtained after 1 and 2 years of UDCA treatment. The change in ALP during the follow-up is shown in Figure 1 . The mean ALP changed from 371 U/L to–240 U/L at the first year and then to 267.5 U/L at 2 years (P = 0.001).
Figure 1: Change in alkaline phosphatase during the first 2 years of follow-up.
Similarly, AST and ALT decreased significantly during the follow-up. The changes in the liver enzymes and bilirubin results are given in Table 2 .
However, the drop in bilirubin and gamma-glutamyl transferase (GGT) during the 2 years of follow-up was not significant [Table 2] . Figure 2 shows error bars with confidence intervals demonstrating the changes in the liver function tests during follow-up.
Table 2: The liver enzymes and bilirubin changes from the presentation and during the 2-years of follow-up
Figure 2: Error bars showing observed values, mean, and confidence intervals of alkaline phosphatase, bilirubin, GGT, and alanine transferase. The mean values are at presentation and during follow-up. Significant changes were observed in alkaline phosphatase, ALT, and AST during follow-up
Treatment response in patients with cirrhosis and AMA-negative PBC
There was no difference in response in patients with cirrhosis and without cirrhosis (P = 0.8). Similarly, the treatment response to UDCA was not different between those with AMA-positive and AMA-negative PBC (P = 0.8).
Biochemical response based on Paris 1, Paris II, Barcelona, and Toronto criteria
The assessment of the biochemical response to treatment with UDCA was done using multiple proposed criteria [Figure 3 ]. The biochemical response rates to UDCA based on Paris I, Paris II, Barcelona, and Toronto criteria were 73.3, 40, 56.7, and 53.3%, respectively.
Figure 3: Biochemical response of PBC patients. N = 30.
Liver biopsy
A total of 23 patients underwent liver biopsy and the histological picture was suggestive of PBC in all of them. The radiological features of cirrhosis were evident at the diagnosis of PBC in nine (30%) patients and no patient developed hepatocellular carcinoma.
DISCUSSION
To the best of our knowledge, this is the first study from Saudi Arabia reporting the clinical characteristics and treatment response to UDCA in PBC patients.
In this study, we found very few cases of PBC across a 10 year period. The study was conducted from a single center in Saudi Arabia. Besides these patients having typical baseline biochemical characteristics as reported in other PBC studies, the treatment response of our PBC population to UDCA was relatively low compared to other studies from other regions of the world (Table 3 ).
Table 3: Comparison of UDCA response of our patients with patients from other studies
The fact that only 30 cases of PBC were reported over 10 years could indicate the low prevalence of PBC in Saudi Arabia or suggest that cases are not being diagnosed. Alternatively, it feasible that PBC cases are being managed in areas where they are being primarily diagnosed, and not being referred to tertiary care referral centers such as ours. Furthermore, it is difficult to determine if environmental and genetic factors may account for the low prevalence of PBC. More research is needed to distinguish the difference in prevalence rates in Saudi Arabia from other countries.
The following observations were made when we compared our results to the previous research papers. The median age of our cohort was 46 years, consistent with the known peak incidence in the fifth decade of life. Also, there was a female gender predominance, and this is in agreement with the existing literature.[ 1 , 5 ]
Pruritus was reported in a majority of our patients with PBC, consistent with previous studies.[ 5 , 15 , 18 ] However, in our cohort of patients, fatigue was underreported compared to the other reports, which may reflect the retrospective study design.[ 1 , 5 ]
The median level of ALP and bilirubin in our patients was higher than in the previously reported literature.[ 18 ] This difference in the lab findings might be due to a referral bias; most cases of PBC might have been referred to our center when their disease was advanced. The presence of cirrhosis observed in 30% of our cohort could support the above argument.
Many of our patients underwent a liver biopsy to confirm the diagnosis, to exclude other etiologies, or to look for reasons for poor response to the treatment.
UDCA treatment was inadequate in agreement with other international studies. A comparison of previous studies with the UDCA treatment responses to our center’s results are given in Table 3 . The low response may possibly be due to a referral bias to a tertiary care center, where a tendency to refer more difficult-to-manage cases may prevail. Again, we could speculate that many patients could have already had advanced liver disease by the time they were referred to our center. The presence of cirrhosis in many of our patients might be another reason for the poor treatment response. Besides, the treatment response was assessed by the end of 1 year from the first presentation; the long-term prognosis of the poor treatment responders needs to be assessed.
The limitation of our study was the small sample size and having data only from a single center. Also, the retrospective nature of our study made the retrieval of some data on the biochemical response less than optimal. Additionally, some patients were referred from other centers already on treatment with UDCA, and their baseline lab results were not available. Besides, given the retrospective design, we could not assess some of the symptom-burdens.
Further multicenter studies on PBC prevalence and treatment strategies in Saudi Arabia are needed, which will help to clarify the reasons for sub-optimal treatment response. Also, further research is warranted in patients with sub-optimum response to UDCA, and the role of second-line agents such as fibrates and obeticholic acid.
In conclusion, over a 10-year period, 30 cases of PBC were diagnosed from a single large referral center in Saudi Arabia, indicating that the prevalence of the disease is potentially low. In addition, the treatment response to UDCA was inadequate and lower than that observed in studies from other parts of the world. More national data are needed to clarify the prevalence and treatment response in PBC patients in Saudi Arabia.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Supplementary Figure 1
Histogram showing the dose of UDCA in mg/day. The numbers displayed in the bars represent the number of patients on a particular dose of UDCA in mg/day
Supplementary Table 1
Mean, median, standard deviation, minimum, and maximum values of the liver enzymes and bilirubin at presentation, after 1 year, and at 2 years of follow-up
The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (https://links.lww.com/SJGA/A106
The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (https://links.lww.com/SJGA/A107
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