Cholangitis After Kasai Procedure for Biliary Atresia

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.

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More Data, More Nuance with MMP-7: Best Biliary Atresia Biomarker

As noted by my previous blog (New Way to Diagnose Biliary Atresia), I am enthusiastic about the development of MMP-7 (Serum Matrix Metalloproteinase-7) as a biomarker for biliary atresia.

A new study (Wu J-F , Jeng Y-M, Chen H-L, Ni Y-H, Hsu H-Y, Chang M-H. Quantification of serum matrix metallopeptide 7 levels may assist the diagnosis and outcome prediction for biliary atresia. J Pediatr. 2019;208:30–7) and associated editorial provide additional data and nuance.

Key points:

  • “Wu et … studied 100 cholestatic infants presenting consecutively to their institution over a 10-year period, including 36 eventually diagnosed with biliary atresia. Median serum MMP-7 levels were significantly higher in biliary atresia at the time of diagnosis, with an optimal serum MMP-7 level of >1.43 ng/mL for predicting biliary atresia.  In comparison, similarly high MMP-7 levels were found in only 1 infant who was cholestatic without biliary atresia.”
  • “The authors found that serum MMP-7 levels were significantly lower in the 14 infants ≤30 days old diagnosed with biliary atresia, compared with the 22 infants >30 days old at diagnosis. In some cases, serum MMP-7 levels in younger infants with biliary atresia overlapped with those from infants with other liver diseases, such as neonatal hepatitis.”
  • After Kasai portoenterostomy: “Serum MMP-7 levels were significantly higher 6 months post-Kasai portoenterostomy in infants who later required liver transplant, with a serum MMP-7 level of >10.30 mg/dL optimally predicting transplant 3-4 years after Kasai portoenterostomy … serum MMP-7 levels are still high even in patients who do not need liver transplant.”
  • The authors “highlight 1 complication with using serum MMP-7 levels: values can vary widely among different enzyme-linked immunosorbent assay kits used.”

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Sagrada Familia -work in progress.  Amazing.


Updated Biliary Atresia Epidemiology

A recent retrospective study (PC Hopkins, N Yazigi, CM Nylund. J Pediatr 2017; 187: 253-7) provides an update on the recent incidence of biliary atresia in the US from 1997-2012. This study relied on coding for biliary atresia or Kasai hepatoportoenterostomy to identify cases using HCUP-KID database.  This database provides a nationally representative sample of pediatric hospitalizations and captures ~96% of pediatric hospitalizations in the US.

Key findings:

  • Incidence of biliary atresia (BA) was 4.47 per 100,000 (1 in 22,371 infants)
  • BA was more common in females (RR 1.43), Asian/Pacific Islanders (RR 1.89), and blacks (RR 1.30)
  • Median age at the time of the Kasai procedure was 63 days with no improvement over the course of the study period.  More than 50% of all children underwent the Kasai procedure after the optimal window of 60 days of life

My take: In my view, at this time, obtaining a blood test for direct bilirubin in the first two weeks of life will need to be adopted broadly if we are going to diagnose biliary atresia at an earlier age.

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Dry Falls, Highlands NC

Dry Falls, Highlands NC


Bad News Bili

A study (BL Schneider et al. J Pediatr 2016; 170: 211-7) from ChiLDReN (Childhood Liver Disease Research Network) shows that infants with biliary atresia whose total bilirubin (TB) does not drop below 2 mg/dL (34.2 microM) at anytime during the first 3 months after hepatoportoenterostomy (HPE) (Kasai) are at high risk for disease progression.

Key findings:

  • 68/137 (50%) had TB <2.0 at some point following HPE.
  • In the cohort with TB ≥ 2.0, the odds ratio for liver transplantation or death was 16.8.  Higher TB was associated with diminished weight gain, coagulopathy, and hypoalbuminemia
  • In the cohort with TB ≥ 2.0, transplant-free survival at 2 year occurred in only 20% compared with 86% in the TB <2.0 group
  • Interestingly, only 6.6% had variceal bleeding among the entire cohort by age 2 years.

The TB was associated with multiple other parameters of worsening liver function, indicating that TB is not the only measure to affect the decision of liver transplantation.

My take: About half of all patients following a Kasai were at high risk for early progressive liver disease.  TB ≥ 2.0 is a useful indicator of high risk.

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Walnut Street Bridge, Chattanooga

Walnut Street Bridge, Chattanooga

Helpful Review on Biliary Atresia

Biliary atresia (BA) remains the leading cause of pediatric liver transplantation and a frequent cause of cholestasis in newborns.  A recent review (AG Feldman, CL Mack. JPGN 2015; 61: 167-75) provides a helpful update. The article begins with a review on pathogenesis, though this remains unknown and continues to be an area of speculation.

The section on evaluation includes a suggested diagnostic algorithm for neonatal cholestasis.  In short, for a 2 week old with jaundice , the authors recommend (STEP 1) fractionating the bilirubin.  The infant is considered cholestasis if the direct bilirubin is ≥1 mg/dL (if total bilirubin is <5 mg/dL) or if direct bilirubin ≥20% of total bilirubin (if total bilirubin is >5 mg/dL).

Among cholestatic infants, the authors recommend (STEP 2) next checking ultrasound and alpha-one antitrypsin (A1AT) (level & phenotype).  The text implies that the authors would check a GGTP.  While this is not in their algorithm, many would suggest checking urine reducing substances, coags, serum glucose, and consideration of sepsis evaluation; these tests can identify issues that are more urgent than identifying biliary atresia.

STEP 3: If U/S and A1AT, are not diagnostic, consider urine culture, urine reducing substances, urine succinylacetone, and additional infectious studies.

STEP 4: Proceed with liver biopsy. If findings of biliary atresia (eg. bile plugs, bile duct proliferation, portal fibrosis), proceed with intraoperative cholangiogram.

Other points:

  • “It is rare for an infant with BA to have a GGTP level <200 U/L.” If low GGTP, consider PFIC, inborn error of bile acid metabolism, and panhypopituitarism.
  • Extensive differential diagnosis table given ((Table 1)
  • “Late diagnosis of BA remains a problem in the United States. The average age of HPE [hepatoportoenterostomy] is 61 days and 44% of patients still undergo HPE after 60 days of life.”  The authors indicate a goal for HPE of taking place  at <45 days of life.
  • Successful HPE can occur even with late diagnosis. 10% to 20% of children who undergo HPE after 100 to 120 days of life still have success in restoring bile flow.”
  • Early/successful HPE is helpful in increasing 10-year transplant-free rate.  Early on, 3 months after HPE, those with a total bilirubin <2 mg/dL compared with those with a total bilirubin of >6 mg/dL have a much lower likelihood of liver transplantation by 2 years of age: 84% vs. 16%.
  • Recommends checking a pulse oximetry at routine followup visits following HPE to look for the possibility of hepatopulmonary syndrome.
  • The article reviews complications including ascites, portal hypertension/GI bleeding, cholangitis, malignancy, and hepatopulmonary syndrome/portopulmonary hypertension.
  • Outcomes: With HPE, “up to two-thirds of patients with BA have short-term clearance of jaundice.” Yet, “80% of patients with biliary atresia will require liver transplantation during childhood.”

Also noted:

“Biliary Atresia is Associated with Hypertension” JPGN 2015; 61: 182-86.

“Pathogenesis of biliary atresia: defining biology to understand clinical phenotypes” A Asai, A Miethke, JA Bezerra. Nat Rev Gastroenterol Hepatol 2015; 12: 343-52.  This review provides in-depth review examines more precise phenotyping, influencing factors (eg. cytomegalovirus), and potential mechanisms.

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From Mt Washburn, Yellowstone

From Mt Washburn, Yellowstone

START Study: Steroids Not Effective For Biliary Atresia (After Kasai)

A recent multicenter study has shown that steroids are not helpful after hepatoportoenterostomy for Bilairy Atresia (BA) (Bezerra JA et al. Hepatoportoenterostomy for Bile Drainage in Infants With Biliary Atresia. JAMA. 2014 May 7;311(17):1750).  Thanks to Saul Karpen for the reference.  I want to congratulate all of the authors, but particularly Jorge Bezerra, Saul Karpen, and Rene Romero for collaborating on this important study.

The randomized, double-blind, placebo-controlled START trial from the NIH-supported ChiLDren study enrolled 140 patients (257 were screened) from 2005-2011.  High-dose steroids, starting with methylprednisolone 4 mg/kg/day for 2 weeks and then tapered was compared with placebo.  No statistically significant improvement was noted.  Ultimately, the steroid intervention did not affect transplant-free survival which was 58.7% in the steroid group and 59.4% in the placebo group at 24 months of age.  Figure 2 (see below -from @JAMA twitter feed) shows Kaplan-Meier analysis plots with regard to transplant-free survival and bile drainage; the latter was slightly better in steroid group, but not statistically significant. In addition, steroids were associated with an earlier onset of first serious adverse events, 37% in steroid group compared with 19% in the placebo group within 30 days of Kasai.

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With regard to safety, the authors note that both groups were “found to have a high incidence of adverse events, indicating that they were most likely the direct consequences of the severe liver disease typical of biliary atresia. However, steroid therapy was associated with…complications at the sites of surgical anastomoses and intestinal perforation.”

Take-home message: Avoid steroids after Kasai procedure.

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