Endocrine Pathology

Pituitary

= Composed of anterior and posterior lobes secreting various hormones

–       Receive both stimulatory and inhibitory influences from hypothalamus

–       Cells present contain eosinophilic cytoplasm (acidophil) or basophilic cytoplasm (basophil)

–       Anterior pituitary (AP) (adenohypophysis) – 5 cell types present:

Posterior pituitary (PP) (neurohypophysis) – modified glial cells and axonal processes extending from hypothalamus to posterior lobe

• Hormones are produced in hypothalamus and stored within axon terminals in posterior pituitary

Clinical manifestations

Hyperpituitarism = excess secretion of trophic hormones

• Cause: Pituitary adenoma, hyperplasia, carcinoma of AP

Hypopituitarism = deficiency of trophic hormones

• Cause:
  • Ischaemic injury, surgery, radiation, inflammatory reactions and non-functional pituitary adenomas
  • Local mass effects
  • Sellar expansion, bony erosion and disruption of diaphragmatic sella
  • Compression of optic chiasm leading to bitemporal hemianopsia
  • Elevated ICP
  • Pituitary apoplexy (acute haemorrhage into an adenoma), can cause sudden death and is a neurosurgical emergency

Pituitary adenomas

= Most common cause of hyperpituitarism, peak incidence age 35-60 years

–       Classified based on hormone (s) produced by neoplastic cells

–       Are functional (associated with hormone excess) or non- functional (nil clinical symptoms of hormone excess)

–       Microadenoma (<1cm in diameter) or macroadenoma (>1cm in diameter)

–       G-protein mutations are most common molecular abnormality

–       Types:

Hypopituitarism

= Decreased secretion of pituitary hormones due to diseases of hypothalamus/ pituitary

Occurs when 75% parenchyma is lost

Posterior pituitary dysfunction – diabetes insipidus

Anterior pituitary dysfunction –  

• Growth failure (dwarfism) due to lack of GH
• Hypothyroidism due to lack of TSH
• Amenorrhea/ infertility due to gonadotropin deficiency
• Lactation dysfunction due to lack of PRL
• Mechanisms:
  • Tumours, mass lesions
  • Traumatic brain injury and SAH
  • Pituitary surgery or radiation
  • Pituitary apoplexy
  • Sheehan Syndrome (ischaemic necrosis of pituitary)
  • Rathke cleft cyst
  • Empty sella syndrome
  • Congenital defects
  • Hypothalamic tumours (eg. craniopharyngioma)
  • Inflammatory/ infective such as sarcoidosis, tuberculous meningitis

Posterior Pituitary Syndromes

Involve ADH, two syndromes:

• Diabetes insipidus = Lack of ADH
  • Excessive urination due to inability of the kidney to reabsorb water, leads to polydipsia, thirst and dehydration.
  • Can result from head trauma, tumours, inflammation and surgery.
  • Central if from ADH deficiency (compared to nephrogenic if due to renal tubular unresponsiveness to ADH)
• Syndrome of Inappropriate ADH (SIADH) = Excess ADH
  • Renal resorption of excessive amounts of free water, leads to hyponatraemia, cerebral oedema and neurologic dysfunction. Can result from ectopic ADH production from neoplasm (paraneoplastic syndrome), CNS disorders, infection and trauma.

Hypothalamic Suprasellar Tumours

May induce hypofunction or hyperfunction of anterior pituitary or diabetes insipidus

Two main lesions:

• Glioma
• Craniopharyngioma = derived from vestigial remnants of Rathke pouch

Endocrine pancreas

= 1 million clusters of cells, Islets of Langerhans which contain 4 major cell types:

Diabetes Mellitus

Group of metabolic disorders sharing common feature of hyperglycaemia

Diagnosis:

• Elevated blood glucose level (BGL) by any one of 3 criteria:
  • Random BGL > 200 mg/ dL (11.1mmol/L)
  • Fasting BGL >126 mg/ dL (>7mmol/L) on >1 occasion
  • Abnormal OGTT = glucose concentration greater than 200 mg/dL (>11.1mmol/L) 2 hours after standard carbohydrate load

Classification:

Glucose Homeostasis

3 processes =

1.     Gluconeogenesis in liver

2.     Glucose uptake and peripheral utilisation

3.     Action of insulin and glucagon (opposite effects)

–       Fasting state: Low insulin and high glucagon levels increase hepatic gluconeogenesis and glycogenolysis, decrease glycogen synthesis to prevent hypoglycaemia

–       Fed state: High insulin and low glucagon levels promotes glucose uptake and utilisation in tissues (mainly skeletal muscle)

Regulation of insulin release =

–       Insulin gene expressed on pancreatic beta cells

–       Pre-proinsulin synthesised in rough ER from insulin mRNA and delivered to Golgi

–       Proteolytic steps generate mature insulin and cleavage peptide (C-peptide)

–       Stored in secretory granules

–       Stimulus for release is glucose itself: Increased glucose uptake into beta cell via GLUT-2 transporter -> metabolism of glucose generates ATP -> inhibition of ATP sensitive K+ channel -> membrane depolarisation -> influx extracellular Ca2+ into the cell -> insulin release

Insulin action and signalling pathways = ANABOLIC

–       Increase rate of glucose transport into cells of the body, providing energy source

–       Particularly to striated muscle cells and adipose tissue

–       Promotes amino acid uptake and protein synthesis

Pathogenesis:

Complications:

Pathogenesis = persistent hyperglycaemia is key mediator

Three distinct metabolic pathways implicated –

1.     Formation of advanced glycation end products -> accelerates vessel injury and microangiopathy by 5 main mechanisms:

a.     Release of pro-inflammatory cytokines and growth factors from intimal macrophages

b.     Generation of ROS in endothelial cells

c.     Procoagulant activity in endothelial cells and macrophages

d.     Proliferation of vascular smooth muscle cells and synthesis of ECM

e.     Cross link ECM matrix proteins, decreases elasticity and predisposes vessels to shear stress

2.     Activation of protein kinase C

a.     Production of angiogenic factors implicated in neovascularisation (diabetic retinopathy)

b.     Elevated endothelin causing vasoconstriction, decreased nitric oxide

c.     Production of pro-fibrinogenic factors (TGF-beta) lead to increased deposition of ECM and basement membrane material

d.     Production of PAI-1 leading to reduced fibrinolysis and vascular occlusion

e.     Pro-inflammatory cytokines

3.     Intracellular hyperglycaemia and disturbances in polyol pathways

a.     Reduction in glutathione (GSH) via glucose metabolism in tissues which do not require insulin for glucose transport (nerves, lens, kidneys, blood vessels)

b.     Leads to increased oxidative stress

Morphology

• Pancreas

Variable

T1DM:

-Reduction in number and size of islets

-Leukocytic infiltration (insulitis)

T2DM:

-Amyloid deposition within islets

Clinical features: Characteristic patterns

Adrenal Glands

= Consist of cortex (synthesises glucocorticoids, mineralocorticoids and sex steroids) and medulla (catecholamines)

Adrenal Cortex

Adrenal Medulla

Phaeochromocytoma

= Neoplasms of chromaffin cells, which synthesise and release catecholamines

Rare cause of surgically correctable hypertension

“Rule of 10s”

• 10% phaeochromocytomas are extra-adrenal (paragangliomas)
• 10% are bilateral
• 10% are biologically malignant
• 10% are associated with hypertension
• 25% patients with phaeochromocytoma and paragangliomas harbor germline mutation

Morphology: Range from small, circumscribed lesions to large haemorrhagic masses, composed of chromaffin cells clustered into small nests (zellballen). No histologic feature that dictates behaviour. Definitive diagnosis of malignancy in phaeochromocytomas is based on presence of metastases.

Clinical features: Caused by sudden release of catecholamines, paroxysmal episodes:

• Hypertension, tachycardia, palpitations, headache, sweating and tremor
• Abdominal or chest pain, vomiting
• Paroxysms may be exacerbated by stress, posture changes, palpation of tumour
• May precipitate CCF, MI, APO, ventricular fibrillation and CVA

Diagnosis:

• Increased urinary excretion of free catecholamines and their metabolites

Treatment:

• Surgical excision
• Pre and intraoperative medications such as adrenergic blocking agents to prevent hypertensive crises

Last Updated on September 24, 2021 by Andrew Crofton