Biliary Atresia: From Pathology to Treatment


Differential diagnosis

Investigation

Results

Alpha-1 antitrypsin deficiency

Level and protein phenotype

Low alpha-1 antitrypsin level

PiZZ phenotype

Hypothyroidism

TFT’s

Raised TSH

Low T4

Hypopituitarism

TFT, cortisol, glucose

Low TSH, cortisol hypoglycaemia

Galactosaemia

Urine-reducing substances

Plasma Gal-1-PUT

Positive-reducing substances

Absent or reduced Gal-1-PUT detected

Tyrosinaemia

Urine succinylacetone

DNA

High succinylacetone

Mutations in FAH

Alagille syndrome

ECHO

Thoracic vertebrae X-ray

Slit lamp examination

DNA

Peripheral pulmonary stenosis, butterfly shaped thoracic vertebrae, posterior embryotoxon

JAG1 or NOTCH2 mutations

Congenital infection

Serology urine and blood, PCR-CMV, toxoplasma

Positive testing

Progressive familial intrahepatic cholestasis 3

Gamma-glutamyl transpeptidase (GGT)

Liver biopsy

DNA

High GGT cholestasis

Specific findings on histology

Mutation ABCB4

Storage disease, e.g. Niemann-Pick C

Liver biopsy

Bone marrow biopsy

Filipin staining

DNA

Storage cells on bone marrow and liver biopsy (can be difficult to see in young children), positive filipin staining of fibroblasts

Mutation in NPC1 & 2

Citrin deficiency

Plasma and urine amino acids

DNA

Increased plasma and urine citrulline and arginine

Mutation in SLC25A13

Peroxisomal disorders

Plasma very long-chain fatty acids

DNA

High levels of very long-chain fatty acids

Mutation in PEX genes

Intestinal failure-associated liver disease

Liver biopsy

Specific findings on liver biopsy





6.6 Investigations



6.6.1 Blood Investigations


Typical biochemical variables are shown in Table 6.2.


Table 6.2
The typical biochemistry of a child with biliary atresia







































 
Typical concentration at presentation

Normal range

Conjugated bilirubin (μmol/L)

>100

<20

Alkaline phosphatase (IU/L)

>600

<500

γ-Glutamyl transferase (IU/L)

>100

20–40

Aspartate aminotransferase (U/L)

80–200

15–40

Alanine aminotransferase (U/L)

80–200

10–55

Albumin (g/L)

Normal at presentation

37–56

Prothrombin time (seconds)

Normal at presentation

9–13

Pitfalls:



  • The conjugated bilirubin is typically >100 μmol/L; however, lower levels can be seen and should not be falsely reassuring.


  • With the commencement of ursodeoxycholic acid and adequate nutrition, the bilirubin may fall, but this is not sustained and should not be falsely reassuring [34].

Synthetic function (albumin and prothrombin time) are usually normal at presentation unless there is vitamin K deficiency or a late presentation with cirrhosis. Cholesterol may be raised, but triglycerides are usually normal.


6.6.2 Bile Investigations


The Japanese and Chinese have reported continuous attempts to aspirate bile from the third part of the duodenum using a nasoduodenal tube. If there are no bile secretions over a 24 h period, then this is strongly suggestive of biliary atresia [35].


6.6.3 Metabolomics


Research looking into the metabolomics profile of infants with biliary atresia has identified a different profile as compared to other children with neonatal cholestasis. This is not currently in clinical practice but may be a useful investigation in the future [36].


6.6.4 Imaging


Ultrasounds: most infants will have an absent or atretic gall bladder on a fasting ultrasound, although in a small number of infants the gall bladder may be identified (up to 20%). To allow the gall bladder, if present, to be seen, a 4 h fast prior to the scan is recommended. Some centres also use the triangular cord sign (a thick tubular or triangular echogenic density (fibrous ductal remnant) along the anterior aspect of the portal vein at its bifurcation into the right and left branches) and have found this to be a sensitive marker (49–73%) for identifying biliary atresia; however, it is operator dependent and not always reproducible [37].

Radionucleotide excretion scan: (TBIDA or HIDA) may be useful if there is uncertainty of stool colour. Historically it was a standard test for bile excretion when biliary atresia was suspected; however, if the stool is visually pale, then it adds little to the diagnostic investigations. The injected isotope is taken up by the liver, but the usual excretion pattern into the intestine is not seen in biliary atresia by 24 h. However, in infants with severe cholestasis from any cause, there may be no excretion within 24 h either. This scan is a sensitive test for biliary atresia, but it is not specific. To aid uptake of the radionucleotide, infants should be given phenobarbitone for 3 days prior to the scan; in a recent study, priming with phenobarbitone or ursodeoxycholic acid, however, did not change the excretion pattern of the test compared with no drug augmentation [38].

Endoscopic retrograde cholangiopancreatography (ERCP): can be used to visualise the biliary tract if diagnosis is uncertain. It is safe and feasible in young infants and may avoid an operative cholangiogram [39].

Magnetic resonance cholangiopancreatography (MRCP): currently this technology may not be detailed enough to identify the luminal patency of infant biliary tract that may only be 1 mm in diameter. It may evolve with technical advances to become a useful test [40].

Operative cholangiogram: this is the gold standard and definitive test. Dye is injected into the biliary tree under direct vision at laparotomy or laparoscopically, and the patency of the bile ducts is assessed.


6.6.5 Liver Histology


A percutaneous liver biopsy provides information regarding extrahepatic biliary obstruction. Typically the findings are those of:



  • Portal tract fibrosis


  • Oedema


  • Ductular proliferation


  • Cholestasis

The findings occur in any large duct obstruction and are not specific for biliary atresia; however, it may be useful for cases in which there is diagnostic uncertainty to exclude other causes of jaundice. The histological features also develop over time and may not be typical if sampled early [41]. Although histological confirmation prior to operative cholangiogram may be desirable, an infant with jaundice and pale stools with no other diagnosis will always require this definitive test. A liver biopsy is typically taken at the time of Kasai to provide information on the extent of fibrosis.


6.7 Management



6.7.1 Medication


The infant should receive fat-soluble vitamin supplementation and ursodeoxycholic acid before surgery and until clearance of jaundice following the operation. Fat-soluble vitamins are absorbed along with the long-chain fats which require bile salt micelles. In biliary atresia vitamin deficiency is possible as bile is not present in the intestine. Table 6.3 provides recommended initial drug doses for vitamins and ursodeoxycholic acid.


Table 6.3
Recommended initial drug doses for fat-soluble vitamins and ursodeoxycholic acid





















Vitamin A

5000 units/day

Vitamin D: ergocalciferol

3000 units/day

Vitamin E: alpha tocopheryl acetate or

50 mg/day

vitamin K

1 mg/day

Ursodeoxycholic acid

10 mg/kg twice daily


6.7.2 Nutrition


Poor absorption of long-chain triglycerides (LCT) occurs due to reduced or absent bile salt micelles. A change of feed from primarily LCT to one containing 60–65% medium-chain triglycerides (MCT) enables absorption of fats without the need for bile salt micelles [42]. This means that the infant will absorb more calories and weight gain will be more effective. For those infants who are breast-fed, an MCT supplement can be provided alongside the breast-feeding which should be continued if possible. If an infant is not feeding well, then early instigation of nocturnal nasogastric tube feeding will enable good nutrition to continue.


6.7.3 Surgery


Without a Kasai portoenterostomy and liver transplant, if necessary, biliary atresia is fatal within the first 2 years of life.

The Kasai portoenterostomy operative procedure was first described by Morio Kasai in the 1950s and revolutionised the management of biliary atresia.

The procedure consists of complete excision of the extrahepatic biliary tree with transection of the porta hepatitis at the liver capsule to expose the microscopic ductules. A jejunal loop (roux loop) is anastomosed to the cut surface to facilitate the drainage of bile from these ductules into the intestine.

A successful Kasai is defined as normalisation of bilirubin levels within 6 months of the procedure. The success of the procedure is dependent on the age at operation, extent of liver damage (fibrosis at time of Kasai, ongoing inflammation and episodes of cholangitis) and experience of the centre [43]. Those infants who have concomitant CMV infection have a poorer outcome with reduced clearance of jaundice, native liver survival and increased mortality [44].

Fibrosis and cirrhosis are more likely to develop with long-standing obstruction; hence, the hypothesis that the earlier the Kasai, the better the outcome.

This is indeed true for those with biliary atresia splenic malformation (BASM) or rarer forms of biliary atresia. However, in isolated biliary atresia cases, even having a Kasai at 100 days can lead to a 45% 5-year survival with the native liver [45].

A UK study of 93 cases of biliary atresia in 15 centres showed a significant difference in success rate in those centres that operated on five or more cases each year (61% vs 14% 5-year survival with native liver) and led to centralisation of the service [1]. Re-auditing after 4 years showed a 51% 4-year survival with the native liver and 89% survival overall [46]. Ten years following centralisation, the median age at Kasai was 54 days with 55% undergoing a successful Kasai. Survival with the native liver at 5 years was 46% and 40% at 10 years. The overall patient survival however continued to be 89% at 10 years [47].

A systematic review of 153 infants showed that those who received post-operative steroids had an improvement in clearance of jaundice. This, however, has not been seen in other smaller studies [48].


6.8 Management Following an Unsuccessful Kasai


In infants in whom the Kasai is unsuccessful (jaundice has not cleared within 6 months of surgery), liver transplant is usually indicated within 6 months to 2 years of age. Living-related transplant is a good option for these infants.

Indications for listing for transplant include:



  • Poor synthetic function – the albumin concentration usually starts to fall initially, whilst the prothrombin time is maintained.


  • Poor nutrition despite adequate calorie intake (nasogastric tube feeding) leading to failure to thrive.


  • Recurrent cholangitis leading to biliary cirrhosis.

Some infants who initially clear their jaundice following surgery become jaundiced again. Increasing inflammation and fibrosis, possibly due to subclinical cholangitis, may be the cause. This scenario can be extremely disappointing for families.

Optimal nutrition is extremely important in infants who continue to be cholestatic, and most will require nasogastric feeding either as bolus feeds during the day or as a continuous overnight feed. If despite these measures poor weight gain occurs, then whilst awaiting transplant, parenteral nutrition may be required.

It is important to monitor the fat-soluble vitamin serum levels to ensure they are within the normal range, and adjustments to doses should be made if necessary.

There is a small group of patients who remain mildly jaundiced but continue to have good synthetic function. Close monitoring is essential to enable optimal timing for transplantation as necessary.


6.9 Management Following Successful Kasai


Thirty per cent of children who have a successful Kasai will have near or complete normalisation of their liver biochemistry. Most, however, will have abnormal transaminases, and despite timely surgery and a successful Kasai portoenterostomy, there is progression of fibrosis with a risk of hepatic decompensation, portal hypertension and malignancy throughout life [49].

It has not proved entirely possible to predict at an early stage which patients will have long-term survival with the native liver and which will require liver transplant. Many different scoring systems such as the APRI (which looks at AST to platelet ratio) have been developed based on the bilirubin levels, AST, age at Kasai and episodes of cholangitis [50, 51].


6.9.1 Fibrosis


Despite a successful Kasai, fibrosis continues to develop in many children with biliary atresia resulting in the development of portal hypertension and potential need for liver transplant later in childhood or adulthood. The reason for the progressive fibrosis is not known but thought to be related to ongoing inflammation. The protein prohibitin is markedly reduced in children with biliary atresia. Prohibitin negatively interacts with histone deacetylase 4 in the presence of bile acids resulting in epigenetic changes leading to fibrosis. Reducing histone deacetylase 4 results in a reduction in fibrosis in animal models of biliary obstruction which is an exciting potential treatment for the future [52].

The cytokine profile of infants with biliary atresia despite a successful Kasai and clearance of jaundice is different than those of children without biliary atresia, with increased profibrotic cytokines IFN-γ and IL-10 [53].

A genetic polymorphism that increases susceptibility to the development of fibrosis may be the reason why fibrosis continues to occur in some but not others. Polymorphisms in genes such as CFC1, ICAM1, macrophage migration inhibitory factor gene, CD14 endotoxin receptor gene and hepcidin have been suggested. Abnormalities in apoptosis due to a specific antigenic stimulation may also occur as there is an upregulation of Kupffer cells, natural killer cells, CD3+ and CD8+ T cells and increased CXCR3+ cells [54].

The fibrosis of biliary atresia may be non-invasively monitored using transient elastography (fibroscan). This will help in the counselling of families and establishing prognosis [55, 56].


6.9.2 Portal Hypertension


Portal hypertension with splenomegaly and/or hypersplenism is prevalent in up to 50% of children after 5 years following Kasai; hence, vigilance for the detection and management of varices is important. Varices at high risk of bleeding in childhood are more likely to occur in children who have portal hypertension within the first 18 months of life and (?) continue to have an abnormal bilirubin level [57].


Prediction for oesophageal varices

Three calculations based on spleen size, platelet count and albumin may help to stratify patients with biliary atresia into those who may require pre-emptive intervention with endoscopic treatment of varices [58]:



  • Clinical prediction rule (CPR) = (0.75 × platelets)/(platelet count to spleen size ratio + 5)+(2.5 × albumin).


  • AST to platelet ratio index (APRI).


  • Varices prediction rule (albumin × platelets/1000).

Acoustic radiation focus impulse (ARFI) elastography of the spleen at the time of Kasai correlates with the diameter of the portal vein, spleen diameter and the development of collateral vessels. Those who underwent subsequent liver transplant had a higher SS score at the time of Kasai.

Occult bleeding may occur due to varices in the roux loop. This may occur with or without transplant. MR angiography may be useful for detecting the exact site [59].


6.9.3 Nutrition


Optimal nutrition is extremely important in infants despite a successful Kasai, and some will require nasogastric feeding supplements. With increasing weight gain and time from surgery, the need for supplemental nutrition decreases.

It is important to monitor the fat-soluble vitamin serum levels to ensure that they are within the normal range and adjustments to doses should be made if necessary.


6.9.4 Cholangitis


Cholangitis can cause decompensation of liver function with falling albumin levels and coagulopathy. Following adequate treatment, the liver synthetic function may improve although a high level of vigilance is required to identify those who require listing for transplantation.

Cholangitis presents with acholic stools, abdominal pain and symptoms of sepsis. Treatment is with intravenous antibiotics for at least 10–14 days. Bacteria may be cultured from the blood or from a liver biopsy specimen. To prevent cholangitis, some centres use low-dose rotating oral antibiotics for the first year following Kasai (e.g. 12 weeks each of amoxicillin, cephalexin and trimethoprim); oral probiotics may also be beneficial. Ursodeoxycholic acid may also be used to aid bile flow. The development of hepatic bile lakes may occur at any time following Kasai and are sources of recurrent infection [60, 61].

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Oct 18, 2017 | Posted by in GASTROENTEROLOGY | Comments Off on Biliary Atresia: From Pathology to Treatment

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