SLIDE 1 Prof Anil Dhawan MD, FRCPCH
Corporate Medical Director Variety Children’s Hospital Director Paediatric Liver GI and Nutrition Center Director Research and Innovation, King’s College Hospital, London, UK,
Areas of Interest: Liver cell transplantation, Liver
transplantation, Wilson's disease Neonatal cholestasis, Acute liver failure, Microbiome in biliary atresia
SLIDE 2 Neonatal Cholestasis Case based discussions
Profesor Anil Dhawan MD, FRCPCH Medical Director Paediatrics Director Pediatric Liver GI and Nutrition Centre Variety Children’s Hospital
King’s College Hospital London
SLIDE 3
Neonatal Cholestasis
~ 1:2700 live births
SLIDE 4 Neonatal Hepatitis 1992-2005 N=1625
PFIC 5%
SLIDE 5 Diagnostic Dilemmas
Exclude ALF as presentation (INR >2 unresponsive to Vit K) Identify treatable conditions Genetic /inherited conditions- PFIC syndromes Exclude Biliary atresia Recogonise and avoid complications
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Charlie Born one week before term by Caesarian section because of maternal UTI No problems during pregnancy No immediate neonatal problems
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At 6 days of age: refuses to feed irritable vomits floppy
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Bilirubin 150 mmol/l (100 conjugated) Albumin 33 g/l GGT 56 IU/l Hb 11.9 g/l AST 10150 IU/l Alkaline Phosphatase 313 IU/l WBC 3.3x109/l, Platelets 80x109/l INR 2.3
GP Local Hospital
SLIDE 9
Local Hospital
D: sepsis/?meningitis + DIC Treated with antibiotics for 3 weeks No improvement
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Liver failure ? cause King’s
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Differential Diagnosis
Galactosaemia Neonatal Haemochromatosis Haemophagocytic Lymphohistiocytosis Neonatal Herpes Infection Tyrosinaemia
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Differential Diagnosis
Galactosaemia ? Neonatal Haemochromatosis Haemophagocytic Lymphohistiocytosis Neonatal Herpes Infection Tyrosinaemia
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Galactosaemia Early treatment essential Commonly presents with sepsis D: galactose 1 phosphate uridyl transferase in red cells
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Differential Diagnosis
Galactosaemia Neonatal Haemochromatosis Haemophagocytic Lymphohistiocytosis Neonatal Herpes Infection Tyrosinaemia ?
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mildly elevated AST and no jaundice Prolonged INR, but Tyrosinaemia D: Succinyl acetone in urine Rx: NTBC, if no response, OLT
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Differential Diagnosis
Galactosaemia Neonatal Haemochromatosis
Haemophagocytic Lymphohistiocytosis
Neonatal Herpes Infection ? Tyrosinaemia
SLIDE 17
Presents during first week of life Maternal history can be negative
Caesarian section not always protective
Neonatal Herpes Infection No skin lesions Transaminases very high
Early treatment with aciclovir essential
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Differential Diagnosis
Galactosaemia Neonatal Haemochromatosis ?
Haemophagocytic Lymphohistiocytosis
Neonatal Herpes Infection Tyrosinaemia
SLIDE 19
Neonatal Haemochromatosis
Hepatic and extra-hepatic non-RES iron deposition Liver failure of neonatal presentation Abnormal LFTs, severe coagulopathy, high serum ferritin MRI shows extra-hepatic iron overload
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Neonatal Haemochromatosis Anti-oxidant cocktail Liver transplant Treatment
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Differential Diagnosis
Galactosaemia Neonatal Haemochromatosis
Haemophagocytic Lymphohistiocytosis ?
Neonatal Herpes Infection Tyrosinaemia
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Haemophagocytic lymphohistiocytosis (HLH)
inherited acquired different entities?
SLIDE 23
high triglicerides low fibrinogen (with or without DIC) high uric acid severe pancytopaenia & coagulopathy liver dysfunction
HLH
haemophagocytosis (bone marrow, liver, spleen, CSF, ascites, skin, lymphonodes etc)
SLIDE 24
HLH
steroids, i.t. metotrexate, i.v. immunoglobulin anti thymocyte globulin/cyclosporin A (anti T cells) bone marrow transplant etoposide (anti histiocytes)
SLIDE 25
HLH lethal without chemotherapy & bone marrow transplant
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Diagnosis in Charlie
Neonatal Herpes Infection
No response to aciclovir (started too late?)
Successful OLT at 6 weeks
SLIDE 27 look normal!!
babies with biliary atresia
Persisting Jaundice 6 weeks Pale stool Bilirubin 134/108,GGT 297 ALT102 INR 3.5 Cholestasis case 1
SLIDE 28 Take home message Please check and correct INR with Vit K in all children with Cholestasis
SLIDE 29 6 week old boy Referral for conjugated hyperbilirubinaemia & local US scan suggestive of biliary atresia Background:
– Born at 36+1, SVD, BW 2.8kg, discharged home same day – Antenatal history: Anti-D during pregnancy for previous Rh incompatibility – Jaundice day 4 of life requiring 3 days of phototherapy
Family history:
– Parents are second cousins (born in Iraq, 5 years ago moved to UK) – 3 elder siblings – alive & well – No FHx of liver or blood disorders
Persisting jaundice -> referred to prolonged jaundice clinic
Cholestasis Case 2
SLIDE 30 Investigations at local hospital
TFT, G6PD, CMV, FBC, urine MC&S – all normal US scan: abnormally small shrunken thick- walled GB with mild splenomegaly. Appearances suggestive of biliary atresia.
Date Total bilirubi n Conj. bilirubi n
16/1 183 29 31/1 125 38 3/2 110 48
SLIDE 31
Review at KCH ( 6 weeks old)
HPC: Growing well. Breastfed with formula top-ups. Weight 4.42kg (19th centile) O/e: pale stools, soft 2cm liver & 2cm spleen palpable. Management:
– Started on Vitamin K & E, & Abidec – Changed to Heparon Junior with BF top-ups
SLIDE 32 Bloods from initial review (6 weeks old)
Hb 86 g/L
104 10^9/L Platelets 196 10^9/L LDH 349 IU/L Haptoglobin <0.1 g/L Potassium 5.8 mmol/L Urea 3.2 mmol/L Creatinine 15 umol/L TSH 4.4 mIU/L Free thyroxine 14.6 pmol/L O Rh positive DAT negative G6PD normal Albumin 39 g/L Bilirubin 111 umol/L
42 umol/L ALP 597 IU/L AST 74 IU/L GGT 17 IU/L ALT 113 IU/L INR 1.17 Ratio Lactate 1.9 mmol/L Glucose 5.8 mmol/L Cortisol 475 nmol/L
US scan –
– Liver parenchyma homogeneous – Normal gallbladder – No duct dilatation – Normal vessels – Spleen is enlarged (length 7.6 cm)
SLIDE 33
Liver biopsy
Portal fibrosis Cholestasis, ductal bile plugs, but no ductular reaction Severe macrovesicular steatosis
SLIDE 34 Investigations (3m old)
- Cholestasis gene panel
- Urinary bile acids
Bilirubin 144 umol/L
109 umol/L ALT 1670 IU/L AST 1090 IU/L GGT 20 IU/L Albumin 39 g/L INR 1.33 AFP 2171123 (kIU/L) Ferritin 4151 ug/L A1AT PIM Gal-1-Put Normal LAL-D Negative CDG Negative Urine organic acids Normal Plasma amino acids Normal Very long chain fatty acids Normal Thyroid function Normal
SLIDE 35 Molecular genetics (4.5m):
12466 combined parents
m/z 200 250 300 350 400 450 500 550 600 650 700 750 800 % 100 m/z 200 250 300 350 400 450 500 550 600 650 700 750 800 % 100 m/z 200 250 300 350 400 450 500 550 600 650 700 750 800 % 100 m/z 200 250 300 350 400 450 500 550 600 650 700 750 800 % 100 m/z 200 250 300 350 400 450 500 550 600 650 700 750 800 % 100 UBA_03-08-17_014 38 (4.256) Cm (4:70) 1: Parents of 85ES- 2.85e3 771 607 595 489 446 420 225 202 320 300 279 236 401 379 338348 421 477 523 491 591 524 564 623 760 624 759 700 671 653 710 783 791 UBA_03-08-17_014 38 (4.275) Cm (3:68) 2: Parents of 97ES- 3.26e3 725 511 250 234 511 481 415 384 265269297 311 379 337 423 445 511 527 658 565 561 531 657 619 600 620 658 659 714 697 736 786 779 UBA_03-08-17_014 29 (3.627) Cm (4:63) 3: Parents of 80ES- 6.58e3 494 494 265 213 218 235 479 311 297 325 362 476 430 423 384 494 495 495 511 511 585 539 562 623 645 702 696 777 713 UBA_03-08-17_014 29 (3.646) Cm (2:71) 4: Parents of 74ES- 2.96e3 445 444 205 444 443 408 230 344 313 259 282 373 378 442 682 460 626 465 510 466 552 511 565 616 645 651 733 711 761 UBA_03-08-17_013 99 (3.630) Cm (4:443) Scan ES- 6.81e4 494 285 213 255 247 225 285 285 449 329 286 342 423 365 392 476 495 510 511 583 527 577 759 607 700 657 623 745
SLIDE 36
Ward admission
5m old Admitted to local hospital - acute bronchiolitis Decompensated liver disease Admitted to commence on cholic acid & chenodeoxycolic acid Assessed for transplant - listed on 1/6
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Liver transplant
Living related transplant from mother (left lateral segment) on 13/6 Explanted liver: Very cholestatic, fine nodularity, irregular surface, large droplets of fat, looks inflammatory. GGT immunostain absent, others expressed appropriately.
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Treatment
Fatal without treatment Cholic acid (5-15mg/kg) Chenodeoxycolic acid Ursodeoxycolic acid Liver transplantation
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Cholestasis 3
6 wks old persisting jaundice Pigmented stool USS –Normal Bili 176/140, AST350, ALT 401, GGT 29 Liver Biopsy –Giant cell Hepatitis Mutational analysis –BSEP def. Tx at 3 years , suspicious nodule HCC
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Biochemistry Molecular genetics
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Hepatocytes Canaliculus Canalicular Membrane Junctional complexes
SLIDE 42 FIC1 BSE P MDR3 MRP2 TJPs Claudin s BA OA PC Actin AL
SLIDE 43 MDR3 ABCG5/8 BSEP MRP2 FIC1
Conjugated bilirubin Bile acids Mixed micelles Phosphatidylcholine Amino Phospholipids
Hepatocyte Canaliculus
SLIDE 44 NGS for cholestasis at King’s
- 3 PFIC genes
- 7 bile acid synthesis defects
- 2 tight junction defects
- Neonatal sclerosing cholangitis
- ARC
- Dubin Johnson
- Citrin deficiency
- FXR
SLIDE 45
Conclusions
Cholestasis is a common presentation of neonatal liver disease Exclude acute liver failure Diagnosis highly investigation dependent Look for treatable conditions Mutational analysis promising for diagnosis
