Natural history of α-1-atd in children

Transcription

1 Natural history of α-1-atd in children Agnieszka Bakuła Dpt of Gastroenterology, Hepatology, Nutrition Disorders and Paediatrics The Children s Memorial Health Institute Warsaw, Poland Topics to be discussed ATD- liver symptoms natural history risk factors of bad prognosis patomechanisms of liver injury liver transplantation in ATD What s new in ATD in Poland? 2

2 Liver manifestations- infancy neonatal hepatitis: prolonged obstructive jaundice (pale stools) bleeding symptomes: bleeding from umbilical stump hematemesis melena intraventicular hemorrhage 3 Liver manifestations- early childhood elevated transaminases (incidentally) asymptomatic hepatomegaly jaundice during an intercurrent illness severe liver dysfunction 4

3 Liver manifestationslate childhood/ adolescence chronic active hepatitis portal hypertension: ascites, coagulopathy esophageal varices, gastrointestinal bleeding cryptogenic cirrhosis hepatocellular carcinoma 5 The course of liver disease 10-20% children with neonatal hepatitis are reported to develop advanced liver disease on histological criteria DIFFICULTY IN SELECTING WHICH CHILDREN AND WHEN NEED LTx 6

4 Natural history- Sveger study : Swedish nationwide screening study: infants 127 PiZZ, followed to now 14: prolonged obstructive jaundice, 9/14- clinically significant liver disease 8: hepatomegaly Sveger T. N Engl J Med 1976;294: During 12 years observation None clinical symptoms of liver disease 5 pts died: 3 of liver cirrhosis, Bil levels: 11% of infants, normalization till 6/12 ALT: from 73% in infants to 15% at 12y GGTP: from 50% of infants to 3% Sveger T Acta Paediatr Scand 77:

5 6%- marginal increase of ALT 7%- elevated GGT liver biopses have not been conducted 9 Center experience - patients and methods screening from 1978 to children (20, 56 ) age at diagnosis: y PiZZ phenotype follow up: - at least 10 years (good prognosis group) - or to Ltx or death (bad prognosis group) 10

6 Dead 4(5%) The results Ltx-14 (18%) Good prognosis 58 (77%) 11 The outcome of the 76 children with alpha-1-atd The results 7 2 Hepatitis+cholest asis: 44 (58%) Cholestasis 13 (17%) with no symptoms 10 (13%) hepatitis 7 (9%) The first symptoms of the 76 children with alpha-1-atd 12

7 The results 100% 80% ns p<0,01 p<0,01 60% 40% good prognosis bad prognosis 20% 0% 1 year 4-7 y 9-14 y The frequency of hepatitis in the group with good and bad prognosis depending on age 13 The results 100% 80% p<0,05 p<0,001 p<0,001 60% 40% Good prognosis Bad prognosis 20% 0% 1 year 4-7 y 9-14 y The frequency of cholestasis in the group with good and bad prognosis depending on age 14

8 Conclusions the prognosis in most of the patients with α-1 ATD was good hepatitis and cholestasis were the most frequent presenting symptoms of ATD in children cholestasis in 1y and at later ages and hepatitis at later ages were risk factors of bad prognosis 15 Risk factors (Ltx)- 97 patients: jaundice for over than 6 weeks higher AST at presentation higher AST and GGTP during follow up initial liver biopsy: severe bile duct proliferation, bridging septa and/or severe fibrosis 16

9 The role of: male sex low birth weight were not confirmed 17 The prognosis in childhood of liver disease associated with alpha 1-ATD (PiZZ). Parameters associated with poor prognosis and death from within 2 weeks to 4 years: persistent hypoalbuminaemia the presence of ascites persistent or recurrent jaundice coagulopathy not responded to vitamin K variceal bleeding Psacharopoulos HT, et al. 18 Japan Medical Research Foundation (eds) Cholestasis in Infancy.1990;

10 The patomechanism of liver injury - gain-of-toxic function mechanism of liver damage - defective mechanisms of mutated protein disposal: autophagy and proteosome - genetic/environmental modifiers predispose/protect? accumulation of mutant ATZ in ER 19 Liver biopsy in ATD periodic acid Shiff positive, diastase resistant globules in the ER: With permission of M. Pronicki

11 Liver biopsy in ATD inflammatory cell infiltration With permission of M. Pronicki 21 Liver biopsy in ATD periportal fibrosis With permission of M. Pronicki 22

12 Liver biopsy in ATD steatosis: macrovacuolar or mixed With permission of M. Pronicki 23 Liver biopsy in ATD bile duct proliferation With permission of M. Pronicki 24

13 Liver biopsy in ATD EM: progressive mitochondrial autophagy Grant no 2011/01/D/NZ5/ Treatment in children no specific therapy for liver disease supportive management of liver dysfunction symptomes: vit. A, D, E, K, ursodeoxycholic acid (UDCA) portal hypertension management 26

14 Treatment in children prevention of complications: propranolol sclerotherapy, variceal endoscopic binding 27 Treatment in children autophagy enhancing drug??? karbamazepine, rapamycin 28

15 An autophagy-enhancing drug promotes degradation of mutant ɑ-1 antitrypsin Z and reduces hepatic fibrosis Carbamazepine: used safely for many years for seizures and depression the autophagy-enhancing drug decreases the hepatic load of ɑ-1atz reverses hepatic fibrosis (mice models) This idea has profound implications for therapy in children Hidvegi T, et al. Science 2010;329(5988): Treatment in children liver transplantation(ltx)- the causative treatment! 30

16 Liver transplantation/ pts: 5, 12 age at LTx: 14.3 ( )years (two infants - 8 and 9 months of age) >10 r.ż.- 14/17 pts oesophageal varices- 14/17 variceal bleeding- 6/17 ascites: 4/17 1-year patient survival after Ltx: 100% 5-year patient survival: 87.5% 31 5-year patient survival after Ltx Author-No pts Age at Ltx (years) 5-year patient survival Follow up (years) Hughes et al ,5% >10 y (1-9) 50% patients Esquivel et al (8 mo-13 years) Francavilla et al ,8 (6 mo-15 years) IP CZD ,3 (8 mo-17,1 years) 83% 2,3 years 92% 3,9 y 87,5% 10,3 y

17 Does the heterozygous state of ɑ-1-atd have a role in chronic liver diseases? no association: the heterozygous PiZ state and the chronic LD/ cryptogenic cirrhosis a significantly higher prevalence of PiMZ in pts with decompensated LD of any etiology compared with patients with compensated LD a significant association between the PiMZ state and the need for liver transplantation in pts with HCV or NAFLD Rogev A, Guaqueta C, Molina EG et al. JPGN, 2006, 43: S30-S35 33 The project supported by National Science Centre, the aim: to determine distinctive features of hepatocytes ultrastructure (mitochondria abnormalities and autophagy in particular) in children with variable course of α-1-atd Grant no 2011/01/D/NZ5/

18 The project supported by National Science Centre, a specific pattern of proteins expression in EM associated with the disposal of the mutated Z protein in patients with good and poor prognosis a marked increase of mitophagy and autophagy in hepatocytes in the group with good prognosis - role in more efficient degradation α-1-at protein? - significant feature of favourable prognosis in children with α-1-atd? 35 Retrospective study of the natural history of childhood alpha-1 antitrypsin deficiency associated liver disease 2015/2016 approximately 600 patients in 4 European centers 150 Polish patients (50 patients currently controlled in outpatient clinic) to identify indicators of a poor prognosis (progression to portal hypertension) to characterize the natural history of disease progression in some children with ATD 36