Pre-operative hepatic artery resistive index is a non-invasive predictive indicator of prognosis in biliary atresia

Deepak Mittal; Veereshwar Bhatnagar; Sandeep Agarwala; Maddur Srinivas; Manisha Jana; Arun Kumar Gupta; Nibhriti Das; Manoj Kumar Singh

doi:10.4103/jiaps.JIAPS_103_17



ORIGINAL ARTICLE

Year : 2017 \| Volume : 22 \| Issue : 4 \| Page : 237-241

Pre-operative hepatic artery resistive index is a non-invasive predictive indicator of prognosis in biliary atresia

Deepak Mittal¹, Veereshwar Bhatnagar¹, Sandeep Agarwala¹, Maddur Srinivas¹, Manisha Jana², Arun Kumar Gupta², Nibhriti Das³, Manoj Kumar Singh⁴
¹ Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi, India
² Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India
³ Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
⁴ Department of Pathology, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication

12-Sep-2017

Correspondence Address:
Veereshwar Bhatnagar
Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi - 110 029
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/jiaps.JIAPS_103_17

Abstract

Aims: The aim of this study is to evaluate hepatic artery resistive index (HARI) as a noninvasive prognostic predictor by correlating it with peripheral blood nitric oxide (NO) levels, portal pressure (PP) and histopathological changes in the liver in patients of biliary atresia (BA).
Materials and Methods: Twenty-five patients were included in the study prospectively from November 2012 to June 2014. All patients underwent Doppler sonography to calculate the HARI preoperatively. Peripheral blood NO was also measured preoperatively. Biochemical liver function tests (LFTs) were measured preoperatively and at 1, 3, and 6 months postoperatively. The PP was measured intraoperatively, and a liver biopsy was taken in all patients. Disappearance of jaundice defined successful surgical treatment. Postoperatively, a hepatobiliary IminoDiacetic Acid scan (HIDA) was done to demonstrate a patent bilio-enteric pathway.
Results: The mean preoperative HARI was 0.78 ± 0.105, and the median was 0.80 (range 0.60–1.0). The median HARI was used to correlate the other parameters; 13 (52%) patients had HARI ≥0.8. The mean PP was 24.96 ± 6.54 mmHg. The HARI had a strong correlation with PP (P = 0.0001) and (NO) (P = 0.0001); with every 0.1 increase in HARI, there was 5.2 mmHg increase in PP and 3.8 μmol/L increase in NO. The histological parameters which reached significance in relation to HARI were hepatocellular damage, bile duct inflammation, portal inflammation, and portal fibrosis. The postoperative improvement in LFT was significantly better in patients with HARI <0.8. All four patients who died during or after the study period had HARI >0.8, elevated PP, and NO levels.
Conclusions: Preoperative HARI was found to have a direct correlation with PP and peripheral blood NO as a measure of portal hypertension. A preoperative HARI ≥0.8 should be considered as a risk factor for poor outcomes in BA.

Keywords: Biliary atresia, hepatic artery resistive index, liver histology, nitric oxide, portal hypertension, portal pressure

How to cite this article:
Mittal D, Bhatnagar V, Agarwala S, Srinivas M, Jana M, Gupta AK, Das N, Singh MK. Pre-operative hepatic artery resistive index is a non-invasive predictive indicator of prognosis in biliary atresia. J Indian Assoc Pediatr Surg 2017;22:237-41

How to cite this URL:
Mittal D, Bhatnagar V, Agarwala S, Srinivas M, Jana M, Gupta AK, Das N, Singh MK. Pre-operative hepatic artery resistive index is a non-invasive predictive indicator of prognosis in biliary atresia. J Indian Assoc Pediatr Surg [serial online] 2017 [cited 2023 Jun 4];22:237-41. Available from: https://www.jiaps.com/text.asp?2017/22/4/237/214441

Introduction

Biliary atresia (BA) is characterized by progressive inflammatory disease of both intra and extrahepatic bile ducts leading to fibrosis and obliteration of the biliary system and resulting in hepatocellular damage.^[1] Extensive research to study the factors affecting prognosis of the disease and its outcomes has not provided consistent results. Doppler sonography of the hepatic blood flow has been shown to be a noninvasive indicator of disease severity and a predictor of patient survival in chronic liver disease.^[2],[3],[4] Levels of nitric oxide (NO) in the peripheral venous blood have been observed to be elevated in patients of BA and thought to be marker of portal hypertension (PHT) and associated pathophysiology of the disease process.^[5],[6]

In this study, an attempt has been made to evaluate the correlation between preoperative hepatic artery resistive index (HARI), portal pressure (PP), peripheral blood NO levels, and liver histopathological findings and its significance in predicting the severity of disease and outcome of treatment in patients of BA.

Materials and Methods

This prospective study was conducted over 19 months (November 2012–June 2014). A total of 25 consecutive patients were empirically enrolled in the study since existing information was not considered adequate to calculate a sample size for statistical validity. Patients were excluded from the study if parental consent was not available. Prior approval for this study was obtained from the Institutional Ethics Committee (IESC/T-244/01.06.2012).

A detailed history and physical findings were recorded. Preoperative investigations included biochemical liver function tests (LFTs) and hepatobiliary scintigraphy (HIDA scan). Peripheral venous NO levels were measured spectrophotometrically by the Griess reaction using the methods reported in a previous study.^[6]

All children were subjected to a detailed ultrasound investigation during morning hours, after a light meal. An ultrasound scanner with color and duplex sonography equipment was used with 3.5 and 5 MHz probes. With the patient in a supine position, the systolic and diastolic flow velocity in the hepatic artery was measured from which the HARI was calculated by the formula:

HARI = (Peak systolic velocity − End diastolic velocity)/Peak systolic velocity.

The flow curve in the middle hepatic vein was registered; with the sample volume located approximately 2 cm from the junction with the inferior vena cava. For all Doppler recordings, the Doppler angle was kept below 30°, and an exact angle adjustment was performed before each measurement. All ultrasound Doppler studies were done by a single radiologist (MJ).

All patients underwent the Kasai's hepatoportoenterostomy (HPE). PP was measured with Datex-Ohmeda S/5^™ monitor (range of measurement = −40–320 mmHg, accuracy = ±5% or ± 2 mmHg, sensitivity 5 μV/V/mmHg). A mean of 3 readings was taken as the PP.

At the end of surgery, a wedge biopsy was taken from the liver and examined for hepatocellular damage. All biopsy specimens were examined by a single pathologist (MKS) and graded according to existing criteria.^[7]

In the postoperative period, LFT was obtained at 1, 3, and 6 months. The patency of the bilio-enteric pathway was determined by the clinical disappearance of jaundice and using the HIDA scan. The minimum follow-up period for this study was 6 months. However, patients who died because of the disease during the study were not excluded from the study.

Statistical analysis

The data analysis was performed using STATA version 11.0 (StataCorp LP, Texas, USA). Data were presented as number (%) or mean ± standard deviation (SD)/median (range) as appropriate. The correlation of NO levels and PP with HARI was calculated using Spearman's rank correlation coefficient. The change in levels of NO from baseline in the patients of BA was compared using paired t-test. The changes in HARI and biochemical parameters from baseline were compared using Wilcoxon signed-rank test since the data were not following normal distribution. The association between histopathological features and HARI was tested using Kruskal–Wallis test and also the risk associated with HARI of ≥0.8 on abnormal histopathological features was tested using Fisher's exact test. The results were reported as risk ratio (95% confidence interval). The P < 0.05 was considered statistically significant.

Results

The mean age at presentation was 2.96 ± 1.19 months and median age was 3 months (range 1–6 months). Of the 25 patients, 11 patients were <2 months of age, 4 were between 2 and 4 months, and 10 patients were >4 months of age. The male:female ratio was 17:8.

The preoperative HARI was <0.8 in 12 patients (48%) and >0.8 in 13 patients (52%). The mean (±SD) of HARI was 0.784 ± 0.105 and median HARI was 0.8 (range 0.6–1).

The preoperative HIDA scan showed an obstruction in the bilio-enteric pathway in all patients. Impaired hepatocyte function was observed in 13 of the 25 patients (52%). At 6 months after surgery, only 4 of 23 patients (17.3%) demonstrated biliary obstruction on the HIDA scan.

The mean PP measured during the Kasai's HPE was 24.96 ± 6.54 mmHg and the median pressure was 24 mmHg (range 15–35). Since all the patients had PP above 15 mmHg, it was inferred that all patients had some degree of PHT.

There was a strong correlation between PP and the preoperative HARI (P = 0.0001). With every 0.1 rises in resistive index (RI), there was 5.2 mmHg increase in PP [Figure 1].

Figure 1: Scatter diagram showing the correlation between preoperative hepatic artery resistive index and portal pressure (mmHg)

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The mean level of NO in the preoperative period was 19.62 ± 4.63 μmol/L, and the median was 20.25 (range 6.72–26.2) μmol/L.

The peripheral blood NO measured preoperatively had a strong correlation with the preoperative HARI (P = 0.0001). With every 0.1 rises in HARI, there was 3.8 μmol/L increase in NO [Figure 2].

Figure 2: Scatter diagram showing the correlation between preoperative hepatic artery resistive index and preoperative nitric oxide (μmoles)

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The HARI measured preoperatively was correlated with various parameters of histopathological changes in the liver. Correlation was done by dividing HARI into two categories - <0.8 and >0.8. The histological parameters which had significant correlation with HARI were hepatocellular damage, bile duct inflammation, portal inflammation, and portal fibrosis [Table 1].

Table 1: Histopathological parameters and preoperative hepatic artery resistive index

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The association of HARI with LFT is summarized in [Table 2]. Values of all biochemical parameters were taken as median values before surgery and at 1, 3, and 6 months follow-up after surgery. The degree of decline in these biochemical parameters was studied in these patients who were categorized according to the value of HARI <0.8 or ≥0.8. Bilirubin and enzyme levels showed a more significant decline in patients with HARI <0.8.

Table 2: Median values of biochemical parameters, measured pre-operatively and at 1, 3 and 6 months after surgery, in relation to pre-operative hepatic artery resistive index (<0.8 or ≥0.8)

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A total of 4 (16%) patients died. Of the 2 (8%) patients who expired in the immediate postoperative period, one died due to massive intraventricular hemorrhage and the other due to sepsis and renal failure. Both of these patients had HARI of 1 and 0.9, PP of 34 and 35 mmHg with NO levels of 25.9 and 26.2 μmol, respectively. Two (8%) other patients expired in follow-up after 6 months. These two patients had HARI of 0.84 in both, PP of 25 and 34 mmHg with NO levels of 23.68 and 23.28 μmol, respectively. All patients who had RI <0.8 were alive; however, the difference did not reach statistical significance (P = 0.096) [Figure 3].

Figure 3: Correlation of preoperative hepatic artery resistive index with survival after surgery

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Discussion

The overall variable nature of the disease course and outcomes in BA suggests that the true etiology and pathogenesis are poorly understood and may be multifactorial despite the abundance of available literature.

The liver biopsy in early stages of BA shows inflammation of the biliary tracts and persistence of the original embryonic duct system. There is hyperproliferation of biliary ductules, which is one of the hallmarks of the histopathologic diagnosis of BA. In general, the liver shows fibrotic changes and signs of cholestasis. The fibrotic changes later progress to cirrhosis.

This study was essentially designed to see the impact of HARI on survival and to see the correlation with other parameters which are thought to have prognostic value in patients of BA.

In this study, the male:female ratio was 2:1. This is contrary to what has been reported in the literature, but due to small sample size, it may not have statistical significance. Of the 25 infants in this study, 10 (40%) were older than 4 months. Age of >90 days is considered as a poor prognostic factor in BA. However, of the 4 (16%) patients who expired in our study, 1 (25%) patient was 6 month old and other 3 (75%) were 1.5, 2, and 3 month old. Thus, poor results were seen even in younger patients. It has been proven in other studies also that there is neither a simple nor linear relationship with age and prognosis depends mainly on the type and variant of BA.^[8]

The mean value of HARI measured preoperatively was 0.78 ± 0.02 and 13 (52%) patients had HARI >0.8. All the four patients who died had a HARI >0.8. Although it has not reached statistical significance due to a small number of patients, it is obvious that HARI >0.8 is a bad prognostic factor in terms of predicting mortality. Other studies have also shown that HARI can predict early death in children with BA.^[4]

Serum bilirubin levels were compared with the HARI preoperatively and at 1, 3, and 6 months postoperatively. Median value of bilirubin preoperatively in patients with HARI of <0.8 was 9.8 mg/dl while in patients with RI >0.8 was 11.2 mg/dl. Although the latter was higher, it was not significantly different (P = 0.21). During follow-up, the fall in levels of bilirubin was significant in relation to the HARI; the P values for 1, 3, and 6 months being 0.016, 0.003, and 0.002, respectively.

A similar relationship was seen with aspartate aminotransferase and alanine transaminase. These liver enzymes had fallen more rapidly after surgery in patients with HARI <0.8 than in patients with HARI ≥0.8 at 1 and 6 months of follow-up. The comparison of fall in values of ALP at 1 month in both groups was not significant, but it reached significance at 3 and 6 months. Hence, it can be suggested that patients with HARI >0.8 are more susceptible to have persistent jaundice and raised liver enzymes after Kasai's HPE.

The mean PP was 24.96 ± 6.54 mmHg and the minimum pressure was 15 mmHg. Thus, all patients had some degree of PHT. The PP had a linear relation with the HARI in this study (P = 0.0001). Correlation of HARI with PP has not been studied in BA before. It has been studied in adult cirrhotics; hepatic arterial resistance increased parallel to a rise in the PP (P ≤ 0.01).^[9] Based on the findings in this study, HARI is a noninvasive means to assess the presence of PHT in patients with BA.

The mean level of NO was 19.62 ± 4.63 μmol/L, and median was 20.25 with range of 6.72–26.2 μmol/L. It also had a linear relation with HARI (P = 0.0001). As mentioned earlier that increase in levels of NO depicts not only PHT but also inflammation and fibrosis in the liver parenchyma. There is no study in the literature which evaluated the relationship of levels of NO and HARI. This study has shown that HARI has direct correlation with blood levels of NO, thus further establishing that HARI is a noninvasive means to diagnose the presence of PHT.

At present, there is no study available in the literature which has evaluated or correlated HARI with histopathological changes in the liver of patients with BA. A study on specimens of extrahepatic biliary trees and wedge liver biopsies in 11 patients of BA also included the morphology of hepatic arteries at the porta hepatis.^[10] The authors concluded that there were progressive epithelial damage and an inflammatory, sclerosing change of both intrahepatic and extrahepatic biliary trees, combined with an arteriopathy manifesting as hyperplasia and hypertrophy of hepatic arteries.^[10] This could be the possible explanation for the correlation between histopathological changes and HARI since HARI is mainly decided by the microvascular bed distal to the site of measurement.

The histological parameters which have reached significance were hepatocellular damage, bile duct inflammation, portal inflammation, and portal fibrosis. The pathological mechanisms resulting in PHT, i.e., compression of vascular space by fibrous tissue and regenerative nodules of cirrhotic liver and increased contractility in response to vasoconstrictors, may also be responsible for increase in HARI.

Conclusions

HARI as measured by ultrasonography is a fair indicator of severity of disease. It has direct correlation with peripheral blood NO levels as a measure of PHT and also has direct correlation with PP measured during surgery. The correlation with the histopathological features has also increased our understanding of the pathogenesis of the disease process. Among all these, HARI is the only noninvasive investigation which can be helpful in prognostication of the child. To further improve our knowledge and understanding, more studies with a larger group of patients may be required.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Fischler B, Lamireau T. Cholestasis in the newborn and infant. Clin Res Hepatol Gastroenterol 2014;38:263-7. [PUBMED]
2.	Sudhamshu KC, Matsutani S, Maruyama H, Akiike T, Saisho H. Doppler study of hepatic vein in cirrhotic patients: Correlation with liver dysfunction and hepatic hemodynamics. World J Gastroenterol 2006;12:5853-8. [PUBMED]
3.	Lee MS, Kim MJ, Lee MJ, Yoon CS, Han SJ, Oh JT, et al. Biliary atresia: Color Doppler US findings in neonates and infants. Radiology 2009;252:282-9. [PUBMED]
4.	Broide E, Farrant P, Reid F, Baker A, Meire H, Rela M, et al. Hepatic artery resistance index can predict early death in children with biliary atresia. Liver Transpl Surg 1997;3:604-10. [PUBMED]
5.	Vejchapipat P, Chongsrisawat V, Theamboonlers A, Chittmittrapap S, Poovorawan Y. Elevated serum nitric oxide metabolites in biliary atresia. Pediatr Surg Int 2006;22:106-9. [PUBMED]
6.	Goel P, Srivastava K, Das N, Bhatnagar V. The role of nitric oxide in portal hypertension caused by extrahepatic portal vein obstruction. J Indian Assoc Pediatr Surg 2010;15:117-21. [PUBMED] [Full text]
7.	Davenport M, Caponcelli E, Livesey E, Hadzic N, Howard E. Surgical outcome in biliary atresia: Etiology affects the influence of age at surgery. Ann Surg 2008;247:694-8. [PUBMED]
8.	Schneider AW, Kalk JF, Klein CP. Hepatic arterial pulsatility index in cirrhosis: Correlation with portal pressure. J Hepatol 1999;30:876-81. [PUBMED]
9.	Ho CW, Shioda K, Shirasaki K, Takahashi S, Tokimatsu S, Maeda K. The pathogenesis of biliary atresia: A morphological study of the hepatobiliary system and the hepatic artery. J Pediatr Gastroenterol Nutr 1993;16:53-60. [PUBMED]
10.	Nambirajan L, Taneja P, Singh MK, Mitra DK, Bhatnagar V. The liver in choledochal cyst. Trop Gastroenterol 2000;21:135-9. [PUBMED]