Endocrine Pathology Flashcards
define diabetes mellitus
a chronic disorder of carbohydrates, fat and protein metabolism due to defective insulin secretory response, resulting in impaired carbohydrate, mainly glucose, use
what are the subtypes of primary diabetes?
type 1; insulin dependent diabetes mellitus
type 2; non-insulin dependent diabetes mellitus
what genetic abnormalities is diabetes associated with?
genetic defects of B-cell function;
including maturity onset diabetes of the young (MODY)
chromosomal abnormalities; 2, 7, 12
some mitochondrial DNA abnormalities
what is associated with secondary diabetes?
chronic pancreatitis
haemochromatosis
infectious; congenital rubella, cytomegalovirus
endocrinopathies; adrenal, pituitary tumours
congenital rubella
cytomegalovirus infection
drugs; corticosteroids, pentamidine, vacor
genetic disorders; downs syndrome
gestational diabetes mellitus
what are the clinical features of type 1 diabetes?
<20yrs onset typically has normal weight decreased blood insulin levels anti-islet cell antibodies in the blood ketoacidosis common
what are the clinical features of type 2 diabetes?
onset later in life, >30yrs typically obese insulin levels normal or increased ketoacidosis rare 90-100% concordance in twins no HLA association
what are the pathological features of type 1 diabetes?
frequently HLA-D linked autoimmune immunopathological mechanism inflammation or insulitis in the islet cells early on in the disease marked atrophy and fibrosis severe beta cell depletion
what are the pathological features of type 2 diabetes?
insulin resistance relative deficiency of insulin no inflammation in the islets of langerhans become focally atrophic amyloid proteins may be deposited only mild beta-cell depletion
describe normal insulin production in normal islet cells
glucose results in stimulation of insulin production
increasing levels of glucose in the blood are transported across the cell boundary by the GLUT-2 transport mechanism
increasing production of preproinsulin and proinsulin
insulin is released into the bloodstream
what are the normal effects of insulin on cells?
attaches to the insulin receptors increased production of glucose transport units increase in glucose uptake by the cell increased protein synthesis transfer of glucose into lipids
how does type 1 diabetes develop?
genetic deposition; HLA-linked gene environmental insult; viral infection direct damage to beta cells immune response develops against normal/altered beta cells increased beta cell destruction
what are the autoimmune factors that are associated with type 1 diabetes?
pre-clinical phase of islet destruction; insulitis presence of CD8 and CD9-positive macrophages increase in class 1 major histocompatibility complex molecules aberrant expression of class 2 MCH 70-80%; islet cell autoantibodies in their circulation 10-20%; other autoimmune diseases, SLE, RA
how is obesity a risk factors for type 2 diabetes?
the peripheral tissues; muscle and fat, develop insulin resistance
unable to adequately utilise the glucose present in the blood
combined with deranged insulin secretion
= hyperglycaemia
the beta cells are unable to produce enough insulin to adequately lower the blood glucose and become exhausted
what are the features of deranged insulin secretion?
loss of the normal pulsatile oscillating secretion of insulin within the blood
abnormal response to hyperglycaemia
possibility of a genetic vulnerability to hyperglycaemia
what are the pathological complications of diabetes?
non-enzymatic glycolysation; glucose becomes linked with haemoglobin or becomes linked to collagen and form advanced glycosylation end products (AGE)
intracellular hyperglycaemia; disturbances of the polyol pathways
accumulation of sorbitol and fructose within the cells
what are the clinical complication of diabetes?
brain; disease of small vessels
eyes; cataracts and glaucoma
MI
diseases of the small vessels of the peripheries; gangrene of the feet and toes
describe the complications of diabetes in the pancreas
more common in type 1 diabetes inflammatory cells/leucocytes are present in the islets; insulitis beta cell degranulation reduction in the islet cell mass amyloid deposition may occur
describe atherosclerosis in diabetes
occurs more rapidly in diabetes
atherosclerotic plaques are complicated by ulceration
marked fibrosis and calcification
origin of many of the vessels are occluded
what are the causes of vascular complications in diabetes?
elevated blood lipid levels
low levels of HDL
increased thromboxane A2 activity; increased platelet stickiness
hyaline arteriosclerosis
describe the complications of diabetes in the kidneys
renal artery narrowing; renal ischaemia and hypertension
diabetic microangiopathy
describe diabetic microangiopathy
diffuse thickening of the basement membrane of small capillaries;
glomerular lesions
vascular lesions
pyelonephritis and necrotising papillitis
describe the glomerular lesions of diabetic microangiopathy
basement membrane thickening; the normal structures of an internal lamina densa, with outer laminar rara is lost
uniform thickening
increased deposition of glycjogenated collagen proteins
diffuse glomerulosclerosis; increase in mesangial matrix and narrowing of the capillary loops
nodular glomerulosclerosis; deposition of abnormal collagen fibres, result in a decrease in glomerular blood flow and development of renal failure
describe the vascular lesions of diabetic microangiopathy
hyaline arteriosclerosis; narrowing of the afferent and efferent arterioles due to deposition of hyaline material, replacing the muscle of the media
describe pyelonephritis and necrotising papillitis associated with diabetic microangiopathy
acute pyelonephritis; mottled appearance, hyperaemia, inflammation and necrosis
tubules filled with polymorphs and inflammatory debris
necrotising papillitis; inflammation, associated ischaemia, necrosis of the papilla, passes into the ureter and may cause obstruction
what are the neurological complications associated with diabetes mellitus?
peripheral symmetrical neuropathy may involve the sensory, motor or autonomic nervous system
gangrene; inadequately supply of nerves with blood, resulting in nerve damage and cerebral haemorrhage
cerebral haemorrhage; microangiopathy
cerebral infarction; loss of blood supply, involvement of vessels within the brain, embolism from atherosclerotic neck vessels
what are the skin complications of diabetes?
recurrent infections; bacterial, fungal
necrobiosis lipodica diabeticorum
granuloma annulare
what are the pregnancy complications of diabetes?
increased chance of pre-elcamptic toxaemia
large and immature babies
risk of neonatal hypoglycaemia
describe the thyroid gland
develops embryologically from a down-growth of the pharyngeal epithelium
descends lower in the neck during embryological development
15-20g
very vascular organ
nerve supply; cervical sympathetic nerves
act on blood vessels to influence secretions
describe the histology of the thyroid gland
thyroid follicles lined by thyroid follicular epithelium
the follicles contain colloid; the store for thyroid hormone
describe the physiology of the thyroid gland
TSH released by the pituitary gland
following the action of trophic factors from the hypothalamus in the base of the brain
TSH acts on thyroid tissue to release T4/thyroxine and smaller amounts of T3/triiodothyronine
T3 and T4 are released into the circulation; reversibly bound to thyroxine-binding globulin/TBG
T3 and T4 have a negative effects on TSH and TRH
describe multi nodular goitre formation
a progressive cycle of hyperplasia, degeneration and fibrosis
the gland becomes overall enlarged and nodular
cystic change within the follicles
surrounded by fibrosis
describe hyperthyroidism
a hyper metabolic state characterised by increased levels of thyroid hormones and gland hyperfunction
causes; diffuse hyperplasia thyroiditis hyper-functioning goitre over-ingestion of hormone
what conditions are associated with hyperthyroidism?
diffuse toxic hyperplasia (Grave's) toxic multi nodular goitre toxic adenoma acute.subacute thyroiditis thyroid stimulating hormone secreting pituitary hormone neonatal thyrotoxicosis in maternal struma ovarii; ovarian teratomatous thyroid iatrogenic (exogenous) hyperthyroidism
what are the clinical features of hyperthyroidism?
overactivity of the sympathetic nervous system
cardiac; output increased, tachycardia, palpitations, arrhythmias, congestive heart failure
neuromuscular; atrophy of musculoskeletal tissues, tremor, hyperactivity, emotional lability, anxiety
osteoporosis
skin; warm and moist, increased sweating
GI; increased appetite, weight loss, increased bowel motility
how is hyperthyroidism diagnosed?
free T4 levels increased
suppressed TSH
radioactive iodine uptake by thyroid; increased activity
what are the causes of hypothyroidism?
insufficient thyroid parenchyma; developmental, radiation injury/surgical ablation, Hashimoto’s thyroiditis
interference with thyroid hormone synthesis; idiopathic primary hypothyroidism, iodine deficiency, drugs
supra thyroidal; pituitary lesions, hypothalamic lesions
describe hypothyroidism in infancy
poor development of CNS and skeleton; severe mental retardation
T3 T4 cross feto/maternal barrier before birth
what are the clinical features of hypothyroidism?
myxoedema decreased sweating constipation accumulation of matrix substances in subcutaneous tissue fatigue mental sluggishness slow speech cold intolerance weight gain reduced cardiac output; shortness of breath, reduced exercise tolerance
how is hypothyroidism diagnosed?
decreased thyroid hormone levels
TSH leve increased
describe the inflammatory conditions of the thyroid gland/thyroiditis
Hashimoto’s and grave’s; immune-related, associated with under activity and overactivity of thyroid hormone production
granulomatous and subacute lymphocytic thyroiditis; diagnosed down the microscope
riddle’s thyroiditis; progressive fibrous replacement of the thyroid tissue
palpation thyroiditis; histological changes after the preoperative handling or palpation of the thyroid tissue
describe the features Hashimoto’s thyroiditis
gross; symmetrical atrophy of the normal bulk of thyroid tissue
microscopy; normal follicles replaced by a lymphoid infiltrate
epithelial cells; abundant eosinophilic/pink cytoplasm, oncocytic/Hurthle cell metaplasia
describe the pathology of Hashimoto’s thyroiditis
the most common cause of thyroiditis
autoimmune; caused by a T cell defect
involves both cellular and humeral immunity
blood; high titres of anti-thyroid antibodies, including anti-thyroid globulin antibody
may have a genetic component
associated with subtypes of HLA
what are the clinical features of Hashimoto’s thyroiditis?
more common in females
typically from 45-65yrs
painless enlargement of the thyroid lobes
rarely associated with an increase in B-cell lymphomas of the thyroid
can be associated with other autoimmune diseases
describe grave’s disease
hyper functional diffuse enlargement of the thyroid tissue
infiltrative ophthalmology; exophthalmos
immune mediated infiltration of the periocular muscles and soft tissue
associated with pretibial myxoedema
more common in females
typically from 20-40yrs
can be genetically linked
describe the pathology of grave’s disease
autoimmune
over-stimulation of the TSH receptor caused by auto-antibodies
increased peripheral levels of thyroid hormone in the blood
decrease in TSH
histology; diffuse hyperplasia which involves both lobes
what clinical features suggest a thyroid neoplasm?
a solitary nodule; clinically palpable or discovered on imaging
enlarged nodes in the neck
a nodule in a younger patient
describe thyroid adenoma
a benign lesion of the thyroid gland
presents as a direct solitary mass
a lesion derived from the follicular epithelium of the thyroid gland
share architectural and nuclear features with follicular carcinoma
generally encapsulated
defining feature; no evidence of capsular or vascular invasion
range of histological subtypes; microfollicular, macrofollicular, oncocytic, hurthle cell
describe a follicular adenoma
composed of follicle of variable sizes many have a micro follicular pattern have a border of fibroconnective tissue must not show breach no vascular invasion
what are the risk factors for thyroid cancer?
mostly sporadic
ionising radiation
genetic susceptibility
FAP
familial papillary thyroid carcinoma syndrome
medullary carcinoma; multiple endocrine neoplasia sydrnomes (MEN)
what are the main types of thyroid carcinoma?
papillary; most common
follicular
medullary
anaplastic
describe papillary carcinomas
differentiated
the tumour cells recapitulate the normal thyroid follicular epithelial cells
metastasises to the lymph nodes
typically 20-40yrs
often presents as a thyroid nodule or mass
describe the diagnosis of a papillary carcinoma
based on a combination of a typically papillary-type architecture and characteristic nuclear features
imaging
fine needle aspiration
describe the histology of a papillary carcinoma
formation of well-formed fibrovascular papillae
lined by neoplastic cells
enlarged nuclei
open/empty chromatin patterns
often overlapping
intranuclear pseudo inclusions; invaginations of the cytoplasm into the nucleus
nuclear membranes are often irregular or wrinkled
describe the follicular carcinoma
10-15%
differentiated
characterised by capsular or vascular invasion, or both
spreads via the blood-borne route
minimally invasive; excellent long-term prognosis
widely invasive; much poorer prognosis
diagnosis requires full thickness breach through the capsule
describe the histology of a follicular carcinoma
full thickness capsular breach
or invasion into the blood vessels
describe medullary carcinoma
consists of neuroendocrine cells derived from the parafollicular C cells
form tumours composed of sheets, trabecular or nests of small, darkly staining cells
may secrete calcitonin
deposition of pink amyloid associated with malignant cells
can be associated with multiple endocrine neoplasia syndrome type 2 or familial medullary thyroid carcinoma syndrome
up to 25% inherited
describe the diagnosis of medullary carcinoma
calcitonin serum levels; diagnostic parameter
describe the histology of medullary carcinoma
darkly staining closely-plaqued tumour cells
pink stromal amyloid
describe anaplastic carcinoma
rare; <5% all thyroid cancers
undifferentiated
consists of pleomorphic or spindled tumour cells which are obviously malignant
high mortality; 90-100%
local invasions; involves important structures of the neck
mean age 65
describe the histology of anaplastic carcinoma
undifferentiated, obviously malignant cells
high mitotic rate
very pleomorphic nuclear features
describe poorly differentiated carcinoma
intermediate morphologically and behaviourally between differentiated and undifferentiated thyroid tumours
composed of insular, solid or trabecular cells
usually shows a widely invasive pattern within the thyroid tissue
associated with necrosis
obvious vascular invasion
describe thyroid lymphoma
rare
may complicated thyroiditis
usually a low-grade B-cell neoplasm
can be high grade and aggressive; diffuse large B-cell
describe carcinoid tumours and the cells they originate from
arise from the cells which generate bioactive compounds
present in various organs throughout the body
derived from epithelial stem cells; islets, biliary tract, liver, C cells, adrenal
most commonly seen in the GI tract
phenotypically resemble endocrine cells
what are the features of carcinoid tumours?
occur at any age; peak between 50-60yrs
synthesise a wide range of bioactive products and hormones; insulin, 5-hydroxytryptamine, calcitonin
describe the behaviour of carcinoid tumours
potentially malignant
variable behaviour; depending on site of tumour, depth of local penetration of tumour, and tumour size
appendices and rectal carcinoids are less aggressive than gastric or small intestinal carcinoids
describe the anatomy of carcinoid tumours
gross; may be quite small, arise at the lower end of the small intestine
histologically; often bland, with a monotonous cell population, shows little pleomorphism
describe carcinoid syndrome
due to elevated levels of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in the blood
associated with carcinoid tumours
GI carcinoids; frequently asymptomatic, small in size
lung carcinoids; may produce a mass lesion
gastric pancreatic carcinoids; may produce gastrin, results in Zollinger-Ellison syndrome or hyper secretion of stomach acid
what are the clinical features of carcinoid syndrome?
vasomotor disturbances; skin flushing and cyanosis
intestinal hypertrophy; diarrhoea, abdominal cramps, nausea, vomiting
asthmatic or bronchoconstrictive attacks; cough, wheezing, dyspnoea
liver enlargement
systemic fibrosis; heart (pulmonary and tricuspid valves), sub-endocardial fibrosis (RV)
bronchial carcinoids; similar effects on the left side of the heart
retroperitoneal and pelvic fibrosis
collagenous pleural and intimal aortic plaques
what are the causes of increased cortisol levels?
anterior pituitary tumour; produces ACTH which acts on the adrenal gland
adrenal gland adenoma
adrenal gland hyperplasia
a lung tumour (SCLC) produces ACTH; paraneoplastic Cushing’s syndrome
excessive steroids; iatrogenic Cushing’s syndrome, atrophy fo the adrenal gland
what are the causes of Cushing’s syndrome?
primary hyper secretion of ACTH; >50%
primary adrenal neoplasm; 15-30%
ectopic ACTH; SCLC, carcinoid tumour, medullary carcinoma of thyroid
what are the clinical features of Cushing’s syndrome?
central obesity moon-like face weakness tiredness increased hair on the face and body high blood pressure high colour glucose intolerance; diabetes osteoporosis psychiatric symptoms
what are the causes of primary adrenal insufficiency?
loss of the cortex; antuommune infections; TB, fungal infection amyloid deposition in the adrenal glands metastatic carcinoma
what are the causes of secondary adrenal insufficiency?
hypo function of the pituitary gland;
tumours
inflammation
describe an adrenal adenoma
a tumour of the adrenal cortex
large, well-defined, circumscribed nodules
histology; encapsulated lesions
proliferation of adrenal cortical cells
describe an adrenal carcinoma
a tumour of the adrenal cortex
large tumour replacing the adrenal gland
destroys surrounding tissue and invades into the surrounding structures
histology; considerable mitotic activity and nuclear proliferation
describe pheochromocytomas
tumours which arise in the medulla
derived from the sympathetic nervous system cells
produce catecholamines
may behave in a malignant fashion
primarily benign
associated with familial multiple endocrine neoplasia
what are the symptoms and signs of a pheochromocytoma?
sweating hypertension increased HR anxiety feeling of impending doom
describe the anatomy of a pheochromocytoma
gross; well circumscribed lesion
does not involve the fat around the adrenal gland
histology; considerable nuclear variability and mitotic activity
malignant behaviour; invasion of adjacent tissue, presence of metastases
what are the consequences of pituitary adenomas?
secrete hormones; ACTH, GH, prolactin
mass effect; press on adjacent structures
can press on the optic nerve; bitemporal hemianopia
what are the clinical features of a pituitary adenoma?
endocrine abnormalitity
mass effect of the lesion
radiographic abnormality of the sella turcica
pressure on the optic chiasm; bitemporal hemianopia
increased intracranial pressure; headache, nausea, vomiting
describe the normal pituitary gland and how this changes in an adenoma
acidophil cells; produce GH, then produce excess
basophil cells; produce ACTH, then produce excess
chromophobe cells; produce no hormones normally, may produce prolactin in adenoma
associated with MEN1
describe a microadenoma
a small pituitary tumour only identified on histology associated with excess prolactin production a caused of infertility no mechanical effect
what are the causes of hypopituitarism?
tumours mass lesions of the pituitary following pituitary surgery or radiation rathke's cleft cyst pituitary haemorrhage ischaemic necrosis/sheehan's syndrome; leads to empty sella syndrome genetic causes metastatic carcinoma
describe Sheehan’s syndrome
hypotension
inadequate blood supply
necrosis of the pituitary gland
what syndromes are associated with the posterior pituitary?
diabetes insipidus
SIADH; leads to hyponatraemia
