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MLD presenting with ALF Talk by Dr SK Yachha
1. Surender K Yachha
Professor and Head
Department 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 al
Prog liver Ds,1970;3:282-98 Clin Liver Dis. 2006 ;10:149-68
3.
4. 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 0
Mitochondrial 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
5. Metabolic causes of ALF in neonates
N= 31(%) Year 2008
Neonatal: Causes PALFSG data set
Neonatal Hemochromatosis 15 (71%)
Metabolic:
Galactosemia 4 (13)
Tyrosinemia
Mitochondrial cytopathy
Dhawan A. Liver Transplantation 2008; 14: S80- S84
6. 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 1
Neonatal hemochromatosis 13 (16.2%)
7. Clues to etiology by evaluating
clinical features
Maternal history as clue’s to etiology: Mother an important link
Sib death especially with jaundice NH, tyrosinemia, galactosemia,
mitochondrial cytopathy, HLH,
Niemann- Pick
Placental edema, intrauterine hydrops NH, Mitochondrial & HLH
Clues as per timing of presentation
At birth or soon after
NH, mitochondrial hepatopathy, tyrosinemia, galactosemia.
8. Clues to etiology by evaluating
clinical features
Clues 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
9. Stages of encephalopathy
Stage 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)
10. 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.
11. 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.
12. Type 1 Tyrosinemia
Inborn error of tyrosine metabolism, inheritance: autosomal recessive;
involves liver, kidneys and peripheral nerves.
Presents as acute hepatic crisis or chronic liver disease. 60 % present
as 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
13. Type 1 Tyrosinemia
Diagnosis
Screening: high alpha-fetoprotein:
mean level: 160,000 µg/mL
vs.
normal full-term baby 84,000 µg/ml
Confirmation: Increased urinary succinylacetone
29. IVIG during pregnancy in NH
Regimen widely practiced at present
Reduction in NH: at-risk pregnancies
administration of intravenous immunoglobulin
at 1 g/kg of body weight weekly from week 18
until the end of gestation
32. Algorithm of management of
infants and younger children with
ALF
Suspect ALF
• Jaundice (conjugated)
• Coagulopathy (even isolated) as per PALFSG definition
• Hepatomegaly and/or splenomegaly
• Ascites
34. 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
36. Wilson disease (ALF)
Difficulty in diagnosis
Usual 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
37. 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 anemia
Renal failure (45%)
AASLD Guidelines. Hepatology 2008
38. How to Diagnose?
Test Value Sensitivity Specificity
ALP/ 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
39. Caveats
• Parameters: Adult studies
• Children ALP/ Bilirubin ratio <1
Sensitivity 86%, Specificity 50%
Tiesseres. Ped Crit Med 2005
40. Treatment options
Medical management
D- Pencillamine/ Trientine (20mg/kg/d)
41. 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 cases
JPGN 2011 All alive 2 survived without OLT. 1 OLT
Score 10: 1 patients received OLT.
42. Outcome in WD with ALF
Case series No of cases Outcome
Emre. 11 FHF All transplanted
Tranpl 2001 9 had I/V 1 year patient survival rate: 87.5%
hemolysis
Elsenbch OLT 3 survived
WJG 2007 7 FHF No OLT: 4 survived (3: D- Pen, 1:Trientine)
Korman. OLT 13 survived
Hepat 2008 16 FHF Without OLT 3 died
43. 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%
44. 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 SGPGI
Prodrome 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
45. 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
