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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Autoimmune hepatitis - AIH Diagnostic Criteria high IgG autoantibodies (ANA/SMA/LKM1) interface hepatitis normal cholangiogram Gregorio et al, Hepatology 2001;33:544-553

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

Autoimmune sclerosing cholangitis - AISC abnormal cholangiogram Diagnostic Criteria high IgG interface hepatitis autoantibodies (ANA/SMA/LKM1) abnormal cholangiogram Gregorio et al, Hepatology 2001;33:544-553

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) 12 11 7 female (%) 55 75 mode of presentation (%) acute hepatitis (often fluctuating course) 37 insidious onset 37 complications of CLD 26 47 38 12 40 25 10 inflammatory bowel disease (%) 44 20 12 Gregorio et al, Hepatology 2001;33:544-553

Laboratory parameters at presentation AIH versus AISC Laboratory parameters at presentation AIH AISC bilirubin 35 (4-306) 20 (4-179) AST 333 (24-4830) 102 (18-1215) INR 1.2 (0.96-2.5) 1.1 (0.9-1.6) AP/AST ratio 1.14 (0.05-14.75) 3.96 (0.20-14.20) GGT 76 (29-383) 129 (13-948) AP 356 (131-878) 303 (104-1710) albumin 35 (25-47) 39 (27-54) Gregorio et al, Hepatology 2001;33:544-553

(King’s prospective study: 54 pts 1984-2013) AIH vs AISC Rx response (King’s prospective study: 54 pts 1984-2013) 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;33:544-553 Scalori et al, Hepatology 2007;46 Suppl 1:555A 23

(King’s prospective study: 54 pts 1984-2013) AIH vs AISC Outcome (King’s prospective study: 54 pts 1984-2013) 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;33:544-553 Scalori et al, Hepatology 2007;46 Suppl 1:555A 24

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

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

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

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

Blood tests Biochemistry: bilirubin 65 µmol/L (nv <20) ALT 189 IU/L, AST 390 IU/L (nv<50) AP 63 IU/L (nv 30-130) 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 11.5-15.5) WCC 4.5x109/L (nv 4.00-11.00) MCV 100.4 fL (nv 77-95) Platelet count 125x109/L (nv 150-450) INR 1.3 (nv 0.8-1.1)

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

Liver Biopsy Steatohepatitis

Hepatocyte ballooning Liver Biopsy Hepatocyte ballooning and Mallory bodies

Increased fibrosis, nodular transformation Liver Biopsy Increased fibrosis, nodular transformation

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

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

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

Blood tests Biochemistry: bilirubin 95 µmol/L (nv <20) ALT 210 IU/L, AST 420 IU/L (nv<50) AP 53 IU/L (nv 30-130) 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 11.5-15.5) WCC 6.5x109/L (nv 4.00-11.00) MCV 100.6 fL (nv 77-95) Platelet count 105x109/L (nv 150-450) INR 1.4 (nv 0.8-1.1) Reticulocyte count 12% (nv 0.2-2) Coombs test negative

Other tests Caeruloplasmin 8 mg/dL (nv 20-35) Urinary copper 18.3 μmol/24hr (nv <5)

Kayser-Fleischer Rings Eye examination Kayser-Fleischer Rings

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

Wilson disease Diagnosis * King’s score: 7 (severe disease ≥11) * Liver Transpl 2005;11:441-448

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 - 100 0 – 1.29 Albumin (g/l) WCC (109/l) AST (IU/l) INR Bilirubin (mmol/l) Score

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

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

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