Jaundice In Early Infancy - Pediatric Oncall

TABLE 1

Specific clinical features

0Disorders	Abnormal physical signs
Hepatic or biliary hemangioma	Cutaneous hemangiomata
Extrahepatic biliary atresia	Situs inversus
Biliary hypoplasia	Systolic murmur, abnormal facies, embryotoxon
Generalized viral infections	Skin lesions, purpura, choroido-retinitis, myocarditis, etc.
Galactosemia, hypoparathyroidism	Cataracts
Trisomy 21, 18 or 13	Multiple congenital anomalies
Choledochal cyst	Cystic mass below the liver
Spontaneous perforation of the bile ducts	Ascites and bite- stained hernia

Q. How do you approach a case of neonatal cholestasis?
A. Newborn babies having jaundice beyond 14 days of age with dark urine with/without acholic stools should be referred immediately to an appropriate center for further investigations and treated without any loss of time.

Unfortunately, it is not possible to differentiate between various disorders causing hyperbilirubinemia by simple liver biochemistry. It has been shown that results of such cases are much better in centers handling a large volume of these cases and where most facilities to carry out the required tests are available, thereby enabling standardization and evolution of optimum investigative and management protocols and surgical techniques.

Our recent experience of these cases is given in Table 2 and our current investigation protocol is outlined in Table 3 and Table 4.

TABLE 2:

Our recent experience (July 1997 - December 1998)

Total no of direct jaundice cases	38
Biliary atresia group (confirmed by operative cholangiogram)	32
Neonatal hepatitis group	6
Portoenterostomies done	29**
Successful portoenterostomy (normal serum bilirubin)	8/29
Partially successful portoenterostomy(serum bilirubin <1/2 of pre op levels)	11/29
Failed portoenterostomy (no decrease in serum bilirubin)	10/29

** Of biliary atresia group: 1 patient refused surgery, 2 were advanced cases and died of liver cell failure prior to surgery.

TABLE 3

Conjugated hyperbilirubinemia investigation protocol

Biochemical/ Routine tests	Special Etiological Tests	Morphological Tests	Other tests	Histopathology
LFT including	Blood culture	USG abdomen	X-ray Wrists:	Closed liver biopsy-
SGOT/SGPT/GTP/Alk.PO4	Urine culture	Hepatobiliary	(Rickets)	Staining with HE and PAS.
RFT	Stool culture	Scan	X-ray spine:	Wedge biopsy/
Hemogram	CRP	Cholangiogram	(Alagille)	Open liver
S.electrolytes	VDRL	(Peroperative/laparoscopic)	X-ray chest:	biopsies-
S.Ammonia	(Both of child and mother)	-	( Cardiom-egaly )	(taken during surgery)
VBG	HbsAg, HIV	-	Fundoscopy:	Biopsy of portahepatis
-	Test for Galactosemia	-	(Chorio-retinitis)	-
-	Antitrypsin levels	-	-	-

Table 4:

Jaundice, dark urine with/without acholic stools at 14 days of life.

Increased Urine bilirubin + serum bilirubin (conjugated)

LFT, administer vitamins and Vitamin K 5mg IM

Refer to a specialized centre

Clinical Examination/Biochemical/Routine tests/Special Etiological Tests/ USG/Radiological tests/Funduscopy and HBS

HBS -Hepatobiliary scan, LFT - Liver function tests, NNH - Neonatal hepatitis, BA - Biliary atresia

Q. How are infants with neonatal jaundice managed?

A. The management is divided into 2 categories:

General Medical Management

Irrespective of the etiology, on presentation these children are given phenobarbitone (a hepatic enzyme inducer), cholestyramine, Tinospora cordifolia (an Ayurvedic Preparation used for cholestasis) and broad-spectrum antibiotics.

Specific Management

Non biliary atresia - Neonatal hepatitis group (Non BA-NH group):The first group, of patients commonly presenting in the first month of life, is that in which treatable infections (septicemia, urinary tract infections, malaria, toxoplasmosis and tuberculosis) or treatable metabolic disorders (galactosemia) are diagnosed. These are treated aggressively with appropriate therapy, which usually halts the progress of the liver disease.

In this group, we also include treatable surgical causes such as choledochal cyst. Choledochal cysts require complete surgical excision and an entero- biliary anastomosis.

Suspected biliary atresia group (BA Group):The second and largest group, is of patients in whom none of the above conditions are diagnosed and the hepatobiliary scan does not show excretion into the gut upto 24 hrs. This group of patients irrespective of the results of the viral studies (such as the TORCH tests) should undergo an early exploratory laparotomy with a pre-operative cholangiogram. If the cholangiogram confirms atresia of the biliary tree then a portoenterostomy (Kasai operation) is performed.

Suspected neonatal hepatitis group (NH Group): The third group, is of patients in whom none of the non BA-NH causes have been diagnosed but the hepatobiliary scan shows definite excretion of tracer into the gut within 24 hrs. Patients in this group may test positive for viral studies- especially cytomegalovirus (CMV). Though it is correct to label these cases as neonatal hepatitis at this stage, they have to be carefully followed up on a weekly basis, because the same etiopathological process may lead to atresia later. It is our policy to follow up these cases with hepatobiliary scans every fortnightly till the bilirubin levels show a sustained downward trend. If at any point of time the scan becomes obstructive (no excretion of tracer into the gut upto 24 hrs.) then an exploratory laparotomy with an operative cholangiogram is performed. If viral hepatitis is diagnosed then use of anti-viral agents may be considered. This is the only group of patients in whom we perform a closed liver biopsy to confirm the diagnosis and study the extent of the liver disease. Although in some leading international centers where experts in pediatric hepatic pathology are available liver biopsies are done in every case.

Q. What is biliary atresia?
A. It is a progressive inflammatory process of unknown etiology (probably viral) which leads to fibrosis and obliteration of the intra and extra hepatic biliary tree. The etiopathogenesis of neonatal hepatitis and biliary atresia is probably the same, both being different points of time in the same clinical spectrum. Innovations and refinements in surgical treatment have improved the prognosis for this disease. Even for patients who do not become jaundice free after Kasai, liver transplantation (which is now becoming available in major Indian cities) brings new hope for cure. The current recommended treatment for all cases of biliary atresia is sequential treatment i.e. Portoenterostomy as the primary treatment followed by a delayed liver transplantation (live-related or cadaveric) in those patients who do not improve with portoenterostomy.

Q. Does viral infection lead to biliary atresia?
A. Many molecular biological studies have supported an inflammatory or infectious etiology for biliary atresia - NH syndrome. Clinically too, the dynamic nature of the disease process, the demonstration of inflammatory and giant cells in the tissues (liver and bile duct), the fibrotic response, presence of prominent lymph nodes at the porta hepatis and the demonstration of viral inclusion bodies indicate the inflammatory nature of this entity, rather than a purely embryological malformation as suggested by some. Of the various microorganisms, a viral etiology has been strongly suspected.

Association of reovirus type 3, rotavirus type CRNA and rotavirus type A have been suggested by serological studies but not confirmed. In our initial experience in this area there seems to be a strong evidence of an association of an association of antenatal or perinatal CMV infection and BA. In our experience the results of surgery also seem to be influence by the CMV positivity status.

Q. What is Kasai operation -Portoenterostomy (PE)?
A. In 1959, Morio Kasai from Sendai, Japan, first proposed that complete excision of the fibrous extrahepatic biliary tree and anastomosis of an intestinal loop to the raw transected area of the porta hepatis lead to a dramatic reduction in bilirubin levels due to bile drainage (Fig.1)

The bile flow after portoenterostomy was because of the microscopically patent biliary channels at the porta, although macroscopically the entire extrahepatic biliary tree was atretic. The chances of obtaining good bile flow after surgery, depend on the size and number of patent biliary channels.

Pre-operative preparation:
Bowel Preparation should begin 48 hours pre-operative orally.

Neomycin 12.5 mg/kg	four times a day
Metronidazole 7.5 mg/kg	three times a day

Postoperative care after portoenterostomy

In the immediate postoperative period attention is given to prevention of accumulation of ascites and maintenance of tissue oxygenation. For first few days, transfusions of fresh frozen plasma are given and if albumin levels are low, album transfusions are indicated. The serum bilirubin, serum electrolytes and hematocrit are monitored every day for 4 days.

It is usually possible to commence oral feeds from the 4^th or 5^th day and the child is discharged on the 8^th or 9^th day. Prior to discharge, massive doses of Vitamin A and D are given and supplemental Vitamin E is given and the child is sent home on long term antibiotics (to be continued for at least 4 months), phenobarbitone, other vitamin supplements, cholestyramine and Tinospora. Patient is then asked to follow up after one and a half-month. LFT is done every once a month for at least 6 months.

Q. What is the outcome after the Kasai Porterostomy (PE) Operation?
A. After the Kasai operation, even though go bile flow may be established, the serum bilirubin levels may take upto 3-4 months to come to normal levels. The liver enzymes (especially alkaline phosphatase) will take much longer to turn to normal levels. We consider a portoenterostomy to be successful if the serum bilirubin is maintained at normal levels at 6 months after surgery. If, at 6 months postop, the bilirubin remains below half of its preoperative level, the PE is considered to be partially successful. If there is no significant drop in bilirubin by 6 months, then the PE is considered to have failed.

Q. What are the complications after portoenterostomy?
A. Every patient of PE, irrespective of the success of the procedure is vulnerable for ascending infection from the anastomosed Roux-en-y intestinal loop and is likely to have one or more episodes of ascending cholangitis (AC). AC is diagnosed by the onset of fever and worsening of the liver biochemistry. Many surgical modifications have been suggested to prevent AC, but none of them are foolproof. We have tried keeping longer Roux-en-y loops, but that has not changed the incidence of AC in our patients. Whenever AC is diagnosed, the child is admitted and liver biochemical tests and a full septic workup is performed (including blood culture). Appropriate parental antibiotic therapy is instituted. If the patient shows no response in 48 hours, then steroids are given.

Ascites and portal hypertension are other problems, which are commonly encountered after portoenterostomy and need proper management.

Q. What is the long-term outcome after the Kasai operation?
A. Ten-year survival can be expected in up to 80% of patients who are jaundice-free after surgery. Those who do not clear their jaundice (unsuccessful operation) will require liver transplant for their early or late liver failure.

Of the 21 of Kasai's earlier successful patients, who are now over 20 years of age, 16 are well and asymptomatic while the others have features of chronic liver disease. The British Paediatric Association commissioned a study of all cases of biliary atresia born in UK and Ireland in 1994-1995. The study showed that the age at diagnosis in UK and Ireland is steadily improving. The current mean age at diagnosis was 53 days. The results of this study also confirmed the early finding of Mcclement et al that PE result are related to the experience of surgeon and center where surgery was performed and that PEs should be confined to centers performing at least 6 such operations per year.

Q. Is there a cut-off age for 'Successful' Kasai operation?
A. Recently several authors have challenged the earlier view that age at operation determines the outcome of PE. It is known that the exact time of onset and rate of progression of disease differs in each patient. Thus the most crucial factor responsible for the success of PE viz. the patency of the biliary remnants at the porta hepatis, is not age specific but patient specific. The 'cut-off' point for a success of operation of 60 days is arbitrary and coming from the statistical research that generated it.

Our data also reflects this fact. Interestingly, all our patients who have become jaundice - free after PE were operated after the so-called cut-off age of 60days. Also, like others, we have had successful results of Kasai at ages upto 120 days.

Of course, generally speaking, the best chance of a successful Kasai must be the first chance and the earlier the operation is performed the better it is.

Q. What is the nutritional support given to these patients?
A. In breastfed babies, breastfeeding is continued and supplemental medium chain triglycerides (MCT) based feeds are given. Older children are given a diet rich in calories (200Kcal/kg/day), rich in MCT, glucose polymers, proteins (1-2g/kg/day), vitamins, minerals and trace elements.

Vitamin A is supplemented in the dose of 50,000IU IM (at diagnosis or day 5 post operatively) and then 10,000 IU monthly till cholestasis diminishes.

Vitamin D is given in the dose of 30,000 IU IM (at diagnosis or day 5 post operatively) and then monthly till cholestasis diminishes. If the child has radiological evidence of rickets, give a dose of 60,000IU.

Oral Vitamin E and Vitamin K supplements are also required.


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