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Prognosis of primary biliary cirrhosis (PBC) in a large unselected cohort
IMMUNOLOGY, AUTOIMMUNE LIVER DISEASE
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P/C09/03
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LIVER DISEASE IN CHILDREN WITH HYPER IgM SYNDROME E Rodrit,ues I. N. Hadzic t, G. Davies 2, A. Jones2, P. Veys2, G. Mieli-Vergani 1 1Department of Child Health, King's College Hospital, Denmark Hill, London, UK. 2Host Defence Unit, Great Ormond Street, London, UK. Hyper IgM syndrome and its X-linked variant CD40 ligand deficiency (CD40LD) are disorders of immunoglobulin isotype switching. The patients have life-threatening infections in infancy, may become colonised with Cryptosporidium parvum (Cp) and develop sclerosing cholangitis (SC). To determine liver involvement and outcome of hyper IgM syndrome, we reviewed 20 children (all boys), from 16 families, referred to us between 1990-99. 17/20 had CD40LD conf'n'med by genetic studies. Patients were assessed by liver function tests (LFTs) (20), ultrasound scan (USS) (20), liver biopsy (19), ERCP (17) and Cp screening by culture and PCR in the stools (17) and bile (7). SC was diagnosed in 9 patients (45%) based on ERCP and histology (5), ERCP (3), and histology (1). Five children had severe, 1 mild and 2 minor radiological changes. USS was abnormal in 6/9 (67%) patients with SC. Of the 13 (65%) with normal LFTs, 2 had minor and 2 mild cholangiopathy. All children with persistently abnormal LFTs (5) (median AST 117 IU/I, GGT 182 IU/I) had abnormal USS, liver biopsy and ERCP. 1/7 bile and 5/17 stool specimens were Cp +. Four Cp + patients have SC. Four patients had bone marrow transplant (BMT) [1 non-myeloablative (nm)] and 1 combined liver transplant (LT) and nm-BMT. Two boys died of disseminated Cp, 1 after conventional BMT and urgent LT for liver failure, the other after re-LT. The boy, Cp -, who had combined LT and nm-BMT has normal immune and liver function 1 year later. In conclusion, children with hyper IgM syndrome end persistently abnormal LFTs have established cholangiopathy. If colonised with Cp their outcome after BIVIT and LT is uncertain. BMT should be considered before liver damage. Combined LT and nm-BMT should be attempted in advanced liver disease.
PRIMARY BILIARY CIRRHOSIS (PBC) IS A MUCOSAL DISEASE A. Floreani. A. Baragiotta, D. Pizzuti, 13. Martines, D. Basso t, C. Venturi, M. Pittoni ~, A. Cecchetto 2. S. ChiareUi3 Dept. of Surg. and Gastroenterol Sci, University of Padova, Italy. ~Clinical Chemistry, University of Padova, Italy. ZPathology, University of Padova, Italy. 3Dept. of Surgical and Oncological Sci, University of Padova, Italy. BACKGROUND: Coexistent PBC and coeliac disease (CD) has been recently reported in 6-11% of cases. However, a pathogenic link between these two conditions has not been explored. AIM: to evaluate the gastrointestinal mucosal function and the role of IgA transglutaminase (tGA) antibodies in PBC. METHODS: 88 consecutive PBC pts. (80F, 8M, mean age 55.5+11 yrs) gave their informed consent to partecipate the study. Each subject underwent: 1) gastrointestinal permeability test assessing the urinary excretion of sucrose, and the ration of lactalose to marmitol excretion; 2) serological test for both endomysial antibody (EMA) by immunofluorescence and IgA-tGA by ELISA (Alifax, Padua Italy); 3) upper gastrointestinal endoscopy with distal duodenum biopsy whenever possible; moreover, distal duodenum specimens were assessed for the peptic-tryptic digest of wheat gliadin in an in-vitro organ culture system. RESULTS: 24/88 pts (27.2%) had IgA-tGA above the normal limits; 19 pts underwent upper endoscopy and 3 of them (3.4%) had a definite diagnosis of CD (EMA positivity, high serum tGA + villous atrophy). An overall impairment of gastrointestinal permeability was found in 29% of pts (12.9% of those with high levels oflgA-tGA and 16.1% of those with normal levels of IgA-tGA). The mean enterocyte height was at baseline 34.29 _+ 3.01 ~tm, and significantly decreased (13<0.05)to 28.57 :l: 2.74 and 27.93 + 2.02 tim after 24h culture in absence or in presence of gluten, respectively. CONCLUSIONS: We confLrm a true association of CD in 3.4% of PBC pts. ELISA IgA-tGA serum levels have a low specificity for CD in PBC, probably recognizing a different IgA epitope. However, an altered gastrointestinal permeability is present in 29% of PBC patients, independently by the toxic effect of gluten.
[ P/C09/02 ]
I PIC09/04
PROGNOSIS OF PRIMARY BILIARY CIRRHOSIS (PBC) IN A LARGE UNSELECTED COHORT M. Prince, J. Metcalf, W. Craig, O.EW. James Centre for Liver Research, University of Newcastle, United Kingdom. The true prognosis of PBC in unselected patients is uncertain, particularly those diagnosed before liver symptoms. Such information will guide new treatment needs. We have studied mortality in a cohort of 770 PBC patients from a defined region recruited by exhaustive case finding over a defined period (prevalent or incident between 1 Jan 1987 and 31 Dec 1994). Follow up was available on all 770 patients to 1 July 1999. Results: 366/770 patients (47%) had died by July 1999. Mean FU 8.07 yrs, total FU 6173 yrs. Median survival (Kaplan Meier) 11.63 yrs. 32 patients had transplants (4 died). Predictors of worst survival from diagnosis were Bill >18mmoFl (6.76 yrs vs 13.5 yrs if Bill <18. P<0.001). Albumin <35g/1 (3.49 yrs vs 14.4 ifalb >35. p<0.001). Also advanced (grade 3 or 4) histology (p<0.001); INR >1.2 (p<0.01); age over 60 at diagnosis (p<0.001). Overall prognosis was not related to presence or absence of liver symptoms at diagnosis. Overall 205/366 deaths (56%) were attributable to liver disease. 69/469 initially asymptomatic patients died liver deaths vs 92/301 initially symptomatic (p<0.0001). 16 patients in each group received transplants. Conclusions: Overall mortality of 46% after mean FU 8.07 yrs is high in unselected patients, not different between initially symptomatic or asymptomatic patients although liver mortality was higher in initially symptomatic. Liver death or Tx was 83/469 (18%) in initially asymptomatic patient. This data supports the need for effective treatment in PBC patients before symptom development.
THI BUT NOT TH0 CELL HELP IS EFFICIENT TO INDUCE CYTOTOXIC T LYMPHOCYTES BY IMMUNIZATION WITH SHORT SYNTHETIC PEPTIDES A. L6pez-Diaz de Cerio, N. Casares, J.J. Lasarte, E Sarobe. L.A. P~rezMediaviUa, M. Ruiz, J. Prieto, E Borr/ts-Cuesta Department of Internal Medicine, University of Navarra, Pamplona, Spain. Immunization of mice with a peptide, encompassing residues 121135 from hepatitis C virus (HCV) E1 protein, induced CD4 ÷ Thl cells as well as a long lasting CD8 + cytotoxic T lymphocyte (CTL) response in vivo when the peptide was administered subcutaneously with or without incomplete Freund's adjuvant. Using truncated peptides from this sequence it was shown that the determinant recognized by cytotoxic T cells was encompassed by residues 123131. Deletion of residues from the N-terminus or the C-terminus of the wild type peptide abrogated its helper character. When Vail22 of the wild peptide was replaced by Ala, the ability to induce a cytotoXic response was lost concomitantly with the loss of the Thl pattern of cytokine production. Interestingly, the Aia-modified peptide when coimmunized with a peptide encompassing residues 323 to 337 from ovalbumin, which is able to induce a Thl response in BALB/c mice, restored the capacity of the modified peptide to induce CTL. However, co-immunization of the Ala-modified peptide with a peptide encompassing residues 106 to 118 from sperm whale myoglobin, which induces a Th0 cytokine profile, was unable to efficiently restore CTL induction. These results demonstrate that CTL induction with a short synthetic peptide requires that this peptide contains domains recognized by T cytotoxic cells as weU as by Thl helper cells. For those peptides that do not contain this type of T helper domain, competent T cell help can be provided by coimmunization with a distinct peptide able to stimulate a Thl response.
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P/C09/03
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LIVER DISEASE IN CHILDREN WITH HYPER IgM SYNDROME E Rodrit,ues I. N. Hadzic t, G. Davies 2, A. Jones2, P. Veys2, G. Mieli-Vergani 1 1Department of Child Health, King's College Hospital, Denmark Hill, London, UK. 2Host Defence Unit, Great Ormond Street, London, UK. Hyper IgM syndrome and its X-linked variant CD40 ligand deficiency (CD40LD) are disorders of immunoglobulin isotype switching. The patients have life-threatening infections in infancy, may become colonised with Cryptosporidium parvum (Cp) and develop sclerosing cholangitis (SC). To determine liver involvement and outcome of hyper IgM syndrome, we reviewed 20 children (all boys), from 16 families, referred to us between 1990-99. 17/20 had CD40LD conf'n'med by genetic studies. Patients were assessed by liver function tests (LFTs) (20), ultrasound scan (USS) (20), liver biopsy (19), ERCP (17) and Cp screening by culture and PCR in the stools (17) and bile (7). SC was diagnosed in 9 patients (45%) based on ERCP and histology (5), ERCP (3), and histology (1). Five children had severe, 1 mild and 2 minor radiological changes. USS was abnormal in 6/9 (67%) patients with SC. Of the 13 (65%) with normal LFTs, 2 had minor and 2 mild cholangiopathy. All children with persistently abnormal LFTs (5) (median AST 117 IU/I, GGT 182 IU/I) had abnormal USS, liver biopsy and ERCP. 1/7 bile and 5/17 stool specimens were Cp +. Four Cp + patients have SC. Four patients had bone marrow transplant (BMT) [1 non-myeloablative (nm)] and 1 combined liver transplant (LT) and nm-BMT. Two boys died of disseminated Cp, 1 after conventional BMT and urgent LT for liver failure, the other after re-LT. The boy, Cp -, who had combined LT and nm-BMT has normal immune and liver function 1 year later. In conclusion, children with hyper IgM syndrome end persistently abnormal LFTs have established cholangiopathy. If colonised with Cp their outcome after BIVIT and LT is uncertain. BMT should be considered before liver damage. Combined LT and nm-BMT should be attempted in advanced liver disease.
PRIMARY BILIARY CIRRHOSIS (PBC) IS A MUCOSAL DISEASE A. Floreani. A. Baragiotta, D. Pizzuti, 13. Martines, D. Basso t, C. Venturi, M. Pittoni ~, A. Cecchetto 2. S. ChiareUi3 Dept. of Surg. and Gastroenterol Sci, University of Padova, Italy. ~Clinical Chemistry, University of Padova, Italy. ZPathology, University of Padova, Italy. 3Dept. of Surgical and Oncological Sci, University of Padova, Italy. BACKGROUND: Coexistent PBC and coeliac disease (CD) has been recently reported in 6-11% of cases. However, a pathogenic link between these two conditions has not been explored. AIM: to evaluate the gastrointestinal mucosal function and the role of IgA transglutaminase (tGA) antibodies in PBC. METHODS: 88 consecutive PBC pts. (80F, 8M, mean age 55.5+11 yrs) gave their informed consent to partecipate the study. Each subject underwent: 1) gastrointestinal permeability test assessing the urinary excretion of sucrose, and the ration of lactalose to marmitol excretion; 2) serological test for both endomysial antibody (EMA) by immunofluorescence and IgA-tGA by ELISA (Alifax, Padua Italy); 3) upper gastrointestinal endoscopy with distal duodenum biopsy whenever possible; moreover, distal duodenum specimens were assessed for the peptic-tryptic digest of wheat gliadin in an in-vitro organ culture system. RESULTS: 24/88 pts (27.2%) had IgA-tGA above the normal limits; 19 pts underwent upper endoscopy and 3 of them (3.4%) had a definite diagnosis of CD (EMA positivity, high serum tGA + villous atrophy). An overall impairment of gastrointestinal permeability was found in 29% of pts (12.9% of those with high levels oflgA-tGA and 16.1% of those with normal levels of IgA-tGA). The mean enterocyte height was at baseline 34.29 _+ 3.01 ~tm, and significantly decreased (13<0.05)to 28.57 :l: 2.74 and 27.93 + 2.02 tim after 24h culture in absence or in presence of gluten, respectively. CONCLUSIONS: We confLrm a true association of CD in 3.4% of PBC pts. ELISA IgA-tGA serum levels have a low specificity for CD in PBC, probably recognizing a different IgA epitope. However, an altered gastrointestinal permeability is present in 29% of PBC patients, independently by the toxic effect of gluten.
[ P/C09/02 ]
I PIC09/04
PROGNOSIS OF PRIMARY BILIARY CIRRHOSIS (PBC) IN A LARGE UNSELECTED COHORT M. Prince, J. Metcalf, W. Craig, O.EW. James Centre for Liver Research, University of Newcastle, United Kingdom. The true prognosis of PBC in unselected patients is uncertain, particularly those diagnosed before liver symptoms. Such information will guide new treatment needs. We have studied mortality in a cohort of 770 PBC patients from a defined region recruited by exhaustive case finding over a defined period (prevalent or incident between 1 Jan 1987 and 31 Dec 1994). Follow up was available on all 770 patients to 1 July 1999. Results: 366/770 patients (47%) had died by July 1999. Mean FU 8.07 yrs, total FU 6173 yrs. Median survival (Kaplan Meier) 11.63 yrs. 32 patients had transplants (4 died). Predictors of worst survival from diagnosis were Bill >18mmoFl (6.76 yrs vs 13.5 yrs if Bill <18. P<0.001). Albumin <35g/1 (3.49 yrs vs 14.4 ifalb >35. p<0.001). Also advanced (grade 3 or 4) histology (p<0.001); INR >1.2 (p<0.01); age over 60 at diagnosis (p<0.001). Overall prognosis was not related to presence or absence of liver symptoms at diagnosis. Overall 205/366 deaths (56%) were attributable to liver disease. 69/469 initially asymptomatic patients died liver deaths vs 92/301 initially symptomatic (p<0.0001). 16 patients in each group received transplants. Conclusions: Overall mortality of 46% after mean FU 8.07 yrs is high in unselected patients, not different between initially symptomatic or asymptomatic patients although liver mortality was higher in initially symptomatic. Liver death or Tx was 83/469 (18%) in initially asymptomatic patient. This data supports the need for effective treatment in PBC patients before symptom development.
THI BUT NOT TH0 CELL HELP IS EFFICIENT TO INDUCE CYTOTOXIC T LYMPHOCYTES BY IMMUNIZATION WITH SHORT SYNTHETIC PEPTIDES A. L6pez-Diaz de Cerio, N. Casares, J.J. Lasarte, E Sarobe. L.A. P~rezMediaviUa, M. Ruiz, J. Prieto, E Borr/ts-Cuesta Department of Internal Medicine, University of Navarra, Pamplona, Spain. Immunization of mice with a peptide, encompassing residues 121135 from hepatitis C virus (HCV) E1 protein, induced CD4 ÷ Thl cells as well as a long lasting CD8 + cytotoxic T lymphocyte (CTL) response in vivo when the peptide was administered subcutaneously with or without incomplete Freund's adjuvant. Using truncated peptides from this sequence it was shown that the determinant recognized by cytotoxic T cells was encompassed by residues 123131. Deletion of residues from the N-terminus or the C-terminus of the wild type peptide abrogated its helper character. When Vail22 of the wild peptide was replaced by Ala, the ability to induce a cytotoXic response was lost concomitantly with the loss of the Thl pattern of cytokine production. Interestingly, the Aia-modified peptide when coimmunized with a peptide encompassing residues 323 to 337 from ovalbumin, which is able to induce a Thl response in BALB/c mice, restored the capacity of the modified peptide to induce CTL. However, co-immunization of the Ala-modified peptide with a peptide encompassing residues 106 to 118 from sperm whale myoglobin, which induces a Th0 cytokine profile, was unable to efficiently restore CTL induction. These results demonstrate that CTL induction with a short synthetic peptide requires that this peptide contains domains recognized by T cytotoxic cells as weU as by Thl helper cells. For those peptides that do not contain this type of T helper domain, competent T cell help can be provided by coimmunization with a distinct peptide able to stimulate a Thl response.
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