Lippincott Williams & Wilkins



Supplementary Digital Content (SDC)S1: Screening evaluation in all patients Etiological EvaluationHepatotrophic viruses- IgM Hepatitis A, IgM Hepatitis E, HbsAg, IgM Anti Hbc.Other viruses- IgM Epstein Barr virus, IgM Cytomegalovirus, IgM Parvo virus (where indicated). Wilson disease-Serum Ceruloplasmin, 24 hour urinary copper, DCT, Evidence of Hemolysis, KF Ring (If possible). Autoimmune- DCT, ANA/ASMA/LKM-1/SLA, IgG.Hemophagocytosis- Serum triglyceride, cholesterol, ferritin and bone marrow biopsy (If Fever/Splenomegaly/Bicytopenia) Subject EvaluationDetailed historical evaluation including age, gender, clinical symptomatology, detailed past, development, birth and family history was elicited from the subjects/parents. Laboratory evaluationAll the subjects underwent detailed lab evaluation including complete liver function test (serum bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma glutamyl transpeptidase, albumin), international normalized ratio, serum creatinine, blood urea, serum electrolytes, serum uric acid, metabolic Screen (random plasma glucose, arterial ammonia, arterial blood gas analysis, urinary ketones, urine non glucose reducing substances, serum creatine phosphokinase). Echocardiography and Ultrasonography of abdomen was performed by trained and experienced operators. Samples for metabolic testing included plasma sample for Tandem Mass Spectrometry (TMS) for Carnitine/Acylcarnitine Profile (and amino-acid analysis) and urine sample for Gas Chromatography and Mass Spectrometry (GCMS) were collected within 4 hours of admission. Age wise cut offs were used for analyzing metabolites’ results [1-4]S2: Specific metabolic abnormalities detected in fatty acid oxidation disordersFatty acid oxidation disorderPlasma acylcarnitineUrine organic acidsCarnitine uptake defect Decreased C0 (free carnitine), Decreased long-chainacylcarnitinesNormal or Elevated dicarboxylic acidsCarnitine palmitoyltransferase-I Elevated C0, Decreased long-chain acylcarnitinesUsually normalCarnitine palmitoyltransferase-II Elevated C16, C18:1, C14, low C2 NormalCarnitine acylcarnitine translocase Elevated C16, C18:1, C14, low C2Normal or Elevated dicarboxylic acidsVery-long-chain acyl-CoAdehydrogenaseElevated C14, C14:1/C12:1Elevated Dicarboxylic acidsLong-chain 3-hydroxyacyl-CoAdehydrogenase/mitochondrialtrifunctional proteinElevated C16 OH, C18:1 OH, C14 OHElevated Dicarboxylic acids, Elevated hydroxydicarboxylic acids (3-hydroxyadipic acid, 3-hydroxysebacic acid)Medium-chain ketoacyl-CoA thiolase UnknownElevated Lactic, 3-hydroxybutyric, saturated and unsaturated C6–C16dicarboxylic acidsMultiple acyl-CoA dehydrogenase/glutaric aciduria IIElevated C4, C5, C5 DC, C6, C8, C10, C12, C14Elevated Glutaric acid, isobutyrylglycine, ethylmalonic acid,dicarboxylic acids, acylglycines (phenylpropionylglycine),2-hydroxyglutaric acidSuccinyl-CoA: oxoacid transferase NormalNormalMedium-chain acyl-CoAdehydrogenaseElevated C8, C10, C10:1Elevated Dicarboxylic acids, acylglycines (suberylglycine,hexanoylglycine), 5-hydroxyhexanoic acid, octanedioic acid, decanedioic acidMedium/short-chain acyl-CoAdehydrogenaseElevated 3-OH-C4Elevated Dicarboxylic acids, 2-hydroxyglutaric acidShort-chain acyl-CoA dehydrogenase Elevated C4 (butyrylcarnitine and butyrylglycine)Elevated Ethylmalonate, methylsuccinateEthylmalonic encephalopathy Elevated C4, C5Elevated Lactic acid, ethylmalonate, methylsuccinate2,4-Dienoyl reductase Hypocarnitinemia, 2-trans, 4-cisdecadienoylcarnitinein both urine and bloodNormal3-Hydroxy-3-methylglutaryl-CoAsynthase 2Normal Normal3-Hydroxy-3-methylglutaryl-CoAlyaseElevated C5OHElevated 3-Methylglutaric acid, 3-methylglutaconic acid, 3-hydroxy-3-methylglutaric acid, 3-methylcrotonylglycineβ-KetothiolaseNormal or Decreased C0Tiglylglycine, acetoacetic acid, 2-methylacetoacetic acidS3: Consort diagram depicting patient selectionGroup 1Children (0-18 years age) with ALF(n= 38)Group 2Adults (> 18 Years age) with ALF(n=26) Step 1History , Baseline and Etiological EvaluationAll ALF Cases(n= 55)Pediatric Group(n= 33)Adult Group(n = 22)Step 2 Metabolic TestingExcluded:On Valproate Therapy (n=2)Delayed sampling beyond 4 hours (n = 3)Excluded:Delayed sampling beyond 4 hours (n = 4)Abbreviation: ALF- Acute liver failureS4- Comparison of proportions for predicting outcome (Death or Liver transplantation/LT vs Survival) in the overall group (n = 55)Parameter(Normal Value)Death/LT(n= 27)Survived (n= 28)OR, 95 % CI , p-ValueHigh Methionine24175.18, 1.25 to 21.41, 0.016High Phenyalanine8111.37, 1.31 to 98.59, 0.012High Tyrosine1564.58, 1.41 to 14.91, 0.009High Arginine422.26, 0.38 to 13.51, 0.422Hyperaminoacidemia (elevation of > 1 aminoacid)24193.789, 0.89 to 15.97, 0.059Low Free Carnitine (C0)12111.236, 0.42 to 3.61, 0.698Abnormal Carnitine profile (any abnormality)14170.69, 0.24 to 2.03, 0.508Abbreviations- OR- Odd’s Ratio, CI- Confidence interval. S5: Liver biopsy figure showing Diffuse Hepatocyte steatosis with minimal fibrosis and inflammation in Case 1abcS6: Liver biopsy figure showing Steatohepatitis with Pericellular fibrosis in Case 2abReferencesSchmidt-Sommerfeld E, Werner E, Penn D: Carnitine plasma concentrations in 353 metabolically healthy children. Eur J Pediatr 1988;147:356-360. . Accessed January 2, 2015.. Accessed January 2, 2015.. Accessed January 2, 2015. ................
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