Hepatosplenomegaly how do we approach

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Hepatosplenomegaly how do we approach

  1. 1. Splenohepatomegaly- How do we approach? Presenter: Viral Shah - KEM Hospital, Mumbai Moderator: Seema Alam - Pediatric Hepatologist, ILBS, New Delhi Panelists: Priya Kishnani – Pediatrician & Geneticist, Duke University, North Carolina, USA Archana Kher – Pediatrician, Columbia Asia, Pune Manoj Ghoda – Gastroenterologist, Gujarat Research & Med. Inst. Ahmd
  2. 2. Splenohepatomegaly How do we approach? Dr Viral K Shah Under guidance of Dr Mamta N Muranjan Genetic Clinic Department of Pediatrics Seth GSMC & KEM Hospital Mumbai
  3. 3. _ 3 years 4 months female child _ 5th degree consanguinity _ Antenatal ,intranatal & postnatal uneventful. _ FTND, APGAR normal, 3.25kg
  4. 4. Presenting Complaints _Progressive upper abdominal distention _Tonic posture of the neck (back arching) at 4 months, 1-2 episode.
  5. 5. We Also Asked For… Feature Jaundice Present or not - Pallor with edema Blood transfusion Joint pain or deformity Repeated infections - Bleeding from any site Seizures, altered sensorium - Fractures
  6. 6. - Global developmental delay - Developmental age 10-11 months
  7. 7. Summary _ Progressive upper abdominal distension most likely Organomegaly with Global delay
  8. 8. Examination Anthropometry : Vitals-Stable, within normal limits Observed Expected Percentile Length (cm) 78 81 15th * Weight (kg) 9.8 10.2 15-50th * Head circumference 45.5 46.5 15-50th * * WHO growth chart
  9. 9. General Examination 1) Pallor 2) Left eye: Convergent squint 3) No icterus,cyanosis,clubbing edema, lymphadenopathy 4) There was absence of _ Hemolytic / coarse facies _ Bleeding manifestation _ Bone tenderness or joint swelling _ Signs of liver cell failure • Old photo of face which I emailed you
  10. 10. Abdomen: Examination _ Distension, umbilicus displaced downward _ Liver: Firm, non-tender, smooth surface _ 6 cm below right mid clavicular line, _ 5 cm in mid axillary line _ Span 9 cm _ Spleen: 14 cm below left costal margin _ No signs of ascites _ All other systems are normal including CNS
  11. 11. Clinical Diagnosis without jaundice, without signs of liver cell failure in a developmentally delayed child 1.5 years old child with splenohepatomegaly with pallor,
  12. 12. What are the Possibilities
  13. 13. Differential Diagnosis •Storage disorder
  14. 14. Investigations Liver functions Hematology Date (Age) 25/2/11 (15 months) 10.6 SGOT/SGPT (U/L) 186/ 126 (10-45) 4700 7100 Alkaline 247 phosphatase (U/L) (125-340) Platelets 1,50,000 1,32,000 GGT (U/L) MCV/ MCHC 64.5/ 33.9 57.92 / 30.2 30 (5-55) Retic / Correcte d retic 2.1 / 1.4 Total protein/ Albumin (gm/dl) 6.6 / 3.8 Bilirubin (mg/dl) 0.28 PT/INR 13.5 / 1.05 Date (Age) 15/2/11 (6 months) 25/2/11 (15 months) Hb/PCV (gm/dl) 10.1 TLC
  15. 15. Investigations _ Chest x ray : Normal, x-ray spine – D9 hemivertebra _ Fundus examination : No cherry red spot _ USG abdomen with doppler : Hepatosplenomegaly with normal liver and spleen echotexture, no portal hypertension _ Hemoglobin electrophoresis : Normal (Hb A-93.7, Hb F – 3.6, HbA2 – 2.7) ruled out hematological disorder _ Bone marrow : Reported as normal
  16. 16. What’s next?
  17. 17. Enzyme Studies _ Leukocyte β-glucosidase : 3.7 (8-32 nmol/hr/mg protein) (46 % of lower limit of normal) _ Plasma Chitotriosidase : 4274.8 ( 28.66-62.94 nmol/hr/ml) (69 times higher than normal) _ Leukocyte Sphingomyelinase : 0.92 (0.77-2.33 nmol/hr/mg protein) Possibility of Neuronopathic Gaucher disease (type 3) (low B-glucosidase with relatively mild neurological impairment) Child was referred to our Institute for enzyme replacement therapy for
  18. 18. However……… _ Anemia and thrombocytopenia was not progressive _ On follow up hepatosplenomegaly was not progressive _ X – ray spine did not show typical features of Gaucher disease _ Gaucher cells were not observed in bone marrow
  19. 19. Further Evaluation ➢ Bone marrow repeated: No Gaucher cells but presence of foamy macrophages ➢ Repeat Beta glucosidase activity: 3 (4-14)(75% of lower limiit of normal) ➢ Plasma Chitotriosidase level : 2879 (8-87)(33 times elevated) ➢ Genotyping: No GBA gene mutations
  20. 20. Bone Marrow Examination Giemsa stain : Storage cells with foamy cytoplasm
  21. 21. Clinical Course 30 months of Age ➢ ➢ Drooling of saliva ➢ Feeding difficulty: Coughing and choking ➢ Dysphagia ➢ Regression of mainly motor milestones (stopped cruising and standing with support) Progression of neurological disease
  22. 22. At 3 years of age _ _ Present Hemoglobin – 11, Total count- 5080, platelets- 3.45 lakh _ Bulbar palsy _ Weight loss because of poor feeding due to dysphagia, on nasogastric tube feed _ Non-ambulatory Anemia corrected with hematinics
  23. 23. Recent Photographs
  24. 24. Summary _ _ Non-progressive pallor and splenohepatomegaly _ Global developmental delay followed by motor regression _ Non-paralytic squint _ Foam cells on bone marrow _ Mildly reduced level B-glucocerebrosidase activity and absence of mutation of GBA gene Early childhood onset of symptoms
  25. 25. Final Diagnosis Pathogenic homozygous mutation in exon 8 Nucleotide change c.1211G>A Amino acid change p.Arg404Gln Final diagnosis: Niemann-Pick disease type C
  26. 26. Take Home Message _ Storage disorders can have overlapping clinical features _ Discrepancies between clinical features, disease course and investigations : Alert for alternative diagnosis _ Mainstay of diagnosis : Genotype with or without estimation of enzyme activity, bone marrow supportive requires expertise for interpretation _ Confirm diagnosis : Must for enzyme replacement therapy as enzyme is disease specific
  27. 27. POSSIBILITIES Saposin – C deficiency Prosaposin deficiency Niemann-Pick disease type C
  28. 28. Metabolic Pathway of Gaucher Disease
  29. 29. Role of Prosaposin and Saposin C in Gaucher disease Glucocerebrosidase(GCase) binding to the membrane and saposin-mediated activation. Saposin molecules are colored in purple; lipid polar groups are blue
  30. 30. Possibilities Possibility Saposin – C deficiency Prosaposin deficiency Niemann-Pick disease type C
  31. 31. Possibilities Possibility Features favoring Saposin – C deficiency Clinical and histopathological features of Gaucher disease and absence of GBA gene mutation Prosaposin deficiency Niemann-Pick disease type C
  32. 32. Cholesterol Transport Defect in NP-C Cells
  33. 33. POSSIBPossibilitiesILITIES Possibility Features favoring Saposin – C deficiency Clinical and histopathological features of Gaucher disease and absence of GBA gene mutation Prosaposin deficiency Niemann-Pick disease type C
  34. 34. POSSIPossibilitiesBILITIES Possibility Features favoring Saposin – C deficiency Clinical and histopathological features of Gaucher disease and absence of GBA gene mutation Prosaposin deficiency Niemann-Pick disease type C _ _ _ _ Progressive neurological disease Foam cells in bone marrow Normal sphingomyelinase activity Mildly elevated chitotriosidase

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