Adrenal and paraganglia diseases

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Diseases of adrenals paraganglia
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Adrenal diseases
Lecture outline

• Introduction
• Hypoadrenalism
• Hyperadrenalism
• Tumors of adrenals and ganglia

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Adrenal Anatomy

• small, triangular glands loosely attached to the
  kidneys
• divided into two morphologically and distinct
  regions

• adrenal cortex (outer)
• adrenal medulla (inner)

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The Adrenal Cortex
Lecture Objectives

• identify the regional production of adrenal
  cortex hormones
• what are the physiological actions of cortisol?
• what are Addisons Disease and Cushings
  syndrome?

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Adrenal Cortex

• Hormones produced by the adrenal cortex are
  referred to as corticosteroids.
• These comprise
• mineralocorticoids glucocorticoids
• androgens.

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• The cortex is divided into three regions
• zona glomerulosa
• zona fasciculata
• zona reticularis

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Zona Glomerulosa

• Outermost zone just below the adrenal capsule
• Secretes mineralocorticoids.
• Mineralocorticoids are aptly termed as they are
  involved in regulation of electrolytes in ECF.
• The naturally synthesized mineralocorticoid of
  most importance is aldosterone.

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Zona Fasciculata

• Middle zone between the glomerulosa and
  reticularis
• Primary secretion is glucocorticoids.
• Glucocorticoids, as the term implies, are
  involved the increasing of blood glucose levels.
• However they have additional effects in protein
  and fat metabolism.
• The naturally synthesized glucocorticoid of most
  importance is cortisol.

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Zona Reticularis

• Innermost zone between the fasciculata and
  medulla
• Primary secretion is androgens.
• Androgenic hormones exhibit approximately the
  same effects as the male sex hormone
  testosterone.
• NB. Overlap in the secretions of androgens and
  glucocorticoids exist between the fasciculata and
  reticularis.

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Hormones of the Adrenal Cortex

• all adrenal cortex hormones are steroid
• not stored, synthesized as needed

testosterone
cortisol
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Aldosterone

• a steroid hormone
• essential for life (acute)
• responsible for regulating Na reabsorption in
  the distal tubule and the cortical collecting
  duct
• target cells are called principal (P) cell

- stimulates synthesis of more Na/K-ATPase pumps
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Effects of Aldosterone

• Renal and circulatory effects covered (ECF
  volume regulation, sodium and potassium ECF
  concentrations)
• Promotes reabsorption of sodium from the ducts of
  sweat and salivary glands during excessive
  sweat/saliva loss.
• Enhances absorption of sodium from the intestine
  esp. colon. absence leads to diarrhea.

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Regulation of Aldosterone Release

• direct stimulators of release
• indirect stimulators of release (RAAS)

• increased extracellular K
• decreased osmolarity
• ACTH

• decreased blood pressure
• decreased macula densa blood flow

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Glucocorticoids - Cortisol

• a steroid hormone
• essential for life (long term)
• the net effects of cortisol are catabolic

- plasma bound to corticosteroid binding globulin
(CGB or transcortin)

• prevents against hypoglycemia

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Physiological Actions of Cortisol

• promotes gluconeogenesis
• promotes breakdown of skeletal muscle protein
• enhances fat breakdown (lipolysis)
• suppresses immune system
• breakdown of bone matrix (high doses)

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Anti-inflammatory Effects of Cortisol

• reduces phagocytic action of white blood cells
• reduces fever
• suppresses allergic reactions
• wide spread therapeutic use

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Effect on Blood Cells and Immunity

• Decrease production of eoisinophils and
  lymphocytes
• Suppresses lymphoid tissue systemically therefore
  decrease in T cell and antibody production
  thereby decreasing immunity
• Decrease immunity could be fatal in diseases such
  as tuberculosis
• Decrease immunity effect of cortisol is useful
  during transplant operations in reducing organ
  rejection.

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Regulation of Cortisol Release

• cortisol release is regulated by ACTH
• release follows a daily pattern - circadian
• negative feedback by cortisol inhibits the
  secretion of ACTH and CRH

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Regulation of Cortisol Release cont
Enhanced release can be caused by

• physical trauma
• infection
• extreme heat and cold
• exercise to the point of exhaustion
• extreme mental anxiety

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Anatomy and Origin

• embryologically derived from pheochromoblasts
  
• differentiate into modified neuronal cells
• acts like sympathetic ganglion

- more gland than nerve - chromaffin cells
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Function of the Adrenal Medulla

• an extension of the sympathetic nervous system
• acts as a peripheral amplifier
• activated by same stimuli as the sympathetic
  nervous system

(examples exercise, cold, stress, hemorrhage,
etc.)
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Hormones of the Adrenal Medulla

• adrenaline (epinephrine)
• noradrenaline(norepinephrine)

• 80 of released catecholamines are epinephrine
• Hormones are secreted and stored in the adrenal
  medulla and released in response to appropriate
  stimuli

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Catecholamine Synthesis
tyrosine hydroxylase
L-aromatic amino acid decarboxylase
dopamine-B-hydroxylase
phenylethanolamine-N-methyltransferase
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Mechanism of Action

• receptor mediated adrenergic receptors
• peripheral effects are dependent upon the type
  and ratio of receptors in target tissues

Receptor ? ?
Norepinephrine
Epinephrine
Relative effects of epinephrine and
norepinephrine on ? and ? adrenergic receptors.
Guyton
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Differences between Epinephrine and Norepinephrine

• Epinephrine gtgt norepinephrine in terms of
  cardiac stimulation leading to greater cardiac
  output (? stimulation).
• Epinephrine lt norepinephrine in terms of
  constriction of blood vessels leading to
  increased peripheral resistance increased
  arterial pressure.
• Epinephrine gtgt norepinephrine in terms of
  increasing metabolism Epi 5-10 x Norepi.
  100 normal

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Effects of Epinephrine

• metabolism

• glycogenolysis in liver and skeletal muscle
• mobilization of free fatty acids
• increased metabolic rate

• can lead to hyperglycemia

• O2 consumption increases

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Adrenal Cortex Dysfunctions

• Hypoadrenalism

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Adrenocortical insufficiency

• Due to
• Deficient synthesis of cortical steroids
• ACTH deficiency
• Three types of hypoadrenalism
• 1 adrenocortical insufficiency
• Acute or adrenal crisis
• Chronic or Addisons disease.
• 2 adrenocortical insufficiency
• Diminished ACTH secretion
• Hypoaldosteronism
• Deficient secretion of aldosterone.

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1 adrenocortical insufficiency

• 1 acute adrenocortical insufficiency (adrenal
  crisis)
• Bilateral adrenelectomy
• Septicaemia
• Rapid withdrawal of steroids
• Acute-on-chronic insufficiency

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1 chronic adrenocortical insufficiency
Hypoadrenalism Addisons Disease

• Progressive chronic obstructiongt90 of cortex
  results in inadequate production of hormones

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• Caused by autoimmunity against cortices 80
  (idiopathic adrenalitis)
• - tuberculosis
• - drugs
• - metastatic cancer
• - histoplasmosis
• - amyloidosis
• - sarcoidosis
• - haemochromatosis.
• Plasma sodium decreases and may lead to
  circulatory collapse

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2chronic adrenocortical insufficiency

• ACTH deficiency
• Prolonged steroid therapy
• Panhypopituitarism

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Mineralocorticoid Deficiency

• Lack of aldosterone (Hypoaldosteronism)
• Isolated aldosterone deficiency, a/w low renin
  normal cortisol levels
• Due to
• deficient synthesis (lack of enzyme
• prolonged heparin therapy
• certain brain dseases
• excision of aldosterone-secreting tumor.

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Mineralocorticoid Deficiency

• Increased sodium, chloride, water loss
• Decrease ECF volume
• Hyperkalemia
• Mild acidosis
• Increase RBC concentration
• Decrease cardiac output shock - death within 4
  days to a 2 weeks if not treated

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Glucocorticoid Deficiency

• Loss of cortisol
• Disruption in glucose concentration
• Reduction in metabolism of fats and proteins
• Patient is susceptible to different types of
  stress
• Sluggishness of energy mobilization result in
  weak muscle even when glucose and other nutrients
  are available cortisol is needed for metabolic
  function

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Melanin Pigmentation

• Characteristic of Addisons disease is uneven
  distribution of melanin deposition in thin skin
  eg. Mucous membranes, lips, thin skin of the
  nipples.
• Feedback and effect on MSH

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Treatment

• Total destruction, if untreated, could lead to
  death within a few days.
• Treatment small quantities of
  mineralocorticoids and glucocorticoids daily.

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Hyperadrenalism
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Hyperadrenalism

1. Cushings Syndrome (chronic hypercortisolism)
2. Conn Syndrome (primary hyperaldosteronism)
3. Adrenogenital syndrome (adrenal virilism)

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CUSHINGS SYNDROME

• Also called chronic hypercortisolism
• 4 major etiological types of Cushings
• Pituitary Cushings Syndrome 60-70
• Excessice secretion of ACTH
• Lesion in pituitary usually corticotroph
  adenoma(s)
• 1st described by US neurosurgeon Harvey Cushing
• Includes non-pituitary hypothalamic excessive
  ACTH
• Show therapeutic responses to high doses of
  dexamethasone which suppresses ACTH lowers
  plasma cortisol

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CUSHINGS SYNDROME

• Adrenal Cushings Syndrome 20-25
• Unilateral/bilateral adrenal disease
• Adrenocortical adenoma, carcinoma less often
  cortical hyperplasia.
• Low serum ACTH levels
• No therapeutic response to high doses of
  glucocorticoid

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CUSHINGS SYNDROME

• Ectopic Cushings Syndrome 10-15
• ACTH elaboration by non-endocrine tumors
• Usually an oat-cell ca.
• Lung, other lung ca malignant thymoma
  pancreatic tumors.
• High serum ACTH levels
• Cortisol levels not suppressed by dexamethasone

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CUSHINGS SYNDROME

• Iatrogenic Cushings Syndrome
• Prolonged steroid/ACTH administration eg
• In organ transplant pts and
• In autoimmune diseases
• Usually a/w bilateral adrenocortical
  insufficiency

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Cushings Syndrome Major Causes

• Exogenous (iatrogenic, factitious)
• ACTH-dependent
• Pituitary adenoma 70
• Ectopic ACTH syndrome 15
• Plasma ACTH
• gt15 pg/ml ACTH dependent
• lt5 pg/ml ACTH independent

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Cushings Syndrome Major Causes

• ACTH-independent
• Adrenal adenoma 10
• /- aberrant receptors (GIP, V1, ßAR)
• Adrenal carcinoma 5
• Bilateral macronodular hyperplasia (AIMAH)
• /- aberrant receptors (GIP, V1, ßAR)
• Primary pigmented nodular adrenal disease (PPNAD)
• /- Carney complex

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Clinical features

• Often btn 20-40yrs
• MF ratio13
• Buffalo torso (central/truncal obesity)
• Redistribution of fat from lower parts of the
  body to the thoracic and upper abdominal areas
• Relatively thin arms legs
• Moon Face
• Edematous appearance of face
• Acne hirsutism (excess growth of facial hair)

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Clinical features

• Increased protein breakdown a/w
• Wasting thinning of skeletal muscles
• Skin subcutaneous tissue atrophy forming striae
  on the abdominal wall
• Easy bruisability
• Osteoporosis
• Systemic HT in 80 due Na water retention
• Impaired glucose tolerance (IGT) DM in 20
• Amenorrhoea infertility in many women
• Insomnia, depression, confusion psychosis

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Cushings Syndrome
moon face
striae
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Effects on Carbohydrate Metabolism

• Adrenal diabetes
• Hypersecretion of cortisol results in increase
  blood glucose levels, up to 2 x normal (200mg/dl)
• Prolonged oversecretion of insulin burns out
  the beta cells of the pancreas resulting in life
  long diabetes mellitus

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Effects on Protein Metabolism

• Decrease protein content in most parts of the
  body resulting in muscle weakness
• In lymphoid tissue decrease protein synthesis
  results in suppression of the immune system
• Lack of protein deposition in bones can result in
  osteoporosis
• Collagen fibers in subcutaneous tissue tear
  forming striae

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Treatment

• Removal of adrenal tumor if this is the cause
• Microsurgical removal of hypertrophied pituitary
  elements to reduce ACTH secretion
• Partial or total adrenalectomy followed by
  administration of adrenal steroids to compensate
  insufficiencies that develop

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Treatment

• Transsphenoidal pituitary surgery
• Pituitary radiation
• Cortisol synthesis inhibitors
• Ketoconazole
• Metyrapone
• Mitotane
• Bilateral adrenalectomy

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CONN SYNDROME

• Uncommon
• Overproduction of aldosterone (salt-retaining
  hormone) due to
• Adrenocortical adenoma
• Bil adrenal hyperplasia esp in children
  (congenital hyperaldosteronism)
• Adrenal carcinoma (rare)
• Primary hyperaldosteronism from any of above
  causes is a/w low plasma renin levels

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CONN SYNDROME

• Secondary hyperaldosteronism occurs in response
  to high plasma renin levels (renal ischaemia,
  reninoma, oedema).

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CONN SYNDROME

• Clinical features
• HT-mild to moderate, diastolic
• Hypokalemia a/w muscular weakness, peripheral
  neuropathy cardiac arrhythmias
• Na water retention
• Polyuria polydipsia due to reduced
  concentrating power of renal tubules

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Adrenogenital syndrome (adrenal virilism)

• Hypersecretion of sex steroids mainly androgens
  than the gonads
• In children due to congenital adrenal
  hyperplasia.
• In adults due to adrenocortical adenoma or
  adrenal carcinoma. Cushings Syndrome is often
  present.

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Adrenogenital syndrome (adrenal virilism)

• Clinical features
• Depend on age sex of pt
• In children distortion of external genitalia in
  girls precocious puberty boys
• In adults virilization in females rarely
  feminization in males
• Increased secretion of 17-ketosteroids in urine

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Tumors of adrenal glands

• Cortical adenoma
• If lt2cm termed hyperplastic nodules
• Benign slow-growing tumor
• Small, non-functional
• Micro resemble cells of ZF

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Tumors of adrenal glands

• Cortical carcinoma
• Uncmon
• Invasive locally mets
• Phaeochromocytoma (Chromaffin tumor)
• Means dusky, brown tumor
• Generally benign, arising from medulla
• Extra-adrenal Phaeochromocytoma are called
  paragangliomas
• Occurs at any age but mostly 20-60s

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Pheochromocytoma

• a catecholamine-secreting tumour of chromaffin
  cells of the adrenal medulla
• paraganglioma a catecholamine secreting tumour
  of the sympathetic paraganglia

adrenal pheochromocytoma (90)
extra-adrenal pheochromocytoma
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Signs and Symptoms of Pheochromocytoma

• treatment resistant hypertension (95)
• headache
• sweating
• palpitations
• chest pain
• anxiety
• glucose intolerance
• increased metabolic rate

classic triad
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Diagnosis and Treatment

• diagnosed by high plasma catecholamines and
  increased metabolites in urine
• no test for adrenal or extra-adrenal
• treatment is surgical resection

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Tumors of adrenal glands

• Myelolipoma
• Uncommon
• Benign
• Adrenal medullary tumor
• /- sx of excessive hormone secretion

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Tumors of adrenal glands

• Neuroblastoma
• Also called sympatheticoblastoma
• Common malignant tumor of embryonic nerve cells
• Mostly in childrenlt5yrs
• Majority abdominal (adrenal medulla or
  paravertebral autonomic ganglia)
• Rarely in cerebral hemisphere
• Sporadic familial autosomal dominant

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Tumors of adrenal glands

• Clinical sx due to
• rapid local growth
• Mets
• Hormone secretion
• Abd dist, fever, wt loss, malaise, focal
  calcification (abd X-ray)
• Mets early widely thru blood lymphatic to
  skull, lungs, liver, LNs

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Tumors of adrenal glands

• Prognosis
• agelt2yrs better
• Extra-abd better
• Clin stage I II better
• Myc TP53 gene amplification poor

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Tumors of adrenal glands

• Ganglioneuroma
• Mature, benign, uncommon
• Adults
• Derived from ganglion cells
• Often in posterior mediastinum
• /- other peripheral, ganglia brain

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Tumors of adrenal glands

• Extra-adrenal paraganglioma (chemodectoma)
• Eg carotid bodies, vagus, jugulotympanic,
  aorticosympathetic (pre-aortic) paraganglioma
• Responsive to chemoreceptors
• Also called Extra-adrenal Phaeochromocytoma