|Year : 2019 | Volume
| Issue : 1 | Page : 151-159
Clinicopathological differentiation between biliary atresia and other causes of neonatal cholestasis
Mona A Kandil1, Hayam A Aiad1, Dina S El-Azab2, Shereen F El-Goday1, Mona S Tantawy2
1 Department of Pathology, Faculty of Medicine, Menoufia University, Shebeen El-Kom, Egypt
2 Department of Pathology, National Liver Institute, Menoufia University, Shebeen El-Kom, Egypt
|Date of Submission||20-Jul-2016|
|Date of Acceptance||31-Aug-2016|
|Date of Web Publication||17-Apr-2019|
Mona S Tantawy
Department of Pathology, National Liver Institute, Menoufia University, Shebeen El-Kom, Egypt
Source of Support: None, Conflict of Interest: None
To differentiate biliary atresia (BA) from other causes of neonatal cholestasis (NC) regarding clinicopathological features.
There is a high degree of overlap in clinical, biochemical, and histological characteristics of BA and other causes of NC. There is an increased need of early diagnosis of BA, as timely surgical portoenterostomy is necessary to prevent liver cirrhosis.
Patients and methods
This retrospective study included 61 (32 diagnosed as BA and 29 as non-BA) infants. Data were collected from the medical records of the Pediatric Hepatology Department, National Liver Institute, and paraffin blocks from the archives of the Pathology Department, National Liver Institute, Menoufia University, during the period from January 2014 to December 2015.
The study showed that clinically, clay stool (P < 0.0001), hepatomegaly (P = 0.003), and noncontractile gallbladder (P < 0.0001) emerged as the best indicators of BA. Regarding laboratory parameters, the mean levels of each of γ-glutamyl transferase (P < 0.0001), aspartate aminotransferase (P = 0.025), alanine aminotransferase (P = 0.012) and platelets (P = 0.002) were significantly higher in BA than that in non-BA cases. γ-Glutamyl transferase was the most accurate test in discrimination between BA and non-BA groups. Of all histopathological data, portal changes [portal tract edema (P < 0.0001), fibrosis of portal tracts (P < 0.0001), bile ductular proliferation (P < 0.0001) and bile plugs (P < 0.0001)] were more prominent in BA than that in non-BA cases, whereas parenchymal changes [hepatocellular swelling (P = 0.004) and extramedullary hematopoiesis (P = 0.004)] were more prominent in non-BA cases.
Combined clinical, laboratory, and histopathological parameters are greatly helpful in differentiating BA from other causes of NC. All of these investigations should be done for all suspected cases of BA to decrease the frequency of negative laparotomy finding and achieve cost–benefit with reduced morbidity.
Keywords: alanine aminotransferase, aspartate aminotransferase, biliary atresia, γ-glutamyl transferase, neonatal cholestasis
|How to cite this article:|
Kandil MA, Aiad HA, El-Azab DS, El-Goday SF, Tantawy MS. Clinicopathological differentiation between biliary atresia and other causes of neonatal cholestasis. Menoufia Med J 2019;32:151-9
|How to cite this URL:|
Kandil MA, Aiad HA, El-Azab DS, El-Goday SF, Tantawy MS. Clinicopathological differentiation between biliary atresia and other causes of neonatal cholestasis. Menoufia Med J [serial online] 2019 [cited 2019 Aug 25];32:151-9. Available from: http://www.mmj.eg.net/text.asp?2019/32/1/151/256106
| Introduction|| |
Neonatal cholestasis (NC) is an emergency. Early recognition of cholestasis in the newborn and demonstrating the causative disorder is important, as timely intervention can prevent liver cirrhosis and death . Hyperbilirubinemia is the most common abnormal physical finding in the first week of life in neonates . NC must always be considered in a newborn who is jaundiced for more than 14–21 days, and a measurement of the serum total and conjugated bilirubin in these infants is mandatory. The incidence of NC is approximately one in 2500 live births in the west , and in India, it constitutes 30% of all hepatobiliary disorders . Biliary atresia (BA) is the most common cause of chronic cholestasis in infants and children .
BA is an idiopathic inflammatory process involving the bile ducts resulting in obstruction of biliary tract, chronic cholestasis, progressive fibrosis, and eventually biliary cirrhosis. Incidence of BA is approximately one in 8000 to one in 15 000 live births, and in developing countries, it constitutes 25.8–34% of all NC cases. The basic etiology of BA is still not clear .
The differential diagnosis of BA includes other disorders of NC like neonatal hepatitis, paucity of interlobular bile ducts, progressive familial intrahepatic cholestasis, and various metabolic diseases like galactosemia and α1 antitrypsin deficiency. The most important objective in such cases is to distinguish obstructive cholestasis from nonobstructive causes .
The diagnosis of BA, particularly distinguishing it from other causes of liver injury in the neonatal period, is challenging as there is a high degree of overlap in clinical, biochemical, imaging, and histological characteristics of BA and other causes of NC. There is an increased need of early and correct diagnosis of BA because timely surgical portoenterostomy is necessary for improved biliary drainage. Surgery therefore in BA has to be performed at the earliest opportunity, preferably within first 8 weeks of life without loss of time . What investigations can distinguish BA from other non-BA conditions has been a matter of debate .
As early diagnosis appears essential for effective surgical treatment, every case of neonatal jaundice lasting more than 2 weeks should be investigated and BA actively excluded .
The aim of this study is to assess clinicopathological parameters that correlate best with the diagnosis of BA and help distinction from other causes of NC.
| Patients and Methods|| |
This retrospective study included 61 infants with NC. Patients were selected from the medical records of the Pediatric Hepatology department, National Liver Institute, Menofia University, and paraffin blocks of selected patients were retrieved from the archives of the Pathology Department, National Liver Institute, Menoufia University, Egypt, during the period from January 2014 to December 2015. Being a retrospective study, a written informed consent was not needed. The study was approved by the Research Ethics Committee of Faculty of Medicine, Menoufia University and National Liver Institute, Menoufia University, Egypt.
All patients were divided into two groups: group I (BA group) included 32 patients with BA, comprising 19 females and 13 males, and their age ranged from 44 to 89 days. Diagnosis of BA was confirmed by operative cholangiography before corrective surgery (Kasai operation), and patients were subjected to intraoperative wedge liver biopsy. Group II (non-BA group) included 29 patients with cholestasis owing to causes other than BA. It had 18 males and 11 females, and their age ranged from 27 to 87 days. The diagnosis of BA was ruled out in these patients depending on a set of specific laboratory tests according to the expected etiology, liver biopsy, negative operative cholangiography finding in some patients, and follow-up. The diagnosis of cholestasis was as follows: progressive familial intrahepatic cholestasis (it included 12 patients, comprising eight males and four females. Their age ranged from 30 to 87 days), cytomegalovirus hepatitis (it included three patients; all were males. Their age ranged from 47 to 82 days), resolving acute hepatitis (it included five patients: three were males, and their age ranged from 60 to 75 days, and two were females, aged 60 and 80 days), galactosemia (it included two patients, who were males, and each aged 60 days), Alagille syndrome (it included one patient; a female aged 80 days), paucity (it included one patient; a female aged 43 days), metabolic liver disease (it included three patients: two were females aged 27 and 40 days and a male aged 30 days), giant cell hepatitis (it included one patient, a male aged 60 days) and idiopathic neonatal hepatitis (it included one patient, a female aged 39 days).
All patients were subjected to full history taking, clinical examination, and routine investigations as follows: complete blood count (was carried out using Sysmex Automated Hematology Analyzer; Kobe, Japan), prothrombin time (catalogue number; M, 450045; using human thromboplastin containing calcium from Behring Diagnostic Inc., Marburg, Germany), and liver function tests, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl transferase (GGT), alkaline phosphatase (ALP), total and direct bilirubin, total proteins and albumin (these tests were carried out using Integra 400 auto analyzer; Roche Diagnostics Corporation, Indianapolis, Indiana, USA), as well as abdominal ultrasound (using Xario and Nemio US devices; Toshiba, Tokyo, Japan) and liver biopsy for histopathological evaluation (using Olympus microscope, model; CX23LEDRFS1; Olympus, Tokyo, Japan).
From each representative paraffin block of the studied cases, 4-μm-thick sections were cut, stained by hematoxylin and eosin, and re-evaluated to confirm the diagnosis and to assess the following:
All lobular changes were assessed according to Lee and Looi  as follows:
- Bile plugs were assessed as follows: 0 = absent, 1 = canalicular only, and 2 = both bile ducts and canalicular
- Hepatocytes swelling was as follows: 0 = absent/rare, 1=<50% of hepatocytes, and 2=>50% of hepatocytes
- Pseudorosette formation and hepatocellular multinucleation, each of them was assessed as follows: 0 = absent/rare, 1 = present, and 2 = prominent
- Hepatocellular necrosis was as follows: 0 = absent/rare, 1 = few hepatocytes, and 2 = many hepatocytes
- Extramedullary hematopoiesis was assessed as follows: 0 = absent/rare, 1 = present, and 2 = extensive
- Lobular fibrosis was assessed whether it was absent (0) or present (1).
Each parameter of portal tract changes was also assessed according to Lee and Looi  as follows:
- Portal tract edema and ductal plate malformation were assessed whether they were absent (0) or present (1)
- Portal cellular infiltrate was assessed as follows: 0 = absent/minimal, 1 = mild, and 2 = moderate
- Acute cholangitis was assessed whether it was absent (0) or present in occasional ducts (1)
- Periductular neutrophils was assessed as follows: 0 = absent, 1 = mild, and 2 = marked
- Mononuclear inflammatory cells in ducts was assessed as follows: 0 = absent, 1 = mild, and 2 = multiple
- Bile ductular proliferation was assessed as follows: 0 = none, 1 = focal, and 2 = generalized, whereas the degree of bile ductular proliferation was assessed as follow: 0 = no proliferation, 1 = mild (average number of bile ductules/portal tract <5), 2 = moderate (average number of bile ductules/portal tract between 5 and 9), and 3 = marked (average number of bile ductules/portal tract ≥10)
- Portal fibrosis in liver biopsies was assessed by scoring method according to Russo et al.  as follows: 0 = absent or fibrous expansion of some portal areas, 1 = fibrous expansion of most portal areas, 2 = focal porto-portal bridging, 3 = marked bridging fibrosis, and 4 = cirrhosis.
The data were collected, tabulated, and statistically analyzed using the statistical package for the social science program for windows (version 20; SPSS Inc., Chicago, Illinois, USA). Quantitative data were expressed as mean ± SD and analyzed by applying Mann–Whitney test (U) for comparison between two groups not normally distributed. Qualitative data were expressed as number and percentage and analyzed by applying χ2 and 2 × 2 table, and if one cell has expected number less than 5, Fisher's exact test was applied. Receiver Operating Characteristic curve was used to determine cutoff points, sensitivity, and specificity for quantitative variables.
| Results|| |
The results of this study are represented in [Table 1], [Table 2], [Table 3], [Table 4] and [Figure 1], [Figure 2], [Figure 3].
|Table 1: Clinical, laboratory, and radiological findings in biliary atresia and nonbiliary atresia groups|
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|Table 2: Histopathological findings (parenchymal changes) in biliary atresia and nonbiliary atresia groups|
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|Table 3: Histopathological findings (portal changes) in biliary atresia and nonbiliary atresia groups|
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|Table 4: Clinical performance of aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transferase, and platelets in discrimination between biliary atresia and nonbiliary atresia groups|
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|Figure 1: ROC curves for significant laboratory tests. (a) ROC curve for aspartate aminotransferase (AST) in biliary atresia (BA) versus non-BA group; (b) ROC curve for alanine aminotransferase (ALT) in BA versus non-BA group; (c) ROC curve for γ-glutamyl transferase (GGT) in BA versus non-BA group; (d) ROC curve for platelets in BA versus non-BA group.|
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|Figure 2: Histopathological changes in cases of biliary atresia (BA). (a) Edema of portal tract (H and E, ×40); (b) bile ductular proliferation with intraluminal bile plugs (red arrows) (H and E, ×200); (c) intraductal bile plugs (red arrows) (H and E, ×400); (d) portal tract expansion by fibrosis (white arrows) (H and E, ×100). H and E, hematoxylin and eosin.|
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|Figure 3: Histopathological changes in nonbiliary atresia (BA) cases. (a) Multinucleated giant cell transformation of hepatocytes (white arrows) (H and E, ×200); (b) intracanalicular bile plugs (yellow arrows) (H and E, ×200); (c) intracellular cholestasis (yellow arrows) (H and E, ×200); (d) extramedullary hematopoiesis (yellow arrows) (H and E, ×200). H and E, hematoxylin and eosin.|
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The results showed that there was a statistically highly significant difference between BA and non-BA groups regarding stool color, as 100% of BA cases presented with clay stool compared with ∼30% in non-BA cases, with P value less than 0.0001 [Table 1].
Hepatomegaly also achieved significant statistical difference between BA group and cholestasis group (P < 0.05), as it was highly observed in BA group (88.5% of cases) compared with non-BA group (50% of cases) [Table 1].
Regarding gallbladder (GB) contractility, almost half of the BA cases (48.1%) showed noncontractile GB, whereas only 26.1% of non-BA group had noncontractile GB. There was a highly significant statistical difference between both the groups (P < 0.0001) [Table 1].
Although triangular cord (TC) sign is known to be very important for BA diagnosis, it showed no statistically significant difference between BA and non-BA groups (P = 1.0) [Table 1].
Regarding liver function tests, liver transaminases (AST and ALT) were significantly higher in BA cases than that in non-BA cases, with P value of 0.025 and 0.012, respectively [Table 1]. Clinical performance of AST in discrimination between BA and non-BA groups was as follows: 72% sensitivity, 54% specificity, and 62% accuracy [Table 4] and [Figure 1]a, whereas ALT showed 66, 54, and 59% as sensitivity, specificity, and diagnostic accuracy, respectively [Table 4] and [Figure 1]b.
Cases of BA showed high level of GGT, with mean ± SD of 856.47 ± 595.49 compared with 304.15 ± 351.835 in non-BA group [Table 1]. It was the most accurate laboratory test as it achieved a clinical performance of 91% sensitivity and 54% specificity in discriminating between both groups [Table 4] and [Figure 1]c.
Platelets were significantly higher in BA cases than that in non-BA cases, with P value of 0.002 [Table 1] and a clinical performance of 75% sensitivity, 56% specificity, and 65% accuracy in discrimination between BA and non-BA groups [Table 4] and [Figure 1]d.
Regarding histopathological findings, of all parenchymal changes, bile plugs, hepatocellular swelling, and extramedullary hematopoiesis achieved significant statistical difference between BA and non-BA groups. Almost all of BA cases (31/32) showed intraductal and intracanalicular bile plugs [Figure 2]c compared with only three cases of 29 in non-BA group (P < 0.0001) [Figure 3]b and [Figure 3]c. In contrast, hepatocellular swelling was more prominent in non-BA cases than that in BA cases (P = 0.004). Extramedullary hematopoiesis was absent/rare in almost all of BA cases (30/32) compared with 58.6% in non-BA group [Figure 3]d; this achieved significant difference between both groups, with P value of 0.004 [Table 2].
Regarding portal changes, portal tract edema showed highly significant difference between BA and non-BA groups (P < 0.0001), as it was present in 100% of BA cases [Figure 2]a compared with 48.3% in non-BA cases [Table 3].
More than half of BA cases (53.1%) showed marked fibrous bridging of portal tracts [Figure 2]d, whereas it was present in only one case of 29 cases of non-BA, with high significant statistical difference between both groups (P < 0.0001) [Table 3].
Generalized bile ductular proliferation showed highly significant statistical difference between BA and non-BA groups (P < 0.0001), as it was present in 29 of 32 cases of BA [Figure 2]b, whereas in non-BA cases, it was present only in two of 29 cases [Table 3]. Degree of ductular proliferation was also assessed, and it was moderate (5–9/prothrombin time) in 43.8% of BA cases compared with 3.4% of non-BA cases, achieving high significant difference between both groups (P < 0.0001) [Table 3].
| Discussion|| |
BA is the most common cause of chronic cholestasis in infants, and if untreated, it leads to cirrhosis, hepatic failure, and death within the first 2 years of life .
It is important to diagnose this condition early, because surgical bile drainage procedures like portoenterostomy are especially effective if performed within 8 weeks of birth .
This study included 61 liver specimens; 32/61 were intraoperative wedge liver biopsy from patients with BA and 29 needle liver biopsy from patients having NC owing to causes other than BA.
In our study, all BA cases were less than 90 days old, and ranged between 44 and 89 days, with mean ± SD of 68.88 ± 10.438, as early detection of BA is extremely important because earlier Kasai portoenterostomy is correlated with the best outcomes and reduced need for liver transplantation . Sira et al.  studied comparable aged patients, with mean age of BA of 72.5 ± 40.5 days.
In this study, sex distribution showed female predominance in BA group, and it is in agreement with other reports where BA is more commonly diagnosed in females ,. This finding may reflect a genetic or autoimmune etiology, as BA shares features with several autoimmune diseases, such as the female predominance, apparent triggering by viral infection, and aberrant major histocompatibility complex expression in bile duct epithelium .
Clinically, clay stool was found in all cases of BA (100.0%), whereas it was present in only 30.4% of non-BA cases. This is in agreement with Lee and Chai  who reported that clay stool was found in 83% of BA group, whereas it was present in 36% of cholestatic patient (owing to causes other than BA).
Pale or clay-colored (acholic) stool is consistent with the pathogenesis of BA in which progressive fibro-inflammatory process occurs involving both the extrahepatic and intrahepatic biliary tree, resulting in obliteration of the ducts .
Our study showed that 88.5 and 44.4% of patients with BA had hepatomegaly and splenomegaly, respectively, whereas only 50.0 and 27.3% of patients without BA, respectively. This is in contrast to other reports that showed that hepatomegaly and splenomegaly presence was nearly equal in both groups of patients ,.
However, only hepatomegaly achieved statistically significant difference between BA and non-BA cases (P < 0.05). This is in agreement with that observed by Lee and Chai  who reported that the size of the liver in infants with BA was significantly bigger (P < 0.001) and harder in consistency than those with other underlying etiologies. Furthermore, Chardot  mentioned that hepatomegaly is considered one of the clinical trial of BA (jaundice, acholic stool and dark urine, and hepatomegaly).
By using abdominal ultrasonography, TC sign and GB abnormalities are the two most accurate and widely accepted ultrasound characteristics for diagnosing or excluding BA .
In our study, GB was noncontractile in 48.1% of BA cases compared with 26.1% in non-BA cases, achieving statistically significant difference between BA and non-BA cases (P < 0.0001), whereas TC sign could not achieve any significant difference between BA and non-BA groups (P > 0.05). This finding is in agreement with Iorio et al.  who found that TC sign was visualized in only one-fourth of the infants with BA, and abnormalities of the GB on ultrasound were detected in 83% of the patients.
Knockout experiments in the mouse have identified several transcription factors that are required for biliary development. Several of these also affect liver and GB development . This finding suggests a developmental link between the hepatobiliary system and GB, and loss of these transcription factors results in BA as well as GB agenesis.
Regarding liver function tests, in this study, the mean level of GGT in BA group (856.47 ± 595.490 U/l) was significantly higher than that in the cholestasis group (304.15 ± 351.835 U/l), with a P value less than 0.0001, and these results are in agreement with Sira et al.  who reported a mean level of GGT in BA group of 634.8 ± 451.8 U/l, which was significantly higher than that in the cholestasis group (290 ± 315.8 U/l), with a P value of 0.0004. Moreover, Chen et al.  reported that GGT had 82.8% sensitivity and 81.6% specificity for the discrimination of BA; similarly, we found that GGT was the most accurate test, achieving 91% sensitivity and 54% specificity in discrimination between BA and non-BA groups.
The significance of GGT in BA cases seems to be acceptable in the pathogenesis of BA. GGT is a microsomal enzyme that is widely distributed in human tissues, particularly the bile canaliculi, so increased serum GGT may be considered a fairly reliable index of bile duct injury and damage .
In this study, liver transaminases (AST and ALT) were significantly higher in BA compared with non-BA group, with P value less than 0.05. In contrast, Sira et al.  found that there was no significant difference between cholestasis group and BA regarding liver transaminases as they were elevated in both groups. In addition, McKiernan  reported that the transaminases, AST and ALT, had little individual diagnostic and prognostic value in BA.
Elevation of transaminases in BA cases may be owing to hepatocellular changes that occur secondary to accumulation of bile in liver.
Our results revealed that the mean level of platelets in BA group (515.68 ± 185.947 IU/l) was significantly higher than that in non-BA group (347.63 ± 144.504 IU/l), with a P value less than 0.0001. There was a single study done by Sira et al.  which reported similar results; it found that the platelet count was significantly higher in the BA group (532±172) than in the non-BA group (406±158), with a P value of 0.001, and this suggests that platelets in BA are activated and may have a role in the inflammatory process in BA.
Assessment of liver biopsy histopathology plays a critical role in evaluating NC. Accuracy of percutaneous liver biopsy was reported in the range of 60–95% . Such a variability may be attributed to the fact that there are no strict histopathological criteria to diagnose BA .
In the present study, bile plugs in both bile ducts and canaliculi were seen in 96.9% of BA patients compared with 10.3% in non-BA group, achieving statistically significant difference between both groups (P < 0.0001).
This finding is in agreement with Rashed et al.  who found that bile plugs were seen in 96.6% of BA compared with 39.1% in cholestatic patients other than BA. Similar results were reported by Rastogi et al.  who found that ductal bile plugs were significantly more frequent in BA compared with other groups.
Bile plugs in ducts are one of the most useful histologic features in the diagnosis of BA, though it is not pathognomonic to BA .
Our results revealed that histological changes in portal tracts were significantly more observed in BA cases than in non-BA cases. Therefore, marked portal tract changes should draw the attention toward BA over other causes of NC.
Generalized bile ductular proliferation was observed in 29/32 (90.6%) of BA cases compared with 2/29 (6.9%) in non-BA patients, with P value less than 0.0001. Similarly, Sira et al.  reported that ductular proliferation was significantly higher in BA (93.3%) than other causes of cholestasis (26.7%). Similar to these results, Rastogi et al.  reported that ductular proliferation was the most important histopathological feature in distinguishing BA from other disorders causing NC, with P value of 0.0002.
Ductular proliferation may be attributed to effect of proinflammatory cytokines, such as osteopontin . It may arise from biliary differentiation of progenitor cells or trans-differentiation of periportal hepatocytes into biliary-type cells . Proliferating bile duct epithelial cells might play a role in portal tract fibrosis .
All BA cases showed portal tract edema (100%) compared with 48.3% in non-BA group, with P value less than 0.0001. This result is in agreement with Aiad et al.  who found that 70% of BA cases showed portal tract edema, whereas it was present in only 30% of cholestatic cases other than BA.
More than 50% (53.1%) of BA cases showed marked portal fibrosis compared with 3.4% in non-BA group, with high statistical significance between both groups (P < 0.0001). This result is similar to Rashed et al.  who found that 55.2% of BA cases showed bridging fibrosis. Moreover, Rastogi et al.  found that portal fibrosis was significantly more frequent in BA compared with other groups.
Portal fibrosis in BA could be explained by the presence of activated hepatic stellate cells which are responsible for the production of increased levels of type I collagen leading to hepatic fibrosis in young patients with BA. In addition, the hyperplastic bile duct epithelium produces profibrogenic cytokine transforming growth factor β1 within the portal tract, which forms the fibrotic scar leading to cirrhosis (32).
Regarding parenchymal changes, hepatocellular swelling (>50% of hepatocytes) was observed in 72.4% of non-BA cases, whereas it presented in only 34.4% of BA cases. It showed statistically significant difference between BA and non-BA groups with P value of 0.004. This result is in accordance with Zerbini et al.  who reported that hepatocellular swelling is one of the variables that had the most powerful predictive value to classify the type of cholestasis.
Russo et al.  showed that there was no difference in the gradient of response between BA and non-BA cases for features indicative of parenchymal injury and inflammatory reaction, such as hepatocellular swelling and extramedullary hematopoiesis. In contrast, we found that extramedullary hematopoiesis was absent/rare in almost all cases of BA (30/32) compared with 17/29 (58.6%) cases in non-BA group and could achieve significant difference between both groups (P = 0.004).
| Conclusion|| |
Clinical, laboratory, and histopathological parameters, all together are greatly helpful in differentiating BA from other causes of NC. All of these investigations should be done for all suspected cases of BA to decrease the frequency of negative laparotomy and to achieve cost–benefit with reduced morbidity.
This study was funded by National Liver Institute, Menoufia University, Egypt.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]