Umberto Volta Coeliac Disease and Malbsorption Unit Digestive Diseases and Internal Medicine Dept St.Orsola-Malpighi Hospital, Bologna
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1 Coeliac disease Umberto Volta Coeliac Disease and Malabsorption Unit Digestive Diseases and Internal Medicine Dept. St. Orsola-Malpighi Hospital University of Bologna President of the Scientific Board of the Italian Association for Celiac Disease
2 Umberto Volta Coeliac Disease and Malbsorption Unit Digestive Diseases and Internal Medicine Dept St.Orsola-Malpighi Hospital, Bologna Il sottoscritto dichiara di non aver avuto negli ultimi 12 mesi conflitto d interesse in relazione a questa presentazione e che la presentazione non contiene discussione di farmaci in studio o ad uso off-label
3 COELIAC DISEASE: Autoimmune food intolerance 1% in the general population onset at all ages polymorphic clinical presentation diagnostic criteria: antibody markers and damage of small intestine
4 Coeliac disease pathogenesis Gliadin extrinsic trigger Precipitating factors: stress, pregnancy HLA-DQ2 or DQ8 close genetic linkage Other environmental factors: bacterial and viral infections, intestinal microbiota Tissue transglutaminase (ttg)
5 Over-expression di zonulina Peptidi di gliadina lume intestinale epitelio intestinale ttg reagisce con peptidi di gliadina ttg Linfociti T CD4+ causano atrofia citochine lamina propria MMP-1,-3,-12 peptidi gliadina peptidi deamidati ttg APC DQ2/DQ8+ Peptidi di gliadina deamidati dalla ttg sono presentati da APC DQ2/DQ8+ ai linfociti T CD4+ Stimolazione dei B linfociti alla sintesi anticorpale
6 Coeliac Disease in and outside the gut joints and muscles nervous system skin and mouth heart bone pancreas Small Bowel Main Target Organ female and male reproductive system liver thyroid blood eyes and salivary glands
7 Spectrum of Liver Disease in CD Cryptogenic disease Mild dysfunction (hypertransaminasaemia) Chronic liver disease (chronic hepatitis or cirrhosis, liver failure) Autoimmune disorders (primary biliary cirrhosis, primary sclerosing cholangitis, type 1 and 2 autoimmune hepatitis, autoimmune cholangitis, overlap syndrome) Volta U, Clin Rev Allerg Immunol 2009
8
9 Characteristics of hypertransaminaemia in CD Retrospective analysis of large series of untreated celiacs revealed a more frequent elevation of alanine than aspartate transaminases with normal levels of other liver enzymes (γ-gt and alkaline phosphatase) and bilirubin Usually the increase in transaminase levels is mild (<2x), but in some cases it can overcome 5 times the UNL. In the majority of CD pts liver enzymes revert to normal within 6 months of GFD, but in some cases they return to normal after 12 months of GFD. Hypertransaminasaemia can be the only sign of CD without any gastrointestinal or other gluten-induced symptoms
10 Liver Biopsy in Coeliac Disease with isolated hypertransaminasaemia Non-specific hepatitis Kupffer cell hyperplasia Mononuclear cell infiltration Mild steatosis Mild fibrosis
11 Patients referred to hepatology outpatient clinic for hypertransaminasaemia (September 1995-April 1997) 560 Pts with ALT 512 with known etiology (viral, autoimmune, toxic/ overload related, enzyme deficiency) (91%) 48 with unknown etiology (9%) Volta U, Lancet 1998
12 Antibody Screening for Coeliac Disease in Cryptogenic Hypertransaminasaemia 48 Patients 43 EmA neg (90%) 5 EmA pos. (10%) 5 SVA (100%) Volta U, Lancet 1998 SVA: subtotal villous atrophy (3c)
13 Clinical and Histological Findings in the 5 Coeliacs with Cryptogenic Hypertransaminasaemia Sex Age years GI signs Absorption tests ALT 0-40 U/L Liver biopsy F 19 none normal 181 Mild fibrosis F 23 none normal 46 Not performed F 27 none normal 73 Mild steatosis M 23 none normal 94 Mild fibrosis M 25 none normal 106 Non-specific hepatitis GI. gastrointestinal Volta U, Lancet 1998
14 Raised transaminase levels in coeliac disease after GFD Center for Coeliac Disease Diagnosis, St. Orsola-Malpighi, Bologna % diagnosis 6 monhts GFD 2 years GFD Volta U, Dig Liv Dis 2001
15 Identification of coeliac disease can avoid OLT in patients with severe liver failure Four adult patients, assessed for liver transplantation because of a severe liver failure (due to cryptogenic cirrhosis in 3 cases and to congenital hepatic fibrosis in the fourth) were identified as coeliacs thanks to a serological screening. Gluten free diet led to a dramatic improvement of hepatic function and transplantation was avoided. Kaukinen K, Gastroenterology 2002
16 Prevalence of Primary Biliary Cirrhosis (PBC) in patients with Coeliac Disease (CD) Country Coeliac population N with PBC Bardella, 1997 Italy (0.3%) Kingham, 1998 Wales (2.8%) Sorensen, 1999 Sweden (0.3%) Denmark (0.2%) Floreani, 2002 Italy (3.7%)* Volta, 2006 Italy (0.6%) *Positive AMA only, with normal liver function test
17 Hepatology 2007; 46:150-58
18 Prevalence of Coeliac Disease (CD) in Autoimmune Cholestatic Liver Disorders PBC n 173 PSC n 61 AIC n 21 PBC+PSC+AIC n 255 Coeliac Disease 7 (4%) 1 (1.6%) 1 (4.8%) 9 (3.5%) PBC: primary biliary cirrhosis; PSC: primary sclerosing cholangitis; AIC: autoimmune cholangitis Volta U, AJG 2002
19 Clinical, histological and biochemical features of liver disease in 9 identified CD pts Patient Signs Liver disease before CD(months) Liver histology AP(xnl) nl 280u/l PBC PBC pruritus pruritus stage I stage II x1.2 x1.6 PBC PBC pruritus jaundice stage II stage IV x1.5 x4.8 PBC PBC none jaundice 9 52 stage II stage IV x1.9 x3.1 PBC none 1 stage I x1.1 AI none 27 Florid bile x1.8 duct lesion PSC jaundice 39 Cirrhosis x3.1
20 Effect of Gluten Withdrawal on Autoimmune Cholestatic Liver Disorders Severe PBC and PSC resolution of malabsorption with clinical improvement liver enzymes and pruritus unchanged after GFD Mild disease (PBC and AIC) Volta U, AJG 2002 the progression of liver disease slows down in a 4-year-follow-up with GFD and ursodeoxycolic treatment
21 Prevalence of Coeliac Disease (CD) in Adult Patients with Autoimmune Hepatitis 5 CD/181 AIH* 2.8% Volta U, % (range %) 3 CD/47 AIH 6.4% Villalta D, 2005 *only serology 8/181= 4.4%
22 Prevalence of Coeliac Disease in Pts with autoimmune hepatitis (AIH) 181 AIH 157 type 1 AIH (ANA, SMA+) 24 type 2 AIH (LKM, LC1+) 6 EmA+ (4%) 2 EmA+ (8%) 3 with SVA (3 not biopsied) 2 with SVA At least 1 coeliac in 36 AIH patients Volta U, Dig Dis Sci %
23 Effect of gluten withdrawal on liver function in pts with autoimmune hepatitis (AIH) and coeliac disease (CD) Clinical improvement due to the regrowth of small intestinal mucosa with normal absorption of nutrients, but autoimmune liver damage is usually unaffected by the diet Obvious benefits produced by the early detection and treatment of CD in pts with AIH in terms of both normal absorption of drugs and maintenance of skeletal integrity (prevention of osteoporosis in corticosteroid-treated AIH pts) Volta U, 1998; Villalta D, 2005
24 High prevalence of coeliac disease (CD) in children with autoimmune liver disease: a multicenter study 23 cases of CD (16%) were identified among 140 children with autoimmune liver disease Of these 23 children identified as celiacs 19 (>80%) had autoimmune hepatitis, 2 autoimmune cholangitis and 2 overlap syndrome Diagnosis of CD preceded that of liver disease in 18 cases, but elevation of ALT was present in 16 when CD was diagnosed Caprai S et al, SIGENP Study Group for Autoimmune Liver Disorders in CD Clin Gastroenterol Hepatol 2008
25 Prevalence of autoimmune hepatitis (AIH) in coeliac disease (CD) children In a 10-year single-centre experience AIH was found in 7 (2%) out of 350 CD children, 133 (38%) of whom displayed cryptogenic hypertransaminasemia. GFD plus prolonged immunosuppressant treatment allowed a high remission rate in the 7 AIH cases (only one relapsed after immunosuppressant withdrawal) (Di Biase AR, 2010) Of 14 coeliac children with AIH, 12 had liver dysfunction during gluten exposure, in only two did it develop after gluten exclusion suggesting that a strict gluten free diet may be protective (Maggiore G, 2001)
26 Coeliac Disease (CD) in patients with hepatitis C The prevalence of CD in patients with Hepatitis C was found to be 1.2% and does not differ from CD finding in the general population. Since both disorders are very frequent, it has been hypothesised that their association is casual. Treatment of hepatitis C in patients with a coexistent CD is recommended only when CD is in remission with negativity for all CD-related autoantibodies Fine KD, AJG 2001; Silano M, Volta U, Eur J Microbiol Infect Dis 2009
27 Coeliac Disease (CD) and NASH/NAFLD Studies in pts with NASH and NAFLD found a prevalence of CD serology (EmA and ttg) ranging from 4% to 10% and duodenal biopsy confirmed CD diagnosis only in 3% of these cases (Nehra 2001; Bardella MT, 2004) Since fatty liver is a very common clinical finding in the general population (up to 25%) in modern industrialized countries, the detection of NASH or NAFLD in CD patients is likely to be coincidental rather than a true association (Rubio-Tapia A, 2007, Volta U, 2009)
28 The Liver in Celiac Disease Rubio-Tapia A and Murray JA, Hepatology 2007 Pathogenesis of liver involvement in Coeliac Disease
29 Long-standing malnutrition Malnutrition of any cause is associated with hepatic dysfunction and may give rise to steatosis Although rarely observed in coeliac disease, malnutrition due to severe malabsorption can concur in determining liver dysfunction found in gluten-sensitive enteropathy Volta U, Clinic Rev Allerg Immunol 2009
30 Increased intestinal permeability Intestinal permeability has been found to be significantly increased in coeliacs with abnormal liver tests It has been postulated that in CD altered permeability of small bowel may allow toxic or infective agents access to the hepatobiliary system leading to liver abnormalities. Volta U, Clin Rev Allerg Immunol 2009
31 Small intestinal bacterial overgrowth (SIBO) SIBO has been postulated as possible cause of liver impairment in CD The prolonged intestinal transit in untreated CD pts leads to bacterial overgrowth with a consequent increase in the bacterial antigen pool available for absorption and enzymatic neoantigen production Kupffer cells could play a pivotal role in the regulation of the immune response to bacterial products from the gut Volta U, Clinic Rev Allerg Immunol 2009
32 Mucosal inflammation of small intestine Chronic mucosal inflammation leads to release of tissue transglutaminase (TG2) from intestinal lamina propria; TG2 cross-links with various antigens (bacterial, viral, food, etc..) being responsible for secondary autoimmunity Autoantibodies directed against TG2 are present in the liver and other extraintestinal tissues in CD, raising the hypothesis for a pathogenic role of the humoral-mediated immune-responses in the liver injury observed in CD Cytokine release in the active phases of CD can be responsible for liver damage Volta U, Clinic Rev Allerg Immunol 2009
33 IgA ttg reactivity from CD sera on extraintestinal tissues Small intestine Liver Pancreas Myocardium Volta U, Int J Clin Lab Res 1995, Korponay-Szabo IR, Gut 2004
34 Shared genetic predisposition A common inherited predisposition for coeliac disease (CD) and autoimmune liver disorders occurs in patients who possess certain HLA class II molecules and haplotypes HLA-DR3 and DQ2 both confer susceptibility to CD The major risk factor for AIH are specific loci in the HLA-DR region, including B8-DR3 which is in close linkage dysequilibrium with HLA-DQ2. Furthermore, HLA-B8/DR3 is found with increased frequency in PSC, associated to other intestinal disorders such as UC. In PBC however no close association with HLA phenotype has been established Volta U, Clinic Rev Allerg Immunol 2009
35 Approach to the diagnosis of liver involvement in celiac disease Rubio-Tapia A, Hepatology 2007
36 Approach to the diagnosis of coeliac disease in autoimmune liver disorders Serological CD-screening by ttg IgA* ttg - ttg +>5x if ttg +<5x, test for IgA EmA Check antibodies Within 5 years *if IgA deficiency, replace ttg IgA with DGP IgG Duodenal biopsy EmA+ EmA- Antibody follow-up Volta U, Exp Rev Gastroenterol Hepatol 2010
37 Take home message Liver abnormalities are a common extraintestinal manifestation in coeliac disease (CD) pts ranging from mild hepatic dysfunction to severe liver disease Cryptogenic liver disease is the diagnostic label applied to a significant number of pts with undefined liver dysfunction; it is mandatory to exclude CD before this label is applied to these pts
38 Take home message The association of CD with autoimmune liver disorder is well established Screening for CD should be performed in all pts with autoimmune liver disorders Liver dysfunction should be sought in pts with CD at the time of diagnosis and its etiology, in particular autoimmune etiology, should be re-explored in those with persistent abnormalities of liver enzymes after gluten exclusion
39 Acknowledments : Dr. Giacomo Caio Prof. Roberto De Giorgio Dr.ssa Angela Fabbri Dr.ssa Erica Fiorini Dr.ssa Claudia Parisi Dr.ssa Maria Piscaglia Dr. Francesco Tovoli Dr Ronny Cicola University of Bologna
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