Lecture 26-DIABETES _ ACUTE COMPLICATIONS 2

Lecture 27-THYROID DISORDERS 35

Lecture 28-PARATHYROID 73
Lecture 29-ADRENAL DISORDERS 107
DLA Notes on THYROID DISORDERS 142
DLA Notes on CHRONIC COMPLICATIONS OF DIABETES _ HYPOGLYCEMIA 173
DLA Notes on HYPOTHALAMUS _ PITUTARY DISORDERS 205
DLA Notes on PHEOCHROMOCYTOMA 278
 Pathophysiology Lecture 26
Topic: DIABETES MELLITUS
&
ACUTE COMPLICATIONS OF DM
Dr. S. Upadhya

1
Patient:
A 6-yr-old girl in previously good health, is brought
to the emergency department because of a 3-
month history of increased thirst and frequent
urination. She gets up several times at night to
urinate, and to drink water. She seems to be eating
twice as much as she used to. She has lost 8
pounds in the past 3 month. No family history for
hypertension or diabetes.
Physical examination: Vital signs are normal;
System examination is normal
Lab results:
Fasting blood glucose = 138 mg/dL (normal 70-90)
Arterial pH = 7.36 (normal 7.35-7.45)
Urine: Tested positive for glucose 2
Most likely diagnosis is:
Diabetes mellitus (type-1)

Other differentials include:

•Diabetes insipidus
•Primary polydypsia
•Fructosuria
•Urinary infection
•Other causes of weight loss

3
 Insulin: Synthesis & Metabolism
•Two peptide chains, A and B are connected by two
disulfide bonds
•Secretion of insulin is accompanied by an
equimolar secretion of C-peptide
•Circulatory half-life is 3–5 minutes: catabolized in
both liver and kidneys
•Liver catabolizes approximately 50% of insulin on
its first pass through it
•In contrast, C-peptide is catabolized only by the
kidney and, therefore, have half-lives three to four
times longer than that of insulin 4
 Factors affecting B-cell Insulin release

Serum Glucose Gut

hormones
+
+
+
-Sympathetic Glucagon
nerves
Insulin
+

+
-
Parasympathetic
Nerves
Somastatin

5
Factors affecting A-cell Glucagon release

Serum Glucose Fatty acids

-
-
+
Amino acids Ketone bodies
Glucagon
-

-
Cortisol
Somastatin

6
 Glucose transporters
Major Sites
Transporter Characteristics
of Expression
Intestinal mucosa & Renal Cotransports glucose or
SGLUT1
tubules galactose with Na+
SGLUT2 Kidney tubules Cotransports glucose & Na+
Brain, erythrocyte, endothelial Transports glucose and
GLUT1
cells, fetal tissues galactose
Hepatocytes, pancreatic beta Serves as a "glucose sensor"
GLUT2
cell, small intestine, kidney in beta cells
Primary glucose transporter
GLUT3 Brain, placenta and testes
for neurons
Skeletal and cardiac Insulin-responsive glucose
GLUT4
muscle, adipocytes transporter

7
Actions of glucagon and insulin

1 2

1 2

1 1
1
1

1
2 8
Major Actions of Insulin on
Glucose and Fat Metabolism

+ Stimulation
- Inhibition
9
 Some Major Actions of Insulin on Glucose
and Fat Metabolism
1. Increases GLUT4 in the membrane and also increases the
activity of Glucokinase/Hexokinase.
2. Increases the activity of Phosphofructokinase but inhibits
Fructose 1,6-bisphosphatase.
3. Increases the activity of Pyruvate kinase but inhibits the
activity Phosphoenolpyruvate carboxykinase.
4. Increases the activity of Pyruvate dehydrogenase,
probably through the insulin mediator
5. Promotes lipogenesis by increasing activity of Acetyl CoA
carboxylase but inhibits the Hormone-sensitive lipase.
6&7. Promotes glycogenesis by increasing the activity of
Glycogen synthase but inhibits Glycogen phosphorylase.
8. Does not favor the activity of Glucose-6-phosphatase.
10
 DIABETES MELLITUS
A syndrome of altered carbohydrate, fat, and
protein metabolism resulting from an absolute or
relative deficiency of insulin resulting in
hyperglycemia.
Approximately 6% of the U.S. population
Types:
-Type 1 - autoimmune, accounts for less than 10%
-Type 2 - accounts for over 90% of all cases
-Borderline diabetes - Impaired fasting glucose
(IFG) and impaired glucose tolerance (IGT)
-Gestational diabetes mellitus (GDM)
11
 Clinical manifestations of diabetes mellitus:
The classic triad:
Polyuria – osmotic diuresis
Polydipsia
Polyphagia (excessive eating)

Other manifestations:
Blurred vision
Weight loss despite excess food intake
Skin infections, vulvovaginitis/balanitis

12
Autoantibodies detectable in Type-1 DM:

Glutamic acid decarboxylase antibodies

(GADA)
Insulin autoantibodies (IAA)
Islet cell antibodies (ICA)

Can be used for screening in first-degree relatives

and in general population

13
ADA Criteria for diagnosis of diabetes mellitus
1. Random plasma glucose greater than 200 mg/dL (11.1
mmol/L) with classical symptoms of hyperglycemia.
OR
2. Fasting venous plasma glucose greater than or equal to
126 mg/dL (7 mmol/L). Fasting is defined as no caloric
intake for at least eight hours.
OR
3. Hemoglobin A1C (Glycated Hb) greater than or equal to
6.5 percent.
OR
4. Oral glucose (75 g) tolerance test (OGTT) showing a 2-
hour plasma glucose greater than or equal to 200 mg/dL.
OGTT is reserved for individuals who have potential symptoms of
diabetes or its complications but the fasting plasma glucose is equivocal
(below 126 mg/dL). 14
Oral glucose tolerance test (OGTT)

15
 Development of Type 2 Diabetes

Insulin Resistance Impaired -Cell Function

Insulin Resistance and

Hyperinsulinemia with
Normal Glucose Tolerance

Insulin Resistance and

Declining Insulin Levels
with Impaired Glucose
Tolerance

Type 2 Diabetes
16
 Insulin resistance in Type2 DM
Definition: Subnormal euglycemic response to
normal insulin.
Pathophysiology:
•Reduced number of GLUT-4 transporters
•Increasing visceral obesity and high BMI
•Malignancies associated with or without obesity

Mechanism:
Phosphorylation of serine/threonine sites on insulin
receptor substrates (IRS-1 and IRS-2) → Reduces or
inhibits the ability of IRS to respond to insulin
receptor signaling (tyrosine kinase mediated) →
Reduced physiological effects of insulin in a cell.
17
 Obesity and Insulin resistance
Factors from
adipose tissue:
•Fatty acids
•TNF-alpha
•Resistin
Reduced effects of
Insulin

↑Plasma Fatty acids

TNF-alpha & Resistin 18

Molecular signaling activated by Insulin

Tyrosine Phosphorylation

Insulin Receptor Substrate (IRS) 1 & 2 PI3K

•GLUT4 transportation to membrane

•Glycogen synthesis
•Lipogenesis Signal
activation
•Lipolysis Inhibition pathways
•Gluconeogenesis Inhibition
•Protein synthesis

PI3K = Phosphatidylinositol 3 kinase

Indicators of Insulin resistance in Type2 DM

Clinical Indicators:
•BMI & Increase in waist-to-hip ratio
(visceral fat>subcutaneous fat)
•Acanthosis nigricans
•Metabolic X syndrome
•An insulin requirement >200 U/day for euglycemia

Laboratory Indicators:
•Increase in serum Triglycerides (TG) not (LDL)
•Increase in TG/HDL-cholesterol ratio (n:120/40)
•Increase in serum Free Fatty Acid level
•Increase in serum fasting insulin concentration
20
Acanthosis nigricans: Sign of Insulin resistance

High circulating Insulin

stimulates proliferation of
epidermal keratinocytes and
dermal fibroblasts.

21
 Lipid abnormality in DM:

• Hypertriglyceridemia is hall mark of lipid abnormality

• Low HDL cholesterol
• Elevated VLDL and LDL cholesterol: Reasons
-Decreased lipoprotein lipase activity → decreased VLDL
clearance → high VLDL & LDL.
-Increased lipolysis → fatty acid flux from adipose tissue to
the liver → increased VLDL production by liver
-Down regulation of LDL receptors by insulin deficiency
leads to less clearance from plasma
• Insulin treatment usually corrects lipoprotein abnormalities
in type 1 diabetes
• Weight reduction and control of hyperglycemia may correct
the abnormality in type 2
22
Patient:
A 10-year-old boy is brought to the emergency department
because of a 2-day history of lethargy, nausea, vomiting,
and vague abdominal pain. He also has weight loss, polyuria
and polydypsia.
Physical examination: He has sunken eyes; dry skin and dry
tongue.
BP 100/60 mm Hg; Pulse 112/min – rapid & low volume;
Respiration 22/min - increased depth of respiration & “fruity”
breath.
Laboratory:
Blood: Blood glucose 430 mg/dL (normal 90 mg/dL); Low
sodium; High potassium; high blood urea
ABGas: Low pH; Low PCO2 & low bicarbonate
Anion gap 22 mEq/L (normal is below 12 mEq/L)
Urine: Sugar ++++; Ketone bodies present
23
The most likely diagnosis is:
Diabetic ketoacidosis (DKA)

Other differentials include:

•Hyperglycemic Hyperosmolar state
•Hypoglycaemia
•Lactic acidosis
•Uremia
•Alcoholic ketoacidosis
•Starvation ketoacidosis
•Salicylate poisoning

24
 Complications of diabetes mellitus:
Acute complications: Metabolic-related
1. Hyperglycemia
2. Diabetic ketoacidosis (DKA)
3. Hyperosmolar coma
4. Hypoglycemia

Chronic complications: Vascular-related

A. Macrovascular diseases:
Accelerated atherosclerosis, Hypertension &
Hypertriglyceridemia
B. Microvascular diseases:
Retinopathy, Nephropathy & Neuropathy
C. Other chronic complications:
Diabetic foot ulcers, Recurrent infections
25
Hyperglycemia initiates complications in DM

Hyperglycemia

Increased Glycosuria
glucose in tissue
fluid Microangiopathy

Osmotic
diuresis
Increased risk of
infections

Hyperosmolarity
of plasma
26
 Shift in fuel metabolism initiates
complications in DM
Decreased glucose availability to cells

Shift to fat & protein metabolism

Production of
ketone bodies Weight loss Hyperlipidemia

Ketoacidosis
Macro &
Gallstones
Microangiopathy
Coma

Cerebrovascular Retinopathy
& peripheral
neural diseases
Cardiovascular Nephropathy
diseases
27
Acute complication 1: Diabetic Ketoacidosis (DKA)

•More common in type 1 (absolute insulin deficiency)

•It can also occur in type 2 diabetes during infections,
severe trauma, or other causes of stress

•Hypovolemia in DKA:
Osmotic diuresis and low water intake (because of
nausea/vomiting) → decrease in blood volume.
Decreased renal blood flow worsens the situation
further (inability of kidney to excrete glucose→
hyperglycemia)

28
Ketogenesis by liver
in insulin deficiency

29
Other features of DKA and their basis:
•Metabolic acidosis (decreased blood pH and serum
bicarbonate)
•Stimulation of respiration – as compensation for the
metabolic acidosis (Kussmaul breathing)
•Fruity odor of the breath due to acetone
•Sodium - Low serum Sodium (due to osmotic
diuresis as well as to the osmotic activity of the
elevated glucose, which draws water into the
extracellular space)
- Depletion of total body Na+
•Potassium - Depletion of total body K+ by diuresis
and vomiting
- Hyperkalemia due to shift of K+ out of
cells with osmotic water movement & insulinopenia.30
 Features of DKA and their basis (cont’d):

•Leukocytosis in the absence of infection and

fever. Infection should be ruled out as it can
precipitate diabetic ketoacidosis.
•Hyperosmolality & coma in DKA:
-Severe hyperglycemia → hyperosmolality → shift of
intracellular fluid in the brain → coma (10%)
-Coma occurs when the effective plasma osmolality
reaches 340 mOsm/L (normal: 280–295)

Coma in DKA is NOT due to acidosis;

it is due to hyperosmolality.
31
Acute complication 2: Hyperosmolar Coma
•Hyperosmolar state in absence of ketosis in type 2.
•Episodes are precipitated by decreased fluid intake
& abnormal renal function in clearing glucose load.
•Mechanism of development of hyperosmolality is
the same as in DKA.
•Profound hyperglycemia & dehydration than in
DKA (serum glucose may be 800–2400 mg/dL)
•As serum osmolality exceeds 340 mOsm/L, there is
a higher incidence of coma than in DKA.
•K+ losses are less severe than in DKA.
•Mortality is 10 times higher than in DKA.
32
 Acute complication 3: Hypoglycemia in DM
• A complication of insulin treatment in both types.
• Precipitated by exercise or fasting.
• Symptoms: shaking, sweating, palpitations, confusion,
coma.
• Nocturnal hypoglycemia (during sleep) is manifested as
night sweats, nightmares, morning headaches
• Response to hypoglycemia is mediated by the
counterregulatory effects of glucagon, catechol & cortisol.
• Type 1 diabetics are more prone to hypoglycemia –
because the glucagon response to hypoglycemia is
diminished/absent in them.
• Rebound hyperglycemia occurs after hypoglycemia due
to overcorrection done by counterregulatory hormones.
This phenomenon is called Somogyi effect 33
 Lecture 27
Topic: THYROID DISORDERS:
HYPERTHYROIDISM
&
THYROID NODULES
Lecturer: Dr. S. Upadhya

1
Patient:
A 28-yr-old woman comes to her physician because of an 8-
month history of restlessness, sleeplessness and fatigue.
She also has loss of weight with good appetite and heat
intolerance. She has sensation of grit in both eyes. She
rushes frequently to the toilet but passes scanty, normal
stools. Her elder sister also had similar symptoms at the age
of 26.
Physical examination: Body temperature 100°F; extremities
are warm and moist; A rapid and irregular pulse; A fine
tremor of hands and fingers when outstretched.
Examination of her eyes: Reddened eyes, Widening of the
space between eyelids, Swelling of the lids and tissues
around the eyes.
There is moderate enlargement of the thyroid gland (goiter).
Blood chemistry: low levels of TSH and high levels of fT4
2
Most likely diagnosis in the patient is:
Graves disease

Other differentials:
•Hashitoxicosis
•Toxic multinodular goiter
•TSH-secreting pituitary adenoma

Further confirmation by:

Detection of TSH-receptor stimulating
antibodies in circulation
3
Anatomy of Thyroid gland

4
Regulation of Thyroid Secretion

5
 Laboratory Tests of the Thyroid
•Measurement of:
-Serum TSH
-Serum free T4 (fT4), and
-occasionally Serum total T3 (tT3)

•TSH concentration responds logarithmically to changes

in T3 and T4.
(Exception to this is : Secondary hypothyroidism.)

•Measurement of non–protein bound or free hormone rather

than total hormone is recommended and allows one to
assess the biologically active level of hormone.
•Any change in binding protein concentrations leads to
changes in the total hormone level but not free hormone.
6
 Imaging Tests of the Thyroid:
Radionuclide uptake and scanning: using 131I,
123I, or 99mTc pertechnetate:

Increased uptake signifies hyperactivity of the

gland and low uptake indicates hypofunction or
damage of the thyroid

Ultrasound: gives information whether nodules

are cystic or solid.
It can detect nodules that are not palpable on
physical examination- used as a supplement to
physical examination
CT and MRI: not routinely used
7
 Radioactive Iodine Uptake (RAIU) curves
Thyrotoxicosis associated with
a small but rapidly turning over
intrathyroidal iodine pool
Radioactive Iodine uptake (%)

(Example: a solitary hot nodule)

Hyperthyroidism

Renal disease

Normal

Hypothyroidism

Hours after injection

Prolonged uptake in renal disease - due to decreased urinary
excretion of the isotope 8
Autoantibodies detectable in various thyroid
dysfunctions:

Thyroid peroxidase antibody (TPO Ab), formerly

termed antimicrosomal antibody - in Hashimoto's
thyroiditis
Thyroglobulin antibody (Tg Ab) - Hashimoto's
thyroiditis
TSH receptor antibody: two different types:
-TSH stimulating (TSH-R [stim] Ab) - in
Graves disease
-TSH blocking (TSH-R [block] Ab) - in maternal
serum of newborns with congenital
hypothyroidism
9
Autoimmune Disorders Associated with
Graves Disease and Hashimoto's Thyroiditis
Endocrine disorders:
-Diabetes mellitus (Type1)
-Hypoadrenalism/Addison's disease Polyglandular
-Orchitis or oophoritis Failure syndrome

-Hypoparathyroidism

Nonendocrine disorders:
-Pernicious anemia
-SLE, Rheumatoid arthritis, Sjogren’s syndrome
-Immune thrombocytopenic purpura
-Myasthenia gravis
-Primary biliary cirrhosis 10
 The disease states of Thyroid

A. Hyperthyroidism (thyrotoxicosis) - an excess of

thyroid hormones
B. Hypothyroidism (myxedema) - deficiency of
thyroid hormones
C. Goiter - diffuse enlargement of the thyroid
gland by prolonged elevation of TSH
D. Thyroid nodule - focal enlargement of a portion
of the gland by a benign or malignant neoplasm
E. Abnormal thyroid function tests in a clinically
euthyroid patient
11
 Hyperthyroidism:
Causes Pathogenetic mechanism

Graves disease: TSH-R [stim] Antibodies

Toxic multinodular goiter: Autonomous hyperfunction
Follicular adenoma: Autonomous hyperfunction
Pituitary adenoma: TSH hypersecretion
Hypothalamic disease: Excess TRH production
Metastatic follicular
thyroid carcinoma: Functioning metastases
Hashimoto's thyroiditis: Transient release of stored
hormone
Thyrotoxicosis
medicamentosa, Ingestion of excessive
12
thyrotoxicosis factitia: exogenous thyroid hormone
Symptoms of Hyperthyroidism
•Nervousness/anxiety
•Increased sweating
•Heat intolerance
•Palpitations
•Weight loss with good appetite
•Tachycardia
•Dyspnea
•Muscle weakness
•Hyperdefecation
•Eye complaints
•Swelling of the legs Only in Graves disease

13
Signs of Hyperthyroidism
•Tachycardia
•Atrial fibrillation & irregular pulse
•Skin changes
•Bruit over thyroid
•Goiter
•Eye signs only in Graves dis

14
 Cardiovascular changes in hyperthyroidism:

•Cardiac output is increased - result of increased heart rate

and contractility and reduced peripheral vascular resistance
•Pulse pressure is increased – High systolic and low
diastolic BP
•Circulation time is shortened – hyperdynamic heart
•Tachycardia - usually supraventricular; due to the direct
effects of thyroid hormone on the SA node. Atrial fibrillation
may occur, particularly in elderly patients
•Patients may manifest acute heart failure as a result of left
ventricular dysfunction.
•Long-standing hyperthyroidism may lead to cardiomegaly
and a "high-output" congestive heart failure
•Flow murmurs may appear due to hyperdynamic circulation
15
Muscle weakness and atrophy in
hyperthyroidism (thyrotoxic myopathy):

•Common if the disease is severe and prolonged

•Proximal muscle weakness may interfere with
walking, climbing or weight lifting
•Muscle weakness - due to increased protein
catabolism, muscle wasting & decreased muscle
efficiency, or changes in myosin
•May be associated with Myasthenia gravis or
periodic paralysis

16
Carbohydrate metabolism in hyperthyroidism:

•Hyperglycemia due to:

-Increased hepatic gluconeogenesis
-Increased carbohydrate absorption
-Increased insulin degradation
•In nondiabetic patients - after ingestion of
carbohydrate, the blood glucose rises rapidly,
sometimes causing glycosuria, and then falls
rapidly. There may be an adaptive increase in
insulin secretion – abnormal glucose tolerance curve

17
 Oral glucose tolerance test (GTT) in thyroid disorders

Hyperthyroid patient has a rapid intestinal absorption and a rapid

combustion of glucose. Hypothyroid patient has a slow
absorption and a slow combustion of glucose. 18
 Reproductive functions in Hyperthyroidism:
In Female:
•Oligomenorrhea and decreased fertility
Reason: An increased basal plasma LH in the early follicular
phase → Impairment in development of the follicle →
Anovulation.

In Male:
•Decreased fertility and erectile dysfunction
Reason: Altered steroid hormone metabolism:
- Increased Estradiol-to-Testosterone ratio due to increased
peripheral conversion of androgen to estrogen
•Gynecomastia - secondary to an altered E/T ratio.

19
 Skin changes in Hyperthyroidism:

•The skin is warm and sweaty – give reason

•Hyperpigmentation of the extremities:

Mostly on the shins, the backs of the feet, and
the nail beds. Reason: Basal melanosis and
deposition of hemosiderin around the dermal
capillaries.

•Pretibial myxedema – only in Graves disease.

20
 Other effects of Hyperthyroidism:

• Low plasma cholesterol - due to an increase in the

number of hepatic low-density lipoprotein (LDL) receptors

•Increased lipolysis - adipocytes show an increase in beta-

adrenergic receptor density and increased responsiveness
to catecholamines.

•Skeletal tissue - enhanced osteoblastic and osteoclastic

activity produces accelerated bone turnover, negative
calcium and phosphorus balance, low bone mineral
density, increased skeletal fragility, calciuria and
sometimes hypercalcemia.
21
 Pathogenesis of Graves disease:
•A defect in suppressor T lymphocytes allows helper
T lymphocytes to stimulate B lymphocytes to
secrete antibodies directed against TSH receptor in
the follicular cells.
•Gland stimulated by TSH-R [stim] Ab (aka long-
acting thyroid stimulator, LATS) – example of type II
hypersensitivity
•Disease is familial - much higher concordance
rates in monozygotic same-sex twin pairs
•Frequently suffer from other autoimmune disorders
22
 Eye signs in Graves disease (Graves
ophthalmopathy):

•The wide-eyed stare and proptosis due to

-increased sympathetic tone;
-infiltration of orbital soft tissues and extraocular
muscles with lymphocytes,
mucopolysaccharides, and edema fluid
•Diplopia – due to fibrosis of the extraocular
muscles and restricted ocular motility
•Blindness – due to pressure on the optic nerve or
keratitis from corneal exposure
23
The pathogenesis of Graves ophthalmopathy:

Cytotoxic lymphocytes (TC)

and cytotoxic antibodies to
an antigen common to
orbital fibroblasts, orbital
muscle, and thyroid tissue
produce inflammatory
reactions
24
 Eye signs in Graves disease

Periorbital swelling, conjunctival hyperemia, lid

retraction, proptosis in both and strabismus in the
right pic.
25
 Skin changes in Graves disease:
Thyrotoxic dermopathy

•Thickened pretibial skin resembling an orange

peel (pretibial myxedema).
•Dermopathy is usually a late manifestation.
•Characterized by nonpitting edema which may
be nodular, plaque-like, and even polypoid forms.
•Pathogenesis of thyroid dermopathy - stimulation
of fibroblasts by cytokines (similar to what
happens in the orbit).

26
Pretibial myxedema in Graves disease

27
 Diagnosis of Graves disease:

By biochemical and clinical evidences

Biochemical:
Thyroid function tests:
-Very low serum TSH
-Elevated serum free T4 (fT4)
-Increased radioiodine uptake
Positive serum TSH-R(stim) antibodies

Clinical:
Ophthalmopathy and/or dermopathy

28
Long term sequel of Graves disease:
Patients may later develop hypothyroidism by
one of several mechanisms:
A. Thyroid ablation by surgery or 131I radiation
B. Autoimmune thyroiditis, leading to thyroid
destruction
C. Development of antibodies that block TSH
stimulation [TSH-R (block) Antibody]

29
 Toxic Multinodular Goiter
Thyroid gland has a nodular enlargement.
Nodules grow and begin to autonomously produce
excess amounts of thyroid hormones.
Equal frequency in both sex & over age of 40 years.
Benign adenomas and do not carry risk of thyroid
cancer.
Present with signs and symptoms of hyperthyroidism.

Diagnosis: History; Neck examination for a nodular

thyroid & Lab shows high T4 and low TSH.
Confirmation: Radionuclide scanning of thyroid shows
areas of increased uptake that correlate to overactive
or “hot” nodules
30
Subacute granulomatous thyroiditis (de
Quervain thyroiditis) Thyroiditis

•Self-limited inflammatory condition.

•Young & middle aged; Female > Male.
•Viral etiology (following a respiratory infection).
•Triphasic clinical course:
Acute phase – Pain, enlarged & tender gland with
dysphagia and symptoms of hyperthyroidism (3-6
weeks);
Hypothyroid phase - Lasts from 2-4 months;
Recovery phase - Characterized by normalization
of thyroid structure and function (by 4-6 months).
31
 Evaluation of hyperthyroidism
Toxic
Graves multinodular
Euthyroid disease goiter Thyroiditis
Thyroid Normal Low Low Low
stimulating
hormone
(TSH)
Total T3 Normal High High High

Free T4 Normal High High High

Radionuclide Normal Increased Focal Decreased

Scanning uptake increase uptake

32
Thyroid uptake in radionuclide scanning findings in
the various common forms of thyrotoxicosis

Normal uptake Graves disease: diffuse, Toxic multinodular goiter:

increased uptake foci of increased uptake

Autonomous nodule: Hashimoto’s thyroiditis:

solitary hot nodule diffuse, decreased uptake 33
 Thyroid Neoplasm: Benign
Tumors present as a solitary mass in the neck
Follicular adenoma:
Most common neoplasm (30%)
It is a solitary, firm, gray or red nodule, up to 5 cm in
diameter.
Although adenomas are non-functional, rarely become toxic
nodules and manifest features of thyrotoxicosis.
Microscopy: normal-appearing follicles of varying size,
encircled by a well-defined fibrous capsule. The
surrounding normal thyroid tissue may be compressed by
the adenoma.
Malignant change occurs in less than 10%.
34
 Thyroid Neoplasms: Malignant

Carcinoma thyroid:
•Types based on microscopic appearance.
•Papillary carcinoma: Metastasizes to regional lymph nodes
in the neck.

•Follicular carcinoma: Spreads via the bloodstream to distant

sites such as bone or lung.

•Anaplastic carcinoma: Most aggressive type.

•Medullary carcinoma: neoplasm of the C cells (parafollicular

cells) of the thyroid that produce calcitonin. It may be
associated with other endocrine tumors, a manifestation of
multiple endocrine neoplasia (MEN) syndromes, type 2 and
35
3.
 Thyroid Neoplasms: Features of Malignant
History:
Compression symptoms (dysphagia, hoarseness)
 Risk factors:
-Age <20 or >60 years (mostly malignant)
-History of neck irradiation (mostly malignant)
-Family history of medullary carcinoma (MEN 2 & 3)
Physical examination:
Rapid growth of nodule, Fixation and Lymphadenopathy
Course:
Growth of nodule while on thyroid hormone suppression
Laboratory:
Euthyroid clinical status
Imaging:
Nodule “cold” on radionuclide scanning.
36
Evaluation of Thyroid Nodules
Step 1:
Determine if any risk factors for thyroid cancer exists
Step 2:
Measure serum TSH to determine if the nodule is
hyperfunctioning. Low TSH indicates that the nodule
is autonomous. Autonomous (hot) nodules are very
rarely thyroid cancer.
Step 3:
If the nodule is cold, do fine needle aspiration or
biopsy for histopathological examination.
37
Subclinical Thyroid Diseases:
Clinically euthyroid individuals having low or high TSH levels
but normal circulating T4 and T3 levels.

Subclinical hypothyroidism:
•Elevated TSH (>5 mU/L) but normal circulating T4 & T3.
•A few with this progress to overt hypothyroidism (5%).
•May be associated with subtle neuropsychiatric
abnormalities.
•Administeration of T4 to normalize serum TSH improves.

Subclinical hyperthyroidism:
•Low TSH (< 0.1 mU/L) but normal circulating T4 & T3.
•Autonomous thyroid nodules accounts for many cases.
•>65 yr. have a greater risk of developing atrial fibrillation.
38
 Lecture 28
Topics: Disorders of
Parathyroid, Calcium,
Vitamin D, and Metabolic
Bone Diseases

Dr. S. Upadhya

1
Patient:
A 53-year-old woman comes to the physician because of a
3-month history of musculoskeletal aches, anorexia and
constipation. She also has frequent micturition. She is a
known hypertensive and on regular treatment for the past 10
years.
Physical examination: Unremarkable

Lab studies:
High serum calcium; high PTH level; low serum phosphorus;
elevated serum vitamin D3.
24-hour urinary calcium: High

Thyroid ultrasound: normal thyroid size but TWO hypoecoic

masses are seen in the left posterior thyroid region.
X-ray of bones: shows significant osteoporosis.
2
The most likely diagnosis in this patient:
Hypercalcemia due to parathyroid adenoma

Other differentials of Hypercalcemia include:

-Vitamin D or A excess
-Immobilization
-Thyrotoxicosis
-Addison's disease
-Neoplastic disease
-Thiazide diuretic
-Rhabdomyolysis
-Parenteral nutrition-Sarcoidosis
3
Parathyroid Anatomy, Embryology & Histology :

The superior parathyroids:

-develops from the fourth pharyngeal pouches
-blood supply is from the inferior thyroid arteries or,
less commonly, the superior thyroid arteries.
The inferior parathyroids:
-develops from the third pharyngeal pouch
-blood supply is from the inferior thyroid arteries

Histology: Chief cells/clear cells: Small cells with

clear cytoplasm, secrete parathyroid hormone
(PTH).
4
 Effects of PTH on
bone, kidney and gut

Low serum
ionized Ca+2
↓
CaSR
↓
PTH release
↓
Rise in serum
Calcium

5
Calcium homeostasis: Interactions of PTH and
blood Calcium

(8.5-10.5 mg/dL)

(8.5 - 10.5 mg/dL)

Sensed
through Ca-
sensing
receptors

6
 Calcium Sensing Receptor
(CaSR)

Expressed in the parathyroid gland and kidney

In parathyroid - it functions to detect changes in
serum calcium concentration and adjusts the rate
of PTH secretion
In kidney – it sets the level of urinary calcium
excretion, based on its perception of the serum
calcium concentration
(see Benign hypocalciuric hypercalcemia)
7
Mechanism of Parathyroid Hormone Action:
Two types of PTH receptors:
Type1-PTH receptor:
•Present in bone & kidney
•Recognizes both PTH and parathyroid
hormone-related peptide (PTHrP)
•Mechanism of action: through activation of
adenylyl cyclase and production of cAMP
•Involved in calcium homeostasis.

Type 2-PTH receptor: specific only for PTH; Expressed in

target tissues such as brain, pancreas, testis, and
placenta; This receptor is not involved in calcium
homeostasis.
8
 Causes of hypercalcemia
Most common (90-95%):
•Primary hyperparathyroidism; Malignancy

Less common:
•Medications (lithium, thiazides)
•Vitamin D intoxication
•Sarcoidosis
•Acute immobilization
•Hyperthyroidism
Factitious:
•Hypergammaglobulinemia – due to increased
calcium binding proteins (total Ca+2 is high but
ionized Ca+2 is normal) 9
Major causes Hypercalcemia:
Primary hyperparathyroidism: results from i) benign
parathyroid adenoma (85%); or ii) diffuse hyperplasia
of all four glands (15%). Usually associated with
multiple endocrine neoplasia (MEN) syndromes.
Patients have high plasma PTH levels.
Malignancies causing hypercalcemia: by two ways –
i) Tumors secrete PTH-related protein (PTHrP) that
produces hypercalcemia. Examples squamous cell ca
of head, neck, lung, and esophagus; renal cell
carcinoma, and breast cancer.
ii) Metastases to bone and Hematologic neoplasms
(e.g., multiple myeloma and lymphoma) produce
hypercalcemia by releasing osteoclast-activating
cytokines with extensive bone destruction (osteolytic
hypercalcemia).
10
Plasma PTH is low/undetectable in (i) and (ii).
 Clinical manifestations of hypercalcemia
Renal: Neuromuscular:
•Nephrolithiasis •Muscle weakness
•Impaired concentrating ability •Hyporeflexia
(polyuria, polydipsia, and
dehydration) Psychiatric:
•Renal tubular defects •Apathy/lethargy
(natriuresis) •Somnolence
•Interstitial nephritis •Depression
•Renal failure •Psychosis
Cardiovascular:
Gastrointestinal:
•Shortened QT interval on
•Constipation
electrocardiogram (characteristic)
•Anorexia
•Nausea Ectopic calcification:
•Peptic ulcer •Pruritus (calcium deposition within the
•Pancreatitis skin)
•Band keratopathy (calcium deposition
within the cornea) 11
 Radiologic features of primary hyperparathyroidism:

“Brown tumors” Nephrolithiasis

•Subperiosteal resorption
•Generalized low bone mass; extensive lytic lesions
•A well marginated cortical lytic lesion with endosteal
scalloping produces the characteristic “brown tumors”
•Abdominal films may show nephrocalcinosis or
nephrolithiasis
12
Osteoporosis causes weak bones

13
 Familial (Benign) Hypocalciuric Hypercalcemia
•Individuals with this condition typically have an elevated
serum calcium with a low urinary excretion and normal or
mildly elevated PTH levels.
•Inherited in an autosomal dominant manner.

Pathogenesis:
•The ability to detect serum calcium is faulty in both the
kidney and parathyroid gland
•Parathyroid chief cells missense the serum calcium as
"low," and secrete PTH. This results in an inappropriately
normal or elevated PTH levels.
•In the kidney, serum calcium is detected as “low”, and
calcium reabsorption increases in the renal tubules. This
results in hypocalciuria (decreased urinary calcium
excretion), typical of this condition. 14
 Laboratory evaluation of hypercalcemia

Initial work-up:
Serum calcium
Serum PTH level
Urine calcium excretion (24-hour urine collection)

Additional tests to find the cause:

•Serum albumin, phosphate, and creatinine
•Serum protein/urine electrophoresis (for hematologic
malignancies)
•Chest radiograph (for sarcoidosis or lung ca)
•Imaging of chest and abdomen (for neoplasms)

15
 Laboratory Differential in Hypercalcemia

Condition Serum Serum Serum Serum Urine

PO4 3– PTH PTHrP 1,25 Ca2+
(OH)D
Primary ↓ ↑ Und ↑ N/↑
Hyperparathyroidism

Malignancy associted ↓ ↓ ↑ N/↓ ↑

hypercalcemia

Familial hypocalciuric N N/↑ Und N ↓

hypercalcemia

Vitamin D-dependent ↑ ↓ Und ↑ ↑

hypercalcemia
↑:Increase; ↓:Decrease; Und:Undetectable; N:Normal 16
Patient:
11-yr-old girl is brought to the physician because of short
stature, obesity, developmental delay and dental
hypoplasia. Infrequently she develops paresthesias,
muscular cramping, tetany and carpopedal spasm. She had
two episodes of seizures recently.
Physical examination: Vitals are normal;
Positive Chvostek sign and Trousseau sign; Bilateral
cataract present;
Brachydactyly - symmetrical shortening of her metacarpals
and shortening of the digits. This is demonstrated in the
physical examination as dimpling over her knuckles of a
clenched fist (ie, Archibald sign)
X-ray hands: shortened distal phalanges and metacarpals
Blood studies: Low calcium; High phosphorus and elevated
PTH. 17
The most likely diagnosis is:

Hypocalcemia due to
Pseudohypoparathyroidism (Albright's
hereditary osteodystrophy)

The differential diagnosis include:

•Hypoparathyroidism
•Rickets (vitamin D deficiency)
•Hyperphosphatemia
•Hypoalbuminemia
•Renal failure
•Seizures
18
Causes of hypocalcemia related to PTH/Vit D:
(as integrated with serum phosphate level)

PTH-related causes Vitamin D-related causes

(Associated with
Hyperphosphatemia)
•PTH deficiency:
Congenital
Acquired:
-Postsurgical
-Autoimmune
-Infiltrative
•Chronic hypomagnesemia
(causes low PTH release)
•Resistance to PTH receptors
(Pseudohypoparathyroidism)
(Associated with
Hypophosphatemia)
• Deficient vitamin D:
-Poor diet or sun exposure
-Malabsorption
•Impaired 1-hydroxylation of
25-hydroxyvitamin D
•Resistance to calcitriol
receptors in target organs
19
Causes of hypocalcemia unrelated to PTH/Vit D:

•Endogenous phosphate load:

-Renal failure
All due to
-Hemolysis
an elevated
-Rhabdomyolysis serum PO4
•Exogenous phosphate load:
-Laxatives and enemas

Pathogenesis of hypocalcemia in renal failure:

a) Renal failure → low GFR → hyperphosphatemia →
hypocalcemia; and also,
b) Renal failure → low 1-alpha activity → low Vit D3 → low
calcium absorption in gut → hypocalcemia
Hypocalcemia in renal failure stimulates PTH and thus
leads to secondary hyperparathyroidism 20
Etiology of hypocalcemia – PTH related:
(associated with hyperphosphatemia)

Hypocalcemia results from:

Reduced PTH secretion (congenital or acquired)
or
PTH receptor defect in the target tissues (bones
and kidney) despite a good levels of the hormone –
termed pseudohypoparathyroidism

Reason for high serum phosphate: PTH normally decreases

renal tubular phosphate reabsorption. Decreased PTH
action results in less amount of phosphate lost in urine and
hence hyperphosphatemia.
21
Etiology of Hypocalcemia - Vit D related:

•Hypocalcemia results from decreased calcium

absorption in the intestine due to the deficient
action of vitamin D3.
•Hypocalcemia is associated with
hypophosphatemia
•Reasons for hypophosphatemia are:
-Vit D3 is also required for intestinal
absorption of phosphate
-Concurrent secondary hyperparathyroidism
increases phosphate loss in urine
-Vit D3 increases renal tubular phosphate
reabsorption 22
Clinical Manifestations of Hypocalcemia:
Symptoms of hypocalcemia occur only if the ionized
fraction of calcium is reduced
The hallmark of severe hypocalcemia is tetany –
Spontaneous sensory and motor discharges in peripheral
nerves and featuring muscular twitching, spasms, or seizure
Chvostek's sign - tapping facial nerve in front of the ear lobe
produces twitching of the lip at the angle of the mouth
Trousseau's sign - tested by inflating a blood pressure cuff
10-20 mm Hg above the patient's systolic blood pressure for
3 to 5 minutes produces spasm of hand giving appearance of
“obstetrician's hand”
EKG: A prolonged QT interval is also a classic manifestation
23
of hypocalcemia
Neurologic manifestations of
hypocalcemia:

•Paresthesias (toes, fingers, and perioral)

•Muscle cramps/fasciculations
•Chvostek's sign
•Trousseau's sign
•Tetany
•Seizures
•Basal ganglia calcifications
•Mental status changes

24
Other Clinical manifestations of hypocalcemia
Cardiac:
•Decreased myocardial contractility
•Congestive heart failure
•Prolonged QT interval

Dental:
•Hypoplasia of teeth/enamel
•Dental caries
•Delayed eruption of teeth

Ophthalmologic:
•Cataracts
•Optic neuritis
•Papilledema 25
 Laboratory differential of common
causes of Hypocalcemia

Serum Hypoparath- Vitamin D Pseudohypopa-

levels yroidism deficiency rathyroidism
Serum ↓ ↑ ↑
PTH
Serum ↓ ↓ ↓
Calcium
Serum ↑ ↓ ↑
PO4

26
Diagnosis of Hypocalcemia:

A. Check serum PTH and phosphate levels:

•PTH low & phosphate high: in conditions of absolute
PTH deficiency.
•PTH high & phosphate low: in disorders of vitamin D.
•PTH high & phosphate is also high: in Renal failure and
Pseudohypoparathyroidism.
•In vitamin D deficiency, measure the metabolite, 25-
hydroxyvitamin D because it is consistently low in all
states of vitamin D deficiency. Circulating 1,25-
dihydroxyvitamin D levels are less sensitive.

B. Check serum magnesium – to rule out

hypomagnesemia as the cause of hypocalcemia.
27
Diagnosis of Pseudohypoparathyroidism:
Serum PTH and serum phosphate are High.
 Confirmation test: Inject synthetic human PTH
and measure urinary cAMP and phosphate
excretion.
Normal response: Increase in urinary cAMP & PO4
In pseudohypoparathyroidism: No urinary rise of
these two.
Associated findings: Pseudohypoparathyroidism is
associated with Albright hereditary osteodystrophy
characterized by short stature, obesity, café au lait
spots, mental retardation, and short fourth and fifth
metacarpophalangeal and metatarsal (MTT) joints. 28
Metabolic Bone Diseases:

•Osteomalacia and Rickets

•Paget’s disease of bone

29
 Osteomalacia and Rickets

•Children present with bowing of long bones, growth

retardation, bone pain, and delayed dentition.
•Adults present with bone pain and fractures.
•Hypotonia, muscle weakness, and tetany in both
(low Ca+2).
•Diagnosis: i) Blood studies: Low serum calcium and
phosphate; high serum alkaline phosphatase and
high serum PTH (secondary hyperparathyroidism).
ii) Imaging studies: diffuse demineralization
(osteopenia), increased trabecular markings and
pseudofractures.
iii) Bone histology: Unmineralized osteoids. 30
 Paget's Disease of Bone (osteitis deformans)
•Characterized by disordered bone remodeling with an
increased bone turnover rate.
•Pelvic bones are most commonly involved, followed by skull,
femur, lumbosacral spine, clavicles, ribs, and tibia.
•Etiology: Slow-viral infection in genetically susceptible
individuals.
•Pathophysiology: Three phases of Paget disease are: Lytic,
mixed lytic and blastic, and sclerotic.
•Pathology: Excessive osteoblastic activity replaces resorbed
bone in a disorganized way with multiple, irregular cement
lines. Histologically, bone has a characteristic mosaic
pattern. Irregular bone structure makes it weaker that leads
to fractures and deformities.
31
Clinical Manifestations of Paget’s disease:

•Swelling, deformity & pain in long, short and skull bones.

-Skull bone enlargement (increase in hat size)
-Temporal bone involvement (hearing loss)
-Structural deformity (Vertebral and long-bone fractures)
•Excessive warmth skin over a long bone due to high
skeletal blood flow due to an increased metabolic activity
of underlying bone.
•Bruits over tibia/femur or skull (due to hypervascularity).
•High cardiac output failure (due to pagetic bone
vascularity).
•Neuromuscular syndromes (spinal cord compression)

32
Diagnosis of Paget’s disease:
•Serum calcium and phosphate are normal.
• High bone-specific alkaline phosphatase
(BSAP) (because of increased osteoblast
activity) and High urine hydroxyproline (reflects
increased osteoclast activity).
•X-ray: Sclerotic bone appears focally
radiodense.
•Bone scans: More sensitive than radiograph;
Demonstrates the extent of bone turnover in
focal areas.
33
Relationship between blood calcium and
serum PTH in various disorders

34
 Lecture 29
Topic: ADRENAL DISORDERS
Lecturer: Dr. S. Upadhya

1
Patient:
A 27-year-old man comes to the physician because of a 6-
month history of extreme muscle weakness, fatigue and
weight loss. He also has darkening of the skin in the areas of
creases and old scars. He craves for salty foods.
Physical examination: BP 90/56 mm Hg; BP falls further when
standing (orthostatic hypotension); Hyperpigmentation of the
skin
Laboratory:
serum sodium: 110 mmol/L(normal 145),
serum potassium: 7.0 mmol/L (normal 4.5),
Serum glucose: 60 mg/dL (normal 80 mg/dL)
Plasma cortisol: < 1.0 ug/dL (normal 8-26),
Plasma ACTH: Elevated, and
Serology: Adrenal antibodies positive
2
The most likely diagnosis in the patient is:
Adrenal insufficiency due to Addison’s disease

Other differentials include:

Hypopituitarism
Hypothalamic tumor
Adrenal Cancer
Anorexia Nervosa
Congenital adrenal hyperplasia
Hypoglycemia

3
The adrenal gland

Aldosterone:
•Mineralocorticoid

Cortisol:
•Glucocorticoid

Adrenal androgens:
•Dehydroepiandro-
sterone (DHEA)
•Androstenedione

Catecholamines:
•Epinephrine
•Norepinephrine
4
 Causes of Adrenal Insufficiency

Primary: Secondary:
•Autoimmune •Abrupt withdrawal of long-
(Addison disease) term steroid use (most
•Tuberculosis common)
•Adrenal hemorrhage •Pituitary necrosis
•Fungal infection (Sheehan's syndrome)
•HIV/AIDS •Neoplasms and
•Metastatic cancer granulomatous diseases of
•Drugs:ketoconazole, pituitary/hypothalamus
metyrapone •Radiation to pituitary

All 3 zones are involved Zona glomerulosa is spared

5
Hypothalamo-hypophysio-adrenal axis

6
Clinical Manifestations of adrenal insufficiency:
•May be gradual or catastrophically sudden
•May be primary or secondary
•Common features in all: Anorexia, nausea,
vomiting, diarrhea, weight loss, hypotension, fatigue,
weakness, fever, and confusion.
•Hyponatremia, hypotension, hypoglycemia is
common in both primary & secondary.
•Primary adrenal insufficiency:
-Aldosterone is also deficient along with cortisol.
-Hyperkalemia and metabolic acidosis – present only
in primary not in secondary.
-Hyperpigmentation of the skin is present only in
primary (because of excess plasma ACTH).
7
 Secondary adrenal insufficiency:

•No hyperpigmentation.
•No hyperkalemia and met acidosis.
•May be associated with deficits of other pituitary
hormones - manifested as growth retardation or
delayed puberty in children and erectile
dysfunction, infertility, amenorrhea, or
hypothyroidism in adults
•May be associated with evidence of local invasion
of the pituitary tumor – manifested as headache,
visual field defects or cranial nerve palsies.
8
Diagnosis of adrenal insufficiency:
1. The plasma ACTH level – helps to distinguish primary
from secondary adrenal failure
High ACTH with low cortisol - Primary type;
Low ACTH with low cortisol - Secondary type.

2. A rapid cosyntropin (ACTH) stimulation test –

Plasma cortisol estimation before and after administering
0.25 mg of cosyntropin IV or IM.
Normal test: Plasma cortisol should increase 8 µg/dL above
the baseline, and it should exceed 20 µg/dL at 30 to 60
minutes. Level <8 µ/g above baseline is diagnostic.

3. Other tests:
-Adrenal autoantibodies in plasma (Addison disease)
-CT of the adrenals for its size and calcification.
9
Patient:
A 39-year-old woman comes to the physician because of a 7-
month history of extreme weight gain, tiredness, muscle
weakness and headache. She also has oligomennorrhea and
increased hair growth over her body and face.
Physical examination:
BP 182/108 mm Hg; Acne on face and upper trunk; Truncal
obesity with thin limbs; moon facies; Hirsutism; Purple striae
over abdomen and breasts.
Laboratory:
Blood: Elevated fasting blood glucose; hypokalemia; Low
total white cell count with significant lymphocytopenia;
elevated plasma cortisol
Urine: Glycosuria ++
X-ray: Generalized osteoporosis.
10
The most likely diagnosis is:
Cushing’s syndrome

Other differentials include:

•Metabolic (X) syndrome
•Chronic alcoholism
•Diabetes mellitus
•Osteoporosis
•Obesity
•Primary hyperaldosteronism
•Anorexia nervosa

11
Cushing's Syndrome: Etiology
Condition caused by hypersecretion of cortisol.

Causes (in order of occurrence):

•Prolonged exposure to high therapeutic doses of
glucocorticoids (most common)
•Cushing's disease: High cortisol secretion
caused by a pituitary tumor that hypersecretes
ACTH .
•Ectopic ACTH (small cell Ca lung, carcinoids)
•Hypersecreting adrenal tumor

12
Cushing's syndrome

Abdominal striae in Cushing’s

syndrome 13
Clinical Manifestations of Cushing’s
 Truncal (centripetal) obesity
 Menstrual irregularities
 Hypertension
 Facial plethora (round face)
 Hirsutism/vellus type hair growth
 Gonadal dysfunction
 Violaceous striae
 Diabetes mellitus
 Hyperlipidemia
 Proximal muscle weakness
14
 Clinical manifestations: Basis
Centripetal obesity: Caused by the accumulation of fat
in trunk, face, and neck, hence the description of “buffalo
hump” and “moon facies.”
Proximal muscle wasting and weakness -by catabolic
effect of high glucocorticoid levels on skeletal muscles
Hypertension, diabetes mellitus, osteoporosis, and
depression
Skin - easy bruisability, violaceous striae (on breasts
and abdomen)
Hyperpigmentation on sun/pressure exposed areas
(elbows, knuckles, waist) - only when ACTH is high.
Hirsutism, virilization – due to hyperandrogenic effects
15
 Diagnosis of Cushings’ syndrome:
Step 1: Screen for evidence of hypercortisolemia:
A 24-hour urinary free cortisol - elevated
A 24-hour salivary cortisol - elevated
Low-dose dexamethasone suppression test:
Normal response: Plasma ACTH and cortisol level
at 8 a.m. following 1 mg dexamethasone ingestion
in the previous night would be low.
Patient response: ACTH and cortisol remain
elevated at 8 a.m. (i.e., No suppression of pituitary
by low dose). This establishes that the Cushing’s
syndrome is secondary to elevated ACTH.
16
 The Over-night low dose dexamethasone
suppression test : Normal response
Serum Levels

17
 The over-night low dose dexamethasone
suppression test : Response in Cushing’s
syndrome of elevated ACTH
600

500
Serum levels

400
ACTH
300
Cortisol
200

100

0
2400 0800 1600 2400 0800
hrs hrs hrs hrs hrs
18
 Diagnosis of Cushings’ syndrome (cont’d):
Step 2: Differentiate as ACTH-dependent type
or ACTH-independent type:
Measurement of plasma ACTH:
High ACTH levels (exceeding 20 pg/mL) indicates
ACTH-dependent type

Low ACTH level (<10 pg/mL) indicates ACTH-

independent type or primary adrenal neoplasms
Confirm further by – CT/MRI scan of abdomen
which would show an adrenal mass.
19
Hypothalamo-hypophysio-adrenal axis

20
Diagnosis of Cushings’ syndrome (cont’d):
Step 3: Find the source of ACTH in ACTH-
dependent Cushing's syndrome. Source of
ACTH is either a pituitary tumor or an ectopic
ACTH-secreting tumor elsewhere:
High-dose dexamethasone supression test:
Test: 10 mg dexa given in the night.
In patients with pituitary ACTH-secreting tumor,
plasma ACTH and cortisol levels decrease in the
morning (ACTH secretion is suppressed).
In patients with ectopic ACTH-secreting tumor,
plasma ACTH & cortisol levels remain high (ACTH
secretion is NOT suppressed).
21
Hypothalamo-hypophysio-adrenal axis

22
Patient:
A 26-yr-old woman comes because of a 5-month history of
headache, dizziness and breathlessness on exertion. She
also has pins and needles sensation in her lower limbs. Two
months back, she was admitted in the ICU for a week and
was diagnosed to be hypokalemic. She was treated
conservatively with potassium supplementation and
recovered fully.
Physical examination:
BP 160/94 mm Hg; A loud S2 in the right second intercostal.
Lab: Serum aldosterone 35 ng/dl (normal 1-16 ng/dl) and
serum aldosterone-renin ratio is elevated
Urinary electrolytes: Low sodium and High potassium
CT-Abdomen: shows a lesion 2.6 cm x 1.9 cm in size in the
right adrenal gland.
23
The most likely diagnosis is:

Primary hyperaldosteronism due to adrenal

adenoma on the right side

Other differentials include:

•Migraine
•Tension headache
•Sinusitis
•Refractive errors of the eye
•Paget’s disease
•Addison’s disease
•Cushing’s syndrome
24
Renin-Angiotensin-Aldosterone system (RAAS)

Retention of salt and water &

Increase in effective circulating volume 25
 Primary Hyperaldosteronism
•An abnormal excess of mineralocorticoid production
by the adrenal gland
•Seen most often in 30-50 yr of age
•Hypertensive patients with spontaneous
hypokalemia (K+ <3.5 mEq/L) – mostly indicates
primary hyperaldosteronism

•Etiology:
-Most common: Aldosterone-producing adenomas
(APA) or Conn syndrome (80%) - solitary, unilateral,
small (<2 cm);
-Less common: Idiopathic hyperaldosteronism (IHA)-
usually bilateral
26
Clinical manifestations of primary
hyperaldosteronism:
Hypertension - usually is moderate and is due to
sodium retention
Easy fatigability, anorexia, muscle weakness,
and cramps – all due to hypokalemia

Hypokalemia – due to increased renal loss of K+

Metabolic alkalosis – due to hypokalemia and
increased H+ loss
27
 Diagnosis of primary hyperaldosteronism:
• Blood studies:
-High plasma aldosterone concentration (PAC)
-Low plasma renin activity (PRA)
-PAC/PRA ratio is >20 (elevated)
-Hypokalemia (↑renal K+ loss)
-Metabolic alkalosis (due to hypokalemia &
increased urinary H+ loss)
• Urine: 24-h urinary potassium(mEq) >30 (↑)

• To differentiate APA and IHA:

i) CT or MRI localizes adenoma (usually solitary)
ii) Bilateral adrenal vein catheterization and look for
a rise in aldosterone in these blood samples.
28
Congenital Adrenal Hyperplasia (CAH)
•Family of autosomal recessive disorders
resulting from defects in glucocorticoid,
mineralocorticoid, and androgen production
•Deficient cortisol biosynthesis causes a
compensatory rise in pituitary ACTH, resulting
in adrenocortical hyperplasia and
overproduction of the steroids that precede the
enzymatic defect

29
Etiology of CAH:
CAH can result from any one of five enzyme
deficiencies: 21-hydroxylase, 11-hydroxylase, 3β-
hydroxysteroid dehydrogenase, 17-hydroxylase,
or 20,22-desmolase
Classic 21-hydroxylase deficiency, the only
human leukocyte antigen–linked type, accounts
for more than 90% of cases of CAH
The next most common - 11-hydroxylase
deficiency, accounts for almost 5% of cases.
30
 Steroid synthetic pathways
Cholesterol ACTH
desmolase
17 17

3 3 3
17 17

21 21
17

11 11
17: 17α Hydroxylase
3: 3β Hydroxysteroid
Aldosterone dehydrogenase
synthase 21: 21 Hydroxylase
11: 11 Hydroxylase
Zona glomerulosa only
Aldosterone
synthase
31
Clinical Manifestations of CAH:
Two forms: a classic, congenital form with nearly
total enzymatic deficiency
A late-onset form with a partial enzymatic deficiency
and onset after puberty
The manifestations of 21-hydroxylase deficiency
include: virilization in females or ambiguous
genitalia, salt-wasting, hypotension, hyponatremia,
and hyperkalemia
11-Hydroxylase deficiency presents with virilization
in females or ambiguous genitalia, hypertension,
and hypokalemic alkalosis. 32
Diagnosis of CAH:
•The steroid precursors to the defective enzymes
are elevated
•In 21-hydroxylase deficiency - plasma 17-OH
progesterone is elevated
•In 11-hydroxylase deficiency - plasma 11-
deoxycortisol is elevated
•In mild or late forms, measurement of the plasma
steroid precursor after exogenous cosyntropin
(ACTH) stimulation may be necessary for
diagnosis
33
 Patient with hypertension: How blood
chemistry helps in the diagnosis
Condition Plasma Plasma
Renin Aldosterone
Primary Low Elevated
hyperaldostero
nism
Renal artery Elevated Elevated
stenosis
Liddle’s Low Low
syndrome &
Cushing’s
syndrome 34
In what condition do you see:
Elevated plasma renin and low plasma
aldosterone?

Ans: Primary adrenal insufficiency

(eg:Addison’s disease);
However, this patient is hypotensive
(not hypertensive)

35
 DLA in Endocrinology
Topic: BASICS OF THYROID GLAND
&
HYPOTHYROID DISORDERS

1
 This DLA covers:
•Some basics of thyroid gland
•Pathophysiology of hypothyroidism

2
Anatomy of Thyroid gland

3
 Histology of Thyroid

•Follicle is lined by a single layer of cuboidal epithelial cells and

filled with colloid (thyroglobulin)
•Active gland shows small follicles lined by cuboidal or columnar
cells with scanty colloid and "reabsorption lacunae“
•Parafollicular cells (C cells)-scattered between the follicles and
secrete calcitonin 4
 Histological differences in Thyroid diseases

Graves disease Hashimoto’s disease

•Packed follicles, •Scattered follicles,

•Tall columnar follicular cells, •Eosinophilic Hurthle cells,
•Scanty colloid •Numerous lymphocytes and
•Marked scalloping germinal centers
•Marked fibrosis 5
 4- Storage
5- Secretion
of T3/T4

3- Coupling
DIT+MIT or DIT+DIT
Thyroid hormones
Synthesis of

2- Organification

I2 + Tyrosine

1- Iodide trap
Iodide pump
6
 Peripheral Circulation and Metabolism of
Thyroid Hormones:
•99% of both T3 and T4 are bound to:
-Thyroxine-binding globulin (TBG) -70%
-Albumin and transthyretin (thyroxine-binding
prealbumin) -30%
•T4 is more abundant than T3 in circulation
•T3 interacts with intranuclear receptors at a higher
affinity and is more important in producing the
biological effects of thyroid hormone
•T4 is converted to T3 in target cells by the action of
5′-deiodinase
•T4 is also metabolized to reverse-T3 (rT3) by
5-deiodinase 7
Change in the position of the Iodine matters for
the biological activity of thyroid hormone

Tetraiodothyronine (T4/Thyroxine)

Removal of Iodine Removal of Iodine

by 5’-Deiodinase by 5-Deiodinase

Triiodothyronine (T3) ReverseT3

Potentially active Inert
hormone metabolite
8
 Physiologic Effects of Thyroid Hormones
Target Tissue Physiological effect & mechanism
Heart Increase number & affinity of beta
adrenergic receptors
Adipose tissue Stimulate lipolysis
Muscle Increase protein breakdown
Bone Promote normal growth and skeletal
development; accelerate bone turnover.
Nervous sys Promote normal brain development.
Gut Increase rate of carbohydrate absorption.
Lipoprotein Stimulate formation of LDL receptors.
Other Stimulate oxygen consumption by
metabolically active tissues (exceptions:
adult brain, testes, uterus, lymph nodes,
9
spleen, anterior pituitary)
Hypothyroidism

10
Patient presentation:
A 52-yr-old woman comes to the physician because of a 9-
month history of progressive onset of cold intolerance,
puffiness, decreased sweating, weight gain and constipation.
She also feels drowsy during most of the time in the day and
not able to concentrate on her work.
Physical examination:
Temp 94°F; Pulse: 46/min; BP: 100/86 mmHg; Pallor ++;
Her skin is dry; There is loss of scalp, axillary & pubic hair
She has puffiness over face, limbs & non-pitting edema
Her speech is slurred & slow and her voice has hoarseness
Nervous system:Hyporeflexia with delayed relaxation & ataxia
Blood chemistry:
Low serum free T4 and elevated serum TSH
Elevated serum cholesterol
Low hemoglobin concentration 11
Most likely diagnosis in this patient is:
Hypothyroidism

Other differentials include:

▪Depression
▪Hypoalbuminemia/malnutrition
▪Hypopituitarism
▪Cirrhosis
▪Nephrotic syndrome
▪Addison’s disease

12
 Major causes of Hypothyroidism
Causes Pathogenetic mechanisms
Congenital: Aplasia/hypoplasia of
Congenital hypothyroidism thyroid or defects in
hormone biosynthesis due
to gene mutation
Acquired:
Hashimoto's thyroiditis Autoimmune destruction
Severe iodine deficiency Diminished hormone
synthesis, release
Inorganic Iodine, Antithyroid Diminished hormone
drugs synthesis, release
Hypopituitarism Deficient TSH secretion
Hypothalamic disease Deficient TRH secretion
13
 Etiology of congenital Hypothyroidism:

•Occurs in approximately 1 in 4000 births

•Sporadic or hereditary
•Causes of sporadic: Thyroid dysgenesis or aplasia
due to mutations in the transcription factors PAX-8
and TTF-2.
•Causes of hereditary: Inborn error of hormone
synthesis due to mutations in the genes coding for
the proteins involved in thyroid hormone synthesis.
•A transient form of congenital hypothyroidism is
caused by transplacental passage of a maternal
TSH receptor blocking antibody (TSH-R [block] Ab)
14
 Symptoms of Hypothyroidism

❖ Cold intolerance
❖ Slow thinking, lethargy, decreased
vigor
❖ Dry skin; brittle hair; hair loss;
broken nails
❖ Hoarseness of voice
❖ Constipation
❖ Menorrhagia; diminished libido
❖ Weight gain
15
 Signs of Hypothyroidism
• Round puffy face; slow speech; hoarseness
• Hypokinesia; generalized muscle weakness;
delayed relaxation of deep tendon reflexes
• Cold, dry, thick, scaling skin; dry, coarse,
brittle hair; dry, longitudinally ridged nails
• Periorbital edema
• Faint cardiac impulse; indistinct
heart sounds; cardiac enlargement;
bradycardia
• Ascites; pericardial effusion; ankle edema
• Mental clouding, depression; mental
retardation in children 16
Basis for neurological manifestations of
Hypothyroidism:

•Thyroid hormones are required for normal development of

the nervous system
•Mental retardation in children due to abnormal development
of synapses, defective myelination – irreversible.
•Reversible neurologic abnormalities in adults are:
slowed mentation, forgetfulness, decreased hearing, and
ataxia, sluggish tendon reflexes with a slowed ("hung-up")
relaxation phase.
•Some patients have severe mental symptoms, including
reversible dementia or overt psychosis ("myxedema
madness")
•Paresthesias – due to compression neuropathies resulting
from accumulation of myxedema (examples: carpal tunnel
17
syndrome and tarsal tunnel syndrome)
Cardiovascular changes in Hypothyroidism:

•Bradycardia due to low frequency of SA node

•Cardiomyopathy - increased thickening of the
intraventricular septum and ventricular wall,
decreased regional wall motion, and decreased
systolic and diastolic ventricular function.
•The above changes are due to deposition of
mucopolysaccharides in the interstitium between
myocardial fibers, leading to fiber degeneration,
decreased contractility, low cardiac output, cardiac
enlargement, and congestive heart failure.
•Pericardial effusion (with high protein content)
•Low voltage EKG. 18
 Skin changes in Hypothyroidism:
•Dry and cool skin – low metabolic rate; low body temp.
•Myxedema:
Normal skin contains a variety of proteins complexed with
polysaccharides, chondroitin sulfate, and hyaluronic acid.
These complexes are cleared by thyroid hormones. In
hypothyroidism, these complexes accumulate, promoting
sodium and water retention and producing nonpitting
puffiness of the skin (myxedema).
•Hair changes: Brittle and lusterless hairs; Loss of body
hair, particularly over the scalp and lateral eyebrows
•Yellow-orange discoloration of the skin – due to
carotinemia and accumulation of carotene in the skin
(usually mistaken for jaundice)
19
 Reproductive dysfunction in Hypothyroidism:
Hyperprolactinemia occurs in hypothyroidism
because:
a)thyroid hormone normally has an inhibitory
effect on prolactin secretion
b) High TRH stimulates prolactin release

Reproductive dysfunctions are mainly due to

high serum prolactin.
In women : menorrhagia and anovulatory cycles;
secondary amenorrhea due to diminished secretion
of gonadotropins; galactorrhea
In men : infertility, low libido and gynecomastia 20
 Dwarfism in Hypothyroid child:

• Height deficit (dwarfism) because of slowed bone

growth
• There is a lack of permissive action of the
thyroid hormone on the growth hormone (GH)
resulting in:
-Decreased width of the epiphysial
growth plate and articular cartilages
-Decreased volume of epiphyseal and
metaphyseal trabecular bone
• Lack of T3 also reduces secretion of GH from the
anterior pituitary.
21
Diagnosis of Hypothyroidism:
❑Serum TSH level should be measured first
❑If high TSH is associated with a goiter, it is
mostly primary hypothyroidism
❑Confirm diagnosis by measuring fT4 (which
will be low)
❑If no goiter, consider secondary hypothyroidism
and measure fT4 along with TSH (both are low)
❑Low or normal TSH level should be interpreted
carefully and obtain always a fT4
22
 Evaluation of hypothyroidism

Primary Secondary
hypothyroidism hypothyroidism
TSH High Low or Normal*
Total T3 Low Low
Free T4 Low Low

(*Normal range of serum TSH is 0.5-5.0 μU/mL)

23
Other Lab findings in Hypothyroidism:

▪Decreased radioiodine uptake by thyroid gland

▪Diminished basal metabolic rate (BMR)
▪Macrocytic anemia (Fat red cells)
▪Elevated serum cholesterol level
▪Elevated serum creatine kinase (CK) level
▪Increased circulation time; low voltage ECG.

24
 Etiology of Secondary Hypothyroidism

•Pituitary and hypothalamic hypothyroidism are

characterized by a low serum TSH.
•Pituitary hypothyroidism - defect in the
functioning thyrotropes in the pituitary gland.
•Hypothalamic hypothyroidism – Thyrotropin
releasing hormone (TRH) is deficient and hence
pituitary is unable to secrete TSH.

•Two are differentiated by TRH administration:

If hypothyroidism is corrected – it is Hypothalamic
If hypothyroidism is not corrected – it is Pituitary
25
 Hypothyroidism secondary to drugs

❑Antithyroid medications (propylthiouracil and

methimazole) inhibit thyroid peroxidase
❑Ingestion of large amount of iodide produces
hypothyroidism by blocking iodide organification in
patients with Graves disease. This effect is known
as the Wolff-Chaikoff block.
❑Lithium gets concentrated in the thyroid and
inhibits the release of hormone from the gland.

26
 Hashimoto’s thyroiditis (Chronic autoimmune
thyroiditis)
•Most common cause of hypothyroidism in adults
•Most common cause of goiter in females
•Pathogenesis - an autoimmune process directed
against the thyroid gland. Lymphocytic infiltration
and fibrosis are commonly seen on histology
•The clinical manifestations are of hypothyroidism
•Transient hyperthyroidism rarely occurs initially.
•Physical examination - nontender goiter
•Thyroid function tests - transiently consistent with
hyperthyroidism; eventually of the hypothyroid
pattern.
27
Pathogenesis of Hashimoto’s thyroiditis:

A defect in suppressor T lymphocytes allows helper T

lymphocytes to interact with specific antigen/s in the
thyroid follicular cells
↓
Sensitized helper T cells interact with B cells to form
autoantibodies to thyroidal tissue
↓
Cytokine release and inflammation cause glandular
destruction and fibrosis (type IV hypersensitivity)

•These patients have an increased frequency of the HLA-

DR5 histocompatibility antigen
•Associated with autoimmunity of other endocrine glands
(polyglandular failure syndrome)
28
Autoimmune Disorders Associated with
Graves Disease and Hashimoto's Thyroiditis
Endocrine disorders:
-Diabetes mellitus (Type1)
-Hypoadrenalism/Addison's disease Polyglandular
-Orchitis or oophoritis Failure syndrome

-Hypoparathyroidism

Nonendocrine disorders:
-Pernicious anemia
-SLE, Rheumatoid arthritis, Sjogren’s syndrome
-Immune thrombocytopenic purpura
-Myasthenia gravis
-Primary biliary cirrhosis 29
Pathology of gland in Hashimoto's Thyroiditis:
▪Early stage - the gland is diffusely enlarged, firm,
rubbery, and nodular
▪As the disease progresses, the gland becomes
smaller
▪Late stage - the gland is atrophic and fibrotic
▪Microscopy: Destruction of thyroid follicles and
lymphocytic infiltration with lymphoid follicles. The
surviving thyroid follicular epithelial cells are large,
with abundant pink cytoplasm (Hürthle cells). As
the disease progresses, there is an increasing
amount of fibrosis. 30
Lab confirmation of diagnosis of
Hashimoto’s:
High serum concentrations of:
1. Antithyroglobulin antibodies (Tg Ab) – in
early stage; disappears in later stage
2. Antithyroid peroxidase antibodies (TPO Ab) -
remain for many years

31
 DLA in Endocrinology:
Topic: DIABETES MELLITUS &
CHRONIC COMPLICATIONS OF DM
&
HYPOGLYCEMIA

1
 This DLA covers:
•Some basics of endocrine pancreas
•Comparison of type1 and type2 diabetes mellitus
•Chronic complications of diabetes mellitus
•Pathophysiology of hypoglycemia

2
Cell Types in Pancreatic Islets of Langerhans

Cell Types Secretory Products

A cells Glucagon, glucagon-like peptide

(20%-peripheral) (GLP)

B cells Insulin, C-peptide, amylin

(80%-central)

D cells Somatostatin
(between A and B)

F cells Pancreatic polypeptide

3
 Insulin: Synthesis & Metabolism
•Two peptide chains, A and B are connected by two
disulfide bonds
•Secretion of insulin is accompanied by an
equimolar secretion of C-peptide
•Circulatory half-life is 3–5 minutes: catabolized in
both liver and kidneys
•Liver catabolizes approximately 50% of insulin on
its first pass through it
•In contrast, C-peptide is catabolized only by the
kidney and, therefore, have half-lives three to four
times longer than that of insulin 4
 Factors affecting B-cell Insulin release

Serum Glucose Gut

hormones
+
+
+
-Sympathetic Glucagon
nerves
Insulin
+

+
-
Parasympathetic
Nerves
Somastatin

5
Factors affecting A-cell Glucagon release

Serum Glucose Fatty acids

-
-
+
Amino acids Ketone bodies
Glucagon
-

-
Cortisol
Somastatin

6
 Comparison of physiological effects of
pancreatic hormones on fuel homeostasis
Effect Insulin Glucagon
•Liver glycogenesis ↑ ↓
•Liver lipid synthesis ↑ ↓
•Liver glycogenolysis ↓ ↑
•Liver gluconeogenesis ↓ ↑
•Liver ketogenesis ↓ ↑
•Kidney gluconeogenesis ↓ ---
•Muscle glucose uptake
and glycogenesis ↑ ---
•Muscle protein catabolism ↓ ---
•Adipose tissue Fatty acid
esterification ↑ ---
•Adipose tissue lipolysis ↓ --- 7
Insulin-Glucagon (I:G) Molar Ratios in Blood in
Various Conditions

Condition I:G ratio Reason

Large CHO meal 70 Glu storage++++

Small CHO meal 7 Glucose storage+

Low CHO diet 1.8 Hepatic glucose

production++

Starvation 0.4 Hepatic glucose

production++++
8
 Some Features Distinguishing Type 1 from
Type 2 Diabetes Mellitus
Type 1 Type 2
Age at onset Usually < 30 Usually > 40
Ketosis Common Rare
Body weight Nonobese Obese (80%)
Prevalence Less (0.4%) More (8%)
Genetics: HLA
(Human leukocyte Yes No
antigen) association (HLA-DR, HLA-DQ)
Monozygotic twin 30–50% 60–80%
studies concordance rate concordance rate
Circulating Yes No
autoantibodies
9
 Some Features Distinguishing Type 1 from
Type 2 Diabetes Mellitus (continued)
Type 1 Type 2
Associated with Occasionally No
other autoimmune
phenomena
Treatment with Always necessary Usually not
insulin necessary
Insulin secretion Severe deficiency Variable: moderate
deficiency to
hyperinsulinemia
Insulin resistance Occasional - with Usual
poor control or
excessive insulin
antibodies
10
Correlation between HbA1C and plasma glucose
• HbA1C (Glycated Hb) levels should be tested at least every
6 months & should be maintained below 7%.
•Its amount is proportional to mean blood glucose level.

HbA1C Mean blood glucose

(%) level (mg/dL)
6 135 HbA1C provides an
7 170 average measurement
8 205 of blood glucose over
9 240
the past 2 to 3
months.
10 275
11 310
12 345
11
 Chronic Complications of Diabetes
Macrovascular Microvascular

Brain:
Cerebrovascular disease Eye:
• Transient ischemic •Retinopathy
attack •Cataracts
• Cerebrovascular •Glaucoma
accident
• Cognitive impairment

Heart: Kidney:
Coronary artery disease Nephropathy
• Microalbuminuria
• Coronary syndrome • Gross
• Myocardial infarction albuminuria
• Congestive heart • Kidney failure
failure

Extremities:
Peripheral vascular Nerves:
disease Neuropathy
• Ulceration • Peripheral
• Gangrene • Autonomic
• Amputation
12
Pathogenesis of macrovascular complications

•Accelerated atherosclerosis leads to:

-Myocardial infarction
-Stroke
-Claudication and gangrene of the lower extremities
•Reasons for the accelerated atherosclerosis in diabetes:
(i) Hyperlipidemia
(ii) Diabetes acts synergistically with other known risk factors
of atherosclerosis
•Pathophysiological mechanism of hypertension in DM:
In type 1 diabetes - hypertension is due to nephropathy,
when renal insufficiency impairs the ability to excrete water
and solutes
In type 2 diabetes - hypertension is due to the metabolic
syndrome (syndrome X)
13
 Clinical features of macrovascular
complication: Peripheral Vascular Disease
❖ History suggestive of claudication
❖ Large or medium-sized blood vessels in the
lower limbs
❖ PE reveals absent or weak peripheral pulses

Abnormal Normal
foot foot

A duplex scan to show the block

14
 Pathogenesis of microvascular
complications in DM:

Major ways to microvascular damage:

A. Activation of Polyol pathway
B. Formation of Advanced glycated end-
products (AGEs)
C. Activation of Protein Kinases

This can occur in any cell; Most evident in

Endothelium, Vascular sm muscles, Lens, Neurons,
Retina and Renal glomeruli. 15
A.The polyol pathway:
Hyperglycemia
↓
Increased Aldose reductase activity

Sorbitol (polyol) Depletion of NADPH &

accumulation Reduced glutathione levels
↓ ↓
Osmotic cell damage Oxidative cell damage

Examples:
• Lens in eye - cataract
• Nerve axon - decreased nerve conduction (neuropathy)
• Endothelium – microangiopathy. 16
B. Advanced glycated end-products (AGEs):
Hyperglycemia
↓
Non-enzymatic link of glucose with amino groups in
tissue proteins to form an unstable intermediate
↓
Formation of stable early glycosylation products
↓
Early glycosylation products undergo a further series
of chemical reactions and form AGEs
↓
AGEs bind to the basement membrane of small and
large vessels and cause vascular damage
(angiopathy) 17
 C. Activation of protein kinases:

Intracellular hyperglycemia in the vascular cells

(endothelium & smooth muscles)

↑Diacyl glycerol Glucosamine or

(DAG) formation galactosamine formation

Activation of protein kinases (Eg.,PKC)

Microvascular damage by: ↑Vascular permeability,

Angiogenesis, Cell apoptosis, ↓NO synthesis,
Cytokine activation, Basement membrane thickening
and extracellular matrix expansion. 18
 Microvascular complication: Retinopathy
Nonproliferative and proliferative retinal change.

Nonproliferative retinopathy:

Microaneurysms of the retinal capillaries appear as tiny red

dots - earliest clinically detectable sign of diabetic retinopathy
↓
Increased vascular permeability cause leakage of fat &
proteins which appears as shiny yellow spots with distinct
borders (hard exudates) forming a ring around the area of
leakage
↓
Macular edema & visual impairment
19
 Non-proliferative
Normal retina
diabetic retinopathy

Macula Optic nerve Microaneurysms (small areas of

balloon-like swelling in the retina's
Retinal blood vessels tiny blood vessels), yellow hard
exudates and macular edema

20
Proliferative retinopathy:
Progressive ischemia in the surrounding areas
↓
Occlusion of capillaries and terminal retinal arterioles
↓
(i) Areas of retinal infarcts that appear as hazy yellow
areas with indistinct borders (cotton wool spots or
soft exudates) that contain axonoplasmic debris
(ii) Areas of retinal hemorrhages
↓
Neovascularization (proliferative retinopathy)
↓
Traction between new vascular networks and vitreous
↓
Vitreous hemorrhage/or retinal detachment & blindness.
21
 Proliferative diabetic retinopathy

•New blood vessels are abnormal and fragile and produce

vitreous and retinal hemorrhages
•Note the fine network of new blood vessels on the surface
of the optic nerve and a vitreous hemorrhage 22
Microvascular complication: Nephropathy
Glomerular Hyperfiltration
↓
Microalbuminuria (20 to 300 mg per 24 hours)
↓
Mesangial expansion, glomerular basement membrane
thickening and glomerular sclerosis.
↓
Gross proteinuria and decreasing GFR
↓
End-stage renal disease

➢The presence of hypertension speeds this process.

➢Hypertension worsens as renal function deteriorates.
➢Control of hypertension is critical in preventing the
progression of diabetic nephropathy.
23
Microvascular complication: Neuropathy
Three major types:

1. Symmetric polyneuropathy – usually sensory type.

2. Asymmetric neuropathy - involving specific nerve/s or
nerve roots.
3. Autonomic neuropathy

Pathology: demyelination of peripheral nerves with

microvascular lesions.

Sensory disturbances: numbness, tingling, burning, pain

and paresthesias; loss of proprioceptive sensations

24
Autonomic neuropathy in diabetes mellitus

Common autonomic dysfunctions:

▪Fixed, resting tachycardia
▪Orthostatic (postural) hypotension
▪Sexual dysfunction in men
▪Neurogenic bladder: loss of bladder sensation,
difficulty emptying the bladder, overflow
incontinence and residual urine
▪Alternating bouts of diarrhea and constipation
(enteropathy)
▪Anhidrosis (mainly in the lower extremities, face)
▪Decreased glucagon and epinephrine responses
to hypoglycemia/fasting
25
Pathophysiology of HYPOGLYCEMIA

26
 General causes of hypoglycemia

Fasting
•Insulin/Insulinoma
•Oral sulfonylurea agents
•Ethanol- Inhibits gluconeogenesis, ↓glycogenesis
•Adrenal insufficiency
•Prolonged starvation
•Liver failure

Postprandial
•Alimentary

27
Patient:
A 29-year-old woman comes to her family physician because
of a 4-week history of intermittent fatigue, diaphoresis, and
tremors. Symptoms occur when she delays her meal and
subsides as soon as she ate food. She had two episodes of
syncope which made her to seek medical advice.

Physical examination:
Not remarkable when she visited the physician

Laboratory:
Serum glucose (random) - 42 mg/dL (normal 70-90);
Serum insulin - 630 pmol/L (normal 40-240)
Serum Proinsulin and C-Peptide are elevated
MR imaging: shows 1.8 cm hypointense nodule in the
midbody of the pancreas
28
The most likely diagnosis is:
Insulinoma

Other differentials include:

•Insulin excess-by exogenous sources
•Over dose of oral hypoglycemics
•Panhypopituitarism
•Addisonian crisis
•Liver disease
•Glycogen storage diseases

29
 Symptoms of hypoglycemia
Symptoms often develop when blood glucose
drops below 45 mg/dL

Adrenergic: Neuroglycopenic:
•Sweating •Headache
•Tremors •Irritability
•Palpitations •Confusion
•Pallor •Seizure
•Hunger •Coma

30
Diagnosis of Hypoglycemia:

Whipple's triad:

❑Adrenergic or neuroglycopenic symptoms

❑Low blood glucose level, and
❑Relief of the symptoms when blood glucose
is restored to normal (oral/intravenous
glucose)

31
Diagnosis in patients with hypoglycemia:

•Serial blood glucose, insulin, and C-peptide

monitoring during a supervised fast

•Insulinoma: High levels of insulin as well as C-

peptide during a fast

•Factitious hypoglycemia with insulin use:

Presence of insulin antibodies, Low C-peptide
level, and high levels of circulating insulin

•Factitious hypoglycemia with sulfonylurea use:

High urinary sulfonylurea 32
 DLA in Endocrinology
Topic: DISORDERS OF
HYPOTHALAMUS & PITUITARY

1
 This DLA covers:
•Some basics of hypothalamus and pituitary
•Disorders of anterior pituitary
•Disorders of posterior pituitary

2
 Anatomy of Hypothalamus-Pituitary

Paraventricular Nu Hypothalamic
Supraoptic Nu neurons
Optic chiasm
Primary cap plexus
Sup Hypo art
Infundibulum
Portal vessels

Posterior Pit

Anterior Pit
Efferent vein
Efferent vein
Inf Hypo art

3
Blood supply of pituitary:

•From paired superior and inferior hypophyseal

arteries (branches of internal carotid arteries)
•Superior hypophyseal arteries - near median
eminance
•Blood supply to the posterior pituitary is from the
inferior hypophyseal arteries directly from the
systemic blood flow
•Venous drainage is into the dural sinuses
surrounding the pituitary gland

4
Anterior pituitary

5
Histology of anterior pituitary

Immunohistochemistry: 5 types of
functional cells.
Somatotropes: 50%, acidophilic
Lactotropes/Mammotropes: 25%,
acidophilic
Corticotropes: 15-20%, basophilic
Thyrotropes: 5-10%, basophilic
Gonadotropes: 5-10%, basophilic

Chromophobes: Nonsecretory,
undifferentiated cells.

6
 Biochemical types of anterior
Pituitary Hormones

• Pro-Opiomelanocortin & ACTH

• Glycoprotein Hormones – TSH, LH &
FSH
• Growth Hormone & Prolactin

7
Synthesis of pituitary hormones:

Activation of HPA axis by stressors (eg, metabolic,

physical, mental stress)
↓
Corticotrophin releasing hormone (CRH)
↓
Synthesis of pro-opiomelanocortin (POMC) in
corticotropes
↓
POMC is further processed to ACTH
↓
ACTH triggers synthesis and secretion of
corticosteroids and adrenal androgens
8
The Hypothalamo-Hypophysio-Target organ axis

9
Pituitary Hormone Hypothalamic Factor

Growth Hormone (GH) Growth hormone releasing-hormone

(Somatotropin) (GHRH)
Growth hormone release inhibiting
hormone (somatostatin)

Prolactin (PRL) Prolactin releasing Hormone (TRH)

Prolactin release inhibiting factor
(Dopamine, D2 receptors)

Thyrotropin (TSH) Thyrotropin releasing hormone

(TRH)

Adrenocorticotropin (ACTH) Corticotropin releasing hormone

& pro-opiomelanocortin (POMC) (CRH)

Follicle-stimulating hormone Gonadotropin releasing hormone

(FSH) & Luteinizing (GnRH)
Hormone (LH) 10
Patient presentation:

A 32-year-old woman comes to the physician because of

extreme weakness and secondary amenorrhea. Nine
months ago, she delivered a baby boy weighing 3200 g and
her postpartum period was complicated by a significant
blood loss from uterine atony. She also had lack of milk
secretion after childbirth.
Physical examination: Patient is sick-looking, thin, with
sunken eyes. Pulse 88/min and BP 90/70mmHg. The skin is
pale with absence of hair from skin, axillae, and groin. She is
dehydrated. Examination of the lungs, heart and abdomen
are normal. Examination of the nervous system shows
generalized muscle wasting and delayed relaxation of the
ankle reflexes
11
The laboratory tests shows a normocytic normochromic
anemia; Hormone levels are:
ACTH <5.00 pg/mL (normal 9–52 ng/l.),
TSH 0.282 μU/mL (normal 0.400–4.000);
Free triiodothyronine 1.02 pg/mL (normal 1.80–4.80);
FSH and LH – below normal; Prolactin (PRL) –below normal
Chest X-ray: normal
MRI of head: normal-sized sella that is empty with no
pituitary parenchyma inside. There is no abnormality in
hypothalamic, suprasellar, or para-sellar regions

Most likely diagnosis is:

Sheehan’s syndrome (Postpartum pit necrosis)

Other differentials include:

Hypopituitarism, Lymphocytic hypophysitis, Empty sella
12
 HYPOPITUITARISM
Insufficiency of any or all of the six major anterior
pituitary hormones
Etiology:
•Pituitary tumors - most common
•Infectious diseases - tuberculosis, fungal
•Infiltrative diseases - sarcoidosis,
hemochromatosis
•Vascular abnormalities - Sheehan's syndrome or
postpartum pituitary necrosis
13
 Clinical features of Hypopituitarism

❑ The most common manifestation of

pituitary hormonal deficiency depends on
which hormones are deficient and to what
degree

❑ In children, growth retardation and

delayed puberty are common presenting
signs

14
 Clinical features of Hypopituitarism
Hormone Clinical features
deficiency
ACTH Adrenal insufficiency: hypotension,
tachycardia, fatigue, vomiting
TSH Hypothyroidism: cold intolerance,
constipation, bradycardia
Thyroid function studies: low TSH, low
T3,T4
FSH/LH Women: infertility, amenorrhea
Men: decreased libido/infertility
GH Decreased lean body mass, and strength

Prolactin Inability to lactate after delivery 15

Diagnosis of Hypopituitarism:
❖Clinical diagnosis: gonadal
failure, hypothyroidism, and
adrenal insufficiency
❖Lab diagnosis: Blood levels of
pituitary and target hormones &
certain specific gold standard
tests

16
 Evaluation for Hypopituitarism
Hormone Laboratory evaluation Abnormal results
ACTH Insulin-induced Low Cortisol level & No rise
hypoglycemia/CRH stimulation after stimulation
test, or ACTH stimulation test
FSH, LH Simultaneous assessment of Low 17 β-estradiol with low
basal FSH/LH/17 β-estradiol in FSH and LH
females Low total testosterone with
Simultaneous assessment of low FSH and LH
basal FSH/LH/testosterone in
males
TSH Simultaneous assessment of Low free T4 with low TSH
TSH/free T4
GH Insulin-induced hypoglycemia Low resting GH level & No
or GHRH stimulation test or rise after stimulation
Arginine stimulation test
17
Patient presentation:
A 26-year-old man comes to the physician because
of a 3-month history of headache and loss of vision
on his lateral sides. He also has loss of libido.
Physical examination: Normal vital signs. Neurologic
examination is notable for bitemporal hemianopia.
Patient Normal

18
Most likely diagnosis is:

PITUITARY MACROADENOMA

Other differentials:
•Rathke's Cleft cyst
•Craniopharyngioma
•Aneurysm in parasellar region
•Parasellar meningiomas
•Chiasmatic and hypothalamic gliomas
•Empty sella
19
 PITUITARY ADENOMA

•Benign tumor of epithelial cell origin

•Account for 10%-15% of intracranial tumors

•Classification of pituitary adenomas:

Microadenomas (<10 mm in diameter)-secretory
tumors; produce hormone overproduction
syndromes.
Macroadenomas (>10 mm in diameter)-usually
nonsecretory tumors & produce mass lesions

20
 Incidence of pituitary adenoma

Prolactin-secreting 20%–30%

Nonsecretory or null cell 20%

Plurihormonal 20%

GH-secreting 10%–15%

ACTH-secreting 10%–15%

LH/FSH/alpha subunit- 10%–15%

secreting
TSH-secreting 1%
21
Pathophysiology of pit adenoma
(macro/micro):

•Single clone origin

•Genetic mutations: Mutations in
genes: MEN-1, CNC, and GNAS1
•Chromosomal instability and
aneuploidy

22
 Clinical Manifestations of pituitary
macroadenomas:
▪Headache: Retro-orbital or bitemporal due to
stretching of the duramater
▪Visual field abnormalities: Classic bitemporal
hemianopia by compression of the optic chiasm
▪Ophthalmoplegia due to cranial nerves III, IV & VI
dysfunction - laterally invasion into the cavernous
sinuses
▪Facial pain due to cranial nerve V dysfunction
▪Signs of pituitary insufficiency – Panhypopituitarism
or Hypopituitarism for one or more hormones 23
 Pituitary &
Cavernous sinus

24
 Variation in endocrine function of
pituitary in macroadenoma:

•Pituitary hormones (some or all) are lost

including prolactin
•Prolactin deficiency is rare and pituitary
macroadenomas may produce mild
hyperprolactinemia
Reason: Loss of dopamine inhibition by
infundibular stalk interruption by tumor

25
Hormone overproduction syndromes:
(usually microadenomas)

▪Gigantism and acromegaly: excess GH

▪Cushing's disease: excess ACTH
▪Galactorrhea: excess Prolactin
▪Tumors secreting TSH, LH, and FSH are rare

26
Patient presentation:
A 45-year-old man comes to his physician because of a 3-
month history of pain in the back, difficulty in biting his food
and increase in the size of his shoes. He gained 30lb weight
during this period.
Physical examination: Blood pressure is 162/94 mmHg.
Patient appears stooped. His head is large for his size. He
has prominent lower jaw, malar and frontal regions. The
hands appear large with stubby fingers.
Radiograph of: i) Head: Marked thickening of the frontal and
occipital areas, thickening of the skull tables and marked
prognathism. ii) Vertebrae - hypertrophic changes.
iii) Hands and feet - enlargement of the
bones, with fanning out of the terminal phalanges.

Lab: Blood samples from the inferior petrosal sinuses

show elevated levels of growth hormone.
27
The most likely diagnosis in the patient:
Acromegaly

28
 Physiological Effects of GH
Bone:
•Increases osteoblast activity
•Increases bone mass by endochondral bone
formation
•Increases linear growth by:
-Stimulating production of local IGF-I
-Differentiating prechondrocytes
-Increasing epiphyseal plate growth

29
 Physiological Effects of GH
Muscle:
•Increases amino acid transport
•Increases nitrogen retention
•Increases metabolism & energy expenditure

Adipose tissue:
•Increases lipolysis
•Stimulates hormone sensitive lipase
•Inhibits lipoprotein lipase
•Decreases glucose entry
•Decreases lipogenesis

Liver: Secretion of IGF-1

30
 Physiological Effects of GH

GH - Direct GH actions-Through IGF-1

actions (Indirect actions)
•Insulin
•Enhanced Protein Synthesis
resistance
•Stimulation of Skeletal
•Lipolysis
growth
•Stimulate IGF-1 •Cell Proliferation

31
 Regulation of GH secretion

Inhibitory Stimulatory
factors factors

Stress,
Amino acids,
Hypoglycemia.
32
 Body composition in adults: Association to GH
Changes in life-style and genetic predispositions

Obesity & Elevated plasma FFA

Insulin resistance and hyperinsulinemia

Suppression of IGF-Binding protein from liver

& increase in free plasma IGF-I level

Inhibition of pituitary GH release and promotion

of increasing body fat mass
Also, endogenous GH is cleared more rapidly in obese person.
33
 ACROMEGALY

•Gradual in older patients - often missed

•Aggressive in younger patients – clinical features
evolve more rapidly
•Patients may have local effects due the sellar
mass itself
•Associated with colonic polyps - 50% of patients
•5% patients develop colon cancer - Risk factors
for neoplasia include age above 50 years &
duration of acromegaly exceeding 10 years

34
 Clinical features of Acromegaly
•Coarsening facial features/soft tissue swelling
•Frontal bossing
•Dental malocclusion with increased spacing
•Soft-tissue swelling in hands/feet
•Increased ring/glove size
•Increased shoe size/width with thick heel pad
•Carpal tunnel syndrome
•Deep, resonant voice/laryngeal thickening
•Obstructive sleep apnea
•Osteoarthritis, especially knees and hips
•Visceromegaly
•Headache
•Hypertension
•Hyperglycemia/Diabetes mellitus
•Gynecomastia & Galactorrhea (rare) 35
 Slow progression of the disease

Before disease

36
Classic facial appearance Acromegalic feet
Diagnosis of Acromegaly:
❖Elevated serum IGF-1 level
❖Diagnostic biochemical criteria:
Elevated IGF-1 and serum GH levels 2 hours
after a 75-g oral glucose load (in a normal
person hyperglycemia would inhibit release
of GH)

37
 HYPERPROLACTINEMIA
•Accounts for at least 20% of infertility in
women
•Approximately 8% of sexual dysfunction and
infertility in men
•Most common cause:
Prolactin-secreting pituitary tumor

38
 Causes of Hyperprolactinemia

Category Examples/disorders
Physiologic Pregnancy, nipple stimulation/suckling,
stress
Pituitary adenoma Prolactin-secreting pituitary tumor &
Plurihormonal-secreting pituitary tumor
Hypothalamic- Pituitary stalk interruption,
pituitary disorders in Tumor like craniopharyngioma, and
the absence of a Sarcoidosis
prolactinoma

Drug-induced Estrogens/oral contraceptives;

Psychotropic drugs; Methyldopa;
Cimetidine; Cocaine
39
Clinical Manifestations:
•In young female: Amenorrhea, oligomenorrhea,
delayed menarche, and galactorrhea.

•In male: Most common symptoms are

decreased libido and erectile dysfunction;
Rarely, gynecomastia and galactorrhea.

•Infertility in both: High prolactin directly

suppresses hypothalamic GnRH secretion
(Hypogonadism).

40
Diagnosis of Hyperprolactinemia:
❖A serum PRL level higher than 200
ng/mL is diagnostic of a prolactinoma
❖Mild PRL elevations (20 to 200
ng/mL): In addtion to prolactinoma,
think of other secondary causes (e.g.,
infundibular stalk compression or
drugs)
❖Evidence of hypogonadism:
↓ GnRH; ↓ LH & FSH; ↓ Sex steroids
41
Laboratory evaluation of pituitary microadenomas
Laboratory test Value Implication

Prolactin >200 ng/mL Prolactinoma

IGF-1 Elevated Acromegaly
GH measurement 2 Nonsuppressible Acromegaly
hours after 75-g oral serum GH
glucose
24-hr urinary cortisol/ Elevated Cushing’s
Salivary cortisol disease
Overnight High-dose Decreased serum Cushing’s
dexamethasone cortisol in the next disease
suppression test morning
TSH/T4 Serum TSH elevated TSH-
with elevated free T4 secreting
42
tumor
Clicker Questions

43
Which of the following hypothalamic
hormones stimulates prolactin secretion
from the anterior pituitary?
A. Somatostatin 0%
B. Somatotropin releasing 0%
hormone
C. Dopamine 0%
D. Thyrotropin releasing 0%
hormone
E. Gonadotropin releasing 0%
hormone 44
A 36-year-old man comes to the physician because
of tiredness, weight gain, bradycardia, hoarseness
of voice, constipation and cold intolerance. He also
has gynecomastia, galactorrhea and decreased
libido. Lab shows a markedly decreased serum
thyroid stimulating hormone (TSH). Which of the
following additional lab findings is also most likely?

A. Increased T4 20%
B. Increased T3 20%
C. Increased TRH 20%
D. Increased GnRH 20%
E. Increased CRH 20%
45
Posterior Pituitary Disorders

46
Patient presentation:
A 7-year-old girl is admitted with complaints of
excessive thirst and voiding very large quantities of
urine. The child has to urinate every hour or two,
day and night and at the same time drinks large
volume of any fluid she gets. She has poor appetite
and has constipation. She had never suffered from
convulsions or any injury to the head. The patient is
very irritable and cranky.

Lab:
Blood electrolytes: high sodium level; normal
glucose.
Urinalysis: Low specific gravity, low osmolarity and
low electrolytes; absent sugar. 47
The most likely diagnosis in patient:

Diabetes Insipidus (DI)

Other differentials to consider:

•Diabetes mellitus (type I)
•Primary or psychogenic polydipsia
•Empty sella syndrome (rarely)
•Lymphocytic hypophysitis
•Suprasellar and intrasellar cysts
•Craniopharyngioma
•Large pituitary adenoma
•Head injury (basilar skull fracture)
48
ANATOMY OF
POSTERIOR
PITUITARY

49
 ADH release and functions

V2 receptor via cAMP-dependent mechanism

50
V1 receptor via IP3 signal transduction pathway
Aquaporin-2 pathway for water reabsorption

51
 DIABETES INSIPIDUS (DI)
Etiology:
The two major types:
• Central/Hypothalamic/Neurogenic DI and
• Nephrogenic DI
DI-like syndromes may result from mineralocorticoid
excess, pregnancy, primary polydipsia.
Primary polydipsia:
-An uncommon condition usually seen in psychiatric
patients produces DI like picture
-Results from overdrinking in the absence of genuine thirst,
with resultant polyuria and plasma dilution with appropriate
ADH suppression
52
-It requires intake of liters of water each day.
Causes of central diabetes insipidus
Idiopathic (30%)

Tumors (20%):
-Craniopharyngioma (most common)
-Pituitary macroadenoma
-Meningioma

Head injury (16%):

-Vascular
-Sheehan's syndrome
-Aneurysms

Granulomatous diseases:
-Sarcoidosis
-Histiocytosis 53
 Causes of Nephrogenic DI
▪Congenital - Mutations in the gene encoding V2
▪Aquired (reversible):
-Hypokalemia
-Hypercalcemia
-Drug-induced: Lithium, Demeclocycline

•Key abnormality in nephrogenic DI is refractoriness to

vasopressin at the level of the kidneys
•True nephrogenic diabetes insipidus must be distinguished
from an osmotic diuresis and medullary washout by
diuretics – How?
•Urine osmolarity: Urine is hypertonic or isotonic rather than
hypotonic in these conditions; urine is always hypotonic
in DI 54
 Clinical hallmarks of DI
Polyuria:
Mild 3 to 4 L/day
Moderate 4 to 6 L/day
Severe >6 L/day

Polydipsia:

Neurological symptoms: If hypernatremia

55
Basis for polyuria in DI:
• Inability to conserve water in the distal nephron
• Up to 13% of the volume of the glomerular filtrate
is lost in urine.
Basis for polydipsia in DI:
• Dehydration with consequent hypernatremia
Basis for neurological symptoms in DI:
• Hypernatremia → neuronal shrinkage →
manifestations such as a decreased response to
verbal & physical stimuli, myoclonus, seizures,
focal deficits and coma. 56
 Lab diagnosis of DI
❖Urine:
Specific gravity ≤1.005
Osmolarity Always LOW (for high
plasma osmolarity)
❖Plasma:
Hypernatremia Serum Na+ >145 mEq/L
Osmolarity >290 mOsm/L
ADH level - Central DI Low
ADH level - Nephrogenic DI High

❖Response to vasopressin
injection following water
deprivation:
Central DI Urine osmolarity increases
Nephrogenic DI No 57
Diagnosis of DI: Water deprivation test
First part of the test: Patient is deprived of all
water intake until dehydration. Urine output,
blood pressure, and urine osmolality are
measured every 2 hours. Normally, after water
deprivation, a decrease in urine output and an
increase in urine osmolality is expected to occur.
In patients with DI, urine output remains high
and urine is diluted.
Second part of the test: Subcutaneous
injection of ADH and measurement of urine and
plasma osmolarity. Patients with nephrogenic DI
lack the ability to concentrate urine even after
58
administration of ADH.
Interpretation of the standard water deprivation test

Urine osmolality
After water After water
Serum deprivation, but deprivation and
Condition ADH before ADH ADH
level administration administration
Normal Normal Increases Increases further

Central DI Low Low (dilute urine) Markedly increases

Nephrog- High Low (dilute urine) No change

enic DI (remains low)
Primary Normal Markedly increases Increases further
polydipsia or Low compared to before
59
Evaluation of a patient
with polyuria
[OsmPl=Plasma Osmolality;
OsmU=Urine Osmolality]

60
Patient :
A 71-year-old man with a 40-pack years of smoking comes
because of dry cough, confusion, lethargy. He has had two
episodes of seizures in the past 2 weeks. The patient is
afebrile with normal vital signs. He appears euvolemic
without evidence of congestion or dehydration.
Laboratory studies:
Serum sodium - 124 mmol/L (136–145 mmol/L)
Serum Osmolarity - 260 mOsm/L (285–295 mOsm/L)
Serum glucose – 5.2 mmol/L (4.2–6.4 mmol/L)
Urine sodium and urine osmolarity – elevated
CT of the head and an EEG are normal
CT of lungs show a solitary nodule in the right lung.

61
Most likely diagnosis in patient :

Syndrome of Inappropriate Antidiuretic

Hormone (SIADH)

Other differentials:
•Adrenal insufficiency
•Cerebral salt wasting syndrome
•Hypothyroidism
•Hypersecretion of ANP

62
Syndrome of Inappropriate Antidiuretic
Hormone (SIADH)

❖SIADH is characterized by continual ADH

release in the face of subnormal plasma
osmolarity or in the absence of other stimuli

❖It accounts for more than 95% of

hyponatremia in the hospitalized population

63
 Conditions associated with SIADH
Malignancy: • Small cell Ca of lung –
(Ectopic ADH) most common
• Ca of pancreas
• Thymoma, Lymphoma
• Mesothelioma

Pulmonary: • Tuberculosis
(Impaired • Chronic obstructive
baroreceptor input pulmonary disease
from thorax)
64
 Conditions associated with SIADH
Intracranial • Meningitis/encephalitis/
conditions: brain abscess
(Interruption of • Head injury
vasopressin • Cerebral hemorrhage,
inhibiting neural subdural hematoma
pathways)

Drug induced: • Carbamazepine,

Chlorpropamide, Narcotics
& Phenothiazine

65
 Pathophysiology of SIADH
Excess plasma ADH & increased water reabsorption
↓
Dilutional hyponatremia
↓
Although a large fraction of this water is intracellular, the
extracellular fraction causes volume expansion
↓
Volume receptor activation and ANP secretion
↓
Natriuresis and some degree of accompanying
potassium excretion (kaliuresis).

Ingestion of water is an essential prerequisite to the

development of the syndrome; Hyponatremia does not
occur if water intake is severely restricted. 66
Clinical Features of SIADH:
•Features due to hyponatremia: Lethargy,
confusion, muscle cramps, seizures, and coma
•Diminished urine output

•CNS symptoms depent on the severity of

hyponatremia, and by the rapidity with which
hyponatremia develops

•Hyponatremia→Osmotic fluid shifts and

neuronal swelling→Brain edema and elevated
intracranial pressures→
Herniation/seizures/Central pontine myelinolysis
67
Pathophysiologic mechanism of euvolemia &
normal blood pressure in SIADH:

•Volume overload edema, hypervolemia and

elevated blood pressure are NOT seen in patients
with SIADH

•Elevated circulating atrial natriuretic peptide

(ANP) is protective and prevents development of
severe water retention and hyponatremia

Clinical euvolemia in the presence of

hyponatremia is the hallmark of SIADH
68
Diagnosis of SIADH:
•Serum Na+ <136 mmol/L (Hyponatremia)
•Normal renal, adrenal, and thyroid function, and
normal triglycerides and glucose
•Urine osmolality is higher than that of plasma:
The plasma osmolality(normal: 275 to 290), is
decreased and the urine osmolality is elevated,
>100 mosmol/kg but more commonly >300.
•Urinary Na+ excretion is >30 mEq/L (due to a
low urine volume & an elevated plasma ANP)
69
Differential diagnosis in SIADH (where
hyponatremia is common):

1. Cerebral salt wasting (CSW) due to an increased

release of natriuretic peptides (eg, BNP, ANP)
A major difference is in the total extracellular
volume: Increased in SIADH but reduced in CSW.

2. Endocrine disorders such as adrenal

insufficiency and hypothyroidism: In these
conditions, sodium deficiency and subsequent
volume depletion has triggered vasopressin
secretion
70
Examples of ADH secretion in certain physiological
and pathological conditions

↑: Increase or High; ↓: Decrease or Low 71

Clicker Questions

72
A 26-year-old woman presents with constant thirst
and polyuria. Her blood glucose is 89 mg/dL . Her
urine osmolality during water deprivation test are:
150 (2 hour) 151 (4 hour) 149 (6 hr)
Her urine osmolality after an injection of
desmopressin is: 410.
What is the most likely diagnosis?

A. Nephrogenic diabetes insipidus 0%

B. Neurogenic diabetes insipidus 0%
C. Primary polydipsia 0%
D. Diabetes mellitus 0%
E. SIADH 0%
 DLA in Endocrinology
Topic: PHEOCHROMOCYTOMA
&
MEN SYNDROMES

1
 This DLA covers:
•Pathophysiology of pheochromocytoma
and MEN syndromes

2
Patient presentation:
A 37-year-old man comes to the physician because of a 3-
month history of episodes of headaches and palpitations.
The frequency and severity of these are increasing over the
last one month. During these episodes, his face turns pale,
he sweats profusely and he develop intense anxiety and
panic attacks.
Physical examination:
BP 220/110 mm Hg during an episode
Laboratory:
Elevated levels of plasma noradrenaline, urinary
noradrenaline, and urinary normetanephrine
CT of abdomen: soft tissue mass in the left adrenal gland
Biopsy of the mass: Polygonal to spindle-shaped cells which
are compartmentalized into small nests (“Zellballen”). The
cytoplasm of cells show granular appearance.
3
Most likely diagnosis is:

Pheochromocytoma

Other differentials include:

•Adr. cortical adenoma
•Metastatic tumor
•Carcinoid syndrome
•Hyperthyroidism
•MEN
•Neurosis
•Panic disorder
4
 Pheochromocytoma
•Catecholamine-secreting, chromaffin-cell
neoplasm
•Benign solitary nodules found within the adrenal
medulla (90%);
•10% are extra-adrenal in location (Intra-
abdominal in close proximity to the celiac or
mesenteric sympathetic ganglia)
•10% are associated with other familial
neoplasms, such as type II (Sipple's syndrome)
or type III multiple endocrine neoplasia syndrome
5
Pheochromocytomas are associated
with certain familial syndromes:

• Multiple endocrine neoplasia (MEN)

syndromes, 2 & 3
• Neurofibromatosis – type1
• vonHippel-Lindau disease
• Sturge-Weber syndrome

6
Clinical Manifestations of Pheochromocytoma:
The hallmark of a pheochromocytoma is
hypertension
The clinical triad:
Episodic headaches, palpitations, and excessive
diaphoresis occurring with hypertension
>80% patients are hypertensive on examination;
50% patients: Exhibit normotensive, symptom-free
periods, interspersed with episodic and transient
symptoms.
7
 Diagnosis of pheochromocytoma:
•Screening test 1: Elevated 24-hour urine
measurement of metabolites of norepinephrine &
epinephrine namely, Normetanephrine,
Metanephrine and Vanillylmandelic acid.
•Screening test 2: Elevated plasma metanephrine &
normetanephrine levels – has higher sensitivity and
specificity than the level of urinary metabolites.
•Screening test 3: CT or MRI to localize lesion.
Radionuclide test with a radioactive amine. Uptake
and concentration by adrenergic chromaffin cells,
are useful in locating extra-adrenal or metastatic
diseases. 8
 MEN syndrome associated disorders
MEN type-1 ❑Parathyroid tumor
(Wermer's ❑Pituitary adenomas
syndrome): ❑Pancreatic islet cell tumor:
-Gastrinoma
“3Ps” -VIPoma
-Insulinoma
-Glucagonoma
MEN type-2A ❖Medullary carcinoma of thyroid
(Sipple's ❖Parathyroid tumor
syndrome): ❖Pheochromocytoma
“TPP”
MEN type-2B ▪Medullary carcinoma of thyroid
(or MEN type-3): ▪Neuromas of oral and intestinal
mucosa
9
“TNP” ▪Pheochromocytoma