AATD is systemic disorder which involve GI tract: Liver Pancreas Intestine

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1 Andrey E. Dorofeyev, Joanna Chorostowska-Wynimko, Radosław Struniawski, Vera Khorunzhaya National Medical University, Kiev, Ukraine, National Institute of Tuberculosis and Lung Diseases Warsaw, Poland Alpha-1-antitrypsin deficiency (AATD) is a genetic disorder characterized by a low serum level of AAT, which predisposes individuals to early-onset of COPD, emphysema. AATD plays role in the development of oxidative stress, systemic inflammation and tissue injury. AATD is systemic disorder which involve GI tract: Liver Pancreas Intestine American Thoracic Society / European Respiratory Society Statement, 2003

2 The pathophysiology of liver disease in AAT deficiency is different from that of lung disease. Although a variety of theories have been proposed to explain liver injury in individuals with homozygous PI*ZZ AAT deficiency, the most widely accepted explanation is the accumulation theory Janciauskiene S, et al, European Journal of Gastroenterology & Hepatology, 2011 National Swedish cohort Larsson of PI*ZZ at years evidence of cirrhosis - 2%, but in patients over 50 years - 19% Sveger T. New England journal of medicine, 2000 The importance of age as a determinant of risk for CLD in adults was also emphasized in a Canadian study, where the risk for cirrhosis was estimated at 15% in males between 50 and 60 years of age. Corda L., et al Respiration, 2011 Never-smokers have more years to develop cirrhosis. Smokers died earlier predominantly from emphysema, COPD. Elzouki AN, et al. European Journal of Gastroenterology & Hepatology, 2001

3 Increase of the prevalence of viral hepatitis in PI*MZ adults with liver disease Nelson D.R., et al.. Clinical Gastroenterology and Hepatology, 2012 Studies in adults have not found such a correlation Pietrangelo A., et alcurrent Opinion in Gastroenterology, 2009 AATD associated liver disease can be exacerbated by viral hepatitis B and C as viruses express proteins that are selectively retained in the hepatocytes Mihalache F, et al. Alimentary Pharmacology & Therapeutics, 2011 Aside from low plasma AAT levels, laboratory and other clinical features are indistinguishable from those of decompensated cirrhosis of any etiology Zhang B., et al.. Blood, 2011 The distribution of patients with the MZ-phenotype was 20.5% in non-b chronic active hepatitis and 21% in cryptogenic cirrhosis compared with only 3.5% in alcoholic cirrhosis and 2.6% in other kinds of cirrhosis. Chappell S., et al. Hepatology, 2008 Prognosis is generally grave, with a mean survival of 2 years after diagnosis American Thoracic Society / European Respiratory Society Statement: Standards for the Diagnosis and Management of Individuals with Alpha-1 Antitrypsin Deficiency, 2003

4 The liver disease caused by alpha-1-antitrypsin deficiency (ATD) is predominantly characterized by fibrosis/cirrhosis with relatively limited inflammation and an increased likelihood of hepatic carcinoma. David H. Perlmutter, MD; Andrew Chu, MD; Kapil B. Chopra, MD Disclosures February 04, 2015 These effects are caused by the "proteotoxicity" of a misfolded protein that accumulates in liver cells Ghouse R, Chu A, Wang Y, Perlmutter DH. Dis Model Mech Incidence of hepatic carcinoma in ATD is not known Tsochatzis EA, Bosch J, Burroughs AK. Liver cirrhosis. Lancet Zhou H, Fischer HP. Am J Surg Pathol Patients with liver diseases and AATD need basic treatment of the main disease. G.Tirado-Conde, et al. Ther Adv in Resp Disease, 2008 Anti-AATD treatment efficacy is controversial. Reuters Health Information, 2008 Liver transplantation is indicated for patients with end-stage CLD. Criteria for transplantation do not differ from other causes of CLD Migliazza L, et al. Journal of Pediatric Surgery, 2003.

5 An association between AATD and chronic pancreatitis (CP) has been reported. AATD is one of etiological factors of chronic pancreatitis. AATD influent on the clinical type of CP? AATD influent on the severity of CP? American Thoracic Society / European Respiratory Society Statement, 2003 TIGAR-O -Toxic-metabolic -Idiopathic -Genetic Autosomal dominant Cationic trypsinogen Autosomal recessive CFTR mutations SPINK1 mutations Cationic trypsinogen α 1 -Antitrypsin deficiency -Autoimmune -Recurrent and severe acute pancreatitis -Obstructive M-ANNHEIM -Multiple -Alcohol -Nicotine -Nutrition -Heredity -Efferent pancreatic duct factors -Immunological factors -Miscellaneous and metabolic factors

6 Smoking and alcohol abusing is the most common risk factors in CP with AATD. Tobacco smoking inhibits pancreatic bicarbonate secretion and reduces both serum trypsin inhibitory capacity and a1- antitrypsin levels. Cumulative risk of CP according to the smoking status: Dhiraj Yadav et al. Pancreatology, 2010 Modering role of AAT in the course of chronic non-alcoholic pancreatitis (Teich N et al. Scandinavian Journal of Gastroenterology, 2002) Role of bioantioxidants depression and deficiency of protease inhibitor AAT in mechanisms activating free radical oxidation and proteolysis in chronic pancreatitis (Zhukova E.N. Terapevticheskiĭ Arkhiv, 2004) (Manoj Bhasin, et al. Cell and Tissue Research, 2010) MMP system imbalance is one of pathogenic mechanisms AATD realization in CP. (Deest G1, Ahmed SN, Causse XGastroenterol Clin Biol. 2008)

7 CP with AATD Age of initial diagnosis 34,2+ 5,1 44,9+ 4,1 CP Ethiological factors + + Number of exacerbations (per year) 5,1+ 0,6 2,9+ 0,4 * Abdominal pain (s.p.) 6,2+ 0,7 7,1+ 0,6 Fecal elastase (mcg/g) 52,9+ 5,6 112,1+ 11,8* COPD co-morbidity 68% 15% Polish-Ukrainian Group, 2012 COPD + CP COPD 3,33% 1,67% 1,67% 95,00% PiMZ PiMS PiMM 98,30 % Heterozygous carriers of deficient alleles were found in 5% of patients with comorbidity COPD and CP (group 1), while in the group without CP (group 2) - only 1.67%.

8 In group 1 there were a large number of people % (11 of 60 patients) compared with data of group 2-8.3% (5 of 60) in whom the pathology of the respiratory and digestive systems potentially was associated with a lack production of AAT Group n Mean Std.Error Range Median MMP-9, ng/ml I * ,01 95,19 27, ,50 242,92*** II** ,71 99,91 24, ,11 131,15*** TIMP-1, ng/ml I ,5±18,36 95,15-329,86 186,94 II ,05±15,16 86,50-334,16 150,79 MMP-3, ng/ml I 60 12,99±2,23 3,13 41,36 10,66 II 60 15,77±1,94 5,17 41,26 13,29 *- I group (COPD + CP), ** - II group (COPD without CP), ***p < 0,05 Normal rates are in the range: MMP-9 = ng/ml, TIMP 1 = ng/ml, MMP-3 = 2-46 ng/ml

9 In patients with low AAT level high proteolytic activity was observed. High activity of proteolysis triggering processes followed by proteolytic degradation of connective tissue components and the development of fibrosis both in lungs and pancreas. Heterozygosity for PiM- polymorphisms and especially both serum AAT and MMP-9 levels are valuable biomarkers for verification predisposition to the occurrence CP among COPD patients.

10 Increased risk of IBD ( ulcerative colitis and Crohn's disease) in a population suffering from COPD Ekbom A., et al. Lung Pulmonary abnormalities, dysfunction or hyperreactivity occurs in association with inflammatory bowel disease (IBD) more frequently than previously recognized. Hui Wang, et al. World J Gastroenterol There are many reports of chronic inflammation of the pulmonary and intestinal mucosa in IBD, the detailed mechanisms of pulmonary-intestinal crosstalk remain unknown. Mudter J, Neurath MF. Abdom Imaging. 2012; Shen J.,et al. Int J Clin Exp Pathol Keely S, Talley NJ, Hansbro PM Mucosal Immunol. 2012

11 Systemic AATD could impact on the mucosal inflammatory response Local mucosal inflammation leads to decreasing of protective systemic anti-trypsin activity Changes of mucosal barrier could be marker of severity of inflammatory process in patients with AATD Modification of inflammatory process in the large intestine and lungs could improve protease/anti-protease imbalance in AATD associated disorders Microbiome changes TLR-2,3,4 Adaptive immune response, apoptosis, autophagy NOD2/CARD15 Cells methabolism and cancer prevention Jak 2, Cancer prevention VDR AATD correlation with NOD2/CARD15 mutations in IBD patients were found

12 UC and AATD UC without AATD UC 3 2,5 Ki-67 SMA * * Ki-67 α-sma UC with AAT 2 1,5 1 0,5 Ki-67 α-sma 0 UC UC UC with AP AATD Inflammatory markers were significantly high in UC with AATD

13 COPD and AATD COPD without AATD

14 Mucosal inflammatory response is the similar in the large intestine and lungs in patients with AATD It characterized by changes of mucus production, secretion, qualitative and quantitative properties Pro-inflammatory markers are significantly high in patients with AATD Conclusions Alfa-1-anti-trypsin deficiency is systemic disorder Gastrointestinal tract is also affected in AATD It leads to high intensity of inflammatory process and co-morbidity of the GI and lungs

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