Category Archives: Pediatric Gastroenterology Liver Disease

Recurrent Acute Liver Failure due to NBAS Deficiency

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A recent case report (V Cardenas et al. J Pediatr 2017; 186: 179-82) describes recurrent acute liver failure (ALF) in the setting of neuroblastoma amplified sequence deficiency (NBAS).

The case report describes a 2 yo who developed very elevated aminotransferases (ALT >14,000), hypoglycemia, severe coagulopathy (INR 4.5)), lactic acidosis (6.5 mmol/L) and hyperammonemia (282 μmol/L) following a febrile illness.

Genetic testing uncovered 2 variants in the NBAS gene consistent with NBAS deficiency.

Key points:

  • Mutations in NBAS “have been identified as a molecular cause of ALF in children, leading to recurrent episodes of ALF after a febrile illness.”
  • NBAS deficiency should be part of the differential diagnosis of ALF in children
  • In a report of 14 patients with this disorder (J Inherit Metab Dis 2016; 39: 3-16), liver function normalized in between episodes.  Typically, episodes were most severe at younger ages.  ALF “may be prevented through early and effective antipyretic therapy and intravenous application of glucose and lipids.”

My take: NBAS deficiency, along with hemophagocytic lymphohistiocytosis (HLH), infections, and Kawasaki’s disease, needs to be considered in children with severe liver dysfunction associated with fevers.

“Big Improvements for Smallest Recipients” with Bad Liver Disease

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A recent study (M Kasahara et al. Liver Transplantation 2017; 23: 1051-7, editorial 977-8) indicates improvement in survival among the smallest liver transplant patients. In this study of 12 patients less than 3 months of age, the cumulative 10-year patient and graft survival for both was 90.9%.

These patients received living donor liver transplantation. Living donors likely contributed to the excellent outcomes both in terms of enhancing the timing of transplantation and also with regard to size.  Whole organs are not likely to fit well in these small abdomens. The size of the patients ranged from 2.8 kg (at 29 days) to 5.5 kg).  11 of 12 had fulminant hepatic failure with 6 of these cases being considered unknown etiology.

Limitation: This was a very small sample size.

Programming for Fatty Liver Disease May Occur Prior to Birth

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A recent study (KP Newton et al. J Pediatr 2017; 187: 141-6; associated editorial pg 13-15)) in a multicenter retrospective cross-sectional study of children (n=538) with biopsy-proven nonalcoholic fatty liver disease (NAFLD) showed that birth weight influenced the development of NAFLD.  The participants were enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN).

Key findings:

  • There was increased NAFLD among both low birth weight (LBW) and high birth weight (HBW).
  • LBW occurred more commonly in the NAFLD cohort 9.3% compared with the general population prevalence 6.1%.
  • HBW occurred more commonly in the NAFLD cohort 14.9% compared with the general population prevalence 10.5%

The authors speculate that the explanation/mechanisms for increase in both LBW and HBW are likely to differ. It has been recognized that LBW is associated with higher cardiovascular disease and type 2 diabetes.  HBW start bigger and often stay bigger; that is, there are increased risks of more severe obesity.

There are numerous limitations to this study -there is a lot of data that is not available, including gestational age, maternal weight, breastfeeding exposure, and antibiotic administration.

My take: These findings add to the literature that risks for NAFLD along with other metabolic problems may be present at birth.  Is there a way to modify this risk?

Related study: ET Jensen et al. J Pediatr 2017; 187: 50-7, editorial pg 10-12.  In this study of 535 ten-year-old children, enrolled in a prospective multicenter extremely low gestational age newborn cohort study, the authors found that maternal overnutrition and undernutrition affected the brain health of these children. The authors used neurocognitive assessment tools.

  • Children born to women with a pregravid BMI >30 scored “lower on measures of general cognitive ability, executive functioning, fine motor function, and academic achievement.”
  • Children born to women with inadequate maternal weight gain during pregnancy had “lower language and academic achievement.”

Hidden Falls, Highlands NC

 

6-Thioguanine Levels in Autoimmune Hepatitis

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A recent retrospective study (MA Sheiko et al JPGN 2017; 65: 80-5) examines the issue of azathioprine (AZA) metabolites and outcomes in pediatric autoimmune hepatitis (AIH).

Study characteristics:

  • 66 children
  • Mean age of diagnosis 9.6 years
  • Mean follow-up 2.9 years
  • Study period 2002-2013

Key findings:

  • 79% achieved biochemical remission (defined as ALT ≤50 U/L); mean time was 6.2 months
  • 6% required liver transplantation
  • 18% were weaned off immunosuppression and remained in remission
  • 6-thioguanine (6-TGN) levels ranging from 50 to 250 (pmol/8 x 10 to 8th red blood cell count) were associated with biochemical remission

“Our study suggests that AZA dosing of approximately 1.2 to 1.6 mg/kg/day will achieve 6-TGN levels of 50 to 250 pmol, which is sufficient to maintain biochemical remission in the majority of patients.“

This is significantly lower than dosing recommended for inflammatory bowel disease (recommended levels 250-450). The associated editorial (pg 2-3, N Kerkar) cautions that while “lower levels are sufficient for maintaining biochemical remission…higher levels, similar to that used in IBD, are required for inducing remission.”

My take: Lower doses of azathioprine are likely to maintain biochemical remission and cause fewer side effects.  Metabolite levels can be helpful to assure reasonable levels of 6-TGN and to assure medication adherence.

Related blog entries:

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

Shem Creek, SC

Neonatal Cholestasis for Neonatologists

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I recently had the opportunity to review the topic of neonatal cholestasis with my neonatal colleagues.  I reviewed two related conditions: parenteral nutrition associated liver disease (PNALD) and neonatal acute liver failure (NALF).  Some of the material incorporates recommendations from NASPGHAN cholestasis guidelines and from NASPGHAN cholestasis slidesets. Much of the slideset information is publicly available on a YouTube lecture by Dr. Linda Book (link at bottom).

Full lecture: Neonatal Cholestasis for Neonatologists

Some screenshots:

Related blog posts:

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

 

Predicting Future Liver Disease with GGT Levels in Biliary Atresia Patients

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A recent study (AJ Freeman, VL Ng, S Harpavat, A Hrycko, Z Apted, P Bulut, T Leong, SJ Karpen. Clin Gastroenterol Hepatol 2017; 15: 1133-35) describes the predictive value of γ-glutamyltransferase (GGT) in predicting thrombocytopenia/portal hypertension among biliary atresia patients.

In this retrospective study from three centers who had followup for at least 4 years, GGT values at 2 years of age were examined among biliary atresia patients (n=46) who continued with their native liver.

Key findings:

  • GGT ≥100 U/L had a predictive positive relationship with thrombocytopenia at 4, 5, and 6 years of age.  Patients with elevated GGT had lower platelet count (160 vs. 211) and their values continued to decline. GGT ≥100 U/L at 2 yrs predicted thrombocytopenia (<150) at age 4 with a sensitivity of 0.88, specificity of 0.57.
  • Patients with normal GGT values had “essentially stable platelet counts over the next 4 years.” GGT <100 U/L at 2 yrs predicted a low risk of thrombocytopenia with negative predictive value of 0.89, 0.92, and 0.93 at age 4, 5, and 6 respectively.

My take: This study quantitates a useful point –patients with biliary atresia and elevated GGT values are likely to develop evidence of portal hypertension.

Brevard, NC

Briefly Noted: Outpatient Liver Biopsy

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A small retrospective study (R Bolia et al. JPGN 2017; 65: 86-88) with 497 patients (626 biopsies) found that all complications were identified within 8 hours.  Thirty (48%) had complications, with a subcapsular hematoma being most common (n=14).  Less common adverse events included fever (n=5), skin site ooze (n=3), intraperitoneal bleeding (n=3), hemobilia (n=2), anaphylaxis to gelfoam (n=2), and sepsis (n=1). In this study, the majority of biopsies were performed by interventional radiology (n=492); though, the complication rate was similar in both groups.

The authors conclude that their data support the outpatient liver biopsies in children.

My take: I disagree with the authors’ conclusion to some extent.  Their population is too small to detect rare but severe complications.  Our empiric practice is watch children older than 6 years of age for 6 hours and watch younger children (or others deemed at increased risk) for 24 hours.

Related blog posts:

Prague

Slim Pickings: Data for 2nd-Line Autoimmune Hepatitis Pediatric Therapy

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A recent study (AN Zizzo et al. JPGN 2017; 65: 6-15) performed a systematic review and meta-analysis of pediatric autoimmune hepatitis (AIH) studies.

The most remarkable finding was that there were only 76 patients from 15 qualifying studies.

Other findings:

  • Response to mycophenolate mofetil (MMF) with 34 patients was 36% (according to abstract) at 6 months  (discrepancy in article –results state 38% response)
  • Response to cyclosporine with 15 patients was 83% (discrepancy in article –results state 86% response)
  • Response to tacrolimus with 4 patients was 50%
  • Adverse effects were very common, particularly with cyclosporine (64% noted at least 1 adverse effect)

The article has an associated editorial (N Kerkar, pg 2-3).  “The adverse event profile of cyclosporine with gingival hyperplasia, hypertrichosis, nephrotoxicity, and neurotoxicity made it challenging for long-term use in children.”  Besides the small number of patients, “the studies that were included were largely “observational”‘ which limits their findings as well.  The study authors recommend MMF as the preferred option for 2nd-line therapy.

My take: Fortunately, most patients with autoimmune hepatitis respond to first line therapy with azathioprine/steroids.  It is unclear what is the optimal 2nd-line treatment for refractory patients.

Related blog entries:

Egret, Shem Creek

Hepatitis B Reactivation Due to Immunosuppressive Therapies

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The topic of Hepatitis B virus (HBV) reactivation has been discussed on this blog before (see link below).  Another excellent review on this topic (R Lomba, TJ Liang. Gastroenterol 2017; 152: 1297-1309) has been published.  The authors examine the course and mechanisms of HBV reactivation.  They divide the risk of reactivation into three groups: high, moderate and low risk and proposed management.

High risk groups, which have >10% risk of reactivation) include the following

  • B-cell-depleting agents including rituximab, ofatumumab, alemtuumab, and ibritumumab
  • High-dose corticosteroids (>20 mg/day in adults)
  • Antracyclines including doxorubicin
  • Potent TNF-α inhibitors: infliximab, adalimummab, certolizumab, and golimumab
  • Local therapy ofr HCC including TACE (transarterial chemoembolization)

Moderate groups (1-10% reactivation) include cytokine-based Rx (eg. abatacept, ustekinumab, natalizumab, vedolizumab), cyclosporine, systemic chemotherapy, moderate corticosteroid dosing

Low risk groups (<1% reactivation) include thiopurines (azathioprine, 6-mercaptopurine), and methotrexate as well as short-term low-dose corticosteroids.

Management:

  • For HBV screening, the authors recommend HBsAg and anti-HBc testing
  • Prophylactic therapy with potent oral anti-HBV therapies are recommended for those at moderate or high risk of reactivation.  In those at low risk, the options include prophylactic treatment or watchful monitoring.
  • A more detailed algorithm is provided in Figure 3.  In those with HBsAg positivity, if HBV DNA is less than 2000 U/mL, this algorithm suggests monitoring labs (HBsAg, ALT, HBV DNA every 3 months)

Mechanisms of HBV reactivation are discussed.  For example, with TNF-α inhibitors “can activate a unique host antiviral pathway, the APOBEC (apolipoprotein B mRNA editing enzyme, catlytic polypeptide-like) proteins, that cause the degradation of cccDNA in HBV-infected cells. Thus, blocking this endogenous antiviral pathway may lead to a higher HBV replication state and HBV reactivation.”

My take: In pediatric gastroenterology, we do not see a lot of HBV reactivation. Nevertheless, we do use many of the medications which can trigger HBV reactivation and need to keep these recommendations in mind.

Related blog post: What HBV Testing is Needed Before TNF Inhibitor Therapy

Suntrust Park

Acute Liver Failure -Pediatric ICU Management

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Full Text Link: Intensive Care Management of Acute Liver Failure

This article provides a very good overview of this topic starting withe diagnosis, epidemiology and proceeding to specific management issues/outcomes.

Table 1 reviews etiologies –indeterminant is most common. Table 2 shown below reviews management principles and Table 3 reviews specific treatments based on etiology. Table 4 reviews grades of encephalopathy.

My take (from authors): “Despite recent advances in supportive care and the improvements in outcomes observed…the practical intensive care management of PALF remains poorly defined…Current treatment options are merely supportive and based on incomplete adult data and local institutional experience.”

Related blog posts: