July 17, 2007
Hepatobiliary Scintigraphy and [Gamma]-GT Levels in the Differential Diagnosis of Extrahepatic Biliary Atresia
By Stipsanelli, K Koutsikos, J; Papantoniou, V; Arka, A; Et al
Aim. The aim of this paper is to identify extrahepatic biliary atresia (EHBA) as the cause of cholestasis in neonates with prolonged jaundice and thus accelerate the decision for surgical intervention, which is critical for prognosis. Methods. We retrospectively studied 21 infants (13 girls, 8 boys) aged 2-16 weeks who have undergone ^sup 99m^Tc-mebrofenin iminodiacetate (^sup 99m^Tc-BrIDA) scintigraphy. They were referred because of direct hyperbilirubinemia and jaundice persisting beyond the 2nd postnatal week. They had received phenobarbitone premedication prior to scintigraphy. Dynamic images for 30 min and then static images (if required) at 1, 2 and 24 h postinjection were acquired. Images were evaluated visually and semiquantitatively, by calculating the liver- to-heart (L/H) ratio. Age, L/H ratios, and serum gamma glutamyl transpeptidase (gamma-GT) levels were compared (Mann-Whitney U test) between infants with EHBA (Group A) and infants without (Group B). The L/H ratios were correlated with age in each group and with gamma- GT in the entire population.
Results. A total of 7/21 infants were classified in Group A and 14/21 in Group B. The L/H ratios were significantly lower in Group A. The correlation between L/H ratio and age was negative in EHBA and positive in nonatretic infants. The gamma-GT levels were inversely correlated with the L/H ratios in the entire population, being significantly higher in Group A.
Conclusion. In long-standing neonatal direct hyperbilirubinemia, ^sup 99m^Tc-BrIDA scintigraphy and the L/H ratio index seem to give useful information in the differential diagnosis of EHBA, especially when associated with markedly elevated serum gamma-GT levels.
Key words: ^sup 99m^Tc-mebrofenin iminodiacetate scintigraphy - Biliary atresia - Neonatal cholestasis - Infantile jaundice - gamma- GT.
Neonatal jaundice is a phenomenon occurring normally between the 2nd and 5th days of life. In the fetus and neonate, the activity of the hepatocellular enzyme glucoronosyi transferase, which catalyzes the conjugation of bilirubin to glucuronic acid, is normally low. The immature hepatocyte, therefore, secretes unconjugated bilirubin; this phenomenon is transient and normally disappears as the neonate enters the 2nd postnatal week.1 Physicians should be alerted by any prolongation of conjugated hyperbilirubinernia and jaundice beyond this time point, as it may be indicative of cholestasis.
Several etiological factors are associated with neonatal cholestasis, such as obstructive causes (extrahepatic biliary atresiaaeEHBA, choledochal cyst), infectious neonatal hepatitis of known etiology (cytomegalo-virus-CMV, toxoplasma, rubella virus, herpes simplex virus type 2-HSV-2, hepatitis B virusaeHBV), metabolic and genetic disorders (galactosemia, tyrosinemia, Down's syndrome, polycystic disease, alpha^sub 1^ antitrypsin deficiency, Niemann-Pick disease, Crigler-Najjar syndrome), endocrine disorders (hypo-thyroidism), idiopathic neonatal hepatitis, idiopathic neonatal cholestasis and several other causes, such as Byler's syndrome, postintestinal surgery and sepsis.1
EHBA is an entity of unknown etiology, appearing in approximately 1/10 000 live births. Typically, the bile duct is normal at the time of birth; but over the next 6 to 12 weeks its lumen gradually becomes obliterated and the duct turns into a fibrotic cord. Without treatment, over 90% of affected children develop biliary cirrhosis and die before their 1st birthday.3 Therefore, the good prognosis of infants with prolonged neonatal jaundice depends on early diagnosis, since it is essential to achieve an accurate differentiation between biliary atresia (that requires prompt surgical management) and intrahepatic disorders causing severe cholestasis (where any radical surgical intervention should be avoided).4,5
The assessment of prolonged neonatal jaundice requires a multimodality strategy, since neither histology, nor sdntigraphy with technetium-99m labeled iminodiacetic acid (IDA) derivatives is sufficiently accurate for the diagnosis of EHBA.4 Several authors have tried to quantitate scintigraphic findings, such as El Tumi etalj by the 10 minute test, or Rutland.6 by calculating the liver uptake and dismission rate of the radiotracer, in order to exclude EHBA. Moreover, Arora et al,2 tried to reduce the false positive results of hepatobiliary scintigraphy in infants with no tracer excretion in the bowel, by proposing a diagnostic algorithm that incorporated serum gamma glutamyl transpeptidase (gamma-GT) levels.
The aim of this retrospective study was to identify infants suffering from EHBA as the cause of prolonged neonatal cholestasis, by calculating the liver-to-heart (L/H) ratio in ^sup 99m^Tc_mebrofenin iminodiacetate (^sup 99m^TcBrIDA) scintigraphy, and thus reduce the delay of a surgical intervention, which has a critical impact on their prognosis.
Materials and methods
The population of this retrospective study consisted of 21 infants (13 girls, 8 boys) aged 2-16 weeks (mean+-SD: 4.4+-3-2) that underwent ^sup 99m^Tc-BrIDA scintigraphy. They were referred because of prolonged conjugated hyperbilirubinemia (direct bilirubin serum levels >2 mg/dL) and presented with jaundice, which persisted after the 2nd postnatal week. They all had received a premedication of 5 mg/kg body weight/day phenobarbitone for 5 days and were also fasting for 2-4 hours prior to scintigraphy.
The kit for the preparation of 99"1Tc-BrIDA (Bridatec(R)) was obtained from Amersham Health S.r.I. (Milan, Italy) and was labeled with technetium-99m within the Nuclear Medicine Department. Informed consent was obtained in each case from the infant's parent or legal guardian.
Scintigraphy was performed on a large field-of-view, single-head tomographic g camera (Sophycamera DS7(R), Sopha Medical Vision International, Buc Cedex, France), equipped with a low-energy (general purpose) parallel hole collimator and connected to a dedicated computer (Sophy NxT(R), Sopha Medical Vision International, Bue Cedex, France). The matrix for the dynamic study was 64x64 pixels and for the planar images 128x128 pixels. The photopeak was centered at 140 keV, with a symmetrical 10% window.
With the infant placed in the supine position, 6 MBq/kg body weight radiotracer bolus was injected intravenously and a 30-min dynamic study was performed, beginning with the injection and consisting of a total of 60 30-s images (frames) of the abdomen. If tracer activity was excreted from the liver in the bowel during dynamic acquisition, the study was considered negative for biliary atresia. If, on the other hand, no such evidence was apparent, then planar abdominal images of approximately 500-700 kcounts were acquired, at 1 h, 2 h, and even delayed images at 24 h after the injection. If no evidence of patency of the biliary system (,i.e., gastrointestinal-GI-activity) occurred even in the 24-h image, then the study was characterized as suspicious for EHBA and the infant was slated for biopsy.
Two independent experienced nuclear medicine physicians, blinded to any clinical data and to the final diagnosis, evaluated the images both visually and semiquantitatively. Disagreement was resolved by consensus, or by obtaining a third opinion.
Semiquantitative analysis of radiotracer uptake by the liver parenchyma was performed by calculating the L/H ratio (i.e., the counts in a region-of-interestROI-in the liver, divided by the counts in an equal ROI in the heart), as follows; one of the early 30-s frames of the dynamic study was chosen (not always the same), in which the liver tracer uptake was depicted sufficiently, while heart blood pool activity was still visible. Two small ROIs of equal shape (rectangular) and size were drawn, one in the liver and another in the heart. The liver ROI (denoting tracer uptake by the hepatocytes) was drawn in the superior lateral aspect of the right lobe of the organ, towards the periphery, in order to avoid the bile ducts and the gallbladder, which are areas of delayed tracer outflow and accumulation that overlap with areas of hepatocellular uptake,6 The heart ROI was drawn in the left ventricle area, denoting tracer concentration in the circulation (cardiac blood pool). Each ROI was then projected in the entire dynamic study and the number of the counts within its borders was calculated for every frame and was depicted as an activity-time (AT) curve, representing the liver and heart activity fluctuation over time.
The L/H ratio was calculated at the 10th minute of the study. Based on literature reports, this minute was considered the most appropriate for this. According to Leonard et al.,7 patients with biliary atresia were found to have a progressive increase in hepatic activity during the first 8 to 10 min of the dynamic study, with little change in the activity thereafter, while other reports5 suggest that separation of infants with atresia from those with intrahepatic disease could be obtained from frames of the dynamic study between 2.5 and 10 min.
In all infants with no evidence of radiotracer excretion in the bowel even at 24 hours, liver biopsy was performed. The diagnosis of biliary atresia was confirmed histologically, based on the association of ductal plaque residuals with biliary thrombi. Thus, the studied population was classified in two separate groups: one consisting of infants that were eventually diagnosed with EHBA (Group A), and one consisting of infants with various other disorders (Group B). In the latter group, EHBA was excluded on a histological basis and/or because of scimigraphic evidence of tracer excretion in the GI tract. Data analysis
Age, L/H ratio values, and serum a-GT levels were compared between the two groups using the MannWhitney U non-parametric test. The L/H ratio values were correlated (exponential regression analysis) with age in each group and with a-GT levels in the entire population. For all tests, P
The data of the studied population are displayed on an individual basis in Table I. Of the 21 infants, 7 were finally diagnosed with EHBA after liver biopsy and thus were classified in Group A (patients 1, 2, 4, 5,7,18 and 19 in Table I). Their age ranged between 3 and 16 weeks (mean+-SD: 6.29+-4.57). In all of them no bowel activity was observed, even in the 24-hrs image (Figure IA). In 4/7 patients with EHBA, the histological lesions were associated with findings consistent with cholestatic cirrhosis. The I/H ratio values in this group ranged between 0.75 and 2.4 (mean+-SD: 1.72+- 0.6l), (Figure IB).
The remaining 14 patients were classified as EHRAnegative (Group B), with their age ranging between 2 and 8 weeks (meantSD: 3.46+- 1.86). Neonatal hepatitis was confirmed in 5/14,1/14 had choledochal cyst and 1/14 suffered from the Niemann-Pick disease. The remaining 7/14 patients were diagnosed with endohepatic cholestasis of uncertain etiology, or their syndrome was considered attributable to prematurity, or total parental nutrition. Bowel visualization was delayed in 12/14 infants of Group B, varying from 2 to 24 hours postinjection (Figure 2A)t while in the remaining two the excretion of the radiotracer in the GI tract occurred in the proper time. The I/H ratio in Group B ranged between 3.3 and 12.2 (mean+-SD: 8.12+- 2.73X(Figure2B).
With reference to age, the difference between the two groups was borderline significant. The population in the EHBA group was relatively older, as compared with the non-EHBA group (meantSD: 6.29+-4.57 weeks versus$,46+-l.86 weeks, respectively; P-0.037).
The L/H ratio values were found significantly lower in infants with EHBA, as compared to those without (meantSD: 1.72+-0.6l versus 8.12+-2.73 respectively; P
TABLE 1.-Data summary of the studied population on an individual basis.
With regard to the correlation between L/H ratio and age (separately assessed for each group), it was negative (.i.e., it displayed a decreasing tendency) in EHBA infants and it was positive (i.e., it displayed an increasing tendency) in non-atretic infants; yet, it was not significant in either group (r-0.67, P> 0.05 in Group A; and r-0.41, P>0.1 in Group B; Figure 4).
The serum a-GT levels were above normal in all cases and were inversely correlated with the L/H ratio in the entire patient population (r-0.81, PO.001), (Figure 5). However, in Group A the a- GT levels were significantly higher, as compared with those in Group B (meanlSD: 512.57*315.24 IU/L versus 115.8u+-122.6a IU/L respectively; PO.001).
Liver ultrasonography is the primary imaging modality one should consider in the evaluation of an infant with prolonged neonatal jaundice. It is very sensitive in detecting choledochal cysts. However, it is not diagnostic for biliary atresia, where the usual finding is non-visualization of the gallbladder, when the obstruction is located above the level of the cystic duct. The visualization of the gallbladder is not considered as a reliable criterion in differentiating EHBA.
In many cases liver biopsy is performed to establish a diagnosis, but the histological findings may not be specific. In EHBA-positive infants they usually reveal ductal plaque residuals with biliary thrombi and a surrounding inflammatory infiltration. The more time elapses to liver biopsy and diagnosis, the more the liver parenchyma deteriorates and the histologie findings of the disease are likely to be associated with lesions of biliary cirrhosis.
99Tc-BrlDA binds to plasma proteins and thus is carried to the liver. It is cleared rapidly from the plasma, due to its uptake into the hepatocytes by an active-transport mechanism, in a manner similar to bilirubin, reaching peak activity in the liver in approximately 12 minutes.4 It has an excellent hepatic extraction fraction (-98%) in normal subjects, and a very good one (>70%) in patients with serum bilirubin levels up to 20 mg/dL, as compared to
Figure 1.-A 4-week-old infant (patient 2), proven by liver biopsy to have extrahepatic biliary atresia (EHBA). A) Dynamic images of ^"TcBrIDA scintigraphy, with no bowel excretion of the radiopharmaceutical. B) An activity-time (AT) curve, giving the count density over the liver and the heart as a function of time. The liver-to-heart (L/H) ratio calculated at the 10th minute of the study is 2.4.
The objective of the present study was to diagnose or exclude EHBA with a high probability, at an early stage of the evaluation of an infant with prolonged neonatal jaundice. This is due to the need for prompt surgical intervention for the good outcome and prognosis of EHBA patients. On the other hand, there is a need for neonates with prolonged jaundice to avoid unnecessary laparotomy and cholangiography, which are radical invasive procedures.
Several authors have attempted to quantitate the liver uptake Of99111Tc labeled hepatobiliary IDA agents in biliary atresia. Their observations sometimes seem to be contradictory. El Tumi et al> described hepatic indices ranging from 0.49 to 4.26 in EHBA and from 5.03 to 12.27 in cases of cholestasis caused by idiopathic hepatitis. They also observed that when the hepatic index was greater than 5, a higher radiotracer liver uptake was apparent, while in index values less than 5, the liver uptake was reduced.
On the other hand, in a study of 16 infants with atresia and 11 with hepatitis, Gerhold et al? concluded that a 4-grade tracer blood retention score systern could be used, ranging from grade-1 - not visible cardiac radioactivity 5 minutes after injection (indicating normal hepatocyte clearance) to grade-4 - tracer retention in the circulation, comparable with, or exceeding hepatic radioactivity (indicating severe hepatocyte dysfunction). They noticed that patients with biliary atresia tended to have lower blood retention scores (therefore better hepatocyte clearance and higher L/H values), while those with hepatitis demonstrated higher radiotracer retention in the circulation. Yet, there was considerable overlap between these two groups. Kirks etal.10 found in a study of 15 cases that liver uptake was delayed in infants with hepatitis and severe hepatoceliular damage (thus giving lower L/H ratios), while it was normal in infants with atresia. Bourdelat et al.,n in a study of 8 infants (3 with atresia), concluded that a good hepatic tracer uptake (as estimated by AT curves) was suggestive of atresia. Leonard etal.7 studied 9 infants with EHBA and 13 with hepatitis and found no appreciable hepatic uptake in patients with hepatitis, but a good hepatic uptake in patients with atresia. Rutland 6 found that patients with hepatoceliular impairment causing neonatal jaundice and complete cholestasis had worse liver tracer uptake, while the uptake in atretic patients was closer to the uptake of normal subjects. However, he noticed that there was no statistically significant difference in the tracer outflow rate (i.e., the tracer fraction leaving the liver each second) from the periphery of the organ between EHBA and non-EHBA cases.
Figure 2,-A 2-week-old infant (patient 9), diagnosed by follow- up to be a case of endohepauc cholestasis of uncertain etiology. A) Dynamic Images Of9910Tc- BrIDA sdnligraphy, wiih no apparent Dowel radioactivity. B) The activity-time (AT) curve for the liver and heart. The Uverto-heart O/H) ratio calculated at the 10th minute of the study is 8.7.
We found that the values of the L/H ratio (also referred to as hepatic index) were significantly lower in Group A, as compared to those in Group B, denoting that liver tracer uptake was worse in infants with biliary atresia, as compared to infants without. These results seem to correspond with the observations by El Tumi et al.5
One possible explanation for this could be age. The patients in the atresia group (Group A) were relatively older, compared with those in Group B. The same may stand for the El Tumi studied population as well; although these authors do not specify the mean age of their EHBA patients, their age range is comparable to ours (2- 16 weeks and 3-16 weeks, respectively). Irreversible prolonged cholestasis in atretic infants most certainly induces hepatocellular damage. In fact, in 4/7 children of our Group A, histology had revealed lesions consistent with cholestatic cirrhosis. EHBA infants aged less than 1 month have a good hepatic uptake of IDA derivatives.6, 7- ^11 Nevertheless, if they are not scanned and diagnosed early, then their hepatic parenchyma progressively deteriorates. In support of this, the I/H ratio in EHBA patients was found to be negatively correlated with age. It displayed a decreasing tendency, as age increased.
On the other hand, in mild inflammatory or bileintrinsic causes of persisting neonatal jaundice, liver function is not severely compromised at any stage and mostly improves with treatment and time. This was also true for the non-EHBA population of the present study, where no cases of fulminant liver damage were observed. The I/ H ratio in these non-atretic infants was found to have an increasing tendency, as age progressed. The fact that neither the negative I/H ratio-age correlation in Group A, nor the positive correlation in Group B was statistically significant may be attributable to the limited number of patients in each group. Another possible explanation for the different results between several studies regarding radiotracer uptake by atretic and non-atretic livers may reside in intrinsic characteristics related to the kinetics and biodistribution of the several IDA derivatives used in different studies. It must be kept in mind that the kinetics and hepatocellular uptake of the various IDA radiotracers may be variably affected by cholestasis. Differences in their liver uptake and distribution and/or excretion rates may account for the more frequent visualization of GI activity with some of them, compared to others.8,12 An example of such an intrinsic radiotracer difference has already been described in cholestasis, where the decline in the hepatic extraction fraction of 99mTc-DISIDA is considerably larger, compared to that of Tc-BrIDA. Therefore, such differences may as well contribute to this observation, the L/H ratios calculated by some IDA derivatives differ from the ratios calculated by others, in similar patient populations.
Figure 3.-Liver-to-heart (LXH) ratio values in the two patient groups. Group A (infants with EHBA): 1.72+-0.61 (mean+-SD); ranging from 0.75 to 2.4. Group B (infants without EHBA): 8.12+-2.73 (meaniSD); ranging from 3.3 to 12.28.
Figure 4.-Exponential correlation of the liver-to-heart (L/H) ratio with age in the two patient groups. In infants with atresia (Group A) it is inverse (negative) (r=-0.67, P>0.05); in non- atretic infants (Group B) it is positive (r-0.41, P
Figure 5.-Exponential correlation of liver-to-heart (L/H) ratio with serum gamma-GT levels in the total population. It is found to be inverse (negative) (r-0.81, P
Moreover, we found that the serum gamma-GT levels were inversely correlated with L/H ratio values in our entire population and that atretic patients had very high serum levels of gamma-GT, compared with patients of Group B. In the literature gamma-GT has been used to differentiate biliary atresia from neonatal hepatitis. The specificity of serum gamma-GT levels in detecting EHBA ranges from 33% to 100%, depending on the thresholds used by each author. Higher cut-off values were associated with higher specificity, w-is while cut-offs between 90 and 162 IU/L were associated with higher sensitivity (but lower specificity) for EHBA detection.16,17 In a biliary atresia-bearing rat model the increase of gamma-GT was up to ten-fold, while in animals with neonatal hepatitis the increase was only two-fold.18
Arora et at.2 reported that when serum gamma-GT levels are interpreted in parallel with scintigrams, in order to differentiate between EHBA and hepatitis, this does not contribute much to the already high sensitivity of the individual tests, although there is some decline in specificity. In their series of 54 infants with no radioactivity excretion in the gut and hyperbilirubinemia of non- specific etiology, a 150 IU/L cut-off level was used. If patients had gamma-GT levels above that value, they underwent operative cholangiogram (42 cases); if the levels were less than 150 IU/L, they did not (14 cases). The biopsy results in the first group were 9/42 (22%) infants with hepatitis and 33/42 (78%) with EHBA, while all the patients in the second group had neonatal hepatitis. These findings imply that if a patient has no tracer excretion in the gut and serum gamma-GT above 150 IU/L, an operative cholangiogram should be performed, with a high probability of revealing EHBA.
In long-standing neonatal jaundice with direct hyperbilirubinemia, prior to the decision for surgical intervention, ^Tc-BrIDA hepatobiliary scintigraphy and the L/H ratio index seem to provide clinicians with useful information in the diagnosis of EHBA as the cause of the syndrome, especially when associated with markedly elevated serum gamma-GT levels. More studies need to be performed, in order to determine to what extent low hepatic indices, in association with high serum gamma-GT levels, can manage to reduce further the false positive scintigrams and therefore the need for laparotomy and operative cholangiograms.
More studies with the same tracer could clarify the relationship between patient age and L/H ratios, possibly resulting in a diagnostic age-interval.
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K. STIPSANELLI1, J. KOUTSIKOS1, V. PAPANTONIOU1, A. ARKA1, C. PALESTIDIS1, S. TSIOURIS1, A. MANOLAKI2, C. ZERVA1
1 Department of Nuclear Medicine
Alexandra university Hospital, Athens, Greece
2 Department of Pediatrics
Agia Sofia University Hospital, Athens, Greece
Presented in part at the EANM'03 Annual Congress, 23-27 August 2003, Amsterdam, The Netherlands.
Address reprint requests to: Dr. K. Stipsanelli, Department of Nuclear Medicine, Alexandra University Hospital, 80, Vas. Sophia's Ave. & 2, K. Lourou Sir., 115 28, Athens, Greece. E-mail: [email protected]
Copyright Edizioni Minerva Medica Mar 2007
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