Alpha-1-antitrypsin. Antal Németh. Barngastro-Hepatologi och Nutrition Karolinska Universitetssjukhus - Huddinge. AAT-Symposium, Malmö

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1 Alpha-1-antitrypsin Antal Németh Barngastro-Hepatologi och Nutrition Karolinska Universitetssjukhus - Huddinge AAT-Symposium, Malmö

2 Synopsis Some facts Pathogenesis The Karolinska-Huddinge experience Conclusions

3 ALPHA-1-ANTITRYPSIN or the story of how our generation has answered all the questions without giving the solutions Antal Németh Groningen, June 28, 2005

4 Citation classics Laurell C-B, Eriksson S. Scand J. Clin. Lab. Inv. 1963;15: Sharp HL, Bridges RA, Krivit W, Freier EF. J. Lab. Clin. Med. 1969;73:934-9 Sveger T. N. Eng. J. Med. 1976; 294: Eriksson S, Carlson J, Velez J. N Engl. J. Med. 1986; 314:736-9.

5 Some facts 1) AATD: - Low serum concentrations - sequestrated ATZ in hepatocyte ER - higher risk of liver disease 2) liver disease is not correlated to - i.u./perinatal infections - class-1 HLA antigens - severity of cholestasis

6 Pathogenesis of liver disease in AATD The mosaics of our knowledge, thanks to - Laurell CB - Eriksson S - Carlson J - Lomas DA - Carrell RW - Perlmutter DH - Teckman JH etc

7 Theories of pathogenesis Protease >< antiprotease imbalance Autoimmunity Secretion defect

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9 Secretion defect Z-protein (ATZ): folding defect loop-sheet polymerisation accumulation in ER

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14 Lomas, 2002

15 Degradation of ATZ Proteosomal Non-proteosomal Mitochondrial autophagy damage Caspase induction (mito + ER): apoptosis? Difference protected >< susceptible persons?

16 Teckman, 2000

17 Secretion defect contradicting findings Inclusion in healthy α-1 ATD persons Congenital liver disease with α-1 ATD Inclusion in PiMM persons Inclusion in extrahepatic tissues Early progress to cirrhosis

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19 ATZ-negative cells Increasing # with increasing age Higher rate of proliferation Difference in response to sex-hormones? Pathogenetic role?

20 Ibarguen et al. J Pediatr 1990;117:864 # of patients: 98 Follow-up time: 1 mo 27 yrs (mean 5.3 yrs) Age at diagnosis: 5 days 16 yrs

21 Ibarguen, 1990 Symptoms and signs: Cholestasis Hepatomegaly Splenomegaly Failure to thrive G.I. bleeding Ascites Vomiting Lethargy/irritability Diarrhoea

22 Ibarguen, 1990 Renal involvement: 15/98 Pulmonary involvement: 16/98

23 Pediatric AATD at Karolinska-Huddinge 174 (101 boys) ZZ: boys SZ:12 8 boys FZ:2 2 boys

24 PiZZ at Karolinska-Huddinge ZZ:160 Neonatal: 75 C.S. 61 alive & well 14 cirrhosis Elevated LFT etc 40 2 cirrhosis 38 alive & well Healthy: alive & well

25 AATD at Karolinska Huddinge SZ:12 Neonatal: 1 Healthy: 11 C.S. Alive & well: 12 FZ: 2 Alive & well: 2

26 AATD at Karolinska-Huddinge 16 infants/children with cirrhosis (9 boys) Onset of symptoms: < 1 yr: 16/16 Evident neonatal cholestasis: 14/16 Age at evident cirrhosis: 2.6 yrs (0,1-3.5 yrs (+14*) EHBA-like course: 3/16 Outcome: 7 dead without OLT 9 OLT 6 alive *: Doctor s delay of 10 years in one case

27 Outcome of EHBA-like AATD Total: 5 Cirrhosis: 3 OLT/death < 2 yrs: 3 Healthy 2 Evidence of good liver function at age 4: 2

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30 OLT for AATD Total: 9 (5 girls) Age at OLT: yrs Indication for OLT: liver failure: 7 HPS: 2 Causes of death: aortic aneurism SSRI-induced liver failure * biliary cirrhosis * * : failed re-olt

31 Unexpected OLT-related complications 2 intra-or sudden deaths (cardiac arrest) 2 late post-olt aortic ruptures (1 lethal) 3/9 dead after OLT Non OLT-related complications: Fulminant pancreatitis after ERCP!

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34 Family K Father Pi ZZ Mother PiMZ Johanna born 1968: Pi ZZ Viveka born 1973 Pi ZZ Rebecca born 1980 Pi ZZ

35 Rebecca K, born 1980, age 1 yr Failure to thrive Distended abdomen Steatorrhea? Celiac disease? Cirrhosis due to AATD Death at 2 years of age

36 Johanna K, born 1968 Clinically always healthy 15 years of age: platelet count 120 Bx: fibrosis 40 years of age: healthy mother of 3

37 Viveka K, born 1973 Clinically always healthy yrs: untreated CD sequestered ATZ in enterocytes 12 y.o.a: LFT normal, biopsy normal 35 y.o.a: LFT normal, healthy mother of 2

38 Sara, born 1988, Pi ZZ Neonatal cholestasis AATD + CMV 0-6 mo: failure to thrive 1 year: fibrosis 4 years: cirrhosis 4-18 yrs: compensated cirrhosis 18 years: decompensated OLT

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42 Jesper, born 1988 Pi ZZ Neonatal cholestasis AATD + CMV 0-6 mo: failure to thrive 1 year: fibrosis 4 years: fibrosis grade yrs: fibrosis + low platelet count 20 yrs: healthy, platelet count

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44 Siblings with PiZZ Robert born 1969: Paula born 1972: EHBA-like onset Death at 7 months Neonatal cholestasis 1 yr: cirrhosis 1-24 yrs: compensated 24.5 yrs: OLT

45 Pi MZ and liver disease Pittschieler, Acta Paed,1995: elevated LFT in higher frequency than in normal population No evidence of progressive liver disease Regev et al, JPGN 2006: no evidence that PiMZ contributes to progress of HCV or NAFLD

46 Provocative question?? Can contraceptives be regarded as prophylactic substitution therapy against COPD for heterozygous women??

47 Conclusions Early reliable prognostic markers not unthinkable Confounding factors not yet found Careful and frequent check-ups identify early most risk patients (Nearly) all future cirrhotic patients can be found at 4 years of age Not proven beyond any doubt that late unexpected progress to cirrhosis occurs

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