Endocrine systemEndocrine system

Fatima Obeidat, MDFatima Obeidat, MD

Department of Pathology and Department of Pathology and Laboratory MedicineLaboratory Medicine

I. Thyroid diseasesI. Thyroid diseases

I. THYROTOXICOSIS I. THYROTOXICOSIS - Is a hypermetabolic state due to elevated circulating levels of - Is a hypermetabolic state due to elevated circulating levels of

free Tfree T33 and T and T44.. - Most commonly, it is caused by hyperfunction of the - Most commonly, it is caused by hyperfunction of the thyroid gland ( called hyperthyroidism)thyroid gland ( called hyperthyroidism) Causes of thyrotoxixosis areCauses of thyrotoxixosis are::II. Associated with hyperthyroidism (Thyroid hyperfunction). Associated with hyperthyroidism (Thyroid hyperfunction)::1. Primary1. Primarya. Diffuse toxic hyperplasia (Graves disease)a. Diffuse toxic hyperplasia (Graves disease)b. Hyperfunctioning (Toxic) multinodular goiter)b. Hyperfunctioning (Toxic) multinodular goiter)c. Hyperfunctioning (toxic ) adenomac. Hyperfunctioning (toxic ) adenoma2. Secondary -- TSH-secreting pituitary adenoma (rare) 2. Secondary -- TSH-secreting pituitary adenoma (rare)

II. Not associated with hyperthyroidismII. Not associated with hyperthyroidism- - Excessive release of pre-formed hormone in thyroiditisExcessive release of pre-formed hormone in thyroiditisClinical manifestations of thyrotoxicosisClinical manifestations of thyrotoxicosisa. Constitutional symptoms : warm flusheda. Constitutional symptoms : warm flushed skin, heat skin, heat

intolerance and excessive sweating intolerance and excessive sweating - Weight loss despite increased appetite.- Weight loss despite increased appetite.b. Malabsorption, and diarrhea. b. Malabsorption, and diarrhea. c. Tachycardia and elderly patients may develop heart c. Tachycardia and elderly patients may develop heart

failure due to aggravation of pre-existing heart diseasefailure due to aggravation of pre-existing heart disease d. Nd. Nervousness, tremor, and irritabilityervousness, tremor, and irritabilitye. Ae. A wide, staring gaze and lid lag because of sympathetic wide, staring gaze and lid lag because of sympathetic

overstimulation of the levator palpebrae superioris overstimulation of the levator palpebrae superioris Note: True Note: True thyroid ophthalmopathythyroid ophthalmopathy associated with associated with

proptosis proptosis

is a feature seen only in Graves diseaseis a feature seen only in Graves disease..f. 50% develop proximal muscle weakness (f. 50% develop proximal muscle weakness ( thyroid thyroid

myopathymyopathy).).g Thyroid storm : Designates the abrupt onset of severe g Thyroid storm : Designates the abrupt onset of severe

hyperthyroidism, and this condition occurs most hyperthyroidism, and this condition occurs most commonly in individuals with Graves disease and it is a commonly in individuals with Graves disease and it is a medical emergency because significant numbers of medical emergency because significant numbers of untreated patients die of cardiac arrhythmiashuntreated patients die of cardiac arrhythmiash

h- h- Apathetic hyperthyroidismApathetic hyperthyroidism : thyrotoxicosis occurring in : thyrotoxicosis occurring in elderly persons, in whom the typical features of thyroid elderly persons, in whom the typical features of thyroid hormone excess seen in younger patients are blunted and hormone excess seen in younger patients are blunted and in these patients the diagnosis is often made during in these patients the diagnosis is often made during

- laboratory workup for unexplained weight loss or worsening - laboratory workup for unexplained weight loss or worsening cardiovascular disease. cardiovascular disease.

Note:Note:- The measurement of serum TSH is the most useful single - The measurement of serum TSH is the most useful single

screening test for hyperthyroidism,screening test for hyperthyroidism, because TSH levels are because TSH levels are decreased even at the earliest stages, when the disease decreased even at the earliest stages, when the disease may still be subclinicalmay still be subclinical

- In rare cases of pituitary or hypothalamus-associated - In rare cases of pituitary or hypothalamus-associated hyperthyroidism, TSH levels are either normal or raised.hyperthyroidism, TSH levels are either normal or raised.

- A low TSH value usually is associated with increased levels - A low TSH value usually is associated with increased levels of free Tof free T44

occasionally hyperthyroidism results predominantly from occasionally hyperthyroidism results predominantly from increased circulating levels of Tincreased circulating levels of T33 (T (T33 toxicosis) and in such toxicosis) and in such cases, free Tcases, free T44 levels may be decreased, and direct levels may be decreased, and direct measurement of serum Tmeasurement of serum T33 may be useful. may be useful.

- Once the diagnosis of thyrotoxicosis has been confirmed - Once the diagnosis of thyrotoxicosis has been confirmed measurement of radioactive iodine uptake by the thyroid gland measurement of radioactive iodine uptake by the thyroid gland often is valuable in determining the etiologyoften is valuable in determining the etiology

For example, such scans may show :For example, such scans may show :a. Diffusely increased (whole-gland) uptake in Graves disease,a. Diffusely increased (whole-gland) uptake in Graves disease,b. Increased uptake in a solitary nodule in toxic adenomab. Increased uptake in a solitary nodule in toxic adenomac.Or decreased uptake in thyroiditis.c.Or decreased uptake in thyroiditis.

HYPOTHYROIDISM : Causes include Primary causesHYPOTHYROIDISM : Causes include Primary causesa. - Worldwide, the most common cause of hypothyroidism a. - Worldwide, the most common cause of hypothyroidism

is dietary deficiency of iodine. is dietary deficiency of iodine. b. In most developed countries, autoimmune diseases b. In most developed countries, autoimmune diseases

predominate such as Hashimoto thyroiditis predominate such as Hashimoto thyroiditis c. Genetic defects such as c. Genetic defects such as Thyroid dysgenesis orThyroid dysgenesis or

CCongenital biosynthetic defect (dyshormogentic goiter)ongenital biosynthetic defect (dyshormogentic goiter) . . II. Secondary causes: II. Secondary causes: Pituitary or hypothalamic disorderPituitary or hypothalamic disorderA. CretinismA. Cretinism : :RRefers to hypothyroidism developing in efers to hypothyroidism developing in

infancy or early childhoodinfancy or early childhood 1. Endemic cretinism1. Endemic cretinism: This disorder formerly was common : This disorder formerly was common

in areas of the world where dietary iodine deficiency is in areas of the world where dietary iodine deficiency is endemic, including endemic, including mountainous areas ( the Himalayas )mountainous areas ( the Himalayas )

- It is now much less frequent because of the widespread - It is now much less frequent because of the widespread supplementation of foods with iodinesupplementation of foods with iodine

2.2. Sporadic cretinism Sporadic cretinism.. Caused by enzyme defects that Caused by enzyme defects that interfere with thyroid hormone synthesisinterfere with thyroid hormone synthesis

Clinical features of cretinism include:Clinical features of cretinism include:- Impaired development of skeletal system- short stature, - Impaired development of skeletal system- short stature, - Coarse facial features, protruding tongue, umbilical hernia. - Coarse facial features, protruding tongue, umbilical hernia. - Central nervous system, with mental retardation - Central nervous system, with mental retardation Note- The severity of the mental impairment seems to beNote- The severity of the mental impairment seems to be

, directly influenced by the timing of onset of the deficient state in , directly influenced by the timing of onset of the deficient state in utero.utero.

- Normally, maternal hormones that are critical to fetal brain - Normally, maternal hormones that are critical to fetal brain development, including Tdevelopment, including T33 and T and T44, cross the placenta., cross the placenta.

1. Severe mental retardation if maternal thyroid deficiency is 1. Severe mental retardation if maternal thyroid deficiency is present before the development of the fetal thyroidpresent before the development of the fetal thyroid

2. Reduction in maternal thyroid hormones later in pregnancy, 2. Reduction in maternal thyroid hormones later in pregnancy, after the fetal thyroid has developedafter the fetal thyroid has developed

allows normal brain development.allows normal brain development.2. M2. Myxedema.yxedema. or Gull syndrome : or Gull syndrome : Hypothyroidism in older Hypothyroidism in older

children and adults and characterized by: children and adults and characterized by:

a. Patients are listless, cold intolerant, and often obese. a. Patients are listless, cold intolerant, and often obese. b. Generalized apathy and mental sluggishness that in the b. Generalized apathy and mental sluggishness that in the

early stages of disease may mimic depressionearly stages of disease may mimic depressionc. Broadening and coarsening of facial featuresc. Broadening and coarsening of facial featuresd. Enlargement of the tongue, and deepening of the voice.d. Enlargement of the tongue, and deepening of the voice.e. Bowel motility is decreased, resulting in constipation. e. Bowel motility is decreased, resulting in constipation. f. Pericardial effusions are common; in later stages, the f. Pericardial effusions are common; in later stages, the

heart is enlarged, and heart failure may supervene.heart is enlarged, and heart failure may supervene.g. Mucopolysaccharide-rich edematous fluid accumulates in g. Mucopolysaccharide-rich edematous fluid accumulates in

skin, subcutaneous tissue, and number of visceral sitesskin, subcutaneous tissue, and number of visceral sitesLaboratory evaluation Laboratory evaluation ::..

- S- Serum TSH is the most sensitive screening test .erum TSH is the most sensitive screening test .

a. The serum TSH is increased in primary hypothyroidisma. The serum TSH is increased in primary hypothyroidismb. The TSH is not increased in persons with hypothyroidism b. The TSH is not increased in persons with hypothyroidism

caused by primary hypothalamic or pituitary disease.caused by primary hypothalamic or pituitary disease.c. Serum Tc. Serum T44 is decreased hypothyroidism of any origin. is decreased hypothyroidism of any origin.

III. ThyroiditisIII. Thyroiditis1. Chronic Lymphocytic (Hashimoto) Thyroiditis1. Chronic Lymphocytic (Hashimoto) Thyroiditis- Is the most common cause of hypothyroidism in areas of - Is the most common cause of hypothyroidism in areas of

the world where iodine levels are sufficient.the world where iodine levels are sufficient.

- It is characterized by gradual thyroid failure secondary - It is characterized by gradual thyroid failure secondary to autoimmune destruction of the thyroid glandto autoimmune destruction of the thyroid gland

- It is most prevalent between the ages of 45 and 65 years - It is most prevalent between the ages of 45 and 65 years and is more common in women than in menand is more common in women than in men

- It can occur in children and is a major cause of non-- It can occur in children and is a major cause of non-endemic goiter in childrenendemic goiter in children

PATHOGENESIS :- Caused by breakdown in self-tolerance PATHOGENESIS :- Caused by breakdown in self-tolerance to thyroid antigens to thyroid antigens

- Circulating autoantibodies against thyroid antigens are- - Circulating autoantibodies against thyroid antigens are- present in the vast majority of patients present in the vast majority of patients

- Multiple immunologic mechanisms may contribute to - Multiple immunologic mechanisms may contribute to thyrocyte damage , thyrocyte damage ,

I. Cytokine-mediated cell death: Excessive T cell activation I. Cytokine-mediated cell death: Excessive T cell activation leads to the production of inflammatory cytokines such as leads to the production of inflammatory cytokines such as

IFN-γ in the thyroid with resultant recruitment and activation IFN-γ in the thyroid with resultant recruitment and activation of macrophages and damage to follicles. of macrophages and damage to follicles.

2. Binding of anti-thyroid antibodies (antithyroglobulin, and 2. Binding of anti-thyroid antibodies (antithyroglobulin, and antithyroid peroxidase antibodies), followed by antibody- antithyroid peroxidase antibodies), followed by antibody- dependent cell-mediated cytotoxicity dependent cell-mediated cytotoxicity

- A significant genetic component is supported by the- A significant genetic component is supported by thea. Concordance of disease in a. Concordance of disease in 40% of monozygotic twins,40% of monozygotic twins, b. And the presence of circulating antithyroid antibodies in b. And the presence of circulating antithyroid antibodies in

50% of asymptomatic siblings of affected patients50% of asymptomatic siblings of affected patients . .

Gross :Gross :- Diffuse and symmetric enlargement of the thyroid - Diffuse and symmetric enlargement of the thyroid but localized enlargement may be seen in some cases to but localized enlargement may be seen in some cases to raise suspicion for neoplasmraise suspicion for neoplasm

Microscopic examination Microscopic examination revealsreveals1. Infiltration by small lymphocytes, plasma cells, and well-1. Infiltration by small lymphocytes, plasma cells, and well-

developed germinal centers developed germinal centers 2. The thyroid follicles are atrophic, some are lined by epithelial 2. The thyroid follicles are atrophic, some are lined by epithelial

cells with abundant eosinophilic, cytoplasm, termedcells with abundant eosinophilic, cytoplasm, termed Hürthle Hürthle cells and it is a metaplastic response to injury; these Hurthle cells and it is a metaplastic response to injury; these Hurthle cells have numerous mitochondria cells have numerous mitochondria

- Less commonly, the thyroid is small due to extensive fibrosis - Less commonly, the thyroid is small due to extensive fibrosis (fibrosing variant) but unlike Reidel thyroiditis, the fibrosis does (fibrosing variant) but unlike Reidel thyroiditis, the fibrosis does not extend beyond the capsule of the gland.not extend beyond the capsule of the gland.

- Clinically , - Clinically , painless thyroid enlargement associated with some painless thyroid enlargement associated with some degree of hypothyroidism,degree of hypothyroidism,

Hashimoto thyroiditisHashimoto thyroiditis

- In the usual clinical course, hypothyroidism develops - In the usual clinical course, hypothyroidism develops gradually.; however, it gradually.; however, it may be preceded by transient may be preceded by transient thyrotoxicosisthyrotoxicosis due to disruption of thyroid follicles ,and due to disruption of thyroid follicles ,and secondary release of thyroid hormones (secondary release of thyroid hormones (hashitoxicosishashitoxicosis). ).

- Patients with Hashimoto thyroiditis often :- Patients with Hashimoto thyroiditis often :1. Have 1. Have other autoimmune diseasesother autoimmune diseases

2. .Are at 2. .Are at increased risk for the development of B cell non-increased risk for the development of B cell non-Hodgkin lymphomasHodgkin lymphomas within the thyroid gland. within the thyroid gland.

NoteNote: The relationship between Hashimoto disease and : The relationship between Hashimoto disease and thyroid epithelial cancers remains controversial, with thyroid epithelial cancers remains controversial, with some morphologic and molecular studies suggesting a some morphologic and molecular studies suggesting a predisposition to papillary carcinomas predisposition to papillary carcinomas

2. Subacute Granulomatous (de Quervain) Thyroiditis 2. Subacute Granulomatous (de Quervain) Thyroiditis - Is much less common than Hashimoto disease- Is much less common than Hashimoto disease- Is most common between the ages of 30 and 50 and,- Is most common between the ages of 30 and 50 and,- More frequently in women than in men. - More frequently in women than in men. - Is believed to be caused by a viral infection and a majority of - Is believed to be caused by a viral infection and a majority of

patients have a history of an upper respiratory infection just patients have a history of an upper respiratory infection just before the onset of thyroiditis.before the onset of thyroiditis.

Gross-Gross- The gland has intact capsule, and may be unilaterally The gland has intact capsule, and may be unilaterally or bilaterally enlarged. or bilaterally enlarged.

Histologic examination reveals Histologic examination reveals 1. Disruption of thyroid follicles, with extravasation of colloid 1. Disruption of thyroid follicles, with extravasation of colloid

leading to a neutrophilic infiltrate, which is replaced by leading to a neutrophilic infiltrate, which is replaced by lymphocytes, plasma cells, and macrophages.lymphocytes, plasma cells, and macrophages.

2. The extravasated colloid provokes a granulomatous 2. The extravasated colloid provokes a granulomatous reaction with giant cells that contain fragments of colloid.reaction with giant cells that contain fragments of colloid.

3. Healing occurs by resolution of inflammation and fibrosis.3. Healing occurs by resolution of inflammation and fibrosis. Clinical FeaturesClinical Features : :-Acute onset characterized by neck pain ( with swallowing) -Acute onset characterized by neck pain ( with swallowing) - Fever, malaise, and variable enlargement of the thyroid. - Fever, malaise, and variable enlargement of the thyroid. - Transient hyperthyroidism may occur as a result of - Transient hyperthyroidism may occur as a result of

disruption of follicles and release of excessive hormones.disruption of follicles and release of excessive hormones. - The leukocyte count is increased.- The leukocyte count is increased.

- With progression of disease and gland destruction, a transient - With progression of disease and gland destruction, a transient hypothyroid phase may ensue. hypothyroid phase may ensue.

- The condition typically is self-limited, with most patients - The condition typically is self-limited, with most patients returning to a euthyroid state within 6 to 8 weeksreturning to a euthyroid state within 6 to 8 weeks

3..3..Subacute Lymphocytic Thyroiditis :Subacute Lymphocytic Thyroiditis :- Also is known as - Also is known as silentsilent or or painlesspainless thyroiditis; thyroiditis;- And in a subset of patients the onset of disease follows - - And in a subset of patients the onset of disease follows -

pregnancy (pregnancy (postpartum thyroiditispostpartum thyroiditis). ). - Most likely to be autoimmune because circulating antithyroid - Most likely to be autoimmune because circulating antithyroid

antibodies are found in a majority of patients antibodies are found in a majority of patients - It mostly affects middle-aged women, who present with a- - It mostly affects middle-aged women, who present with a-

painlesspainless neck mass or features of thyrotoxicosis neck mass or features of thyrotoxicosis

- The initial phase of thyrotoxicosis (which is likely to be secondary to - The initial phase of thyrotoxicosis (which is likely to be secondary to thyroid tissue damage) is followed by return To euthyroid state within thyroid tissue damage) is followed by return To euthyroid state within a few months. a few months.

- In a minority of affected persons the condition eventually progresses - In a minority of affected persons the condition eventually progresses to hypothyroidism.to hypothyroidism.

- The histologic features consist of lymphocytic infiltration- The histologic features consist of lymphocytic infiltration4/ Riedel thyroiditis,:4/ Riedel thyroiditis,: A rare disorder of unknown etiology, A rare disorder of unknown etiology, - Characterized by extensive fibrosis involving the thyroid and - Characterized by extensive fibrosis involving the thyroid and

contiguous structures simulating a thyroid neoplasmcontiguous structures simulating a thyroid neoplasm- May be associated with idiopathic fibrosis in other parts of the body, - May be associated with idiopathic fibrosis in other parts of the body,

such as the retroperitoneumsuch as the retroperitoneum

- The presence of circulating antithyroid antibodies in most - The presence of circulating antithyroid antibodies in most patients suggests an autoimmune etiology. patients suggests an autoimmune etiology.

IV. GRAVES DISEASE LIV. GRAVES DISEASE L- - Is the most common cause of Is the most common cause of endogenous hyperthyroidism with a peak incidence in endogenous hyperthyroidism with a peak incidence in women women between the ages of 20 and 40 between the ages of 20 and 40

- It is characterized by a triad of manifestations:- It is characterized by a triad of manifestations: A. ThyrotoxicosisA. Thyrotoxicosis,, caused by a diffusely enlarged, hyper- caused by a diffusely enlarged, hyper-

functional thyroid, is present in all cases. functional thyroid, is present in all cases. B. Infiltrative B. Infiltrative ophthalmopathyophthalmopathy with resultant exophthalmos is with resultant exophthalmos is

noted in 40% of patients as a result of increased volume noted in 40% of patients as a result of increased volume of the retroorbital connective tissues byof the retroorbital connective tissues by

1. Marked infiltration T cells with inflammatory edema1. Marked infiltration T cells with inflammatory edema

2. Accumulation of glycosaminoglycans2. Accumulation of glycosaminoglycans3. Increased numbers of3. Increased numbers of adipocytes (fatty infiltration).adipocytes (fatty infiltration).- These changes displace the eyeball forward, potentially - These changes displace the eyeball forward, potentially

interfering with the function of the extraocular musclesinterfering with the function of the extraocular muscles- Exophthalmos may persist after successful treatment of - Exophthalmos may persist after successful treatment of

the thyrotoxicosis, and may result in corneal injury. the thyrotoxicosis, and may result in corneal injury. C. A localized, infiltrative C. A localized, infiltrative dermopathydermopathy ( p( pretibial myxedemaretibial myxedema) is ) is

seen in a minority of cases and involves the skin overlying seen in a minority of cases and involves the skin overlying the shins, and manifests as scaly thickening the shins, and manifests as scaly thickening

PATHOGENESISPATHOGENESIS : :- Genetic factors are important in the - Genetic factors are important in the causation of Graves disease, the incidence is increased in causation of Graves disease, the incidence is increased in relatives of affected patients, and the concordance rate inrelatives of affected patients, and the concordance rate in

monozygotic twins is 60%. monozygotic twins is 60%. - A genetic susceptibility is associated with the presence of - A genetic susceptibility is associated with the presence of HLA-DR3,and the diseases is characterized by a HLA-DR3,and the diseases is characterized by a

breakdown in self-tolerance to thyroid autoantigens, and breakdown in self-tolerance to thyroid autoantigens, and is the production of multiple autoantibodies, including:is the production of multiple autoantibodies, including:

1. Thyroid-stimulating immunoglobulin:1. Thyroid-stimulating immunoglobulin:- An IgG antibody binds to the TSH receptor and mimics the - An IgG antibody binds to the TSH receptor and mimics the

action of TSH, with resultant increased release of action of TSH, with resultant increased release of hormones and all persons have detectable amounts of hormones and all persons have detectable amounts of this autoantibody, so it is specific for Graves diseasethis autoantibody, so it is specific for Graves disease

2. Thyroid growth-stimulating immunoglobulins2. Thyroid growth-stimulating immunoglobulins::- Directed against the TSH receptor, and have been- Directed against the TSH receptor, and have been

implicated in the proliferation of follicular epitheliumimplicated in the proliferation of follicular epithelium 3. TSH-binding inhibitor immunoglobulins3. TSH-binding inhibitor immunoglobulins: : - Prevent TSH from binding to its receptor on thyroid cells and in - Prevent TSH from binding to its receptor on thyroid cells and in

so doing may actually inhibit thyroid cell function, a finding so doing may actually inhibit thyroid cell function, a finding explains why some patients with Graves spontaneously explains why some patients with Graves spontaneously develop episodes of hypothyroidism.develop episodes of hypothyroidism.

Note: Note: The coexistence of stimulating The coexistence of stimulating andand inhibiting inhibiting immunoglobulins in the serum of the same patient may explain immunoglobulins in the serum of the same patient may explain why some patients with Graves disease spontaneously develop why some patients with Graves disease spontaneously develop episodes of hypothyroidismepisodes of hypothyroidism

- - Autoimmune disorders of the thyroid thus span a continuum on Autoimmune disorders of the thyroid thus span a continuum on which Graves disease, characterized bywhich Graves disease, characterized by

hyperfunction of the thyroid, lies at one extreme and hyperfunction of the thyroid, lies at one extreme and Hashimoto disease, manifesting as hypothyroidism, Hashimoto disease, manifesting as hypothyroidism, occupies the other end.occupies the other end.

..GrossGross: Symmetrical enlargement of the thyroid gland with : Symmetrical enlargement of the thyroid gland with intact capsule,intact capsule,

On microscopic examination,On microscopic examination, a. The follicular cells in untreated cases are tall, and more a. The follicular cells in untreated cases are tall, and more

crowded and may result in formation of small papillaecrowded and may result in formation of small papillaeb. Lymphoid infiltrates, consisting predominantly of T cells, b. Lymphoid infiltrates, consisting predominantly of T cells,

with few B cells and plasma cells are present throughout with few B cells and plasma cells are present throughout the interstitium; with formation of germinal centersthe interstitium; with formation of germinal centers

Laboratory findings and radiologic findingsLaboratory findings and radiologic findings- Elevated serum free T- Elevated serum free T44 and T and T33 and depressed serum TSH and depressed serum TSH

- Because of ongoing stimulation of the thyroid follicles - Because of ongoing stimulation of the thyroid follicles byTSIs, radioactive iodine uptake is increased, byTSIs, radioactive iodine uptake is increased, andradioiodine scans show a andradioiodine scans show a diffuse uptakediffuse uptake of iodine. of iodine.

V. DIFFUSE AND MULTINODULAR GOITER V. DIFFUSE AND MULTINODULAR GOITER - Enlargement of the thyroid, or - Enlargement of the thyroid, or goiter,goiter, is the most common is the most common

manifestation of thyroid diseasemanifestation of thyroid disease

Mechanism :Mechanism : The goiters reflect impaired synthesis of The goiters reflect impaired synthesis of thyroid hormonethyroid hormone often caused by dietary iodine often caused by dietary iodine deficiency and this leads to to a compensatory rise in the deficiency and this leads to to a compensatory rise in the serum TSH, which in turn causes hyperplasia of the .serum TSH, which in turn causes hyperplasia of the . ,,

Graves DiseaseGraves Disease

follicular cells and, ultimately, gross enlargement of the follicular cells and, ultimately, gross enlargement of the thyroid gland .thyroid gland .

- The compensatory increase in functional mass of thegland - The compensatory increase in functional mass of thegland is enough to overcome the hormone deficiency, ensuring is enough to overcome the hormone deficiency, ensuring a a euthyroideuthyroid state in the vast majority of persons state in the vast majority of persons

- If the underlying disorder is sufficiently severe (congenital - If the underlying disorder is sufficiently severe (congenital biosynthetic defect), the compensatory responses may be biosynthetic defect), the compensatory responses may be inadequate to overcome the impairment in hormone inadequate to overcome the impairment in hormone synthesis, resulting in synthesis, resulting in goitrous hypothyroidism goitrous hypothyroidism ..

- The degree of thyroid enlargement is proportional to the - The degree of thyroid enlargement is proportional to the level and duration of thyroid hormone deficiencylevel and duration of thyroid hormone deficiency

Goiters can be endemic or sporadicGoiters can be endemic or sporadic . . I. Endemic goiter I. Endemic goiter :Occurs in geographic areas where the :Occurs in geographic areas where the

soil, water, and food supply contain little iodine.soil, water, and food supply contain little iodine.- The term - The term endemicendemic is used when goiters are present in is used when goiters are present in

more than 10% of the population in a given region. more than 10% of the population in a given region. - Such conditions are common in mountainous areas of the - Such conditions are common in mountainous areas of the

world, including the Himalayas and the Andes but with world, including the Himalayas and the Andes but with increasing availability of iodine supplementation, the increasing availability of iodine supplementation, the frequency and severity of endemic goiter have declinedfrequency and severity of endemic goiter have declined

II. Sporadic goiterII. Sporadic goiter : Less common than endemic goiter. : Less common than endemic goiter.- The condition is more common in females than in males, - The condition is more common in females than in males,

with a peak incidence in puberty or young adulthood, with a peak incidence in puberty or young adulthood,

when there is an increased physiologic demand for Twhen there is an increased physiologic demand for T44..

- It may be caused by several conditions, including the:- It may be caused by several conditions, including the:a. Ingestion of substances that interfere with thyroid a. Ingestion of substances that interfere with thyroid

hormone synthesis , such as excessive calcium and hormone synthesis , such as excessive calcium and vegetables such as cabbage, cauliflower, sprouts, . vegetables such as cabbage, cauliflower, sprouts, .

b. Hereditary enzymatic defects that interfere with thyroid b. Hereditary enzymatic defects that interfere with thyroid hormone synthesis hormone synthesis (dyshormonogenetic goiter).(dyshormonogenetic goiter).

-In most cases, the cause of sporadic goiter is not apparent.-In most cases, the cause of sporadic goiter is not apparent. MORPHOLOGY :MORPHOLOGY :- Initially, the gland is diffusely and symmetrically enlarged - Initially, the gland is diffusely and symmetrically enlarged

(diffuse goiter) but later on it becomes multinodular goiter. (diffuse goiter) but later on it becomes multinodular goiter.

On microscopic examination,On microscopic examination,a. The follicular epithelium may be hyperplastic in the early a. The follicular epithelium may be hyperplastic in the early

stages of disease or flattened and cuboidal during periods stages of disease or flattened and cuboidal during periods of involution.of involution.

b. Colloid is abundant in the latter periods (colloid goiter). b. Colloid is abundant in the latter periods (colloid goiter). c. With time, recurrent episodes of hyperplasia and c. With time, recurrent episodes of hyperplasia and

involution produce ainvolution produce a more irregular enlargement of thee more irregular enlargement of thee thyroid, termed multinodular goiter and thyroid, termed multinodular goiter and vvirtually all long-irtually all long-standing diffuse goiters convert into multinodular goiters. standing diffuse goiters convert into multinodular goiters.

- Multinodular goiters cause multilobulated, asymmetrically - Multinodular goiters cause multilobulated, asymmetrically enlarged glands which attain massive size and old lesions enlarged glands which attain massive size and old lesions often show fibrosis, hemorrhage, calcification often show fibrosis, hemorrhage, calcification

Multinodular GoiterMultinodular Goiter

- Multinodular goiters are typically are hormonally silent,- Multinodular goiters are typically are hormonally silent,- 10% of patients can manifest with thyrotoxicosis due to - 10% of patients can manifest with thyrotoxicosis due to

the development of autonomous nodules producing the development of autonomous nodules producing hormone independent of TSH stimulation and this hormone independent of TSH stimulation and this condition, called toxiccondition, called toxic multinodular goiter or multinodular goiter or Plummer Plummer syndromesyndrome

Clinical Features :Clinical Features :a. The dominant features are a. The dominant features are mass effectsmass effects of the goiter of the goiter b. In addition to the cosmetic problem of a large neck mass b. In addition to the cosmetic problem of a large neck mass

goiters also may cause airway obstruction, dysphagia, goiters also may cause airway obstruction, dysphagia, and compression of large vessels in the neck and upper and compression of large vessels in the neck and upper thorax (so-called thorax (so-called superior vena cava syndromesuperior vena cava syndrome). ).

c. The incidence of malignancy in long-standing multinodular c. The incidence of malignancy in long-standing multinodular goiters is low (less than 5%) but not zero and concern for goiters is low (less than 5%) but not zero and concern for malignancy arises with goiters that demonstrate sudden malignancy arises with goiters that demonstrate sudden changes in size or associated symptoms ( hoarseness).changes in size or associated symptoms ( hoarseness).

VI. Thyroid tumors :VI. Thyroid tumors : From a clinical standpoint, the From a clinical standpoint, the possibility of a cancer is of major concern in patients who possibility of a cancer is of major concern in patients who present with thyroid nodules but fortunately, thepresent with thyroid nodules but fortunately, the majority of majority of solitary nodules of the thyroid prove to be either solitary nodules of the thyroid prove to be either

a. Follicular adenomas a. Follicular adenomas b. A dominant nodule in multinodular goiterb. A dominant nodule in multinodular goiterc. Simple cysts or foci of thyroiditisc. Simple cysts or foci of thyroiditis- Carcinomas of the thyroid, are uncommon, accounting for- Carcinomas of the thyroid, are uncommon, accounting for

much less than 10% of solitary thyroid nodules.much less than 10% of solitary thyroid nodules.- Several clinical criteria provide a clue to the nature of a - Several clinical criteria provide a clue to the nature of a given thyroid nodule: given thyroid nodule: a. Solitary nodules,a. Solitary nodules, in general, are more likely to be in general, are more likely to be

neoplastic than are multiple nodules.neoplastic than are multiple nodules.b. Nodules in younger patientsb. Nodules in younger patients are more likely to be are more likely to be

neoplastic than are those in older patients.neoplastic than are those in older patients. c. Nodules in malesc. Nodules in males are more likely to be neoplastic than are more likely to be neoplastic than

are those in females.are those in females. d. A history of d. A history of radiationradiation therapy to the head and neck therapy to the head and neck

associated with an increased incidence of thyroid cancer.associated with an increased incidence of thyroid cancer.

e. Nodules that take up radioactive iodine in imaging studies (e. Nodules that take up radioactive iodine in imaging studies (hot hot nodulesnodules) are more likely to be benign than malignant,) are more likely to be benign than malignant,

NoteNote: : It is the morphologic evaluationIt is the morphologic evaluation of a given thyroid nodule of a given thyroid nodule by pathological study of surgically resected thyroid tissue that by pathological study of surgically resected thyroid tissue that provides the most definitive diagnosisprovides the most definitive diagnosis

1. Follicular adenomas1. Follicular adenomas- Are benign neoplasms derived from follicular epithelium. - Are benign neoplasms derived from follicular epithelium. - Usually are solitary. - Usually are solitary. - The tumor is demarcated and compressed the adjacent thyroid - The tumor is demarcated and compressed the adjacent thyroid

parenchyma by a well-defined, intact capsuleparenchyma by a well-defined, intact capsule- These features are important in making the distinction from - These features are important in making the distinction from

multinodular goiters,multinodular goiters,

1. Which contain multiple nodules on their cut surface (even 1. Which contain multiple nodules on their cut surface (even if the patient may present with a solitary nodule), if the patient may present with a solitary nodule),

2. Do not compress the adjacent thyroid parenchyma,2. Do not compress the adjacent thyroid parenchyma,3. Lack a well-formed capsule. 3. Lack a well-formed capsule. Microscopic examination of follicular adenoma,Microscopic examination of follicular adenoma,- The cells are arranged in follicles and its variants- The cells are arranged in follicles and its variantsa. Hurthle cell adenoma: The neoplastic cells show oxyphil a. Hurthle cell adenoma: The neoplastic cells show oxyphil

or Hürthle cell change) and its behavior is not different or Hürthle cell change) and its behavior is not different from those of a conventional adenoma. from those of a conventional adenoma.

b. Atypical adenoma: The neoplastic cells exhibit focal b. Atypical adenoma: The neoplastic cells exhibit focal nuclear atypia, (endocrine atypia);and these features do nuclear atypia, (endocrine atypia);and these features do not constitute evidence of malignancy not constitute evidence of malignancy

Follicular adenomaFollicular adenoma

Note:Note:- The hallmark of all follicular adenomas is the presence of an - The hallmark of all follicular adenomas is the presence of an

intact well-formed capsule encircling the tumor. intact well-formed capsule encircling the tumor. - Evaluation of the integrity of the capsule is critical in - Evaluation of the integrity of the capsule is critical in

distinguishing adenomas from follicular carcinomasdistinguishing adenomas from follicular carcinomas ,, which which demonstrate capsular and/or vascular invasion and due to this , demonstrate capsular and/or vascular invasion and due to this , the the definitive diagnosis of thyroid adenoma can be made after definitive diagnosis of thyroid adenoma can be made after histologic examination of the resected nodulehistologic examination of the resected nodule

- Suspected adenomas of the thyroid are therefore removed - Suspected adenomas of the thyroid are therefore removed surgically to exclude malignancysurgically to exclude malignancy

Clinical Features Clinical Features - Manifest as painless nodules, - Manifest as painless nodules,

.- Larger masses may produce difficulty in swallowing. .- Larger masses may produce difficulty in swallowing. - On radionuclide scanning most adenomas take- On radionuclide scanning most adenomas take up iodine less avidly than normal thyroid parenchyma. so- up iodine less avidly than normal thyroid parenchyma. so-

adenomas appear as adenomas appear as coldcold nodules nodules - Toxic adenomas can present with thyrotoxicosis and will - Toxic adenomas can present with thyrotoxicosis and will

appear as appear as warmwarm nodules in the scan nodules in the scan - Thyroid adenomas carry an excellent prognosis and do not - Thyroid adenomas carry an excellent prognosis and do not

recur or metastasize and are recur or metastasize and are notnot forerunners to forerunners to carcinomas; but shared genetic alterations support the carcinomas; but shared genetic alterations support the possibility that a few follicular carcinomas arise in possibility that a few follicular carcinomas arise in preexisting adenomaspreexisting adenomas

Note:About 10% of Note:About 10% of coldcold nodules prove to be malignant and nodules prove to be malignant and by contrast, malignancy is rare in by contrast, malignancy is rare in hot hot nodulesnodules

2. Carcinomas :2. Carcinomas :Accounting for about 1.5% of all cancersAccounting for about 1.5% of all cancers - A female predominance has been noted among patients - A female predominance has been noted among patients

who develop thyroid carcinoma in the early and middle adult who develop thyroid carcinoma in the early and middle adult years and cases manifesting in childhood and late adult life years and cases manifesting in childhood and late adult life are distributed equally between men and womenare distributed equally between men and women

- The major subtypes of thyroid carcinoma are are - The major subtypes of thyroid carcinoma are are 1. Papillary carcinoma ( for more than 85% of cases)1. Papillary carcinoma ( for more than 85% of cases)2. Follicular carcinoma (5% to 15% of cases)2. Follicular carcinoma (5% to 15% of cases)3. Anaplastic carcinoma (less than 5% of cases)3. Anaplastic carcinoma (less than 5% of cases)

4. Medullary carcinoma (5% of cases) 4. Medullary carcinoma (5% of cases) PATHOGENESISPATHOGENESISI.I. Genetic alterations Genetic alterations in follicular cell-derived malignancies are in follicular cell-derived malignancies are

clustered along two oncogenic pathways-clustered along two oncogenic pathways-a. The mitogen-activated protein (MAP) kinase pathway a. The mitogen-activated protein (MAP) kinase pathway b. Phosphatidylinositol-3-kinase (PI-3K)/AKT pathwayb. Phosphatidylinositol-3-kinase (PI-3K)/AKT pathwayA. A. Papillary thyroid carcinomasPapillary thyroid carcinomas: :

1. The first mechanism involves rearrangements of 1. The first mechanism involves rearrangements of RETRET - The - The RETRET gene is not normally expressed in follicular cells but gene is not normally expressed in follicular cells but

in papillary cancers, chromosomal rearrangements place the in papillary cancers, chromosomal rearrangements place the tyrosine kinase domain of tyrosine kinase domain of RETRET under the under the

transcriptional control of genes that are constitutively transcriptional control of genes that are constitutively expressed in the thyroid epithelium and the novel fusion expressed in the thyroid epithelium and the novel fusion proteins so formed are known as RET/PTC and are present proteins so formed are known as RET/PTC and are present in 20% to 40% of papillary thyroid cancers.in 20% to 40% of papillary thyroid cancers.

- The frequency of - The frequency of RET/PTCRET/PTC rearrangements is significantly rearrangements is significantly higher in papillary cancers arising in the backdrop of higher in papillary cancers arising in the backdrop of radiation exposureradiation exposure

2. The second mechanism involves activating point2. The second mechanism involves activating point mutations in mutations in BRAFBRAF, whose product is an intermediate , whose product is an intermediate

signaling component in the MAP kinase pathway signaling component in the MAP kinase pathway Note: RET/PTCNote: RET/PTC rearrangements and rearrangements and BRAFBRAF point mutations are point mutations are

not observed in follicular adenomas or carcinomas. not observed in follicular adenomas or carcinomas.

B. Follicular thyroid carcinomas: B. Follicular thyroid carcinomas:

a. Gain-of-function point mutations of a. Gain-of-function point mutations of RASRAS and and PIK3CA,PIK3CA,

b. Loss-of-function mutations of b. Loss-of-function mutations of PTEN,PTEN, a suppressor gene a suppressor genec. A unique (2;3) translocation presents in one third to one c. A unique (2;3) translocation presents in one third to one

half of follicular carcinomas which creates a fusion gene half of follicular carcinomas which creates a fusion gene composed of portions of composed of portions of PAX8PAX8, a gene that is important in , a gene that is important in thyroid development, and the peroxisome proliferator-thyroid development, and the peroxisome proliferator-activated receptor gene (activated receptor gene (PPARGPPARG), whose product is a ), whose product is a nuclear receptor implicated in cell differentiationnuclear receptor implicated in cell differentiation

C. Anaplastic carcinomas:C. Anaplastic carcinomas: - Molecular alterations include: - Molecular alterations include: 1. Those also seen in well-differentiated carcinomas (e.g., 1. Those also seen in well-differentiated carcinomas (e.g.,

RASRAS or or PIK3CAPIK3CA mutations), at a significantly higher rate, mutations), at a significantly higher rate,

suggesting that the presence of these mutations may suggesting that the presence of these mutations may predispose existing thyroid neoplasms to transform predispose existing thyroid neoplasms to transform

2. Inactivation of 2. Inactivation of TP53TP53, restricted to anaplastic carcinomas , restricted to anaplastic carcinomas and may also relate to their aggressive behaviorand may also relate to their aggressive behavior

D.Medullary thyroid carcinomas:D.Medullary thyroid carcinomas: Arise from the C cells,. Arise from the C cells,. a. Familial medullary thyroid carcinomas occur in multiple a. Familial medullary thyroid carcinomas occur in multiple

endocrine neoplasia type 2 (MEN-2) and are associated endocrine neoplasia type 2 (MEN-2) and are associated with germline with germline RETRET proto-oncogene mutations . proto-oncogene mutations .

b. RETb. RET mutations are also seen in approximately one half mutations are also seen in approximately one half of nonfamilial (sporadic) medullary thyroid cancers. of nonfamilial (sporadic) medullary thyroid cancers. Note: - Chromosomal rearrangements involving Note: - Chromosomal rearrangements involving RET,RET, are are

not seen in medullary carcinomas.not seen in medullary carcinomas.B. Environmental FactorsB. Environmental Factors.. a. The major risk factor to thyroid cancer is exposure to a. The major risk factor to thyroid cancer is exposure to

ionizing radiationionizing radiation,, during the first 2 decades of life. during the first 2 decades of life. b. Deficiency of dietary iodine: b. Deficiency of dietary iodine: and by extension, an and by extension, an

association with goiter is linked with a higher frequency of association with goiter is linked with a higher frequency of follicular carcinomas. follicular carcinomas.

Papillary Carcinoma :Papillary Carcinoma : Is most the most common form Is most the most common form- accounts for the majority of thyroid carcinomas - accounts for the majority of thyroid carcinomas

associated with previous exposure to ionizing radiation. associated with previous exposure to ionizing radiation. - May occur at any age,- May occur at any age,

Gross: Gross: Either solitary or multifocal lesions Either solitary or multifocal lesions - Some are well circumscribed and even encapsulated; others - Some are well circumscribed and even encapsulated; others

infiltrate the adjacent parenchyma and the definitive infiltrate the adjacent parenchyma and the definitive diagnosis is made by microscopic examinationdiagnosis is made by microscopic examination

Microscopically:Microscopically: The diagnosis of papillary carcinoma is based The diagnosis of papillary carcinoma is based on nuclear features even in the absence of a papillary on nuclear features even in the absence of a papillary architecture. architecture.

1. The nuclei of papillary carcinoma cells 1. The nuclei of papillary carcinoma cells a. Are optically clear nuclei, or "Orphan Annie eye" nuclei a. Are optically clear nuclei, or "Orphan Annie eye" nuclei b. Have invaginations of the cytoplasm to the nucleus b. Have invaginations of the cytoplasm to the nucleus

( pseudoinclusions) ( pseudoinclusions)

2. A papillary architecture is common2. A papillary architecture is common3. Concentrically calcified structures(psammoma bodies)3. Concentrically calcified structures(psammoma bodies)4. Foci of lymphatic permeation by tumor cells are present, 4. Foci of lymphatic permeation by tumor cells are present,

but invasion of blood vessels is relatively uncommonbut invasion of blood vessels is relatively uncommon5. Metastases to cervical lymph nodes in half of cases. 5. Metastases to cervical lymph nodes in half of cases. Variant:Variant:The most common is follicular variant associated with The most common is follicular variant associated with

a lower incidence of lymph node metastases and a lower incidence of lymph node metastases and extrathyroidal extension than that for conventional typeextrathyroidal extension than that for conventional type

Clinical Features of papillary carcinomasClinical Features of papillary carcinomasa. Are nonfunctional tumors manifest as painless mass in the a. Are nonfunctional tumors manifest as painless mass in the

neck, either within the thyroid or as metastasis in a cervical neck, either within the thyroid or as metastasis in a cervical lymph node. lymph node.

Papillary carcinomaPapillary carcinoma

b. Are indolent lesions, with 10-year survival rates of 95%. b. Are indolent lesions, with 10-year survival rates of 95%. c. The presence of isolated cervical nodal metastases does c. The presence of isolated cervical nodal metastases does

not have a influence on good prognosis of these lesions. not have a influence on good prognosis of these lesions. d. In a minority of patients, hematogenous metastases are d. In a minority of patients, hematogenous metastases are

present at the time of diagnosis, most commonly to lung. present at the time of diagnosis, most commonly to lung. - The bad prognostic factors are:- The bad prognostic factors are:a. Tumors arising in patients older than 40 years a. Tumors arising in patients older than 40 years b. The presence of extrathyroidal extensionb. The presence of extrathyroidal extensionc. Presence of distant metastases (stage)c. Presence of distant metastases (stage)Follicular Carcinoma :Follicular Carcinoma :

- - Account for 5% to 15% of primary thyroid cancers. Account for 5% to 15% of primary thyroid cancers. --

- More common in women and in areas with dietary iodine - More common in women and in areas with dietary iodine deficiency (accounting for 25% to 40% of thyroid cancers). deficiency (accounting for 25% to 40% of thyroid cancers).

- The peak incidence between the ages of 40 and 60 years- The peak incidence between the ages of 40 and 60 yearsOn microscopic examination,On microscopic examination,- Are composed of fairly uniform cells forming small follicles, - Are composed of fairly uniform cells forming small follicles, - In other cases, follicular differentiation is less apparent- In other cases, follicular differentiation is less apparent- It may be- It may bea. widely invasive, infiltrating the thyroid parenchyma and a. widely invasive, infiltrating the thyroid parenchyma and

extrathyroidal soft tissues, or extrathyroidal soft tissues, or b. Minimally invasive that may be impossible to distinguish from b. Minimally invasive that may be impossible to distinguish from

follicular adenomas on gross examination and the . follicular adenomas on gross examination and the .

. .

- requires extensive histologic sampling to exclude capsular - requires extensive histologic sampling to exclude capsular and/or vascular invasion and/or vascular invasion

Clinical Features Clinical Features - Manifest most frequently as solitary - Manifest most frequently as solitary cold thyroid nodules.cold thyroid nodules.

- Tend to metastasize through the bloodstream - Tend to metastasize through the bloodstream ((hematogenous disseminationhematogenous dissemination) to lungs, bone, and liver. ) to lungs, bone, and liver.

- Regional nodal metastases are uncommon . - Regional nodal metastases are uncommon . - As many as half of patients with widely invasive carcinomas - As many as half of patients with widely invasive carcinomas

succumb to their disease within 10 years,succumb to their disease within 10 years, while less than 10% of patients with minimally invasive while less than 10% of patients with minimally invasive follicular carcinomas die within the same time span. follicular carcinomas die within the same time span.

- Are treated with surgical excision. - Are treated with surgical excision. - Well-differentiated metastases may take up radioactive iodine, so - Well-differentiated metastases may take up radioactive iodine, so

it is used to identify and ablate such lesions. it is used to identify and ablate such lesions. - Because better-differentiated lesions may be stimulated by TSH, - Because better-differentiated lesions may be stimulated by TSH,

patients usually are placed on a thyroid hormone regimen after patients usually are placed on a thyroid hormone regimen after surgery to suppress endogenous TSH.surgery to suppress endogenous TSH.

3. Anaplastic Carcinoma 3. Anaplastic Carcinoma - Are undifferentiated tumors of the thyroid epithelium,- Are undifferentiated tumors of the thyroid epithelium,- The mean age of 65 years.- The mean age of 65 years.- They are aggressive, with a mortality rate of 100%. - They are aggressive, with a mortality rate of 100%. - Approximately a quarter of patients have a past history - Approximately a quarter of patients have a past history ..

a well-differentiated carcinoma, and a 1/4a well-differentiated carcinoma, and a 1/4 thth harbor a well-differentiated harbor a well-differentiated tumor in the resected specimen. tumor in the resected specimen.

- Metastases to distant sites are common, but death occurs in less - Metastases to distant sites are common, but death occurs in less than 1 year as a result of aggressive local growth which than 1 year as a result of aggressive local growth which compromise of vital structures in the neck. compromise of vital structures in the neck.

4. Medullary Carcinoma 4. Medullary Carcinoma - Are neuroendocrine neoplasms.- Are neuroendocrine neoplasms.- Secrete calcitonin, the measurement of which plays an important role - Secrete calcitonin, the measurement of which plays an important role

in the diagnosis and postoperative follow-up evaluation of patients.in the diagnosis and postoperative follow-up evaluation of patients.- In some cases, the tumor cells elaborate somatostatin, serotonin, - In some cases, the tumor cells elaborate somatostatin, serotonin,

and vasoactive intestinal peptide (VIP)and vasoactive intestinal peptide (VIP)--

- Are sporadic in about 70% of cases and the remaining 30% - Are sporadic in about 70% of cases and the remaining 30% are are familialfamilial cases cases

a. Occurring in the setting of MEN syndrome 2A or 2B,a. Occurring in the setting of MEN syndrome 2A or 2B,b. or familial medullary thyroid carcinoma without an associated b. or familial medullary thyroid carcinoma without an associated

MEN syndromeMEN syndromeNote: Both familial and sporadic forms demonstrate activating Note: Both familial and sporadic forms demonstrate activating

RETRET mutations mutations. . - Sporadic medullary carcinomas, as well as familial cases - Sporadic medullary carcinomas, as well as familial cases

without an associated MEN syndrome, occur in adults , with a without an associated MEN syndrome, occur in adults , with a peak incidence in the fifth and sixth decades. peak incidence in the fifth and sixth decades.

- Cases associated with MEN-2A or MEN-2B have been- Cases associated with MEN-2A or MEN-2B have been

reported in younger patients, including children. reported in younger patients, including children. MORPHOLOGY MORPHOLOGY - Multicentricity- Multicentricity is particularly common in familial cases. is particularly common in familial cases. On microscopic examinationOn microscopic examination, , - Are composed of polygonal to spindle-shaped cells, which - Are composed of polygonal to spindle-shaped cells, which

may form nests, trabeculae, and even follicles. may form nests, trabeculae, and even follicles. - Amyloid deposits- Amyloid deposits,, derived from calcitonin molecules, are derived from calcitonin molecules, are

present in the adjacent stroma in many cases present in the adjacent stroma in many cases - Calcitonin is readily demonstrable both within the cytoplasm - Calcitonin is readily demonstrable both within the cytoplasm

of the tumor cells or amyloidof the tumor cells or amyloid- Familial cases are characterized by the- Familial cases are characterized by the presence ofpresence of

Medullary carcinomaMedullary carcinoma

multicentric C cell hyperplasia in the surrounding thyroid multicentric C cell hyperplasia in the surrounding thyroid parenchyma, a feature usually absent in sporadic lesions. parenchyma, a feature usually absent in sporadic lesions.

- And these foci are believed to represent the precursor - And these foci are believed to represent the precursor lesions from which medullary carcinomas arise. lesions from which medullary carcinomas arise.

Clinical Features Clinical Features - The sporadic cases manifests most often as a mass in - The sporadic cases manifests most often as a mass in

the neck, sometimes associated with compression effects the neck, sometimes associated with compression effects such as dysphagia or hoarseness. such as dysphagia or hoarseness.

- In some instances, the initial manifestations are caused by - In some instances, the initial manifestations are caused by the secretion of a peptide hormone (e.g., diarrhea caused the secretion of a peptide hormone (e.g., diarrhea caused by the secretion of VIP). by the secretion of VIP).

- Screening of the patient's relatives for elevated calcitonin - Screening of the patient's relatives for elevated calcitonin levels or levels or RETRET mutations permits early detection of tumors in mutations permits early detection of tumors in familial cases. , familial cases. ,

- All members of MEN-2 kindreds carrying - All members of MEN-2 kindreds carrying RETRET mutations are mutations are offered prophylactic thyroidectomies to prevent theoffered prophylactic thyroidectomies to prevent the

development of medullary carcinomasdevelopment of medullary carcinomas- Often, the only finding in the resected thyroid of these - Often, the only finding in the resected thyroid of these

asymptomatic carriers is the presence of C cell asymptomatic carriers is the presence of C cell hyperplasia or small (<1 cm) hyperplasia or small (<1 cm) micromedullarymicromedullary carcinomas carcinomas..

- - Recent studies have shown that specific Recent studies have shown that specific RETRET mutations mutations correlate with an aggressive behavior in medullary correlate with an aggressive behavior in medullary carcinomas. carcinomas.

II. Parathyroid glandII. Parathyroid gland

I. HYPERPARATHYROIDISM : 3 categoriesI. HYPERPARATHYROIDISM : 3 categories

a. Primarya. Primary type typeb. Secondary,b. Secondary, and, less commonly, and, less commonly,c. Less commonly c. Less commonly tertiarytertiary hyperparathyroidism. hyperparathyroidism. a. Primary Hyperparathyroidisma. Primary Hyperparathyroidism

Is a common disorder and important cause of hypercalcemia Is a common disorder and important cause of hypercalcemia - There has been an increase in the detection of cases in as a - There has been an increase in the detection of cases in as a

result of the routine inclusion of serum calcium assays in testing result of the routine inclusion of serum calcium assays in testing for a variety of clinical conditions for a variety of clinical conditions

Causes of primary hyperparathyrpoidismCauses of primary hyperparathyrpoidism1. Parathyroid adenoma (85% to 95%)1. Parathyroid adenoma (85% to 95%)

2. Primary parathyroid hyperplasia-5% to 10%. 2. Primary parathyroid hyperplasia-5% to 10%. 3. Parathyroid carcinoma-(1%)3. Parathyroid carcinoma-(1%)- In more than 95% of cases, primary hyperparathyroidism is - In more than 95% of cases, primary hyperparathyroidism is

caused by a sporadic adenoma or sporadic hyperplasia.caused by a sporadic adenoma or sporadic hyperplasia. Genetic changes:in familial casesGenetic changes:in familial cases- The genetic defects identified in - The genetic defects identified in familial primaryfamilial primary

hyperparathyroidismhyperparathyroidism include multiple endocrine neoplasia include multiple endocrine neoplasia syndromes, specifically MEN-1 and MEN-2A due to syndromes, specifically MEN-1 and MEN-2A due to mutation of MEN genemutation of MEN gene

PATHOGENESIS PATHOGENESIS 1. Cyclin D1 is overexpressed in 40% of adenomas, 1. Cyclin D1 is overexpressed in 40% of adenomas, 2. MEN1 mutations2. MEN1 mutations:: About 20% to 30% of parathyroid tumors About 20% to 30% of parathyroid tumors

not associated with the MEN-1 syndrome have mutations in not associated with the MEN-1 syndrome have mutations in both copies of the both copies of the MEN1MEN1 gene gene

- The spectrum of - The spectrum of MEN1MEN1 mutations in the sporadic tumorsis mutations in the sporadic tumorsis virtually identical to that in familial adenomas.virtually identical to that in familial adenomas.

1. The typical adenoma:1. The typical adenoma: lie in close proximity to the thyroid lie in close proximity to the thyroid gland or in an ectopic site (the mediastinum) gland or in an ectopic site (the mediastinum)

a. Invested by a capsule and is almost invariably confined to a. Invested by a capsule and is almost invariably confined to single gland , and the remaining glands are normal in size or single gland , and the remaining glands are normal in size or somewhat shrunken, as a result of feedback somewhat shrunken, as a result of feedback

Parathyroid tumorsParathyroid tumors

inhibition by elevated serum calcium inhibition by elevated serum calcium c. Most parathyroid adenomas weigh between 0.5 and 5 g. c. Most parathyroid adenomas weigh between 0.5 and 5 g. On microscopic examination, parathyroid adenomasOn microscopic examination, parathyroid adenomas - Are composed predominantly of chief cells - Are composed predominantly of chief cells - A few nests of larger oxyphil cells also are also present. - A few nests of larger oxyphil cells also are also present. - A rim of compressed, non-neoplastic tissue, separated by - A rim of compressed, non-neoplastic tissue, separated by

a fibrous capsule, is visible at the edge of the adenoma.a fibrous capsule, is visible at the edge of the adenoma.- Cells with pleomorphic nuclei may be seen (endocrine - Cells with pleomorphic nuclei may be seen (endocrine

atypia) and must not be taken as a sign of malignancy. atypia) and must not be taken as a sign of malignancy. - Mitotic figures are rare with inconspicuous adipose tissue - Mitotic figures are rare with inconspicuous adipose tissue 2. Parathyroid hyperplasia2. Parathyroid hyperplasia Is a multiglandular process. Is a multiglandular process.

- In some cases, however, enlargement may be grossly - In some cases, however, enlargement may be grossly apparent in only one or two glands, complicating the apparent in only one or two glands, complicating the distinction between hyperplasia and adenoma. distinction between hyperplasia and adenoma.

- The combined weight of all glands rarely exceeds 1.0 g . - The combined weight of all glands rarely exceeds 1.0 g . Microscopically, Microscopically, - The most common pattern seen is that of chief cell- The most common pattern seen is that of chief cell hyperplasia, and less commonly, the cells contain abundant hyperplasia, and less commonly, the cells contain abundant

clear cytoplasm due to accumulation of glycogen- “ called clear cytoplasm due to accumulation of glycogen- “ called water-clear cell hyperplasia)water-clear cell hyperplasia)

- stromal fat is inconspicuous within foci of hyperplasia. - stromal fat is inconspicuous within foci of hyperplasia. 3. Parathyroid carcinomas : enlarge one gland3. Parathyroid carcinomas : enlarge one gland

- Consist of irregular masses that sometimes exceed 10 g in - Consist of irregular masses that sometimes exceed 10 g in weight with a dense, fibrous capsule enclosing the mass. weight with a dense, fibrous capsule enclosing the mass.

- The diagnosis of carcinoma based on cytologic detail is - The diagnosis of carcinoma based on cytologic detail is unreliable, and invasion of tissues and metastasis are the unreliable, and invasion of tissues and metastasis are the only definitive criteriaonly definitive criteria

- Local recurrence occurs in one third of cases,- Local recurrence occurs in one third of cases,- More distant dissemination occurs in another third- More distant dissemination occurs in another thirdMorphologic changes in other organsMorphologic changes in other organs I. Skeletal changes includeI. Skeletal changes include::a. Osteitis fibrosa cystica) characterized bya. Osteitis fibrosa cystica) characterized by

1. Increased osteoclastic activity, resulting in erosion of1. Increased osteoclastic activity, resulting in erosion of

bone and mobilization of calcium salts, particularly in the bone and mobilization of calcium salts, particularly in the metaphyses of long tubular bones.metaphyses of long tubular bones.

- Bone resorption is accompanied by increased - Bone resorption is accompanied by increased osteoblastic activity and the formation of new bone .osteoblastic activity and the formation of new bone .

- In more severe cases the cortex is grossly thinned and - In more severe cases the cortex is grossly thinned and the marrow contains increased amounts of fibrous tissue the marrow contains increased amounts of fibrous tissue accompanied by foci of hemorrhage and cystsaccompanied by foci of hemorrhage and cysts

b. Brown tumors of hyperparathyroidism)b. Brown tumors of hyperparathyroidism)

- Aggregates of osteoclasts,, and hemorrhage occasionally - Aggregates of osteoclasts,, and hemorrhage occasionally form masses that may be mistaken for neoplasmsform masses that may be mistaken for neoplasms

II. Kidney changesII. Kidney changes

a. PTH-induced hypercalcemia favors the formation ofa. PTH-induced hypercalcemia favors the formation of

urinary tract stones (nephrolithiasis) surinary tract stones (nephrolithiasis) sb. Calcification of the renal interstitium (nephrocalcinosis)b. Calcification of the renal interstitium (nephrocalcinosis)3. Metastatic calcification may be seen in the stomach, lungs, 3. Metastatic calcification may be seen in the stomach, lungs,

myocardium, and blood vessels.myocardium, and blood vessels.Clinical FeaturesClinical Features- Primary hyperparathyroidism is a disease of adults and is much - Primary hyperparathyroidism is a disease of adults and is much

more common in women than in men. more common in women than in men. - The most common manifestation is an increase in serum - The most common manifestation is an increase in serum

calcium and icalcium and is the most common cause of s the most common cause of clinically silent clinically silent hypercalcemia.hypercalcemia.

- The most common cause of clinically apparent hypercalcemia in - The most common cause of clinically apparent hypercalcemia in adults is paraneoplastic syndromesadults is paraneoplastic syndromes

associated with associated with malignancymalignancy and bone metastases and bone metastases- In persons with hypercalcemia caused by parathyroid - In persons with hypercalcemia caused by parathyroid

hyperfunction, serum PTH is inappropriately elevatedhyperfunction, serum PTH is inappropriately elevated- Whereas serum PTH is low to undetectable in those with - Whereas serum PTH is low to undetectable in those with

hypercalcemia caused by nonparathyroid diseases,hypercalcemia caused by nonparathyroid diseases,- Other laboratory alterations include :- Other laboratory alterations include :a. Hypophosphatemia a. Hypophosphatemia b. Increased urinary excretion of calcium and phosphateb. Increased urinary excretion of calcium and phosphateClinical Manifestations :Clinical Manifestations : It traditionally has been It traditionally has been

associated with a constellation of symptoms "painful associated with a constellation of symptoms "painful bones, renal stones, abdominal groans, psychic moans.“bones, renal stones, abdominal groans, psychic moans.“

1. Pain was at one time a prominent manifestation of primary 1. Pain was at one time a prominent manifestation of primary hyperparathyroidism and is secondary to hyperparathyroidism and is secondary to

a. Fractures of bones a. Fractures of bones b. and resulting from renal stones b. and resulting from renal stones - Because serum calcium is now routinely assessed in the - Because serum calcium is now routinely assessed in the

most patients who need blood tests for other conditions, most patients who need blood tests for other conditions, clinically silent hyperparathyroidism is detected early. clinically silent hyperparathyroidism is detected early.

- Hence, many of the classic clinical manifestations, , are - Hence, many of the classic clinical manifestations, , are seen much less frequently .seen much less frequently .

2. 2. Gastrointestinal disturbances,Gastrointestinal disturbances, including constipation, including constipation, nausea, peptic ulcers, pancreatitis, and gallstonesnausea, peptic ulcers, pancreatitis, and gallstones

3. CNS alterations,3. CNS alterations, - depression, lethargy, and seizures - depression, lethargy, and seizures4. Neuromuscular abnormalities,-4. Neuromuscular abnormalities,- weakness and hypotonia weakness and hypotonia5. Polyuria5. Polyuria and secondary polydipsia and secondary polydipsiab. Secondary Hyperparathyroidism b. Secondary Hyperparathyroidism - Is caused by any - Is caused by any

condition causing a chronic decreases in the serum condition causing a chronic decreases in the serum calcium level, because low serum calcium leads to calcium level, because low serum calcium leads to compensatory overactivity of the parathyroids. compensatory overactivity of the parathyroids.

- Renal failure is the most common cause - Renal failure is the most common cause

1. Chronic renal insufficiency causes decreased phosphate 1. Chronic renal insufficiency causes decreased phosphate excretion, which in turn results in hyperphosphatemia. excretion, which in turn results in hyperphosphatemia. and the elevated serum phosphate levels depress serum and the elevated serum phosphate levels depress serum calcium levels and so stimulate parathyroid gland activitycalcium levels and so stimulate parathyroid gland activity

2.Loss of renal substances reduces the availability of α2.Loss of renal substances reduces the availability of α11--hydroxylase enzyme necessary for the synthesis of the hydroxylase enzyme necessary for the synthesis of the active form of vitamin D, which in turn reduces intestinal active form of vitamin D, which in turn reduces intestinal absorption of calcium absorption of calcium

GrossGross-- The parathyroid glands are hyperplastic The parathyroid glands are hyperplastic ..

On microscopic examinationOn microscopic examination

- The hyperplastic glands Contain an increased number of - The hyperplastic glands Contain an increased number of chief cells, or chief cells, or ((water-clear cellswater-clear cells) ) andand Fat cells are Fat cells are decreased in number .decreased in number .

Clinical Features Clinical Features - Are dominated by those related to chronic renal failure- Are dominated by those related to chronic renal failure

- Bone abnormalities (- Bone abnormalities (renal osteodystrophyrenal osteodystrophy) are less severe ) are less severe than those seen in primary type than those seen in primary type

- Serum calcium remains near normal because - Serum calcium remains near normal because compensatory increase in PTH levels sustains serum compensatory increase in PTH levels sustains serum calcium.calcium.

- The metastatic calcification of blood vessels (secondary - The metastatic calcification of blood vessels (secondary to hyperphosphatemia) occasionally may result in to hyperphosphatemia) occasionally may result in significant ischemic damage to skin and other organs-a significant ischemic damage to skin and other organs-a process sometimes referred to as process sometimes referred to as calciphylaxis.calciphylaxis.

Note- In a minority of patients, parathyroid activity may Note- In a minority of patients, parathyroid activity may become autonomous and excessive, with resultant become autonomous and excessive, with resultant hypercalcemia-a process sometimes termed hypercalcemia-a process sometimes termed tertiarytertiary

.. hyperparathyroidism hyperparathyroidism

- Parathyroidectomy may be necessary to control the - Parathyroidectomy may be necessary to control the hyperparathyroidism in such patients. hyperparathyroidism in such patients.

HYPOPARATHYROIDISM:HYPOPARATHYROIDISM: is less common than is less common than hyperparathyroidism and the major causes are:. hyperparathyroidism and the major causes are:.

a. Surgically induced hypoparathyroidisma. Surgically induced hypoparathyroidism : inadvertent : inadvertent removal of parathyroids during thyroidectomy.removal of parathyroids during thyroidectomy.

b. Congenital absenceb. Congenital absence: This occurs in conjunction with : This occurs in conjunction with thymic aplasia (Di George syndrome) and cardiac defects, thymic aplasia (Di George syndrome) and cardiac defects, secondary to deletions on chromosome 22q11.2 secondary to deletions on chromosome 22q11.2

c. Autoimmune hypoparathyroidismc. Autoimmune hypoparathyroidism :This is a hereditary :This is a hereditary polyglandular deficiency syndrome polyglandular deficiency syndrome

arising from autoantibodies to multiple endocrine arising from autoantibodies to multiple endocrine organs(parathyroid, thyroid, adrenals, and pancreas). organs(parathyroid, thyroid, adrenals, and pancreas).

- Mucocutaneous candidiasis) are sometimes encountered in - Mucocutaneous candidiasis) are sometimes encountered in affected persons affected persons

Clinical manifestations Clinical manifestations

- A- Are secondary to hypocalcemia and include:re secondary to hypocalcemia and include:a. Increased neuromuscular irritability (tingling, muscle a. Increased neuromuscular irritability (tingling, muscle

spasms, facial grimacing, and sustained carpopedal spasm spasms, facial grimacing, and sustained carpopedal spasm or tetany), or tetany),

b. Cardiac arrhythmias, and, on occasion, increasedb. Cardiac arrhythmias, and, on occasion, increasedc. Seizures.c. Seizures.

III. Endocrine PancreasIII. Endocrine Pancreas

Diabetes MellitusDiabetes Mellitus

PrediabetesPrediabetes : : Is defined as elevated blood sugar that does Is defined as elevated blood sugar that does not reach the criterion accepted for an outright diagnosis not reach the criterion accepted for an outright diagnosis of diabetes and persons with prediabetes have an of diabetes and persons with prediabetes have an elevated risk for development of frank diabetes. elevated risk for development of frank diabetes.

Laboratory studiesLaboratory studies::- Blood glucose levels normally are maintained in a very - Blood glucose levels normally are maintained in a very

narrow range, usually 70 to 120 mg/dL. narrow range, usually 70 to 120 mg/dL. - Diabetes Mellitus is diagnosed by any one of three criteria- Diabetes Mellitus is diagnosed by any one of three criteria1. A random blood glucose concentration of 200 mg/dL or 1. A random blood glucose concentration of 200 mg/dL or

higher, with classical signs and symptomshigher, with classical signs and symptoms2. A fasting glucose concentration of 126 mg/dL or higher on 2. A fasting glucose concentration of 126 mg/dL or higher on

more than one occasionmore than one occasion

3. An abnormal oral glucose tolerance test (OGTT), in which 3. An abnormal oral glucose tolerance test (OGTT), in which the glucose levels is 200 mg/dL or higher 2 hours after a the glucose levels is 200 mg/dL or higher 2 hours after a standard carbohydrate load (75 g of glucose). standard carbohydrate load (75 g of glucose).

Notes:Notes:a. Persons with serum fasting glucose values < 110 mg/dL, a. Persons with serum fasting glucose values < 110 mg/dL,

or < 140 mg/dL for an OGTT, are considered euglycemicor < 140 mg/dL for an OGTT, are considered euglycemicb. Those with fasting glucose > 110 but < 126 mg/dL, or b. Those with fasting glucose > 110 but < 126 mg/dL, or

OGTT values of >140 but < 200 mg/dL, have OGTT values of >140 but < 200 mg/dL, have impaired impaired glucose toleranceglucose tolerance, known as , known as prediabetesprediabetes

c. Persons with impaired glucose tolerance have a c. Persons with impaired glucose tolerance have a significant risk for progression to overt diabetes over time significant risk for progression to overt diabetes over time and 5% to 10% advancing to diabetes mellitus per year. and 5% to 10% advancing to diabetes mellitus per year.

Note: Note: Those with impaired glucose tolerance are at Those with impaired glucose tolerance are at risk for risk for cardiovascular disease,cardiovascular disease, due to abnormal carbohydrate due to abnormal carbohydrate metabolism and coexistence of other risk factors metabolism and coexistence of other risk factors

Classification of Diabetes MellitusClassification of Diabetes Mellitus

TYPE 1 DiabetesTYPE 1 Diabetes :- It accounts for 10% of all cases :- It accounts for 10% of all cases - Is an autoimmune disease destructing Pancreatic B cell - Is an autoimmune disease destructing Pancreatic B cell

leading to an absolute deficiency of insulinleading to an absolute deficiency of insulin- Most commonly develops in childhood, becomes manifest - Most commonly develops in childhood, becomes manifest

at puberty, and patients depend on exogenous insulin for at puberty, and patients depend on exogenous insulin for survival; without insulin they develop complications survival; without insulin they develop complications

- The classic manifestations of the disease occur late in its - The classic manifestations of the disease occur late in its course, after 90% of the beta cells have been destroyedcourse, after 90% of the beta cells have been destroyed

Pathogenesis:Pathogenesis:- The fundamental immune abnormality in - The fundamental immune abnormality in type 1 diabetes is a failure of self-tolerance in T cells that type 1 diabetes is a failure of self-tolerance in T cells that may be be a result of combination of: may be be a result of combination of:

a. Defective deletion of self-reactive T cells in the thymus, a. Defective deletion of self-reactive T cells in the thymus, b. And defects in the functions of regulatory T cellsb. And defects in the functions of regulatory T cells- Thus, autoreactive T cells not only survive but are poised - Thus, autoreactive T cells not only survive but are poised

to respond to self-antigens. to respond to self-antigens. - Autoantibodies against B cell antigens, including insulin - Autoantibodies against B cell antigens, including insulin

and enzyme glutamic acid decarboxylase, are detected in and enzyme glutamic acid decarboxylase, are detected in the blood of 70% to 80% of patientsthe blood of 70% to 80% of patients

I. Genetic factorsI. Genetic factors: 20 susceptibility loci have been identified.: 20 susceptibility loci have been identified.

a. The principal susceptibility locus resides in thea. The principal susceptibility locus resides in the locus 6p locus 6p

(HLA-D)(HLA-D) that encodes the class II MHC molecules , 95% of that encodes the class II MHC molecules , 95% of white patients have white patients have HLA-DR3,HLA-DR3, or or DR4,DR4, in contrast with in contrast with about 40% of normal subjects and despite the high about 40% of normal subjects and despite the high relative risk in persons with particular class II alleles, most relative risk in persons with particular class II alleles, most people who inherit these alleles do not develop diabetes.people who inherit these alleles do not develop diabetes.

b. Polymorphisms in the insulin gene may reduce expression b. Polymorphisms in the insulin gene may reduce expression of this protein in the thymus, thus reducing the elimination of this protein in the thymus, thus reducing the elimination of T cells reactive with this self protein of T cells reactive with this self protein

c. Polymorphism of PTPN-22 is a protein tyrosinec. Polymorphism of PTPN-22 is a protein tyrosine phosphatase ; that T cell responses, so polymorphisms phosphatase ; that T cell responses, so polymorphisms

that interfere with their functional activity set the stage for that interfere with their functional activity set the stage for

excessive T cell activation. excessive T cell activation. II. II. Additional evidence suggests that infections, may be Additional evidence suggests that infections, may be

involved in type 1 diabetes and it has been proposed that involved in type 1 diabetes and it has been proposed that certain viruses (mumps, coxsackie B viruses), may be an certain viruses (mumps, coxsackie B viruses), may be an initiating trigger, perhaps because some viral antigens are initiating trigger, perhaps because some viral antigens are antigenically similar to beta cell antigens leading to islets antigenically similar to beta cell antigens leading to islets damage , but this idea is not conclusively established. damage , but this idea is not conclusively established.

Type 2 diabetes :Type 2 diabetes : Accounts for 80% to 90% of cases Accounts for 80% to 90% of cases- Caused by a combination of- Caused by a combination ofa. Peripheral resistance to insulin action and a. Peripheral resistance to insulin action and b. An inadequate compensatory response of insulin b. An inadequate compensatory response of insulin

secretion by B-cells (secretion by B-cells (relative insulin deficiencyrelative insulin deficiency

Pathogenesis : IPathogenesis : Is a complex multifactorial disease. s a complex multifactorial disease. 1. Environmental factors, such as a sedentary life style and 1. Environmental factors, such as a sedentary life style and

dietary habits, unequivocally play a role, dietary habits, unequivocally play a role, 2. Genetic factors are also involved , as evidenced by 2. Genetic factors are also involved , as evidenced by a. The disease concordance rate is 35% to 60% in a. The disease concordance rate is 35% to 60% in

monozygotic twins and such concordance is even greater monozygotic twins and such concordance is even greater than in type 1 diabetes, suggesting perhaps an even than in type 1 diabetes, suggesting perhaps an even larger genetic component in type 2 diabetes.larger genetic component in type 2 diabetes.

b. Diabetogenic genes have been identified but the disease b. Diabetogenic genes have been identified but the disease is not linked to genes involved in immune tolerance and is not linked to genes involved in immune tolerance and evidence of an autoimmune basis is lacking.evidence of an autoimmune basis is lacking.

Metabolic defects that characterize type 2 DM are:Metabolic defects that characterize type 2 DM are: I. Insulin resistanceI. Insulin resistance: : :: Is defined as the failure of target Is defined as the failure of target

tissues to respond normally to insulin and it predates the tissues to respond normally to insulin and it predates the development of hyperglycemia and accompanied by development of hyperglycemia and accompanied by compensatory B- cell hyperfunction and compensatory B- cell hyperfunction and hyperinsulinemia in the early stages of the diabeteshyperinsulinemia in the early stages of the diabetes

- It leads to decreased uptake of glucose in muscle, - It leads to decreased uptake of glucose in muscle, reduced glycolysis and fatty acid oxidation in the liver, reduced glycolysis and fatty acid oxidation in the liver,

MechanismMechanisma. Functional defects in the insulin signaling pathwaya. Functional defects in the insulin signaling pathway- Reduced phosphorylation-dependent activation of the - - Reduced phosphorylation-dependent activation of the -

insulin receptor and its downstream components, whichinsulin receptor and its downstream components, which

attenuate signal transduction.attenuate signal transduction.b. Obesity and Insulin Resistance :Vb. Obesity and Insulin Resistance :Visceral obesity is isceral obesity is

common in majority of affected patients and insulin common in majority of affected patients and insulin resistance is present even with simple obesity un-resistance is present even with simple obesity un-accompanied by hyperglycemia, indicating a fundamental accompanied by hyperglycemia, indicating a fundamental abnormality of insulin signaling in states of fatty excess. abnormality of insulin signaling in states of fatty excess.

Metabolic syndromeMetabolic syndrome characterized by the following characterized by the following ::a. Visceral obesity, accompanied by insulin resistance, a. Visceral obesity, accompanied by insulin resistance, b. Glucose intolerance and cardiovascular risk factors such b. Glucose intolerance and cardiovascular risk factors such

as hypertension and abnormal lipid profiles as hypertension and abnormal lipid profiles - In the absence of weight loss and lifestyle modifications, - In the absence of weight loss and lifestyle modifications,

persons with metabolic syndrome are at significant risk persons with metabolic syndrome are at significant risk

for development of frank type 2 diabetes,. for development of frank type 2 diabetes,. - The risk of diabetes increases as the body mass index - The risk of diabetes increases as the body mass index

increases, suggesting a dose-response relationship increases, suggesting a dose-response relationship between body fat and insulin resistance. between body fat and insulin resistance.

Putative pathways leading to insulin resistance Putative pathways leading to insulin resistance A. Role of excess free fatty acidsA. Role of excess free fatty acids (FFAs): (FFAs): The level of The level of

intracellular triglycerides often is markedly increased in intracellular triglycerides often is markedly increased in muscle and liver tissues in obese persons because muscle and liver tissues in obese persons because excess circulating FFAs are deposited in these organs excess circulating FFAs are deposited in these organs

- Intracellular triglycerides are potent inhibitors of insulin - Intracellular triglycerides are potent inhibitors of insulin signaling and result in an acquired insulin resistance signaling and result in an acquired insulin resistance

- These - These lipotoxiclipotoxic effects of FFAs are mediated through a effects of FFAs are mediated through a

.decrease in activity of key insulin-signaling proteins.decrease in activity of key insulin-signaling proteinsb.b. Role of inflammation Role of inflammation: : An inflammatory milieu mediated by An inflammatory milieu mediated by

cytokines secreted in response to excess FFAs results in cytokines secreted in response to excess FFAs results in peripheral insulin resistance and beta cell dysfunctionperipheral insulin resistance and beta cell dysfunction

- Excess FFAs within macrophages and beta cells can engage - Excess FFAs within macrophages and beta cells can engage the the inflammasomeinflammasome, leading to secretion of the IL-1β which , leading to secretion of the IL-1β which mediates secretion of additional cytokines from macrophages, mediates secretion of additional cytokines from macrophages, islets, that are released into the circulation and act on the islets, that are released into the circulation and act on the major sites of insulin action to promote insulin resistancemajor sites of insulin action to promote insulin resistance

- There are now ongoing trials of cytokine antagonists - There are now ongoing trials of cytokine antagonists (particularly IL-1β) in patients with type 2 diabetes(particularly IL-1β) in patients with type 2 diabetes

c. Role of adipokinesc. Role of adipokines:: Adipose tissue release Adipose tissue release adipokinesadipokines 1. IL-1β which promote peripheral insulin resistance.1. IL-1β which promote peripheral insulin resistance.2. 2. AdiponectinAdiponectin that has insulin sensitizing activity, that has insulin sensitizing activity, d. Peroxisome proliferator-activated receptord. Peroxisome proliferator-activated receptor-γ (PPARγ-γ (PPARγ):):- A nuclear recepto rin adipose tissue, its activation leads to - A nuclear recepto rin adipose tissue, its activation leads to

secretion of adiponectin so shifts the deposition of FFAs secretion of adiponectin so shifts the deposition of FFAs in adipose tissue away from liver and skeletal muscle..in adipose tissue away from liver and skeletal muscle..

- An antidiabetic drug known as thiazolidinediones acts as - An antidiabetic drug known as thiazolidinediones acts as agonist ligands for PPARγ so improves insulin sensitivity.agonist ligands for PPARγ so improves insulin sensitivity.

II. Beta Cell Dysfunction :II. Beta Cell Dysfunction : Reflects their inability to adapt Reflects their inability to adapt themselves to the long-term demands of peripheral insulin themselves to the long-term demands of peripheral insulin resistance and increased insulin secretion.resistance and increased insulin secretion.

- In states of insulin resistance, insulin secretion initially is - In states of insulin resistance, insulin secretion initially is higher for each level of glucose than in controls and this higher for each level of glucose than in controls and this state is a compensation for peripheral resistance and can state is a compensation for peripheral resistance and can maintain normal plasma glucose for years but eventually, maintain normal plasma glucose for years but eventually, B cell compensation becomes inadequate, leads to hyper-B cell compensation becomes inadequate, leads to hyper-glycemia, accompanied by an absolute loss in beta cells. glycemia, accompanied by an absolute loss in beta cells.

- The molecular mechanisms underlying B-cell dysfunction- The molecular mechanisms underlying B-cell dysfunctiona. Excess FFAs and glucose promote secretion of a. Excess FFAs and glucose promote secretion of

cytokines from cytokines from ββ- cells, leading to recruitment of T-cells - cells, leading to recruitment of T-cells and macrophages into islets, resulting in and macrophages into islets, resulting in ββ- cell death- cell death

b. Amylin, is secreted by the b. Amylin, is secreted by the ββ- cell in conjunction with - cell in conjunction with insulin, and its abnormal aggregation results ininsulin, and its abnormal aggregation results in

amyloid that replaces the isletsamyloid that replaces the isletsb. IAPP also engages the inflammasome and promotes IL-1β b. IAPP also engages the inflammasome and promotes IL-1β

secretion, thus sustaining the inflammatory onslaught on secretion, thus sustaining the inflammatory onslaught on surviving beta cells even late in the disease.surviving beta cells even late in the disease.

Monogenic Forms of Diabetes Monogenic Forms of Diabetes ::- Are uncommon examples of - Are uncommon examples of the the diabetic phenotype occurring as a result of loss-of-function diabetic phenotype occurring as a result of loss-of-function mutations within a single gene.mutations within a single gene.

1. The largest subgroup of patients in this category traditionally 1. The largest subgroup of patients in this category traditionally was designated as having was designated as having maturity-onset diabetes of the young maturity-onset diabetes of the young (MODY)(MODY) because of its superficial because of its superficial

resemblance to type 2 diabetes and its occurrence in younger resemblance to type 2 diabetes and its occurrence in younger patients; and can be the result of inactivatingpatients; and can be the result of inactivating

mutations in one of six genes. mutations in one of six genes. 2. 2. Maternally inherited diabetes and bilateral deafnessMaternally inherited diabetes and bilateral deafness,,

secondary to mitochondrial DNA mutations, and secondary to mitochondrial DNA mutations, and mutations within the mutations within the insulininsulin gene itself, and most gene itself, and most commonly manifests in the neonatal period.commonly manifests in the neonatal period.

Long term complications of Diabetes :Long term complications of Diabetes : There is extreme There is extreme variability among patients in the time of onset , severity, variability among patients in the time of onset , severity, and the particular organs involved but in persons with and the particular organs involved but in persons with tight control of their diabetes, the onset may be delayed. tight control of their diabetes, the onset may be delayed.

The pathogenesis of the long-term complications The pathogenesis of the long-term complications

I. I. Formation of advanced glycation end productsFormation of advanced glycation end products (AGEs (AGEs) as ) as a result of nonenzymatic reactions between intracellulara result of nonenzymatic reactions between intracellular

glucose-derived precursors (glyoxal ,3-deoxyglucosone) glucose-derived precursors (glyoxal ,3-deoxyglucosone) with the amino groups of both intra- and extracellular with the amino groups of both intra- and extracellular proteins. proteins.

- The natural rate of AGE formation is greatly accelerated - The natural rate of AGE formation is greatly accelerated in the presence of hyperglycemia. in the presence of hyperglycemia.

- AGEs bind to a specific receptor (RAGE), expressed on - AGEs bind to a specific receptor (RAGE), expressed on macrophages, endothelium and vascular smooth muscle. macrophages, endothelium and vascular smooth muscle.

- The effects of the AGE-RAGE signaling within vessels- The effects of the AGE-RAGE signaling within vesselsa. Release of a. Release of cytokines and growth factorscytokines and growth factors from intimal from intimal

macrophagesmacrophagesb. Generation of b. Generation of reactive oxygen speciesreactive oxygen species in endothelial cells in endothelial cellsc. Increased c. Increased procoagulant activityprocoagulant activity on endothelial cells and on endothelial cells and

d. Enhanced d. Enhanced proliferation of vascular smooth muscle cells proliferation of vascular smooth muscle cells

and synthesis of extracellular matrixand synthesis of extracellular matrix

e.e. Can Can directly cross-link extracellular matrix proteins and directly cross-link extracellular matrix proteins and AGEs cross-linked proteins can AGEs cross-linked proteins can traptrap plasma or interstitial plasma or interstitial proteins such as; proteins such as;

1. Low-density lipoprotein (LDL) gets trapped within AGE-1. Low-density lipoprotein (LDL) gets trapped within AGE-modified large vessel walls, accelerating atherosclerosismodified large vessel walls, accelerating atherosclerosis

2. Albumin can get trapped within capillaries, accounting in 2. Albumin can get trapped within capillaries, accounting in part for the basement membrane thickening that is part for the basement membrane thickening that is

characteristic of diabetic microangiopathycharacteristic of diabetic microangiopathy II. Activation of intracellular protein kinase C (PKC) II. Activation of intracellular protein kinase C (PKC)

- Intracellular hyperglycemia can stimulate the de novo - Intracellular hyperglycemia can stimulate the de novo synthesis of DAG from glycolytic intermediates causing synthesis of DAG from glycolytic intermediates causing activation of PKC and the effects of this activation activation of PKC and the effects of this activation includeinclude production of production of proangiogenic moleculesproangiogenic molecules such as such as

A, Vascular endothelial growth factor (VEGF ), implicated A, Vascular endothelial growth factor (VEGF ), implicated inthe neovascularization seen in diabetic retinopathy, inthe neovascularization seen in diabetic retinopathy,

b.b. Transforming growth factor-β, leading to increased Transforming growth factor-β, leading to increased deposition of extracellular matrix and basement deposition of extracellular matrix and basement membrane material.membrane material.

III. Disturbances in polyol pathways.III. Disturbances in polyol pathways. - In some tissues that do not require insulin for glucose - In some tissues that do not require insulin for glucose

transport (e.g., nerves, lens, kidneys, blood vessels), transport (e.g., nerves, lens, kidneys, blood vessels),

hyperglycemia leads to an increase in intracellular glucose hyperglycemia leads to an increase in intracellular glucose that is metabolized by the enzyme that is metabolized by the enzyme aldose reductasealdose reductase to to sorbitol, a polyol, and eventually to fructose, in a reaction that sorbitol, a polyol, and eventually to fructose, in a reaction that uses NADPH as a cofactor. uses NADPH as a cofactor.

- NADPH is also required by the enzyme glutathione reductase - NADPH is also required by the enzyme glutathione reductase in a reaction that regenerates reduced glutathione (GSH). in a reaction that regenerates reduced glutathione (GSH).

- GSH is important antioxidant and any reduction in GSH - GSH is important antioxidant and any reduction in GSH increases cellular susceptibility to increases cellular susceptibility to oxidative stress.oxidative stress.

NoteNote- In neurons, persistent hyperglycemia appears to be the - In neurons, persistent hyperglycemia appears to be the major underlying cause of diabetic neuropathy (major underlying cause of diabetic neuropathy (glucose glucose neurotoxicityneurotoxicity).).

MORPHOLOGYMORPHOLOGY in Pancreas in Pancreas

a. a. Reduction in the number and size of isletsReduction in the number and size of islets, most often in , most often in type 1 particularly with rapidly advancing disease.type 1 particularly with rapidly advancing disease.

bb. Leukocytic infiltration of the islets. Leukocytic infiltration of the islets: seen in both type 1 : seen in both type 1 and type 2 DM although it is more severe in type 1and type 2 DM although it is more severe in type 1

- In both types inflammation is often absent ,by the time the - In both types inflammation is often absent ,by the time the disease is clinically evidentdisease is clinically evident

c. c. Amyloid replacement Amyloid replacement of islets in long-standing type 2 of islets in long-standing type 2 diabetes, appear as deposition of pink, amorphous diabetes, appear as deposition of pink, amorphous material beginning in capillaries between cells material beginning in capillaries between cells

d. At advanced stages the islets may undergo fibrosis d. At advanced stages the islets may undergo fibrosis e. Increase in the number and size of islets, in nondiabetic e. Increase in the number and size of islets, in nondiabetic

newborns of diabetic mothers, presumably, fetal islets newborns of diabetic mothers, presumably, fetal islets undergo hyperplasia due to maternal hyperglycemia undergo hyperplasia due to maternal hyperglycemia

Morphology and clinical manifesations of complicationsMorphology and clinical manifesations of complications

1. Diabetic Macrovascular Disease1. Diabetic Macrovascular Disease.: .: - The hallmark is - The hallmark is accelerated atherosclerosis accelerated atherosclerosis affecting the affecting the

aorta , large and medium-sized arteries and it is more aorta , large and medium-sized arteries and it is more severe with early onset in diabetics than in nondiabetics severe with early onset in diabetics than in nondiabetics

- Myocardial infarction due to Coronary artery athero-- Myocardial infarction due to Coronary artery athero-sclerosis is the most common cause of death in diabetics sclerosis is the most common cause of death in diabetics and is as common in diabetic women as in diabetic men and is as common in diabetic women as in diabetic men

- Gangrene of the lower extremities is 100 times more - Gangrene of the lower extremities is 100 times more common in diabetics than in the general population .. common in diabetics than in the general population ..

2. Hyaline arteriolosclerosis2. Hyaline arteriolosclerosis,, - Is the vascular lesion associated with hypertension - Is the vascular lesion associated with hypertension - Is both more prevalent and more severe in diabetics than - Is both more prevalent and more severe in diabetics than

in nondiabetics, but it is not specific for diabetes and may in nondiabetics, but it is not specific for diabetes and may be seen in elderly persons who do not suffer from either be seen in elderly persons who do not suffer from either diabetes or hypertension. diabetes or hypertension.

- It takes the form of hyaline thickening of the wall of the - It takes the form of hyaline thickening of the wall of the arterioles, which causes narrowing of the lumenarterioles, which causes narrowing of the lumen

- In diabetic patients, its severity is related not only to the - In diabetic patients, its severity is related not only to the duration of the disease but also to the presence or duration of the disease but also to the presence or absence of hypertension.absence of hypertension.

3. Diabetic Microangiopathy.3. Diabetic Microangiopathy. : Diffuse thickening of : Diffuse thickening of basement membranes, is most evident in the capillaries of basement membranes, is most evident in the capillaries of the skin, skeletal muscle, retina and , renal glomeruli, the skin, skeletal muscle, retina and , renal glomeruli,

- It may be seen in renal tubules, nerves, and placenta.- It may be seen in renal tubules, nerves, and placenta.- Despite the increase in the thickness of basement - Despite the increase in the thickness of basement membranes, diabetic capillaries are more leaky than membranes, diabetic capillaries are more leaky than

normal to plasma proteins.normal to plasma proteins.- It underlies the development of diabetic nephropathy, - It underlies the development of diabetic nephropathy,

retinopathy , and some forms of neuropathyretinopathy , and some forms of neuropathy- An indistinguishable microangiopathy can be found in - An indistinguishable microangiopathy can be found in

aged nondiabetic patients, but rarely to the extent seen in aged nondiabetic patients, but rarely to the extent seen in persons with long-standing diabetes.persons with long-standing diabetes.

4. Diabetic Nephropathy4. Diabetic Nephropathy.:.:- The kidneys are prime targets of diabetes and renal - The kidneys are prime targets of diabetes and renal

failure is second only to myocardial infarction as a cause failure is second only to myocardial infarction as a cause of death from this disease and of death from this disease and lesions encountered arelesions encountered are::

1. Glomerular lesions1. Glomerular lesions

a. Capillary basement membrane thickening :a. Capillary basement membrane thickening :can be can be detected by electron microscopy within a few years of detected by electron microscopy within a few years of onset of diabetes without any change in renal functiononset of diabetes without any change in renal function

b. Diffuse mesangial sclerosisb. Diffuse mesangial sclerosis,: Consists of a diffuse ,: Consists of a diffuse increase in mesangial matrix and mesangial cell increase in mesangial matrix and mesangial cell proliferation and it is found in most individuals with proliferation and it is found in most individuals with disease than 10 years' duration.disease than 10 years' duration.

- Diffuse mesangial sclerosis also may be seen in - Diffuse mesangial sclerosis also may be seen in association with old age and hypertension association with old age and hypertension

c.Nodular glomerulosclerosisc.Nodular glomerulosclerosis (Kimmelstiel-Wilson lesion (Kimmelstiel-Wilson lesion ) ) - Are ball-like deposits of a laminated matrix situated in the - Are ball-like deposits of a laminated matrix situated in the

periphery of the glomerulus and are PAS-positiveperiphery of the glomerulus and are PAS-positiveNoteNote: Diffuse and the nodular forms of glomerulosclerosis : Diffuse and the nodular forms of glomerulosclerosis

induce sufficient ischemia to cause kidney scarring induce sufficient ischemia to cause kidney scarring 2. Renal atherosclerosis and arteriolosclerosis 2. Renal atherosclerosis and arteriolosclerosis ..- Hyaline arteriolosclerosis affects not only the afferent but - Hyaline arteriolosclerosis affects not only the afferent but

also the efferent arterioles and such efferent also the efferent arterioles and such efferent arteriolosclerosis is rarely if ever encountered in persons arteriolosclerosis is rarely if ever encountered in persons who do not have diabeteswho do not have diabetes

Nodular glomerulosclerosisNodular glomerulosclerosis

.. 3. Pyelonephritis 3. Pyelonephritis,: Is inflammation that usually begins in the ,: Is inflammation that usually begins in the interstitial tissue and involve the tubules and it has both interstitial tissue and involve the tubules and it has both acute and chronic forms that occur in nondiabeticsacute and chronic forms that occur in nondiabetics

as well as in diabetics but are more common and and more as well as in diabetics but are more common and and more severe in diabetics than in the general population;severe in diabetics than in the general population;

- One special pattern of acute pyelonephritis, necrotizing - One special pattern of acute pyelonephritis, necrotizing papillitis (or papillary necrosis), is much more prevalent in papillitis (or papillary necrosis), is much more prevalent in diabetics than in nondiabeticsdiabetics than in nondiabetics

Diabetic nephropathyDiabetic nephropathy: Is a leading cause of end-stage renal : Is a leading cause of end-stage renal disease in USA and the earliest manifestation is the disease in USA and the earliest manifestation is the appearance of small amounts of albumin in the urine (> 30 appearance of small amounts of albumin in the urine (> 30 but < 300 mg/day-( microalbuminuria).but < 300 mg/day-( microalbuminuria).

- Without specific interventions, approximately 80% of- Without specific interventions, approximately 80% of patients with type 1 diabetes and 20% to 40% of those patients with type 1 diabetes and 20% to 40% of those

with type 2 diabetes will develop overt nephropathy withwith type 2 diabetes will develop overt nephropathy with macroalbuminuria (excretion of more than 300 mg/day) macroalbuminuria (excretion of more than 300 mg/day)

over the succeeding 10 to 15 years, usually accompanied over the succeeding 10 to 15 years, usually accompanied by the appearance of hypertension. by the appearance of hypertension.

- 20 years after diagnosis, 75% of persons with type 1 - 20 years after diagnosis, 75% of persons with type 1 diabetes and 20% of those with type 2 diabetes with diabetes and 20% of those with type 2 diabetes with overt nephropathy will develop end-stage renal disease, overt nephropathy will develop end-stage renal disease,

5. Ocular Complications of Diabetes5. Ocular Complications of Diabetes :: - Visual impairment, and blindness, is one of the more - Visual impairment, and blindness, is one of the more

feared consequences of long-standing DM. feared consequences of long-standing DM. - Retinopathy, the most common pattern, consists of - Retinopathy, the most common pattern, consists of

changes that are considered by many ophthalmologists to changes that are considered by many ophthalmologists to be virtually diagnostic of the disease be virtually diagnostic of the disease

a. Nonproliferative (background) retinopathy includesa. Nonproliferative (background) retinopathy includes1. Intraretinal or preretinal hemorrhages, :1. Intraretinal or preretinal hemorrhages, :2. Retinal exudates, can be either "soft" (microinfarcts) or“ 2. Retinal exudates, can be either "soft" (microinfarcts) or“

hard" (deposits of plasma proteins and lipids hard" (deposits of plasma proteins and lipids 3. Microaneurysms, are dilated retinal capillaries that appear 3. Microaneurysms, are dilated retinal capillaries that appear

through the ophthalmoscope as small red dotsthrough the ophthalmoscope as small red dots4. Venous dilations and retinal edema 4. Venous dilations and retinal edema

5. Thickening of the retinal capillaries (microangiopathy)5. Thickening of the retinal capillaries (microangiopathy) b. Proliferative retinopathy: b. Proliferative retinopathy: - A- A process of neo-vascularization and fibrosis leads to process of neo-vascularization and fibrosis leads to

serious consequences , including blindness, especially if it serious consequences , including blindness, especially if it involves the macula involves the macula

- Vitreous hemorrhages can result from rupture of newly - Vitreous hemorrhages can result from rupture of newly formedformed capillaries; the subsequent organization of the capillaries; the subsequent organization of the hemorrhage can cause (retinal detachment) hemorrhage can cause (retinal detachment)

Note: Note: - DM currently is the fourth leading cause of acquired - DM currently is the fourth leading cause of acquired

blindness in the United States.blindness in the United States.- About 60% to 80% of patients develop a form of diabetic- About 60% to 80% of patients develop a form of diabetic

retinopathy approximately 15 to 20 years after diagnosis retinopathy approximately 15 to 20 years after diagnosis - diabetic patients also have an increased propensity for - diabetic patients also have an increased propensity for

glaucoma and cataract formationglaucoma and cataract formation6. Diabetic Neuropathy6. Diabetic Neuropathy.:.: The most frequent pattern of The most frequent pattern of

involvement is that of a peripheral, symmetric neuropathy of the involvement is that of a peripheral, symmetric neuropathy of the lower extremities affecting motor and sensory nerves lower extremities affecting motor and sensory nerves particularly the latter and other forms include particularly the latter and other forms include

a. Autonomic neuropathy produces disturbances in bowel and a. Autonomic neuropathy produces disturbances in bowel and bladder function and sometimes sexual impotence,bladder function and sometimes sexual impotence,

b. Mononeuropathy, which may manifest as sudden foot drop or b. Mononeuropathy, which may manifest as sudden foot drop or wristdrop or isolated cranial nerve palsieswristdrop or isolated cranial nerve palsies

- The neurologic changes may be the result of- The neurologic changes may be the result of

microangiopathy and increased permeability of capillaries that microangiopathy and increased permeability of capillaries that supply the nerves, as well as direct axonal damage. supply the nerves, as well as direct axonal damage.

Clinical Features of Type 1 DM Clinical Features of Type 1 DM In the initial 1 or 2 years after In the initial 1 or 2 years after manifestation of overt manifestation of overt type 1 diabetestype 1 diabetes ( "honeymoon period"), ( "honeymoon period"), exogenous insulin requirements may be minimal to none exogenous insulin requirements may be minimal to none because of residual ongoing endogenous insulin secretionbecause of residual ongoing endogenous insulin secretion but but thereafter the beta cell reserve is exhausted and insulin thereafter the beta cell reserve is exhausted and insulin requirements increase dramatically requirements increase dramatically

- Although beta cell destruction is a gradual process, the - Although beta cell destruction is a gradual process, the transition from impaired glucose tolerance to overt diabetes transition from impaired glucose tolerance to overt diabetes may be abrupt, heralded by an event associated with increased may be abrupt, heralded by an event associated with increased insulin requirements such as infectioninsulin requirements such as infection

- The onset is marked by polyuria, polydipsia, polyphagia, - The onset is marked by polyuria, polydipsia, polyphagia, a. The hyperglycemia exceeds the renal threshold for a. The hyperglycemia exceeds the renal threshold for

reabsorption, and glycosuria induces an osmotic diuresis and reabsorption, and glycosuria induces an osmotic diuresis and polyuria,polyuria,

b. The obligatory renal water loss combined with the b. The obligatory renal water loss combined with the hyperosmolarity tends to deplete intracellular water, triggering hyperosmolarity tends to deplete intracellular water, triggering the thirst centers of the brain and this generates intense thirst the thirst centers of the brain and this generates intense thirst ((polydipsiapolydipsia).).

c. Deficiency of insulin leads to catabolism of proteins and fats c. Deficiency of insulin leads to catabolism of proteins and fats which tends to induce a negative energy balance, which in turn which tends to induce a negative energy balance, which in turn leads to increasing appetite (leads to increasing appetite (polyphagia) polyphagia)

- - Despite the increased appetite, catabolic effects prevail Despite the increased appetite, catabolic effects prevail

, resulting in weight loss and muscle weakness. , resulting in weight loss and muscle weakness. - The combination of polyphagia and weight loss should - The combination of polyphagia and weight loss should

always point to the diagnostic possibility of diabetes.always point to the diagnostic possibility of diabetes.Acute complication of type 1 is Acute complication of type 1 is Diabetic ketoacidosis Diabetic ketoacidosis :: - Deviations from normal dietary intake, unusual physical - Deviations from normal dietary intake, unusual physical

activity, infection, or any other forms of stress may rapidly activity, infection, or any other forms of stress may rapidly influence the fragile metabolic balance influence the fragile metabolic balance

- The plasma glucose usually is in the range of 500 to 700 - The plasma glucose usually is in the range of 500 to 700 mg/dL as a result of absolute insulin deficiency and mg/dL as a result of absolute insulin deficiency and unopposed effects of epinephrine and glucagon unopposed effects of epinephrine and glucagon

1. The marked hyperglycemia causes an osmotic diuresis1. The marked hyperglycemia causes an osmotic diuresis

and dehydration characteristic of the ketoacidotic stateand dehydration characteristic of the ketoacidotic state2. Insulin deficiency leads to activation of lipoprotein lipase, 2. Insulin deficiency leads to activation of lipoprotein lipase,

resultanting in excessive breakdown of adipose stores , resultanting in excessive breakdown of adipose stores , giving rise to increased FFAs which are oxidized by the giving rise to increased FFAs which are oxidized by the liver to produce liver to produce ketones so ketones so ketogenesis is an adaptive ketogenesis is an adaptive phenomenon in times of starvation, generating ketones as phenomenon in times of starvation, generating ketones as a source of energy for consumption by brain.a source of energy for consumption by brain.

- The rate at which ketones are formed may exceed the rate - The rate at which ketones are formed may exceed the rate at which they can be used by peripheral tissues, leading at which they can be used by peripheral tissues, leading to to ketonemiaketonemia and and ketonuriaketonuria and if the urinary excretion of and if the urinary excretion of ketones is diminished by dehydration, the accumulating ketones is diminished by dehydration, the accumulating ketones decrease pH, resulting in metabolic ketoacidosis. ketones decrease pH, resulting in metabolic ketoacidosis.

Clinical manifestations of Type 2 diabetes mellitusClinical manifestations of Type 2 diabetes mellitus

- A- Also may manifest with polyuria and polydipsia, but unlike lso may manifest with polyuria and polydipsia, but unlike in type 1 DM patients are older than 40 years and obesein type 1 DM patients are older than 40 years and obese

- Unfortunately, with the increase in obesity and sedentary - Unfortunately, with the increase in obesity and sedentary life style in Western society, type 2 diabetes is now seen life style in Western society, type 2 diabetes is now seen in children and adolescents with increasing frequency.in children and adolescents with increasing frequency.

- In some cases, medical attention is sought because of - In some cases, medical attention is sought because of unexplained weakness or weight loss. unexplained weakness or weight loss.

- Most frequently, however, the diagnosis is made after - Most frequently, however, the diagnosis is made after routine blood or urine testing in asymptomatic personsroutine blood or urine testing in asymptomatic persons..

- Acute complication is called non-ketotic hyperosmolar - Acute complication is called non-ketotic hyperosmolar coma coma – which engendered by severe dehydration – which engendered by severe dehydration

- resulting from sustained osmotic diuresis and urinary fluid - resulting from sustained osmotic diuresis and urinary fluid loss due to chronic hyperglycemia and the affected loss due to chronic hyperglycemia and the affected person is an elderly diabetic who is disabled by a stroke person is an elderly diabetic who is disabled by a stroke or infection and unable to maintain adequate water intake.or infection and unable to maintain adequate water intake.

- The absence of ketoacidosis and its symptoms (nausea, - The absence of ketoacidosis and its symptoms (nausea, vomiting, respiratory difficulties) delays recognition of the vomiting, respiratory difficulties) delays recognition of the seriousness of the situation until the onset of severe seriousness of the situation until the onset of severe dehydration and coma. dehydration and coma.

Note:- In both types of diabetes patients have enhanced Note:- In both types of diabetes patients have enhanced susceptibility to skin infections , tuberculosis, and susceptibility to skin infections , tuberculosis, and pyelonephritis and such infections cause about 5% of pyelonephritis and such infections cause about 5% of diabetes-related deathsdiabetes-related deaths

- In a person with diabetic neuropathy, a trivial infection in a toe - In a person with diabetic neuropathy, a trivial infection in a toe may be the first event in a long succession of complications may be the first event in a long succession of complications (gangrene, bacteremia, pneumonia)(gangrene, bacteremia, pneumonia)

NoteNote- Several studies have demonstrated that complications, and the - Several studies have demonstrated that complications, and the

associated morbidity and mortality from diabetes are attenuated associated morbidity and mortality from diabetes are attenuated by strict glycemic control. by strict glycemic control.

- For patients with type 1 diabetes, insulin replacement therapy is - For patients with type 1 diabetes, insulin replacement therapy is the mainstay of treatment, while dietary restrictions and the mainstay of treatment, while dietary restrictions and exercise (that improves insulin sensitivity) are the "first line of exercise (that improves insulin sensitivity) are the "first line of defense" for type 2 diabetes. defense" for type 2 diabetes.

- Most patients with type 2 diabetes will eventually- Most patients with type 2 diabetes will eventually

require therapeutic intervention achieved by administration of a require therapeutic intervention achieved by administration of a number of agents that lower glucose levelsnumber of agents that lower glucose levels

- Glycemic control is assessed clinically by measuring the - Glycemic control is assessed clinically by measuring the percentage of glycosylated hemoglobin, also known as percentage of glycosylated hemoglobin, also known as HbA1C, which is formed by non-enzymatic addition of HbA1C, which is formed by non-enzymatic addition of glucose moieties to hemoglobin in red cells. glucose moieties to hemoglobin in red cells.

- HbA1C is a measure of glycemic control over long periods of - HbA1C is a measure of glycemic control over long periods of time (2 to 3 months) and is relatively unaffected by day-to-time (2 to 3 months) and is relatively unaffected by day-to-day Variations and an HbA1C below 7% is taken as evidence day Variations and an HbA1C below 7% is taken as evidence of tight glycemic control, but patients with HbA1C levels in of tight glycemic control, but patients with HbA1C levels in this range also have an increased risk of potentially life-this range also have an increased risk of potentially life-threatening episodes of therapy-related hypoglycemia, threatening episodes of therapy-related hypoglycemia,

Pancreatic neuroendocrine tumors Pancreatic neuroendocrine tumors (PanNETs(PanNETs- Also known as islet cell - Also known as islet cell tumors, aretumors, are most common in most common in

adults and account for 2% of all pancreatic neoplasms.adults and account for 2% of all pancreatic neoplasms.- These tumors have a propensity to elaborate pancreatic - These tumors have a propensity to elaborate pancreatic

hormones, but some are nonfunctional which are larger hormones, but some are nonfunctional which are larger lesions at diagnosis, since they come to clinical attention lesions at diagnosis, since they come to clinical attention later in their natural history than functional PanNETs,.later in their natural history than functional PanNETs,.

- All PanNETs, with the exception of insulinomas are - All PanNETs, with the exception of insulinomas are regarded as having malignant potential, and 65% to 80% regarded as having malignant potential, and 65% to 80% of PanNETs manifest with malignant features of biologic of PanNETs manifest with malignant features of biologic aggressiveness such as invasion or distant metastases aggressiveness such as invasion or distant metastases

I. InsulinomasI. Insulinomas are the most common type of PanNET are the most common type of PanNET - May be responsible for the elaboration of sufficient insulin - May be responsible for the elaboration of sufficient insulin

to induce clinically significant hypoglycemia. to induce clinically significant hypoglycemia. - Clinically characterized by attacks of hypoglycemia, which - Clinically characterized by attacks of hypoglycemia, which

occur when blood glucose levels fall below 50 mg/dL and occur when blood glucose levels fall below 50 mg/dL and consist mainly of central nervous system manifestations consist mainly of central nervous system manifestations such as confusion, and loss of consciousness. such as confusion, and loss of consciousness.

- They are precipitated by fasting or exercise and relieved - They are precipitated by fasting or exercise and relieved by feeding or parenteral administration of glucose by feeding or parenteral administration of glucose

- Insulinomas exhibit favorable biologic behavior ,because- Insulinomas exhibit favorable biologic behavior ,because the majority are identified while they are small <( 2 cm in - the majority are identified while they are small <( 2 cm in -

diameter) and localized to the pancreas diameter) and localized to the pancreas

.- Less than 10% of insulinomas, are malignant and .- Less than 10% of insulinomas, are malignant and diagnosed on the basis of local invasion or metastases. diagnosed on the basis of local invasion or metastases.

II. Gastrinomas :II. Gastrinomas :Marked hypersecretion of gastrin Marked hypersecretion of gastrin usually has its origin in (usually has its origin in (gastrinomasgastrinomas), which may arise in ), which may arise in the duodenum and peripancreatic soft tissues as in the the duodenum and peripancreatic soft tissues as in the pancreas (the so-called gastrinoma triangle) pancreas (the so-called gastrinoma triangle)

- In approximately 25% of patients, gastrinomas arise in - In approximately 25% of patients, gastrinomas arise in MEN-1 syndrome MEN-1 syndrome

- Zollinger and Ellison first called attention to the - Zollinger and Ellison first called attention to the association association of pancreatic islet cell lesions with hypersecretion of of pancreatic islet cell lesions with hypersecretion of gastric acid and severe peptic ulceration ,gastric acid and severe peptic ulceration , which are which are present in 90% to 95% of patients with gastrinomaspresent in 90% to 95% of patients with gastrinomas

-the clinical hallmark of Zollinger-Ellison syndrome-the clinical hallmark of Zollinger-Ellison syndrome- In this condition, hypergastrinemia stimulates extreme - In this condition, hypergastrinemia stimulates extreme

gastric acid secretion, which causes gastric acid secretion, which causes peptic ulceration.peptic ulceration. - The duodenal and gastric ulcers often are - The duodenal and gastric ulcers often are multiplemultiple; , they ; , they

often are often are unresponsiveunresponsive to usual therapy to usual therapy- Ulcers may occur in - Ulcers may occur in unusual locationsunusual locations such as the such as the

jejunum; and when intractable jejunal ulcers are found, jejunum; and when intractable jejunal ulcers are found, Zollinger-Ellison syndrome should be considered. Zollinger-Ellison syndrome should be considered.

- More than half of the affected patients have diarrhea; in - More than half of the affected patients have diarrhea; in 30%, it is the presenting manifestation.30%, it is the presenting manifestation.

- Over half of gastrin-producing tumors are locally invasive - Over half of gastrin-producing tumors are locally invasive or have already metastasized at the time of diagnosisor have already metastasized at the time of diagnosis . .

The Adrenal glandThe Adrenal gland

I. Adrerenocortical Hyperfunction (HyperadrenalismI. Adrerenocortical Hyperfunction (Hyperadrenalism ))1. Hypercortisolism (Cushing Syndrome) 1. Hypercortisolism (Cushing Syndrome) - In clinical practice, most cases are caused by the - In clinical practice, most cases are caused by the

administration of exogenous glucocorticoids (Iatrogenic)administration of exogenous glucocorticoids (Iatrogenic)- The remaining cases are endogenous and caused by - The remaining cases are endogenous and caused by

one of the following one of the following A. Primary hypothalamic-pituitary diseases associated A. Primary hypothalamic-pituitary diseases associated

with hypersecretion of ACTH (Cushing disease) with hypersecretion of ACTH (Cushing disease)

- A- Accounts for 70% of cases of spontaneous, endogenous ccounts for 70% of cases of spontaneous, endogenous Cushing syndrome . Cushing syndrome .

- Occurs most frequently during young adulthood (the 20s - Occurs most frequently during young adulthood (the 20s and 30s) and mainly affecting womenand 30s) and mainly affecting women

- - In the vast majority of cases, the In the vast majority of cases, the pituitary gland contains pituitary gland contains an ACTH-producing microadenomaan ACTH-producing microadenoma

- In the remaining patients, the anterior pituitary contains - In the remaining patients, the anterior pituitary contains areas of areas of corticotroph cell hyperplasiacorticotroph cell hyperplasia which may be: which may be:

a. Primarya. Primaryb. or, less commonly, secondary to excessive ACTH b. or, less commonly, secondary to excessive ACTH

release by a hypothalamic (CRH)-producing tumorrelease by a hypothalamic (CRH)-producing tumor- The adrenal glands in Cushing disease show bilateral - The adrenal glands in Cushing disease show bilateral

nodular cortical hyperplasia secondary to the elevated nodular cortical hyperplasia secondary to the elevated levels of ACTH ("ACTH-dependent" Cushing syndrome).levels of ACTH ("ACTH-dependent" Cushing syndrome).

- The cortical hyperplasia, in turn, is responsible for the - The cortical hyperplasia, in turn, is responsible for the hypercortisolismhypercortisolism

B. Primary adrenal hyperplasia and neoplasmsB. Primary adrenal hyperplasia and neoplasms

- Are responsible for about 10% to 20% of- Are responsible for about 10% to 20% of cases of cases of endogenous Cushing syndrome and this form is called endogenous Cushing syndrome and this form is called ACTH-independent Cushing syndrome,ACTH-independent Cushing syndrome, or adrenal or adrenal Cushing syndrome Cushing syndrome and its biochemical hallmark is and its biochemical hallmark is elevated levels of cortisol with low serum levels of ACTH elevated levels of cortisol with low serum levels of ACTH

- In most cases, adrenal Cushing syndrome is caused by a - In most cases, adrenal Cushing syndrome is caused by a unilateral adrenocortical neoplasm, which may be either unilateral adrenocortical neoplasm, which may be either benign (adenoma) or malignant (carcinoma). benign (adenoma) or malignant (carcinoma).

NoteNote- The overwhelming majority of hyperplastic adrenals - The overwhelming majority of hyperplastic adrenals are ACTH-dependent, and primary cortical hyperplasia of are ACTH-dependent, and primary cortical hyperplasia of the adrenal cortices is a rare cause of Cushing syndromethe adrenal cortices is a rare cause of Cushing syndrome

C. Secretion of ectopic ACTHC. Secretion of ectopic ACTH by nonpituitary tumors by nonpituitary tumors

- Accounts for about 10% of cases of Cushing syndrome mostly - Accounts for about 10% of cases of Cushing syndrome mostly caused by caused by small cell carcinoma of the lungsmall cell carcinoma of the lung, ,

- T- The adrenal glands undergo bilateral hyperplasia due to he adrenal glands undergo bilateral hyperplasia due to elevated ACTH, but the rapid downhill course of patients with elevated ACTH, but the rapid downhill course of patients with these cancers cuts short the adrenal enlargementthese cancers cuts short the adrenal enlargement

MORPHOLOGY of the pituitary in Cushing syndrome MORPHOLOGY of the pituitary in Cushing syndrome

Crooke hyaline change :Crooke hyaline change : Results from high levels of Results from high levels of glucocorticoids, and in this condition, the normal basophilic glucocorticoids, and in this condition, the normal basophilic cytoplasm of the ACTH-producing cells is replaced by cytoplasm of the ACTH-producing cells is replaced by homogeneous slightly basophilic material homogeneous slightly basophilic material

- This alteration is the result of the accumulation of - This alteration is the result of the accumulation of

intermediate keratin filaments in the cytoplasm. intermediate keratin filaments in the cytoplasm. Changes in adrenal in cases of Cushing syndrome:Changes in adrenal in cases of Cushing syndrome:1) Cortical atrophy 1) Cortical atrophy :If the syndrome results from :If the syndrome results from

exogenous glucocorticoids ,suppression of endogenous exogenous glucocorticoids ,suppression of endogenous ACTH results in bilateral cortical atrophyACTH results in bilateral cortical atrophy ,, due to a lack of due to a lack of stimulation of the zona fasciculata and reticularis by stimulation of the zona fasciculata and reticularis by ACTH, ACTH,

- The zona glomerulosa is of normal thickness because it - The zona glomerulosa is of normal thickness because it functions independently of ACTHfunctions independently of ACTH

2. Diffuse and nodular hyperplasia:2. Diffuse and nodular hyperplasia: I Is found in 60% to s found in 60% to 70% of Cases of endogenous Cushing syndrome.70% of Cases of endogenous Cushing syndrome.

-- Secondary hyperplasia is found in patients with ACTH- Secondary hyperplasia is found in patients with ACTH- dependent Cushing syndrome (due to Cushing disease or dependent Cushing syndrome (due to Cushing disease or ectopic production of ACTH)ectopic production of ACTH)

- In primary cortical hyperplasia, the cortex is replaced - In primary cortical hyperplasia, the cortex is replaced almost entirely by macro- or pigmented micronodules, and almost entirely by macro- or pigmented micronodules, and the pigment is believed to be lipofuscinthe pigment is believed to be lipofuscin

3. Primary adrenocortical neoplasms 3. Primary adrenocortical neoplasms

- Are more common in women in their 30s to 50s. - Are more common in women in their 30s to 50s. a. Adrenocortical adenomas: Are yellow tumors surrounded a. Adrenocortical adenomas: Are yellow tumors surrounded

by thin capsules, and most weigh less than 30 g by thin capsules, and most weigh less than 30 g b. Carcinomas tend to be nonencapsulated masses , b. Carcinomas tend to be nonencapsulated masses ,

exceeding 200 to 300 g in weight,exceeding 200 to 300 g in weight, NoteNote: With both functioning benign and malignant tumors, : With both functioning benign and malignant tumors,

the adjacent adrenal cortex and that of the contralateral the adjacent adrenal cortex and that of the contralateral adrenal gland are atrophic because of suppression of adrenal gland are atrophic because of suppression of endogenous ACTH by high cortisol levels endogenous ACTH by high cortisol levels

Clinical Course.: Clinical Course.: Cushing syndrome develops gradually but Cushing syndrome develops gradually but a major exception to this insidious onset is with Cushing a major exception to this insidious onset is with Cushing syndrome associated with small cell carcinomas syndrome associated with small cell carcinomas

ManifestationsManifestations a. Hypertension and weight gain are early manifestationsa. Hypertension and weight gain are early manifestations ..

b. With time, truncal obesity, "moon facies,“ accumulation b. With time, truncal obesity, "moon facies,“ accumulation of fat in the posterior neck and back ("buffalo hump") of fat in the posterior neck and back ("buffalo hump")

c. Selective atrophy of fast-twitch (type II) myofibers, with c. Selective atrophy of fast-twitch (type II) myofibers, with decreased muscle mass and proximal limb weakness. decreased muscle mass and proximal limb weakness. d. Glucocorticoids induce gluconeogenesis with resultant d. Glucocorticoids induce gluconeogenesis with resultant

hyperglycemia, glucosuria,hyperglycemia, glucosuria, and and polydipsia,polydipsia,

e. The catabolic effects on proteins cause loss of collagen e. The catabolic effects on proteins cause loss of collagen and resorption of bone and bone resorption results in and resorption of bone and bone resorption results in thetheosteoporosis,osteoporosis, susceptibility to fractures. susceptibility to fractures.

f. The skin is thin, fragile, and easily bruised; cutaneous f. The skin is thin, fragile, and easily bruised; cutaneous striae are particularly common in the abdominal area striae are particularly common in the abdominal area

g. Patients are at increased risk for a variety of infections. g. Patients are at increased risk for a variety of infections. h. Hirsutism and menstrual abnormalities h. Hirsutism and menstrual abnormalities i. Mental disturbances ,mood swings, depression, psychosisi. Mental disturbances ,mood swings, depression, psychosisNote:Note: Extraadrenal Cushing syndrome caused by pituitary Extraadrenal Cushing syndrome caused by pituitary

or ectopic ACTH secretion usually is associated with . or ectopic ACTH secretion usually is associated with . increased skin pigmentation secondary to melanocyte-increased skin pigmentation secondary to melanocyte-stimulating activity in the ACTH precursor moleculestimulating activity in the ACTH precursor molecule

2. Hyperaldosteronism2. Hyperaldosteronism1. In secondary hyperaldosteronism1. In secondary hyperaldosteronism::- Aldosterone release occurs in response to activation of - Aldosterone release occurs in response to activation of

renin-angiotensin system and characterized by renin-angiotensin system and characterized by increased levels of plasma renin and is encountered in increased levels of plasma renin and is encountered in conditions associated with:conditions associated with:

a. Decreased renal perfusion a. Decreased renal perfusion b. Arterial hypovolemia and edema like in heart failure b. Arterial hypovolemia and edema like in heart failure c. Pregnancy (caused by estrogen-induced increases in c. Pregnancy (caused by estrogen-induced increases in

plasma renin substrate)plasma renin substrate) 2. Primary hyperaldosteronism:2. Primary hyperaldosteronism: Indicates primary , Indicates primary ,

autonomous overproduction of aldosterone with autonomous overproduction of aldosterone with secondary suppression of renin- angiotensin system and secondary suppression of renin- angiotensin system and decreased plasma renin activity and the causes are:decreased plasma renin activity and the causes are:

a. a. Bilateral idiopathic hyperaldosteronismBilateral idiopathic hyperaldosteronism,, - Characterized by bilateral nodular hyperplasia of adrenals - Characterized by bilateral nodular hyperplasia of adrenals - Is the most common underlying cause of primary - Is the most common underlying cause of primary

hyperaldosteronism, accounting for about 60% of cases.hyperaldosteronism, accounting for about 60% of cases.b. Adrenocortical neoplasmb. Adrenocortical neoplasm,, either an adenoma (the most either an adenoma (the most

common cause) or, rarely, an adrenocortical carcinoma.common cause) or, rarely, an adrenocortical carcinoma.- In approximately 35% of cases, the cause is a solitary - In approximately 35% of cases, the cause is a solitary

aldosterone-secreting Aldosterone-producing aldosterone-secreting Aldosterone-producing adrenocortical adenoma referred to as adrenocortical adenoma referred to as Conn syndromeConn syndrome

c. Rarely, familial hyperaldosteronism may result from a c. Rarely, familial hyperaldosteronism may result from a genetic defect that leads to overactivity of the genetic defect that leads to overactivity of the aldosterone synthasealdosterone synthase gene, gene, CYP11B2.CYP11B2.

MORPHOLOGYMORPHOLOGY

1. Aldosterone-producing adenomas 1. Aldosterone-producing adenomas : Are solitary yellow lesion, : Are solitary yellow lesion, less than 2 cm in diameter , composed of lipid-laden cells less than 2 cm in diameter , composed of lipid-laden cells more closely resembling fasciculata cells more closely resembling fasciculata cells

- The cells tend - The cells tend to to be uniform in size and shape; with be uniform in size and shape; with occasional nuclear and cellular pleomorphism. occasional nuclear and cellular pleomorphism.

- A characteristic feature of aldosterone-producing adenomas is - A characteristic feature of aldosterone-producing adenomas is the presence of eosinophilic, laminated cytoplasmic the presence of eosinophilic, laminated cytoplasmic inclusions, known as spironolactone bodies inclusions, known as spironolactone bodies

- These typically are found after treatment with the - These typically are found after treatment with the antihypertensive agent spironolactone, which is the drug- of antihypertensive agent spironolactone, which is the drug- of choice in primary hyperaldosteronism. choice in primary hyperaldosteronism.

- Adenomas associated with hyperaldosteronism do not - Adenomas associated with hyperaldosteronism do not usually suppress ACTH secretion;Therefore, the adjacent usually suppress ACTH secretion;Therefore, the adjacent cortex and that of the contralateral gland are not atrophic.cortex and that of the contralateral gland are not atrophic.

2. Bilateral idiopathic hyperplasia: 2. Bilateral idiopathic hyperplasia: marked by hyperplasia of marked by hyperplasia of cells resembling those of the normal zona glomerulosa. cells resembling those of the normal zona glomerulosa. often occurs in children and young adults often occurs in children and young adults

Clinical Features :Clinical Features :- The clinical hallmark is hypertension- The clinical hallmark is hypertension

- Hyperaldosteronism may be the most common cause of - Hyperaldosteronism may be the most common cause of secondary hypertension secondary hypertension

- Hypokalemia- Hypokalemia results from renal potassium wasting and, results from renal potassium wasting and, can cause neuromuscular manifestations, including can cause neuromuscular manifestations, including weakness, paresthesias,, and occasionally frank tetany. weakness, paresthesias,, and occasionally frank tetany.

- Adenomas are amenable to surgical excision. - Adenomas are amenable to surgical excision. - Surgical intervention is not very beneficial in bilateral - Surgical intervention is not very beneficial in bilateral

hyperplasia, and best managed medically with anhyperplasia, and best managed medically with an aldosterone antagonistaldosterone antagonist such as spironolactone such as spironolactone - The treatment of secondary hyperaldosteronism rests on - The treatment of secondary hyperaldosteronism rests on

correcting the underlying cause of the renin-angiotensin correcting the underlying cause of the renin-angiotensin system hyperstimulation.system hyperstimulation.

ADRENAL INSUFFICIENCYADRENAL INSUFFICIENCY :The patterns are::The patterns are:1. Acute Adrenocortical Insufficiency : causes1. Acute Adrenocortical Insufficiency : causesa. Crisis in patients with chronic adrenocortical a. Crisis in patients with chronic adrenocortical

insufficiency precipitated by stressinsufficiency precipitated by stress b. In patients maintained on exogenous corticosteroids, b. In patients maintained on exogenous corticosteroids,

rapid withdrawal of steroids or failure to increase steroid rapid withdrawal of steroids or failure to increase steroid doses in response to an acute stress, because of the doses in response to an acute stress, because of the inability of the atrophic adrenals to produce glucocorticoidinability of the atrophic adrenals to produce glucocorticoid

c. c. Massive adrenal hemorrhageMassive adrenal hemorrhage may destroy enough of the may destroy enough of the adrenal cortex to cause acute adrenocortical insufficiency.adrenal cortex to cause acute adrenocortical insufficiency.

- This condition may occur :- This condition may occur :1. In patients maintained on anticoagulant therapy1. In patients maintained on anticoagulant therapy2. Patients suffering from sepsis : a condition known as 2. Patients suffering from sepsis : a condition known as

the Waterhouse-Friderichsen syndrome the Waterhouse-Friderichsen syndrome - This catastrophic syndrome is associated with- This catastrophic syndrome is associated with Neisseria Neisseria

meningitidismeningitidis septicemia but can also be caused by septicemia but can also be caused by PseudomonasPseudomonas spp., , and spp., , and Haemophilus influenzaeHaemophilus influenzae

The pathogenesis remains unclear but probably involves The pathogenesis remains unclear but probably involves endotoxin-induced vascular injury endotoxin-induced vascular injury

2. Primary Chronic Adrenocortical Insufficiency 2. Primary Chronic Adrenocortical Insufficiency (Addison (Addison Disease)Disease):: I Is an uncommon disorder resulting from s an uncommon disorder resulting from progressive destruction of the adrenal cortex. progressive destruction of the adrenal cortex.

- More than 90% of all cases are attributable to :. - More than 90% of all cases are attributable to :. a. Autoimmune adrenalitisa. Autoimmune adrenalitis - Accounts for 60% to 70% of cases and is the most - Accounts for 60% to 70% of cases and is the most

common cause of primary adrenal insufficiency in common cause of primary adrenal insufficiency in developed countriesdeveloped countries

- There is autoimmune destruction of steroid-producing - There is autoimmune destruction of steroid-producing cells, and autoantibodies to several key steroidogenic cells, and autoantibodies to several key steroidogenic enzymes have been detected in affected patients enzymes have been detected in affected patients

Adrenal hemorrhageAdrenal hemorrhage

- Occurs in one of two- Occurs in one of two a autoimmune utoimmune ppolyendocrine olyendocrine ssyndromes: yndromes: 1. APS1, caused by mutations in the 1. APS1, caused by mutations in the autoimmune regulator autoimmune regulator

(AIRE)(AIRE) gene on chromosome 21 and is characterized by gene on chromosome 21 and is characterized by a. Chronic mucocutaneous candidiasis a. Chronic mucocutaneous candidiasis b. Abnormalities of skin, dental enamel, and nails (ectodermal b. Abnormalities of skin, dental enamel, and nails (ectodermal

dystrophy)dystrophy)- It occurs in association with a other autoimmune disorders - It occurs in association with a other autoimmune disorders

(autoimmune adrenalitis, autoimmune hypoparathyroidism, (autoimmune adrenalitis, autoimmune hypoparathyroidism, that result in destruction of target organs.that result in destruction of target organs.

b. APS2, which manifests in early adulthood as b. APS2, which manifests in early adulthood as

a combination of adrenal insufficiency and autoimmune a combination of adrenal insufficiency and autoimmune thyroiditis or type 1 diabetes.thyroiditis or type 1 diabetes.

- Mucocutaneous candidiasis, ectodermal dysplasia, and - Mucocutaneous candidiasis, ectodermal dysplasia, and autoimmune hypoparathyroidism do not occur.autoimmune hypoparathyroidism do not occur.

B. InfectionsB. Infections,: ,: Tuberculosis and Fungal infectionsTuberculosis and Fungal infections- Tuberculous adrenalitis, which once accounted for as - Tuberculous adrenalitis, which once accounted for as

many as 90% of cases of Addison disease, has become many as 90% of cases of Addison disease, has become less common with the advent of anti-tuberculosis therapyless common with the advent of anti-tuberculosis therapy

- With resurgence of tuberculosis in many urban centers, - With resurgence of tuberculosis in many urban centers, this cause of adrenal deficiency must be borne in mind.this cause of adrenal deficiency must be borne in mind.

- When present, tuberculous adrenalitis usually associated - When present, tuberculous adrenalitis usually associated with active infection in lungs and genitourinary tractwith active infection in lungs and genitourinary tract

- Disseminated infections caused by - Disseminated infections caused by Histoplasma Histoplasma capsulatumcapsulatum and and Coccidioides immitisCoccidioides immitis also may result in also may result in chronic adrenocortical insufficiency.chronic adrenocortical insufficiency.

- Patients with AIDS are at risk for the development of - Patients with AIDS are at risk for the development of adrenal insufficiency from several infectious adrenal insufficiency from several infectious (cytomegalovirus) and noninfectious (Kaposi sarcoma)(cytomegalovirus) and noninfectious (Kaposi sarcoma)

C- Metastatic neoplasmsC- Metastatic neoplasms involving the adrenals involving the adrenals- Although adrenal function is preserved in most such - Although adrenal function is preserved in most such

instances, the metastatic growths sometimes destroy instances, the metastatic growths sometimes destroy sufficient adrenal cortex to produce a degree of adrenal sufficient adrenal cortex to produce a degree of adrenal insufficiency.insufficiency.

- Carcinomas of the lung and breast are the source of a - Carcinomas of the lung and breast are the source of a

majority of metastases in the adrenalsmajority of metastases in the adrenalsSecondary Adrenocortical InsufficiencySecondary Adrenocortical Insufficiency - Caused by any disorder of the hypothalamus and - Caused by any disorder of the hypothalamus and

pituitary, that reduces the output of ACTH such as pituitary, that reduces the output of ACTH such as a. Metastatic cancera. Metastatic cancerb. Infection, infarction, or irradiation,b. Infection, infarction, or irradiation,- ACTH deficiency may occur alone, but in some instances, - ACTH deficiency may occur alone, but in some instances,

it is only one part of panhypopituitarism, it is only one part of panhypopituitarism, Clinical manifestation of adrenocortical insufficiencyClinical manifestation of adrenocortical insufficiency- The destruction of the adrenal cortex does not permit a - The destruction of the adrenal cortex does not permit a

response to exogenously administered ACTH in the form response to exogenously administered ACTH in the form of increased plasma cortisolof increased plasma cortisol

- Secondary adrenocortical insufficiency is characterized by - Secondary adrenocortical insufficiency is characterized by low serum ACTH and a prompt rise in plasma cortisol low serum ACTH and a prompt rise in plasma cortisol levels in response to ACTH administrationlevels in response to ACTH administration

- Clinical manifestations of adrenocortical insufficiency do - Clinical manifestations of adrenocortical insufficiency do not appear until at least 90% of the adrenal cortex has not appear until at least 90% of the adrenal cortex has been compromised. been compromised.

a. The initial manifestations often include progressive a. The initial manifestations often include progressive weakness and easy fatigability . weakness and easy fatigability .

b. Gastrointestinal disturbancesb. Gastrointestinal disturbances are common and include are common and include anorexia, nausea, vomiting, weight loss, and diarrhea anorexia, nausea, vomiting, weight loss, and diarrhea

c. In patients with primary adrenal disease, increased levels c. In patients with primary adrenal disease, increased levels of ACTH precursor hormone stimulate melanocytes, with of ACTH precursor hormone stimulate melanocytes, with

resultant resultant hyperpigmentationhyperpigmentation of the skin and mucosal of the skin and mucosal surfaces: The face, axillae, nipples, areolae, and surfaces: The face, axillae, nipples, areolae, and perineum are mainly affectedperineum are mainly affected

- By contrast, hyperpigmentation is not seen in patients with - By contrast, hyperpigmentation is not seen in patients with secondary adrenocortical insufficiency.secondary adrenocortical insufficiency.

d. Decreased mineralocorticoid (aldosterone) activity in d. Decreased mineralocorticoid (aldosterone) activity in patients with primary adrenal insufficiency results in patients with primary adrenal insufficiency results in potassium retention and sodium loss , with consequentpotassium retention and sodium loss , with consequent - - hyperkalemia, hyponatremia, volume depletion,hyperkalemia, hyponatremia, volume depletion, and and hypotensionhypotension, ,

- In secondary hypoadrenalism is characterized by deficient - In secondary hypoadrenalism is characterized by deficient cortisol and androgen output but normal or near-normal cortisol and androgen output but normal or near-normal aldosterone synthesisaldosterone synthesis

. . - Hypoglycemia occasionally may occur as a result of - Hypoglycemia occasionally may occur as a result of

glucocorticoid deficiency and impaired gluconeogenesis.glucocorticoid deficiency and impaired gluconeogenesis.- Stresses such as infections, trauma, or surgical - Stresses such as infections, trauma, or surgical

procedures in affected patients may precipitate an acute procedures in affected patients may precipitate an acute adrenal crisis, manifested by adrenal crisis, manifested by

a. intractable vomiting,and abdominal pain,a. intractable vomiting,and abdominal pain,b. Hypotension, coma, and vascular collapse. b. Hypotension, coma, and vascular collapse. - Death follows rapidly unless corticosteroids are replaced - Death follows rapidly unless corticosteroids are replaced

immediately. . immediately. .

TUMORS OF THE ADRENAL TUMORS OF THE ADRENAL MEDULLAMEDULLA

PheochromocytomaPheochromocytoma

- Are neoplasms composed of chromaffin cells, synthesize - Are neoplasms composed of chromaffin cells, synthesize and release catecholamines . and release catecholamines .

- These tumors are of importance because they give rise to - These tumors are of importance because they give rise to a surgically correctable form of hypertension. a surgically correctable form of hypertension.

- Pheochromocytomas usually subscribe to "rule of 10s": - Pheochromocytomas usually subscribe to "rule of 10s": a. 10% of pheochromocytomas are extraadrenal,a. 10% of pheochromocytomas are extraadrenal, occurring occurring

in sites such as the organ of Zuckerkandl and the carotid in sites such as the organ of Zuckerkandl and the carotid body, where they usually are called body, where they usually are called paragangliomas,paragangliomas, rather than pheochromocytomasrather than pheochromocytomas

b. b. 10% of adrenal pheochromocytomas are bilateral10% of adrenal pheochromocytomas are bilateral ; this ; this proportion may rise to 50% in cases that are associated proportion may rise to 50% in cases that are associated with familial syndromes.with familial syndromes.

c. 10% of adrenal pheochromocytomas are malignant,c. 10% of adrenal pheochromocytomas are malignant, - Frank malignancy is somewhat more common in tumors - Frank malignancy is somewhat more common in tumors

arising in extraadrenal sites.arising in extraadrenal sites. Note: One "traditional" 10% rule that has since been Note: One "traditional" 10% rule that has since been

modified pertains to familial cases. modified pertains to familial cases. - - 25% of persons with pheochromocytomas and 25% of persons with pheochromocytomas and

paragangliomas harbor a germ line mutationparagangliomas harbor a germ line mutation in one of at in one of at least six known genes including:least six known genes including:

1. 1. RETRET, which causes type 2 MEN syndromes, which causes type 2 MEN syndromes2. NF12. NF1, which causes type 1 neurofibromatosis, which causes type 1 neurofibromatosis3. VHL3. VHL, which causes von Hippel-Lindau disease ; , which causes von Hippel-Lindau disease ; 4. Three genes encoding subunits within the succinate 4. Three genes encoding subunits within the succinate

dehydrogenase complex (dehydrogenase complex (SDHB, SDHC,SDHB, SDHC, and and SDHDSDHD), ), involved in mitochondrial oxidative phosphorylationinvolved in mitochondrial oxidative phosphorylation

Gross Gross

- Range from small,lesions confined to the adrenal to large, - Range from small,lesions confined to the adrenal to large, hemorrhagic masses weighing several kilogramshemorrhagic masses weighing several kilograms

- On cut surface, smaller pheochromocytomas are yellow-, - On cut surface, smaller pheochromocytomas are yellow-, well-defined lesions that compress the adjacent adrenal well-defined lesions that compress the adjacent adrenal

. .

- Larger lesions tend to be hemorrhagic, necrotic, and - Larger lesions tend to be hemorrhagic, necrotic, and cystic and typically efface the adrenal gland. cystic and typically efface the adrenal gland.

- Incubation of the fresh tissue with potassium dichromate - Incubation of the fresh tissue with potassium dichromate solutions turns the tumor dark brown, as noted previously. solutions turns the tumor dark brown, as noted previously.

On microscopic examinationOn microscopic examination- Are composed of polygonal to spindle-shaped chromaffin - Are composed of polygonal to spindle-shaped chromaffin

cells and their supporting cells,compartmentalized into cells and their supporting cells,compartmentalized into small nests, or small nests, or Zellballen,Zellballen, by a rich vascular network by a rich vascular network

- The cytoplasm has a finely granular appearance, because - The cytoplasm has a finely granular appearance, because of the presence of granules containing catecholamines. of the presence of granules containing catecholamines.

- The nuclei of the neoplastic cells are often pleomorphic- The nuclei of the neoplastic cells are often pleomorphic

- Both capsular and vascular invasion may be encountered - Both capsular and vascular invasion may be encountered in benign lesions, and the mere presence of mitotic in benign lesions, and the mere presence of mitotic figures does not imply malignancy. figures does not imply malignancy.

- Therefore, the definitive diagnosis of malignancy in - Therefore, the definitive diagnosis of malignancy in pheochromocytomas is based exclusively on the pheochromocytomas is based exclusively on the presence of metastases. presence of metastases.

- These may involve regional lymph nodes as well as more - These may involve regional lymph nodes as well as more distant sites, including liver, lung, and bone.distant sites, including liver, lung, and bone.

Clinical Features Clinical Features - The predominant clinical manifestation is - The predominant clinical manifestation is hypertensionhypertension - The characteristic presentation with hypertensive episode - The characteristic presentation with hypertensive episode

is one of abrupt, precipitous elevation in blood pressure,is one of abrupt, precipitous elevation in blood pressure, associated with tachycardia, palpitations, headache, associated with tachycardia, palpitations, headache,

sweating, tremor, and a sense of apprehension .sweating, tremor, and a sense of apprehension .- Such episodes also may be associated with pain in the - Such episodes also may be associated with pain in the

abdomen or chest, nausea, and vomiting.abdomen or chest, nausea, and vomiting.- In clinical practice, - In clinical practice, isolated, paroxysmal episodes of isolated, paroxysmal episodes of

hypertension occur in fewer than half of patientshypertension occur in fewer than half of patients with with pheochromocytoma. pheochromocytoma.

- In about two thirds of patients the hypertension occurs as a - In about two thirds of patients the hypertension occurs as a chronic, sustained elevation in blood pressure, although an chronic, sustained elevation in blood pressure, although an element of labile hypertension often ispresent as well.element of labile hypertension often ispresent as well.

- Sudden cardiac death may occur, probably secondary to Sudden cardiac death may occur, probably secondary to catecholamine-induced myocardial irritability and ventricular catecholamine-induced myocardial irritability and ventricular arrhythmias.arrhythmias.

- In some cases, pheochromocytomas secrete hormones such - In some cases, pheochromocytomas secrete hormones such as ACTH and somatostatin. as ACTH and somatostatin.

- The laboratory diagnosis of pheochromocytoma is based on - The laboratory diagnosis of pheochromocytoma is based on demonstration of increased urinary excretion of free demonstration of increased urinary excretion of free catecholamines and their metabolites, such as vanillylmandelic catecholamines and their metabolites, such as vanillylmandelic acid and metanephrines.acid and metanephrines.

• Isolated benign pheochromocytomas are treated with surgical Isolated benign pheochromocytomas are treated with surgical excision. With multifocal lesions, long-term medical treatment excision. With multifocal lesions, long-term medical treatment for hypertension may be required. for hypertension may be required.

MULTIPLE ENDOCRINE NEOPLASIA SYNDROMESMULTIPLE ENDOCRINE NEOPLASIA SYNDROMES

- Are a group of inherited diseases resulting in proliferative - Are a group of inherited diseases resulting in proliferative lesions) of multiple endocrine organs. lesions) of multiple endocrine organs.

- Endocrine tumors arising in the context of MEN - Endocrine tumors arising in the context of MEN syndromes have certain distinctive features that are not syndromes have certain distinctive features that are not shared with their sporadic counterparts: shared with their sporadic counterparts:

1. Occur at a 1. Occur at a younger ageyounger age than that for sporadic cancers. than that for sporadic cancers. 2. They arise in 2. They arise in multiple endocrine organs,multiple endocrine organs, - Even in one organ, the tumors often are - Even in one organ, the tumors often are multifocal.multifocal.

- Usually are preceded by an - Usually are preceded by an asymptomatic stage of asymptomatic stage of endocrine hyperplasiaendocrine hyperplasia involving the cell of origin of tumor involving the cell of origin of tumor

3. Are usually 3. Are usually more aggressivemore aggressive and and recurrecur in a higher in a higher proportion of cases than tumors that occur sporadically.proportion of cases than tumors that occur sporadically.

- Unraveling the genetic basis of the MEN syndromes with - Unraveling the genetic basis of the MEN syndromes with clinical application of this knowledge in therapeutic decision clinical application of this knowledge in therapeutic decision making has been one of the success stories of translational making has been one of the success stories of translational research. research.

MEN type 1 MEN type 1

- Is an autosomal dominant syndrome and the gene (- Is an autosomal dominant syndrome and the gene (MEN1MEN1) ) is located at 11and is a tumor suppressor gene;.is located at 11and is a tumor suppressor gene;.

- Organs most commonly involved are the parathyroid, the - Organs most commonly involved are the parathyroid, the pancreas, and the pituitary-the "3 Ps.“pancreas, and the pituitary-the "3 Ps.“

a. Parathyroida. Parathyroid: : Primary hyperparathyroidism Primary hyperparathyroidism is the most is the most common manifestation of MEN-1 (80% to 95% of patients) common manifestation of MEN-1 (80% to 95% of patients) and is the initial manifestation of the disorder appearing in and is the initial manifestation of the disorder appearing in almost all patients by age 40 to 50.almost all patients by age 40 to 50.

- Abnormalities include both hyperplasia and adenomas.- Abnormalities include both hyperplasia and adenomas.b. Pancreasb. Pancreas: Endocrine tumors of the pancreas are the : Endocrine tumors of the pancreas are the

leading cause of death in MEN-1. leading cause of death in MEN-1. - Are aggressive tumors manifest with metastatic disease.- Are aggressive tumors manifest with metastatic disease.- May find multiple microadenomas" scattered throughoutthe - May find multiple microadenomas" scattered throughoutthe

pancreas in conjunction with the dominant lesionspancreas in conjunction with the dominant lesions- Pancreatic endocrine tumors often are functional - Pancreatic endocrine tumors often are functional

- Zollinger-Ellison syndrome, associated with gastrinomas,is - Zollinger-Ellison syndrome, associated with gastrinomas,is common and gastrinomas are far more likely to be located common and gastrinomas are far more likely to be located within the duodenum than in the pancreaswithin the duodenum than in the pancreas

- Hypoglycemia, related to insulinomas, is also common- Hypoglycemia, related to insulinomas, is also commonc. Pituitaryc. Pituitary: : The most frequent pituitary tumor in patients with The most frequent pituitary tumor in patients with

MEN-1 is a prolactin-secreting macroadenoma. MEN-1 is a prolactin-secreting macroadenoma. - In some cases, acromegaly develops in association with - In some cases, acromegaly develops in association with

somatotropin-secreting tumors.somatotropin-secreting tumors.Multiple Endocrine Neoplasia Type 2A Multiple Endocrine Neoplasia Type 2A

a. Thyroida. Thyroid:: Medullary carcinoma of the thyroid develops in Medullary carcinoma of the thyroid develops in virtually all untreated cases, and the tumors usually occur in the virtually all untreated cases, and the tumors usually occur in the first 2 decades of lifefirst 2 decades of life

.- The tumors commonly are multifocal, and foci of C cell .- The tumors commonly are multifocal, and foci of C cell hyperplasia can be found in the adjacent thyroid. hyperplasia can be found in the adjacent thyroid.

- Familial medullary thyroid cancer- Familial medullary thyroid cancer is a variant of MEN-2A is a variant of MEN-2A characterized by medullary thyroid cancers, but not the characterized by medullary thyroid cancers, but not the other characteristic manifestations listed here. other characteristic manifestations listed here.

- In comparison with MEN-2, familial medullary carcinoma - In comparison with MEN-2, familial medullary carcinoma typically occurs at an older age and follows a more typically occurs at an older age and follows a more indolent course.indolent course.

b. Adrenal medullab. Adrenal medulla: Pheochromocytomas develop in 50% : Pheochromocytomas develop in 50% of the patients; and 10% of these tumors are malignant.of the patients; and 10% of these tumors are malignant.

c. Parathyroidc. Parathyroid: 10% to 20% of patients develop parathyroid : 10% to 20% of patients develop parathyroid hyperplasia resulting in primary hyperparathyroidismhyperplasia resulting in primary hyperparathyroidism

Multiple Endocrine Neoplasia Type 2BMultiple Endocrine Neoplasia Type 2B

- Patients with MEN-2B harbor a distinct germline - Patients with MEN-2B harbor a distinct germline RETRET mutation mutation involving a single-amino acid change. involving a single-amino acid change.

a. Organs commonly involved include the thyroid and the a. Organs commonly involved include the thyroid and the adrenal medulla and the spectrum of thyroid and adrenal adrenal medulla and the spectrum of thyroid and adrenal medullary disease is similar to that in MEN-2A, medullary disease is similar to that in MEN-2A,

b. Primary hyperparathyroidism does not developb. Primary hyperparathyroidism does not develop in patients in patients with MEN-2B.with MEN-2B.

c. Extraendocrine manifestations c. Extraendocrine manifestations include :include :1. Ganglioneuromas of mucosal sites (gastrointestinal tract, lips, 1. Ganglioneuromas of mucosal sites (gastrointestinal tract, lips,

tongue) tongue)

2. a 2. a marfanoid habitus,marfanoid habitus, in which overly long bones of the axial in which overly long bones of the axial skeleton give an appearance resembling that in Marfan skeleton give an appearance resembling that in Marfan syndrome syndrome

- Before the advent of genetic testing, relatives of patients - Before the advent of genetic testing, relatives of patients with the MEN-2 syndrome were screened with annual with the MEN-2 syndrome were screened with annual biochemical tests, which often lacked sensitivity.biochemical tests, which often lacked sensitivity.

- Now, routine genetic testing identifies - Now, routine genetic testing identifies RETRET mutation mutation carriers earlier and more reliably in MEN-2 kindreds;carriers earlier and more reliably in MEN-2 kindreds;

- All persons carrying germline RET mutations are advised to - All persons carrying germline RET mutations are advised to have prophylactic thyroidectomy to prevent the inevitable have prophylactic thyroidectomy to prevent the inevitable development of medullary carcinomasdevelopment of medullary carcinomas..

I. Pituitary glandI. Pituitary gland

I.I. Hyperpituitarism Hyperpituitarism-related effects:-related effects: Causes of hyperpituitarism:Causes of hyperpituitarism:

1. The most common cause is anterior lobe adenoma 1. The most common cause is anterior lobe adenoma 2, Other, less common, causes include:2, Other, less common, causes include:a. Hyperplasia and carcinoma of the anterior pituitary a. Hyperplasia and carcinoma of the anterior pituitary b. Secretion of hormones by some extrapituitary tumors, b. Secretion of hormones by some extrapituitary tumors, - Some features of pituitary adenomas are as follows: - Some features of pituitary adenomas are as follows: 1. Adenomas are classified on the basis of hormone(s) 1. Adenomas are classified on the basis of hormone(s)

produced by the neoplastic cellsproduced by the neoplastic cells

2. Pituitary adenomas can be:2. Pituitary adenomas can be: a. a. FunctionalFunctional : Hormone excess and clinical manifestations : Hormone excess and clinical manifestations

b. b. Nonfunctioning Nonfunctioning : : DDemonstration of hormone production at emonstration of hormone production at the tissue level only, without clinical manifestations of the tissue level only, without clinical manifestations of hormone excesshormone excess

c Adenomas may be c Adenomas may be hormone negative, hormone negative, as indicated by as indicated by absence of immunohistochemical reactivity or absence of immunohistochemical reactivity or ultrastructural evidence of hormone production. ultrastructural evidence of hormone production.

3- Both functional and nonfunctioning pituitary adenomas 3- Both functional and nonfunctioning pituitary adenomas usually are composed of a single cell type and produce a usually are composed of a single cell type and produce a single predominant hormone, but there are exceptions: single predominant hormone, but there are exceptions:

- Some adenomas can secrete two different hormones - Some adenomas can secrete two different hormones (growth hormone and prolactin being the most common (growth hormone and prolactin being the most common

4. Most pituitary adenomas occur as sporadic and in about 4. Most pituitary adenomas occur as sporadic and in about

5% of cases, adenomas are familial5% of cases, adenomas are familial5. Pituitary adenomas are 5. Pituitary adenomas are microadenomasmicroadenomas if they are < 1 cm if they are < 1 cm

in diameter and in diameter and macroadenomasmacroadenomas if they exceed 1 cm . if they exceed 1 cm . 6. Nonfunctioning and hormone-negative adenomas come 6. Nonfunctioning and hormone-negative adenomas come

to clinical attention at a later stage and are more likely to to clinical attention at a later stage and are more likely to be macroadenomasbe macroadenomas

7. Nonfunctioning adenomas may cause 7. Nonfunctioning adenomas may cause hypohypopituitarism as pituitarism as they encroach on adjacent anterior pituitary parenchymathey encroach on adjacent anterior pituitary parenchyma

Genetic changesGenetic changes

1- 40% of GH-secreting adenomas and a minority of 1- 40% of GH-secreting adenomas and a minority of (ACTH)-secreting adenomas bear (ACTH)-secreting adenomas bear GNAS1 GNAS1 mutationsmutations

.2. In familial adenomas: .2. In familial adenomas: a. Germline inactivating mutations of the a. Germline inactivating mutations of the MEN1MEN1 gene are responsible gene are responsible

for (MEN-1).for (MEN-1).b. b. AIPAIP germline mutations: patients develop GH-secreting adenomas at germline mutations: patients develop GH-secreting adenomas at

a younger age (before 35 years) than that for sporadic GH adenomaa younger age (before 35 years) than that for sporadic GH adenoma c. Mutations of c. Mutations of TP53TP53 in pituitary adenomas are associated with a in pituitary adenomas are associated with a

propensity for aggressive behaviorpropensity for aggressive behaviorGross features of adenomasGross features of adenomas - The usual adenoma is a well-circumscribed, lesion that if small, be - The usual adenoma is a well-circumscribed, lesion that if small, be

confined by the sella turcica confined by the sella turcica - Larger lesions may Compress the optic chiasm :- Larger lesions may Compress the optic chiasm :

. Erode the sella turcica and anterior clinoid processes,and . Erode the sella turcica and anterior clinoid processes,and extend into the cavernous and sphenoidal sinusesextend into the cavernous and sphenoidal sinuses

- In 30% of cases, the adenomas are non-encapsulated - In 30% of cases, the adenomas are non-encapsulated and infiltrate adjacent bone, dura , and brainand infiltrate adjacent bone, dura , and brain

Microscopic:Microscopic: are composed of polygonal cells . are composed of polygonal cells .- The connective tissue, or reticulin, is sparse, accounting - The connective tissue, or reticulin, is sparse, accounting

for the soft, consistency of many of these tumors.for the soft, consistency of many of these tumors. - The nuclei may be uniform or pleomorphic- The nuclei may be uniform or pleomorphic- The cytoplasm of the cells may be acidophilic, basophilic - The cytoplasm of the cells may be acidophilic, basophilic

or chromophobic, depending on the type and amount of or chromophobic, depending on the type and amount of secretory product but it is uniform throughout the tumor secretory product but it is uniform throughout the tumor

Pit adenomaPit adenoma

Pit adenomaPit adenoma

Note;Note;- This cellular monomorphism and the absence of a - This cellular monomorphism and the absence of a

significant reticulin network distinguish pituitary adenomas significant reticulin network distinguish pituitary adenomas from non-neoplastic anterior pituitary parenchyma from non-neoplastic anterior pituitary parenchyma

- The functional status of the adenoma cannot be reliably - The functional status of the adenoma cannot be reliably predicted from its histologic appearance. predicted from its histologic appearance.

- Adenomas that harbor - Adenomas that harbor TP53TP53 mutations demonstrate mutations demonstrate briskmitotic activity and are designated atypical briskmitotic activity and are designated atypical adenomas to reinforce their potential for aggressive adenomas to reinforce their potential for aggressive behavior.behavior.

I. Prolactinomas I. Prolactinomas - Are the most common type of hyperfunctioning adenomas.- Are the most common type of hyperfunctioning adenomas.

- Hyperprolactinemia- Hyperprolactinemia causes: causes:a. Amenorrhea and galactorrhea,a. Amenorrhea and galactorrhea,b. Loss of libido, and infertilityb. Loss of libido, and infertility

- Because many of the manifestations of hyper-- Because many of the manifestations of hyper-prolactinemia (amenorrhea) are more obvious in pre- - prolactinemia (amenorrhea) are more obvious in pre- - menopausal women than in men or postmenopausal menopausal women than in men or postmenopausal women, prolactinomas usually are diagnosed at an women, prolactinomas usually are diagnosed at an earlier stage in women of reproductive age than in other earlier stage in women of reproductive age than in other persons persons

- By contrast, hormonal manifestations may be subtle in - By contrast, hormonal manifestations may be subtle in men and older women, in whom the tumor may reach men and older women, in whom the tumor may reach considerable size before coming to clinical attentionconsiderable size before coming to clinical attention

Other causes of hyperprolactinemia Other causes of hyperprolactinemia a. Pregnancy, and high-dose estrogen therapy, a. Pregnancy, and high-dose estrogen therapy, b. Dopamine-inhibiting drugs (e.g., reserpine).b. Dopamine-inhibiting drugs (e.g., reserpine).c. Any mass in the suprasellar compartment may disturbc. Any mass in the suprasellar compartment may disturb the normal inhibitory influence of hypothalamus on the normal inhibitory influence of hypothalamus on

prolactin secretion, resulting in hyperprolactinemia-a prolactin secretion, resulting in hyperprolactinemia-a mechanism known as the mechanism known as the stalk effect.stalk effect.

- Thus, - Thus, mildmild elevations of serum prolactin (less than 200 elevations of serum prolactin (less than 200 μg/L) in a patient with a pituitary adenoma do not μg/L) in a patient with a pituitary adenoma do not necessarily indicate a prolactin-secreting neoplasm necessarily indicate a prolactin-secreting neoplasm

II. II. Growth Hormone-Producing (Somatotroph) AdenomasGrowth Hormone-Producing (Somatotroph) Adenomas- These adenomas including those that produce a mixture of - These adenomas including those that produce a mixture of

growth hormone and , prolactin, constitute the second most growth hormone and , prolactin, constitute the second most common type of functional pituitary adenoma. common type of functional pituitary adenoma.

- May be quite large at time of diagnosis because the clinical - May be quite large at time of diagnosis because the clinical manifestations of excessive growth hormone may be subtle, manifestations of excessive growth hormone may be subtle,

-- Small amounts of immunoreactive prolactin often are -- Small amounts of immunoreactive prolactin often are present as well. present as well.

- Persistent hypersecretion of GH stimulates the hepatic - Persistent hypersecretion of GH stimulates the hepatic secretion of insulin-like growth factor I (somatomedin secretion of insulin-like growth factor I (somatomedin

which causes many of the clinical manifestations.which causes many of the clinical manifestations.

a. If a growth hormone-secreting adenoma occurs before a. If a growth hormone-secreting adenoma occurs before the epiphyses close, as is the case in prepubertal children the epiphyses close, as is the case in prepubertal children excessive levels of growth hormone result in excessive levels of growth hormone result in gigantism.gigantism.

- This condition is characterized by :- This condition is characterized by :a. generalized increase in body size, with disproportionately a. generalized increase in body size, with disproportionately

long arms and legs.long arms and legs.b. If elevated levels of growth hormone persist, or develop b. If elevated levels of growth hormone persist, or develop

after closure of the epiphyses, affected persons develop after closure of the epiphyses, affected persons develop acromegaly,acromegaly, in which: in which:

. 1. Growth is most conspicuous in soft tissues, skin, and . 1. Growth is most conspicuous in soft tissues, skin, and viscera and in the bones of the face, hands, and feetviscera and in the bones of the face, hands, and feet

2. Enlargement of the jaw results in its protrusion 2. Enlargement of the jaw results in its protrusion (prognathism), with eparation of the teeth. (prognathism), with eparation of the teeth. 3. Enlarged hands and feet with broad, sausage-like fingers3. Enlarged hands and feet with broad, sausage-like fingersNote.Note.1. In clinical practice, the gigantism typically is accompanied by 1. In clinical practice, the gigantism typically is accompanied by

evidence of acromegalyevidence of acromegaly. . 2. Prolactin is demonstrable in a number of growth2. Prolactin is demonstrable in a number of growthhormone-producing adenomas and in some cases may be hormone-producing adenomas and in some cases may be released in sufficient quantities to produce signs and symptoms of released in sufficient quantities to produce signs and symptoms of

hyperprolactinemia. hyperprolactinemia. III.Corticotroph Adenomas III.Corticotroph Adenomas :Most of are microadenomas. :Most of are microadenomas.

, ,

- Are positively with (PAS) stains, as a result of the - Are positively with (PAS) stains, as a result of the accumulation of glycosylated ACTH protein-accumulation of glycosylated ACTH protein-

- Corticotroph cell adenomas may be:- Corticotroph cell adenomas may be:a. Clinically silent ora. Clinically silent orb. May cause b. May cause hypercortisolism, mhypercortisolism, manifested clinically as anifested clinically as

Cushing syndrome,Cushing syndrome, and when the hypercortisolism is and when the hypercortisolism is caused by excessive production of ACTH by the pituitary, caused by excessive production of ACTH by the pituitary, the process is designated the process is designated Cushing disease,Cushing disease,

c. Large, clinically aggressive corticotroph cell adenomas c. Large, clinically aggressive corticotroph cell adenomas may develop after surgical removal of the adrenal glands for may develop after surgical removal of the adrenal glands for treatment of Cushing syndrome, this condition is treatment of Cushing syndrome, this condition is Nelson Nelson syndromesyndrome,, results from loss of the inhibitory results from loss of the inhibitory

effect of adrenal corticosteroids on a preexisting effect of adrenal corticosteroids on a preexisting corticotroph microadenoma.corticotroph microadenoma.

- Because the adrenals are absent in Nelson syndrome, - Because the adrenals are absent in Nelson syndrome, hypercortisolism does not develop, and patients present hypercortisolism does not develop, and patients present with the mass effects of the pituitary tumor.with the mass effects of the pituitary tumor.

d. Because ACTH is synthesized as part of a larger pro-d. Because ACTH is synthesized as part of a larger pro-hormone substance that includes melanocyte-stimulating hormone substance that includes melanocyte-stimulating hormone (MSH), hyperpigmentation may be a feature hormone (MSH), hyperpigmentation may be a feature

IV. IV. Gonadotroph LH]-producing and FSHGonadotroph LH]-producing and FSH adenomas adenomas- Can be difficult to recognize, because they secrete - Can be difficult to recognize, because they secrete

hormones inefficiently, and the secretory products usually hormones inefficiently, and the secretory products usually do not cause a recognizable clinical syndrome. do not cause a recognizable clinical syndrome.

- They are typically detected when the tumors have become - They are typically detected when the tumors have become large enough to cause neurologic manifestations such as large enough to cause neurologic manifestations such as impaired vision, headaches, diplopia, or pituitary apoplexy impaired vision, headaches, diplopia, or pituitary apoplexy

- The neoplastic cells demonstrate immunoreactivity for the- The neoplastic cells demonstrate immunoreactivity for the common gonadotropin α-subunit and the specific β-FSH common gonadotropin α-subunit and the specific β-FSH

and β-LH subunits and SH usually is the predominant and β-LH subunits and SH usually is the predominant secreted hormone.secreted hormone.

V. Thyrotroph adenomaV. Thyrotroph adenoma : : - Account for about 1% of all - Account for about 1% of all pituitary adenomas and constitute a rare cause of pituitary adenomas and constitute a rare cause of hyperthyroidism.hyperthyroidism.

VIVI. Nonfunctioning pituitary adenomas. Nonfunctioning pituitary adenomas - Constitute 25% of all pituitary tumors and comprise:- - Constitute 25% of all pituitary tumors and comprise:-

a. Clinically silent counterparts of the functioning adenomasa. Clinically silent counterparts of the functioning adenomas justjust (for example, a (for example, a silent gonadotroph adenomasilent gonadotroph adenoma))b. And true b. And true hormone-negativehormone-negative (null cell) adenomas;. (null cell) adenomas;. - - The typical presentation is mass effects and destruct The typical presentation is mass effects and destruct

residual anterior pituitary to produce hypopituitarism.residual anterior pituitary to produce hypopituitarism. Pituitary carcinomas Pituitary carcinomas

- are exceedingly rare and i- are exceedingly rare and in addition to local extension n addition to local extension beyond the sella turcica, these tumors virtually always beyond the sella turcica, these tumors virtually always demonstrate distant metastases.demonstrate distant metastases.

II.HYPOPITUITARISMII.HYPOPITUITARISM occur with loss or absence of 75% occur with loss or absence of 75% of the anterior pituitary parenchyma and this may beof the anterior pituitary parenchyma and this may be

a. Ca. Congenitalongenital absence(exceedingly rare) absence(exceedingly rare)b. Hypothalamic tumors that interfere with the delivery of hormone-b. Hypothalamic tumors that interfere with the delivery of hormone-

releasing factors from the hypothalamus, releasing factors from the hypothalamus, Note:- Hypopituitarism accompanied by evidence of posterior pituitary Note:- Hypopituitarism accompanied by evidence of posterior pituitary

dysfunction in the form of diabetes insipidusdysfunction in the form of diabetes insipidus is almost always of is almost always of hypothalamic origin.hypothalamic origin.

c Most cases of anterior pituitary hypofunction are caused by c Most cases of anterior pituitary hypofunction are caused by Nonfunctioning pituitary adenomas Nonfunctioning pituitary adenomas

d. Ischemic necrosis of the anterior pituitary, d. Ischemic necrosis of the anterior pituitary, - The anterior pituitary has substantial reserve capacity; as a result, - The anterior pituitary has substantial reserve capacity; as a result,

destruction of 75% of pituitary tissue must occur before destruction of 75% of pituitary tissue must occur before manifestations hypopituitarism developmanifestations hypopituitarism develop

Sheehan syndromeSheehan syndrome,, or postpartum necrosis of anterior or postpartum necrosis of anterior pituitary, is the most common form of clinically significant pituitary, is the most common form of clinically significant ischemic necrosis of the anterior pituitary. ischemic necrosis of the anterior pituitary.

- During pregnancy, the anterior pituitary enlarges - During pregnancy, the anterior pituitary enlarges considerably, because of an increase in the size and considerably, because of an increase in the size and number of prolactin-secreting cells and this physiologic number of prolactin-secreting cells and this physiologic enlargement is not accompanied by an increase in blood enlargement is not accompanied by an increase in blood supply from the low-pressure portal venous system.supply from the low-pressure portal venous system.

- The enlarged gland is thus vulnerable to ischemic injury, - The enlarged gland is thus vulnerable to ischemic injury, especially in women who experience significant especially in women who experience significant hemorrhage and hypotension during the peripartal periodhemorrhage and hypotension during the peripartal period

- The posterior pituitary, because it receives its blood - The posterior pituitary, because it receives its blood

directly from arterial branches, is much less susceptible to directly from arterial branches, is much less susceptible to ischemic injury and therefore usually is not affected. ischemic injury and therefore usually is not affected.

e. Ablation of the pituitary by surgery or irradiatione. Ablation of the pituitary by surgery or irradiationf. Inflammatory lesions such as sarcoidosis or tuberculosisf. Inflammatory lesions such as sarcoidosis or tuberculosisg. Trauma and Metastatic neoplasms involving the pituitaryg. Trauma and Metastatic neoplasms involving the pituitary. - The clinical manifestations of hypopituitarism depend on the . - The clinical manifestations of hypopituitarism depend on the

specific hormones that are lackingspecific hormones that are lacking 1. In children, growth failure (1. In children, growth failure (pituitary dwarfismpituitary dwarfism) may occur ) may occur as a result of growth hormone deficiency.as a result of growth hormone deficiency.2. Gonadotropin or gonadotropin-releasing hormone (GnRH) 2. Gonadotropin or gonadotropin-releasing hormone (GnRH)

deficiency leads to amenorrhea and infertility indeficiency leads to amenorrhea and infertility in

women and to decreased libido, impotence, and loss of pubic and women and to decreased libido, impotence, and loss of pubic and axillary hair in men. axillary hair in men.

3. TSH and ACTH deficiencies result in symptoms of 3. TSH and ACTH deficiencies result in symptoms of hypothyroidism and hypoadrenalism,hypothyroidism and hypoadrenalism,

4. Prolactin deficiency results in failure of postpartum lactation. 4. Prolactin deficiency results in failure of postpartum lactation. 5. The anterior pituitary also is a rich source of MSH, synthesized 5. The anterior pituitary also is a rich source of MSH, synthesized

from the same precursor molecule that from the same precursor molecule that produces ACTH; so one of the manifestations of is pallor from produces ACTH; so one of the manifestations of is pallor from

loss of stimulatory effects of MSH on melanocytesloss of stimulatory effects of MSH on melanocytes

III. Local mass effectsIII. Local mass effects: :

a. Among the earliest changes referable to mass effect a. Among the earliest changes referable to mass effect . .

are are radiographic abnormalities of the sella turcica,radiographic abnormalities of the sella turcica, including including sellar expansion, bony erosion, and disruption of the sellar expansion, bony erosion, and disruption of the diaphragma sellae. diaphragma sellae.

b. expanding pituitary lesions often compress decussating fibers b. expanding pituitary lesions often compress decussating fibers in the optic chiasm , this gives rise to in the optic chiasm , this gives rise to visual field visual field abnormalities,abnormalities, in the form of defects in the lateral (temporal) in the form of defects in the lateral (temporal) visual fields--called visual fields--called bitemporal hemianopsia.bitemporal hemianopsia.

c. signs and symptoms of c. signs and symptoms of elevated intracranial pressure,elevated intracranial pressure, including headache, nausea, and vomiting including headache, nausea, and vomiting

d. Pituitary adenomas that extendthe sella turcica into the base d. Pituitary adenomas that extendthe sella turcica into the base of the brain (invasive pituitary adenoma) produce of the brain (invasive pituitary adenoma) produce seizures seizures or or obstructive hydrocephalusobstructive hydrocephalus; ;

e. Involvement of cranial nerves result in e. Involvement of cranial nerves result in cranial nerve palsy.cranial nerve palsy. f. acute hemorrhage into an adenoma is associated with f. acute hemorrhage into an adenoma is associated with

clinical evidence of rapid enlargement of the lesion and clinical evidence of rapid enlargement of the lesion and depression of consciousness, a situation appropriately depression of consciousness, a situation appropriately termed termed pituitary apoplexy.pituitary apoplexy.

- Acute pituitary apoplexy constitutes a neurosurgical - Acute pituitary apoplexy constitutes a neurosurgical emergency, because it may be rapidly fatal.emergency, because it may be rapidly fatal.

POSTERIOR PITUITARY SYNDROMESPOSTERIOR PITUITARY SYNDROMES..- Impairment of oxytocin synthesis and release has not- Impairment of oxytocin synthesis and release has not been associated with significant clinical abnormalities. been associated with significant clinical abnormalities. - The clinically important- The clinically important posterior pituitary syndromes posterior pituitary syndromes

involve ADH production which include involve ADH production which include diabetes insipidusdiabetes insipidus and and secretion of inappropriately high levels of ADH.secretion of inappropriately high levels of ADH.

I. ADH deficiency causes I. ADH deficiency causes diabetes insipidus,diabetes insipidus, characterized characterized by excessive urination (polyuria) caused by an inability of by excessive urination (polyuria) caused by an inability of the kidney to properly resorb water from the urinethe kidney to properly resorb water from the urine

- Diabetes insipidus can result from several causes, - Diabetes insipidus can result from several causes, a. Head trauma, Neoplasms,a. Head trauma, Neoplasms,b. Inflammatory disorders and surgical procedures of the b. Inflammatory disorders and surgical procedures of the

hypothalamus and pituitary, hypothalamus and pituitary, d. The condition may be idiopathic. d. The condition may be idiopathic. Note:- Diabetes insipidus from ADH deficiency is Note:- Diabetes insipidus from ADH deficiency is

designated as designated as central,central, to differentiate it from to differentiate it from nephrogenicnephrogenic

diabetes insipidus as a result of renal tubular diabetes insipidus as a result of renal tubular unresponsiveness to circulating ADHunresponsiveness to circulating ADH. .

- The clinical manifestations of both diseases are similar and - The clinical manifestations of both diseases are similar and include:include:

a. The excretion of large volumes of dilute urine with an a. The excretion of large volumes of dilute urine with an inappropriatelyinappropriately low specific gravitylow specific gravity

b. Serum sodium and osmolality are increased as a result of b. Serum sodium and osmolality are increased as a result of excessive renal loss of free water resulting in thirst and excessive renal loss of free water resulting in thirst and polydipsia polydipsia

- Patients who can drink water generally can compensate - Patients who can drink water generally can compensate for urinary losses; patients who are obtunded, bedridden, for urinary losses; patients who are obtunded, bedridden, or otherwise limited in their ability to obtain water may or otherwise limited in their ability to obtain water may

develop life-threatening dehydrationdevelop life-threatening dehydration..

- In - In (SIADH)(SIADH) ADH excess is caused by several extracranial and ADH excess is caused by several extracranial and intracranial disordersintracranial disorders. .

- - This condition leads to resorption of excessive amounts of free This condition leads to resorption of excessive amounts of free water, with resultant hyponatremia. water, with resultant hyponatremia.

- The most common causes of SIADH include;- The most common causes of SIADH include;a. The secretion of ectopic ADH by malignant neoplasms ,a. The secretion of ectopic ADH by malignant neoplasms ,b. Non-neoplastic diseases of the lung,b. Non-neoplastic diseases of the lung,c. local injury to the hypothalamus or neurohypophysis. c. local injury to the hypothalamus or neurohypophysis. - The clinical manifestations of SIADH are dominated by - The clinical manifestations of SIADH are dominated by

hyponatremia, cerebral edema, and resultant neurologic hyponatremia, cerebral edema, and resultant neurologic dysfunction.dysfunction.