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ENDOCRINE PATHOLOGY
(Hipothalamus – Hypophisis,
Thyroid, Parathyroid & The
Endocrine Pancreas)
dr. Nirwansyah Parampasi, SpPA
The Endocrine system
• The endocrine system consists of a highly
integrated and widely distributed group of organs
that orchestrate a state of metabolic equilibrium,
or homeostasis, among the various organs of the
body.
• In endocrine signaling, the secreted molecules,
which are frequently called hormones, act on
target cells that are distant from their site of
synthesis.
Hypothalamus
Hypothalamic Releasing Hormones
Seven releasing hormones are made in the
hypothalamus
–
–
–
–
–
Thyrotropin-releasing hormone (TRH)
Corticotropin-releasing hormone (CRH)
Gonadotropin-releasing hormone (GnRH)
Growth hormone-releasing hormone (GHRH)
Growth hormone-release inhibiting hormone
(GHIH)
– Prolactin-releasing factor (PRF)
– Prolactin-inhibiting hormone (PIH)
Endocrine Control: Three Levels of Integration
Hypothalamic stimulation–from
CNS
Pituitary stimulation–from
hypothalamic trophic Hs
Endocrine gland stimulation–
from pituitary trophic Hs
Endocrine Control: Three Levels of Integration
Figure 7-13: Hormones of the hypothalamic-anterior pituitary pathway
Disease divided into :
1- Diseases of overproduction of secretion
( Hyperfunction )
2- Diseases of underproduction
( Hypofunction )
3- Mass effects ( Tumors )
N.B. Correlation of clinical picture , hormonal
assays , biochemical findings , together with
pathological picture are of extreme
importance in most conditions.
PITUITARY GLAND
(Hypophysis)
PITUITARY GLAND
• Pituitary in sella turcica,& weighs about 0.5gm.
• Connected to the HYPOTHALAMUS with stalk.
• Composed of :
A-ADENOHYPOPHYSIS (Anterior Pituitari)
– Blood supply is through portal venous plexus
– Hypothalamic-Hypophyseal feed back control
B- NEUROHYPOPHYSIS (Posterior Pituitari)
– From floor of third ventricle
– Modified glial cells & axons hypothalamus.
– Has its own blood supply.
CELLS & SECRETIONS :
A- Anterior pituitary ( Adenohypophysis )
1-Somatotrophs from acidophilic cells → Growth H.
2-Gonadotrophs from basophilic cells → FSH, LH
3- Corticotrophs from basophilic cells → ACTH,MSH .
4- Thyrotrophs from pale basophilic cells → TSH
5- Lactotrophs from chromophobe cells → Prolactin
B- Posterior pituitary ( Neurohypophysis )
1- Oxytocin
2- ADH
HYPERPITUITARISM & PITUITARY ADENOMA
In most cases, excess is due to ADENOMA
arising in the anterior lobe.
Less common causes include :
* Hyperplasia
* Carcinoma
* Ectopic hormone production
* Some hypothalamic disorders
Pathogenesis of pituitary adenomas :
• Mutations in G-proteins ( α subunit) in the GNAS1
gene on chromosome 20q13 lead to activation
• 40% of GH secreting adenomas & less in ACTH
• G-proteins involved in signal transduction :
GDP
G proteins
GTP
cAMP
GTPase
• Mutations in α subunit interfere with GTPase function
Features common to all pituitary adenomas :
• 10% of all intracranial neoplasms & 3% occur with
MEN (Multiple Endocrine Neoplasia) syndrome
• 30-50 years of age
• Primary pituitary adenomas usually benign
• May or may not be functional
• If functional, the clinical effects are secondary to the
hormone produced.
• Although most are localized, invasive adenomas
erode sella turcica & extend into cavernous &
sphenoid sinus
CLINICAL FEATURES of PITUITARY ADENOMA:
1- Symptoms of hormone produced
2- Local mass effects :
i- Radiological changes
ii-Visual field abnormalities
iii-Elevated intracranial pressure
3- Pituitary apoplexy
Mass effect of pituitary adenoma
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Morphology of pituitary adenomas :
• Well circumscribed,invasive in up to 30%
• Size 1cm. or more, specially in nonfunctioning
tumor
• Hemorrhage & necrosis seen in large tumors
Microscopic picture :
• Uniform cells, one cell type (monomorphism)
• Absent reticulin network
• Rare or absent mitosis
Sella turcica with pituitary adenoma
Uniform cells of pituitary adenoma
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Types of Pituitary Adenomas
• Previously classified according to histological
picture e.g :
Acidophilic Adenoma
• Now according to immunohistochemical
findings & clinical picture ….. e.g.
Growth hormone secreting adenoma
Immunoperoxidase for GH
1- PROLACTINOMA :
• 30% of all adenomas, chromophobe or weakly
acidophilic
• Functional even if small, but related to size
• Other causes of  prolactin include : estrogen
therapy, pregnancy, reserpine , hypothyroidism……
• Any mass in the suprasellar region may interfere
with normal prolactin inhibition   Prolactin
( STALK EFFECT )
• Mild elevation of prolactin does NOT always indicate
prolactin secreting adenoma !
Symptoms :
•
•
•
•
Galactorrhea
Amenorrhea
Decrease libido
Infertility
2- Growth hormone secreting adenoma :
• 40% Associated with GNAS 1 gene mutation
• Persistent secretion of growth hormone leads
to secretion of Insulin – like GF → symptoms
• Composed of granular ACIDOPHILIC cells
• May be mixed with prolactin secretion.
• Symptoms delayed so adenomas are usually
large
• Produce GIGANTISM or ACROMEGALLY
• Other symptoms : diabetes, arthritis, large
jaw & hands, osteo porosis, BP, HF…..etc
3- Corticotroph cell adenoma
•
•
•
•
•
Usually microadenomas
Higher chance of becoming malignant
Chromophobe or basophilic cells
Functionless or Cushing ‘s Disease (  ACTH )
Bilateral adrenalectomy or destruction may
result in aggressive adenoma:
Nelson’s Syndrome
4- Non functioning adenoma 20%
silent or null cell ,nonfunctioning & produce mass
effect only
5- Gonadotroph producing LH &FSH- ( 10-15%)Function silent or is minimal , late presentation
mainly mass effect produced.
Produce gonadotrophin α subunit, β- FSH & β-LH
6- TSH producing ,(1%) rare cause of
hyperthyroidism
7- Pituitary carcinoma - Extremely rare, diagnosed
only by metastases.
HYPOPITUITARISM :
• Loss of  75% of ant. Pituitary  Symptoms
• Congenital or acquired, intrinsic or extrinsic
• Symptoms include dwarfism, & effect of individual
hormone deficiencies. Loss of MSH → Decreased
pigmentation
• Acquired causes include :
1- Nonsecretory pituitary adenoma
2- Ischemic necrosis e.g.
SHEEHAN’S SYNDROME (post partum hmg.)
sickle cell anemia, DIC, Pituitary apoplexy…
3- Iatrogenic by radiation or surgery
4- Autoimmune ( lymphocytic) hypophysitis
5- Inflammatory e.g sarcoidosis or TB …..
6- Empty Sella Syndrome : Radiological term
for enlarged sella tursica, with atrophied or
compressed pituitary.
May be primary due to downward bulge of
arachnoid into sella floor compressing
pituitary.
Secondary is usually surgical.
7- Infiltrating diseases in adjacent bone e.g.
Hand Schuller – Christian Disease
8- Craniopharyngioma
Craniopharyngioma :
* 1-5 % of intracranial neoplasms
* Derived from remnants of Rathke’s Pouch
* Suprasellar or intrasellar ,often cystic with
calcification
* Children or adolescents most affected
* Symptoms may be delayed ≥ 20yrs( 50%)
* Symptoms of hypofunction or hyperfunction
of pituitary and /or visual disturbances,
diabetes insipidus
* Benign & slow growing
POSTERIOR PITUITARY SYNDROMES:
1-A- ADH deficiency causes Diabetes Insipidus
Excessive urination,dilute urine , due to
inability to reabsorb water from the
collecting tubules. Causes include head
trauma, tumors & inflammations in pituitary
or hypothalamus…etc.
B- Syndrome of inappropriate ADH secretion
Causes excessive resorption of water
hyponatremia e.g Small Cell CA of Lung
2-Abnormal oxytocin secretion :
Abnormalitis of synthesis & release have not
been associated with any significant
abnormality.
THYROID GLAND
This is the normal
appearance of the thyroid
gland on the anterior
trachea of the neck
• Weight 15-20gm. Responsive to stress
• Structure : varying sized follicles lined by
columnar epithelium , filled with colloid,
interfollicular C cells
• Secretion of T3 & T4 is controlled by trophic
factors from hypothalamus & ant.pituitary
THYROTOXICOSIS:
• Hypermetabolic state caused by  T4, T3.
A- Associated with hyperthyroidism:
Primary : Graves Disease
Toxic multinodular goiter
Toxic adenoma
Secondary : TSH secreting pit. adenoma
B- Not associated with hyperthyroidism :
Thyroiditis
Struma ovarii
Exogenous thyroxine intake
Clinical Picture related to Sympathetic
Stimulation
• Constitutional symptoms : heat intolerance,
sweating, warm skin, appetite but ↓weight
• Gastrointestinal : hypermotility, malabsorption
• Cardiac : palpitation, tachycardia, CHF
• Menstrual disturbances
• Neuromuscular : Tremor, muscle weakness
• Ocular : wide staring gaze, lid lag, thyroid
ophthalmopathy
• Thyroid storm : severe acute symptoms of
sympathetic overstimulation
• Apathetic hyperthyroidism : incidental
Upper, thyrotoxicosis
Lower, after therapy
Diagnosis of Hyperthyroidism :
• Measurement of serum TSH (↓ ) + free T4 is
the most useful screening test for
thyrotoxicosis
• TSH level is normal or  in secondary
thyrotoxicosis
• In some patients , T3 but T4 normal or ↓
• Measurement of Radioactive Iodine uptake is
a direct indication of activity inside the gland
Normal radioactive I uptake
HYPOTHYROIDISM :
Primary :
1- Loss of thyroid tissue due to surgery or
radiation Rx.
2- Hashimoto’s thyroiditis
3- Iodine deficiency specially in endemic areas
4- Primary idiopathic hypothyroidism
5- Congenital enzyme deficiencies
6- Drugs e.g. iodides, lithium…..
7- Thyroid dysgenesis ( developmental )
Secondary :
Pituitary or hypothalamic failure
Hypothyroidism is commoner in endemic areas
of iodine deficiency
CRETINISM : hypothyroidism in infancy & is
related to the onset of deficiency .
If early in fetal life Mental retardation ,
short stature, hernia, skeletal abnormalities,
MYXEDEMA in adults Apathy, slow mental
processes, cold intolerence,accumulation of
mucopolysaccharides in subcutaneous tissue
Lab.tests :  TSH in primary hypothyroidism,
unaffected in others.  T4 in both.
THYROIDITIS :
• Mostly autoimmune mechanisms
• Microbial infection is rare
• Types include :
1- Chronic lymphocytic ( Hashimoto’s )
thyroiditis
2- Subacute granulomatous ( de Quervain)
thyroiditis
3- Subacute lymphocytic thyroiditis
4- Riedel thyroiditis
5- Palpation thyroiditis
HASHIMOTO’s THYROIDITIS :
Chronic Lymphocytic Thyroiditis
• Autoimmune disease characterized by
progressive destruction of thyroid tissue
• Commonest type of thyroiditis
• Commonest cause of hypothyroidism in areas
of sufficient iodine levels
• F:M = 10-20 :1, 45-65 yrs.
• Can occur in children
Pathogenesis :
A - T cell sensitization to thyroid antigens
1- Sensitized CD4 T cells  Cytokine mediated
( IFN- γ)cell death inflammation,macrophage
activation
2- CD8+ cytotoxic T cell mediated cell death:
Recognition of AG on cell  killed
3- Presence of thyroid AB  Antibody dependent
cell mediated cytotoxicity by NK cells
B- Genetic predisposition :
↑ in relatives of 1st.degree
Association with HLA – DR 3 & DR- 5
Morphology:
• Gland is a smooth pale goitre, minimally
nodular, well demarcated.
• Microscopically :
- Dense infiltration by lymphocytes &
plasma cells
- Formation of lymphoid follicles, with
germinal centers
- Presence of HURTHLE CELLS
- With or without fibrosis
• Clinically :
– Painless symmetrical diffuse goiter
– May show initial toxicosis ( Hashitoxicosis ).
– Later marked hypothyroidism.
– Patients have  risk of B-Cell lymphoma
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SUBACUTE GRANULOMATOUS
THYROIDITIS :
• Middle aged , more in females. Viral etiology ?
• Self-limited (6-8w)
• Acute onset of pain in the neck , fever,
 ESR,  WBC
• Transient thyrotoxicosis.
• Morphology :
– Firm gland.
– Destruction of acini leads to mixed inflammatory
infiltrate.
– Neutrophils , Macrophages & Giant cells &
formation of granulomas
SUBACUTE LYMPHOCYTIC THYROIDITIS :
(Silent)
• Middle aged females & post partum patients
• Probably autoimmune with circulating AB
• May recur in subsequent pregnancies
• May progress to hypothyroidism
• Histology similar to Hashimoto’s thyroiditis
without Hurthle cell metaplasia
• Reidel’s Thyroiditis –
Dense fibrosis without prominent inflammation
? Considered as fibromatosis rather than thyroiditis
GRAVE’S DISEASE :
• Commonest cause of endogenous
hyperthyroidism
• Age 20- 40 yrs.,
• M: F ratio is 1: 7
• More common in western races
Main features of GRAVES DISEASE :
1 - Thyrotoxicosis with smooth symmetrical
enlargement of thyroid
2 - Infiltrative ophthalmopathy with
exophthalmus in 40%
3- Pretibial myxedema in a minority
• Lab findings :  T4, T3 , TSH
• Radioactive study: Diffuse uptake of
radioactive I
Pathogenesis of GRAVE’S DISEASE :
•
•
•
•
•
Genetic etiology + Autoimmune processes
GENETIC EVIDENCE :
May be familial
60% concordance in identical twins
Susceptibility is associated with
HLA-B8 & - DR3
• May exist with other similar diseases e.g.
SLE, Pernicious anemia, Diabetes type I,
Addison’s dis.
IMMUNE MECHANISMS :
• Antibodies to thyroid peroxisomes & thyroglobulin
• Patients develop autoantibodies to TSH receptor
– Thyroid Stimulating Immunoglobulin ( TSI) binds
to TSH receptor → thyroxin ***
– Thyroid Growth Stimulating Immunoglobulin
(TGI) → proliferation of thyroid epithelium
– TSH binding inhibitor immunoglobulins (TBIIs)
prevent TSH from binding to receptor
• Both stimulation & inhibition may coexist
Morphology :
• Smooth enlargement of gland with diffuse
hyperplasia & hypertrophy
• Lining epithelium of acini :
Tall & hyperplastic ± papillae
• Colloid :
Minimal thin colloid with scalloped edge
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Changes in Extrathyroid tissue :
•
Generalized lymphoid hyperplasia
•
Ophthalmopathy : Edematous orbital
muscles &infiltration by lymphocytes
followed by fibrosis
•
Thickening of skin & subcutaneous tissue
•
Accumulation of glycosaminoglycans which
are hydrophilic
• Result :
Displacement of eyeball & exophthalmus →
redness, dryness, ulceration, infection in
conjunctiva
• Cause :
Expression of aberrant TSH receptor
responding to circulating anti TSH receptor
AB → inflammatory lymphocytic reaction
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DIFFUSE NONTOXIC & MULTINODULAR GOITRE
GOITER = Enlargement of thyroid
Most common cause is iodine deficiency
impaired hormone synthesis TSH 
hypertrophy & hyperplasia of follicles 
Goiter
Endemic :  10% of population have goiter
Sporadic : 1- Physiological demand
2- Dietary intake of excessive
calcium & cabbages…etc
3- Hereditary enzyme defects
MORPHOLOGY :
• Initially diffuse → nodular with degenerative
changes: colloid cysts, hemorrhage, fibrosis,
calcification
• If large may extend retrosternally
• Pressure symptoms are a common complaint
• Picture is that of varying sized follicles,
hemorrhage , fibrosis , cysts, calcification
• Patient is often EUTHYROID. but may be
toxic or hypofunctioning.
Normal radioactive I uptake
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NODULES in the thyroid :
• Nodules in thyroid may be multiple or solitary
• Any solitary nodule in the thyroid has to be
investigated as some are neoplastic.
Investigations include FNA , Radioactive image
technique, Ultrasound, & (T4,T3 & TSH ) levels
• HOT nodule takes up radioactive substance
( functional)
• COLD nodule does not it take up
( nonfunctional )
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General rules of nodules in the thyroid :
1- Solitary nodule is MORE likely to be
NEOPLASTIC than multiple
2- Hot nodules are more likely to be BENIGN
3- Not every cold nodule is malignant .
Many are nonfuctioning adenomas, or colloid
cysts , nodules of nodular goitre….etc
Up to 10% of cold nodules prove to be
malignant.
4- Nodules in younger patients are more likely
to be NEOPLASTIC
5- Nodules in males are more likely to be
NEOPLASTIC .
6- History of previous radiation to the neck is
associate with increased risk of malignancy
NEOPLASMS of the THYROID :
ADENOMAS:
• Usually single.
• Well defined capsule
• Commonest is follicular± Hurthle cell change
• May be toxic
• Size 1- 10cm. Variable colour
• 20% have point mutation in RAS oncogene
Microscopical Picture :
• 1- Uniform follicles , lined by cuboidal epithelial
cells.
• 2- Focal nuclear pleomorphism, nucleoli ….
( Endocrine atypia )
• 3- Presence of a capsule with tumor compressing
surrounding normal thyroid outside .
* Integrity of capsule is important in differentiating
adenoma from well differentiated follicular
carcinoma.
• Capsular and/ or vascular invasion →Carcinoma
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Adenoma with intact capsule
© 2005 Elsevier
Capsular invasion)
CARCINOMAS of THYROID :
• Incidence about 1-2% of all malignancies.
• Wide age range ,depending on type.
• Generally commoner in females, but in
tumors occurring in children or elderly ,
equal incidence in both sexes.
• Most are derived from follicular cells
• Few are derived from ‘C’ cells
TYPES of THYROID CARCINOMA :
1- Papillary Carcinoma ( 75- 85% ),any age,but usual
type in children.
2- Follicular Carcinoma ( 10- 20% )More in middle age
3- Medullary Carcinoma ( 5% ) age 50-60 but younger
in familial cases with MEN syndrome
4- Anaplastic Carcinoma (  5% ) , old age
Presenting symptom is usually a mass , maybe
incidental in a multinodular goitre specially papillary,
& follicular
Pathogenesis of Thyroid Cancer :
1- Genetic lesions :
Most tumors are sporadic
Familial is mostly Medullary CA , Papillary CA
• Papillary CA :
– Chromosomal rearrangement in tyrosin
kinase receptor gene (RET) on chr.10q11
 ret/PTC  tyrosine kinase activity
( 1/5 of cases specially in children)
– Point mutation in BRAF oncogene (1/3-1/2)
• Follicular Carcinoma :
– RAS mutation in ½ of cases OR
– PAX8- PPAR γ 1 fusion gene in 1/3 of
cases
• Medullary Carcinoma :
– RET mutation  Receptor activation
• Anaplastic Carcinoma :
– Probably arising from dedifferentiation of
follicular or papillary CA  inactivation of
P53
2- Environmental Factors :
• Ionizing radiation specially in first two
decades
• Most common is Papillary CA. with RET
gene rearrangement
3- Preexisting thyroid disease :
• Incidence of thyroid CA is more in endemic
areas
• Long standing multinodular goiter →
Follicular CA
• Hashimotos thyroiditis → Papillary CA &
B cell lymphoma
• TYPES OF THYROID CARCINOMAS
PAPILLARY CARCINOMA :
• Cold on Scan by radioactive Iodine
• Solitary or multifocal
• Solid or cystic,  calcification
• Composed of papillary architecture
• Less commonly ‘Follicular Variant’
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Diagnosis based on NUCLEAR FEATURES
• Nuclei are clear (empty) ,with grooves &
inclusions ( Orphan Annie nuclei)
• Psammoma bodies
• Metastases mainly by L.N., sometimes from
occult tumor
• Hematogenous spread late & prognosis is
GOOD
FNA of Papillary CA (nuclear changes)
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Psammoma body in Papillary CA
FOLLICULAR CARCINOMA :
• Usually cold but rarely functional ( warm )
• Well circumscribed with thick capsule
(minimally invasive) or diffusely infiltrative
• Composed of follicles
• Diagnosis is based on CAPSULAR &
VASCULAR invasion
• Metastasize usually by blood  Lungs,
Bone, Liver ..etc.
• Treatment by surgery  Radioactive Iodine
 Thyroxin
• Prognosis is not as good as papillary except
in minimally invasive very well differentiated
forms
Follicular Carcinoma
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Capsular invasion)
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MEDULLARY CARCINOMA:
• Arise from C cells  CALCITONIN,
serotonin, VIP
• 80% Sporadic , or familial  MEN Syndrome
• Composed of polygonal or spindle cells ,
usually with demonstrable AMYLOID in the
stroma
• Calcitonin demonstrated in tumor cells
• Level of calcitonin in serum may be useful
for follow up
• Family members may show C cell
hyperplasia ,↑ Calcitonin, & RET mutation
( Marker for early diagnosis)
• Metastases by blood stream
• Prognosis intermediate
Medullary CA with amyloid
Congo red for amyloid
ANAPLASTIC CARCINOMA :
• Elderly patients with multinodular goitre in
50%
• Foci of papillary or follicular CA may be
present in 20%- 30% , probable
dedifferentiation process
• Markedly infiltrative tumor , invading the
neck → pressure on vital structures
• Rapid progression, death within 1 year
• Morphology : Composed of pleomorphic
giant cells, spindle cells or small cell
anaplastic varients, which may be confused
with lymphoma
• Radiosensitive tumor , no surgery
• P53 mutation identified , consistent with
tumor progression
PARATHYROID GLAND
Actively secreting: Chief cells
Contains mitochondria: Oxiphilic cells
Action of parathyroid hormone
Through vit D it regulates absorption of calcium and
phosporous according to blood vessels
Increases reabsorbtion of calcium and excretion
of phosphate
Increases mobilisation of calcium and phosphat
from bone
Maintains relative concentrations of calcium and phosphourus
in the blood and helps control acid/base balance
Hyperparathyroidism : Primary OR Secondary
Primary Hyperparathyroidism:
• Commonest cause of asymptomatic hypercalcemia
• Female:Male ratio = 2-3 : 1.
• Causes : Adenoma 75%-80%
Hyperplasia 10-15%
Carcinoma < 5%
• Majority of adenomas are sporadic
• 5% familial associated with MEN-1 or MEN-2A
Genetic abnormalities :
• PRAD 1 on chromosome 11 q  cell cycle
control  cyclin D1 overexpression(10%-20%)
• MEN 1 on 11q13 is a cancer suppressor gene
- Germ line mutation in MEN-1 syndrome
 loss of function  cell proliferation
- *20% - 30% of sporadic cases may also show
mutation of MEN1
*Either of above may cause tumor or hyperplasia
• Biochemical findings :
PTH ,  Ca , ↓ phosphate ,alkaline
phosphatase
• In other causes of hypercalcemia, PTH is ↓
Gland morphology in Hyperparathyroidism
• Adenomas :
• Usually single , rarely multiple
• Well circumscribed, encapsulated nodule
(0.5-5g.)
• The cells are polygonal, uniform chief cells,
few oxyphil cells. Adipose tissue is minimal in
the tumor
• Compressed surrounding parathyroid tissue in
periphery, other glands normal or atrophic .
• Hyperplasia :
Enlargement of all 4 glands.
Microscopically chief cell hyperplasia, or clear
cell, usually, in a nodular or diffuse pattern.
Note : Diagnosis of adenoma versus hyperplasia
may depend on the size of the other glands
Parathyroid carcinoma :
• Larger than adenoma (5-10g)
• Very adherent to surrounding tissue.
• Pleomorphism & mitoses not reliable criteria
for malignancy
• Most reliable criteria for malignancy are :
* Invasion
**Metastases
Morphology in other organs:
• Skeletal system:
– Bone resorption by osteoclasts, with fibrosis, cysts
formation and hemorrhage Osteitis Fibrosa
Cystica
– Collections of osteoclasts form ‘ Brown Tumors”
– Chondrocalcinosis and pseudogout may occur.
• Renal system:
– Ca. Stones. & Nephrocalcinosis.
• Metastatic calcification in other organs:
Blood vessels & myocardium , Stomach, Lung …etc
Hyperparathyroidism, clinical picture
• 50% of patients are asymptomatic.
• Patients show  Ca & PARATHORMONE levels in
serum
• Symptoms and signs of hypercalcemia:
Musculoskeletal, Gastrointestinal tract, Urinary
and CNS symptoms
• Commonest cause of silent hypercalcemia .
• In the majority of symptomatic hypercalcemia
commonest cause is wide spread metastases to bone
Painful Bones, Renal Stones, Abdominal Groans & Psychic Moans
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Secondary Hyperparathyroidism :
• Occur in any condition associated with chronic
hypocalcemia, mostly chronic renal failure.
• Glands are hyperplastic
• Renal failure phosphate excretion 
increased serum phosphate,  CaPTH
Tertiary Hyperparathyroidism
• Extreme activity of the parathyroid 
autonomous function & development of
adenoma (needs surgery)
Hypoparathyroidism :
• Causes:
– Damage to the gland or its vessels during
thyroid surgery.
– Idiopathic, autoimmune disease.
– Pseudohypoparathyroidism, tissue
resistance to PTH
• Clinical features:
-Tetany, convulsion, neuromuscular
irritability, cardiac arrhythmias……
ENDOCRINE PANCREAS
Pancreas
15 cm in length, 60-140 gm, consists of head, body & tail;
pancreatic duct empty into duodenum or common bile duct
Histologically, consists of 2 components:
• 1) Exocrine: 80-85%, consists of numerous glands
(acini) lined by columnar basophilic cells containing
zymogen granules, which form lobules; ductal system
• Trypsin, chemotrypsin, aminopeptidase, amylase
• 2) Endocrine: islets of Langerhans, which are invaded
by capillaries. Islets consist of:
• 4 main cell types: B (insulin), A (glucagon), D
(somatostatin), PP cells (pancreatic polypeptide)
• 2 minor cell types: D1 (VIP) & enterochromaffin cells
(serotonin)
The islets of Langerhans form 1-2%
Consists of four types of cells:
α cells
β cells
δ cells
γ cells :
Pancreatic polypeptide (PP)
α cells
Secrete glucagon
Catabolic action
Glycogen converted to glucose and utilized by
tissue
Amino acid converted to glucose in liver; increased
metabolism via citric acid cycle
Increased conversion of fat to glucose
β cells
Secrete insulin
Anabolic action
Glucose uptake and conversion to glycogen; in liver
and muscles
Uptake of amino acid synthesis of protein
Storage of fat depots and conversion of glucose to fat
δ cells
Produce Somatostatin
Control of secretion of hormones of islets
• Diseases mainly include :
– Diabetes
– Islet Cell Tumors
DIABETES
DIABETES :
• Chronic disorder in which there is abnormal
metabolism, of carbohydrate, fat & protein ,
characterized by either relative or absolute
insulin deficiency, resulting in hyperglycemia.
• Most important stimulus that triggers insulin
synthesis from β cells is GLUCOSE
• Level of insulin is assessed by the level of
C - peptide
• Diagnosis :
1- Random glucose ≥ 200g / dL + symptoms
2- Fasting glucose of ≥ 126 / dL on more
than one occasion
3- Abnormal OGTT when glucose level is
more than 200g / dL 2hrs. after standard
glucose load of 75 g.
Classification :
Causes could be Primary in the pancreas OR
secondary to other disease conditions
Primary diabetes is classified into :
A- Type 1
B- Type 2
C- Genetic & Miscellaneous causes
Whatever the type, complications are the same
Secondary Miscellaneous Causes :
• Diseases of exocrine pancreas e.g. chronic
pancreatitis
• Endocrinopathies e.g. Cushing’s Syndrome,
Acromegally
• Infections e.g. CMV
• Drugs e.g. glucocorticoids
• Gestational diabetes
• Other genetic syndromes associated with
diabetes
Biochemical Changes and Clinical Effects
1. Inability to control carbohydrate metabolism
Hyperglycaemia
Glucosuria
Increased plasma
osmolarity
Osmotic diuresis
Hypovelaemia
Thirst
Polydipsia
Loss of Na+ and K+
2. Increased fat catabolism
Excess production of acetyl CoA
Conversion to ketone bodies (acetone + hydroxybutiric acid)
Ketosis
Acidosis
Acid excreted in combination with Na+ and K+
Further electrolyte depletion
3. Increased catabolism of amino acids
Prevents proper protein synthesis
Together with (1) and (2)
above leads to loss of
weight despite polyphagia
TYPE 1 INSULIN-DEPENDENT DIABETES:
Juvenile immune-mediated diabetes
• Due to actual destruction of β cells in the islets of
Langerhans.
• Onset is acute, peak of incidence ± 13 yo now known
to occur at any age
• absolute deficiency of insulin
• Idiopathic
• Histologically: β cells progressively destroyed, α and δ
cells persist, lymphocytic infiltrate may be present.
• Factors that appear to be of importance in the
aetiology:
1. Familial incidence and in 80% of cases have association
with Class II HLA antigens, particularly HLA DR3,DR4
2. Cell-mediated immunity against islet antigen and humoral
antibodies are present
TYPE 2 NON- INSULIN-DEPENDENT
DIABETES (NIDDM)
• The commonest form of diabetes, more frequent in
female, the incidence increases with age.
• The onset is slow, changes in glucose metabolism
mild.
• Complications; particularly vascular.
• Aetiology:
multifactorial, involving environmental and genetic
factors
Prolonged insulin resistance in tissue
inadequate secretion of insulin by β cells
• “Syndrome X”: combination of obesity, NIDDM and
hyperlipidaemia with inceased risk of cardiovascular
disease
FIGURE 24-31 Development of type 2 diabetes.
Insulin resistance associated with obesity is induced by adipokines, free fatty acids, and chronic inflammation in
adipose tissue. Pancreatic β cells compensate for insulin resistance by hypersecretion of insulin. However, at
some point, β-cell compensation is followed by β-cell failure, and diabetes ensues.
(Reproduced with permission from Kasuga M: Insulin resistance and pancreatic β-cell failure. J Clin Invest 116:1756, 2006.)
Type 1 Vs Type 2
Type 3 : Miscellaneous causes
• Genetic defects :
– β cell function
e.g. Maturity Onset Diabetes of the Young
( MODY) caused by a variety of mutations
– Genetic defects of insulin processing or
action
e.g. Insulin gene or Insulin receptor
mutations
COMPLICATIONS
• Macrovascular complications: as myocardial
infarction, renal vascular insufficiency, and
cerebrovascular accidents
• Diabetic nephropathy
• Visual impairment, sometimes even total
blindness
• Diabetic neuropathy
• Enhanced susceptibility to infections of the skin
and to tuberculosis, pneumonia, and
pyelonephritis.
A, Insulitis, shown here from a rat (BB) model of
autoimmune diabetes, also seen in type 1 human diabetes.
B, Amyloidosis of a pancreatic islet in type 2 diabetes
.
(A, Courtesy of Dr. Arthur Like, University of Massachusetts, Worchester,
MA.)
Severe renal hyaline arteriolosclerosis.
Note a markedly thickened, tortuous afferent arteriole. The amorphous
nature of the thickened vascular wall is evident. (PAS stain). (Courtesy of
M.A. Venkatachalam, MD, Department of Pathology, University of Texas Health
Science Center at San Antonio, TX.)
FIGURE 24-38 Nephrosclerosis in a patient with long-standing diabetes. The kidney has been bisected
to demonstrate both diffuse granular transformation of the surface (left) and marked thinning of the
cortical tissue (right). Additional features include some irregular depressions, the result of
pyelonephritis, and an incidental cortical cyst (far right).
FIGURE 24-36 Renal cortex showing
thickening of tubular basement membranes
in a diabetic patient (PAS stain)
FIGURE 24-37 Diffuse and nodular diabetic
glomerulosclerosis (PAS stain). Note the diffuse
increase in mesangial matrix and characteristic
acellular PAS-positive nodules.
Pancreatic Endocrine Neoplasms
• Rare, 2% of all pancreatic neoplasms.
• Resemble in appearance their counterparts,
carcinoid tumors.
• May be single or multiple and benign or malignant,
± 90% are benign.
• Unequivocal criteria for malignancy include
metastases, vascular invasion, and local
infiltration
HYPERINSULINISM (INSULINOMA)
• the most common of pancreatic endocrine neoplasms
 induce clinically significant hypoglycemia.
• Clinical characteristic :
(1)occur with blood glucose levels below 50 mg/dL of serum
(2)consist principally of central nervous system manifestations
(confusion, stupor, and loss of consciousness);
(3)precipitated by fasting or exercise promptly relieved by
feeding or parenteral administration of glucose.
ZOLLINGER-ELLISON SYNDROME
(GASTRINOMAS)
• Association of pancreatic islet cell lesions,
hypersecretion of gastric acid and severe peptic
ulceration
• May arise in the pancreas, the peripancreatic region,
or the wall of the duodenum.
• ± 25% of patients, arise in conjunction with other
endocrine tumors, as part of the MEN-1 syndrome;
• MEN-1–associated gastrinomas are frequently
multifocal, while sporadic gastrinomas are usually
single.
OTHER PANCREATIC ENDOCRINE
NEOPLASMS
• α-cell tumors (glucagonomas)
- associated with syndrome consisting of mild
diabetes mellitus, a characteristic skin rash
(necrolytic migratory erythema), and anemia.
- frequently in perimenopausal and postmenopausal
women and are characterized by extremely high
plasma glucagon levels.
• δ-cell tumors (somatostatinomas)
- associated with diabetes mellitus, cholelithiasis,
steatorrhea, and hypochlorhydria.
- difficult to localize preoperatively.
- High plasma somatostatin levels are required for
diagnosis.
• VIPoma (Vasoactive Intestinal Peptide )
- Associated with watery diarrhea, hypokalemia,
achlorhydria - WDHA syndrome
- Locally invasive and metastatic.
- Neural crest tumors, such as neuroblastomas,
ganglioneuroblastomas, and ganglioneuromas and
pheochromocytomas can also be associated with
the VIPoma syndrome.
Thank you!
Dewiyani Indah Widasari
Department of Anatomical Pathology
RSUP Dr.Sardjito Yogyakarta /
Faculty of Medicine Gadjah Mada University
[email protected]