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Clinical applications of auto antibodies
Brig Tahir Aziz AhmedConsultant Immunologist
Armed Forces Institute of Pathology (AFIP)Rawalpindi-Pakistan
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Dr Paul Ehrlich• 1854-1915• German• Nobel laureate• Diphtheria antiserum (with von Boehring)
only Boehring won Nobel prize-1901Ehrlich won it for Salvarsan a treatment for Syphilis-five years later
• Side-chain theory• Dr Paul Ehrlich’s magic bullet 1945
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Auto antibodies
• Horror autotoxicus
• Auto antibodies relatively easy to detect• Some well defined disease and subset
associations• Some auto antibodies with defined role in
immunopathogenesis• Antibody levels may relate with disease activity
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Thyroid
• Thyroid– Anti thyroid peroxidase antibodies
(anti thyroid microsomal antibodies)– Anti thyroglobulin antibodies– Anti TSH receptor antibodies
• Activating antibodies (Grave’s ophthalmopathy)• Inhibitory antibodies (thyrotropin binding inhibitory
immunoglobulins TBII-Thyroiditis)
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Anti thyroid microsomal & thyroglobulin antibodies
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Euthyroid Hyperthyroid Hypothyroid Total100-500
IU/ml2 7 7 16
501-1000 IU/ml
6 4 7 17
>1000 IU/ml
5 1 1 7
Anti Thyroglobulin antibodies< 100 IU/ml Normal> 100 IU/ml Elevated100-500 IU/ml High501-1000 IU/ml Very high>1000 IU/ml Extremely high(103 positive out of 248. One year local unpublished data)
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Euthyroid Hyperthyroid Hypothyroid Total30-300 IU/ml 5 - 5 10>300 IU/ml 4 1 6 11
Anti thyroid peroxidase antibodies< 30 IU/ml Normal30-300 IU/ml High>300 IU/ml Very high(109 positive out of 496. One year local data unpublished)
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When to test for thyroid antibodies
• Autoimmune thyroid disease– Grave’s disease– Hashimotos thyroiditis– Postpartum thyroiditis (OR: 11.5)– Idiopathic painless thyroiditis
• Thyroglobulin monitoring in thyroid cancer• Recurrent miscarraige (OR: 3.73)• Unexplained subfertility (OR: 1.5)• Preterm birth (OR: 1.9)• Autoimmune polyendocrine syndromes
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• Anti thyroid antibodies in subclinical hypothyroidismTPO Abs positive: 11.2% of 1500 euthyroid pregnant Pakistani womenMiscarriage rate: 36.3% (1.8% in Ab neg women)Prematurity: 26.8% (8% in Ab neg women)(Ghaffor F et al. JCPSP 2006: 16(7); 468-471)
• Anti thyroid antibodies in population surveys– Overt hypothyroidism, Thyrotoxicosis = 0.4%– Subclinical hypothyroidism = 4.0%– TPO antibodies 8.6% males; 18.5% females
(Hoodgendoorn et al. Clin Chemistry 2006: 52(1); 104-111)
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Pregnancy loss
• Anti cardiolipin antibodiesIgG, IgA, IgM
• Anti beta-2 glycoprotien 1 antibodiesIgG, IgA, IgM
• Lupus anti coagulant testTest to be positive with an interval of 8 weeks
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Infertility
• Anti sperm agglutinating antibodies (12 /83)
• Anti sperm cytotoxic antibodies(Microagglutinating and complement mediated cytotoxicity tests)
• Anti ovarian cell antibodies(Indirect immunofluoroscence-ovarian tissue)
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• Anti parathyroid antibodies(Indirect immunofluorescence-parathyroid tissue)
– 38% Idiopathic hypoparathyroidism– 26% Idiopathic addison’s diseases– 12% Hashimoto’s thyroiditis– 6% Control groupBlizzard RM. Clin. exp. Immunol. (1966) 1, 119-128.
• Anti calcium sensor receptor antibodies(Anti CaSR antibodies. Activating; inhibitory)(Brown EM. Endocrinol Metab Clin North Am. 2009 June ; 38(2): 437-)
• Anti pituitary antibodies
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Interferon and antibodies• Seven out of 50 patients after interferon treatment developed thyroid
dysfunction(Hypothyroid: 5; Hyperthyroid: 2)
(Chaudhry N et al. PAFMJ 2011.)
(Chutto MA et al. JCPSP 2009.)
• Antibodies after interferon treatmentTPO (p=0.036); ANA (p=0.014)
Chronic HCV infected patients (32/106; 30%)
Interferon treatment (22/36; 61%)No treatment (12/32; 37.5%)
increase in autoimmunity significant in males: p=<.04(accepted for publication: Ahmad D et al. PAFMJ 2012;..)
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Autoantibodies in liver disease
Antibody Disease Association CommentsMitochondrial antibody
Primary biliary cirrhosis >95%
Smooth muscle antibody
Autoimmune hepatitis
Primary biliary cirrhosis
70%
30%
LKM Autoimmune hepatitis
Drug induced hepatitis
Uncommon but specific antibody
ANA Autoimmune hepatitis 30%
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Autoimmune hepatitis
• AFIP data (March 2010-March 2011)• Smooth muscle antibodies 397 38• SLA 11 1• LKM 307 3• AMA 275 5• Anti parietal cell antibodies
(Ahmed D et al. Pakistan J of Pathology 2009; 20(3): 70-73)
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Anti pancreatic duct antibodies
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Autoimmune pancreatitis
• IgG4 antibody levels• Anti pancreatic duct antibodies
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Anti parietal cell antibodies
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• Anti parietal cell antibodiesAtrophic gastritis & pernicious anemia(3 positive out of 46)
• Anti intrinsic factor antibodies(0 positive out of 27)– 12 patients positive for anti intrinsic factor
antibodies out of 78 vitamin B12 deficient patients(local study unpublished data)
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Anti islet cell antibodies
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Total Positive• Anti islet cell antibodies 10 0
1st degree relatives of IDDM
• Anti insulin antibodies1st degree relatives of IDDMInsulin resistance
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Anti adrenal antibodies
• Addisons disease– 50% of idiopathic addison’s disease(Brown RM. Clin. exp. Immunol. (1967) 2, 19-30.)
– 83% of primary addison’s disease positive for anti adrenal antibodies (IF)
– 100% positive for anti 21-alpha hyroxylase antibodies in autoimmune addison’s disease(Betterle C et al.Endocrine Reviews 2002. 23(3):327–364)
• Premature ovarian failure– 3.2%positive for anti adrenal antibodies
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Anti adrenal antibodies
• APS type 1 13%• APS type 2 41%• APS type 4 5%• Isolated autoimmune adrenal disease 41%
(Betterle C et al.Endocrine Reviews 2002. 23(3):327–364)
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Autoimmune polyendocrine syndrome, type 1. candidiasis-hypoparathyroidism-Addison's disease-syndrome, Autoimmune Polyglandular Syndrome I,[2] APECED, or APS-IOther disease associations are:
– hypothyroidism– hypogonadism and infertility– vitiligo (depigmentation of the skin)– alopecia (baldness)– malabsorption– pernicious anemia– chronic active (autoimmune) hepatitis
Autoimmune polyendocrine syndrome, type II. autoimmune adrenal insufficiency
autoimmune thyroid disease and/or type 1 autoimmune diabetes mellitus defines
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Conclusion
• Auto antibodies remain the only test to identify autoimmune nature of endocrine diseases.
• Auto antibodies may be tested using relatively simple laboratory techniques to help establish the diagnosis of relatively rare diseases.