Category Archives: Pediatric Gastroenterology Liver Disease

Therapeutic Misadventures with Acetaminophen

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I first heard the title expression “Therapeutic Misadventure” from one of my mentors, Jim Heubi (J Pediatr 1998; 132: 22-27), though he did not coin the term.  As a personal aside, Jim interviewed me prior to my pediatric residency and helped convince me to train in Cincinnati.

Some have said the phrase is a ‘nice medical term for a mistake.’  A more precise definition: “therapeutic misadventure can be defined as an injury or an adverse event caused by medical management rather than by an underlying disease” (from the following link: Therapeutic misadventure).

The latest data on therapeutic misadventures with acetaminophen has emerged in a recent report: Pediatrics 2013; 131; e740-e746.

This observational cohort study analyzed a group of 666 children from 22 sites who were enrolled in the Pediatric Acute Liver Failure (PALF) study.  The children were subdivided based on acetaminophen (N-acetyl-p-aminophenol [APAP]) exposure: 85 with single toxic dose exposure (SE), 83 with chronic exposure (CE) ≥ 2 doses, and 498 with no exposure.

Among the CE group, 22% were assigned a final diagnosis of APAP toxicity; the majority in the CE group had 3 to 7 days of exposure to APAP.  The median dose was 31 mg/kg/day. Only 31 CE patients had serum APAP levels performed; in this group, a similar proportion to SE patients had elevated APAP levels ≥10 mg/L (68% in CE and 66% in SE).   Besides APAP toxicity, final diagnosis included indeterminate in 31 (37%), autoimmune (7%), metabolic (5%), infection (8%), and other (21%).

Among the SE group, 82 (96.5%) had APAP overdose as final diagnosis and 3 (3.5%) as indeterminate.

Among the NE group, 234 (47%) had a final diagnosis of indeterminate; other diagnosis in the remaining: infection 51 (10.2%), metabolic 72 (14.5%), autoimmune 34 (6.8 %), and other 107 (21.5%)

Clinical outcomes: 21 days after enrollment, 68% of CE patients were alive without liver transplantation; this compared with 92% of SE patients and 48% of NE patients.  In both the CE and NE patients, there was a high percentage of patients with indeterminate etiology.  Indeterminate ALF is associated with increased risk of liver transplantation and death.

Conclusions from the authors: a low serum bilirubin and high ALT should raise suspicion for CE to APAP.  CE patients outcomes were not as favorable as SE patients.  Better communication between physicians and families about the risk of prolonged use of APAP is needed.

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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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Hepatitis C Virus Sexual Transmission and Monogamy

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Numerous sources state that there is a low risk of transmitting Hepatitis C virus (HCV) among monogamous heterosexual couples.  More information on this subject has been published (Hepatology 2013; 57: 881-89).

In this study, 500 couples were studied; all were long-term heterosexual partners and all were HIV-negative.  The index partner was anti-HCV positive with a median age of 49 years and had a median of 15 years with their partner.  Condom use was infrequent among the study participants.

Key finding: HCV prevalence among partners was 4% (n=20) and ~2% (n=9) had concordant genotype/serotype.  The maximum prevalence of HCV transmission among these sexual partners was 1.2%.  Based on 8,377 person-years of follow-up, the maximum incidence rate of HCV transmission was reported as 0.07% per year or approximately one per 190,000 sexual contacts.

Some of the interesting aspects of the study included details of sexual activity and discussion of factors that may increase HCV transmission.  With regard to sexual activity, 30.4% of the couples reported prior anal intercourse and more than 90% reported oral sex (by both partners); however, both of these activities were reported as infrequent: typically 0 per month for anal intercourse and 3 contacts per month for oral sex.  With regard to HCV transmission, the authors did not identify any risk factors in the current study but did note that this may be influenced by viral titer, integrity of mucosal surfaces, and the presence of other infections.

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Increasing prevalence of pediatric NAFLD

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A recent study shows that the prevalence of nonalcoholic fatty liver disease (NAFLD) in adolescents has increased over a 20 year period in the U.S. (J Pediatr 2013; 162: 496-500).

Using a cross-sectional data from 12,714 adolescents, aged 12-19, from the National Health and Examination survey, the prevalence of suspected NAFLD has more than doubled over the past 20 years and currently affects nearly 11% of adolescents.  Approximately one-half (48%) of obese males have NAFLD.

Suspected NAFLD was defined as elevated ALT in an overweight or obese child.  Specific ALT values were chosen using sex-specific cut points (>25.8 U/L for boys and >22.1 for girls).

  • Besides increased NAFLD, the prevalence of obese BMI (≥95%) and severe obesity (BMI ≥99%) also increased steadily.  Between 1988-1994, obese BMI accounted for 11.2% and severe obese BMI 1.5%.  By 2007-2010, these increased to 20.% and 5.5% respectively.
  • For suspected NAFLD, in 1988-94 compared to 2007-2010, the prevalence went from 3.9% to 10.7%.

Probably the biggest limitation of this study was considering “suspected NAFLD” only in overweight or obese children.  The authors chose to do this to increase the specificity of their diagnosis and avoid overestimating the prevalence of NAFLD.

Related blog posts:

NAFLD Guidelines 2012 | gutsandgrowth

Pediatric NAFLD histology score | gutsandgrowth

Predicting outcome in Pediatric Acute Liver Failure

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In a recent study, soluble interleukin 2 receptor alpha (sIL2Rα) was identified as a marker associated with patient outcome in pediatric acute liver failure (JPGN 2013; 56: 311-5).

Because systemic inflammatory response and immune function have potential effects on the outcomes of patients with acute liver failure (ALF), the authors decided to study markers of T-cell immune activation in patients enrolled in the pediatric ALF (PALF) cohort. The PALF cohort was derived from the PALF study group which consists of 20 sites.  All of the enrollees from this study were from the 17 U.S. sites.

Design: Blood was collected within 48 hours of enrollment into the PALF cohort.  Blood had to received by the testing laboratory within 24 hours of collection.  The final study group included 77 patients, though outcomes for two patients (who were discharged alive within 10 days of enrollment) were not known.  Blood was tested for numerous markers including “CD56 bright,” perforin, Natural Killer T-cell (NKT) perforin, NK lytic activity, granzyme B, CD8, CD16, CD56 and others.  Outcomes were assessed within 21 days of enrollment.

Results:

  • Acetaminophen was the most common identifiable reason for PALF (n=13) and all acetaminophen patients survived without liver transplantation.
  • Other etiologies included autoimmune marker positive-ALF (n=8), Drug-induced ALF (n=2), viral ALF (n=6), metabolic (n=7), hemophagocytic lymphohistiocytosis (HLH) (n=3), and shock/ischemia (n=3).  Besides indeterminant ALF (n=27), all other diagnosis had n=1.
  • Age was distributed across all pediatric groups: < 5 years (n=24), 5-9 years (n=19), >9 years (n=34).
  • Of all the markers of T-cell immune activation, only sIL2Rα was identified as being able to discriminate between survival with native liver, liver transplantation, and death.
  • Of the 15 subjects with markedly elevated sIL2Rα (>5000 IU/mL), 5 (33%) survived with native liver, 2 died, and 8 underwent liver transplantation. In contrast, all 37 patients with normal sIL2Rα lived, 30 (81%) with their native livers.

Study limitations included the cross-sectional design which entailed measuring sIL2Rα at a single point in time.  In addition, it is not clear whether sIL2Rα levels reflect a causal role in liver injury or a response to liver injury.

Take home message:

sIL2Rα along with traditional measures could improve the ability to predict hepatic recovery in PALF.

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Copper in Cholestasis

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More data indicate that copper levels in infants receiving parenteral nutrition are usually not affected by cholestasis (JPEN 2013; 37: 92-96).

A retrospective study reviewed all patients younger than 1 year who had copper levels measured between 1999-2009 at Riley Hospital for Children.  Inclusion criteria: parenteral nutrition for at least 50% of caloric needs and cholestasis (direct bilirubin >2 mg/dL).

Key findings:

  • 26 of 28 patients had gastrointestinal disorders.  82% were receiving standard parenteral nutrition (PN) dose of copper (20 mcg/kg/day).
  • Only one elevated copper level was found in a child with congenital heart disease.
  • 46% (n=13) of cholestatic infants had low copper levels.  Three of theses infants had no copper in their PN.
  • There was no correlation between bilirubin level and measured copper values.

Bottomline:

Measure copper values periodically in patients requiring parenteral nutrition.  Most patients, even cholestatic patients, will require standard dosing but some will need less and some more.

Additional References:

  • -JPGN 2010; 50: 650-54.  n=28.  (only 2 had elevated Cu). Typical Cu supplementation in HAL did not lead to significant increase in Cu toxicity or worsening of liver disease in cholestatic infants.  Study prompted by single infant who developed Cu deficiency/anemia.
  • -Clin Gastro & Hepatol 2004; 2: 1074. Two patients with Cu deficiency after bariatric surgery
  • -JPGN 2000; 31: 102-111. (review)

More options for Hepatitis C

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As noted in numerous blog entries (see below), there has been increasing availability of new and more effective treatments for Hepatitis C virus (HCV).  Two more drugs have promising results:

  • NEJM 2013; 368: 34-44
  • NEJM 2013; 368; 45-53

The first study provides encouragement with regard to sofosbuvir (previously known as GS-7977) which is a direct-acting nucleotide polymerase inhibitor targeting the NS5B polymerase.

In this open-label study, there were eight groups of patients.  Of 40 previously untreated patients (genotype 2 or 3), all patients received sofosbuvir (400 mg daily) for 12 weeks.  All 10 who received the study drug with ribavirin (& without interferon) and all 30 who received the study drug with ribavirin and peginterferon had a sustained virologic response (SVR) at 24 weeks.  Among patients with sofosbuvir monotherapy, 6 of 10 had a SVR.  Among HCV genotype 1 patients, 21 of 25 (84%) previously untreated patients had a SVR. The most common adverse effects were headache, fatigue, insomnia, rash and anemia.

The second study also was a phase 2a, open-label study for HCV genotype 1 non-cirrhotic patients using ABT-333 and ribavirin.  ABT-333 is a nonnucleoside NS5B polymerase inhibitor.  Results: 17 of 19 (89%) patients in group 1 (Rx with ABT-333, ribavrin, ABT-450, and ritonavir), 11 of 14 (79%) patients in group 2 (Rx with same drugs at lower doses of latter two drugs) had extended rapid virologic response.  SVR was achieved in 95% and 93% respectively.  Groups 1 and 2 were previously untreated.  Group 3 were patients who had either a null or partial response to previous treatment achieved a 47% SVR.  The most common adverse effects were abnormalities in liver function tests, headache, fatigue, insomnia, pruritus, nausea and rash.

Bottom-line:

These preliminary results suggest that Sofosbuvir is effective in all genotypes and may allow a short duration all-oral regimen.  ABT-333 similarly is effective in an all oral regimen in genotype 1 patients.

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Pediatric NAFLD histology score

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Pathologists may be more interested in this article than many pediatric gastroenterologists (J Hepatol 2012; 57: 1312-18).  Yet, the development of the pediatric NAFLD (non-alcoholic fatty liver disease) histological score (PNHS) is likely to be helpful, particularly in research of NAFLD.

In this study, an initial training set of 203 children with biopsy-proven NAFLD were examined.  After designing a scoring system, the PNHS was validated in another 100 children.  The mean age was 12.4 years.

PNHS = 100 x esp(Zphs)/[1 + exp(Zphs)]

Zphns = -8.4 + (2.5 x steatosis) + (3.5 x ballooning) + (3.4 x lobular inflammation) + (0.87 x portal inflammation)

This score is easily calculated by entering the individual histological features at the following website:

  • steatosis 1-3 (1=5%-33%, 2=34%-65%, 3=≥66%)
  • ballooning 0-2 (0=none, 1=few, 2=many)
  • lobular inflammation 0-3 (0=none, 1=<2 under 20x, 2=2-4 under 20x, 3=>4 under 20x)
  • portal inflammation 0-2 (0=none, 1=mild, 2=more than mild)
  • http://rcc.simpal.com/RCEval.cgi?RCID=RPCxtv#Result

Results:

  • In NASH patients, the mean PNHS was 89 ± 20.5 compared to 21.9 ± 24.5 in the non NASH patients.
  • There was a high level of agreement between categorization of NAFLD cases using PNHS compared with pathologist diagnosis.
  • NASH patients were much more likely to have metabolic syndrome (64%) compared with 38% for non-NASH patients
  • Of the histologic features, ballooning was the feature that most distinguished the cohorts.  In 66% of NASH patients, few or many ballooning hepatocytes were noted, whereas 96% of non-NASH patients had no ballooning noted.
  • With PNHS of ≥85, the sensitivity is 76-77% and the specificity is 91-97% for NASH.  This will decrease the number of ‘borderline NASH’ cases in pediatric cohorts.

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Liver transplant outcomes in the boonies

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It looks like living in the boonies (URBAN DICTIONARY: BOONIES) does not make a big difference in pediatric liver transplantation (LT) outcomes (J Pediatr 2013; 162: 313-8).

The authors analyzed 3307 pediatric patients using the United Network Organ Sharing (UNOS) database between 2004-09.

Key outcomes for rural location:

  • Associated with greater risk of allograft rejection in the first 6 months after LT with an OR 1.27 (27% compared with 22.9% of urban patients).  The risk allograft rejection was not statistically significant at 1 year post LT (OR 1.18).
  • Associated with lower risk of post transplantation lymphoproliferative disorder (PTLD) with an OR of 0.64.  In total, 2.4% of rural patients experienced PTLD compared with 3.8% of urban patients.
  • Allograft loss and survival were similar for rural patients as for patients: 21.3% and 14.1% respectively compared with 20.7% and 12.7%.

The opposite risk ratios with regard to rejection and PTLD indicates that rural status may have greater rates of nonadherence with maintenance immune-suppression. However, the lack of a larger discrepancy in outcomes comes as a pleasant surprise, particularly as rural status is a known risk factor for worse health outcomes in many other complex chronic diseases.  Perhaps, this study validates the high level of skill and teaching on the part of pediatric liver transplant teams as well.

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Could Cysteamine help NAFLD?

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Maybe (J Pediatr 2012; 161: 639-45, editorial p 579).

Cysteamine bitartrate has been used in cystinosis and reduces intralysosomal Cys accumulation.  It has potential antioxidant and antiapoptotic effects.  A pilot study has shown that cysteamine may improve NAFLD through unclear mechanisms and may reduce aminotransferase levels in the serum along with increasing adiponectin levels (reduced in NAFLD).

Adiponectin is produced by adipocytes and helps regulate glucose and lipid homeostasis.  It has insulin-sensitizing properties as well as anti-inflammatory effects. Adiponectin levels inversely correlate with degree of obesity and insulin resistance.

In this study of 10 children with biopsy-proven NAFLD, cysteamine therapy was administered for 24 weeks.

  • Following therapy, multimers of adiponectin were increased and total adiponectin level increased 49.3% (P = 0.05).
  • ALT dropped from a mean of 123 IU/L at baseline to 55 IU/L at 24 weeks.
  • AST dropped from a mean of 61 IU/L at baseline to 32 IU/L at 24 weeks.
  • Adiponectin values returned to baseline 16 weeks after completing treatment while aminotransferase values remained low.

The editorial notes that an NIH-funded NASH clinical research network study will investigate cysteamine in a much larger cohort.

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