Neonatal Surgical Jaundice Revisited
http://www.100md.com
《美国医学杂志》
1 Department of Pediatric Surgery, Maulana Azad Medical College and Associated Hospitals, New Delhi, India., India
2 Department of Pediatric Surgery, Maulana Azad Medical College and Associated Hospitals, New Delhi, India, India
Abstract
Abstract. Neonatal hyperbilirubinemia is a common problem in newborn nurseries and manifest clinically as jaundice. Nearly 25-50% of all newborns and a much higher percentage of premature babies develop hyperbilirubinemia. This is mostly physiological, but a small percentage of these babies have pathological jaundice, requiring detailed investigations and management. It is also absolutely essential to consider a possibility of extra-hepatic biliary atresia early, during management of a case of neonatal direct hyperbilirubinemia as early surgical intervention results in a better outcome in EHBA. This article aims to descride the diagnostic approach to neonatal hyperbilirubinemia with special emphasis on conditions requiring surgical intervention also it throws light on present status of EHBA in Indian circumstances. [Indian J Pediatr 2005; 72 (5) : -423]
Keywords: Neonatal jaundice; Extra-hepatic biliary atresia; Neonatal hepatitis
Although both Hippocrates and Galen mention jaundice as a sign of disease, first mention of jaundice in newborn is found in Ein Regiment der Jungen Kinder, a 'pediatric text', written by Bartholomeus Metlinger in 1473. In 1847, Virchow observed the accumulation of microscopic yellow crystals in bruises, in wound fluids and in subcutaneous hematomas following phagocytosis of RBCs.[1] This observation provided the first experimental evidence for a link between bilirubin and heme. Since then, much effort has been spent exploring various aspects of this relationship, including mechanisms that control or influence the chemical reactions producing the pigment, its transport systems, movement across tissue barriers and cell walls, and the conjugation, excretion, elimination, absorption and clinical consequences associated with the presence of bilirubin in vital organs.
Physiology of Bilirubin Metabolism
In neonates, approximately 80% of the heme derived from the hemoglobin of disintegrated RBC's catabolizes into bilirubin. The other 20% comes from the breakdown of non-erythropoietic heme. The first step in the catabolic pathway of the heme molecule is also the rate-limiting step, i.e., the creation of biliverdin through the action of microsomal enzyme Heme-Oxygenase.
1. CO (excreted via lungs)
Heme 2. Fe (re-utilized)
3. Biliverdin
Biliverdin converts to bilirubin by biliverdin reductase. Bilirubin is lipophilic and hydrogen binding; it partitions readily into cellular membranes and is virtually insoluble at normal pH. For the body to rid itself of this insoluble product, transport and elimination mechanisms are necessary.
Bilirubin is transported to liver, reversibly bound to albumin. Many drugs also bind with albumin at the predominant binding site for bilirubin. They compete with bilirubin and are capable of displacing the bilirubin molecule from the albumin molecule thus raising the level of circulating bilirubin. At an average, serum albumin concentration of a term neonate is 3.5-5.0 mg/dl, which has enough binding sites to carry bilirubin up to a maximum serum bilirubin concentration of 25-30 mg/dl, with a small amount remaining unbound and in equilibrium with the bound bilirubin. The bilirubin-albumin complex is taken up at the surface of the liver parenchymal cells, where the bilirubin is transferred across the cell membrane without the albumin molecule. The liver converts bilirubin to an excretable, relatively polar (hence water soluble) conjugate. Conjugation consists of transfer of one or two glucuronic acid residues from uridine diphosphoglucuronic acid (UDPGA), resulting in formation of bilirubin mono- or diglucuronide. This enzyme is shown to be induced by phenobarbitone, suggesting a clinical mode for enhancing conjugation and elimination of bilirubin. This conjugated bilirubin is excreted through bile into the intestine.
Unlike adults, newborns have a-glucuronidase enzyme in their intestinal mucosa, which deconjugates the bilirubin to un-conjugated form. This un-conjugated bilirubin is again reabsorbed. Also unlike in adults, in whom bacteria in the intestinal lumen degrade conjugated bilirubin to a non-absorbable stercobilin, the newborn gut is relatively sterile. Thus the neonate is at risk of enhanced entero-hepatic circulation.
Evaluation of a Jaundiced Baby
Questions to be answered when a neonate with hyperbilirubinemia presents:
1. Is the jaundice physiological
2. What is the etiology
3. Which babies require further investigation
4. What are the investigations required
4. Is the jaundice a threat to the infant
Physiological Jaundice
In full term babies, physiological jaundice appears between 30-72 hours of age, reaches a peak by 4-5th day and disappears by 7-10th day of age. Total serum bilirubin does not exceed 12 mg%. Physiological jaundice in preterm babies appears earlier but not before 24 hours of age, reaches maximum by 5-6th day and disappears by 8-14th day. Serum bilirubim may go up to 15 mg %. Table 1 lists the probable mechanism of physiological jaundice.
Following circumstances prolong physiological jaundice:
ImmaturityCephalhematoma
Birth asphyxiaHypothyroidism
AcidosisConcealed haemorrhage
HypothermiaPolycythemia
HypoglycemiaBreast milk syndrome
Pathological Jaundice
Maisels[2][ 3]in 1981 proposed the following criteria for diagnosis of pathologic jaundice:
1. Jaundice within 1st 24 hours of life.
2. Total serum bilirubin increasing by more than 5 mg%.
3. Total serum bilirubin exceeding 12.9 mg% in a full term or 15mg% in a premature infant.
4. Direct serum bilirubin exceeding 1.5-2.0 mg%.
5. Clinical jaundice persisting for more than one week in full term or 2 weeks in a premature infant.
In the management, the first issue that needs to be resolved is whether one is dealing with unconjugated or conjugated hyperbilirubinemia. A baby with conjugated hyperbilirubinemia, will have:
1. History of jaundice persisting even after 2 weeks, along with high colored urine and clay colored stools.
2. Biochemically, direct hyperbilirubinemia >2mg% or >20% of the total bilirubin (if total serum bilirubin < 10 mg%).
The etiologies of both unconjugated and conjugated hyperbilirubinemia are tabulated in Table 2 and 3 below.
Proper history taking and detailed physical examination is essential for arriving at a working diagnosis. Some of the relevant points are summarized in Table 4 and 5. Further work up of the patient is directed towards establishing a specific diagnosis and to rule out any obstructive lesion.
Diagnosis
0Clinical differentiation among the common causes of cholestasis is difficult. There is plethora of hematological, biochemical, serological and microbiological investigations described to help reach a precise diagnosis. The laboratory work-up for the mother includes blood group and indirect Coomb's test to rule out ABO and Rh incompatibility and serology for TORCH infections. The laboratory work-up for the neonate with hyperbilirubinemia is tabulated in Table 6. From a surgeon's point of view, extra-hepatic biliary atresia (EHBA) is the most important diagnosis that needs to be settled at the earliest. Detailed below are the radiological and other techniques that help in diagnosing EHBA.
Ultrasonography (USG)
0USG, by an expert, of liver and biliary tract is quite helpful. USG is performed after 12 hours fasting with intravenous fluid infusion. If it shows no bile duct dilatation and a shrunken gall bladder despite fasting, it is highly suggestive of EHBA. It can also determine the features of polysplenia syndrome, which is strongly associated with EHBA. Visualization of dilated hepatic or common bile duct is also possible. Choi et al reported a unique triangular or tabular echogenic density (triangular cord sign) representing the fibrous cone of the bile duct remnant at the porta hepatis as a specific sonographic finding in EHBA. [4,5] Another study has suggested that a higher frequency (13 MHZ rather than 7 MHZ) transducer may identify abnormalities in gallbladder (GB) shape, wall thickness and morphology that are characteristic of EHBA. [6,7]
Magnetic Resonance Cholangio -Pancreaticography (MRCP)
0MRCP using T2 - weighted turbo spin-echo sequences holds promise as a non-invasive method for diagnosis of EHBA. However, there are limitations of MRCP for differentiating severe intra-hepatic cholestasis from EHBA, because the ability of MRCP to identify extra-hepatic bile ducts depends on the bile flow.[8] Jaw et al diagnosed EHBA, if there was non-visualization of GB, common bile duct (CBD) and common hepatic duct (CHD).[ 9] However, MRCP is quite informative in a case of choledochal cyst (CDC).
Endoscopic Retrograde Cholangio-Pancreaticography (ERCP)
ERCP has been proposed for visualization of biliary tree. Its use in children requires considerable technical expertise, generally unavailable in most centers and general anesthesia. With the advent of side-viewing pediatric miniature endoscopes, ERCP is now being performed in some centers. It is particularly valuable in CDC, CBD stones, and biliary strictures. ERCP can also be used to obtain duodenal fluid sample. [10,11]
Duodenal Fluid Specimen
Presence of bile in duodenal fluid, excludes EHBA. Sensitivity and specificity of this test is 100% and 85% respectively. [12, 13, 14, 15] Surprisingly, not many centers report use of this non-expensive easy to perform test.
Hepato-Biliary Scintiscan
0Technetium-99m labeled imino-di-acetic acid (HIDA) derivatives is being used extensively in diagnosis EHBA in cases of neonatal cholestasis. The di-isopropyl compound DISIDA is the preferred agent because of its greater hepatic uptake than HIDA. Initial dynamic images are obtained over one hour. In a normal subject, following isotope injection, there is visualization of the bile ducts after 10-20 minutes and the tracer reaches small bowel after 30-40 min. If no tracer activity is seen in the gut, delayed images are acquired at 4- and 24-hr. The key finding in EHBA is absence of tracer in the bowel by 24-hr. Neonatal hepatitis also leads to non-visualization in 25% of cases.[16] Scintigraphy has been widely used in differentiating EHBA from other causes of neonatal cholestasis. There is 25-30% incidence of false positive results with these tracer studies. Priming the patient with phenobarbitone and/or steroids for 5-7 days before the test is said to increase the yield. It has also been shown that infants with low birth weight (weight <2.5kg), preterm babies, infants on TPN and infants with severe neonatal hepatitis are prone to have no gut excretion of tracer.[17]
Liver Biopsy
0This is considered by some as the most accurate diagnostic test for differentiating biliary atresia from other causes of neonatal cholestasis. When obtained before laparotomy, it has a diagnostic accuracy of 90-95%.[6] Liver biopsy shows bile ductular proliferation, canalicular and cellular bile stasis, portal or peri-portal inflammation and fibrosis with presence of bile plugs in portal tract bile ducts.[18] Hepatocyte giant cell transformation is found in at least 25% of patients especially if the biopsy is obtained during the first 6 weeks of life. It is important to note that liver histology in patients with alfa-1-antitrypsin deficiency, and occasionally in those with Alagille syndrome, cystic fibrosis and TPN - related cholestasis, can mimic the features of EHBA, necessitating use of other diagnostic studies to differentiate between these disorders.[6] Liver biopsy specimens from patients of neonatal hepatitis show lobular disarray, a variable inflammatory infiltrate with marked giant cell transformation of individual hepatocytes, individual hepatocyte necrosis and apoptosis, increased extra-medullary hematopoiesis and cellular bile stasis. However, bile plugs in portal tract bile ducts are absent and bile ductular proliferation is usually minimal or absent.
Mini-laparotomy and Per-Operative Cholangiography (POC)
0Perhaps the most valuable diagnostic tool where the GB is surgically exposed and radio-contrast studies are performed to visualize the biliary tree and drainage of contrast into bowel. An atretic GB or non-excretion of dye into small bowel is indication for proceeding with formal dissection of porta hepatis.[19] The cholangiography can be performed intra-operaively (open or laparoscopically), endoscopically (ERCP) or by percutaneous route. It also flushes the biliary channels and can be therapeutic for inspissated bile syndrome. Caution must be entertained in assigning the diagnosis of biliary atresia and performing porto-enterostomy if the only findings are failure to visualize the common hepatic duct and intrahepatic duct on cholangiography because these findings may represent hypoplastic but patent proximal biliary structures in those with Alagille syndrome.[20] Currently the per-operative cholangiography, easily performed and interpreted, remains the gold standard of diagnosis. Contrary to earlier beliefs, it is safe and the yield is enough to warrant its routine use in diagnosis.
Laparoscopy
0In expert hands laparoscopy may help in avoiding laparotomy[21 ]for performing cholangiography, which can refute or confirm the diagnosis of EHBA. If an atretic GB or duct is seen or the dye instilled in the GB is not seen in the biliary ducts, exploration of porta is indicated. Laparoscopy and laparoscopic cholangiography has helped the authors to distinguish between EHBA and giant cell hepatitis with 96% accuracy with minimal morbidity.[22] Laparoscopic cholangiography because of its minimal morbidity should be considered as diagnostic modality, to arrive at a definite diagnosis. This in turn will save a lot of time that is wasted, in search for non-surgical causes of jaundice. Laparoscopy also provides liver biopsy specimen during the laparoscopic evaluation. However, Schier et al have found no advantage of laparoscopy over mini-laparotomy about anesthesia time, morbidity, diagnostic accuracy or complications.[23]
Advances in Biochemical Markers
There are certain biochemical markers in EHBA, which predict and prognosticate hepato-cellular damage.[24 ] These are:
Urinary - D - glucaric acid levels -Marker of viability of hepatocytes
Pro-collagen - III - peptide - Marker of fibrinogenesis and ongoing inflammation
Type IV collagen - Marker of ongoing inflammation
Plasma endothelin - Levels are higher in patients with EHBA, especially if there is severe biliary cirrhosis and this may also contribute to the development of portal hypertension.
Validity of Various Diagnostic Parameters in the Diagnosis of EHBA.
The large number of investigative modalities indicates unsatisfactory state of diagnostic approach, which may confuse the treating physician. Their significance in terms of sensitivity and specificity is depicted in Table 7.
Status of EHBA in India
In India, the exact incidence of EHBA is not known. However, extrapolating the world incidence of EHBA and India's current birth rate, approximately 1200 babies are born with EHBA each year. According to a consensus report published in year 2000, only 391 cases of EHBA were reported from six major surgical centers over 15 years.[25] Thus a large group of patients of EHBA do not have the privilege to even report to the health care facilities.
Most of the available literature indicates that the age at surgery is one of the most important factors determining surgical outcome. If the porto-enterostomy is performed within first 60-days of life by 'experienced' pediatric surgeons, it should yield bile drainage in at least 70-80% of patients. However, on the other hand if surgery is performed between 60 and 90-days approximately 40 to 50% show bile drainage; while in those between 90-120 days, up to 25% show bile drainage and only 10-20%, at best, show evidence of bile drainage if surgery is delayed beyond 120 days.[26][ 27][28]
In India, once a patient of suspected EHBA attends health care system, there is a considerable delay before the baby reaches a center for definitive surgery. The average age of the few patients of EHBA that are lucky to reach a qualified pediatric surgeon is 3.5 months. In Japan and UK, this delay averages about 2 months and occurs at two levels.
First level delay occurs before seeking medical attention. This delay is usually of 4-5 weeks. Though the ominous signs in jaundiced infant- high colored urine and acholic stools - are easily observed but are rarely taken seriously by parents. Various factors including, misapprehensions of parents, distance from a health centre, and ignorance of health care workers are responsible. A major public health campaign- to educate primary health care workers to follow all infants with jaundice and to refer such babies to higher centers for investigations- is necessary. Parental education is equally important. Japan and Taiwan have developed large-scale screening programs with stool color card to help reduce the average age for diagnosis of EHBA.Study group in USA has recommended a major public health campaign to educate primary care providers to follow all infants with jaundice at the 2-week well-baby examination clinic and to obtain a total and direct bilirubin if the jaundice persists when infant is aged more than 2 to 3 weeks or if the infant has pale stools, dark urine or hepatomegaly.[6]
Second-level delay results from overzealous time consuming investigations. It is a common practice to carry out laboratory investigations on a patient of conjugated hyperbilirubinemia to exclude medical causes thus losing out in the optimal, timeframed management of EHBA. In Japan, where patients present early, two-week period is allocated to exclude disorders that mimic EHBA, prior to subjecting the baby to POC.
Also in this era, when developed countries are carrying out hepatic transplant for EHBA either as an adjuvant to porto-enterostomy or as a primary procedure with good success rate, the feasibility of such a procedure in India is rather remote. Poor infrastructure, high cost of surgery and post-operative immuno-suppression and non-availability of information has been the greatest impediments. Even in developed countries like USA, expenditure on hepatic transplant is a matter of concern. Though children with EHBA represent 0.0003% of the total pediatric population in USA, about 0.1% of total health care allocation is spent on them. Although a few centers in India have started hepatic transplants, the procedure and results are yet to be streamlined.
Thus the optimal results in patients with EHBA depends a lot on the first contact physician and general practitioners who should refer them early for diagnosis and management to a well equipped centre where an experienced team in handling such cases is available. Centers which dabble in EHBA once in a while should resist from undertaking the demanding and meticulous surgery required to achieve good results.
Conclusions
0All newborns with jaundice should be followed at 2-3 week of age in a well-baby clinic. It is essential that infants who remain jaundiced beyond this period be evaluated expeditiously for cholestasis. Prompt surgical exploration and intraoperative cholangiogram must be performed if biliary atresia cannot be excluded using other diagnostic tests. A simple flow chart for work-up protocol has been displayed as Fig. 1.
It needs to be emphasized that a delay in treatment beyond 8 weeks can be the difference between a good and a poor result. It is more relevant for developing countries like India where pediatric liver transplant is not within reach of a 'common' child. 'Early surgical intervention results in a better outcome in EHBA
References
1. Virchow R. Die pathologischen pigmenten. Arch Pathol Anat Physiol Klin Med 1847; 1:379-486.
2. Maisels MJ. Jaundice. In Avery, Fetcher GB, eds. Neonatology , Pathophysiology and Management of the Newborn , 4th edn., Lippincott, Philadelphia, 1994, 630.
3. Cloherty JP. Neonatal hyperbilirubinemia. In Cloherty JP, Stark AR, eds. Manual of Neonatal Care , Lippincott- Raven, Philadelphia, 1997; 175-209.
4. Choi So, Park WH, Lee HJ. Ultrasonic triangular cord - The most definitive finding for non-invasive diagnosis of extrahepatic biliary atresia. Eur J Pediatr Surg 1998; 8: 12-16.
5. Choi so, Park WH, Lee HJ. Triangular cord: a sonographic finding applicable in the diagnosis of biliary atresia. J Pediatr Surg 1996; 31 : 363-366.
6. Sokol RJ, Mack C, Narkewicz MR. Pathogenesis and outcome of biliary atresia: recent concepts. J Pediatr Gastoenterol Nutr 2003; 37 : 4-22.
7. Farrant P, Meire HB, Mieli-Vergoni G. Improved diagnosis of extrahepatic biliary atresia by high frequency ultrasound of gall bladder. Br J Radiol 2001; 74 : 952-954.
8. Norton KI, Glass RB, Kogan D, Lee JS, Emre S, Shneider BL. MR cholangiography in the evaluation of neonatal cholestasis: initial results. Radiology 2002; 222 : 687-691.
9. Jaw TS, KuoYT, Liu GC, Chen SH, Wang CK. MR cholangiography in the evaluation of neonatal cholestasis. Radiology 1999; 212 : 249-256.
10. Allendroph M, Werlin SL, Geenan JE, Hogan WJ, Venu RP, Stewart ET. Endoscopic retrograde cholangio-pancreaticography in children. J Pediatr 1987; 110 : 206-211.
11. Wilkinson ML, Mieli-Vergani G, Ball C, Portmann B, Mowat AP. Endoscopic retrograde cholangio-pancreaticography in infantile cholestasis. Arch Dis Child 1991; 66 : 121-123.
12. Hung WT, Su CT. Diagnosis of atretic prolonged obstructive jaundice; technetium 99m hepatolite excretion study. J Pediatr Surg 1990; 25(7) : 797-800.
13. Ohi R, Mio M. Recent progress in biliary atresia. In Gupta DK ed. Textbook of Neonatal Surgery , Modern Publishers, New Delhi, 2000; 280-287.
14. Meisheri IV, Kasat LS, Kumar A, Bahety G, Sawant V, Kothari P. Duodenal aspiration and test for bile - a reliable method to rule out biliary atresia. Pediatr Surg Int 2002; 18 : 392-395.
15. Larrosa-Haro A, Caro-Lopez AM, Coello-Ramirez P, Zavala-Ocampo J, Vazquez-Camacho G. Duodenal tube test in the diagnosis of biliary atresia. J Pediatr Gastroenterol Nutr 2001;32 : 311-315.
16. Gilmour SM, Hershkop M, Reifen R, Gilday D, Roberts EA. Outcome of hepatobiliary scanning in neonatal hepatitis syndrome. J Nucl Med 1997; 38: 1279-1282.
17. Spiwac WS, Sarkar S, Winter D. Diagnostic utility of hepatobiliary scintigraphy with 99m Tc DISIDA in neonatal cholestasis. J Pediatr Surg 1987; 110 : 855-861.
18. Balistrery WF, Bove K, Ryckman FC. Biliary atresia and other disorders of extrahepatic biliary tree. In Suchy FJ, Sokol RJ, Balistrery WF, eds. Liver Diseases in Children . Philadelphia: Lippincott, Williams and Wilkins; 2001: 253-274.
19. Suchy FJ. Approach to infant with cholestasis. In Suchy FJ, Sokol RJ, Balistrery WF, eds. Liver Diseases in Children . Philadelphia: Lippincott, Williams and Wilkins; 2001: 187-194.
20. Marcowitz J, Daum F, Kahn E. Arteriohepatic dysplasia: I Pitfalls in diagnosis and management. Hepatology 1983; 3 : 74-76.
21. Shah AA, Sitapara AM, Shah AV. Laparoscopy in diagnosis of prolonged neonatal jaundice. Indian Pediatr 2002; 39 : 1138-1142.
22. Hay SA, Soleman HE, Sherif HM. Neonatal jaundice: The role of laparoscopy. J Pediatr Surg 2000; 35 : 1706-1709.
23. Schier F, Waldschmidt J. Experience with laparotomy for the evaluation of cholestasis in newborns. Surg Endosc 1990; 4 : 13-14.
24. Miyano T, Kobayashi H, Chen SC. Long-term results of biliary atresia. In Gupta DK ed. Textbook of Neonatal Surgery, Modern Publishers, New Delhi, 2000; 288-291.
25. Pediatric Gastroenterology Subspecialty Chapter of Indian Academy of Pediatrics. Consensuses report on Neonatal Cholestasis Syndrome. Indian Pediatr 2000; 37 : 845-851.
26. Ohi R. Biliary atresia. A surgical perspective. Clin Liver Dis 2000; 4 : 779-804.
27. Chardot C, Carton M, Spire-Bendelac N, Le Pommelet C, Golmard JL, Auvert B. Epidemiology of biliary atresia in France: a national study 1986-96. J Hepatol 1999; 31 : 1006-1013.
28. Davenport M, Kerkar N, Mieli-Vergani G, Mowat AP, Howard ER. Biliary atresia: The King's College Hospital experience (1974-1995). J Pediatr Surg 1997; 32 : 1387-1390(Gupta R, Nagdeve NG, Sari)
2 Department of Pediatric Surgery, Maulana Azad Medical College and Associated Hospitals, New Delhi, India, India
Abstract
Abstract. Neonatal hyperbilirubinemia is a common problem in newborn nurseries and manifest clinically as jaundice. Nearly 25-50% of all newborns and a much higher percentage of premature babies develop hyperbilirubinemia. This is mostly physiological, but a small percentage of these babies have pathological jaundice, requiring detailed investigations and management. It is also absolutely essential to consider a possibility of extra-hepatic biliary atresia early, during management of a case of neonatal direct hyperbilirubinemia as early surgical intervention results in a better outcome in EHBA. This article aims to descride the diagnostic approach to neonatal hyperbilirubinemia with special emphasis on conditions requiring surgical intervention also it throws light on present status of EHBA in Indian circumstances. [Indian J Pediatr 2005; 72 (5) : -423]
Keywords: Neonatal jaundice; Extra-hepatic biliary atresia; Neonatal hepatitis
Although both Hippocrates and Galen mention jaundice as a sign of disease, first mention of jaundice in newborn is found in Ein Regiment der Jungen Kinder, a 'pediatric text', written by Bartholomeus Metlinger in 1473. In 1847, Virchow observed the accumulation of microscopic yellow crystals in bruises, in wound fluids and in subcutaneous hematomas following phagocytosis of RBCs.[1] This observation provided the first experimental evidence for a link between bilirubin and heme. Since then, much effort has been spent exploring various aspects of this relationship, including mechanisms that control or influence the chemical reactions producing the pigment, its transport systems, movement across tissue barriers and cell walls, and the conjugation, excretion, elimination, absorption and clinical consequences associated with the presence of bilirubin in vital organs.
Physiology of Bilirubin Metabolism
In neonates, approximately 80% of the heme derived from the hemoglobin of disintegrated RBC's catabolizes into bilirubin. The other 20% comes from the breakdown of non-erythropoietic heme. The first step in the catabolic pathway of the heme molecule is also the rate-limiting step, i.e., the creation of biliverdin through the action of microsomal enzyme Heme-Oxygenase.
1. CO (excreted via lungs)
Heme 2. Fe (re-utilized)
3. Biliverdin
Biliverdin converts to bilirubin by biliverdin reductase. Bilirubin is lipophilic and hydrogen binding; it partitions readily into cellular membranes and is virtually insoluble at normal pH. For the body to rid itself of this insoluble product, transport and elimination mechanisms are necessary.
Bilirubin is transported to liver, reversibly bound to albumin. Many drugs also bind with albumin at the predominant binding site for bilirubin. They compete with bilirubin and are capable of displacing the bilirubin molecule from the albumin molecule thus raising the level of circulating bilirubin. At an average, serum albumin concentration of a term neonate is 3.5-5.0 mg/dl, which has enough binding sites to carry bilirubin up to a maximum serum bilirubin concentration of 25-30 mg/dl, with a small amount remaining unbound and in equilibrium with the bound bilirubin. The bilirubin-albumin complex is taken up at the surface of the liver parenchymal cells, where the bilirubin is transferred across the cell membrane without the albumin molecule. The liver converts bilirubin to an excretable, relatively polar (hence water soluble) conjugate. Conjugation consists of transfer of one or two glucuronic acid residues from uridine diphosphoglucuronic acid (UDPGA), resulting in formation of bilirubin mono- or diglucuronide. This enzyme is shown to be induced by phenobarbitone, suggesting a clinical mode for enhancing conjugation and elimination of bilirubin. This conjugated bilirubin is excreted through bile into the intestine.
Unlike adults, newborns have a-glucuronidase enzyme in their intestinal mucosa, which deconjugates the bilirubin to un-conjugated form. This un-conjugated bilirubin is again reabsorbed. Also unlike in adults, in whom bacteria in the intestinal lumen degrade conjugated bilirubin to a non-absorbable stercobilin, the newborn gut is relatively sterile. Thus the neonate is at risk of enhanced entero-hepatic circulation.
Evaluation of a Jaundiced Baby
Questions to be answered when a neonate with hyperbilirubinemia presents:
1. Is the jaundice physiological
2. What is the etiology
3. Which babies require further investigation
4. What are the investigations required
4. Is the jaundice a threat to the infant
Physiological Jaundice
In full term babies, physiological jaundice appears between 30-72 hours of age, reaches a peak by 4-5th day and disappears by 7-10th day of age. Total serum bilirubin does not exceed 12 mg%. Physiological jaundice in preterm babies appears earlier but not before 24 hours of age, reaches maximum by 5-6th day and disappears by 8-14th day. Serum bilirubim may go up to 15 mg %. Table 1 lists the probable mechanism of physiological jaundice.
Following circumstances prolong physiological jaundice:
ImmaturityCephalhematoma
Birth asphyxiaHypothyroidism
AcidosisConcealed haemorrhage
HypothermiaPolycythemia
HypoglycemiaBreast milk syndrome
Pathological Jaundice
Maisels[2][ 3]in 1981 proposed the following criteria for diagnosis of pathologic jaundice:
1. Jaundice within 1st 24 hours of life.
2. Total serum bilirubin increasing by more than 5 mg%.
3. Total serum bilirubin exceeding 12.9 mg% in a full term or 15mg% in a premature infant.
4. Direct serum bilirubin exceeding 1.5-2.0 mg%.
5. Clinical jaundice persisting for more than one week in full term or 2 weeks in a premature infant.
In the management, the first issue that needs to be resolved is whether one is dealing with unconjugated or conjugated hyperbilirubinemia. A baby with conjugated hyperbilirubinemia, will have:
1. History of jaundice persisting even after 2 weeks, along with high colored urine and clay colored stools.
2. Biochemically, direct hyperbilirubinemia >2mg% or >20% of the total bilirubin (if total serum bilirubin < 10 mg%).
The etiologies of both unconjugated and conjugated hyperbilirubinemia are tabulated in Table 2 and 3 below.
Proper history taking and detailed physical examination is essential for arriving at a working diagnosis. Some of the relevant points are summarized in Table 4 and 5. Further work up of the patient is directed towards establishing a specific diagnosis and to rule out any obstructive lesion.
Diagnosis
0Clinical differentiation among the common causes of cholestasis is difficult. There is plethora of hematological, biochemical, serological and microbiological investigations described to help reach a precise diagnosis. The laboratory work-up for the mother includes blood group and indirect Coomb's test to rule out ABO and Rh incompatibility and serology for TORCH infections. The laboratory work-up for the neonate with hyperbilirubinemia is tabulated in Table 6. From a surgeon's point of view, extra-hepatic biliary atresia (EHBA) is the most important diagnosis that needs to be settled at the earliest. Detailed below are the radiological and other techniques that help in diagnosing EHBA.
Ultrasonography (USG)
0USG, by an expert, of liver and biliary tract is quite helpful. USG is performed after 12 hours fasting with intravenous fluid infusion. If it shows no bile duct dilatation and a shrunken gall bladder despite fasting, it is highly suggestive of EHBA. It can also determine the features of polysplenia syndrome, which is strongly associated with EHBA. Visualization of dilated hepatic or common bile duct is also possible. Choi et al reported a unique triangular or tabular echogenic density (triangular cord sign) representing the fibrous cone of the bile duct remnant at the porta hepatis as a specific sonographic finding in EHBA. [4,5] Another study has suggested that a higher frequency (13 MHZ rather than 7 MHZ) transducer may identify abnormalities in gallbladder (GB) shape, wall thickness and morphology that are characteristic of EHBA. [6,7]
Magnetic Resonance Cholangio -Pancreaticography (MRCP)
0MRCP using T2 - weighted turbo spin-echo sequences holds promise as a non-invasive method for diagnosis of EHBA. However, there are limitations of MRCP for differentiating severe intra-hepatic cholestasis from EHBA, because the ability of MRCP to identify extra-hepatic bile ducts depends on the bile flow.[8] Jaw et al diagnosed EHBA, if there was non-visualization of GB, common bile duct (CBD) and common hepatic duct (CHD).[ 9] However, MRCP is quite informative in a case of choledochal cyst (CDC).
Endoscopic Retrograde Cholangio-Pancreaticography (ERCP)
ERCP has been proposed for visualization of biliary tree. Its use in children requires considerable technical expertise, generally unavailable in most centers and general anesthesia. With the advent of side-viewing pediatric miniature endoscopes, ERCP is now being performed in some centers. It is particularly valuable in CDC, CBD stones, and biliary strictures. ERCP can also be used to obtain duodenal fluid sample. [10,11]
Duodenal Fluid Specimen
Presence of bile in duodenal fluid, excludes EHBA. Sensitivity and specificity of this test is 100% and 85% respectively. [12, 13, 14, 15] Surprisingly, not many centers report use of this non-expensive easy to perform test.
Hepato-Biliary Scintiscan
0Technetium-99m labeled imino-di-acetic acid (HIDA) derivatives is being used extensively in diagnosis EHBA in cases of neonatal cholestasis. The di-isopropyl compound DISIDA is the preferred agent because of its greater hepatic uptake than HIDA. Initial dynamic images are obtained over one hour. In a normal subject, following isotope injection, there is visualization of the bile ducts after 10-20 minutes and the tracer reaches small bowel after 30-40 min. If no tracer activity is seen in the gut, delayed images are acquired at 4- and 24-hr. The key finding in EHBA is absence of tracer in the bowel by 24-hr. Neonatal hepatitis also leads to non-visualization in 25% of cases.[16] Scintigraphy has been widely used in differentiating EHBA from other causes of neonatal cholestasis. There is 25-30% incidence of false positive results with these tracer studies. Priming the patient with phenobarbitone and/or steroids for 5-7 days before the test is said to increase the yield. It has also been shown that infants with low birth weight (weight <2.5kg), preterm babies, infants on TPN and infants with severe neonatal hepatitis are prone to have no gut excretion of tracer.[17]
Liver Biopsy
0This is considered by some as the most accurate diagnostic test for differentiating biliary atresia from other causes of neonatal cholestasis. When obtained before laparotomy, it has a diagnostic accuracy of 90-95%.[6] Liver biopsy shows bile ductular proliferation, canalicular and cellular bile stasis, portal or peri-portal inflammation and fibrosis with presence of bile plugs in portal tract bile ducts.[18] Hepatocyte giant cell transformation is found in at least 25% of patients especially if the biopsy is obtained during the first 6 weeks of life. It is important to note that liver histology in patients with alfa-1-antitrypsin deficiency, and occasionally in those with Alagille syndrome, cystic fibrosis and TPN - related cholestasis, can mimic the features of EHBA, necessitating use of other diagnostic studies to differentiate between these disorders.[6] Liver biopsy specimens from patients of neonatal hepatitis show lobular disarray, a variable inflammatory infiltrate with marked giant cell transformation of individual hepatocytes, individual hepatocyte necrosis and apoptosis, increased extra-medullary hematopoiesis and cellular bile stasis. However, bile plugs in portal tract bile ducts are absent and bile ductular proliferation is usually minimal or absent.
Mini-laparotomy and Per-Operative Cholangiography (POC)
0Perhaps the most valuable diagnostic tool where the GB is surgically exposed and radio-contrast studies are performed to visualize the biliary tree and drainage of contrast into bowel. An atretic GB or non-excretion of dye into small bowel is indication for proceeding with formal dissection of porta hepatis.[19] The cholangiography can be performed intra-operaively (open or laparoscopically), endoscopically (ERCP) or by percutaneous route. It also flushes the biliary channels and can be therapeutic for inspissated bile syndrome. Caution must be entertained in assigning the diagnosis of biliary atresia and performing porto-enterostomy if the only findings are failure to visualize the common hepatic duct and intrahepatic duct on cholangiography because these findings may represent hypoplastic but patent proximal biliary structures in those with Alagille syndrome.[20] Currently the per-operative cholangiography, easily performed and interpreted, remains the gold standard of diagnosis. Contrary to earlier beliefs, it is safe and the yield is enough to warrant its routine use in diagnosis.
Laparoscopy
0In expert hands laparoscopy may help in avoiding laparotomy[21 ]for performing cholangiography, which can refute or confirm the diagnosis of EHBA. If an atretic GB or duct is seen or the dye instilled in the GB is not seen in the biliary ducts, exploration of porta is indicated. Laparoscopy and laparoscopic cholangiography has helped the authors to distinguish between EHBA and giant cell hepatitis with 96% accuracy with minimal morbidity.[22] Laparoscopic cholangiography because of its minimal morbidity should be considered as diagnostic modality, to arrive at a definite diagnosis. This in turn will save a lot of time that is wasted, in search for non-surgical causes of jaundice. Laparoscopy also provides liver biopsy specimen during the laparoscopic evaluation. However, Schier et al have found no advantage of laparoscopy over mini-laparotomy about anesthesia time, morbidity, diagnostic accuracy or complications.[23]
Advances in Biochemical Markers
There are certain biochemical markers in EHBA, which predict and prognosticate hepato-cellular damage.[24 ] These are:
Urinary - D - glucaric acid levels -Marker of viability of hepatocytes
Pro-collagen - III - peptide - Marker of fibrinogenesis and ongoing inflammation
Type IV collagen - Marker of ongoing inflammation
Plasma endothelin - Levels are higher in patients with EHBA, especially if there is severe biliary cirrhosis and this may also contribute to the development of portal hypertension.
Validity of Various Diagnostic Parameters in the Diagnosis of EHBA.
The large number of investigative modalities indicates unsatisfactory state of diagnostic approach, which may confuse the treating physician. Their significance in terms of sensitivity and specificity is depicted in Table 7.
Status of EHBA in India
In India, the exact incidence of EHBA is not known. However, extrapolating the world incidence of EHBA and India's current birth rate, approximately 1200 babies are born with EHBA each year. According to a consensus report published in year 2000, only 391 cases of EHBA were reported from six major surgical centers over 15 years.[25] Thus a large group of patients of EHBA do not have the privilege to even report to the health care facilities.
Most of the available literature indicates that the age at surgery is one of the most important factors determining surgical outcome. If the porto-enterostomy is performed within first 60-days of life by 'experienced' pediatric surgeons, it should yield bile drainage in at least 70-80% of patients. However, on the other hand if surgery is performed between 60 and 90-days approximately 40 to 50% show bile drainage; while in those between 90-120 days, up to 25% show bile drainage and only 10-20%, at best, show evidence of bile drainage if surgery is delayed beyond 120 days.[26][ 27][28]
In India, once a patient of suspected EHBA attends health care system, there is a considerable delay before the baby reaches a center for definitive surgery. The average age of the few patients of EHBA that are lucky to reach a qualified pediatric surgeon is 3.5 months. In Japan and UK, this delay averages about 2 months and occurs at two levels.
First level delay occurs before seeking medical attention. This delay is usually of 4-5 weeks. Though the ominous signs in jaundiced infant- high colored urine and acholic stools - are easily observed but are rarely taken seriously by parents. Various factors including, misapprehensions of parents, distance from a health centre, and ignorance of health care workers are responsible. A major public health campaign- to educate primary health care workers to follow all infants with jaundice and to refer such babies to higher centers for investigations- is necessary. Parental education is equally important. Japan and Taiwan have developed large-scale screening programs with stool color card to help reduce the average age for diagnosis of EHBA.Study group in USA has recommended a major public health campaign to educate primary care providers to follow all infants with jaundice at the 2-week well-baby examination clinic and to obtain a total and direct bilirubin if the jaundice persists when infant is aged more than 2 to 3 weeks or if the infant has pale stools, dark urine or hepatomegaly.[6]
Second-level delay results from overzealous time consuming investigations. It is a common practice to carry out laboratory investigations on a patient of conjugated hyperbilirubinemia to exclude medical causes thus losing out in the optimal, timeframed management of EHBA. In Japan, where patients present early, two-week period is allocated to exclude disorders that mimic EHBA, prior to subjecting the baby to POC.
Also in this era, when developed countries are carrying out hepatic transplant for EHBA either as an adjuvant to porto-enterostomy or as a primary procedure with good success rate, the feasibility of such a procedure in India is rather remote. Poor infrastructure, high cost of surgery and post-operative immuno-suppression and non-availability of information has been the greatest impediments. Even in developed countries like USA, expenditure on hepatic transplant is a matter of concern. Though children with EHBA represent 0.0003% of the total pediatric population in USA, about 0.1% of total health care allocation is spent on them. Although a few centers in India have started hepatic transplants, the procedure and results are yet to be streamlined.
Thus the optimal results in patients with EHBA depends a lot on the first contact physician and general practitioners who should refer them early for diagnosis and management to a well equipped centre where an experienced team in handling such cases is available. Centers which dabble in EHBA once in a while should resist from undertaking the demanding and meticulous surgery required to achieve good results.
Conclusions
0All newborns with jaundice should be followed at 2-3 week of age in a well-baby clinic. It is essential that infants who remain jaundiced beyond this period be evaluated expeditiously for cholestasis. Prompt surgical exploration and intraoperative cholangiogram must be performed if biliary atresia cannot be excluded using other diagnostic tests. A simple flow chart for work-up protocol has been displayed as Fig. 1.
It needs to be emphasized that a delay in treatment beyond 8 weeks can be the difference between a good and a poor result. It is more relevant for developing countries like India where pediatric liver transplant is not within reach of a 'common' child. 'Early surgical intervention results in a better outcome in EHBA
References
1. Virchow R. Die pathologischen pigmenten. Arch Pathol Anat Physiol Klin Med 1847; 1:379-486.
2. Maisels MJ. Jaundice. In Avery, Fetcher GB, eds. Neonatology , Pathophysiology and Management of the Newborn , 4th edn., Lippincott, Philadelphia, 1994, 630.
3. Cloherty JP. Neonatal hyperbilirubinemia. In Cloherty JP, Stark AR, eds. Manual of Neonatal Care , Lippincott- Raven, Philadelphia, 1997; 175-209.
4. Choi So, Park WH, Lee HJ. Ultrasonic triangular cord - The most definitive finding for non-invasive diagnosis of extrahepatic biliary atresia. Eur J Pediatr Surg 1998; 8: 12-16.
5. Choi so, Park WH, Lee HJ. Triangular cord: a sonographic finding applicable in the diagnosis of biliary atresia. J Pediatr Surg 1996; 31 : 363-366.
6. Sokol RJ, Mack C, Narkewicz MR. Pathogenesis and outcome of biliary atresia: recent concepts. J Pediatr Gastoenterol Nutr 2003; 37 : 4-22.
7. Farrant P, Meire HB, Mieli-Vergoni G. Improved diagnosis of extrahepatic biliary atresia by high frequency ultrasound of gall bladder. Br J Radiol 2001; 74 : 952-954.
8. Norton KI, Glass RB, Kogan D, Lee JS, Emre S, Shneider BL. MR cholangiography in the evaluation of neonatal cholestasis: initial results. Radiology 2002; 222 : 687-691.
9. Jaw TS, KuoYT, Liu GC, Chen SH, Wang CK. MR cholangiography in the evaluation of neonatal cholestasis. Radiology 1999; 212 : 249-256.
10. Allendroph M, Werlin SL, Geenan JE, Hogan WJ, Venu RP, Stewart ET. Endoscopic retrograde cholangio-pancreaticography in children. J Pediatr 1987; 110 : 206-211.
11. Wilkinson ML, Mieli-Vergani G, Ball C, Portmann B, Mowat AP. Endoscopic retrograde cholangio-pancreaticography in infantile cholestasis. Arch Dis Child 1991; 66 : 121-123.
12. Hung WT, Su CT. Diagnosis of atretic prolonged obstructive jaundice; technetium 99m hepatolite excretion study. J Pediatr Surg 1990; 25(7) : 797-800.
13. Ohi R, Mio M. Recent progress in biliary atresia. In Gupta DK ed. Textbook of Neonatal Surgery , Modern Publishers, New Delhi, 2000; 280-287.
14. Meisheri IV, Kasat LS, Kumar A, Bahety G, Sawant V, Kothari P. Duodenal aspiration and test for bile - a reliable method to rule out biliary atresia. Pediatr Surg Int 2002; 18 : 392-395.
15. Larrosa-Haro A, Caro-Lopez AM, Coello-Ramirez P, Zavala-Ocampo J, Vazquez-Camacho G. Duodenal tube test in the diagnosis of biliary atresia. J Pediatr Gastroenterol Nutr 2001;32 : 311-315.
16. Gilmour SM, Hershkop M, Reifen R, Gilday D, Roberts EA. Outcome of hepatobiliary scanning in neonatal hepatitis syndrome. J Nucl Med 1997; 38: 1279-1282.
17. Spiwac WS, Sarkar S, Winter D. Diagnostic utility of hepatobiliary scintigraphy with 99m Tc DISIDA in neonatal cholestasis. J Pediatr Surg 1987; 110 : 855-861.
18. Balistrery WF, Bove K, Ryckman FC. Biliary atresia and other disorders of extrahepatic biliary tree. In Suchy FJ, Sokol RJ, Balistrery WF, eds. Liver Diseases in Children . Philadelphia: Lippincott, Williams and Wilkins; 2001: 253-274.
19. Suchy FJ. Approach to infant with cholestasis. In Suchy FJ, Sokol RJ, Balistrery WF, eds. Liver Diseases in Children . Philadelphia: Lippincott, Williams and Wilkins; 2001: 187-194.
20. Marcowitz J, Daum F, Kahn E. Arteriohepatic dysplasia: I Pitfalls in diagnosis and management. Hepatology 1983; 3 : 74-76.
21. Shah AA, Sitapara AM, Shah AV. Laparoscopy in diagnosis of prolonged neonatal jaundice. Indian Pediatr 2002; 39 : 1138-1142.
22. Hay SA, Soleman HE, Sherif HM. Neonatal jaundice: The role of laparoscopy. J Pediatr Surg 2000; 35 : 1706-1709.
23. Schier F, Waldschmidt J. Experience with laparotomy for the evaluation of cholestasis in newborns. Surg Endosc 1990; 4 : 13-14.
24. Miyano T, Kobayashi H, Chen SC. Long-term results of biliary atresia. In Gupta DK ed. Textbook of Neonatal Surgery, Modern Publishers, New Delhi, 2000; 288-291.
25. Pediatric Gastroenterology Subspecialty Chapter of Indian Academy of Pediatrics. Consensuses report on Neonatal Cholestasis Syndrome. Indian Pediatr 2000; 37 : 845-851.
26. Ohi R. Biliary atresia. A surgical perspective. Clin Liver Dis 2000; 4 : 779-804.
27. Chardot C, Carton M, Spire-Bendelac N, Le Pommelet C, Golmard JL, Auvert B. Epidemiology of biliary atresia in France: a national study 1986-96. J Hepatol 1999; 31 : 1006-1013.
28. Davenport M, Kerkar N, Mieli-Vergani G, Mowat AP, Howard ER. Biliary atresia: The King's College Hospital experience (1974-1995). J Pediatr Surg 1997; 32 : 1387-1390(Gupta R, Nagdeve NG, Sari)