Through the many causes of persistent cholestatic jaundice in infancy, BA and NH account for 70–80% of cases . Yet, both conditions had completely different therapeutic schedule and prognosis . BA is a surgical emergency, Kasai portoenterostomy surgical treatment ideally performed in the first 60 days of life. If the surgery is not performed within 90 days, it will progress into liver cirrhosis and hepatic failure which is difficult to recover a normal condition . On the other hand, conservative treatment is very effective in the management of almost all cases of NH . So, it is pretty important to accurately differentiate BA from medical causes, mainly NH. However, no preoperative diagnostic algorithm has proven 100% diagnostic accuracy for BA .
Consistent with many previous studies [9, 11,12,13,14,15], the current study demonstrated that NC is more frequent in male patients (37 males vs. 24 females). Based on histopathological examination of liver biopsy, 21 cases (12 males and 9 females, 34.4%) were diagnosed as BA while the remaining 40 cases (25 males and15 females, 65.6%) were diagnosed as NH. In keeping with other studies [12, 16, 17], we found that BA tend to present at a relatively younger age compared to NH (mean age at the time of HBS was 70 ± 30.5 days for BA vs. 84.7 ± 33.3 days for NH). On the other contrary, Zhou et al. found that both BA and NH groups had approximately the same age at the time of HBS . We did not find a significant relationship between BA and acholic stool (reported in only 33.3% of BA cases, P = 0.635). This comes in contrast to Abou-Taleb et al. and Dehghani et al. who observed a significant correlation (acholic stool was found in 100% (P = 0.0001) and 95% (P = 0.003) of BA cases), respectively [12, 17]. However, similar to both of them, our study did not reveal a significant association between BA and the level of serum direct bilirubin. In agreement with relevant reports, we found that HBS had an overall accuracy of 83.6% in diagnosing BA [12, 18]. Several studies reported variable degrees of sensitivity (84.6–100%) and specificity (61.1–88.6%) for the HBS in diagnosing BA [19,20,21,22,23]. In a large meta-analysis discussing the accuracy of 99mTc-IDA HBS in differentiating BA from NH, Kianifar et al. have reported a pooled sensitivity of 98.7% and a pooled specificity of 70.4%; the reported high sensitivity was due to the extremely rare false negative results recorded . In the current study, HBS had a sensitivity of 90.5% and a specificity of 80% in diagnosing BA. We observed bowel activity in two cases ultimately diagnosed as BA (false negative for BA), at 30-min image in one case and 2-h image in the other (Fig. 7). Given the progressive obliterative nature of BA, it is not surprising for HBS to show tracer excretion owing to the scan timing in respect to the degree of occlusion of extra-hepatic bile ducts. Muthukanagarajan et al. recorded that only 20% of BA showed complete fibroinflammatory obliteration . This is matched with a recent case series study that reported biliary excretion in 6 infants finally diagnosed as BA. Despite the presence of tracer excretion, yet it was abnormal in all of the included infants (either delayed (6- and 24-h image) or subtle detected activity). Thus, they hypothesized that excluding BA relying on detection of any radioactivity in the intestine without consideration of the degree or timing of excretion is an erroneous conclusion that could result in delayed diagnosis and treatment of BA with subsequent inevitable negative impact on the outcome . Kim et al., in a case report, found bowel activity at 4-h image during HBS for an infant with NC, finally diagnosed to have BA. It was attributed to the presence of a remnant slit-like patent lumen in the pathological specimen that allowed bile/tracer transit into the duodenum in this patient .
On the other hand, we encountered 8 cases with false positive results for BA in our study (did not demonstrate tracer excretion up to 24-h imaging despite final diagnosis of NH, Fig. 8). In part, this could be attributed to severe NH which was evident in 6 cases resulting in poor hepatocellular extraction, no tracer excretion, and consequently non-visualization of bowel. Low birth weight, prematurity, and total parenteral nutrition also decrease the capacity to excrete the radiotracer into the intestine, any of them could be another contributing factor . However, due to the retrospective nature of our study, these clinical data were not amenable for us.
In the other part, co-existing mechanical obstruction of non-BA origin might be suggested in the remaining two cases, as both of them showed reasonable hepatic extraction with persistent hepatogram up to 24-h image. However, one infant had lost to follow up while the other infant died before further diagnostic interventional procedures were conducted. Brittain et al. falsely interpreted 4 cases as BA, finally proved to have mechanical obstruction of non-BA etiology on laparotomy .
Adding single-photon emission computed tomography/computed tomography (SPECT/CT) in cases of no or atypical drainage could be helpful for evaluating the non-BA origin. A previous study documented that combining HBS with SPECT/CT resulted in improved specificity and accuracy in diagnosing BA .
As shown by the present study, the false-positive results are the major constraint for HBS. Accordingly, we aimed to retrospectively evaluate the diagnostic efficiency of the semi-quantitative approach of HBS in an attempt to improve the specificity in addition to reducing the examination time required to reach a correct diagnosis. We utilized semiquantitative methods to calculate LKR, KLR, ILR, and BLR. To our knowledge, no previous study has evaluated the last 3 parameters (KLR, ILR, and BLR) as semi-quantitative parameters of HBS for suspected BA. We found that all of them demonstrated high specificity (97.5%) and sensitivity (95.5–100%) in diagnosing BA. We noticed that LKR was significantly lower for BA group than for NH group (P = 0.006), which comes in contrast to Liu et al. who used the same index to differentiate BA from NH and demonstrated that LKR of BA group was slightly higher than for NH group (P < 0.05) . In the current study, significantly higher time of blood pool clearance noted in cases of BA (P = 0.034) could explain this un-expected finding which denoting impaired hepatic extraction efficiency with consequently alternative renal excretion. The higher mean of age (79.62 ± 32.8 days) of our study population compared to that of Liu et al.’s study (45.9 ± 23.4 days) might be the main underlying etiology for this discrepancy. Furthermore, a relatively small sample size and different IDA agent used in our study could be other aiding factors for different results.
In contrast, KLR, ILR, and BLR were significantly higher in cases with BA (P = 0.008, 0.011, and 0.016 respectively). It is worth noting that KLR had a higher AUC (0.707) than ILR and BLR (0.698 for both) indicating that KLR was the best semi-quantitative parameter to predict BA.
Regarding the 15-points histopathological scoring system, our results revealed that the median histopathological score to be 9 for BA and 3.5 for NH, which is comparable to 10 for BA and 4 for NH in a recent similar study . As mentioned above, we encountered a total of 10 false results for BA in our HBS evaluation. Two false negative results, both of them demonstrated high histopathological scoring (≥ 7). On the other hand, 8 false positive results were reported, except for only one result had score (≥ 7); the other 7 demonstrated low histopathological scoring (< 7). Comparable to the results of previous studies [29, 30], we found that histopathological scoring with a cutoff point ≥ 7 had 85.7% sensitivity and 95% specificity for predicting BA. Also, Prasath Sathiah et al. reported a similar specificity (96% vs. 95%), yet a higher sensitivity (92% vs. 85.7%) for histopathological scoring. Different reported sensitivity may be attributable to different reference standard used for analysis; we relied on histopathological examination of liver biopsy as a reference standard while the gold standard in the other study was per-operative cholangiogram .
Being a retrospective study, clinical data were not completely accessible. In addition, sonographic evaluation of the gall bladder as well as the serum level of gamma-glutamyl transpeptidase which were previously reported as strong indicators for BA [12, 16, 31] were not available. On the other hand, the advantages of the current study included utilization of novel time saving semi-quantitative parameters in addition to histopathological scoring that was conducted by an experienced pathologist.