Endocrine Pathology

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Endocrine Pathology
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Pathology of the Endocrine System

• The endocrine system is a highly integrated and
  widely distributed group of tissues that
  orchestrates homeostasis between the bodys
  organs organ systems. Secreted hormones act on
  target cells distant from the site of synthesis.
  Increased activity of the target tissue
  frequently results in a down-regulation of the
  signaling gland (feedback inhibition).
• Endocrine disorders can be generally classified
  as
• Disorders of over or under production of hormones
• Disorders associated with the development of mass
  lesions which may cause over or under production
  of hormones or are nonfunctional

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Pituitary Gland

• In conjunction with the hypothalamus the
  pituitary gland plays a critical role in the
  regulation of most other endocrine glands. It is
  composed of 2 functionally distinct components
• 1. Anterior lobe (adenohypophysis)
• Cell types
• Somatothrophs -Growth hormone
• Lactotrophs Prolactin
• Corticotrophs Corticotrophin other hormones
• Thyrotrophs - Thyroid stimulating hormone
• Gonadotrophs FSH LH
• Secretion of these hormones is regulated by
  stimulatory hypothalamic releasing factors or
  inhibitory factor (dopamine inhibits prolactin
  release)
• 2. Posterior lobe (neurohypophysis)
• An extension of axonal processes from the
  hypothalamus that store secrete oxytocin and
  vasopressin (ADH).

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Disorders of the Anterior Pituitary

• Anterior pituitary disorders come to attention
  due to either increased (hyperpituitarism) or
  decreased (hypopituitarism) hormonal secretion.
• In most cases hyperfunction is intrinsic to the
  gland resulting from a functional benign
  (adenoma) tumor.
• Hypofunction can be the result of various
  destructive processes including ischemia,
  radiation, inflammation and non-functioning
  neoplasms.
• Disorders of the anterior lobe may be manifest by
  local mass effects including cranial nerve
  defects, visual field defects, CSF leaks,
  increased ICP, etc..
• Posterior pituitary disorders present with
  symptoms due to increased or decreased hormone
  secretion

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Pituitary Adenomas Hyperpituitarism

• Excess inappropriate production of anterior
  pituitary hormones is most often caused by an
  adenoma of the anterior lobe.
• Adenomas may be nonfunctional and cause
  hypopituitarism by impairing or destroying
  adjacent normal parenchyma.
• Pituitary adenomas account for 10 of
  intracranial tumors and are found incidentally in
  25 of routine autopsies.
• Most pituitary adenomas are monoclonal in origin
  (even if they secrete more than one hormone
  rare).
• Tumors are classified by the hormone they produce

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Prolactinomas

• These are the most common functional pituitary
  tumors accounting for 30 of all adenomas.
• Prolactin secretion is extremely efficient a
  microscopic adenoma can produce enough prolactin
  to produce symptoms.
• Prolactin production is proportional to tumor
  size. This allows a convenient method for
  monitoring recurrence.
• Normally prolactin production is inhibited by
  dopamine released from the hypothalamus,
  interruption of dopamine due to head injury or
  drugs can also result in hyperprolactinemia.
• Symptoms of hyperprolactinemia
• 1. Amenorrhea 25 of 2amenorrhea is due to
  prolactin secreting pituitary tumors.
• 2. Galactorrhea
• 3. Loss of libido
• 4. Infertility

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Somatotroph Adenomas

• Gigantism
• Hypersecretion of GH stimulates hepatic secretion
  of insulin-like growth factors which cause the
  clinical manifestations of this disorder.
• Prior to bone maturity excess GH results in
  gigantism generalized increase in body size
  long limbs.
• After bony maturity it results in acromegaly
  enlargement of the head, hands, feet, jaw, tongue
  and soft tissues resulting in characteristic
  features. Excess GH results in diabetes and
  accelerated atherosclerotic cardiovascular disease

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Acromegaly
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Pituitary Adenomas

• Corticotroph adenomas
• Excess production of corticotrophin results in
  increased cortisol production by the adrenal
  glands causing hypercortisolism (Cushing
  syndrome) which has many other causes.
• Gonadotroph producing tumors
• 10-15 of adenomas produce FSH or LH these are
  frequently found in middle aged men women when
  they become symptomatic due to mass effect.
• Nonfunctioning pituitary adenomas
• These account for 25 of pituitary adenomas,
  these tumors either produce no hormone product or
  a non-functioning product. They present due to
  mass effect.
• Pituitary Carcinomas
• These are very rare and the diagnosis requires
  demonstration of metastatic disease.

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Hypopituitarism

• This is caused by disorders that result in
  decreased section of pituitary hormones this may
  be caused by disorders of the pituitary itself or
  the hypothalamus. The pituitary is robust and
  75 of the parenchyma must be destroyed before
  symptoms occur.
• Tumors and mass lesions
• Pituitary surgery and/or radiation
• Rathke cleft cyst
• Pituitary apoplexy acute hemorrhage
• Ischemic necrosis associated with precipitous
  hemorrhagic events, DIC, sickle cell anemia,
  trauma, increased ICP.
• Empty sell syndrome anything that results
  destruction of part or the entire gland
• 1. Primary due to a defect in the diaphragma
  sellae or increased ICP allowing the encroachment
  of arachnoid and CSF into the sella and
  compressing the gland.
• 2. Secondary due to intervention for a pituitary
  process usually adenoma which results in the
  destruction/removal of the pituitary.

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Posterior Pituitary Syndromes

• The posterior pituitary is composed of modified
  glial cells and axonal processes extending from
  the hypothalamus the supraventricular and
  paraventricular nuclei. These neurons produce
  and release ADH (vasopressin) and oxytocin.
• Inappropriate oxytocin production has not been
  associated with any clinical abnormalities
• ADH is involved in the control of water
  conservation by the kidney.
• ADH deficiency (diabetes insipidis) this
  condition is characterized by excessive urination
  due to the inability of the kidney to resorb
  water, this results in polydipsia and
  hypernatermia.
• Syndrome of inappropriate ADH secretion (SIADH)
  ADH causes the resorbtion of excessive amounts of
  water resulting in hyponatremia, the most
  frequent causes of excess ADH is secretion by
  malignant neoplasms (a paraneoplastic syndrome)
  this is most often associated with small cell
  tumors of the lung, non-malignant lung processes
  head injuries are also common causes. SIADH
  results in hyponatremia which may cause seizures,
  cerebral edema, coma and death.

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Thyroid Gland

• Thyroid follicular epithelial cells convert
  thyroglobulin to thyroxine and triiodothyronine
  that are released to the circulation. They are
  transported by plasma proteins to tissues here
  thyroxine is converted to triiodothryonine (the
  active form). Thyroid hormone binds with a
  nuclear receptor to form a complex that binds
  with thyroid hormone response elements that bind
  to target genes to regulate their transcription.
  
• Thyroid hormone has diverse effects including
  increased carbohydrate lipid metabolism and
  increased protein synthesis in a wide range of
  tissues the net result is an overall increase in
  basal metabolic rate.
• Thyroid disorders are relatively common and are
  amenable to medical surgical intervention if
  they are recognized.
• A common cause of thyroid dysfunction is improper
  treatment of a thyroid disorder

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Hyperthyroidism

• Thyrotoxicosis a hypermetabolic state caused by
  increased levels of thyroxine triiodothryonine,
  the most common cause is hyperfunction of the
  thyroid gland (hyperthyroidism)
• Causes
• Primary hyperthyroidism
• Diffuse hyperplasia of the gland associated with
  Gravess disease
• Hyperfunctional multinodular goiter
• Hyperfunctional adenoma
• Secondary hyperthyroidism
• Thyrotrophic pituitary adenomas
• Excess thyroxine (over medicated hypothyroidism)
• Thyroid inflammation

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Hyperthyroidism

• Clinical manifestations referable to a
  hypermetabolic state with over activity of the
  sympathetic nervous system
• Cardiac manifestations increased cardiac output,
  palpitations, cardiomegaly, arrhythmias
• Ocular changes wide, staring gaze, due to
  sympathetic over stimulation
• Neuromuscular system tremor, hyperactivity,
  emotional lability, inability to concentrate,
  insomnia
• Skin warm, moist and flushed
• GI tract hypermotility, malabsorption, diarrhea

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Causes of Hyperthyroidism

• 1. Graves disease is an autoimmune disorder
  resulting from the production of autoantibodies
  to the TSH receptor, thyroglobulin and T3 T4.
  The underlying mechanism is thought to be the
  breakdown of helper t-cell tolerance. These
  antibodies cause a mild diffuse functional
  enlargement of the gland with the associated
  findings of hyperthyroidism. Graves is also
  associated with an infiltrative ophthalmopathy
  resulting in increased peri- and retro orbital
  tissue (muscle, fat and connective tissue) due to
  T-cell infiltration, inflammatory edema and
  production of ECM components.
• 2. Toxic Thyroid adenoma consists of the rare
  adenoma of the thyroid that produces active
  hormone.
• 3. TSH- secreting pituitary adenomas are a rare
  cause of hyperthyroidism these represent 1 of
  all pituitary adenomas.

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Graves infiltrative ophthalmopathy
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• Gail Devers
• 1992 1996 Gold Medal 100 meter dash

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Hypothyroidism

• A disorder of inadequate production of thyroid
  hormone this can be divided into primary,
  secondary tertiary categories. 1-2 of the US
  population suffers from overt hypothyroidism, but
  it occurs much more frequently in selected
  groups. 10 of the population suffers from
  subclinical hypothyroidism, older females have a
  20 incidence. 5 of postpartum females
  experience thyroiditis in the year following
  delivery.
• Primary Due to intrinsic thyroid failure causes
  the vast majority of cases. Two forms goitrous
  enlarged gland or thyroprivic loss of gland
  tissue.
• Secondary caused by inadequate TSH
• Tertiary due to inadequate TRH from the
  hypothalamus.
• Clinical features
• Cretinism when experienced during perinatal
  period or infancy. Cretinism presents with
  impaired development of skeleton CNS, sever
  mental retardation, short stature, coarse facial
  features.
• Myxedema Insidious slowing of physical and
  mental activity, fatigue, cold intolerance
  apathy, cardiomegaly, pericardial effusion,
  periorbital edema, hair loss, accumulation of
  mucoploysaccharide-rich ground substance within
  the dermis.

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Causes of hypothyroidism

• 1. Congenital hypothyroidism results from
  agenesis of the thyroid gland or deficiency of
  the enzymatic pathways for the production of
  thyroxine.
• 2. Endemic iodine deficiency, although absent in
  the US this is still a common cause worldwide
  particularly among populations of mountainous
  South America and Southeast Asia. In children
  this presents as cretinism and in adults causes
  enlargement of the thyroid gland (due to
  increased glandular activity) termed a goiter.
• 3. Thyroiditis

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Thyroiditis

• Hashiomoto Thyroiditis is an insidiously
  developing condition that is the most common
  cause of hypothyroidism in areas of the world
  with adequate iodine levels. This is an
  autoimmune disordere associated with gradual
  thyroid failure due to thyroid destruction. The
  initiating event appears to be the development of
  autoreactive T-helper cells to thyroid antigens,
  thyrocyte death is mediated through killer
  T-cell activation, cytokine mediated cell death
  and antibody dependent cell mediated cytotoxicity
  directed at a number of thyrocyte specific cell
  surface antigens.

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Thyroiditis

• It is most prevalent in females (10-20/1) between
  45-65 years old. It presents as a painless
  enlargement of the thyroid gland with mild
  hypothyroidism. Hyperthyroidism may occur early
  in the disease and is associated with anti-TSH
  receptor antibodies if present its course is
  transient. There is increased risk of concomitant
  autoimmune disorders.
• Rare forms of thyroiditis are associated with
  viral infections or lymphocytic infiltration of
  unknown etiology. These forms often are
  associated with an acute hyperthyroid episode
  (1-2 weeks) followed by either a gradual or
  precipitous decline in thyroid function.

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Neoplasms of the Thyroid

• Solitary thyroid nodules are present in 1-10 of
  the US population. They are four times as common
  in women and increase in incidence throughout
  life. Most solitary nodules are benign with
  10/1 ratio adenoma to carcinoma.
• Characteristics Carcinoma vs. Adenoma
• 1. Solitary nodules are more likely to be
  neoplastic than multiple nodules
• 2. Nodules in younger (lt40) patients are more
  likely to be neoplastic.
• 3. Nodules in men are more likely to be
  neoplastic
• 5. A history of radiation exposure especially to
  the head neck region is associated with
  increased risk of malignancy
• 6. Nodules that are functional (take up
  radioactive iodine) are more likely benign

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Adenomas

• These are the most common form of thyroid
  neoplasm, they present as discrete, solitary
  masses. The vast majority are nonfunctioning but
  some may cause thyrotoxicosis. They are rarely
  precursors to carcinoma.
• Mutations in the TSH receptor-signaling pathway
  play an important role in the development of
  adenomas, resulting in the clonal expansion of a
  thyrocyte to produce a discrete mass.
• These present as a painless mass which take up
  radioactive iodine at a lesser rate than normal
  functioning tissue. These cold nodules have
  10 chance of malignancy, hot nodules (gtiodine
  up-take) have .1 risk of malignancy.

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Cystic Thyroid Adenoma
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Thyroid Scans with I125
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Carcinomas

• These account for 1.5 of all cancers in the US,
  most occurs in females and 90-95 are well
  differentiated and do not have an aggressive
  character but must be treated appropriately.
• A particular risk factor for thyroid carcinoma is
  the exposure to ionizing radiation particularly
  in the first 2 decades of life (tonsillitis
  prevention).
• 4 Types
• 1. Papillary carcinoma (70)
• This is the most common form of thyroid cancer
  it most commonly affects women between 20-50
  years of age and accounts for the vast majority
  of radiation induced malignancies. Often presents
  as a mobile painless nodule. Symptoms related to
  location indicate advanced disease.
• At the time of diagnosis this tumor has regional
  nodal involvement, despite this the prognosis for
  survival is gt95 at 10 years with proper
  treatment. Poorer outcome is associated with age
  gt40, extrathyroidal extension and distant mets at
  the time of diagnosis.

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• 2. Follicular carcinoma (20)
• These peak between ages 40-60 and have a 3/1
  female predominance. There is a weak association
  with iodine deficiency. These are aggressive
  tumors and prognosis is based on the extent of
  invasion at the time of diagnosis with 75-80 of
  patients whom have local invasion also developing
  metastatic disease. Locally isolated disease has
  a 10year 90 survival while the rate is 50 for
  aggressive disease.
• 3. Medullary Carcinoma (5)
• These arise from parafollicular cells of the
  thyroid and secrete calcitonin and occasionally
  some other active peptides (VIP). Sporadic cases
  have 50 5 years survival rate. There is a
  familial form associated with a better prognosis,
  possibly due to earlier detection through
  screening. Both forms are associated with
  mutations in a proto-oncogene (RET).
• 4. Anaplastic Carcinoma (1)
• These tumors present in older patients and are
  particularly aggressive showing rapid growth and
  metastasis most patients survive less than one
  year.

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Graves disease
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