1. Siamo tutti apprendisti: casi clinici epatologici pediatrici
Spunti di Epatologia Pediatrica, 13 gennaio 2018
Siamo tutti apprendisti:
casi clinici epatologici pediatrici
Giorgina Mieli –Vergani
Paediatric Liver, GI & Nutrition Centre, MowatLabs
King’s College Hospital
London, UK

2. Case 1
3 year-old girl presenting with jaundice
bilirubin 150 μmol/l
AST/ALT 1500/2000 IU/l
albumin 33 g/l
INR 2.5
? acute hepatitis: observe
fluctuating LFTs → specialised centre

3. family history of IDDM and AI thyroiditis
Case 1
family history of IDDM and AI thyroiditis
US: mildly enlarged spleen
anti-LKM1 1/5120, mildly elevated IgG
anti-liver kidney
microsomal type 1

4. Case 1
liver biopsy:
severe interface hepatitis,
multilobular collapse,
moderately increased fibrosis

5. prototype of well managed
Case 1
prednisolone 2mg/kg/day → rapid improvement
of AST/ALT & INR
azathioprine added two weeks after starting
steroids as transaminase levels plateaued while
decreasing prednisolone dose
prototype of well managed
AIH type 2
20 yrs later: normal LFTs, AI thyroiditis on Rx
no signs of portal hypertension
Rx: prednisolone 2.5mg/day
azathioprine 37.5mg/day

6. Duchini et al, Am J Gastroenterol 2000;95:3238
Case 2
16 yrs old female, Hispanic
student, from Southern California
high IgG
transaminases 21X UNV
bilirubin 14X UNV
ANA, SMA, AMA negative
no treatment
diagnosis: cryptogenic hepatitis
Duchini et al, Am J Gastroenterol 2000;95:3238

7. stored serum re-tested: anti-LKM1 1/320
Case 2
stored serum re-tested:
anti-LKM1 1/320
25 years of age: end-stage liver disease
prototype of badly managed
AIH type 2
liver transplant → death
Duchini et al, Am J Gastroenterol 2000;95:3238

8. Case 3
15 year-old girl with amenorrhoea, acne,
tiredness, decreased school performance
bilirubin 65 μmol/l
AST/ALT 150/190 IU/l
GGT/AP 102/280 IU/l
albumin 31 g/l
IgG 21 g/l
INR 1.2
family history of colitis and rheumatoid arthritis

9. anti-nuclear antibody anti-smooth muscle antibody
Case 3
OE: splenomegaly, spider nevi
US: splenomegaly
ANA 1/320; SMA 1/160
anti-nuclear antibody
anti-smooth muscle antibody

10. Case 3
liver biopsy: interface hepatitis
increased fibrosis
? cirrhotic transformation
MRCP: normal
colonoscopy: normal

11. prototype of AIH type 1 Case 3 Rx: pred → pred + azathioprine
normal LFTs & IgG levels,
negative autoantibodies for 4 years
liver biopsy planned for possible
treatment withdrawal

12. Case 4
14 year-old boy with tiredness, mild abdominal
pain (no diarrhoea), poor school performance
bilirubin 55 μmol/l
AST/ALT 102/130 IU/l
GGT/AP 90/210 IU/l
albumin 38 g/l
IgG 29 g/l
INR 1.1
family history of colitis and AI thyroiditis

13. Case 4
OE: splenomegaly, spider nevi
US: splenomegaly
ANA 1/320; SMA 1/160

14. Case 4
liver biopsy: interface hepatitis
increased fibrosis
bile duct damage
copper binding protein +ve

15. Case 4
MRCP: intrahepatic cholangiopathy
colonoscopy: indeterminate colitis (?UC)

16. Case 4
Rx: pred/azathioprine/UDCA/mesalazine
normal LFTs, but persistently high IgG
and positive autoantibodies
difficult to control IBD → UC diagnosed
two years after presentation
escalation of IBD treatment (MMF, CI):
poor histological control

17. prototype of severe AISC
Case 4
progression of bile duct disease
→ jaundice
→ end-stage liver disease
liver transplant 8 years after diagnosis
prototype of severe AISC
persistent UC
AISC recurrence 2 years after transplant
listed for re-transplant 4 years after recurrence

18. Autoimmune hepatitis - AIH
Diagnostic Criteria
high IgG
autoantibodies (ANA/SMA/LKM1)
interface hepatitis
normal cholangiogram
Gregorio et al, Hepatology 2001;33:

19. Autoimmune hepatitis type 1 (ANA/SMA positive): 2/3 of patients
anti-nuclear antibody
type 1 (ANA/SMA positive):
2/3 of patients
anti-smooth muscle antibody
type 2 (LKM1/LC1 positive):
1/3 of patients
anti-liver kidney
microsomal type1
anti-liver liver
cytosol type1

20. Autoimmune sclerosing cholangitis - AISC abnormal cholangiogram
Diagnostic Criteria
high IgG
interface hepatitis
autoantibodies (ANA/SMA/LKM1)
abnormal cholangiogram
Gregorio et al, Hepatology 2001;33:

21. Clinical features and mode of presentation
AIH versus AISC
Clinical features and mode of presentation
AISC
AIH-1
AIH-2
ANA/SMA+
LKM1+
median age at diagnosis (yrs) 11 7
female (%) 75
mode of presentation (%)
acute hepatitis (often fluctuating course)
insidious onset
complications of CLD 47 38 12 40 25 10
inflammatory bowel disease (%) 20 12
Gregorio et al, Hepatology 2001;33:

22. Laboratory parameters at presentation
AIH versus AISC
Laboratory parameters at presentation
AIH
AISC
bilirubin
35 (4-306)
20 (4-179)
AST
333 ( )
102 ( )
INR
1.2 ( )
1.1 ( )
AP/AST ratio
1.14 ( )
3.96 ( )
GGT
76 (29-383)
129 (13-948) AP
356 ( )
303 ( )
albumin
35 (25-47)
39 (27-54)
Gregorio et al, Hepatology 2001;33:

23. (King’s prospective study: 54 pts 1984-2013)
AIH vs AISC
Rx response
(King’s prospective study: 54 pts )
AIH-1
AIH-2
AISC
remission rate
89%
87%
97%
median time to remission
6 mts
9 mts
2 mts
relapse rate
45%
46%
42%
cessation of treatment
19% 0% 5%
Gregorio et al, Hepatology 2001;33:
Scalori et al, Hepatology 2007;46 Suppl 1:555A 23

24. (King’s prospective study: 54 pts 1984-2013)
AIH vs AISC
Outcome
(King’s prospective study: 54 pts )
AIH-1
AIH-2
AISC
LT rate
27%**
14%*
6%*
recurrence post LT 0%
71%
* 8-14 yrs after D
** 1-12 yrs after D
Gregorio et al, Hepatology 2001;33:
Scalori et al, Hepatology 2007;46 Suppl 1:555A 24

25. Transplant-free survival
AIH vs AISC
Transplant-free survival
P<0.009, Log Rank
ASC
AIH
survivors
years
Scalori et al, Hepatology 2007;46 Suppl 1:555A

26. Autoimmune sclerosing cholangitis King’s prospective study
progression of liver disease and recurrence post transplant are associated to
active inflammatory bowel disease

28. Case 5 39-year-old man with history of nausea, jaundice and fatigue
Works as bar attendant in a pub in London
Denies excessive alcohol intake & drug taking
Moderate smoker
No previous history of liver disease
Since adolescence deterioration of school performance and difficult behaviour

29. On examination
Pale
Scleral jaundice
7 spider naevi
Well nourished (BMI 23.7)
Liver palpable 1 cm below costal margin
Spleen palpable 3 cm below costal margin

30. Blood tests
Biochemistry: bilirubin 65 µmol/L (nv <20)
ALT 189 IU/L, AST 390 IU/L (nv<50)
AP 63 IU/L (nv )
Albumin 30 g/L (nv 35-50)
GGT 69 IU/L (nv <55)
Immunology: SMA positive (titre 1/40)
IgG 16.3 g/L (nv 7-16)
Haematology: Hb 9.9 g/dL (nv )
WCC 4.5x109/L (nv )
MCV fL (nv 77-95)
Platelet count 125x109/L (nv )
INR (nv )

31. Other tests
Hepatitis A, B, C and E excluded
Normal ferritin and transferrin saturation
Liver ultrasound:
enlarged diffusely hyperechoic liver
heterogeneous parenchymal pattern
moderate splenomegaly

32. Liver Biopsy
Steatohepatitis

33. Hepatocyte ballooning
Liver Biopsy
Hepatocyte ballooning
and Mallory bodies

34. Increased fibrosis, nodular transformation
Liver Biopsy
Increased fibrosis, nodular transformation

35. Alcoholic hepatitis Diagnosis Maddrey score*: 21.3
(severe disease ≥32)
* [4.6 x (PT-control)] + serum bilirubin
Gastroenterology 1978;75:193–9

36. Management
Alcohol withdrawal
Improved quality of nutrition
Vitamins and minerals supplements:
folate and thiamine
vitamin K

37. Three months later
Deterioration of
clinical symptoms/signs
(nausea, jaundice and fatigue)
liver function tests

38. Blood tests
Biochemistry: bilirubin 95 µmol/L (nv <20)
ALT 210 IU/L, AST 420 IU/L (nv<50)
AP 53 IU/L (nv )
Albumin 28 g/L (nv 35-50)
GGT 72 IU/L (nv <55)
Immunology: SMA positive (titre 1/80)
IgG 17.3 g/L (nv 7-16)
Haematology: Hb 8.9 g/dL (nv )
WCC 6.5x109/L (nv )
MCV fL (nv 77-95)
Platelet count 105x109/L (nv )
INR (nv )
Reticulocyte count 12% (nv 0.2-2)
Coombs test negative

39. Other tests
Caeruloplasmin 8 mg/dL (nv 20-35)
Urinary copper μmol/24hr (nv <5)

40. Kayser-Fleischer Rings
Eye examination
Kayser-Fleischer Rings

41. Copper-associated protein on Orcein staining
Liver Biopsy
Copper-associated protein on Orcein staining

42. Wilson disease Diagnosis * King’s score: 7 (severe disease ≥11)
* Liver Transpl 2005;11:

43. King’s Wilson Predictive Score Liver Transpl 2005;11:441-448
0 – 20
> 15.4
> 301
> 2.5 4
21 – 24
10.4 – 15.3
201 – 300
2.0 – 2.4 3
25 – 33
8.4 – 10.3
151 – 200
1.7 – 1.9 2
34 – 44
6.8 – 8.3
101 – 150
1.3 – 1.6 1
>45
0 – 6.7
0 – 1.29
Albumin
(g/l)
WCC
(109/l)
AST
(IU/l)
INR
Bilirubin
(mmol/l)
Score

44. King’s Wilson Predictive Score Liver Transpl 2005;11:441-448
35.0 92 91 98 71
³ 12
45.5 93
> 11
22.8 88 96
= 11
16.3
100 83 94
³ 10
6.1 63 84
³ 9 LR
NPV
PPV
Specificity
Sensitivity
Cut off

45. Management
Penicillamine 250 mg bd
increased slowly to 1 gram bd
Pyridoxine 10mg daily
Wilson score weekly to monitor response

46. Outcome
12 months after staring treatment:
normal liver function
marked improvement of social behaviour