Tag Archives: N-acetylcysteine

Precision Prediction of Biliary Atresia Survival

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Though young age at the time of Kasai and surgical experience have been identified as factors in the long-term outcome of patients with biliary atresia (BA), why is it that some with timely intervention still fail to respond?  Conceptually, I’ve considered those who had progressive disease as probably having an intrahepatic component of their biliary disease that a Kasai operation cannot help.

New research (Z Luo, P Shivakumar, R Mourya, S Gutta, JA Bezerra. Gastroenterol 2019; 157: 1138-52) identifies genetic factors that are likely a more powerful predictor of Kasai response then the traditional clinical factors.

The science in this study is fascinating –combining genetic heat maps, and survival curves.  The prediction with a 14-gene signature is amplified with serum total bilirubin at 3 months post-Kasai.  In addition, these studies are combined with a mouse model treated with N-acetylcysteine (NAC).  Histologic changes were then assessed.

Key findings:

  • The 14-gene mRNA expression pattern predicted shorter and longer survival times in both the discovery (n=121) and validation sets (n=50) of children with BA (see figure below: red curve vs blue curve)
  • When this 14-gene expression pattern was paired with total bilirubin level 3 months after Kasai, this identified children who survived with their native liver at 24 months with an area under the curve of 0.948 in the discovery set and 0.813 in the validation set (P<.001).
  • In those with transplant-free survival, many of the mRNAs expressed had increased scores for glutathione metabolism.  Subsequently, mice with BA were treated with NAC (which promotes glutathione metabolism) & had reduced bile duct obstruction, liver fibrosis, and increased survival times.
  • In children with lower survival rates, there was increased mRNA expression of proteins encoding fibrosis genes in the liver tissues.

My take: This 14-gene signature has the potential to change our approach to children with BA.  Also, when evaluating surgical success rate, these underlying genetic factors will need to be incorporated.

Image available online

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Exceptions for Valproate-Associated Liver Failure

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Recent guidelines (AASLD/NASPGHAN 2014 Guidelines for Evaluation of Pediatric …) have included valproate-associated acute liver failure (VPA-ALF) as an absolute contraindication to liver transplantation.  The reason is that most of these VPA-ALF patients have Alpers-Huttenlocher syndrome (AS) and have done poorly after transplantation due to progressive neurological decline.

AS in turn has been recognized as secondary to mutations in DNA polymerase subunit gamma (POLG1).  This gene product’s role is to maintain the integrity of mitochondrial DNA (mtDNA).

New data (Liver Transplantation 2014; 20: 1402-14, editorial 1287-89) suggests that there are exceptions for some cases of VPA-ALF.  In this report, 4 VPA-ALF patients with POLG1 mutations underwent successful liver transplantation.  Three are alive at followup 4-19 years later and one died suddenly 2 years after transplantation.

Key findings:

  • These cases had mutations in POLG1 associated with later onset and milder disease.
  • In the three long-term survivors, VPA was introduced at 14, 20 , and 21 years of life.

Take-home points:

  • For children less than 10 years of age, “VPA-ALF should remain an absolute contraindication to LT because neurological progression is almost inevitable.”  Supportive treatment, including N-acetylcysteine and carnitine should continue.
  • There is a “strong case for screening for POLG1 mutations before VPA use…even a single mutation should be seen as a contraindication to VPA.”

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Also, I added a link on yesterday’s post regarding measles to a story on NPR which explores the most recent increase in cases and provides background information.  For example: “Before a vaccine was developed in the 1960s, measles caused more than 2 million deaths per year.”  And worldwide, even now, “nearly 400 kids die from measles each day. In 2013, more than 70 percent of measles deaths were confined to six countries: the Democratic Republic of Congo (DRC), Ethiopia, India, Indonesia, Nigeria and Pakistan.”

NASPGHAN Postgraduate Course 2014 -Liver Module

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This blog entry has abbreviated/summarized the presentations. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.  I’ve attached the course syllabus as well:

PG Course Syllabus – FINAL

Primary Sclerosing Cholangitis –Dennis Black (Le Bonheur Children’s Hospital)

  • Up-to-date review provided
  • GWAS (genome-wide association study) identified 16 significant risk loci which account for only 7.3% of overall risk; environmental influences need to be worked out
  • Pediatric studies –total of 328 patients reported to date

Is pediatric disease the same disease as in adults?

  • Incidence in pediatrics: 0.23/100,000 incidence vs 1.1/100,000 in adults
  • Mean age at diagnosis 13 years in pediatrics.
  • 30% of pediatric patients have overlap with autoimmune hepatitis which is higher than in adult patients.

Other pointers:

  •  Discussed “Autoimmune cholangitis.” Imaging needed in autoimmune hepatitis to look for primary sclerosing cholangitis.
  • IBD Association with PSC: IBD occurs in about 55% of PSC patients. If PSC diagnosed first, usually with right-sided colitis.  If IBD diagnosed first, than pancolitis is more commonly noted.
  • Add IgG4 as part of workup to rule out IgG4 cholangiopathy (sensitive to immunosuppression).

Treatment:

  • Supportive care for cholestasis (vitamins, pruritus management, etc
  • Monitoring for complications (rare cases of cholangiocarcinoma in pediatric population).  14 drugs tested to date –mainly in adults.  “All without proven positive impact on long-term outcome.”
  • Ursodeoxycholic acid –widely used but controversial because higher doses associated with worsened outcomes in adult study (Lindor et al).  Ongoing study in pediatric population with ursodeoxycholic acid.
  • Vancomycin (Aliment Pharm 37: 2013; 604.  Adults n=35). Both Flagyl and Vanc seemed to be helpful. Uncontrolled pediatric studies with vancomycin reviewed. Vancomycin study in the works for pediatric/adults.
  • No prospective randomized controlled trials in children and very little data in adults. Hard endpoints –very difficult in children/not practical in children (eg. portal hypertension, transplant, death).

PSC and Transplantation: PSC 2.6% of total transplants –long-term outcome is similar.

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The Jaundiced Infant –Saul Karpen (Emory)

  •  “We don’t estimate jaundice very well… Our eyes do an awful job.”
  • Breastmilk Jaundice: Archives of Disease in Childhood 1978; 53: 506-16.  Only 12 of 853 had jaundice beyond 3 weeks of life.
  • Cholestasis. One of the best studies looking at etiology was recently published:  Hoerning A, et al Front Pediatr. 2014; 2: 65. N=82.  Only 1 patient had CMV.  41% had biliary atresia.

Biliary atresia (BA):

  • Reviewed study indicating that liver biopsy was most accurate means of making diagnosis of biliary atresia (blog comment: this study result may not be accurate in all settings as the interpretation relies on the ability/reliability of pathologist).  High utility of stool pigment & ultrasound (including flow).
  • In retrospective study (Pediatrics 2011; 128 e1428-33), all the BA patients had elevated direct bilirubin by 24-48 hrs of life.
  • Genetic panels and whole exome sequencing (~$4-7K) are happening now. Cost-effective.

Take-home message: Molecular understanding possible for conjugated/unconjugated hyperbilirubinemias. Direct bilirubin >1 is abnormal

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Acute Liver Failure –Estella Alonso (Children’s Hospital of Chicago) (pg 43)

Points:

  • Few patients receive a full diagnostic workup (J Pediatr 2009;155:801‐6)–especially with regard to metabolic and autoimmune disorders.
  • Reviewed etiologies –most frequently “indeterminant” especially in younger patients.  Acetaminophen is most frequent etiology in teenagers and adults.
  • Systemic inflammation is common in acute liver failure (Bucuvalas, J JPGN 2013;56: 311–315). Soluble IL2 receptor alpha –significantly higher in patients that died.  Immune regulation important aspect regarding survival. Should steroids be used in cases with high inflammation?

Prognosis: Squires et al. J Pediatr 2006;148:652-8, Lee et al. JPGN 2005;40:575-81, Baliga et al. Liver Transpl 2004;10:1364-71

  • 33% ‐53% survival with native liver
  • 61% survival including LT
  • 70%‐80% after LT
  • Multiorgan failure is most common etiology of death. Bleeding is “a rare cause of mortality.”

Management:

  • Reviewed including coagulopathy/bleeding, cardiovascular collapse, hepatic encephalopathy/cerebral edema
  • Pediatric N-acetylcysteine Trial Squires, et al Hepatology 2013;57:1542‐9 N=182.  Patients with NAC seemed to do worse, but not statistically proven.  This study has stopped the widespread use of NAC in acute liver failure.
  • Discussed approach to neurological complications in ALF. Hussain et al, JPGN 2014;58:449‐56. Retrospective study (n=18). Early EEGs obtained. Hypertonic saline may be more effective than mannitol.  Hypothermia may be helpful adjunct.
  • Timing of Transplantation discussed (pg 54 in syllabus). Difficult to predict spontaneous survival.

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  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.

This Year's Pumpkin

This Year’s Pumpkin

N-acetylcysteine for Acute Liver Failure

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A study which took 8 years to complete (2001-2009) and involved more than 20 pediatric liver transplant centers has shown that N-acetylcysteine (NAC) is NOT effective for nonacetaminophen acute liver failure in the pediatric population (Hepatology 2013; 57: 1542-49).

Eligible patients were drawn from a registry of pediatric acute liver failure (PALF) patients.  Among 607 who were enrolled in the registry, 271 were eligible for the NAC trial and 184 of these patients (families) agreed to participate.  The most common reasons for patients to be ineligible for the study included acetaminophen toxicity, previous NAC treatment, sepsis, and “reason unknown.”

The design of the study was doubly masked with patients stratified by age and hepatic encephalopathy.  Patients either received intravenous NAC (150 mg/kg/d) or D5W for up to 7 consecutive days.

Key findings:

  • No significant difference in 1-year survival: 73% of NAC patients and 82% of placebo patients
  • NAC patients had lower 1-year liver transplant free survival (p = 0.03): 35% in NAC group compared to 53% of placebo patients.

The study did have several limitations.  Despite the lengthy enrollment period, the absolute number of patients was only 92 in each group.  In addition, there were differences in the diagnoses in both groups and the ages of the groups, though these were unlikely to change the results.  With regard to diagnoses, both groups had ~60% with an indeterminate reason for PALF.  However, the NAC group had an increased number with metabolic diseases (14% compared with 5% in placebo group); the most common metabolic disease was Wilson’s disease (7 in NAC group and 3 in placebo group).  The NAC group had a median age of 3.7 years compared with 4.5 years for the placebo group.

Another limitation was in testing for acetaminophen-cysteine adducts (A-CA) which can be used as a marker of acetaminophen exposure.  This was performed retrospectively in 84 of the participants.  A-CA was positive in 9 (six from placebo and three from treatment arm).  Again, this was unlikely to change the results as there were no statistical differences in clinical features of those who were tested for A-CA compared with those who were not.

In some ways, the results are surprising due to prospective studies in adults showing benefit of NAC in ALF and a previous retrospective uncontrolled pediatric study suggesting efficacy in PALF.  Ultimately, this study proves again that pediatric patients are not “small adults” and highlights the need for prospective pediatric drug trials.

Bottom-Line:

NAC works for acetaminophen-induced ALF but is not helpful for other causes of PALF.

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