ENDOCRINE PATHOLOGY OF THE

THYROID GLAND

MD SEMESTER 4
JULY 2025
LECTURE OUTLINE
• Introduction.
• Thyroid hormone regulation
• Anatomy and Biochemistry involved in thyroid hormone
synthesis
• Physiological functions of thyroid hormones
• Overview of common causes and signs and symptoms of hyper-
and hypothyroidism
• Autoimmune thyroid diseases (Graves’ disease and
Hashimoto’s thyroiditis
• Thyroid function is special groups (neonates, pregnant
women)
• Laboratory testing of thyroid function
Introduction

Thyroid disorders:
1. Among the most frequent endocrine disorders
2. Very varied Clinical Presentation
3. Importance of laboratory assessment
Thyroid hormone regulation
ANATOMY AND BIOCHEMISTRY INVOLVED IN THYROID HORMONE
SYNTHESIS

1. Thyroglobulin synthesis

2. Iodine trapping

3. MIT and DIT

4. T3 and T4 formation

5. T3 and T4 release
and MIT/DIT recycling
STEPS
1. Thyroglobulin synthesis:
Tg is a glycoprotein (synthesized by follicular cells and
stored within the colloid)
Precussor: Tyrosine
About 20%, and are involved in thyroid hormone synthesis.
2. Iodine transportation and processing
I- from dietary sources
Transported into thyroid follicular cells via ((Na+/I-
symporter)
TPO oxidizes I- to I2 . form iodinated tyrosine residues on
thyroglobulin.
3. Monoiodo tyrosine and diiodotyrosine formation:
Iodine binds to tyrosine residues of thyroglobulin to form monoiodo tyrosine
(MIT) or diiodotyrosine (DIT) in the follicular lumen.
This coupling reaction, catalyzed by thyroid peroxidase (TPO), is called
organification.
Excess iodine inhibits organification, known as the Wolff-Chaikoff effect, to
prevent excess thyroid hormone synthesis.
4. Triiodothyronine and thyroxine formation:
Triiodothyronine (T3) and thyroxine (T4) are formed from MITs and DITs within
the colloid.
T3 is formed from one MIT coupled to one DIT, while T4 is formed from two DITs
coupled.
Reverse triiodothyronine (rT3) is formed similarly to T3 but in the opposite
spatial configuration.
The iodinated thyroglobulin serves as the storage compartment for iodine in the
thyroid, allowing for readily available thyroid hormone secretion.
5. Thyroid hormone release and MIT/DIT recycling:
Thyroid hormone release is regulated by thyroid-stimulating
hormone (TSH) and the hypothalamic-pituitary-thyroid axis
(HPTA).
Thyroglobulin is taken up from the colloid into follicular cells via
pinocytosis and digested to release T3, T4, MIT, and/or DIT.
T3 and T4 are transported out of follicular cells into circulation,
while MIT and DIT are deiodinated by thyroid deiodinase for
recycling of iodine
THYROID HORMONES AND THEIR PRECUSSORS

The phenol ring positioned nearest the amino acid terminal is referred to as
the alpha ring, and the ring located on the hydroxyl terminal is the beta ring.
Relative secretion of T4an d T3 & further conversion of thyroxine into
T3 or rT3.
IN THE CIRCULATION
• 100% of T4 is from the
thyroid gland
• Majority of T3 is from
peripheral conversion of T4
• T3 is the biologically active
species
• rT3 is inactive.
Mechanism of action
Inside the target cells, T3 exerts most of its actions
through regulation of gene transcription. Briefly, T3 can:
1. Bind to thyroid hormone nuclear receptors inside
the nucleus
2. Form a complex that can bind to specific DNA
sequences and
3. Upregulate or downregulate the transcription of
specific target genes. This subsequently affects the
amount of the target mRNAs transcribed and
proteins synthesized
PHYSIOLOGICAL FUNCTIONS OF THYROID
HORMONES
System Effects
Nervous System - Maturation and development of the CNS
- Increased sensitivity to catecholamines (via induced expression of catecholamine
receptors)
- Increased linear growth (via promotion of hypertrophic differentiation of the growth
Musculoskeletal System
plate chondrocytes)
Metabolism - Increase basal metabolic rate
- Increase oxygen consumption
- Increase body heat production/thermogenesis
- Increase carbohydrate metabolism
- Increase gluconeogenesis
- Increase glycogenolysis
- Increase glucose absorption
- Increase lipolysis
- Protein metabolism (overall more catabolic state)
Cardiovascular System - Increase cardiac output
- Increase blood flow
- Increase heart rate
- Increase sensitivity to catecholamines (leading to Increase in heart rate)
OVERVIEW OF COMMON CAUSES AND SIGNS AND
SYMPTOMS OF HYPER-AND HYPOTHYROIDISM
HYPERTHYROIDIM (THYROTOXICOSIS)
COMMON CAUSES SIGNS AND SYMPTOMS
ENDOGENOUS  Increased metabolism
• Autoimmune Thyroid Disease  Increased cardiac output
(Graves Disease)  Weight loss
• Toxic nodule/Toxic multi-nodular  Heat intolerance
goitre  Hyperventilation
• Solitary toxic adenoma  Tremors
• Gestational thyrotoxicosis  Warm and moist skin
• Pituitary tumor  Goitre
• Thyroid neoplasm  Eyelid retraction
EXOGENOUS  Exophthalmos
 Myxedema
• Excess T4 and T3 intake
HYPOTHYROIDIM
COMMON CAUSES SIGNS AND SYMPTOMS
ENDOGENOUS  Decreased metabolism
• Autoimmune Thyroid Disease  Decreased cardiac output
(Hashimoto thyroiditis)  Weight gain
• Congenital e.g. inborn error of  Cold intolerance
thyroid hormone synthesis(  Goitre
• Idiopathic atrophic hypothyroidism  Lethargy
• Pituitary tumor

EXOOGENOUS
• Iodine deficiency
• Iatrogenic (irradiation, surgery,
Anti-thyroid drugs)
AUTOIMMUNE
THYROID DISEASES
Hashimoto’s Thyroiditis

• Hakaru Hashimoto, a Japanese

surgeon working in Berlin, Germany
• Part of the spectrum of autoimmune
thyroid diseases (AITDs).
• By strict criteria: Histologic diagnosis
Destruction of thyroid cells
Cell- and antibody-mediated.
Epidemiology of Hashimoto’s
Thyroiditis

F:M ratio: 10-15.

The most common: 30-50 years
In men occurring 10-15 years later.
Evolution of events

• Leakage of stored hormones

• Transient hyperthyroidism:
• Hypothyroidism
PATHOGENESIS
Abnormal T cell activation

Subsequent B cell stimulation

Secrete a variety of autoantibodies

DESTRUCTION OF THYROCYTES
MECHANISM OF THYROCYTE DESTRUCTION IN
Hashimoto’s Thyroiditis

BREAKDOWN OF SELF TOLERANCE AND INDUCTION OF

AUTOIMMUNITY
MECHANISM 1 MECHANISM 2 MECHANISM 3
GROSS APPEARANCE OF THE THYROID

Goitrous
Atrophic
Normal in size
.

This symmetrically small thyroid gland

demonstrates atrophy.
This patient was hypothyroid.
Initially, the thyroid is enlarged
Transient hyperthyroidism
Euthyroid state
Hypothyroidism
Granulomatous (de Quervain) thyroiditis

• Less common than Hashimoto’s disease.

• 30 and 50 years of age
• Women > Men
• Viral infection or an inflammatory process
triggered by viral infections
• History of URTI Thyroiditis.
• Spontaneously remission (6-8wks)
Clinical presentation
• Acute onset
• Neck pain (particularly with swallowing)
• Fever
• Malaise
• Variable enlargement of the thyroid.
• Transient hyperthyroidism
• Increased: WBC count, ESR
• Transient hypothyroid phase may ensue.
MORPHOLOGY

• The gland is firm, with an intact capsule, and may be

unilaterally or bilaterally enlarged.
• Histologic examination reveals disruption of thyroid
follicles, extravasation of colloid, and infiltrating
neutrophils, which are replaced over time by
lymphocytes, plasma cells, and macrophages.
• The extravasated colloid provokes ganulomatous
reaction with giant cells, some containing fragments of
colloid.
• Healing: Resolution of inflammation and fibrosis.
Sub-Acute Lymphocytic Thyroiditis

• AKA: Silent or painless thyroiditis

• In a subset of patients, the onset follows pregnancy
(postpartum thyroiditis).
• Antithyroid antibodies are found in a majority of patients.
• Mostly affected: Middle-aged women
• Painless neck mass or features of thyroid hormone excess.
• Thyrotoxicosis then return euthyroid state within a few
months.
Minority of cases Hypothyroidism.
Lymphocytic infiltration
Riedel’s thyroiditis
• Rare disorder that is a manifestation of IgG4-
related disease
• Characterized by extensive fibrosis
involving the thyroid and contiguous neck
structures.
• Hard and fixed thyroid mass, simulating a
thyroid neoplasm.
• May be associated with idiopathic fibrosis in
other sites in the body, such as the
retroperitoneum.
Graves’ Disease
Graves’ Disease

• Robert J. Graves (MD) 1835

• Autoimmune disease (T & B
cells) Autoantibodies.
• Autoimmune polyglandular
syndromes (pernicious anemia,
DM 1, SLE)
• Most common cause of thyrotoxicosis
• F:M ratio of 7-8:1.
• Age: 20-40 years.
• Antibodies vs Thyroid antigens:
- Thyrotropin receptor.
- Thyroglobulin
- Thyroid peroxidase
- Sodium-iodide symporter
PATHOGENESIS
• Autoantibodies, primarily thyroid-
stimulating immunoglobulins (TSIs)
• Mimic the action of thyroid-
stimulating hormone (TSH).
• Excessive synthesis T4/T3.
• Genetic predisposition and
environmental triggers (Stress or
infections)
Classical Presentation
1. Diffusely enlarged gland
2. Ophthalmopathy.
3. Dermopathy.
4. Myxedema : Pretibial areas.
Laboratory findings
fT4 and fT3 levels are elevated
TSH is decreased
NB: Subclinical hyperthyroidism
T3 toxicosis.
TSH receptor antibodies
ALMOST ALWAYS ARE POSITIVE.
ACCUMULATION OF MATRIX SUBSTANCES
1. Glycosaminoglycans
2. Hyaluronic acid
Where ?
Skin
Subcutaneous tissue
Viscera.
Results in:
oNonpitting edema
oBroadening and coarsening of facial features
oEnlargement of the tongue
oDeepening of the voice
EXOPHTHALMOS
PRETIBIAL
MYXEDEMA
HISTORICAL CASES
• George H. W. Bush, U.S. president, developed new
atrial fibrillation and was diagnosed in 1991 with
hyperthyroidism due to the disease and treated
with radioactive iodine.

• The president's wife Barbara Bush also developed

the disease about the same time, which in her case
produced severe infiltrative exopthalmos.
THYROID FUNCTION IS SPECIAL GROUPS
Neonatal Hypothyroidism

• Decreased or absent thyroid

hormones
Causes
• Thyroid
• Pituitary
• Formation of abnormal
hormones
Symptoms of Neonatal Hypothyroidism
• Puffy-appearing face
• Dull look
• Thick, protruding tongue
• The child may also have (Dry, brittle hair, Low
hairline, Jaundice, Poor feeding, Choking
episodes, Lack of muscle tone (floppy infant),
Constipation, Sleepiness
• Sluggishness, Short stature)
• Treatment good results
• Failure of treatment = Mental retardation
NEONATAL HYPERTHYROIDISM
• Born to mothers who have or have
had Graves’ disease.

• IgG) crossing the placenta

• Transient.
Thyroid Function in Normal
Pregnancy
High T4; Normal fT4 (Estrogen,
TBG)
↑Goitre frequency
Revert to normal 6 – 8 weeks
postpartum
Laboratory Testing of Thyroid Function
Objectives of laboratory testing of Thyroid Function
1. Define the level of thyroid function (hyper- or
hypothyroid)
2. Identify the nature and location of the disorder
3. Monitor the effectiveness of the treatment
Overview of Clinical Assessment of Thyroid Function
• Hyperthyroidism leads to hypermetabolic symptoms and vice
versa
• Thyroid diseases can arise: Endogenous (e.g., autoantibodies) or
exogenous (e.g., drugs)
• Overt (symptoms and abnormal thyroid lab results)
• Subclinical conditions (minimal symptoms and slightly
abnormal lab results).
• Primary, Secondary or Tertiary
• Laboratory investigation: TSH, T4, FT4, T3, and/or FT3.
• Primary and secondary hyperthyroidism and hypothyroidism
are more common than central conditions.
• Testing algorithms typically involve TSH, T4, and T3.
Example of a Typical Thyroid Disorder Diagnostic Algorithm
Relative concentrations of thyroid hormones
(triiodothyronine and thyroxine) and thyroid-
stimulating hormone in different hyperthyroid and
hypothyroid states.

• Hyper- or Hypothyroidism (Primary and central) can be

differentiated by T4, T3 and TSH measurements.
• Subclinical Hyper- or Hypothyroidism
1. Often asymptomatic
2. TSH values outside of the reference interval
3. Free T4 remains normal.
T4, T3 AND TSH DIRECTIONAL CHANGES
T4 T3 TSH
PRIMARY HYPERTHYROIDSM HIGH HIGH LOW

CENTRAL HYPERTHYROIDSM HIGH HIGH HIGH

SUBLINICAL HYPERTHYROIDSM NORMAL NORMAL LOW

PRIMARY HYPOTHYROIDSM LOW LOW HIGH

CENTRAL HYPOTHYROIDSM LOW LOW LOW

SUBLINICAL HYPOTHYROIDSM NORMAL NORMAL HIGH

AUTOANTIBODIES IN AITDs
• AITDs include Graves’ disease (hyperthyroidism) and
Hashimoto’s thyroiditis (hypothyroidism).
Role of Autoantibodies (AutoAbs)
• AutoAbs target self-antigens in thyroid diseases.
• Not always necessary for diagnosis but can be helpful in
conjunction with other tests and clinical presentation.
• Targets: Thyroid regulation, Synthesis (e.g., TPO), and
Transport (e.g., Tg) of thyroid hormones.
TSH Receptor Antibodies
TSHRAbs stimulate or block the function of the TSH receptor.
1. Thyroid-stimulating immunoglobulins (TSIs)
2. Thyrotropin-binding inhibitory immunoglobulins (TBIIs)
TRAbs are not routinely detected in the general population.
TSIs and TBIIs may coexist in the same patient.
AutoAbs Against TPO and Tg
Their prevalence increases with age and is higher in women.
Presence of TPO Ab and TgAb is common but their clinical significance
varies.
TPO Ab and TgAb presence may not always predict future thyroid
dysfunction.
Serum levels of thyroid hormones
• Take into Consideration:
1. Reference intervals (Analytical Methods, Local)
2. Free hormone is the active form.
3. T3 is 3 to 4 times more active than T4
4. T3 - Toxicosis
TOTAL T4
• Keep in mind the altered levels of TBG
• Elevated TBG (drugs-e.g. estrogen, OC;
diseases-chronic liver diseases, acute
Hepatocellular disease; congenital excess of
TBG)
• Decreased TBG (drugs-androgens, steroids,
glucocorticoids; hypoproteinaemia,
congenital deficiency)
TOTAL T3
 Less influenced by TBG
 Influenced by Non-thyroidal illnesses and certain drugs
 T3 toxicosis
 Normal T3 (sick euthyroid syndrome)
 Hypothyroidism due to iodine deficiency: synthesis T3
> T4
Relationship between serum concentrations
of TSH and FT4
HYPOTHALAMIC
PITUITARY ADRENAL
AXIS
MD 2
3 JULY 2025
RD
Review of Adrenal Physiology
• General overview of the Hormones of the adrenal Gland
Adrenal Cortex-Disease States
• CUSHING'S SYNDROME- HYPERCORTISOLISM
• CONN'S SYNDROME- PRIMARY HYPERALDOSTERONISM
• ADDISON’S DISEASE - PRIMARY HYPOADRENALISM
• SECONDARY-HYPOADRENALISM
Adrenal Medulla-Disease States
• PHEOCHROMOCYTOMAS
The Adrenal Gland
An inner medulla
General
Epinephrine and Norepinephrine (chromaffin
cells)

Innervated by preganglionic sympathetic fibers –

ext of SNS).
3 major classes of hormones
An outer cortex

Glucocorticoids and
Response to small and large
stresses
Mineralocorticoids.

Glucocorticoids and 3 zones of cells (hormone sources)

mineralocorticoids – essential for
life
What are the zones
Adrenal Steroids

In total, at least two to three dozen different steroids are synthesized

Two classes are of particular importance:

Class of Steroid Major Physiologic Effects

Representative

Mineralocorticoids Aldosterone Na+, K+ and water

homeostasis

Glucocorticoids Cortisol Glucose homeostasis

and many others
• Additionally, the adrenal cortex produces some sex
steroids
Major Pathways in Steroid Biosynthesis
MAJOR GLUCOCORTICOID
CORTISOL
Cortisol Effects on Metabolism

On Glucose metabolism Effects on Inflammation Immune

Function

Stimulation of gluconeogenesis,
particularly in the liver: Potent anti-inflammatory and
immunosuppressive properties.
Mobilization of amino acids from
extrahepatic tissues:
Evident at pharmacologic doses
Inhibition of glucose uptake by
cells
Treatment of inflammatory
Stimulation of fat breakdown in conditions (e.g. arthritis) or
adipose tissue: dermatitis, autoimmune diseases.
Other Effects of Glucocorticoids

Lung maturity-Surfactant

Excessive glucocorticoid levels may be deleterious

Inhibition of bone formation (Osteoporosis)

Suppression of calcium absorption

Delayed wound healing.

Mineralocorticoids
Aldosterone: Deficiency State
• Principal mineralocorticoid  Isolated OR
activity  In conjunction with
• Distal tubule of the kidney glucocorticoid
- Increases reabsorption of Na+ deficiency (Addison's
disease).
- Increases reabsorption of
H2O,
Major manifestations
- Increases renal excretion of K+ -Electrolyte imbalances
Aldosterone regulation: -Hypotension
Is by K+ Na+ Angiotensin II -Cardiac failure
OUTLINE
• General Overview of the Hormones of the Adrenal
Cortex
Adrenal Cortex-Disease States
• HYPERCORTISOLISM (CORTISOL
OVERPRODUCTION/CUSHING'S SYNDROME)
• PRIMARY HYPERALDOSTERONISM (CONN'S
SYNDROME)
• HYPOADRENALISM
• CONGENITAL ADRENAL HYPERPLASIA (CAH)
• GENERAL OVERVIEW OF THE HORMONES OF THE
ADRENAL MEDULLA
• ADRENAL MEDULLA-DISEASE STATES
(PHEOCHROMOCYTOMA)
CUSHING’S SYNDROME
Cushing's syndrome

Hyperadrenocorticism or Hypercorticism

Described by Dr. Harvey Cushing in 1932.

Cushing's disease refers to one specific cause, a

non-cancerous tumor (adenoma) in the pituitary
gland that produces large amounts of ACTH.
Etiology of Cushing Syndrome

•.
Pituitary CS Adrenal CS Paraneoplastic
• Benign pituitary adenoma CS
(Cushing's disease) • Pathology in the
• 65% of endogenous CS Adrenal gland: • small cell lung
• Tumors cancer.
• Hyperplasia

• (ACTH dependent)
• ACTH Independent
• ACTH dependent
Signs and symptoms
Physical Features: Metabolic
- Central obesity. - Insulin resistance (DM).
- Buffalo hump - Hypokalemia
- Moon face.
-
- Hirsutism.
Physiological
- Hyperpigmentation
• Other features: • Persistent HT
- Opportunistic infections • Oligomenorrhea
• Osteoporosis. Psychological:
- Others (insomnia, reduced libido, sleep disturbances:
impotence, amenorrhoea and
infertility).
euphoria, psychosis,
depression and anxiety
CUSHING’S AT A GLANCE
• C - Central obesity, Clavical fat pads, Collagen fibre
weakness, Comedones (acne).
U - Urinary free cortisol and glucose increase.
S - Striae, Suppressed immunity.
H - Hypercortisolism, Hypertension. Hyperglycemia,
Hypercholesterolemia. Hirsutism, Hypernatremia,
Hypokalemia.
I - Iatrogenic (Increased administration of
corticosteroids).
N - Noniatrogenic (Neoplasms).
G - Glucose intolerance, Growth retardation.
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CUSHING’S SYNDROME
INVESTIGATIONAL APPROACH TO DIAGNOSIS
OF CUSHING’S SYNDROME

The three objectives in investigating Cushing's

syndrome are:

1. Establish exposure to sustained excessive

cortisol (confirm hypercortisolism)

2. Establish the cause of excessive cortisol

production

3. Localize the lesion

A. ESTABLISH EXPOSURE TO
EXCESSIVE CORTISOL

The following tests are used to establish the presence of

hypercortisolism, whatever the cause

Loss of diurnal rhythm i.e. failure of midnight cortisol to

drop < 50nmol/l in an unstressed patient

Elevated urinary free cortisol (dU cortisol)

Failure of a low dose of dexamethasone (a synthetic

glucocorticoid) to suppress plasma cortisol.
LOW DOSE DEXAMETHASONE SUPPRESSION TEST

Short version
• Give a single dose of dexamethazone (1mg at 11 pm).
• This should suppress plasma cortisol to < 50nmol/l by next
morning.
• This is a useful outpatient screening test.
• If the short test (above) gives ambiguous results do the long
test.

Long Version
• Give 2mg dexamethazone (0.5 mg 12-hourly) for 2
days, and measure 9 a.m. plasma cortisol on day 3
B. ESTABLISH THE CAUSE OF EXCESSIVE
CORTISOL PRODUCTION.

The following tests are used to establish the cause of

excessive cortisol production
•.

High dose dexamethazone suppression test

Measurement of Plasma ACTH Levels

Corticotrophin Releasing Factor Stimulation test

1. High dose Dexamethazone Suppression Test

Dosing EXPECTED RESULTS

Pituitary Ectopic CS due to
e.g. 8 mg for 2 Cushing's ACTH -CS adrenal
days, and Most cases Do not lesions
measure 9 a.m. do suppress suppress do not
cortisol on day 3.
to < ½ the NB: suppress
pretreatment CRF Not ACTH-
value producing dependent
tumor.
2. MEASUREMENT OF PLASMA ACTH LEVELS

1. In adrenal tumors : ACTH is undetectable

2. In pituitary Cushing's disease ACTH is in the

upper normal range or slightly above normal

In CS due to ectopic ACTH-producing tumors

ACTH is highly elevated (>40 pmol/l)

NB: The hormone is extremely labile

PLASMA ACTH LEVELS IN DIFFERENTIAL
DIAGNOSIS OF CS
CRF Stimulation Test

CS due to Pituitary ACTH -producing tumors

Generally retain responsiveness to CRF

CS due to ectopic ACTH producing

No change in response to injected CRF

CS due to Adrenal tumors

No change in response to injected CRF
Radiological studies

• Radiological studies for pituitary and ectopic tumours

as well as adrenal tumours.
• These include CAT and MRI scans, and/or radioactive
iodo-cholesterol uptake and scanning for adrenal
tumors
DIAGNOSTIC PITFALLS
Many patients with Cushingoid features are
merely obese.
They may have slightly raised cortisol but usually
suppress on low dose dexamethazone and have a
normal circadian rhythm.

They always respond to the insulin stress test, unlike

true Cushing's patients.
Alcoholism and severe depressive disease have clinical and
biochemical pictures akin to pituitary Cushing's and are best
distinguished by their positive cortisol response to insulin-
induced hypoglycaemia.
PRIMARY HYPERALDOSTERONISM (CONN'S
SYNDROME)
PRIMARY HYPERALDOSTERONISM (CONN'S
SYNDROME)
• Excessive, PATHOPHYSIOILOGY
inappropriate Excessive Na+ and H20 Reabsorption,
secretion of with renal K+ and H+ ion Wasting.
aldosterone.
• 80%) CLINICALS
autonomous Hypertension, Muscle weakness
aldosterone- Polyuria/polydipsia, Parasthesia and
secreting tumor
Tetany
• Less commonly:
CHEMICAL PATHOLOGY
Bilateral diffuse
hyperplasia. Hypernatremia, Hypokalemia,
Alkalosis, Increased renal potassium
loss.
HINTS AT DIAGNOSIS OF CONN’S SYNDROME

• Primary hyperaldosteronism should be suspected in any

HYPERTENSIVE patient with a LOW PLASMA K+
CONCENTRATION who is NOT ON DIURETIC TREATMENT.
.

• Ongoing renal K+ wasting in the face of

hypokalaemia in a patient not on diuretics is
highly suggestive of Conn’s syndrome.
Hypoadrenalism
HYPOADRENALISM
Adrenal cortex insufficiency
CAN BE:
Primary within the gland (Cortisol and Aldosterone)
Secondary (a lack of ACTH stimulation (Cortisol).

CAUSES OF 10 HYPO CAUSES OF 20 HYPO

(ADDISON’S DISEASE)
1. Adrenal destruction by TB, 1. ACTH deficiency, either
autoimmune disease, isolated, or more
metastatic tumor, commonly, part of
haemochromatosis or
haemorrhage. generalized hypopituitarism
2. Inherited enzyme deficiency 2. Iatrogenic; due to rapid
in steroidogenesis withdrawal of prolonged
(CONGENITAL ADRENAL
HYPRPLASIA ) steroid therapy.
CLINICAL FEATURES OF ADDISON'S DISEASE
1
A; Lack of cortisol: B: Lack of aldosterone
• Non-specific symptoms, (but also of cortisol, which
including tiredness, maintains vasomotor tone):
weakness, lethargy • Hypotension, which can
• GIT symptoms, including progress to frank
anorexia, nausea, vomiting, hypovolaemic shock
diarrhoea
• Weight loss (cortisol is a • Salt craving is
powerful appetite stimulant) experienced by some
• Hypoglycaemia patients
• Depression
CLINICAL FEATURES OF ADDISON'S
DISEASE 2
D: Excess ACTH: C: Lack of androgens:
• Pigmentation (in • Loss of body hair (mainly in
naturally dark-skinned women)
people, this is easily E; Associated auto-immune
seen on the palmar destruction of other
creases, over the endocrine organs
knuckles and inside Parathyroid, thyroid, gonads,
the mouth)
and even non-endocrine tissue,
e.g. gastric Parietal cells,
resulting in pernicious anaemia
RAPIDITY OF ONSET
• Onset is generally gradual, with patients feeling
relatively well provided they maintain a high salt
intake.
• An acute presentation ‘Addisonian crisis’
- Usually secondary to episode of isotonic fluid loss
- Adrenal haemorrhage (eg in meningococcal
septicaemia)
Hypovolaemic
Shock and
Profound hypoglycaemia

Constitutes a medical emergency.

BIOCHEMICAL FEATURES
• Elevated plasma UREA
Lack of aldosterone - - and CREATININE.
Na+ and water loss in
the urine (dilutional
HYPONATREMIA • Fasting hypoglycaemia

- Retention of K+ and • Urine Na+ wasting

H+ (HYPERKALEMIA and
mild ACIDOSIS). (inappropriately high urine
Na+)
DIAGNOSIS
• Definitive diagnosis Plasma Levels of cortisol and
aldosterone.
• A 9 a.m. cortisol < 50nmol/l confirms the diagnosis
(provided the patient is not taking synthetic
glucocorticoids)
• A value of > 550nmol/l excludes it.
• Most patients require an ACTH stimulation test
Synacthen Stimulation Test
SHORT TEST LONG TEST
• Synthetic ACTH is injected • ACTH given for 3 days, the
• Blood sampling at 0, 30 test repeated on day 4.
and 60min. • If Cortisol response remains
• A blunted cortisol absent or blunted Primary
response in primary and adrenal failure
secondary adrenal failure. • If Cortisol response
• To differentiate, the ‘long’ normalizes:
ACTH stimulation test is Secondary adrenal
performed
failure
Other useful findings to confirm
Addison’s disease include:

• Low plasma aldosterone with a high plasma

renin activity

• Greatly elevated plasma ACTH – this test is

excellent for discriminating primary from
secondary adrenal failure, since in the latter
condition, ACTH levels are low.
SECONDARY HYPOADRENALISM
• Secondary hypoadrenalism is hypocortisolism due to a
deficient adrenal stimulation by ACTH.
• It is similar clinically and biochemically to Addison’s
disease.
• Patients with hypoadrenalism due to lack of ACTH are
not salt-losing (aldosterone is not regulated by ACTH)
• Thus hyperkalaemia is not a problem.
• Hyperpigmentation is not a feature of secondary
hypoadrenalism, since ACTH levels are low.
BIOCHEMICAL DIAGNOSIS OF SECONDARY
HYPOADRENALISM
• Hyponatraemia
• Hypoglycaemia,
• ↓ cortisol,
• Normal aldosterone
• ↓ ACTH

Confirmation by demonstrating a response

to repetitive ACTH stimulation (see Fig)
Adrenal Medullary Hormones
PHEOCHROMOCYTOMA
Adrenal Medullary Hormones
• Epinephrine and
Norepinephrine.
• ~80% of the
catecholamine output is
epinephrine
• bind adrenergic receptors
on target cells
• Effects = direct SNS
Stimulation (BUT longer
lasting)
Synthesis and Secretion

•"stresses“ exercise, trauma, hypoglycemia)

•acetylcholine (preganglionic sympathetic
fibres)
•Loosely bound by albumin other proteins
Major effects mediated by
Catecholamines

• Increased rate and force of contraction of the

heart muscle:
• Constriction of blood vessels.
• Dilation of bronchioles:
• Stimulation of lipolysis
Disease State-Adrenal
Medulla
Pheochromocytoma

• A rare tumor • Catecholamine secretion

in pheochromocytomas
- Pheochromocytomas are
• Life-threatening
not innervated
hypertension or cardiac
(secretion?)
arrhythmias.
- Triggers: direct pressure,
• Undiagnosed disastrous, medications, tumor blood
even fatal flow.
• Potentially curable. • Normal adrenal medulla
(~85% epinephrine)
- Most heochromocytomas
mostly secrete NE
The clinical Manifestations
• Stimulation of a adrenergic receptors
- Elevated blood pressure
- Increased cardiac contractility
- Glycogenolysis, gluconeogenesis, and
intestinal relaxation.
• Stimulation of b-adrenergic receptors
- Increase in heart rate and contractility.
Clinics

CVS CNS
- Hypertension • Hypertensive
- Cardiac arrhythmias encephalopathy
- MI • Seizures
- Stroke
Laboratory Studies
 Plasma metanephrine testing
highets sensitivity (96%)
 24-hour urinary collection for
catecholamines and
metanephrines .
• VMA
SUMMARY
• General Overview of the Hormones of the
Adrenal Cortex
• HYPERCORTISOLISM (CORTISOL
OVERPRODUCTION/CUSHING'S
SYNDROME)
• PRIMARY HYPERALDOSTERONISM
(CONN'S SYNDROME)
• HYPOADRENALISM
• GENERAL OVERVIEW OF THE HORMONES
OF THE ADRENAL MEDULLA
• ADRENAL MEDULLA-DISEASE STATES
(PHEOCHROMOCYTOMA)
SUMMARY
• Cushing’s Syndrome
• Conn’s Syndrome
• Addison’s Disease
• Pheochromocytoma

-Pathophysiology
-Important Clinical features
-Laboratory findings
DIABETES MELLITUS

3RD JULY 2025

CLINICAL SCENARIO
A 15 year’s patient presents
with
following complaints
1. Excessive thirsty and
2. Increased frequency of
passing large amounts of
urine.

CAN YOU SUGGEST A DIAGNOSIS ?

Mention ANY 3 laboratory tests you may do
to confirm the diagnosis
WHAT DO YOU UNDERSTAND BY THE
FOLLOWING:

1. TYPE 1 AND TYPE 2 DIABETES MELLITUS

2. RANDOM BLOOD SUGAR
3. FASTING BLOOD SUGAR
4. ORAL GLUCOSE TOLERANCE TEST
DIABETS MELLITUS
LECTURE OUTLINE
• Definition
• Types
• Classification
• Clinical presentation
• Complications
• Laboratory Diagnosis
Pancreatic Hormones, Insulin &
Glucagon Regulate
• Beta cells Metabolism
produce insulin –
cellular uptake of blood
glucose
• Alpha cells produce
glucagon –  blood glucose
(from cells)
• D cells produce
somatostatin –  gastric
secretion
Pancreatic Hormones, Insulin &
Glucagon Regulate Metabolism

Figure 22-7 b: The endocrine pancreas

Islet of Langerhans Cross-section
• Three cell types are
present, A (glucagon
secretion), B (Insulin
secretion) & D
(Somatostatin secretion)
• A & D cells are located
around the perimeter
while B cells are located
in the interior
• Venous return containing
insulin flows by the A
cells on its way out of
the islets
Pancreatic Hormones, Insulin &
Glucagon Regulate Metabolism

Figure 22-8:
Metabolism is
controlled by insulin
Insulin Action on Cells:
Dominates in Fed State
Metabolism

•  glucose uptake in most

cells
•  glucose use & storage
•  protein synthesis
•  fat synthesis
Glucagon Action on Cells:
Dominates in Fasting State
Metabolism

• Glucagon prevents
hypoglycemia by  cell
production of glucose
• Liver is primary target to
maintain blood glucose levels
Glucagon Action on Cells:
Dominates in Fasting State Metabolism

Figure 21-14: Endocrine response to hypoglycemia

DIABETES MELLITUS.
DESCRIPTION:
• Chronic disorder of
carbohydrate, fat and protein
metabolism.
• A defective or deficient insulin
secretion leads to an impaired
glucose metabolism and subsequent
hyperglycaemia.
• Affects about 3% of the world
population
CLASSIFICATION A
a) Type 1 diabetes, also called IDDM
accounts for about 10% of all cases
of primary diabetes.
b) Type 2 diabetes, also known as
NIDDM accounting for 80% to 90%
of all adult diabetics.
c) Maturity onset diabetes of the
young (MODY) results from a genetic
defect of the β- cell function
accounts for less than 5% of cases
and transmitted as an autosomal
dominant trait.
CLASSIFICATION B
a) Primary DM.
- Type 1. (IDDM).
- Type 2 (NIDDM).
- Genetic defects of β- cell function
including MODY.
(MODY1),
(MODY2),
(MODY3),
Iv) Other genetic defects.
b) Secondary DM
(i) Infections : congenital
rubella, cytomegalovirus,
ii) Endocrinopathies: eg
adrenal, pituitary tumours,
iii) Drugs: corticosteroids,
pentamidine, vacor
iv) Other genetic disorders:
Down syndrome,
v) Gestational diabetes
mellitus.
Comparison between type 1 and type 2 diabetes
mellitus.
Type 1 (IDDM) Type 2 (NIDDM)
Clinical Onset < 20 Onset > 40 years.
years. Obese
Normal body Normal or increased
weight blood insulin.
Decreased blood No anti islet cell
insulin antibodies
Anti islet cell Ketoacidosis rare.
antibodies
Ketoacidosis
common
Genetic 50% 90% to 100%
s concordance in concordance in
Type 1 (IDDM) Type 2 (NIDDM)

Pathog Autoimmuni Insulin resistant.

enesi ty, Relative insulin
s Immunopat deficiency.
hologic
mechanisms
Severe
insulin
deficiency
Islet Early No insulitis
cells insulitis Focal atrophy and
Marked amyloid deposits
atrophy No Beta cell
UNIFYING PHENOMENON
Types of DM
Have different pathogenic
mechanisms, the
Long term complications are the
same

Chronicaly Affects Blood

vessels, Kidneys, Eyes, and
Nerves
THEY ARE THE MAJOR CAUSES
Pathogenesis of type 1 diabetes
mellitus.
• Results from a severe, absolute
lack of
insulin caused by a reduction in β-
cell
mass.
Patients depend on insulin for
survival;
hence term Mellitus (IDDM).
• Without insulin (develop serious
Three interlocking mechanisms
are
responsible for the destruction
of the
islet cells:
i) Genetic susceptibility,
ii) Autoimmunity,
iii) Environmental insult.
[Link] susceptibility.
• Type 1 diabetes mellitus occurs frequently in young
persons of the Northern European descent.
• It is rare among Africans, Native Americans and Asians.
• It is thought that genetic susceptibility linked to specific
alleles of the class II major histocompatibility complex
(MHC) predisposes certain persons to the development of
autoimmunity against β- cells of the islets.
• The autoimmune reaction either develops spontaneously
or, more likely, is triggered by an environmental event that
alters β- cells, making them immunogenic.
[Link].
• Although the clinical onset of type 1 diabetes mellitus is
abrupt, this disease results from a chronic autoimmune
attack of β- cells that usually exists for many years before
the disease becomes evident.
• The clinical manifestation of the disease occurs after
more than 90% of the β- cells have been destroyed.
• The autoimmune implication was evidenced by the
finding of:
i) a lymphocyte rich inflammatory infiltrate (mainly CD8
T lymphocytes, plus variable numbers of CD4 T cells and
macrophages).
[Link] factors.
• It is not clear what triggers autoimmune reaction in
patients with genetic predisposition to autoimmune
destruction of the islet cells
• There is compelling evidence that environmental
factors are involved.
• For example, Finish children have 60 to 70 fold greater
risk of type 1 diabetes than their Korean counterpart.
• Nothing could explain this other than environmental
factors.
1. Viruses.
• Epidemiologic studies have long noted the seasonal
trends that often correspond to the prevalence of
common viral infections to the diagnosis of new
cases of pancreatic diseases;
- cocksakie viruses of group
- mumps,
- Cytomegalovirus
- rubella and
- infectious mononucleosis.
2. COWS MILK:
It has been reported that children who ingest cow’s milk
products before 4 moths of age have a 1.5 fold increased
risk of developing diabetes type 1 relative to those who did
not.
• There’s suspicion of a cross reacting antigen in cow’s milk.
3. Chemical toxins, streptozotocin, alloxan and
pentamidine (a drug used for treatment of parasitic
infections) have been associated with an abrupt onset of
diabetes.
• Cases of diabetes have been reported after accidental or
suicidal ingestion of Vacor, a pharmacological agent used
to kill rats.
• These chemicals act either directly on islet cells or
indirectly by triggering a destructive autoimmune
reaction.
TYPE 2 PATHOGENESIS
The pathogenesis remains unclear
Genetic factors more important
than type one i.e. 60-80%
concordace in identical twins, and
20-40 % in non identical twins.
Life style plays an important role.
HLA linkage but multiple defects
plus environment modify it.
Type 2 diabetes mellitus is a
complex, multifactorial disorder
involving:
 Impaired insulin release leading to
relative insulin
deficiency and end organ
insensitivity.
 Insulin resistance, frequently
associated with obesity, produces
excessive stress on beta cells,
which may fail in the face of
sustained need for a
Genetic defects of beta cell function.
• Maturity onset Diabetes mellitus of the young (MODY).
• About 2% to 5% of diabetic patients do not fall clearly
into either type 1 or type 2 diabetes phenotype.
• MODY is the outcome of a heterogeneous group of
genetic defects in beta cell function characterized by:
i) Autosomal dominant inheritance as monogenic defect,
with high penetrance.
ii) Early onset, usually before the age of 25, as opposed to
after age 40 for most patients with type 2 diabetes.
Metabolic Syndrome
• Associated with an increased risk of cardiovascular
disease and of developing diabetes.
• Criteria defining the metabolic syndrome:
IN adults are the presence of three or more of the
following:
(1) impaired fasting glucose
(2) blood pressure ≥ 130/85 mmHg
(3) waist circumference > 102 cm in men and > 88 cm
in women
(4) serum triglycerides ≥ 150 mg/dL (1.695 mmol/L)
(5) HDL-cholesterol < 40 mg/dL (1.036 mmol/L) in men
and < 50 mg/dL (1.295 mmol/L) in women.

• Most commonly, these individuals are insulin resistant

and have smaller, denser, more atherogenic LDL-
ACUTE COMPLICATIONS OF DM
1. Hypoglycaemia
Blood glucose < 2.2 mmol/L

Signs and symptoms;

Autonomic – sweating, hunger,
trembling, anxiety, pounding heart
Neuroglycopenic – confusion,
drowsiness, speech difficulty,
incoordination, inability to
concentrate.
Non specific – nausea, tiredness,
2. Diabetic ketoacidosis
Occurs mainly in type I DM.
Caused by insulin deficiency and
increased catabolic hormones
leading to hepatic overproduction
of glucose and ketone bodies.
Cardinal features
Hyperglycaemia
Hyperketonaemia
Metabolic acidosis
3. Non ketotic hyperosmolar
diabetic coma
Characterised by severe
hyperglycaemia > 50 mmol/L
without signs of hyperketonaemia
or acidosis.
• Affects elderly especially
previously undiagnosed.
• Signs/symptoms
Severe dehydration
Pre renal uraemia
LONG TERM COMPLICATIONS
They include diabetic Retinopathy,
Nephropathy, Neuropathy, Diabetic foot
and
Diabetic heart disease.
Diabetic Retinopathy
 Is the most common cause of blindness
in diabetic adults
• Another cause of visual loss in DM
include cataract formation (lens harden)
• CATARACT: distance vision, blurring of
vision, decreased night vision, sensitivity
to glare and bright light
RETINOPATHY
 Disease of the retina, the light
sensitive membrane at the back of
the eye, cause of new blindness.
After 20 years of diabetes, nearly
all people with type 1 diabetes and
>60% of people with type 2
diabetes develop retinopathy.
Reduced blood supply
Neovasculation
, Leakage of blood into vitrous
tissue →opacity
Diabetic Nephropathy

About 30% of patients with type I DM

Have developed DN after 20 yrs.
Commonest cause of end stage renal
failure
Diabetic foot
Aetiology
somatic neuropathy, autonomic
neuropathy and peripheral vascular
disease lead to increased foot
pressure, callus formation, infection
and +/- amputation.
Clinical features
• Neuropathy - paraesthesia,
numbness
• Structural damage - ulcer, sepsis,
abscess, osteomylitis, gangrene.
ATHEROSCLEROSIS IN DM

 Atherosclerosis can also affect blood

vessels in the rest of the body
Peripheral vascular disease
(developing gangrene of the feet).
Can cause hypertension.
DIABETIC BLADDER:
• Caused by diabetic
autonomic neuropathy.
• Urinate less often, with
difficulty emptying the
bladder, weak stream.
• Have silent, painless urine
retention.
Gestational diabetes
• Placental hormones
• Insulin Insensitivity.
• Gestational diabetes' refers to
hyperglycaemia occurring for the
first time during pregnancy
• Repeated pregnancy may increase
the likelihood of developing
irreversible diabetes, particularly
in obese women;
• 80% of women with gestational
diabetes ultimately develop
permanent diabetes.
RISK FACTORS FOR GESTATIONAL
DIABETES
1. Obesity
2. Ethnicity (South Asian, black,
Hispanic, Native American)
3. Family history of type 2 diabetes
4. Previous glucose abnormalities in
pregnancy
5. Previous macrosomia
Implications for the
mother

• Delivery by operation
• Gestational diabetes is
associated with an
increased risk of later
development of type 2
diabetes..
Implications for the fetus
• Increased perinatal
morbidity for the baby.
• Fetal insulin production
which stimulates growth.
• Macrosomia
• Reduction of maternal
blood glucose by insulin
therapy can reduce fetal
growth
GLYCOSYLATED HEMOGLOBIN
• Non enzymatic glycosylation of Hb
• Reference range (Healthy persons)
- 20-40 mmol/mol (4.0% -5.9%)
• Measure of long term glycemic
control (8-13 weeks)
• Modified by e.g. Hemoglobin
variants,
treatment changes, red cell life
span etc.
• Useful in diagnosis of DM ( >/=
DIAGNOSIS OF DM
4. CRITERIA FOR THE LABORATORY DIAGNOSIS OF
DM
[Link] of diabetes plus
casual plasma glucose
concentration 200 mg/dl (11.1
mmol/l). Casual is defined as
any time of day without regard
to time since last meal. The
classic symptoms of diabetes
include polyuria, polydipsia, and
unexplained weight loss

OR
2. FPG 126 mg/dl (7.0 mmol/l). Fasting
is defined as no caloric intake for at
least 8 h.
OR
3. 2-h postload glucose 200
mg/dl (11.1 mmol/l) during an
OGTT using a glucose load
containing the equivalent of
75 g anhydrous glucose
dissolved in water.

OR
4 Glycosylated Hemoglobin > 6.5%
IFG and IGT
• Group of subjects whose glucose
levels, although not meeting
criteria for diabetes, are
nevertheless too high to be
considered normal
IFG: Fasting plasma glucose 5.6
mmol/l - 7.0 mmol/l.

IGT : 2-h values in the oral glucose

tolerance test
• 7.8 mmol/l - 11.1 mmol/l.
LECTURE OUTLINE

• Definition
• Types
• Classification
• Clinical presentation
• Complications
• Laboratory Diagnosis