AIM: To describe the ages at diagnosis and operation of biliary atresia (BA) and its incidence over a 15-year period in Taiwan.

METHODS: This was a population-based cohort study. BA cases were identified from the Taiwan National Health Insurance Research Database based on the International Classification of Diseases, Ninth Revision (ICD-9) code of BA 751.61 plus Kasai operation (ICD-9 procedure code 51.37) or liver transplantation (LT, ICD-9 procedure code 50.5). The patients’ characteristics including sex, age at diagnosis, age at receiving Kasai operation and age at receiving LT were compared among three birth cohorts: (1) 1997 to 2001; (2) 2002 to 2006; and (3) 2007 to 2011.

RESULTS: There were a total of 540 BA cases (275 females) with an incidence of 1.62 per 10000 live births. No seasonality of BA was noted. The mean ages at diagnosis of three cohorts were 57.9, 55.6 and 52.6 d. A linear regression model demonstrated a decreasing trend of the mean age at diagnosis (1.27 d per year). The proportion of BA cases that received the Kasai operation within 60 d of age increased from 76% to 81%. A total of 189 (35%) BA patients underwent LT. The mean age at LT was reduced from 3-year-old to 1-year-old. The rates of LT were 25.6% and 32.3% in patients who received the Kasai operation within 60 d or after 60 d of age, respectively. All patients who did not undergo a Kasai operation eventually required LT.

CONCLUSION: The ages at diagnosis and operation in BA cases have decreased over time. Kasai operation performed at younger age reduces the need for LT. The incidence of BA in Taiwan fluctuates, but without certain trend.

Biliary atresia (BA) is the leading cause of liver-related deaths and the most frequent reason for liver transplantation (LT) in children. Its outcome highly relates to the timing of diagnosis and surgical treatment[1-4]. The Kasai operation (hepatoportoenterostomy) as the primary surgical treatment for BA cases is recommended to be performed as early as possible[1,2,5,6], because increased age at the time of surgery may result in a deleterious effect on the outcomes of BA cases[2,4,7]. Usually, delayed identification of pale stools and delayed visits to a physician are the major causes of a delayed Kasai operation.

In 2004, Taiwan began a national screening program using an infant stool color card (SCC) to early detect BA case[8,9]. This program has been approved to be a very sensitive and specific screening method for BA in infants[9,10]. It can enhance earlier referral, which may lead to timely performance of the Kasai operation and better postoperative outcome in infants with BA[10-12]. One study found a significant decrease in the age at diagnosis and Kasai operation of BA cases following the implementation of this screening program[13]. However, this study just observed the BA cases until 2008, four years after the screening program. Whether the decreasing trend of the ages at diagnosis and Kasai operation after 2008 is continued is not clear.

In addition, we would like to update the incidences of BA and check its trend in Taiwan over a longer period from 1997 to 2011. The incidence of BA varies worldwide and tends to be higher in Asian countries than in Europe and North America[14]. It ranges 0.51-0.73 per 10000 in western countries[7,15,16], 1.04-1.10 per 10000 in Japan[17,18] and 1.46-1.85 per 10000 in Taiwan[10,19,20]. Two studies from Taiwan have reported contradicting trends[19,20]. Tiao et al[19] observed an increase in the incidence of BA in Taiwan from 1996 to 2003, but Lin et al[20] found a decrease in the BA incidence in Taiwan from 2004 to 2009. One possible explanation for the different conclusions is the different observation periods. Moreover, these observation periods may be too short to make any definitive conclusion regarding long-term trends. Therefore, the objectives of this study are to describe the ages of BA cases at their diagnosis and operation and to update their incidences from 1997 until 2011.

This study was a 15-year population-based epidemiological analysis of BA. The overall incidence of BA in Taiwan was 1.62 (range, 1.17 to 2.07) per 10000 live births; this incidence is higher than that of western countries and Japan[7,15-18]. A systematic review has suggested that ethnicity may play some role in the occurrence of BA[21]. As shown in Figure 1, the incidence of BA increased from 1.17 per 10000 live births in 1997 to the highest rate of 2.07 per 10000 live births in 2003; this incidence then declined to an ultimate low of 1.28 per 10000 live births in 2008. These observations explain why Tiao et al[19] reported an increasing trend in the incidence of BA from 1996 to 2003, but Lin et al[20] observed a decreasing trend from 2004 to 2009. However, the incidence of BA returned to 1.53 per 10000 live births in 2009, 1.78 per 10000 live births in 2010, and 1.44 per 10000 live births in 2011. Thus, we may conclude that although there have been fluctuations in the incidence of BA, there is no significant trend in the long-term incidence in Taiwan.

Lin et al[20] said the decrease of BA incidence in Taiwan during 2004-2009 may be related to improvements of the general socioeconomic status and the popularity of rotavirus vaccination. However, as mentioned above, this present study found the decrease of BA incidence was not continued after 2010, though the general socioeconomic status and the coverage of rotavirus vaccination in Taiwan did not decline at that time. Moreover, as the recommended schedule for rotavirus vaccines is during the ages of 2 to 6 mo[22], it would be strange to expect the rotavirus vaccine to prevent the occurrence of BA which is usually diagnosed by the age of 2 mo. Therefore, we think the previous assumption about the association between rotavirus vaccination and BA incidence needs to be further examined.

Tseng et al[13] found that the median age at first admission for BA cases decreased from 47 d of age before implementing the SCC program to 43 d of age in the era of the SCC program. However, as shown in Figure 3, we found the reducing trend of the age at diagnosis has been started before 2004, when the national SCC screening was begun. The linear regression model demonstrated a decreasing trend in the age at diagnosis (1.27 d per year) (Figure 3). The age at diagnosis of the late cohort was averagely advanced 2-3 d earlier than that of the early cohort (Table 1). Therefore, this decrease in ages at BA diagnosis and subsequent operation was not entirely due to the SCC screening program alone. Other factors such as medical resource availability and better accessibility to surgical interventions may also have contributed to these changes. Regardless, we agree that SCC screening has the potential benefit of increasing BA awareness in both parents and physicians. Therefore, we would continue to recommend the widespread use of SCC screening. Notably, several countries have already implemented SCC as their national screening program[11,23,24].

As the observed decreasing trend in the age at diagnosis of BA continues, more BA cases can be treated in a timely manner. As shown in the Figure 3, the proportions of Kasai operations within 60 d of age increased from 60% in 1997 to 75% in 2011. One study in France estimated that 5.7% of all LTs might be avoided if all BA patients received a Kasai operation before 46 d of age[4]. Our data also found that the rate of LT was much less in BA patients who received a Kasai operation within 60 d of age than in those who received the operation at over 60 d of age (Table 2). We believe the need for LT can further be reduced if the average age at Kasai operation is reduced to 50 or even 45 d of age in the future.

One astonishing finding in this study is the decrease in the age at LT. The age at LT decreased from almost three years of age in the first cohort to one year of age in the third cohort (Table 1). Historically, the efficacy of LT and postoperative management of these patients have been limited; the donor pool for LT was also limited[25]. Therefore, the timing of LT was delayed. Over time, however, LT has become much more effective with an increase in satisfactory results[26-28]. In addition, the use of living-related donors has become more acceptable and there has been an overall increase in the general population’s attitude toward organ donation. Physicians therefore may perform an LT at an earlier stage in patients with potential hepatic failure before many complications occur. These factors help decrease the age at LT.

The seasonality of BA occurrence was controversial in the literature[14,15,17,29-32]. One review paper said the BA cases occurred mainly during the months of August to March[14]. Nakamizo et al[32] observed that the incidence of BA had a negative correlation with the average temperature of each month and found a higher incidence of BA during December to March in Japan. However, other studies did not find the seasonality of BA occurrence[15,17,29-31]. Our study did not show certain seasonal distribution of BA occurrence in Taiwan either, though May and June had more female cases (Figure 2).

In conclusion, The ages at diagnosis, Kasai operation and LT in BA cases have decreased over time. The need for LT in BA cases may be reduced if patients receive the Kasai operation as early as possible. The incidence of BA in Taiwan has fluctuated, and has no overall increasing or decreasing trend. No seasonality of BA was found in Taiwan.

This study was based in part on data from the National Health Insurance Research Database provided by the Bureau of National Health Insurance, Department of Health and Welfare and managed by National Health Research Institutes. The interpretations and conclusions mentioned in this report do not represent those of the Bureau of National Health Insurance, Department of Health and Welfare or National Health Research Institutes.