Category Archives: biliary atresia

Ultrasonography to Distinguish Biliary Atresia from Alagille Syndrome

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AM Upton et al. J Pediatr Gastroenterol Nutr. 2025;81:212–216. The “maximum echogenicity” at the right portal vein: Biliary atresia versus Alagille syndrome

See related ultrasound study from last week: Improving Ultrasound Examination to Identify Biliary Atresia

Background/Methods: One way clinicians can distinguish between biliary atresia and Alagille syndrome is with a positive “triangular cord sign.” This ultrasound finding refers to a thickened echogenicity at the anterior aspect of the right portal vein…the maximum echogenicity at the anterior aspect of the right portal vein (“maximum echogenicity” or “MxE”) was measured in a group of infants with cholestasis (Cohort 1, n=64) and in another group of infants with Alagille syndrome (Cohort 2, n=30).

Key findings:

  • “Thin echogenicity at the anterior aspect of the right portal vein may help distinguish between biliary atresia and Alagille syndrome…None of the 12 infants with biliary atresia in Cohort 1 had a MxE < 1.0 mm”
  • “A MxE < 1.0 mm could help identify Alagille syndrome. 2 of the 64 infants with cholestasis in Cohort 1 had a MxE < 1.0 mm. Both infants were eventually diagnosed with Alagille syndrome. In the Cohort 2 infants with Alagille syndrome, 16 of 30 infants had a MxE < 1.0 mm”
Infant with biliary atresia
Infant with Alagille Syndrome

Discussion Point:

“Infants with Alagille syndrome can have smaller bile ducts which may be inapparent on invasive testing such as cholangiography. As a result, they may be presumptively diagnosed with biliary atresia and inappropriately treated with the Kasai portoenterostomy. Unfortunately, these infants have poorer outcomes compared to infants with Alagille syndrome who do not receive the Kasai portoenterostomy.” Thus, distinguishing Alagille from biliary atresia is very important.

My take: This study shows that MxE (a refinement of what has previously been called the triangular cord sign) on ultrasound may help distinguish biliary atresia from Alagille syndrome. As this is a single-center study, it will be important to determine if this ultrasound finding can be replicated in other centers and whether the finding is operator-dependent.

Related blog posts:

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition

Dr. William Balistreri: Whatever Happened to Neonatal Hepatitis (Part 2)

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Recently Dr. Balistreri gave our group an excellent lecture. I have taken some notes and shared some slides. There may be inadvertent omissions and mistakes in my notes.

Key Points:

  • Producing enough bile acids and recycling bile acids in enterohepatic circulation is crucial for bile acid flow. In addition, there are ‘good’ bile acids like cholic acid that have trophic properties and ‘bad’ bile acids like lithocholic acid that cause liver toxicity
  • In addition to defects in the metabolic pathway of bile acids, discoveries identified defects in the membrane transporters (eg. FIC1, BSEP, MDR3), trafficking proteins (eg. MYO5B, VPS33B), nuclear control receptors (eg. FXR), and tight junction proteins (eg. TJP2). Tight junction protein defects are associated with bile leakage from bile canaliculus
  • Alagille syndrome, a disorder of embryogenesis, related to JAG1-NOTCH2 signaling pathways affects organs throughout the body
  • Many of these genetic mutations are now being identified in adults with unexplained liver diseases (eg. intrahepatic cholestasis of pregnancy and cryptogenic cirrhosis)
  • Cholestasis panels and whole exome sequencing are important tools
  • Ileal bile acid transporter (IBAT) inhibitors have emerged as important therapies for conditions like Alagille which were previously treated with biliary diversion

Cholestasis Evaluation:

See blog post: Identifying Biliary Atresia in Infants: New Guidelines

Baby with Carbamoyl-phosphate synthetase 1 (CPS1) deficiency (urea cycle defect)

My take: This lecture really shows how the field of pediatric liver disease has been a puzzle. Now one can see how almost all of the pieces of the puzzle work together.

Related blog posts:

How Well Does BARD Criteria Work for Diagnosing Cholangitis Following a Kasai Repair for Biliary Atresia

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M Madadi-Sanjani et al. JPGN Reports 2024: https://doi.org/10.1002/jpr3.12071. Open Access! Retrospective analysis of the standardized BARD criteria for acute cholangitis in biliary atresia patients

This retrospective study examined the Biliary atresia and Related Diseases (BARD) criteria for diagnosis of acute cholangitis in BA patients within the first year following Kasai hepatoportoenterostomy (HPE).

Key findings:

  • Of 185 consecutive BA patients, 59 (32%) had at least one episode of cholangitis within the first year after HPE
  • The correlation between the clinician’s impression and the standardized BARD definition was very strong (r = 0.8)
  • Only 41% of patients believed by their physicians to have cholangitis had fever
  • 70% had increased WBC and/or CRP, and/or procalcitonin
  • 90% had increased bilirubin/GGT, 68% had increased transaminases
  • Only one (1/59) patient in their cohort had a positive blood culture and only one (1/59) patient had bile lakes identified
  • 56/59 children (94.9%), at least one laboratory or radiological item (group B) was pathologic at cholangitis diagnosis

My take: There really is not a precise way to diagnose cholangitis following HPE. Given how infrequently they are identified, it looks like both blood culture and bile lakes are not useful in establishing the diagnosis given. Overall, these criteria correlate well with how clinicians establish the diagnosis of cholangitis in at-risk children.

The Standardized Biliary Atresia and Related Diseases (BARD) cholangitis guidelines for the diagnosis of suspected and confirmed cholangitis within the first year following hepatoportoenterostomy for biliary atresia. *Vomiting, poor feeding, irritability. PCT, procalcitonin.

Related blog posts:

Customized Postoperative Therapy for Biliary Atresia -Does It Help?

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S Pandurangi et al. J Pediatr Surg 2023; 58: 1483-1488. Customized Postoperative Therapy Improves Bile Drainage in Biliary Atresia: A Single Center Preliminary Report

This single center retrospective study compared  20 consecutive infants underwent hepatoportoenterostomy (HPE) (beginning in 2017) for biliary atresia (BA) to a historical cohort. Analysis of successful biliary drainage 3 months after HPE (defined as serum total bilirubin (TB) <2 mg/dL) was the primary endpoint; survival with native liver at 2 years was the secondary endpoint.

Protocol:

  • Cefoxitin was administered to all infants following HPE for 3-4 days.
  • Standard protocol: If the stool color normalized (pigmented), the infant received “conventional” treatment with trimethoprim-sulfamethoxazole cholangitis prophylaxis, fat-soluble vitamin supplementation with DEKAsPlus or AquaADEKs (1 mL daily), and ursodeoxycholic acid (5 mg/kg twice daily).
  • Customized protocol: If the stools were acholic (or not consistently pigmented) and </=45 days, the infants received intravenous cefoxitin or piperacillin-tazobactam and methylprednisolone, initial dose 5 mg/kg/day and decreased by 1 mg/kg/day each day thru day 5; then orally treated with dose dropped 0.25 mg/kg weekly. When switched to oral steroids, IV antibiotics were stopped and infant was placed on amoxicillin-clavulanate which was continued until TB <2 mg/dL or discontinuation of corticosteroids (whichever came first).
  • If stools were acholic and infant was >45 days, then the same treatment was given if there was liver inflammation on histology.

Key findings:

  • 8 had pigmented stools after HPE and received standard protocol.
  • 12 had acholic/inconsistent stools. All of those >45 days had liver inflammation; thus, all 12 received the customized protocol. Two infants had two cycles of steroids/antibiotics who had initial response to treatment and then worsened.
  • Sixteen of 20 (80%) infants had successful bile drainage, compared to 8 of 20 (40%) infants in the historical cohort (P = 0.0225)
  • Among the sixteen who have reached two years of age, 11 (68.8%) are alive with native livers versus 10 of 20 (50%) in the historical cohort (P = 0.0970).  This did not achieve statistical significance.

The authors established their protocol based on data from Kings College in 2016 suggesting that steroids appeared effective in younger patients who underwent HPE prior to 45 days (Peg Surg Int 2016; 32: 193-200). The START study showed no significant improvement in biliary drainage between patients receiving corticosteroids and placebo. However, in the group <70 days, 72% of infants receiving corticosteroids achieved biliary drainage compared with 57% of the placebo group (P=0.36).

My take: This is a small sample size. Perhaps, this protocol will help improve outcomes. If so, we still don’t know which factor is more important —the IV antibiotics or the high dose steroids. If these agents are helpful, are there other predictive factors –microbiome? MMP-&?

Related blog posts:

Pictures from the Villa Ephrussi de Rothschild

Don’t Put the Cart Before the Horse: Biliary Atresia Screening

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R Lerer et al. JPGN Reports2023; 4(4):p e345. Open Access! Evaluation of Newborn Direct Bilirubin As Screening for Cholestatic Liver Disease

This retrospective study analyzed data from 11,965 infants who had fractionated bilirubin obtained in the nursery (2016-2019). Key findings:

  • DB of 0.6 mg/dL was chosen as the cut-off based on a high sensitivity (100%) and specificity (99%) for screening newborns for CLD
  • Out of 60 infants who met criteria for DB ≥0.6 mg/dL, only 15 (25%) had a repeat level drawn after nursery discharge; 3 (5%) were eventually diagnosed with CLD (2 with BA and 1 with Alagille syndrome)

It is fairly easy to get fractionated bilirubins on infants. Many need to get a bilirubin check and in many centers, a fractionated bilirubin is automatically generated at no additional costs. The hard part is making sure that those with abnormal values receive timely followup.

My take: It is a mistake to get fractionated bilirubins in newborns unless one has developed a plan/infrastructure to make sure those with abnormal values receive appropriate followup.

Related blog posts:

Off the coast of Southern France (near Juan-Les-Pines)

Bone Health in Children with Biliary Atresia

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S Ruuska et al. JPGN 2020; 71: 707-712. Impaired Bone Health in Children With Biliary Atresia

This retrospective study from Finland details the bone health of children with biliary atresia (BA). Key findings:

  • Out of 49 patients, 7 (14%) were diagnosed with rickets during infancy. Clearance of jaundice [odds ratio 0.055, 95% confidence interval [CI] 0.00266–0.393; P < 0.01] was a protective factor against rickets.
  •  In DXA measurements, median lumbar spine aBMD anthropometrically adjusted z-scores were as follows:
    • in native liver survivors 0.8 (interquartile range [IQR] −1.9 to 1.4) at 5 and −0.3 (IQR −1.3 to 0.8) at 10 years
    • in liver transplanted patients 0.4 (IQR −0.2 to 1.1) at 5 and 0.6 (IQR −0.1 to 1.3) at 10 year.
  • Most BA patients have aBMD within normal range between 5 and 10 years of age irrespective of liver transplantation status.

My take: This study shows that early in life there is frequent bone impairment in children with BA. This generally improves in most children as cholestasis resolves (with or without liver transplantation).

Related blog posts:

Indian Rocks Beach, FL

Cholangitis After Kasai Procedure for Biliary Atresia

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K Cheng et al. JPGN 2020; 71: 452-458. Cholangitis in Patients With Biliary Atresia Receiving Hepatoportoenterostomy: A National Database Study

This study, which relied on data from a pediatric database (PHIS) with 48 pediatric centers, identified 1112 subjects with biliary atresia (2004-2013).

Key findings:

  • Median age at time of Kasai (hepatoportoenterostomy) procedure: 63 days
  • Median number of admissions for cholangitis within 2 years was 2 episodes. The presence of portal hypertension (OR 2.24) and black race (OR 1.51) were associated with higher risk of cholangitis
  • When Kasai was performed at >90 days, this lowered the likelihood of cholangitis (OR 0.46)
  • With regards to those with 5 or more bouts of cholangitis, risk factors included Asian ethnicity (OR 2.66), public insurance (OR 1.72), and portal hypertension (OR 2.88)
  • 56% of patients had portal hypertension and 15.6% had esophageal varices
  • Neither steroids nor ursodeoxycholic acid were found to affect patient outcome
  • Limitations: lack of clear definition for cholangitis diagnosis and episodes of cholangitis may not have been captured if patients received care outside the participating centers

My take: Cholangitis is a common problem following hepatoportoenterostomy. Earlier diagnosis of biliary atresia provides the best opportunity for improving long-term outcomes.

Related blog posts:

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Learning a lot from ChiLDREN (part 2)

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As noted in previous post (Learning a lot from ChiLDREN (part 1) | gutsandgrowth), several recent studies highlight the benefits of multisite collaboration to study infrequent pediatric liver problems.  In these studies, the Childhood Liver Disease Research and Education Network (ChiLDREN) has collected prospective longitudinal observational date from multiple centers; data from 10 centers provides useful information on the frequency of portal hypertension (PHT) in young adults with biliary atresia (BA) (JPGN 2012; 55: 57-73).

163 subjects were enrolled between May 2006 and December 2009.  Seven patients were excluded due to the presence of polysplenia which interferes with the assessment of PHT.

Demographics: subjects ranged in age from 1 to 25 years with a mean of 9.2 years.  56% were female, 75% were caucasian.

PHT was considered definite if there was either a history of a PHT complication (variceal bleeding, ascites) or if there were clinical findings c/w PHT (both splenomegaly and thrombocytopenia).  PHT was considered “possible” if either splenomegaly or thrombocytopenia was present and “absent” if no criteria were met.

  • PHT: definite in 80 (49%), possible in 27 (17%) and absent in 56 (34%)
  • 43 subjects had a history of PHT complications: 32 with esophageal variceal (EV) bleeding, 14 with ascites, and 8 with hepatopulmonary syndrome.
  • Of the patients with EV, only 3 had normal platelet count and normal spleen size.

Teaching points:

  1. One-third of subjects with EV bleeding survived with their native liver for at least 5 years.
  2. EV age of onset was highly variable; 7 had bleeding in the first two years of life.
  3. Growth parameters were fairly unremarkable in those with definite PHT.
  4. Long-term followup will be needed to identify factors which predict progression of PHT and the development of adverse outcomes.

Previous related blog posts:

Diagnosing biliary atresia earlier

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Biliary atresia (BA) is often suspected among infants with prolonged jaundice. In fact, efforts have been underway for a long time to encourage fractionation of the bilirubin values to look for conjugated hyperbilirubinemia, especially in infants that remain jaundiced at three weeks of life.  While this is still good advice, given the lack of success in implementation, there is good evidence that obtaining a fractionated bilirubin at any time point can help identify cholestasis associated with BA.

A recent article by Karpen et al (Pediatrics 2011; 128:. e1428 -e1433) indicates that direct bilirubin values are elevated beginning within the first one to two days in patients with BA.  In their cohort of 61 BA subjects, 56% had newborn fractionated bilirubin values.  Every BA patient had elevated direct bilirubin, on average 1.4 ± 0.43 mg/dL (normal <0.5) (compared with control patients:  0.19 ± 0.075 mg/dL, P < .0001).  Also, another important finding was that early on the ratio of direct bilirubin to total bilirubin was normal in 79%; normally this ratios is ≤0.2.  As such, all patients with increased direct bilirubin need to be followed closely.

Related blog entries:

Outcomes of Biliary Atresia

MicroRNAs and biliary atresia

Bleeding due to vitamin K deficiency

Bleeding due to vitamin K deficiency

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With cholestasis in infancy, Bill Balistreri taught me that there were four potential emergencies:

  • Bleeding due to vitamin K deficiency or coagulopathy
  • Hypoglycemia
  • Sepsis
  • Metabolic poisoning with formula (in patients with galactosemia)

Once these issues have been considered, then it is appropriate to start investigating the etiology of the cholestasis.

One of the more dramatic complications is intracranial hemorrhage (ICH). While ICH is a well-recognized complication of cholestasis in infancy, the long-term outcomes are not well-characterized. A report from Japan adds some insight (JPGN 2012; 54: 552-57).

Among a retrospective review of 83 infants with biliary atresia (BA) between 1979 to 2009, ICH occurred in 8% despite oral vitamin K prophylaxis (2 mg).  The onset of ICH was between 47-76 days after birth and was prior to surgery.  Coagulopathy was noted in all cases, which improved with vitamin K intravenously.  Two infants required craniotomy.  In 5 of 7 cases, neurologic sequelae were noted including developmental delay in three, epilepsy in one, and mild hemiparesis in two.

Additional references:

  • Blood Rev 2009; 23: 49-59.  Review of vitamin K deficiency.
  • Pediatrics 2008; 121:e857.  Vitamin K deficiency common in cholestatic breastfed babies.  Can be prevented with 1mg po each week or single IM dose of 2mg.
  • Eur J Pediatr Surg 2005; 15: 295-9.  Bleeding disorder as 1st symptom of BA.
  • Pediatr Neurosurg 2006; 42: 362-7.  ICH due to vitamin K deficiency.
  • Pediatrics 2006; 118: e1657.  dose of 0.2mg effective for median of 25days (w/o toxicity/accumulation of K1O) in infants <32weeks gestation.