studies

1044A AASLD ABSTRACTS HEPATOLOGY, October, 2015
grated clusters with diagnosis-based groups was 0.44(perfect
similarity =1). Within the 8 groups, children with PSC were
divided into 2. Those with AIH clustered across multiple groups
that mostly did not include lupus patients. Conclusion:Our data
suggests AIH and SLE-associated hepatitis exist as 2 distinct
conditions that cluster differently with other causes of elevated
liver enzymes. Identifying key differentiating groups of features
that drive the similarities between children with elevated liver
enzymes may assist in better future management and understanding
of their disease.
Disclosures:
The following authors have nothing to disclose: Andreanne Benidir, Brian M.
Feldman, Anna Goldenberg, Earl Silverman, Sindhu Johnson, Binita M. Kamath
1714
Screening for Mitochondrial Disease in Pediatric Acute
Liver Failure: The Role of Lactate and Pyruvate
Amy G. Feldman 1,5 , Ronald J. Sokol 1,5 , Regina M. Hardison 4 ,
Estella M. Alonso 2,6 , Robert H. Squires 3,7 , Michael R. Narkewicz
1,5 ; 1 Pediatric Gastroenterology, Hepatology and Nutrition,
Children’s Hospital Colorado, Aurora, CO; 2 Department of Pediatrics,
Ann and Robert H Lurie Children’s Hospital of Chicago,
Chicago, IL; 3 Division of Gastroenterology, Children’s Hospital
of Pittsburgh, Pittsburgh, PA; 4 Graduate School of Public Health,
University of Pittsburgh, Pittsburgh, PA; 5 University of Colorado
School of Medicine, Aurora, CO; 6 Northwestern University Feinberg
School of Medicine, Chicago, IL; 7 University of Pittsburgh
School of Medicine, Pittsburgh, PA
Objectives: Mitochondrial disorders can cause pediatric acute
liver failure (PALF). Screening for mitochondrial disorders using
serum lactate and lactate/pyruvate (L:P) molar ratio has been
recommended, yet the diagnostic utility of these tests in PALF
has not been systemically analyzed. The goals of this study
were to determine whether 1) the L:P ratio is a sensitive and
specific test to screen for a mitochondrial, respiratory chain, or
fatty acid oxidation (Mito) disorder in children with PALF and
(2) the L:P ratio correlates with clinical outcome at 21 days.
Study Design: A retrospective review was conducted of demographic,
clinical, laboratory, and outcome data for patients in
the NIH-supported PALF Study dataset who had lactate and
pyruvate levels collected on the same day (within 7 days of
enrollment) and a serum lactate level ≥2.5 mmol/L. The Kruskal-Wallis
test and Pearson chi-square were used to compare
continuous variables and proportions, respectively, among the
diagnosis groups. Spearman correlations were used to estimate
the association between L:P and clinical labs. Multinomial
logistic regression was used to estimate the effect of L:P group
on outcome. Results: Of 986 subjects, 110 had lactate and
pyruvate levels collected on the same day, 74 (67 %) of whom
had a lactate level ≥2.5 mmol/L. Of these 74 participants,
39 (53%) were male; median age was 2.0 years (IQR 0.36-
5.9). Six (8%) had a Mito disorder, 22 (29.7%) had another
confirmed diagnosis, and 46 (62.2%) had an indeterminate
diagnosis. There were no significant differences in the lactate
levels, pyruvate levels, or L:P ratios between these three groups.
Although 6 Mito group subjects had lactate ≥2.5mmol/L, only
2 had L:P ratio ≥25. The percent with elevated L:P ratio≥ 25 did
not differ by diagnostic group (33% Mito, 64% other diagnosis
and 54% indeterminate diagnosis). There was no significant
relationship between the L:P ratio and the AST/ALT ratio, INR,
ammonia, creatinine kinase, acylcarnitine profile, or glucose
levels nor was there a significant relationship between initial
L:P ratio and clinical outcomes at 21 days (alive with native
liver, alive with transplanted liver, dead). Conclusions: A high
serum lactate and/or elevated L:P ratio were common in all
causes of PALF, were not diagnostic for a mito cause, and did
not predict 21 day clinical outcome. This suggests that either
mito dysfunction is common in all causes of PALF, that mito
disorders are misdiagnosed, or that L:P ratio is not specific for
mito disorders. Patient age and clinical features remain the
most helpful diagnostic clues for mito disorders, which must be
confirmed by genetotyping or tissue enzymology.
Disclosures:
Ronald J. Sokol - Advisory Committees or Review Panels: Yasoo Health, Inc.; Consulting:
Roche, Ikaria, Otsuka American Pharmaceuticals, Alnylam, Retrophin;
Grant/Research Support: Mead Johnson Nutritionals, Lumena, FFF Enterprises
Michael R. Narkewicz - Consulting: Vertex; Grant/Research Support: Novartis,
Vertex; Stock Shareholder: Merck
The following authors have nothing to disclose: Amy G. Feldman, Regina M.
Hardison, Estella M. Alonso, Robert H. Squires
1715
Nocturnal Hypoxia is associated with Hedgehog Signaling
and Severity of Pediatric Non-Alcoholic Fatty Liver
Disease (NAFLD)
Shikha Sundaram 1 , Marzena Swiderska-Syn 2 , Ronald J. Sokol 1 ,
Zhaoxing Pan 1 , Ann C. Halbower 1 , Kelley E. Capocelli 1 , Kristen
N. Robbins 1 , Anna Mae Diehl 2 ; 1 Children’s Hospital Colorado,
Aurora, CO; 2 Duke University, Durham, NC
Chronic intermittent nocturnal hypoxia is associated with
NAFLD progression. Deregulation of the Hedgehog (Hh) pathway
has also been implicated in NAFLD pathogenesis and
progression. Objective: To determine relationships between
obstructive sleep apnea (OSA), hypoxia, and Hh signaling in
pediatric NAFLD. Methods: 31 adolescents with biopsy-proven
NAFLD (mean age: 13 ± 1.9 yrs; mean BMI z score: 2.2 ±
0.3, 65% male, 87% Hispanic) underwent polysomnogram,
liver histology scoring, and laboratory testing. Sonic hedgehog
(SHh), Indian Hh (IHh), Glioblastoma associated oncogene
2 (Gli2), and markers of progenitors (keratin 7- K7) and
myofibroblasts (α-SMA) were evaluated by immunohistochemistry.
Results: Subjects with (68%) and without (32%) OSA/
hypoxia had similar aminotransferases, serum lipids, inflammatory
and insulin resistance markers. As expected, α-SMA
generally correlated with fibrosis stage (r=0.44, p=0.02). Steatosis
was inversely correlated with IHh (r=-0.48, p=0.009)
and the NAS score correlated with SHh (r=0.39, p=0.03) and
α- SMA (r=0.42, p=0.02). SHh correlated with AST (r=0.64,
p=0.0001) and ALT (r=0.51, p=0.003). Gli2 also correlated
with AST (r=0.47, p=0.007) and ALT (r=0.43, p=0.02). AST
correlated with K7 (r=0.45, p=0.01), and ALT with α-SMA
(r=0.51, p=0.005). Subjects with OSA/hypoxia had higher
mean Apnea Hypopnea Index (AHI), % time oxygen saturation
(SaO 2
)