PATHOLOGY OF ENDOCRINE SYSTEM 2009

PATHOLOGY OF ENDOCRINE SYSTEM 2009
Dr. Huda M Zahawi, FRC.Path

The Endocrine system is divided into :
Endocrine organs dedicated to production of hormones e.g. pituitary,thyroid….etc Endocrine components in clusters in organs having mixed functions e.g. pancreas, ovary, testes….. Diffuse endocrine system comprising scattered cells within organs acting locally on adjacent cells without entry into blood stream

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

PITUITARY GLAND Pituitary in sella turcica,& weighs about 0.5gm.
Connected to the HYPOTHALAMUS with stalk. Composed of : A-ADENOHYPOPHYSIS- (80%) Blood supply is through portal venous plexus Hypothalamic-Hypophyseal feed back control B- NEUROHYPOPHYSIS 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- Lactotrophs from chromophobe cells → Prolactin 3- Corticotrophs from basophilic cells → ACTH,MSH . 4- Thyrotrophs from pale basophilic cells → TSH 5- Gonadotrophs from basophilic cells → FSH, LH 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 GTP cAMP Mutations in α subunit interfere with GTPase function Mutations in RAS, overexpression in C- MYC & NM23 inactivation found in more aggressive tumor Other mutations : MEN-1 gene ( Menin) G proteins GTPase

Features common to all pituitary adenomas :
10% of all intracranial neoplasms & 25% incidental 3% occur with MEN 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. More than one hormone may be produced by same cell 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- Hypopituitarism 4- 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 Corticotroph microadenoma  Macroadenoma  ICP

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 : * Derived from remnants of Rathke’s Pouch
* 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

Development from evagination of pharyngeal tissue into neck
Abnormal descent Lingual thyroid , subhyoid, substernal Weight gm. 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

Hypermetabolic state caused by  T4, T3.
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

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 : 1- Loss of thyroid tissue due to surgery or
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) 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 = :1, 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 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.

Both stimulation & inhibition may coexist
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

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

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 )

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 Activating somatic mutation in TSH receptor is identified leading to overproduction of cAMP 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

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 ( % ),any age,but usual type in children. 2- Follicular Carcinoma ( % )More in middle age 3- Medullary Carcinoma ( 5% ) age 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

Ionizing radiation specially in first two decades
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’

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 , sometimes of Hurthle Cells 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

MEDULLARY CARCINOMA: Arise from C cells  CALCITONIN, CEA, 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 , worse in MEN. 2B

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 Derived from the third and fourth pharyngeal pouches. 90% of people have four glands. Location: mostly close to the upper or lower poles of the thyroid. Can be found anywhere along the line of descent of the pharyngeal pouches. There are two types of cells with intervening fat : - Chief & Oxyphil cells Secretion of PTH is controlled by level of free calcium

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

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: thyroid surgery.
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

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 Other agents stimulate insulin release 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.

secondary to other disease conditions
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

Type 1 :- Absolute deficiency of insulin due to β cell destruction ( 10%)  90% of ‏‏‏ cells lost before metabolic changes appear Age ≤ 20 yrs but may be latent Normal or decreased weight Ketoacidosis is common

Type 2 : Due to a combination of peripheral resistance to insulin action & inadequate secretory response by the pancreatic β cells Commoner ( % ) Insulin normal (relative insulin deficiency) Patient is overweight Rare ketoacidosis

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

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

PATHOGENESIS

Pathogenesis of Type 1 Diabetes :
1- Genetic susceptibility 2- Autoimmunity 3- Environmental factors It is a combination of autoimmunity & environmental insult in a person with a known genetic susceptibility leading to destruction of β cells

1- Genetic susceptibility
Principal susceptibility genes located in region of MHC class II on chromosome 6p21 90% Associated with HLA- DR3,or HLA- DR4, or both Racial predisposition, (Caucasians) but majority have no family history 6- 20% familial ,< 40% in identical twins Second susceptibility gene encodes a T cell inhibitory receptor (CTLA-4) interfering with normal T cell function

2- Autoimmunity - Presence of CD 8+ & CD 4+ in islet cells “ Insulinitis” Presence of islet cell antibodies ( insulin & GAD) in 80% of patients & in relatives several months or years before onset Antibodies are highly selective against β cells Relatives at risk have similar AB years before onset 10% - 20% other autoimmune disease

3- Environmental factors
An environmental insult may damage β cells rendering them antigenic. Viruses : measles , coxsackie , rubella Chemicals Cow’s milk

Pathogenesis of Type 2 diabetes :
1- Genetic factors 2- Insulin resistance & obesity 3 - cell secretion dysfunction

1- Genetic factors : Genetic factors are more important than in type 1 diabetes, but this is multifactorial 50% - 90% in identical twins  risk by 20%-40% in first degree relatives No association with HLA & no autoimmune basis Point mutation in insulin receptor identified affecting signaling pathway but rare ( 1-5%)

2 – Insulin resistance : Decrease ability of peripheral tissue to respond to insulin Early : insulin resistance →  insulin secretion due to compensatory  of  cell mass Later : relative  insulin &   cell mass to 20-50% MAIN FACTOR IN INSULIN RESISTANCE IS OBESITY

Explanation : Adipocytokines : Resistin ↑ obesity → Insulin resistance Leptin & Adiponectin contribute to insulin sensitivity but are ↓in obesity → resistance PPAR γ is a nuclear receptor that regulates level of adipocytokines FFA in tissues (lipotoxic effect) →  insulin resistance

3-  cell Dysfunction : Defective glucose recognition due to ↑ intracellular levels of a mitochondrial protein ( UCP2) in β cells Amylin : A protein normally produced by  cells secreted with insulin in response to food ingestion Amylin accumulates outside  cells, forming amyloid like deposits & may impair  cell glucose sensing. Seen in up to 90% of cases of Type II diabetes

Pathogenesis of complications :
1- Nonenzymatic glycosylation of proteins Glucose + Free amino acids Later → Irreversible combination Advanced Glycosylation End products =AGES Measured by level of glycosylated Hb ( HbA1c) AGES inactivate proteins & cross link with more proteins, deposited in vessels, renal glomeruli, …..etc

Effects : Induce cytokine production, GF : ↑ vascular permeability ↑ procoaggulant activity ↑ fibroblasts & SM in ECM Complications in blood vessels, kidney, nervous system ….etc Complications are proportional to the degree of hyperglycemia of whatever type

2- The Polyol Pathway Persistent hyperglycemia facilitates entry of glucose & its accumulation into some cells & metabolized into  SORBITOL (a polyol) & FRUCTOSE Creation of osmotic gradient  Influx of fluid + Toxic lens, retina, peripheral nerves, kidney…etc

3- Activation of Protein Kinase C :
Activation of signal transduction Leads to production of pro-angiogenic factors (VEGF) Important in retinal neovascularization Production of pro-fibrogenic factors → ↑ECM & BM thickening

COMPLICATIONS

Pathology in the Pancreas
i -Type I : - Leukocytic infiltration of islets ( T cells) ‘Insulinitis’ with progressive depletion of  cells. - Later small indistinct or absent islets. ii - Type II : - Ill defined reduction in islet cell mass - Fibrous tissue accumulation in some islets - Amyloid deposition in islets Newborn of diabetic mother : islet cell hyperplasia

COMPLICATIONS

1- Atherosclerosis : - Cardiovascular - CNS complications - Peripheral circulation 2- Diabetic microangiopathy - Hyaline arteriolosclerosis , exaggerated in hypertension - Diffuse thickening in capillaries of skin, retina peripheral nerves, renal medulla → Leaky vessels→ nephropathy, retinopathy, neuropathy

3- Diabetic nephropathy
I - Glomerular lesions- - Capillary BM thickening - Nodular glomerulosclerosis 15% -30% ( Kimmelstiel - Wilson lesion) - Diffuse mesangial sclerosis II - Renal vascular lesions - Renal atherosclerosis - Hyaline arteriolosclerosis

Kimmelstiel- Wilson lesion

III – Pyelonephritis - Acute & chronic interstitial inflammation - Necrotizing papillitis / papillary necrosis

4- Ocular complications :
I - Retinopathy : - Nonproliferative : hemorrhage, exudate, microaneurysm, edema… - Proliferative : Neovascularization, fibrosis, retinal detachment II - Cataract formation III - Glaucoma

5- Diabetic neuropathy I - Peripheral sensory & autonomic nerve dysfunction ( microangiopathy & demyelination ) II - Neuronal degeneration III - Degenerative spinal cord lesions 6- Recurrent infections : Bacterial & mycotic

Clinical Features in Diabetes :
Type 1 : Age < 20 , but some are latent (LADA) May present with metabolic acidosis, weight loss, dehydration,& electrolyte imbalance. Polyuria , Polydipsia, Polyphagia ( 3P’s) Findings : Hyperglycemia - Glucosuria ± Ketonuria - Electrolyte imbalance

Type 2 : Age > 40yrs., often present incidentally Patients may have the 3 P’s  symptoms of complications Hyperosmolar nonketotic coma caused by dehydration due to uncompensated hyperglycemic diuresis. No keto acidosis Increased susceptibility to infections

ISLET CELL TUMORS

Islet Cells & Secretions :
β cells  insulin α cells  glucagon δ cells  somatostatin Pancreatic polypeptide ( PP)  VIP

Islet Cell Tumors of Pancreas :
Include insulinomas, gastrinomas, glucagonomas….etc Less frequent than pancreatic CA Maybe functioning or nonfunctioning Tumors ≤ 2 cm. diameter likely to be benign Associated clinical syndromes : 1- Hyperinsulinism (Insulinomas) 2- Zollinger - Ellison Syndrome ( Gastrinomas) 3- Multiple endocrine neoplasia (MEN)

Insulinoma : Commonest type Hypoglycemia ≤ 50 mg./dl.
Attack precipitated by fasting or exercise, relieved by eating or glucose administration Lab. :  serum glucose , serum insulin Most tumors in pancreas but can be ectopic Most tumors solitary ( < 2cm.), can be multiple Majority are benign, 10% can be malignant Histologically difficult to diagnose malignancy

Gastrinomas : More in middle aged females
Located in pancreas , duodenum or peripancreatic tissue Single or multiple, or associated with other tumors > 50% locally invasive or have metastasized at diagnosis Present with Zollinger- Ellison Syndrome

Zollinger - Ellison Syndrome :
Peptic ulcer disease Ulcer features : Multiple ulcers Unusual locations specially jejunum Intractable Gastrin hypersecretion Diarrhea in > 50% & may be the presenting symptom

Rare tumors : α- Cell tumors : Middle aged women
Glucagon secretion , mild diabetes, skin rash, anemia δ- Cell tumors : Somatostatin secretion  Diabetes, malabsorption, GB stones… VIPomas : VIP secretion  Watery diarrhea, hypokalemia, achlorhydria

ADRENAL GLAND

ADRENAL GLAND Weight of normal gland is 4 gm.
Adrenal Cortex - Derived from mesoderm & composed of 1- Zona glomerulosamineralocorticoids (aldosteron) 2- Zona fasciculata  glucocorticoids ( cortisol ) 3- Zona reticularis  estrogens & androgens Diseases are those of hyperfunction & hypofunction & tumors

Adrenal Medulla – Derived from neural crest & is part of sympathetic system. Composed of Chromaffin cells secreting catecholamines Diseases are mainly tumors

Congenital Anomalies Incidental finding of adrenal tissue in the inguinoscrotal path , mainly in males Fusion of adrenals Congenital adrenal hyperplasia Ectopic tissue in adrenal : liver, thyroid & ovarian tissue

ADRENOCORTICAL HYPERFUNCTION :
There are 3 syndromes associated with hyperfunction: 1- Cushing’s Syndrome & Cushing’s Disease 2- Conn’s Syndrome & Hyperaldosteronism 3- Adrenogenital Syndrome

CUSHING’Syndrome Elevation of cortisol level , which occurs in one of four ways A- Endogenous causes : i- ACTH*secreting pituitary microadenoma, few macroadenomas, OR hyperplasia (CUSHING’s DISEASE) ii-Adrenal tumor or hyperplasia iii- Paraneoplastic syndrome

B- Exogenous cause : Steroid Therapy Tests used are : Level cortisol in plasma,or excretion of 17hydroxy steroids in urine, diurnal pattern , level of ACTH, & Dexamethasone Suppression test.

Morphology of adrenals in Cushing’s Syndrome :
This depends on the cause : 1- Exogenous increase glucocorticoids ACTH Bilateral atrophy of adrenals 2 -Endogenous hypercorticolism: a- Presence of adrenal adenoma or carcinoma, with atrophy of adjacent & contralateral adrenal b- Secondary to ACTH secreting adenoma bilateral diffuse or nodular hyperplasia c- Primary adrenal nodular hyperplasia

The pituitary in all forms of Cushing’s syndrome shows
Alteration in ACTH producing cells : Granular basophilic cells show lighter homogenized cytoplasm due to accumulation of intermediate keratin filaments in cytoplasm , called : Crooke’s Hyaline Change

Clinical features of Cushing’s syndrome :
Main symptoms include : Central obesity/ moon face Hypertension Hirsutism/ menstrual disturbances Diabetes Osteoporosis Increased risk of infections Pigmentation of skin

HYPERALDOSTERONISM : Excess level of aldosterone cause sodium retension, potassium excretion, resulting in hypertension & hypokalemia. Type could be primary OR secondary

A- Primary : Conn Syndrome
Caused by Adenoma (80%) F:M is 2:1 Single or multiple Or primary adrenal hyperplasia ( 15% ) , Carcinoma is rare Adjacent adrenal cortex is NOT atrophic There is aldosteron Na retention & K excretion  BP , Hypokalemia , RENIN Correctable cause of HYPERTENSION

B- Secondary : Due to decreased renal perfusion, activation of the renin - angiotensin system  aldosteron Differentiate from primary by  RENIN

VIRILIZING Syndromes :
Could be caused by - primary gonadal disorders - Adrenocortical Neoplasms - Congenital adrenal hyperplasia Neoplasms can occur at any age, frequently malignant Congenital adrenal hyperplasia is caused by an enzyme defect in cortisol synthesis (21 hydroxylase) NO CORTISOLACTH androgenic steroids Virilization , precocious puberty, ambiguous genitalia Patients have risk for acute adrenocortical insufficiency

MORPHOLOGY in ALL ADRENAL TUMORS:
Encapsulated , usually yellow Size variable 1-2 cm. ( 30gms.)Up to large tumors Most incidental nonfunctioning tumors, may be functioning Malignant tumors with necrosis, hemorrhage (≥ 300gms) Usually larger , more aggressive in adults Both may show same appearance of uniform or slightly pleomorphic cells ,may be eosinophilic or clear Local invasion ,& the presence of metastases differentiate benign from malignant tumors

Adrenocortical carcinoma

ADRENOCORTICAL INSUFFICIENCY :
May be primary adrenal or secondary to destruction of the pituitary as in SHEEHAN’s syndrome….etc Primary in adrenal may be : A- Acute : 1- Massive adrenal hemorrhage as in anticoaggulant therapy, DIC, sepsis by N.meningitidis,pseudomonas ( Waterhouse- Friderichsen syndrome) 2- Sudden withdrawal of steroid therapy 3- Stress in a pt.with underlying chronic insufficiency

Adrenal insufficiency (continued )
B- Chronic :( Addison’s disease ) Progressive destruction of the adrenal by : 1- Autoimmune Disorder: % , may be sporadic or familial, linked to HLA-B8 , DR3, HLA-DQ5 Often multisystem involvement 2- Infections e.g. Tuberculosis , fungii ( AIDS) 3- Metastatic tumors destroying adrenal e.g. lung, breast , …others

Morphology & Clinical features in Chronic Adrenal Insufficiency :
Morphology depends on cause : Autoimmune : Irregular small glands, cortex infiltrated by lymphocytes, medulla normal. T.B. Caseating Granuloma Metastatic disease  Type of primary tumor Secondary to pituitary cause : the adrenal is shrunken

Clinical features : Weight loss, hypotension, hypoglycemia, pigmentation…. There is Hyperkalemia & Hyponatremia due to ↓ mineralocorticoids

THE ADRENAL MEDULLA : Composed of CHROMAFFIN CELLS & nerve endings
Secretetes cholamines in response to sympathetic stimulation Also present in extra-adrenal sites Pathology includes tumors : A- Pheochromocytoma B- Neuroblastoma

PHEOCHROMOCYTOMA : Secretes catecholamines → VMA
Sometimes described as The 10% Tumor because : * 10% bilateral * 10% extra adrenal ( Paraganglioma) * 10% familial, maybe part of MEN syndrome * 10% Malignant Usually well circumscribed,small to large in size,maybe pleomorphic. Malignancy confirmed by METASTASES Clinically sustained or paroxysmal attacks of  BP CORRECTABLE cause of HYPERTENSION

NEUROBLASTOMA : Commonest extracranial solid tumor of childhood
Usually adrenal but maybe extra-adrenal Familial or sporadic Associated with deletion of short arm of chromosome 1 90% associated with catecholamine secretion VMA excreted in 24 hr. urine helpful in diagnosis. Morphologically it is composed of small round blue cells which may differentiate to ganglion cells Spread to adjacent organs, lymph nodes, renal vein. Prognosis : STAGE , AGE , N myc amplification

MULTIGLANDULAR SYNDROMES

POLYGLANDULAR SYNDROME :
Autoimmune disease Familial or sporadic Isolated involvement of adrenals Multiorgan involvement Type I : autosomal recessive associated with mutation on immune regulator gene on Chr. 21 Type II : multifactorial, linked to HLA-B8 , HLA-DR3 , HLA-DQ5 Include Hashimoto’s thyroiditis,adrenalitis, diabetes type I, pernicious anemia

MEN SYNDROME : Inherited syndrome with multiple endocrine tumors & or hyperplasia of component cells Tumors occur at younger age Often preceded by asymptomatic OR symptomatic hyperplasia in involved organ Tumors may be multifocal in the same organ Often more aggressive than the same tumor without MEN syndrome

Types of MEN syndromes :
Type MEN 1 : ( 3 Ps) Autosomal dominant Involves suppressor gene on 11q.13 Parathyroid : multiglandular parathyroid hyperplasia (95%] Pancreas: aggressive,multifocal functional gastrinomas & insulinomas Pituitary: Prolactinoma ± GH

Autosomal dominant Proto-oncogen mutation : RET/10q 11 MEN 2 A :
Type MEN 2 : Autosomal dominant Proto-oncogen mutation : RET/10q 11 MEN 2 A : Medullary carcinoma of thyroid + C cell hyperplasia Pheochromocytoma (50%) Parathyroid hyperplasia MEN 2 B : As above but no parathyroid hyperplasia Extra endocrine manifestations : e.g. mucosal neurofibromas

PATHOLOGY OF ENDOCRINE SYSTEM 2009

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