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MLD presenting with ALF Talk by Dr SK Yachha

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  • 1. Surender K Yachha Professor and HeadDepartment of Pediatric Gastroenterology Sanjay Gandhi Postgraduate Institute of Medical sciences, Lucknow, India
  • 2. Definition Acute liver failure Encephalopathy within 8 weeks of Jaundice* Trey C, Davidson CS. Bucuvalas J et alProg liver Ds,1970;3:282-98 Clin Liver Dis. 2006 ;10:149-68
  • 3. Metabolic etiology of ALF (N= 36, 10%) Etiology < 3 years of age (n=23) > 3 years of age (n=13)Respiratory chain defect 7 0 FAOD 4 13 0Mitochondrial cytopathy 2 2 Tyrosenemia 4 6 0 Galactosemia 2 0 A-1 AT deficiency 1 0 Fructose-intolerance 1 0 Niemann-Pick type C 1 0 Urea cycle defect 1 1 Reyes Syndrome 0 1 Wilson’s disease 0 9
  • 4. Metabolic causes of ALF in neonates N= 31(%) Year 2008 Neonatal: Causes PALFSG data setNeonatal Hemochromatosis 15 (71%)Metabolic: Galactosemia 4 (13) Tyrosinemia Mitochondrial cytopathy Dhawan A. Liver Transplantation 2008; 14: S80- S84
  • 5. Causes of ALF in 80 infants Causes of ALF (n = 80) Total number (%)Metabolic disorders 34 (42.5%) Type I tyrosinemia 12 Mitochondrial cytopathy 17 Urea cycle disorder Ornithine carbamyl-transferase deficiency (1) 2 Argininosuccinic aciduria (1) Galactosemia 2 Hereditary fructose intolerance 1Neonatal hemochromatosis 13 (16.2%)
  • 6. Clues to etiology by evaluating clinical featuresMaternal history as clue’s to etiology: Mother an important link Sib death especially with jaundice NH, tyrosinemia, galactosemia, mitochondrial cytopathy, HLH, Niemann- PickPlacental edema, intrauterine hydrops NH, Mitochondrial & HLHClues as per timing of presentation At birth or soon after NH, mitochondrial hepatopathy, tyrosinemia, galactosemia.
  • 7. Clues to etiology by evaluating clinical featuresClues to etiology by examining the baby• IUGR: NH, mitochondrial cytopathy• Cataract: Galactosemia• Abnormal odor: tyrosinemia , Fatty acid oxidation defects• Skin rash: HLH, Fatty acid oxidation defects• Large spleen: HLH, Leukemia, Niemann-Pick• Seizure: HSV, HLH, secondary sepsis
  • 8. Stages of encephalopathyStage Clinical Reflexes Neurological sign Inconsolable crying, Normal or I inattention to task; child is hyper-reflexic not acting like self to Difficult or parents impossible to test II same as in stage I same as in adequately stage I Somnolence, stupor, Hyper-reflexic III combativenes Comatose, arouses with Decerebrate or IV painful stimuli (4a) or Absent decorticate no response (4b)
  • 9. Neonatal Hemochromatosis (NH)• Onset of organ damage in utero• Abnormal iron deposition in liver, pancreas, heart, CNS and salivary glands• End stage liver disease present by birth• Possible pathogenesis gestational alloimmune.Clinical features:• Maternal : Still births, previous sib deaths; antenatal period : IUGR, oligohydramnios, placental edema; small for date baby.• Presents usually few hours to sometimes weeks after birth• Hypoglycemia, coagulopathy, jaundice, anemia, ascites, anasarca, splenomegaly with shrunken liver.
  • 10. Neonatal Hemochromatosis (NH)Investigations: Low to normal transaminases, hypoalbuminemia, hypofibrinogenemia, thrombocytopenia.Diagnosis: High serum ferritin median 2448 (415 -100,000) μg/L for screening, Low serum transferrin, high transferrin saturation (95 % to 100 % up to 157 % vs. normal newborn 80%) Lip biopsy: salivary gland biopsy showing iron deposition on staining (best for Indian situations) OR MRI pancreas with low signal intensity on T2 imaging confirms the diagnosis.
  • 11. Type 1 TyrosinemiaInborn error of tyrosine metabolism, inheritance: autosomal recessive;involves liver, kidneys and peripheral nerves.Presents as acute hepatic crisis or chronic liver disease. 60 % presentas ALF in first 2 years of life including neonatal period.Presentation: Cogaulopathy, mildly raised transaminases and no jaundice in the neonate Neonatal cholestasis with liver failure “Boiled cabbage” or “rotten mushroom” odour Hypoglycemia, coagulopathy, hepatomegaly, ascites Rapid decompensation with death unless promptly treated
  • 12. Type 1 TyrosinemiaDiagnosis Screening: high alpha-fetoprotein: mean level: 160,000 µg/mL vs. normal full-term baby 84,000 µg/ml Confirmation: Increased urinary succinylacetone
  • 13. Galactosemia
  • 14. Mitochondrial Cytopathy (FAOD and RCD)
  • 15. 24%8% FAOD & RCD - Clinical features8%3% Neurological8% 36%8%20% Lee ,Sokol Semin Liver Dis5% 2007;27:259–273.
  • 16. Non-ketotic hypoglycemia ± High CPK ± Developmental delay FAOD
  • 17. Mitochondrial Cytopathy (FAOD and RCD)
  • 18. Biochemical differentiation Acidosis Urine Blood sugar Serum Serum ketones Lactate AmmoniaFAOD +/- Nil Low ± + (non-ketotic hypoglycemia)RCD ++ ++ Normal ++++ ±OA +++ ++/+++ Low/ Normal/ Normal ++ (persistent) HighUCD Normal ++++
  • 19. Hereditary Fructose Intolerance Infant on breast milk
  • 20. Wolman’s disease Stormy onsetFirst 2 weeks of life Death 3-6mo
  • 21. Wolman’s disease: SGPGIMS
  • 22. Treatment of major disorders
  • 23. Neonatal Hemochromatosis (NH)
  • 24. Neonatal Hemochromatosis (NH)
  • 25. Neonatal Hemochromatosis (NH) New regimen with better outcome Liver transplantation if no response
  • 26. Neonatal Hemochromatosis (NH) N= 16, treated
  • 27. IVIG during pregnancy in NH Regimen widely practiced at present Reduction in NH: at-risk pregnanciesadministration of intravenous immunoglobulinat 1 g/kg of body weight weekly from week 18 until the end of gestation
  • 28. IVIG during pregnancy Pediatrics 2008; 121: e 1615-21.
  • 29. Treatment optionFAOD Carnitine (100mg/kg) life saving in primary carnitine def. + Cocktail (Co Q10: 3-5mg/kg + Vitamin E: 25 IU/kg)RCD Poor prognosis Coenzyme Q + Cocktail (Carnitine + vitamin E)
  • 30. Algorithm of management ofinfants and younger children with ALF Suspect ALF • Jaundice (conjugated) • Coagulopathy (even isolated) as per PALFSG definition • Hepatomegaly and/or splenomegaly • Ascites
  • 31. Proposed investigations in asuspected infant with ALF
  • 32. Algorithm of management Start treatment• Stop oral feeds• Broad spectrum antibiotics• Fluconazole iv• Consider iv acyclovir for suspected Herpes simplex. Best is to start till investigations are available as the condition is potentially treatable and common.•Treat fast if suspicion of neonatal hemochromatosis is high.• Albumin infusion if serum levels low• Avoid fluid overload• Correction for losses: warmer/ventilator• Euglycemia, Na, K, Ca, Mg, phosphate• Coagulopathy: Fresh frozen plasma, exchange transfusion if necessary
  • 33. Algorithm of management Search for etiology Specific Treatment
  • 34. Wilson disease (ALF) Difficulty in diagnosisUsual diagnostic criteria…Diagnostic difficulty in WD: ALF  S Ceruloplasmin: Acute phase reactant … falsely normal  45% renal failure: Urinary Cu cannot be assessed (less)  S Cu and urinary Cu not readily available, time consuming  Liver biopsy cannot be done: transjugular may be possible  KF ring: absent in 50 % of WD patients with ALF and not a bedside test
  • 35. Wilson Disease presenting as ALF When to suspect?Modest elevations of transaminases (<2000 IU/L)Normal or subnormal alkaline phosphatase (<40 IU/L)Coomb’s negative hemolytic anemiaRenal failure (45%) AASLD Guidelines. Hepatology 2008
  • 36. How to Diagnose?Test Value Sensitivity SpecificityALP/ Bilirubin <4 94% 96%AST/ ALT > 2.2 94% 86% Combined: above two 100% 100%Serum Cu > 200 mcg/dL 75% 96%S Ceruloplasmin < 20 mg/dL 21% 84%Hemoglobin < 10g/dL 94% 74% Korman et al. Hepat 2008
  • 37. Caveats• Parameters: Adult studies• Children ALP/ Bilirubin ratio <1 Sensitivity 86%, Specificity 50% Tiesseres. Ped Crit Med 2005
  • 38. Treatment options Medical managementD- Pencillamine/ Trientine (20mg/kg/d)
  • 39. OLT in whom? New Wilson Index Score ≥11/20: Transplant Sensitivity: 93% Score <11/20: Medical Mx Specificity: 98% Dhawan et al. Liv transpl 2005 Fischer. 6 WD Score >11 in 3 casesJPGN 2011 All alive 2 survived without OLT. 1 OLT Score 10: 1 patients received OLT.
  • 40. Outcome in WD with ALFCase series No of cases Outcome Emre. 11 FHF All transplantedTranpl 2001 9 had I/V 1 year patient survival rate: 87.5% hemolysisElsenbch OLT 3 survivedWJG 2007 7 FHF No OLT: 4 survived (3: D- Pen, 1:Trientine) Korman. OLT 13 survivedHepat 2008 16 FHF Without OLT 3 died
  • 41. WD: ALF with IV Hemolysis Case series Cases with Coomb’s Percentage negative hemolytic anemia Emre.Tranpl 2001 9/11 transplanted cases 81.8%Wang L. Ped Neonat 2010 2/11 18%Chapoy P. Sem Hop 1979 1/6 16.6%
  • 42. LDH : 2723 10yr boy Plasma Hb: high IV Hemolysis PS: hemolysis HAV- Hb:11 Hb:12 HEV- HBV- PRBC G6PD normal Hb:6 Grade II DCT/ICT - INR:5 INR: 3 INR: 1.8 No SGPGIProdrome TB/DB: 3.2/1.5 Jaundice 10days AST/ALT:58/44 Cola col. urine ALP: 266 D- Pen Pallor May 2011 June 2011 Aug 2011
  • 43. International scenario of Reyes syndrome No. of Period Age Association cases USA 172 1986-99 6-7yr(Belay et al,1999) 93% antecedent UK 2600 1977-99 10-15 mo viral illness(Newton and Hall) Australia 8 1993-2001 1yr-19yr (Halpin 2003) 5-100%: aspirin Peak in 1970-80 Decrease in 30 yrs 1970-80 2010
  • 44. Presentation ofReyes Syndrome
  • 45. Laboratory values in Reyes Syndrome USG: Fatty LiverMore of cerebral component than liver failure
  • 46. Natural History Recovery20-40% Normal LFTmortality No organomegaly 60-80% No CLD Survive ± Neurological deficit Follow up