Tag Archives: biliary atresia

“What Makes A “Successful” Kasai Portoenterostomy “Unsuccessful”?

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M Matcovici et al. JPGN 2023; 76: 66-71. What Makes A “Successful” Kasai Portoenterostomy “Unsuccessful”?

Methods: This review of a single-center prospective biliary atresia (BA) database examined which factors were associated with long-term success of a Kasai portoenterostomy (KPE). Successful KPE was defined by achieving a postoperative bilirubin of ≤20 µmol/L. Cholangitis was based on Tokyo (Adult) Guidelines (Calculator MD Calc: Tokyo Guidelines for Acute Cholangitis 2018). Explanation of Tokyo Guidelines: Tokyo Classification Cholangitis

Key findings:

  • 90 (67%) achieved clearance of jaundice after KPE. From these 20 (22%) (Cohort A) underwent LT with the remainder continuing with native liver (Cohort B) (median follow-up of 4.15 years)
  • Postoperatively, both cholangitis [any episode, 18/20 (90%) vs 15/70 (21%); P < 0.0001] and portal hypertension (PHT) [gastrointestinal (GI) bleed, 10/20 (50%) vs 2/70 (2.8%); P < 0.0001] were significantly more common in cohort A

My take: The authors assert that “failure is not preordained at KPE but due to recurrent cholangitis and/or symptoms of PHT.” In my view, this study shows an association but not causation of cholangitis/PHT with increased likelihood of KPE failure. It is quite possible that the cholangitis develops in those with suboptimal bile flow; thus, cholangitis (as well as PHT) may be an indicator that the KPE is not working as well, rather than the reason. Yet, it is also likely that episodes of cholangitis exacerbate any underlying problems.

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MMP-7 Helps Sort Out Biliary Atresia from Parenteral Nutrition-Associated Liver Disease

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PS Salvi et al. J Pediatrics 2022; 249: 97-100. Open access! Comparing Serum Matrix Metalloproteinase-7 in Parenteral Nutrition-Associated Liver Disease and Biliary Atresia

In this single-center retrospective study with 19 patients, MMP-7 and GGT values were compared in children who were diagnosed with Parenteral Nutrition-Associated Liver Disease (PNALD, n=15) and Biliary atresia (n=4). Key findings:

  • Median MMP-7 values for PNALD patients 37.8 ng/mL was much lower than MMP-7 values for biliary atresia 112.3 ng/mL.
  • GGT values were not statistically significantly different 116 for PNALD vs 248 for biliary atresia
  • In this cohort, a MMP-7 threshold of 52.8 ng/mL had a sensitivity of 100% and specificity of 93.5% for biliary atresia.

My take: MMP-7 values reduce diagnostic uncertainty between PNALD and biliary atresia. However, there are infrequent cases of biliary atresia with lower values of MMP-7.

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Two Sisters Pierre-August’s Renoir

Liver Shorts: Malnutrition in Biliary Atresia, Cholestasis with ECMO, Impaired Cognition After Pediatric Liver Transplantation

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JM Boster et al. Liver Transplantation 2022; 28: 483-492. Malnutrition in Biliary Atresia: Assessment, Management, and Outcomes Good review article. Malnutrition and sarcopenia negatively impact pretransplant, peritransplant, and posttransplant outcomes and survival in children with BA.

E Alexander et al. JPGN 2022; 74: 333-337. Clinical Implications for Children Developing Direct Hyperbilirubinemia on Extracorporeal Membrane Oxygenation Key findings: 36/106 (34%) children developed direct hyperbilirubinemia (DHB) on ECMO. Illness acuity scores were significantly higher in the DHB group on ECMO day 2 (P = 0.046) and day 7 (P = 0.01). Mortality rate was higher in the DHB group 72%, versus 29% in the control group (P < 0.001).

A Ostensen et al. J Pediatr 2022; 243: 135-141. Open Access: Impaired Neurocognitive Performance in Children after Liver Transplantation In this study with 65 participants, key findings:

  • Compared with the patients who underwent transplantation a age >1 year (n = 35), those who did so at age <1 year (n = 30) had a lower FSIQ (87.1 ± 12.6 vs 96.6 ± 13.8; P = .005) and lower verbal comprehension index (87.3 ± 13.8 vs 95.4 ± 13.0; P = .020).
  • Transfusion of >80 mL/kg (P = .004; adjusted for age at transplantation: P = .046) was also associated with detrimental effects on FSIQ.
  • No difference in IQ between tests was found in those patients tested more than once, indicating no significant improvement with more time after transplantation (first testing was at median of 4.1 years after transplantation and the second testing was at a median age of 6.7 years after transplantation)
  • “Our findings indicate that transplantation at early age has a pronounced effect on later neurocognitive impairment, and that this effect is separate from and more pronounced than the effect of cholestasis before transplantation.”

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Onion Headline:

Liver Shorts: Biliary Atresia Organoids, AIH Pregnancy Outcomes, ALT Levels in Primary Care, Polyreactive IgG for AIH

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SP Amarachintha et al. Hepatology 2022; 75: 89-103. Open Access: Biliary organoids uncover delayed epithelial development and barrier function in biliary atresia

This is a super cool article documenting a new human model for studying biliary atresia. The authors “generated biliary organoids from liver biopsies of infants with biliary atresia and normal and diseased controls…Organoids from biliary atresia are viable and have evidence of halted epithelial development. The induction of developmental markers, improved cell-cell junction, and decreased epithelial permeability by EGF and FGF2 identifies potential strategies to promote epithelial maturation and function.”

The authors note that delayed development of cholangiocytes impair barrier function and leave the liver susceptible to various insults which can trigger an inflammatory response with potential progression to obliteration of the bile ducts.

CW Wang et al. Hepatology 2022; 75: 5-12. Open Access: Outcomes of pregnancy in autoimmune hepatitis: A population-based study

Among 18,595,345 pregnancies, 935 (<0.001%) had AIH (60 with cirrhosis) and 120,100 (0.006%) had other CLD (845 with cirrhosis). Key findings:

  • AIH was not associated with postpartum hemorrhage, maternal, or perinatal death
  • AIH was associated with preterm births when compared with women without CLD (OR: 2.0)
  • The odds of gestational diabetes (GDM) and hypertensive complications (pre-eclampsia, eclampsia, or hemolysis, elevated liver enzymes, low platelets) were significantly higher in AIH compared to other CLD (GDM: OR 2.2 and hypertensive complications: OR: 1.8) and also compared to no CLD in pregnancy (GDM: OR: 2.4 and  hypertensive complications: OR: 2.4)

SJ Wu et al. J Pediatr 2022; 240: 280-283. The Prevalence of Elevated Alanine Aminotransferase Levels Meeting Clinical Action Thresholds in Children with Obesity in Primary Care Practice

In this brief report, the authors identified 7.8% of children from a cross-sectional California cohort (n=12,945) with ALT >44 U/L and BMI in the 95% or higher (2012-2014). Males were twice as likely to have elevated ALT. Ethnicity rates were higher in hispanics, asians than white and black children (in males: 12%, 10.4%, 7.3% and 3.1%, respectively)

R Taubert et al. Hepatology 2022; 75: 13-27. Quantification of polyreactive immunoglobulin G facilitates the diagnosis of autoimmune hepatitis

Key findings: Polyreactive IgGs (pIgGs) are a common finding in untreated AIH and have “the highest overall accuracy for the distinction between AIH and non-AIH LD compared to the most common conventional autoantibodies.” In addition, in this study with 1568 adutls, pIgGs were present in “up to 88% of patients with seronegative AIH and in up to 71% of AIH patients with normal IgG levels. Under therapy, pIgG returns to background levels of non-AIH-LD.”

Neurologic Impairment with Biliary Atresia at Time of Diagnosis

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Previous studies have indicated that prolonged cholestasis before liver transplantation is associated with adverse neurodevelopmental outcomes. LH Rodijk et al (JPGN 2021; 72: 592-596. Full text: Early Motor Repertoire in Infants With Biliary Atresia: A Nationwide Prospective Cohort Study) prospectively investigate early neurologic impairment in infants with biliary atresia (n=35).

The author’s utilized Prechtl’s General Movement (GM) Assessment which is a noninvasive, cost-effective, and worldwide used method to identify infants who are at risk of neurodevelopmental impairments. This requires video recordings of 10 minutes; this was avoided in the 24 hours following liver biopsy or general anesthesia.

Key finding:

  • The proportion of infants with atypical GMs was significantly higher in BA (46%) than in 2 reference groups of healthy infants (vs 10%, P < 0.001; vs 18%, P < 0.001).

My take (from authors): “At the time of diagnosis, almost half of the infants with BA showed an atypical early motor repertoire, suggesting that neurological impairment is present already in early infancy. Compared to healthy infants, approximately 2 to 3 times more infants showed an atypical motor repertoire.”

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Arlington, VA -February 2021. Thanks to Seth for this image

Liver Shorts -February 2021 (part 2)

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M Biewenga et al. Liver Transplantation 2020; 26: 1573-1581. Full text: Early Predictors of Short-Term Prognosis in Acute and Acute Severe Autoimmune Hepatitis

Key points:

  •  After the start of immunosuppressive therapy, bilirubin, albumin, and INR normalized in 70%, 77%, and 69%, respectively, in a median of 2.6 months, 3 months, and 4 weeks, respectively, in patients with A-AIH and AS-AIH
  • Deterioration of liver function (bilirubin, INR) after 2 weeks of treatment should lead to rapid evaluation for LT and consideration of second-line medication.

I Ziogas et al. J Pediatr 2021; 228: 177-182. Mortality Determinants in Children with Biliary Atresia Awaiting Liver Transplantation

Key points:

  • The cumulative incidence of waitlist mortality was 5.2%. Median waitlist time was 83 days.
  • In multivariable analysis (n = 2253), increasing bilirubin level ( P < .001), portal vein thrombosis ( P = .03), and ventilator dependence ( P < .001) at listing were associated with a higher risk, whereas weight ≥10 kg at listing ( P = .009) was associated with a lower risk of waitlist mortality. 

References Only:

HM DuBrokc, MJ Krowka. Hepatology 2020; 1455-1460. The Myths and Realities of Portopulmonary Hypertension

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H Oh et al. Clin Gastroenterol Hepatol 2020; 18: 2793-2802. Full text: No Difference in Incidence of Hepatocellular Carcinoma in Patients With Chronic Hepatitis B Virus Infection Treated With Entecavir vs Tenofovir Related blog post: Is Tenofovir the Best Medication for HBV?

Evanston, IL

Favorite Posts of 2020

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These are some of my favorite posts of the past year.

Humor:

GI:

Endoscopy:

Liver:

Nutrition

COVID-19:

Other:

From Picnic Island, Tampa Bay

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).

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Indian Rocks Beach, FL

Landmark Study on Universal Screening for Biliary Atresia -It Works!

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S Harpavat et al. JAMA 2020; 323: 1141-50. Link:  Diagnostic Yield of Newborn Screening for Biliary Atresia Using Direct or Conjugated Bilirubin Measurements

This article provides details on how to improve the outcomes of children with biliary atresia by detecting cases at an earlier age.  The authors provide details on their 2-stage approach at near-universal screening of 124,385 infants in South Texas/Texas Medical Center from 2015-2018 and compare their results to a prior cohort.

Methods: The authors sought to have all infants have a fractionated bilirubin within the first 60 hours of life.  This information can easily be obtained due to preexisting policy of testing total bilirubin in this time-frame.  Those with any abnormal direct bilirubin or conjugated bilirubin had a 2nd stage screening at 2 weeks of life.  At stage 2, any infant with a direct bilirubin >1 mg/dL or higher than 1st stage were considered abnormal.  The stage 2 screening aligned with AAP-recommended 2 week check up. During the screening time-frame (2015-2018), 7 patients were identified with BA (one treated at outside institution), 7 more from nonstudy hospitals who had replicated protocol, and 6 referred due to clinical symptoms.

Key findings:

  • 7 infants with biliary atresia were detected with 100% sensitivity and 100% NPV. The PPV was 5.9% and specificity was 99.9%.  Due to the small number of infants identified, the confidence limits for sensitivity was 56%-100%.
  • During the first stage, 1354 infants (1.1%) had abnormal values. At stage 2, 119 had abnormal values (0.1% of initial cohort and 8.9% of those with 1st stage abnormalities).
  • Range of direct/conjugated bilirubins in those with eventual biliary atresia: Stage 1 —0.4-2.3,and Stage 2 —1.6-3.5
  • In the 2015-2018 time-frame, age at time of Kasai was lowered from 56 days to 36 days, P=.004.
    • The actual time between presentation to specialist to time of Kasai was unchanged ~12 days.
    • In the 2015-18 time-frame, 11 of 19 (58%) had Kasai at less than 30 days (optimal timing) compared to 3 of 24 in historical cohort.
  • Many (n=53) other cholestatic conditions were identified in the stage 2 cohort.  52.7% of abnormal stage 2 tests had no diagnosis determined.
    • Nine had cholestatic diseases: Alagille (n=4), A1AT (n=3), ABCB11 (n=1), Choledochal cyst (n=1).
    • Twelve were heterozygous for a liver disease.
    • Seventeen had conditions associated with neonatal cholestasis: Trisomy 21 (n=5), Trisomy 18 (n=3), portosystemic shunt (n=2), maternal lupus, omphalocele, and panhypopituitarism.
    • Eight had infections including CMV (n=3), and syphilis (n=3). Seven had excessive red blood cell turnover.
  • Many of those with abnormal stage 2 evaluations required minimal workup.  Additional fractionated bilirubin alone were needed for 28 (25%).
  • Premature infants were more likely to have abnormal screening.
  • Transplant-free survival at 1 year was greater in cohort during screening period: 94.7% vs. 70.8% with historical cohort (this did not reach statistical significance)

Discussion:

  • This 2-stage approach is much more promising than stool color cards.  These cards have shown some modest success in countries like Japan and Taiwan which have a national call center and standard 1-month checkups; however, even in these countries, age at time of Kasai were 60 days and 46 days respectively.
  • “The challenge specialists [and pediatricians] face was highlighted by an infant who had a true positive screening result in the study, but underwent the Kasai portoenterostomy at 75 days.”
  • The cost-effectiveness of this approach is unclear.

My take: The best chance for transplant-free survival in biliary atresia involves establishing an early diagnosis.  This study shows one way to accomplish this goal -nothing else has worked despite more than 30 years of trying.

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Online Aspen Webinar (Part 5) -Biliary Atresia Diagnosis and Screening

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Online Webinar –Annual Aspen Conference  —July 14, 2000

Below I’ve included a few slides and some notes; my notes may have errors of omission or transcription.

Biliary Atresia -Prompt Diagnosis and Screening Ronald Sokol

Key Points:

  • We have NOT improved age of diagnosis in biliary atresia in the past 30 years
  • Uniform screening of fractionated bilirubin has been effective in Texas:  Diagnostic Yield of Newborn Screening for Biliary Atresia Using Direct or Conjugated Bilirubin Measurements S Harpavat et al. JAMA 2020; 323: 1141-50
  • Pale stools are usually NOT due to biliary atresia but should prompt investigation (eg. fractionated bilirubin)
  • MMP-7 may improve diagnostic approach; unclear if MMP-7 performs well in all populations (eg. prematurity)
  • Outcome key factors: age at diagnosis (goal less than 30-45 days) and surgeon/center

 

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