ENDOCRINOLOGY

Clinical Immunological aspects of

endocrine diseases.
HN LUMA
MD,FRCP

PLAN
1. Introduction
2. Mechanisms of endocrine
autoimmunity
3. Thyroid Disease
4. Pancreatic Disease

1. INTRODUCTION
Endocrine cells:
Localised e.g thyroid
Distributed in non endocrine organ

INTRODUCTION
GLANDULAR DYSFUNCTION

Autoimmunity
Tumour infiltration
Enzymatic defects of synthesis
Congenital
Drugs
Infarction
Infection
Post surgical and Post Irradiation

2- AUTO IMMUNE DISEASE

Multifactorial
-Genetic factors
Run families
Pattern of inheritance ?
Concordance rates 50 %
Incomplete association with MHC
- Environmental factors
Genetically predisposed
Infectious agents
Chemical toxins
- Female preponderance : Puberty, Pregnancy, Post partum,
menopause.

2. MECHANISMS OF ENDOCRINE AUTO IMMUNITY

AI reactions may be directed against

Endocrine cells
Receptors on cells
Hormones
Receptors on target cells

2 -MECHANISMS OF ENDOCRINE AUTO

IMMUNITY

2. MECHANISMS OF ENDOCRINE AUTO

IMMUNITY
Auto antibodies are organ specific (Non organ specific disease e.g
SLE = ANA
Several auto antibodies to endocrine glands may be found in a single
patient
Auto antibodies may be :
Primary : involved in pathogenesis
Secondary : to organ damage.

2. MECHANISM OF AUTO IMMUNE DAMAGE

Several mechanisms
More than one mechanism in a given disease
Antibodies cause more damage than cells
Sensitized lymphocytes damage
- Direct lysis by cytotoxic T cells
- Lymphokine productivity

Antibodies
- Stimulating
- Blocking
- Cell growth.

3. THYROID DISEASE
Thyroid antigens :
Thyroglobulin
Thyroid Peroxidase (microsomal Ag)
Surface and Other Cytoplasmic Antigens
Thyroid auto antibodies :
Primary : TSH receptors (blocks or stimulate)
Secondary : high titres especially of microsomes reflect damage

AUTO-IMMUNE THYROID
DISEASE

THYROTOXICOSIS
Excessive thyroid hormone (T3, T4)
Aetiology

Graves Disease
Solitary hyperfunctioning nodule
Toxic Multinodular Gotre
Exogenous Thyroid Intake
Iodine Induced Hyper-Thyroidism
Subacute Thyroiditis.

3A. GRAVES DISEASE

Immunological mechanism involved in pathogenesis
a) LATS = Thyroid Stimulating Antibody (TSI)
IgG antibody to TSH receptor
Stimulate thyroid cell
90 % of patients
b) Thyroid Growth Stimulating Immunoglobulin (TGI)
Graves disease with Goitre
Correlates with goitre size and not production of T3 &
T4

AUTO-IMMUNE THYROID
DISEASE

AUTO-IMMUNE THYROID
DISEASE

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2005 Elsevier

GRAVES DISEASE
Diffusely enlarged goiter
Graves ophthalmopathy
Pretibial myxoedema
Thyrotoxicosis
o Tachycardia
o Tremor
o Nervousness
o Weight Loss
o Sweating
o Heat Intolerance
o Muscular Weakness
o Emotional lability
o Diarrhoea.

GRAVES OPHTHALMOPATHY

40-50 % patients
Lid retraction, lag, proptosis, extraoccular muscle involvement, optic nerve
compression
May be hyperthyroid, euthyroid or hypothyroid
Infiltration of lymphocytes (myositis) in eye muscles and retro-orbital space
Antibodies to eye muscle extract
Some antibodies cross react with orbital antigens and thyroid antigens

Pretibial myxoedema

3-5 % of patients
Well demarcated, subcutaneous thickening
Anterolateral aspect of legs
Shinning
Reddish Brown
No Pitting
Infiltration of Mucco Polysaccarides in Dermis
Not related to duration, extent or severity of thyroid disease

Neonatal Graves Disease

Transplacental transfer of thyroid stimulating IgG from mother to

fetus
Affected babies : goiter, exolphtalmos, fever, tachycardia, heart
failure, etc
Spontaneous recovery over 2-3 months as maternal IgG is
metabolized

Post partum thyroiditis

Fluctuation in Thyroid Autoantibodies

Transient Disturbances in Thyroid Function.
Thyroid antibodies in patients with Graves disease and Hashimotos
Thyroiditis
- Fall during pregnancy
- Rebound post partum

Pregnant women without overt thyroid disease may have

underlying thyroiditis
Develop Thyroid dysfunction post partum.

GRAVES DISEASES

a) Diagnosis :
Clinical picture
T3 T4 TSH
Immunology.
b) Treatment :
Antithyroid Drugs
Radioactive Iodine (231I)
Surgery (Subtotal Thyroidectomy)

3B. HASHIMOTOS THYROIDITIS

Chronic Auto Immune Disease

More Common in women
Commonest cause of goiter in Western World
At presentation :
75 % Euthyroid
20 % hypothyroid
5 % hyperthyroid = Graves disease = Hashitoxicosis
Longterm > 50 % Hypothyroid
Differential diagnosis DE QUERVAINS thyroiditis (subacute thyroiditis).

HASHIMOTOS THYROIDITIS

Causes of Hypothyroidism

3C. PRIMARY HYPOTHYROIDISM

- Myxoedema :
Severe form of hypothyroidism
Deposition of mucinous substances with thickening of skin and
subcutaneous tissues.
- Pathogenesis :
Lymphocytic infiltration, fibrosis and atrophy
Antibodies which block growth and metabolism
- Cretinism : thyroid deficiency during fetal life stunted physical and
mental development
- Athyreotic cretinism : maternal growth blocking antibodies failure of
thyorid gland development in utero.

Autoimmune thyroid disease: balance between

immunological mechanisms operating at any one
time

4. PANCREATIC DISEASE

4. PANCREATIC DISEASE

Pancreas

Exocrine : enzymes via pancreatic duct

Endocrine : hormones blood stream

Autoimune mechanism sometimes involved in disease process

Diabetes mellitus (DM)

A syndrome of chronic
hyperglycaemia due to relative
insulin deficiency, resistance, or
both.
It affects more than 120 million
people world-wide, and it is
estimated that it will affect 370
million by the year 2030.

WHO diagnostic criteria

Diagnosis of diabetes are:
Fasting plasma glucose > 7.0 mmol/L (126
mg/dL)
Random plasma glucose > 11.1 mmol/L (200
mg/dL)
One abnormal laboratory value is diagnostic in
symptomatic individuals; two values are needed
in asymptomatic people.
The glucose tolerance test is only required for
borderline cases and for diagnosis of gestational
diabetes.

TYPES OF DIABETES
MELLITUS

PATHOGENESIS OF IDDM

Polygenic, multifactorial disease

Environmental Factors
Auto Immunity
Genetic factors.

ENVIRONMENTAL FACTORS

Play a role in triggering IDDM

Some cases in childhood can be linked to viruses
(rubella, coxsackie B4, mumps, CMV)
Type 1 : a minimal difference between the sexes
Seasonal variation in onset of new cases (autumn &
winter peaks).

AUTO IMMUNITY
a) Islet cell antibodies ICA

May precede clinical onset of IDDM

Secondary to beta cell destruction
Abs to surface of Beta-cells
Block glucose stimulated insulin release in vitro
Abs to glucose transporter protein (95 % of new IDDM)
Cause B-cell atrophy

b) Anti GAD antibodies

(enzyme : glutamic acid decarboxylase = Ag
c) Histology :
Lymphocytic infiltration of the islet (insulitis)
Damage to islets
Reduction in number of islets.

GENETIC FACTORS

Probably involving multiple genes

95 % IDDM HLA-DR3+ and/or DR4+
HLA-DR2 confers some protection
Family studies
1st degree relatives 6 %
0.4 % random
Individual
MHC . Identical sibling 15 %
. Monozygotic twins 40 %

VALUE OF IMMUNOLOGICAL TESTS

Not necessary for diagnosis of DM

Markers of predictive value for risk of developing DM
ICA
Insulin antibodies
Anti GAD
Abnormal insulin response to IV Glucose load

EXAMPLES OF VALUES OF ICA

Type II DM : need for insulin

Pregnant women ICA : DM post partum
Titre of ICA is of significance.

INSULIN ANTIBODIES

Spontaneous insulin antibodies at or before clinical diabetes

Immunogenes may be pro-insuline, C-peptide or insulin
Evidence of autoimmunity
Acquired antibodies from animal insulin (beef, porc)

Insulin Resistance

Patients who need more than 200 units/day (normal ...50 units/day)
Causes :
Excessive hormone secretion e.g cortisol, GH, Glucagon, catecholamine
Infection
Altered physiological states
Antibodies to insulin receptors affects sensitivity of target cells to
insulin.

Acanthosis nigricans
Hyperpigmented areas of skin
Associated with Insulin resistance
IgG ab block insulin receptors
DM + ovarian hyper androgenism in premenopausal
women