Endocrine Pathology

Dr. Osama Elkhider

MBBS, MD-Path, MRCP

St George’s University
School of Medicine
Endocrine Pancreas

Pituitary and Hypothalamus

Thyroid gland

Adrenal gland

Metabolism of Ca, PO4 and Mg

Multiple endocrine neoplasia
 Hormones of the islets of Langerhans
• α-Cells:
– 20% of the islets cells
– Secrete Glucagon
• β-Cells:
– 60-75% of the islets cells
– Secrete insulin and c-peptide
• δ-Cells:
– 5% of the islets cells
– Secrete somatostatin
 Disorders of the endocrine pancreas
The most commonly encountered are disorders
related to the β-Cells:
• Hypofunction:
– Diabetes mellitus
• Hyperfunction:
– Hormone secreting tumor (insulinoma)
 Diabetes Mellitus

Definitions
• The term diabetes mellitus describes a metabolic
disorder of multiple aetiologies characterized by
chronic hyperglycaemia with disturbances of
carbohydrate, fat and protein metabolism
resulting from defects in insulin secretion, insulin
action, or both
WHO 1999
 The Burden of Diabetes
• A worldwide epidemic:
– 150m in the year 2000
– 300m in the year 2025
• According to American Diabetes Association:
• In 2015, 30.3 million Americans, or 9.4% of the
population, had diabetes.
• 1.5 million Americans are diagnosed with diabetes every
year.
• Cost of diagnosed diabetes in the USA:
• $245 billion in 2012 (from $174 billion in 2007)
 Synthesis of insulin

• A 43 year old man was found in deep coma by

his wife who alerted the Ambulance services.
He died shortly after arrival in hospital. Blood
obtained just before his death showed severe
hypoglycaemia. Laboratory results suggested
that he has been injected with insulin.
Q: Discuss the laboratory results
Structure and Synthesis of insulin

Endoplasmic  Golgi 
reticulum apparatus

Insulin

Preproinsulin Proinsulin C‐peptide

 Synthesis of insulin
In case of overdose of insulin injection patient will have:
– Glucose level: low
– Insulin level: High
– C-peptide: normal/low

In case of a tumor secreting insulin patient will have:

– Glucose level: Low
– Insulin level: High
– C-peptide: High
 Action of insulin
• Insulin is a major anabolic hormone
 Action of insulin
• Effect of insulin in Potassium:
– It promotes K+ movement into cells
– Possibly through increasing the action of the Na+- K+ 
ATPase
– This effect is used in treating life threatening
hyperkalemia by co-administering insulin and glucose.
 Classification of Diabetes Mellitus
• Type 1 DM
• Type 2 DM
• DM secondary to other causes:
– Pancreatic diseases
– Hormonal antagonists to insulin (e.g. cortisol, growth
hormone, catecholamines)
– Drug & chemical induced
– Infections: CMV, Mumps, Coxackie B virus
– Genetic syndromes: Down and turner syndrome
– Gestational DM (is typically resolved after delivery)
 Features of Type1 and Type 2 DM
Feature Type 1 Type 2
Burden 10% of all cases 90% of all cases
Age of onset < 40 years > 40 years
Rate of onset Rapid Slow
Weight Lean/Normal Obese
Ketosis Prone Rare
Insulin Low/ Absent Increased/Normal/Reduced
HLA Link Present Absent
Auto-antibodies Common Absent
 Etiopathogenesis of Type 1 DM
• Type 1 diabetes is caused by immune-mediated
destruction of the pancreas
• Genetic and environmental factors are important in the
pathogenesis of DM:
• Genetic susceptibility:
– Concordance between monozygotic twins is 40%
– Association with HLA-DR3 & DR4/DQA1& DQB1
• Environmental factors:
– Viruses: Coxsackie B, Rubella, CMV and Mumps
– Drugs and toxins
 Etiopathogenesis of Type 1 DM
• Autoimmunity:
– Characterized by immune effector cells reacting against
endogenous  cells antigens due to failure of self-
tolerance in T-cells.
– Islet cell antibodies (ICA) and other antibodies may
play a role (detected in 70-80% of patients)
– There is a long pre-diabetic phase during which the
destruction of  cells continues
– Manifestation of the disease occur after more than 90%
of the  cells have been destroyed.
 Etiopathogenesis of Type 1 DM
Etiological Hypothesis
• Viral/Chemical attacks on  cells can lead to exposure of
new  cell antigens or can cause molecular mimicry
between viral and  cell structures. These antigens trigger
the activation of T-cells in the peripancreatic lymph nodes.
• CD4+ and CD8+ cells are involved in  cells damage
• The HLA system is relevant because it is involved in
antigen presentation.
• Cytokines from TH1 can also activate B-cells to produce
auto-antibodies against  cell antigens
 Etiopathogenesis of Type 1 DM
HLA-linked genes
Viral infection:
Immune response
• Damage to Beta cell
against normal
• Molecular mimicry
and/or altered Beta
Chemical/Drugs:
cells
• Damage to Beta cell

Beta cell destruction

Type 1 DM
 Etiopathogenesis of Type 2 DM
• Type 2 DM is complex disease that involves genetic and
environmental factors and a proinflammatory state.
• These factors are involved in causing:
1. Insulin resistance
2.  cell failure
• No evidence of autoimmune basis
 Etiopathogenesis of Type 2 DM
• Evidence of genetic involvement in type 2 DM:
– >90 % concordance in identical twins (stronger than
Type1)
– First degree relatives have 5-10 fold increase in risk
– No HLA associations
– Typically a polygenic disorder:
• There is simultaneous presence of several genes
associated with the presence of environmental
factors (e.g. obesity)
 Etiopathogenesis of Type 2 DM
• Environmental factors involved in type 2 DM:
1. Obesity
• 80% of patients with Type 2 DM are obese
• The risk increases with the increase in BMI
• Distribution of fat also plays a role (patient with
central obesity has higher risk of DM than those with
peripheral obesity)
2. Lack of exercise
• The risk is independent to obesity
 Etiopathogenesis of Type 2 DM
• How does obesity lead to type 2 DM?
– Obesity contributes to insulin resistance and beta cell
dysfunction by several ways:
1. Production of free fatty acid
• Antagonizing insulin action
• Lipotoxicity
2. Change in adipokines levels
• Decrease leptin and adiponectin levels in obesity
3. Inflammation
• Role of IL-1
• Amyloidosis within the islets
Etiopathogenesis of Type 2 DM
 Pancreatic pathology in DM
• Type 1 DM:
– selective destruction of insulin-secreting beta cells.
– insulitis, a chronic inflammatory infiltrate of the islets
affecting primarily insulin containing islets.
• Type 2 DM:
– Moderate reduction islet tissue
– Variable degrees of deposition of amyloid
Pancreatic pathology in DM

Type 1 DM Type 2 DM
 Presentation of diabetes is variable
1. Asymptomatic: A 49 year old man was found to have a
fasting glucose of 256 mg/dl (14 mmol/L) in the well-man
clinic
2. Classical symptoms: A 58 year old man complained of
increasing polyuria and thirst. BMI 30 (Normal 20 – 25).
A random plasma glucose: 257 mg/dl (14.3 mmol/L)
3. Severe acute presentation or coma
Normal blood glucose values are:
– Fasting: 70 – 100 mg/dl (4.0 – 5.6 mmol/L)
– Random: 79 -140 mg/dl (4.4 – 7.8 mmol/L)
 Pathophysiology and clinical Features

• Clinical features directly related to metabolic

disturbances caused by insulin deficiency or
insensitivity to insulin action
• They have variable presentation
• Long-term complications:
– Including : nephropathy, neuropathy, eye disease, heart
disease, stroke and problems of feet.
Reverse of the processes
 Glucose uptake
 Lipogenesis
 Lipolysis

 Glucose uptake  Gluconeogenesis
 Glycogen synthesis  Glycogen synthesis
 Protein synthesis  Lipogenesis
 Biochemical signs in DM

• Hyperglycaemia • Hyperlactatemia
• Glycosuria • Hyperlipidemia
• Ketoacidosis • Hypovolemia
• Ketonuria • Hyperosmolarity
 Clinical symptoms in DM
(prominent in uncontrolled Type1)

Classic Triad of DM are:

1. Polyuria/Nocturia
– Due to osmotic diuresis
2. Polydipsia (Thirst)
– Dehydration
3. Polyphagia
– Due to persistent catabolic state
 Clinical symptoms in DM
(prominent in uncontrolled Type1)

Other symptoms of DM:

• Weight loss (specially in Type1): Catabolic state
• Tiredness: Muscular weakness due to proteolysis and  glucose
• Blurred vision: Dehydration of lens, aqueous and vitreous humour
And in severe conditions (DKA)
• Vomiting: Ketones stimulate the area postrema
• Hyperventilation (kussmaul breathing): Respiratory
compensation to metabolic acidosis
 Diagnosis of DM
• According to ADA and WHO criteria, DM can be
diagnosed by either of the following:
1. Random glucose level > 200 mg/dL (11.1 mmol/L) plus
classical signs and symptoms of DM
2. Fasting plasma glucose level > 126 mg/dL (7 mmol/L)
3. Two-hour plasma glucose > 200 mg/dL (11.1 mmol/L)
during an oral glucose tolerance test (OGTT)
4. Glycated haemoglobin (HBA1c) level > 6.5%
Except for the first criteria, these tests need to be repeated
and confirmed in a separate day!
 Diagnosis of DM
• What is the OGTT (oral glucose tolerance test)?
– Patient fasts overnight
– Measure the basal glucose level at 0 time
– Give 75 gram of a mixture of glucose dissolved in
water
– Measure the blood glucose level at 120 minutes (2 hrs)
 Oral Glucose Tolerance Test (OGTT)
14 14
P l a sm a g l u c o se (m m o l / l )

P l a sm a g l u c o se (m m o l / l )
12 12

10 10
8 8
6 6
4 4
2 2
0 0
0 30 60 90 120 0 30 60 90 120
Time (minutes) Time (minutes)

Normal Diabetic
 Oral Glucose Tolerance Test (OGTT)

Interpretation of the OGTT

OGTT Normal Diabetic Pre-diabetes

At 0 time < 100 mg/dL ≥126 mg/dL ≥100 but <126
At 2 hours < 140 mg/dL ≥200 mg/dL ≥140 but <200
 Prediabetic states
• Impaired fasting glycaemia (IFG):
– A fasting plasma glucose above normal and below the
diabetic range
– 100 -125 mg/dl (5.6 - 6.9 mmol/L)
• Impaired glucose tolerance (IGT):
– 140 -199 mg/dl (7.8 -11.0 mmol/L) value in 2hrs OGTT
• Patients with HBA1c levels 5.7 – 6.4% are
considered prediabetic
 Prediabetic states
Clinical significance of prediabetes:
• 10-25% of Western populations are IGT or IFG
• The annual conversion of prediabetic state to clinical
diabetes is 4-9%
• Individuals with prediabetes harbour a significant risk of
cardiovascular complications
• It is possible to prevent this conversion by encouraging
weight loss through diet, exercise and/or medications
 Management of DM
• Aims of treatment:
– To alleviate symptoms
– Prevent acute and long-term complications
– Management of cardiovascular risk factors
• Methods:
– Education
– Dietary control
– Hypoglycemic agents:
• Insulin
• Oral hypoglycemic
 Monitoring of management
• Clinical Monitoring
• Urine glucose:
– A poor guide to severity of hyperglycemia
– Can not detect hypoglycemia
• Blood glucose measurement:
– Self-monitoring is very important (meters, charts, reagents)
• Glycosylated hemoglobin:
– Hemoglobin reacts with glucose non-enzymatically to produce
Glycosylated hemoglobins HBA1 (a,b and c)
– Levels give an integrated measure of glucose concentrations over
the previous 2-3 months (RBCs live for 100 days)
 Elution profile of Glycosylated Hemoglobin

HbAo = Non reacted hemoglobin

HbA1a + HbA1b + HbA1c = Glycosylated hemoglobin
HbA1c (the main fraction of glycosylated hemoglobin) is usually
measured in practice
 Acute Complications of DM
1. Hypoglycemia
2. Diabetic ketoacidosis
3. Hyperosmolar non-ketotic coma
4. Lactic acidosis
 Hypoglycemia
• Is a complication of diabetes treatment
• Defined as blood glucose <70 mg/dL
• Risk factors:
– Skipping or delaying a meal
– Increasing physical activity
– Medication overdose
• Symptoms:
– Mild: tremor, sweating, palpitations, tiredness, dizziness
– Severe: convulsions, loss of consciousness
 Diabetic Ketoacidosis (DKA)
• Severe metabolic complication of Type 1 DM (rare in
Type 2 DM)
• Precipitating factors:
– Missed insulin dose (most common)
– Infection or acute illness
– Trauma
– Emotional disturbance
• Plasma glucose levels are 250 – 600 gm/dL
• The hyperglycemia causes the characteristic osmotic
diuresis and dehydration in DKA
 Pathophysiology of DKA
• A vicious cycle of progressive metabolic disruption
• Acute insulin deficiency and the rise in stress hormones
levels lead to:
– Progressive hyperglycaemia  osmotic diuresis and
dehydration  cellular starvation and hypovolemia 
development of ketosis.
– Ketosis can cause vomiting
– Osmotic diuresis and vomiting  electrolyte disturbance
– Ketosis and lactic acidosis  Metabolic acidosis
Pathophysiology of DKA
Insulin deficiency

Hyperglycaemia Ketosis Acidosis

Electrolyte
imbalance

Osmotic Vomiting Cellular starvation

diuresis

Dehydration

Hypovolemia

Stress hormones Vasoconstriction

 Clinical presentation of DKA
• Excessive urination
• Dehydration and excessive thirst
• Fatigue and loss of appetite
• Vomiting
• Hyperventilation (kussmaul breathing)
• Fruity-scented breath
• Mental confusion
 Investigations
• Urine:
– Positive for sugar and ketones
• Blood:
– Glucose: usually >250 mg/dL
– Electrolytes: K and  Na
• Arterial blood gas
– Low pH (<7.3) (high anion gap metabolic acidosis)
– Low Bicarbonate
• Investigations for the precipitating factor
 Management of DKA
• Saline infusion to replace fluid loss
• Restore metabolic control
– Insulin IV (why not subcutaneous?)
– Potassium supplements
– Bicarbonate “sometimes”
 Hyperosmolar Hyperglycemic State (HSS)

• Previously called hyperosmolar nonketotic coma

• Occurs in elderly patients with type 2 DM
• Relative insulin deficiency - sufficient to prevent ketosis
but cannot suppress hyperglycaemia
• Usually very high glucose levels causing dehydration.
• The glucose level is usually 600 – 1200 mg/dL
Managment
– fluid replacement and insulin
 Long-term Complications of DM
• Caused by vascular complications and are divided into:
1. Microangiopathic Complications:
– Affects capillaries, arterioles and small blood vessels
– Characterized by thickening of basement membranes,
which causes leakiness
– Manifestation: Nephropathy, Retinopathy, Neuropathy
2. Macroangiopathic Complications:
– Atherosclerosis in large-to-medium-size arteries
– Manifestation: IHD, Stroke, peripheral vascular disease
 Diabetic nephropathy
• Is an important cause of end-stage renal failure (ESRF)
• First functional change: hyperfiltration
• Microalbuminuria (urinary albumin 30 - 300 mg/day), is
the first biochemical sign
• Proteinuria (urinary albumin >300mg/day) is associated
with established nephropathy
 Diabetic nephropathy
• Three lesions are encountered:
(1) Glomerular lesions:
First morphological sign: basement membrane thickening
and mesangial expansion. Subsequently nodular deposits
(Kimmelstiel-Wilson disease) and diffuse
glomerulosclerosis
(2) Renal vascular lesions (arteriolosclerosis)
(3) Papillary necrosis
• Renal impairment is delayed by excellent glucose control
and treating hypertension
Diabetic nephropathy
 Diabetic Ocular Complications
• Diabetic retinopathy, cataract, glaucoma
• Diabetic retinopathy:
– Commonest cause of blindness in adults between 30
and 65 years of age
– Proliferative Vs Non proliferative
 Diabetic Neuropathy
• Depends on the duration of the disease
• Diabetic neuropathy can present as:
– Paresthesia of the limbs, pain (sensory neuropathy)
– Muscle atrophy and weakness (Motor neuropathy)
– Impotence, orthostatic hypotension, changes in bowel
habits (Autonomic neuropathy)
• Diabetic foot, Caused by:
– Ischemia - Macroangiopathy
– Neuropathy – Sensory
– Infection – Specially anaerobic microorganisms
 Mechanisms of Long-term complications
1. Glycosylation:
– Involves basement membrane of capillaries and structural
proteins. After glycosylation of proteins, further metabolism
of glycosylated proteins produce advanced glycosylation end
products (AGE). AGE has been implicated in some diabetic
complications like retinopathy
2. Accumulation of sugar alcohols (polyols), in tissues which do
not require insulin for glucose uptake:
– Glucose  (sorbitol)  fructose
– Sorbitol accumulation cause osmotic effects and depletion of
myoinositol, amino acids and potassium. This mechanism is
probably involved in mediating neuropathy and cataract
 Mechanisms of Long-term complications
3. Free radicals:
– Production of free radicals is increased in DM. Free
radicals are capable of tissue destruction and they likely
contribute to complications in diabetes.

4. Hypertension, dyslipidemia, obesity and insulin

resistance:
– These are associated with DM and they are known risk
factors for atherosclerosis. It is therefore likely that they
contribute to diabetic complications.
 Prevention of type 2 diabetes

Normal  IGT/IFG  Type 2 diabetes  Complications  Disability

& Death

Pre-clinical state Clinical disease Complications

Primary prevention 2ry prevention Tertiary prevention
The pituitary and hypothalamus
 Clinical Anatomy
• Located in the Sella Turcica in the sphenoid bone.
 Formation of the pituitary gland

Posterior pituitary is
Anterior pituitary is formed
formed by a downgrowth
as an evagination from the
from the floor of the third
roof of the pharynx
ventricle of the brain

Adenohypophysis Neurohypophysis
Blood supply of the pituitary gland
Transport of the hypothalamic releasing
g hormones
and inhibiting
• The production of most pituitary hormones is controlled by
positively and negatively acting factors from the hypothalamus
• The nerve endings all come together in the median eminence
region of the hypothalamus where the hormones are released
into these hypophyseal portal veins
• The hypophyseal portal veins arise from the primary capillary
network of the superior hypophyseal arteries in the median
eminence
• In the anterior pituitary, the portal veins form a secondary
capillary network into which the hormones of the anterior
pituitary are secreted
Anterior Pituitary Disorders
Anterior pituitary hormones, their cell types
and hypothalamic regulatory factors
Hormone Cell types Hypothalamaic regulatory hormones

Growth hormone Acidophil Growth hormone releasing hormone GR‐HR

(GH) Growth Hormone release‐inhibiting factor 
(somatostatin) 
Prolactin Acidophil Prolactin release inhibiting hormone‐ PIF
(PRL) (dopamine)
Thyroid stimulating hormone  Basophil Thyrotropin releasing hormone‐ TRH
(TSH)
Adrenocorticotropic hormone  Basophil Corticotopin releasing hormone‐ CRH
(ACTH)

Luteinizing hormone  Basophil Gonadotrophin‐releasing hormone‐ Gn‐RH

(LH)
Follicle stimulating hormone  Basophil Gonadotrophin‐releasing hormone‐ Gn‐RH
(FSH)
Anterior pituitary hormones, their cell types
and hypothalamic regulatory factors
Control of secretion of hypothalamic-releasing
hormones and the pituitary hormones
Higher center

Anterior pituitary 
Negative 
hormones
feedback
 Pituitary Disorders
• Most pituitary disorders involve the anterior pituitary
• Pituitary disorders are divided into:
1. Hypopituitarism: underactive pituitary gland, which can
result from pituitary diseases (infarction, radiation, non
functioning adenoma) or from hypothalamic diseases
2. Hyperpituitarism: excess production of pituitary
hormones by a tumour.
3. Local effects, specially if the cause is a tumor: Visual
disturbances (bitemporal hemianopia), headaches, ICP,
destruction of secretary cells by the enlarging tumor and
cranial nerves palsy
 Causes of hypopituitarism
• Tumors: adenoma, craniopharyngioma, cerebral and
secondary tumors
• Vascular: Sheehan’s syndrome, severe hypotension
• Infection: meningitis, TB, syphilis, HIV/AIDS
• Hypothalamic disorders: tumors, functional disorders,
isolated deficiency of GHRH and GnRH secretion
• Iatrogenic: irradiation, hypophysectomy
• Miscellaneous: sarcoidosis, hemochromatosis
 Clinical features of Hypopituitarism
• Hormone deficiency follows the following pattern:
– The 1st to be lost is GH (Not observed in adults)
– Then LH and FSH
– Then TSH
– The last is ACTH
• Hypofunction of the anterior pituitary occurs when
approximately 75% of the parenchyma is lost or absent
• Vasopressin secretion is usually maintained because the
posterior pituitary is typically preserved
 Clinical features of Hypopituitarism
• GH deficiency:
– In children: Growth retardation
– In adults: Muscle weakness, lethargy and impaired life
style scores
• Gonadotrophins (LH and FSH) deficiency:
– In females: menstrual disturbance and delayed puberty
– In males: loss of libido, loss of facial & body hair,
impotence
 Clinical features of Hypopituitarism
• Prolactin deficiency:
– Results in failure of postpartum lactation
• ACTH deficiency:
– Loss of adrenal secretions, leads to hypoadrenalism:
• TSH deficiency:
– Loss of thyroid secretions, leads to hypothyroidism

• Panhypopituitarism may cause coma

 Investigations of suspected
yp p
hypopituitarism
1. Basal levels of pituitary and target hormones:
These are influenced by:
(i) The residual capacity in the pituitary gland
(ii) The pulsatility of pituitary hormone secretion
(iii) Stress
(iv) Time of day e.g. Cortisol hormone
(v) Time of menstrual cycle e.g. FSH, estrogen, progesterone
 Investigations of suspected
yp p
hypopituitarism
2. Stimulation and suppression tests:
• The combined pituitary function tests: is a stimulation test
used to confirm pituitary deficiency:
• The test is consisting of the simultaneous administration of
insulin, TRH and Gn-RH
• The insulin is given to induce hypoglycemia i.e. creating a
stress state, which allows assessment of the capacity of the
anterior pituitary to secrete stress hormones: prolactin,
GH, ACTH
 Investigations of suspected
yp p
hypopituitarism
3. Localization of the tumor:
• MRI or CT scans

4. Immunostaining:
• Immunohistochemistry
 Hyperpituitarism
• The most common cause of hyperpituitarism is an
adenoma arising in the anterior lobe
• Peak incidence is from 35 to 60 years of age
• Some pituitary adenomas can secrete one hormone, others
can secrete two hormones (GH and prolactin being the
most common combination)
• Microadenoma <1 cm or Macroadenomas >1 cm
 Hyperpituitarism
The most frequent types of hyperfunctioning pituitary
adenomas are:
1. Lactotrophs Adenomas
• PRL secreting adenoma causes
Hyperprolactinemia
2. Somatotroph Adenomas
• GH-releasing adenoma causes
Acromegaly
3. Corticotroph Adenomas
• ACTH secreting adenoma causes
Cushing Syndrome
 Hyperprolactinemia
Causes:
• Physiological i.e. stress
• Drugs: e.g. antipsychotics, oral contraceptive pill,
antidopamine drugs
• Tumors:
– Prolactinoma
– Stalk section which removes inhibitory signal on
prolactin secretion
• Renal failure
• Ectopic source
 Clinical features and investigation
• Gonadal dysfunction:
– Amenorrhea or anovulation, infertility in women
– Decreased libido, erectile impotence in men
• Galactorrhea
Investigations:
• Blood levels of prolactin
• MRI or CT scanning of the head
Treatment:
• Initially medications but surgery may be needed
 Acromegaly
• Occurs due to GH excess after fusion of the epiphysis
(gigantism occurs due to GH excess occurring before
epiphyseal fusion)
• Almost always due to adenoma (v. Rarely ectopic GHRH )
Clinical features:
–Increased growth of skeletal and soft tissue, hypertension,
arthritis, headaches and local effects of the tumor
– Menstrual disturbances, loss of libido and loss of potency
in men, diabetes mellitus because GH antagonizes the
action of insulin.
Acromegaly
 Acromegaly
Diagnosis:
• Measure GH and IGF-1(Insulin-like growth factor-1):
– GH acts on liver to produce IGF-1
– IGF-1 level is more stable than GH and therefore more
important in diagnosis of acromegaly.
• OGTT with GH measurement:
– In normal individuals, GH levels fall following oral
glucose, and at least one of the samples during the test
should have undetectable GH levels. Failure of suppression
or a paradoxical rise in GH suggests acromegaly.
 Acromegaly
Management of acromegaly:
• Surgical
• Medical
• Radiotherapy
Posterior Pituitary Disorders
 Disorders of the posterior pituitary
• The posterior pituitary secretes two hormones:
1. Antidiuretic hormone (ADH)
– ADH is clinically important.
– Deficiency causes diabetes insipidus (DI)
– Excessive secretion of ADH causes the syndrome of
inappropriate ADH secretion (SIADH)
2. Oxytocin
 Physiology of ADH
• ADH is secreted in response to decreased blood
volume and raised plasma osmolality.
• It causes water retention by increasing
permeability in the distal convoluted tubules and
collecting ducts in the kidney.
• ADH will tend therefore to restore blood volume
and normalize plasma osmolality.
• The action of ADH will cause a decrease in urine
volume and an increase in urinary osmolality
 Diabetes Insipidus (DI)
• Caused by deficiency or resistance to the action of the antidiuretic
hormone (ADH). It is characterized by polyuria and thirst
• There are two types:
1. Central DI; caused by absolute deficiency of ADH:
– Genetic
– Hypothalamic or high pituitary stalk lesion
– Head trauma, tumors, inflammatory disorders
– Idiopathic
2. Nephrogenic DI; caused by resistance to ADH action
– Genetic
– Metabolic: hypokalemia, hypercalcemia
– Drugs: Lithium
 Investigations for DI
Water Deprivation Test
• Fluid restriction for 8 hours
• Ask the patient to pass urine and discard it!
• Weigh patient at start of test; continue weighing at 1-hour
intervals
• Measure serum and urine osmolality, urine volume and
weight hourly for up to 8 hours.
• Stop test after 8 hours or if patient’s weight is <5% of his
initial weight
• If results suggest DI, give Desmopressin:
– Measure plasma osmolality, urine volume and
osmolality
 Investigations for DI
Water Deprivation Test: Interpretation
• In normal patients the serum osmolality should not
exceed 295 mOsmol/kg and the urine osmolality
should exceed 600 mOsmol/kg at some time
during the test
• Some patients show intermediate values and partial
defects.
 Investigations for DI

Water Deprivation Test: Interpretation

After fluid After administration
Condition
deprivation of vasopressin

Central DI < 300 mOsmol/kg > 600 mOsmol/kg

Nephrogenic DI < 300 mOsmol/kg < 300 mOsmol/kg

 SIADH
• SIADH results from inappropriate secretion of
ADH i.e. ADH secretion which continues despite
lack of physiological stimuli
• This will cause water retention and hyponatremia.
• Presentation:
o Hyponatremia can be asymptomatic or
associated with nonspecific symptoms
o Severe hyponatremia, specially if there is rapid
fall in serum sodium, can cause cerebral edema,
neurological symptoms, coma and death
 SIADH
Causes of SIADH:
• Post-operative
• Intra-cranial disease: encephalitis, meningitis, head
injury
• Neoplasms: e.g. small cell carcinoma of the lung
• Pulmonary disease: pneumonia, tuberculosis
• Drugs/Medications
Thyroid gland
 The Thyroid Gland
• Originates from the floor of the pharynx
• The functional unit of the gland is the follicle
• Produces: Thyroxine (T4) and Tri-iodothyronine (T3)
• 85% of T3 is produced peripherally, by conversion
from T4
• 70% of thyroid hormones are bound to TBG, the
reminder are bound to thyroxine-binding prealbumin
(transthyretin) and albumin
Structure of T4 and T3
The structure of thyroid follicle

Synthesize calcitonin
 Functions of the thyroid hormones
• Metabolic functions:
– Increase the metabolic rate (heat production)
– Accelerate cholesterol clearance from plasma
– Have hyperglycemic effect ( GI glucose absorption)
• Growth and maturation:
– Essential for brain maturation and fetal growth and
development
• Effect on GIT:
– Increase the GI motility
 Functions of the thyroid hormones
• Cardiovascular effects:
– Increase the sensitivity of the cardiovascular and
nervous system to catecholamines
– Have inotropic and chronotropic effects
• Skeletal effects:
– Increase bone turn over
– Can cause hypercalcemia
• Effects on reproductive system:
– Essential for normal menstrual cycles and normal
ovulation
The control of thyroid hormone
 Hyperthyroidism (thyrotoxicosis)
• Thyrotoxicosis is a hypermetabolic state caused by
elevated circulating levels of free T3 and T4
• Can be classified as:
1. Primary hyperthyroidism
– Arising from an intrinsic thyroid abnormality
2. Secondary hyperthyroidism
– Arising from processes outside of the thyroid, such as a
TSH-secreting pituitary tumor
 Causes of Hyperthyroidism
• Primary hyperthyroidism:
– Diffuse hyperplasia (Grave’s disease)
– Toxic adenoma
– Toxic multinodular goiter
• Secondary hyperthyroidism:
– TSH-secreting pituitary adenoma (rare)
• Other causes:
– Thyroiditis
– Struma ovarii
– Factitious thyrotoxicosis
 Clinical features of Hyperthyroidism
General symptoms: GIT: Diarrhea
• Weight loss CVS: Palpitations, AF and
• Sweating high-output HF
• Heat intolerance Others:
• Fatigue • Goiter
• Anxiety • Menstrual disturbances
• Proximal myopathy and infertility
• Lid-lag • Bone (osteoporosis)
Hyperthyroidism
 Graves Disease
• An autoimmune disease with HLA associations
• Causes goiter with diffuse thyroid enlargement
• Due to thyroid stimulating immunoglobulins which bind
and activate the TSH receptors
Clinical features:
• In addition to the symptoms of hyperthyroidism, the
disease is characterized by:
– Ophthalmopathy (Exophthalmos)
– Pretibial myxedema
– Finger clubbing (thyroid acropachy )
 Thyroiditis
• inflammation of the thyroid gland
• It includes a group of disorders causing thyroidal
inflammation but presenting in different ways
• Can cause temporary thyrotoxicosis followed by
temporary hypothyroidism
1. Subacute (De Quervain’s) thyroiditis:
– Pain, tenderness, fever
2. Postpartum thyroiditis
– Due to natural immunosuppression during pregnancy
3. Hashimoto thyroiditis:
– Most common cause of Hypothyroidism
 Hypothyroidism
• Hypothyroidism is a condition caused by a structural or
functional derangement that interferes with the production
of thyroid hormone
• is divided into primary and secondary forms, depending
on whether the hypothyroidism arises from an intrinsic
abnormality in the thyroid itself, or occurs as a result of
pituitary and hypothalamic disease
• Primary hypothyroidism may be accompanied by an
enlargement in the size of the thyroid gland (goiter)
 Causes of Hypothyroidism
Primary Hypothyroidism:
• Autoimmune Hypothyroidism (Hashimoto disease)
• Iatrogenic hypothyroidism
• Congenital hypothyroidism
• Iodine deficiency
Secondary hypothyroidism
• Pituitary or hypothalamic disease
Clinical features of Hypothyroidism
• Lethargy, tiredness • Xanthelasma
• Cold intolerance • Psychosis
• dryness of skin and hair • Carpal tunnel syndrome
• Hoarseness • Angina, bradycardia
• Weight gain • Menstrual disturbances
• slow relaxation of • Hyperprolactinemia
tendon reflexes • galactorrhea, infertility
• Constipation • Generalized myxedema
 Hashimoto thyroiditis
• Most common cause of hypothyroidism in the US
• Characterized by HLA-associated antibody-mediated
immune destruction of thyroid cells
• Including antimicrosomal, antithyroid peroxidase, and
antithyroglobulin antibodies
• Patient present with symptoms of hypothyroidism with
diffusely enlarged goiter. There might be an initial phase
of hyperthyroidism (Hashitoxicosis)
• Histology of the thyroid shows diffuse lymphocytic and
plasma cell infiltration with formation of lymphoid
follicles increase the risk of thyroid B-cell Lymphoma
Hashimoto thyroiditis
Hashimoto thyroiditis

Thyroid B-cell Lymphoma

 Congenital hypothyroidism
• Is inadequate thyroid hormone production in newborn
infants
• Can be due to:
– An anatomic defect in the gland
– Dyshormonogenesis: deficiency of the enzymes that
make thyroid hormones
– iodine deficiency (most common)
• Hypothyroidism in infants and young children causes
cretinism
Cretinism caused by hypothyroidism
 Investigation of thyroid disorders
• TSH measurement:
– Used alone for screening purposes ± FT4 and FT3
– To determine the state of thyroid function (hyper-, hypo-, or
euthyroid) you need to measure both TSH and FT4

Condition TSH T4
Primary hyperthyroidism  
Secondary Hyperthyroidism  
Primary Hypothyroidism  
Secondary Hypothyroidism  
 Investigation of thyroid disorders
• Thyroid autoantibodies:
– Antimicrosomal, antithyroid peroxidase, and
antithyroglobulin antibodies are present in high titres in
Hashimoto’s disease
– Thyroid stimulating immunoglobulins (TSI) occur in
Grave’s disease
• TRH test (not commonly used)
• Thyroid isotope scan (not commonly used)
• Fine-needle aspiration: Useful for diagnosis of thyroid
malignancies
 Goiter
• A goiter is any visible enlargement of the thyroid gland
• A goiter may be associated with hyper-, hypo- or
euthyroid state
• A goiter may produce mass effects
– Dysphagia
– Hoarseness
Types of goiter:
– Simple diffuse goiter
– Simple multinodular goiter
– Solitary thyroid nodule
Goiter
 A clinical case
• A 46 year-old woman complained of hot flushes
• O/E: The thyroid gland was mildly enlarged.
• No other symptoms
Patient value Normal range
TSH 7.0 mIU/l (0.3 – 5.0)
FT4 12.0 pmol/l (9.0 - 26.0)

What is the diagnosis?

 Sub-clinical hypothyroidism
• Characterized by high TSH levels and normal
FT4/FT3 levels in an asymptomatic individual
• Can convert to hypothyroidism, specially if anti-
thyroid antibodies present
• May be associated with endothelial dysfunction
which may lead to atheroma
• Treat when TSH >10 mU/L (Normal below 5
mU/L)
 Another clinical case
• A 55 year-old man who was admitted to ICU following
severe trauma
• Thyroid function tests are done and revealed:
Patient value Normal range
TSH 0.1 mIU/l (0.3 – 5.0)
FT4 10.0 pmol/l (9.0 – 26.0)
T3 0.3 nmol/L (0.9 - 2.8)

What is the diagnosis?

 Non-thyroidal illness (NTI)
• Definition: Abnormal TFTs in severe illness
• (TFTs =Thyroid function tests ie TSH, FT4 and FT3 levels)
• Usually (N or ) TSH, () T3, (N or ) T4
• Possible mechanisms:
– Suppression of TRH release
– Decreased peripheral conversion of T4 to T3
– Abnormality of binding protein
– Effects of circulating inflammatory mediators on
metabolism of thyroid hormones
 Tumors of the thyroid gland
• Mostly benign adenomas but tissue diagnosis is the only
way to exclude carcinoma
• Adenomas of the thyroid are typically discrete, solitary
masses, derived from follicular epithelium, and hence they
are also known as follicular adenomas
• Carcinomas (rare):
– Papillary carcinoma:
– Follicular carcinoma:
– Anaplastic carcinoma of the thyroid
– Medullary carcinoma of the thyroid
 Tumours of the thyroid gland
• Diagnosis
– Tissue diagnosis is a must
• Treatment:
• Total Thyroidectomy. This operation is designed to
remove all of the thyroid gland. It is the operation of
choice for all thyroid cancers.
• Patients receive thyroid hormones to suppress TSH levels.
• Monitoring:
– TSH, calcitonin, Thyroglobulin (levels should be )
Follicular Adenomas
 Papillary carcinoma
• >85% of cases of thyroid cancers
• Characterized by presence of papillae +
calcifications (Psammoma bodies)
• They tend to spread to local lymph nodes
• Pathogenesis is related to several gene mutations
• The major risk factor predisposing to papillary
carcinoma is exposure to ionizing radiation
Papillary carcinoma
 Follicular carcinoma
• 5% to 15% of cases
• More frequent in areas with dietary iodine
deficiency
• Well differentiated follicles, which can be difficult
to differentiate from normal thyroid tissue
• Invade the capsules and spread into blood vessels
• Lymph node involvement in rare
Follicular carcinoma
Anaplastic carcinoma of the thyroid
• Anaplastic carcinomas are undifferentiated tumors
of the thyroid follicular epithelium
• Accounts for less than 5% of thyroid tumors.
• Aggressive, mortality rate approaching 100%
 Medullary carcinoma of the thyroid
• Originates from the parafollicular cells (C-cells) of the
thyroid, they produce calcitonin
• Occurs in the following clinical Settings:
– Sporadic (80% of all cases of medullary thyroid cancer)
– Part of Multiple Endocrine Neoplasia Syndromes (MEN
2A or MEN 2B)
– Inherited medullary carcinoma not associated with
endocrine disorders
• Treatment: total thyroidectomy; Calcitonin measurement is
useful in monitoring of treatment
The adrenal gland
 Structure of the adrenal gland
• The adrenal glands are paired endocrine organs consisting
of a cortex and a medulla
• Adrenal Cortex consist of 3 distinct zones:
– Zona glomerulosa  Mineralocorticoids (Aldosterone)
– Zona fasiculata (75%) Glucocorticoids (Cortisol)
– Zona reticularis  Sex steroids (Androgens & Estrogens
• Adrenal Medulla:
– Composed of chromaffin cells, which synthesize and
secrete catecholamines, mainly epinephrine
Structure of the adrenal gland
Biosynthesis of adrenal hormones
 Biological effects
• Cortisol:
– Protein: increase degradation pf proteins
– Lipid: promotes lipolysis
– Carbohydrates: promotes hyperglycaemia through
antagonizing insulin action in the tissues and increasing
gluconeogenesis
– Anti-inflammatory
– It enhances the capacity of glucagon and catecholamines
– Has weak mineralocorticoid properties
– It is one of the hormones that are released during stress
 Biological effects
• Aldosterone:
– Increases sodium and water reabsorption in the kidney in
exchange for potassium and hydrogen ions
– Its level increases with decreasing blood pressure and vice versa
• Androgens:
– Produced in small amounts. Excessive production can cause
precocious puberty in boys and masculinizing effects in women
• Estrogens:
– Produced in small amounts; rarely an estrogen-producing tumor
can produce significant amounts
 Transport of adrenocortical hormones

• Cortisol:
– 95% of cortisol is protein-bound; mostly to Cortisol-
binding globulin (CBG)
• Aldosterone:
– Only 60% is bound to albumin
• Adrenal androgens and estrogens:
– Are transported mainly bound to Sex Hormone
Binding Globulin (SHBG)
• Note that levels of cortisol, and testosterone in women are
influenced by the concentration of the binding proteins
The Hypothalamic-Pituitary-Adrenal Axis
Control of secretion of cortisol and Adrenal
Sex Hormones
• Cortisol:
– Level is controlled by ACTH and CRH by the negative
feedback mechanism
– Circadian rhythm: highest concentration of ACTH and
cortisol in the morning and lowest at mid-night
– Stress can override the circadian rhythm
• Adrenal Sex Hormones:
– like cortisol the secretion is controlled by ACTH and
CRH.
 Control of secretion of Aldosterone
• Aldosterone:
– The primary stimulator of aldosterone synthesis and
secretion is the renin-angiotensin system, which is
activated in response to hypotension and sodium loss.
– Also sympathetic nervous system and high potassium
concentrations stimulate aldosterone release
– The zona glomerulosa is not under the influence of
ACTH
 Control of secretion of Aldosterone
Hypotension
Low Na delivery to macula densa
Increased sympathetic activation
 Disorders of the adrenal cortex
• Overactivity of the adrenal cortex:
– Cushing’s syndrome
– Hyperaldosteronism
Or
• Underactivity of the adrenal cortex:
– Adrencortical insufficiency
 Adrencortical insufficiency
• Adrenocortical insufficiency may be caused by:
1. Primary adrenal disease (primary hypoadrenalism)
• Also called Addison disease

2. Decreased stimulation of the adrenals due to a

deficiency of ACTH (secondary hypoadrenalism)
• Usually due to pituitary disorders.
• Not associated with hyperpigmentation (No ACTH)
• No electrolytes disturbances because of normal
aldosterone levels
 Adrencortical insufficiency
• Primary Adrencortical insufficiency (Addison’s disease)
Causes:
– Autoimmune disease: 60-70% of cases, can affect the
adrenal gland alone or in association with other
autoimmune diseases e.g. thyroid disease, premature
ovarian failure and type 1 DM
– Infections: TB, AIDS, meningitis (causing Water-
house-Fridericksen syndrome), which cause hemorrhage
and destruction of the adrenal glands
– Bilateral secondary carcinoma
 Clinical features of adrencortical
insufficiency
• The Clinical features of adrenal insufficiency depends on
whether it is primary or secondary hypoadrenalism:
• Primary Adrenal insufficiency:
– Presentation can be:
• Chronic: most common presentation
• Acute
• Secondary Adrenal insufficiency:
– Usually chronic presentation
– Similar to chronic primary insufficiency with few differences
 Clinical features of adrencortical
insufficiency
Primary chronic adrenal insufficiency (Addison’s disease)
• Tiredness, weakness, anorexia, apathy
• Abdominal pain
• Hyperpigmentation ( ACTH)
• Postural hypotension ( aldosterone)
Primary Acute adrenal insufficiency (Adrenal crisis)
• often precipitated by:
– Infection in a patient with adrenocortical insufficiency
– Rapid withdrawal of steroids
– Acute adrenal hemorrhages (meningococcemia)
• Characterized by circulatory shock, volume depletion,
anorexia, nausea and vomiting
 Clinical features of adrencortical
insufficiency
Secondary adrenal insufficiency
• Tiredness, weakness, anorexia, apathy
• Abdominal pain
• NO Hyperpigmentation (ACTH)
• NO electrolytes disturbances (N aldosterone)
• Can also be complicated by adrenal crisis
 Investigations of adrenal insufficiency

1. Serum Electrolytes
Plasma Sodium Low
Potassium High
Serum Bicarbonate Low
Glucose Low
Urea High
2. Morning Cortisol level
– Low or Normal
 Investigations of adrenal insufficiency

3. Short Synacthen© test:

• Administration of ACTH analogues to assess the residual
capacity of the adrenal gland
• Within 15-30 minutes of ACTH infusion, the normal
adrenal cortex releases 2-5 times its basal plasma cortisol
output
• Failure of response confirms a diagnosis of primary
adrenal insufficiency
4. ACTH levels: High in Addison’s disease
5. High renin activity/low aldosterone levels
 Management of Addison’s disease
• Supportive treatment:
– IV Fluids
• Definitive treatment:
– Replacement of Glucocorticoids: Prednisolone
– Replacement of Mineralocorticoids: Fludrocortisone
 Hyperadrenalism

• This disorder is caused by conditions that produce

elevated glucocorticoid levels
• Cushing’s Syndrome is the most common
Causes of Cushing Syndrome:
• Exogenous steroids
• Pituitary dependent (ACTH-secreting pituitary tumor)
• Primary Adrenal Neoplasms (Cortisol secreting adenoma)
– Also called cushing disease
• Ectopic ACTH
Clinical Features of Cushing syndrome

• Moon facies, truncal obesity, buffalo hump

• Hypertension
• Thin limbs and muscular weakness
• Purple striae, fragile skin
• Impaired glucose tolerance
• Psychiatric disturbances
• Menstrual disturbances, hirsutism
• Decreased immunity
Clinical Features of Cushing syndrome
 Diagnosis of Cushing’s syndrome
• You need to exclude exogenous glucocorticoids!
• The following is the approach to reach a final diagnosis:
Frist:
• Establish the presence of Hypercortisolism
Second:
• Determine the source of the excess cortisol
Third:
• Check for metabolic derangements associated with
Cushing syndrome
 Diagnosis of Cushing’s syndrome
Screening tests to confirm hypercortisolism:
1. 24 hour urinary free cortisol: most common screening test
2. Low Dose Dexamethasone suppression test:
– Requires administration of 1 mg of dexamethasone (cortisol-like) at
11 PM with subsequent measurement of cortisol level at 8 am
– Normal individuals typically have very low levels of cortisol in
these samples (<50 nmol/L) (due to ACTH suppression)
– Cortisol level is not suppressed in patients with Cushing's disease
3. Late-night serum or salivary cortisol
– Salivary cortisol level is a new test which is more convenient
 Diagnosis of Cushing’s syndrome
• After confirming hypercortisolism (Cushing
syndrome) the source of excess cortisol needs to be
determined whether it is:
– ACTH-producing pituitary tumor
– Or ectopic ACTH production
– Or adrenal gland tumor
 Diagnosis of Cushing’s syndrome
The following tests can help differentiate between them:
1. Plasma ACTH
– If low adrenal gland tumor
– If High ACTH-secreting pituitary tumor or ectopic ACTH
2. High Dose Dexamethasone suppression test
– Requires administration of 8 mg of dexamethasone at 11 PM with
subsequent measurement of cortisol level at 8 am.
– Suppression of serum cortisol level to less than 50% of baseline is
suggestive of a pituitary source of ACTH rather than ectopic
ACTH
 Diagnosis of Cushing’s syndrome
3. MRI or CT scan: for localization
4. Inferior petrosal sinus sampling (IPSS):
– Used to identify the source of the ACTH secretion (if
no adenoma was found by MRI)
Other investigations:
– Serum electrolytes: Na and K
– pH = alkalosis
– Glucose: 
Diagnosis of Cushing’s syndrome
 Hyperaldosteronism
• Primary hyperaldosteronism (Conn’s syndrome):
– Adenoma (benign, most of the cases), hyperplasia,
carcinoma
– It causes sodium retention leading to hypertension,
hypokalemia and metabolic alkalosis.
• Secondary hyperaldosteronism:
– is caused by increased activity of the renin-angiotensin
system, in response to decreased effective blood volume as
in liver cirrhosis, heart failure and nephrotic syndrome or
due to decreased renal blood flow in some forms of
hypertension
 Diagnosis of Hyperaldosteronism
A. Hyperaldosteronism is suspected if the patient has:
– Hypertension,  K and  Bicarbonate
– Increased Aldosterone: Renin Ratio (ARR) (Screening test)
B. Confirmatory tests (there are many tests):
1. Oral sodium loading test
2. Fludrocortisone suppression test (FST)
• Cause low urinary and plasma aldosterone levels in normal
people
C. CT scanning: for subtype classification:
– Unilateral or bilateral micro-or macro-adenoma
– Or bilateral hyperplasia
D. Adrenal venous sampling: For lateralizing the aldesterone source
 A clinical case
• A 35 year old woman is found to have a blood pressure of
180/110 mmHg. She was started on a thiazide diuretic. A week
later she returned to the surgery complaining of severe muscle
weakness and constipation. Initial investigations reveals:
• Plasma Sodium 145 (135 – 145) mmol/L
• Potassium 2.2 (3.5 – 5)
• Chloride 102 (98 – 108)
• Bicarbonate 33 (22 – 32)
• Urea 7 (3 – 8)
What is the differential diagnosis?
 Continued
Further evaluation reveals:
• Plasma Cortisol 8 AM 470 nmol/L
• Plasma Cortisol midnight 110 nmol/L

• Plasma Aldosterone 1280 pmol/l High

• Renin <0.5 ng/ml/hr Suppressed
 Congenital adrenal hyperplasia (CAH)
• Autosomal recessive disorders characterized by partial or
total enzyme deficiency in the synthesis of adrenal steroids
• Steroid precursors that build behind the defective step in
the pathway are channeled into other pathways
• The deficiency of cortisol leads to increased secretion of
ACTH, culminating in adrenal hyperplasia
• Three recognized enzymes deficiencies:
– 21-hydroxylase deficiency (90% of the cases)
– 11-hydroxylase deficiency
– 17-hydroxylase deficiency
Biosynthesis of adrenal hormones
21-hydroxylase deficiency
 21-hydroxylase deficiency
Have variable clinical presentations:
1. Adrenal crisis (salt-wasting):
– Occurs with total deficiency of the enzyme
– No aldosterone production  K, Na, Hypotension
– Females present with virilization
2. Simple virilizing (Non salt-wasting):
– Partial enzyme deficiency.
– Generate sufficient mineralocorticoid to prevent a salt-wasting “crisis”
– Girls: Norn with ambiguous genitalia. (enlarged clitoris ± labial fusion)
– Boys: Normal at at birth. Penile enlargement, early pubic hair and rapid
growth in height when the child is 4 or 5 years old.
3. Late-onset CAH: hirsutism, infertility
 21-hydroxylase deficiency
Investigation of CAH due to 21-hydroxylase deficiency:
• In the presence of clinical features suggestive of the
disease, diagnosis made by finding of
– high Level of 17- hydroxyprogesterone in blood in
a morning sample.
– In borderline cases, short synacthen test with
measurement of 17 hydroxyprogesterone in blood
before and after synacthen administration
• Urinary steroid profile
 21-hydroxylase deficiency
• Neonatal screening for 21-hydroxylase deficiency:
– by measuring 17  hydroxyprogesterone in a blood
spot
• Prenatal diagnosis:
– by mutational analysis obtained by chorionic villous
sampling or amniocentesis
– Mothers are treated with dexamethasone, which is
started early
11-hydroxylase deficiency
 11-hydroxylase deficiency
• Deficiency causes overproduction of steroids
above the blockade including:
1. Androgen excess:
– Females: ambiguous genitalia and virilization
– Male: precocious puberty
2. 11-deoxycorticosterone, a mineralocorticoid:
– Most patients have hypertension
– Decrease in circulating angiotensin II
– Varying degree of Hypokalemia and alkalosis
17-hydroxylase deficiency
 17-hydroxylase deficiency
• Deficiency causes decreased production of glucocorticoids
and sex steroids and increased synthesis of mineralocorticoid
precursors
• Reduced levels of both gonadal and adrenal sex hormones
result in:
• Males: ambiguous genitalia
• Females: delayed puberty, absent 2ry sexual characteristics or
primary amenorrhea.
• Excessive mineralocorticoid activity produces varying
degrees of hypertension and hypokalaemia
 Disorders of the adrenal Medulla
• It is composed of specialized neural crest
(neuroendocrine) cells, termed chromaffin cells, and
their supporting (sustentacular) cells
• Secretes catecholamines
• The most important diseases of the adrenal medulla
are neoplasms:
– Chromaffin cells neoplasm (pheochromocytomas)
– Neuronal neoplasms (neuroblastoma)
The synthesis and degradation of
catecholamines
 Pheochromocytoma
• A tumor of Chromaffin cells
• Secrets mostly adrenaline and noradrenaline and rarely
dopamine
• The 10% rule (approximate rule):
– 10% extra-adrenal; 10% malignant; 10% bilateral; 10% in
childhood;10% component of multiple endocrine neoplasia,
MEN2a and MEN2b
– 10% inherited (old rule now up to 25% are possibly inherited)
Clinical features:
– Episodic hypertension, anxiety, palpitations, headache,
excessive sweating, cardiac arrhythmias
 Investigations of pheochromocytoma
• Plasma metanephrine testing (more sensitive)
• 24-hour urinary catecholamines and Metanephrines (more
specific)
• Imaging studies for tumor localization
– MRI or CT scanning
– 123I-metaiodobenzylguanidine (MIBG) scintigraphy
• Reserved for biochemically confirmed cases in
which CT scanning or MRI does not show a tumor
 Neuroblastoma
• Common childhood tumour (8% of childhood malignancies)
• Occurs mostly in the adrenals, but occasionally in the
sympathetic chain
• Most common product is dopamine and the metabolite
homovanillic acid (HVA) and vanillylmandelic acid (VMA),
but catecholamines are also secreted
• 123I-metaiodobenzylguanidine (MIBG) scintigraphy:
– It concentrates in >90% of the tumors and therefore used in the
assessment of spread and response to therapy
 Clinical case
• A 40-year old male was found to have an elevated
blood pressure, 160/100mmHg. He had few
episodes of anxiety, palpitation, headache and
sweating in the last two days. On two previous
occasions his BP was normal
Laboratory investigations:

Serum Levels Reference Ranges

Sodium 138 mEq/L 135 – 145 mEq/L

Potassium 4.5 mEq/L 3.5 – 5.0 mEq/L
Chloride 108 mEq/L 95 – 108 mEq/L
BUN 10 mg/dL 8-20 mg/dL
Creatinine 1.0 mg/dL 0.6-1.2 mg/dL
Bicarbonate 26 mEq/L 24 – 32 mEq/L
TSH 1.6 mU/L 0.3 – 4.5 mU/L
FT4 17 pmol/L 9 – 25 pmol/L
24 Hour Urine:

VMA 14mg/24 hrs (2 – 7 mg/24 hrs)

Epinephrine 106 ug/24 hrs (0 – 20 ug/24 hrs)
Metanephrine 2.2 mg/24 hrs (0.3-0.9 mg/24 hrs)
Normetanephrine 84 ug/24 hrs (15 – 80 ug/24 hrs)
 Questions
1. Explain the relevance of the following laboratory
tests in the investigation of hypertension:
– Serum: Sodium, Potassium, Creatinine and Bicarbonate
2. Why did the physician request a thyroid function test?
3. What is the likely diagnosis?
4. Is this tumor benign or malignant?
5. What is the possible site of the tumor?
6. How do you manage this patient?
 Metabolism of calcium,
phosphate and magnesium
 Calcium in the body
• There is 1 Kg of calcium in the body; 98% in bone mainly as hydroxyapatite
crystals
• only 1% in extracellular fluid, which is involved in:
• regulation of neuromuscular excitability
• acting as co-factor for clotting enzymes
• Role of calcium within cells:
• regulates activity of many enzymes
• exerts second messenger hormonal function
• About one half of plasma calcium is Ionized calcium and this is the part which is
physiologically active; the other half is bound to albumin
• Total calcium levels are affected by protein concentrations
• Ionized calcium levels are affected by blood pH; ionization of calcium is
increased in acidosis and decreased in alkalosis
 Hormonal control of calcium metabolism

Parathyroid hormone:
• Is a hypercalcemic hormone; its release is regulated by the level of
ionized calcium in the blood.
• It acts on bone to release calcium and on the kidney to increase
calcium reabsorption and decrease reabsorption of phosphates and
bicarbonates
• It also activates vitamin D in the kidney.
1,25-Dihydroxycholecalciferol
• Activated vitamin D acts on the gut to enhance absorption of calcium
and phosphates and acts on bone to facilitate bone resorption and
release of calcium
Calcitonin: Is probably not involved in the regulation of Ca metabolism
Hormonal control of calcium
metabolism
 A clinical case
A 66 year old lady fainted while at the hairdresser and was
brought to emergency dept. Nothing remarkable on
examination. Laboratory results below:
Na 136 mmol/l 135 – 145
K 4.5 mmol/l 3.5 – 5
Urea 8.7 mmol/l 3 –8
Ca (total) 2.8 mmol/l 2.2 – 2.6
Phosphate 0.7 mmol/l 0.8 – 1.4
Bilirubin 15 µmol/l < 20
ALT 32 U/l < 40
Alkaline phosphatase 135 U/l < 120
 Hypercalcemia: causes
• 90% of cases of genuine hypercalcemia are due to
two causes:
1. Hyperparathyroidism
2. Malignant disease
Other causes:
• Excessive vitamin D: vitamin D intoxication
• Granulomas (tuberculosis, lymphoma, sarcoidosis)
because they activate vitamin D
• High bone turnover
– Thyrotoxicosis & Paget’s disease
 The clinical case

• The Medical Officer sent her home but 8 months later she
came back to the hospital and her blood biochemistry was
very similar
• What other symptoms and signs of hypercalcemia do you
want to check?
• What is the differential diagnosis?
• How do you investigate her further?
 Hyperclacaemia: Clinical features
1. Asymotomatic: One half of patients are asymptomatic
2. Renal
– Polyuria and thirst, Stones, Nephrocalcinosis; deposition f calcium
crystals in kidney and may lead to renal failure
3. Musculoskeletal
– Muscle weakness
– Rarely demineralization, subperiosteal bone resorption, bone cysts
(osteitis fibrosa cystica)
4. Neurological
– Psychiatric/neurological symptoms
5. Gastrointestinal
– Anorexia, constipation and ulcers
 Hyperparathyroidism
• Primary hyperparathyroidism:
– mostly solitary adenoma, rarely hyperplasia or carcinoma
• Secondary hyperparathyroidism:
– is the reaction of the parathyroid glands to a hypocalcaemia
caused by something other than a parathyroid pathology
• Tertiary hyperparathyroidism:
– Occurs when PTH increases to maintain normocalcemia in the
setting of vitamin D deficiency; eventually parathyroid
hyperplasia occurs and PTH secretion becomes independent of
calcium level; often seen in patients with chronic renal failure.
• Hyperparathyroidism can be part of multiple endocrine
neoplasia (MEN1 and MEN2 syndromes)
 Investigation and management of
hypercalcemia
Clinical features
• Plasma calcium (usually total calcium is measured)
• Plasma phosphate
• Plasma alkaline phosphatase,
• Plasma PTH
• Management:
– Correct dehydration
– Frusemide
– Bisphosphonates
– Calcitonin
 Clinical case
• The MO referred her to the metabolic clinic.
• She gave a history of dry cough. She never smoked
but her husband who died 16 years earlier was a
heavy smoker. She worked in a Pub for 8 years.
• She is a known hypertensive, on thiazide diuretics.
Laboratory Tests

Na 138 mmol/l 135 – 145

K 4.6 mmol/l 3.5 – 5

Urea 10 mmol/l 3 –8
Ca 2.8 mmol/l 2.2 – 2.6
Phosphate 0.65 mmol/l 0.8 – 1.4
Bilirubin 17 µmol/l < 20
ALT 35U/l < 40
Alkaline phosphatase 155 U/l < 120
 Clinical case
• The Physician asked for a Chest x-ray, which showed a
mediastinal shadow. Subsequent bronchoscopy and
cytology confirmed bronchogenic cancer.
• Plasma PTH level was: 33 (1.5-7.0 pmol/L)
• Treatment given was bisphosphonates but only mild
change in plasma calcium level was observed
• 5 months later serum calcium level rose to 3.9 mmol/l.
• The patient was given bisphosphonates and calcium level
decreased significantly
• Comments?
 Hypocalcemia
Causes:
• Hypoalbuminemia (will cause a low total plasma calcium
but the ionized calcium level will be normal)
• Chelation by EDTA
• PTH-related: hypoparathyroidism,
pseudohypoparathyroidism, hypomagnesemia
• Defect in vitamin D metabolism: rickets, osteomalacia,
Chronic renal failure, vitamin D resistant rickets, liver
disease, anticonvulsive therapy
• Acute pancreatitis
 Hypocalcemia
Clinical features:
• Increased neuromuscular excitability with tetany,
parathesiae and muscle cramps.
• Prolonged hypocalcaemia is associated with
cataract, mental retardation, psychosis, increased
intracranial pressure and seizures.
 Hypoparathyroidism
• Congenital absence of parathyroid glands:
– isolated or as Di-George syndrome which also cause
underdevelopment of thymus, and congenital heart defects
• An autoimmune syndrome
– Could be associated with other autoimmune problems e.g. adrenal and
ovarian failure
• Thyroidectomy or neck surgery
• Pseudohypoparathyroidism:
• decreased responsiveness of target organs because of problems with
PTH receptors. Sex-linked; males affected twice as often as females.
• Skeletal features : short stature, short metacarpals and short metatarsals
• Other features: cataracts, mental retardation and testicular atrophy
 Hypophosphatemia: causes

• Reduced absorption: • Increased excretion:

– Malabsorption – hyperparathyroidism,
• Increased cellular hypomagnesaemia, renal
tubular defect, dialysis
uptake:
– treated diabetic • Dilution:
ketoacidosis, – volume expansion
hyperalimentation, • Chronic alcohol abuse
alkalosis
 Hypophosphatemia: effects
• Muscle weakness
• Hemolysis
– depletion of 2,3-diphosphoglycerate
• Respiratory failure
– Severe hypophosphatemia in critically ill patients
• Rhabdomyolysis: is the rapid breakdown of skeletal
muscle tissue. Myoglobin released by muscle destruction
may lead to acute renal failure.
 Hyperphosphatemia
Causes
• Artefactual – hemolysis or delay in separation of blood
samples
• Chronic renal failure
• Hypoparathyroidism
Effects
• High plasma calcium and phosphate levels promote
metastatic calcification which is defined as the deposition
of calcium salts in previously normal tissues
 Magnesium
Hypomagnesemia:
• Associated with hypocalcaemia and/or hypokalemia
Causes: malabsorption, malnutrition, alcoholism, diuretics,
chronic mineralocorticoid excess
Effects: Tetany, agitation, ataxia, tremors, convulsions
Hypermagnesemia:
• Causes: renal failure is the most important cause
• Effects: High levels > 6 mg/L can cause respiratory
paralysis and cardiac arrest
 Multiple endocrine neoplasia (MEN)
• Definition:
• Two or more endocrine tumor types, occur as a part of one
of the defined MEN syndromes, in a single patient and
there is evidence for either a causative mutation or
hereditary transmission.
• Type 1(MEN1) is caused by a mutation in the MEN1,
tumor-suppressor gene and type 2 (MEN2) is caused by
mutations in the RET proto-oncogene. MEN2 has three
clinical variants referred to as MEN2A, MEN2B and MTC
only.
• MEN1 and MEN2 are autosomal dominant disorders
 Clinical manifestations
• They have wide syndromic manifestations

• Most tumors are benign but they can be malignant

• Clinical manifestations result from mass effects

and hormone production by the tumor
 Classification
• MEN I (3 Ps) – characterized by occureceof tumors
predominanntly in the anterior pituitary, parathyroid and pancreatic
islets

• MEN IIa (1M,2Ps) - Medullary Thyroid Cancer (MTC),

Pheochromocytoma, Parathyroid adenoma

• MEN IIb (2Ms,1P) - Medullary Thyroid Cancer, Marfanoid

habitus/mucosal neuroma, Pheochromocytoma
• MTC only
 Multiple endocrine neoplasia (MEN1)

• Parathyroid tumors
• Entero-pancreatic endocrine tumors (Gastrinoma,
Insulinoma, Vipoma, Glucagonoma)
• Pituitary tumor (mostly prolactinoma).

• Other endocrine and non-endocrine neoplasms

including adrenocortical and thyroid tumors,
lipomas, and carcinoids
 Carrier detection
• Is done by biochemical tests or genetic testing which is
preferable: MEN1 gene mutation in MEN1 and RET
mutation in MEN2.

• In MEN2, carrier detection should be the basis for

recommending thyroidectomy to prevent or cure MTC
QUESTIONS?