dr. Nirwansyah Parampasi, SpPA

dr. Nirwansyah Parampasi, SpPA
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 GTP cAMP Mutations in α subunit interfere with GTPase function G proteins GTPase

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 : * 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

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

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

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 : 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 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
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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 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, 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: 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

Pancreas 15 cm in length, 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)

Pancreatic polypeptide (PP)
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 Glycogen converted to glucose and utilized by tissue
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

Control of secretion of hormones of islets
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.

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

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
Inability to control carbohydrate metabolism Hyperglycaemia Glucosuria Increased plasma osmolarity Osmotic diuresis Hypovelaemia Thirst Loss of Na+ and K+ Polydipsia

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

Prevents proper protein synthesis
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:
Familial incidence and in 80% of cases have association with Class II HLA antigens, particularly HLA DR3,DR4 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.

multifactorial, involving environmental and genetic factors
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
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
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 : occur with blood glucose levels below 50 mg/dL of serum consist principally of central nervous system manifestations (confusion, stupor, and loss of consciousness); 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

dr. Nirwansyah Parampasi, SpPA

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dr. Nirwansyah Parampasi, SpPA

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