Anatomical pathology Flashcards
General approach to endocrine and metabolism disorders
Recognise/think of possibility of endocrine disorder
Confirm quantitatively with testing
Investigate cause
Manage
Functions of endocrine organs
Growth, reproduction, energy metabolism, stress responses, electrolyte and water handling, mineral metabolism
Common symptoms in endocrine disorders
- weight change
- lethargy
- BP high or low
- fractures
- electrolyte/mineral changes
Clinical consequences of pituitary pathology
Mechanical:
- raised ICP
- bony erosion
- local pressure
Altered hormonal secretion:
- hyperpituitarism
- hypopituitarism
Hypopituitarism
Inadequate functional tissue
• Absence or destruction of pituitary Bssue
e.g. injury, ischaemia, infec/on, pressure from adjacent tumour,
Rathke’s cleA cyst, trauma, previous surgery or radiotherapy
• Sheehan’s syndrome: post partum hypopituitarism (enlarged ant pit during pregnancy, intra or post partum haemorrhage leads to ischaemia of pituitary)
• Simmond’s syndrome: hypopituitarism due to other causes
Lack of stimulus driving secreBon (e.g. hypothalamic disease)
Hyperfunc/on of one product may be associated with Hypofunc/on of others (as a result of ‘pressure’ atrophy), and pituitary hypofuncBon leads to secondary hypofuncBon of pituitary dependent endocrine glands (through feedback inhibiBon).
Hyperpituitarism
• Excess secretion of trophic hormones • Can be caused by: – Pituitary adenoma – Secondary hyperplasia – Pituitary carcinoma (rare) – Secretion of hormones by non-pituitary tumours – Hypothalamic disorders
Posterior pituitary syndromes
(1) Diabetes insipidus: passage of large volumes of dilute urine
2 main forms:
- central - decreased ADH secretion
- nephrogenic - ADH resistance in the kidney
(2) Syndrome of inappropriate ADH secretion
- resorption of XS amounts of water
- usually caused by ectopic ADH secretion
Clinical consequences of thyroid disease
Mechanical
• Thyroid enlargement = ‘goitre’ (unilateral, bilateral, localised, diffuse), usually not painful
• Compression effects (airway, oesophagus, large vessels, nerves)
Functional
• Hyperthyroidism
• Hypothyroidism
• Euthyroid
Examples of hyper plastic, neoplastic and inflammatory thyroid pathologies
Hyperplasia
– Diffuse / Graves (Autoimmune)
– Mul2nodular goitre / Nodular colloid goitre
Neoplasia
– Adenomas
• Follicular/HurthleCell/Other – Carcinomas
• Papillary/Follicular/Anaplastic/Medullary
Inflammatory
– Hashimoto (Autoimmune)
– Lymphocytic, Granulomatous (De Queryvain)
Cause of hypothyroidism
Defect anywhere in the hypothalamic-pituitary-thyroid axis
- iodine deficiency
- thyroiditis (hashimoto’s, lymphocytic)
Children: cretinism (iodine deficiency usually)
Adults: myxoedema (TSH raised if normal feedback inhibition is lost)
Hashimoto’s thyroiditis
Autoimmune disease - anti-TPO found
Symptoms and signs of hyperthyroidism
Symptoms:
– Nervousness, Anxiety, Increasedperspiration, – Heat intolerance, Hyperactivity,
– Palpitations
Signs
– Tachycardia or atrial arrhythmia
– Systolic hypertension with wide pulse pressure
– Warm, moist, smooth skin
– Lid lag
– Stare
– Hand tremor
– Muscle weakness
– Weight loss despite increased appetite (although a few patients may gain weight, if excessive intake outstrips weight loss)
– Reduction in menstrual flow or oligomenorrhea
Most common causes of hyperthyroidism
- Grave’s disease
- Multi nodular goitre (hyper functional)
- thyroid adenoma (hyper functional)
Grave’s disease antibodies and diagnosis
Auto-antibodies against TSH receptor and other thyroid antibodies
- presence of these antibodies indicates Grave’s
Actions of PTH
Bone resorption
Renal tubular resorption of calcium
Increases conversion of Vit D to active (hydroxy) form in kidney
With Vitamin D, promotes calcium resorption from small intestine
Increases urinary phosphate excretion causing phosphaturia
Net effect is to increase serum calcium
Common cause of chronic hypocalcaemia
Usually due to chronic renal failure, vitamin D deficiency, drugs or intestinal malabsorption of calcium
Signs/symptoms of hypocalcaemia
Convulsions, arrhythmias, tetany, numbness and parasthesia, cramps, fatigue, depression, altered cognition
Most common causes of hypercalcaemia and clinical manifestations
- hyperparathyroidism
- hypercalcaemia of malignancy - adenoma
Clinical - renal stones, bones (pain, arthritis), groans (confusions, lethargy, weakness) and moans (nausea, vomiting, weight gain or anorexia, pain)
4 Classifications of hyperparathyroidism
Primary HP: XS PTH production
Secondary HP: other disease process drives increased PTH levels
Tertiary HP: autonomous PTH secretion, caused by longstanding secondary HP
Ectopic secretion - paraneoplastic from other malignancies
MEN syndromes in endocrine disorders
MEN-1 - loss of tumour suppressor gene, primary hyperparathyroidism (adenoma or hyperplasia)
MEN-2 - medullary thyroid carcinoma is main manifestation, usually due to RET protocol-oncogene mutation
6 types of cells in the Islet’s of Langherans and their function
- β – Insulin (regulates glucose in tissues, reduces blood glucose)
- α - Glucagon (stimulates glycogenolysis in the liver, increases blood sugar)
• δ – Somatostatin (suppresses both insulin and glucagon release)
• PP – secretes pancreatic polypeptide (stimulates gastric and intestinal enzymes and inhibits intestinal motility)
– Also
• D1 – Vasoactive intestinal polypeptide (VIP), induces glycogenolysis and hyperglycaemia
• Enterochromaffin cells – Serotonin
Diagnosis criteria for Diabetes
- Fasting plasma glucose ≥ 126 mg/dL,
- Random plasma glucose ≥ 200 mg/dL (in a patient with classic hyperglycemic signs),
- 2-hour plasma glucose ≥ 200 mg/dL during an oral glucose tolerance test (OGTT) with a loading dose of 75 gm
- Glycated hemoglobin (HbA1C) level ≥ 6.5%
Clinical presentation of T2DM vs T1
T1: indolent onset (years) but sudden presentation (decompensation)
Polyuria, polydipsia, polyphagia, subsequently DKA
T2: unexplained fatigue, dizziness, blurred vision, often asymptomatic and may become hyperosmolar non-ketotic state
Pathogenesis of T1DM
¥ Develops in childhood, manifests at puberty, progresses with age
¥ Without exogenous insulin patients become ketotic → coma → death
¥ Interplay of genetics (esp HLA-DR3 or HLA-DR4) and environment (still unclear)
¥ β cell destruction follows loss of self tolerance for T cells specific islet antigens (insulin receptor, GAD, others)
o Autoreactive T cells are not removed
o Are able to attack islets
Pathogenesis of T2DM
¥ Interplay of genetics (multiple loci, all small to moderate increase in risk) and environment (central/visceral obesity, sedentary lifestyle)
¥ Develops in adulthood, slow progression, initially high insulin but peripheral insulin resistance, later low insulin due to β cell dysfunction
¥ Insulin sensitivity decreases due to
o Free fatty acids
o Adipokines (secreted by adipocytes)
o Inflammation (pro-inflammatory cytokines secreted in response to nutrient excess)
¥ This results in β cell dysfunction develops later as cells exhaust their capacity to increase secretion
Two scenarios of gestational diabetes
o Patients with pre-existing DM may become pregnant
o Pregnancy may result in impaired glucose tolerance
Acute consequence more common in T1DM
DKA - insufficient insulin
Causes hyperglycaemia, osmotic diuresis and dehydration
Activates ketogenic pathway
Fatigue, nausea, vomiting, abdo pain, ketotic breath, laboured breathing, coma
Acute consequence more common in T2DM
Hyperosmolar hyperosmotic state: severe dehydration due to severe osmotic diuresis due to hyperglycaemia
Chronic conséquences of diabetes
Microvascular complications
Macrovascular complications
Predisposition to infection
Diabetic nephropathy
Macroangiopathy associated with diabetes
- accelerated atherosclerosis involving aorta + medium sized vessels
- widespread hyaline atherosclerosis
- MI most common cause of death
- gangrene of legs 100x more common in diabetics
Microangiopathy associated with diabetes
- diffuse thickening of basement membrane of capillaries
- in skin, muscles, retina, glomerulus
- poor wound healing
- underlies complications including diabetic nephropathy, retinopathy and some neuropathies
Aetiology of bladder cancer
- Cigarette smoking
- Occupational exposure; eg: aniline dyes
- Phenacetin
- Drugs such as cyclophosphamide, exposure to radiation
- Chronic infections
b. Schistosoma Haematobium - Squamous cell carcinoma. Recurrent UTI, Calculi etc. - Arsenic
- Genetic alterations: chromosome 9 monosomy or deletions of 9p and 9 q as well as deletions of 17p, 13q, 11p and 14q. Second pathway – p53 mutations.
Clinical features of bladder cancer
- Painless gross haematuria.
- Clotting and painful micturition
- Dysuria, urgency and frequency.
- Hydronephrosis
- Palpable pelvic mass, lower extremity oedema
- Weight loss, abdominal or bone pain.
Imaging used to diagnose bladder cancer
US, IVU, CT, MRI; used for detection and staging
TNM classification
¥ Ta – non invasive papillary carcinoma
¥ Tis – carcinoma in situ
¥ T1- invades subepithelial connective tissue
¥ T2- invades muscle; T2a- superficial muscle, T2b- deep muscle
¥ T3 – invades perivesical tissue T3a – microscopically
T3b – macroscopically
¥ T4 – invades prostate, uterus, vagina (T4a), pelvic wall, abdominal wall (T4b).
¥ N – Regional lymph nodes.
¥ N1- metastasis in I LN 2cm or less in greatest dimension.
¥ N2 - >2cm but <5cm in one or multiple LNs.
¥ N3 - >5cm.
¥ M – Distant metastasis.
Grading of urothelial tumours
¥ Urothelial papilloma
¥ Urothelial neoplasm of low malignat potential
¥ Papillary carcinoma, low grade
¥ Papillary carcinoma, high grade
Treatment for localised papillary low grade tumour
Transurethral resection
Treatment for high grade papillary tumours, multifocal, rapid recurrence
Intravesical BCG therapy
Treatment for tumour invading muscularis propria, extending to prostatic urethra/ducts
Radical cystectomy
Difference between invasive and non invasive urothelial tumours
Invasive - invades the lamina propria/muscularis propria
Non-invasive is limited to the epithelium
Grading of urothelial tumours - 4
¥ Urothelial papilloma
¥ Urothelial neoplasm of low malignant potential
¥ Papillary carcinoma, low grade
¥ Papillary carcinoma, high grade
Benign tumours of the kidney
¥ Renal papillary adenoma
¥ Renal fibroma or Hamartoma
¥ Juxtaglomerular cell tumour
¥ Angiomyolipoma
¥ Oncocytoma
Malignant tumours of the kidney
¥ Renal cell carcinoma: Clear cell renal cell carcinoma, papillary carcinoma, Chromophobe renal carcinoma, Collecting duct carcinoma, renal medullary carcinoma, Xp11translocation carcinoma, mucinous tubular and spindle cell carcinoma, multilocular clear cell renal cell carcinoma.
¥ Nephroblastoma
¥ Mesenchymal tumours – children and adults.
Clinical features for kidney tumours
¥ Haematuria
¥ Pain
¥ Flank mass
¥ Paraneoplastic syndromes: polycythemia, hypercalcemia etc
Most common renal tumour in childhood
Nephroblastoma
Which tumours arise from the renal tubular epithelium?
Renal papillary adenoma and renal cell carcinoma
TNM staging of renal cell carcinoma
TNM staging:
T1- 7cm or less confined to kidney,
T2 - >7cm limited to kidney, T3 – extends into major veins, directly invades adrenal gland or perinephric tissue,
T4- invades beyond Gerota fascia.
Classification of renal disease (3)
- Glomerulonephritis
- Tubulointerstitial diseases
- Vascular diseases of the kidney
Clinical presentation of renal disease
¥ Acute renal failure ¥ Chronic renal failure ¥ Nephritic syndrome – rapidly progressive glomerulonephritis ¥ Nephrotic syndrome ¥ Asymptomatic urinary abnormalities
What is acute renal failure characterised by?
¥ Azotaemia/uraemia
o Rapid rise in serum urea/creatinine
o Over days to week
o Renal function more reliably assessed by estimated GFR
Often with oligonuria/anuria
It may resolve or progress to chronic renal failure
Characteristics of chronic renal failure
¥ Gradual persistent and progressive rise in serum urea/creatinine for months to years
¥ Accompanied by symptoms and signs of renal dysfunction
¥ Eventual progression to end stage renal failure requiring dialysis/transplantation
Clinical manifestations of renal dysfunction
¥ Lethargy ¥ Anorexia ¥ SOB ¥ Peripheral neuropathy ¥ Oedema
What is nephritic syndrome?
¥ Azotaemia/uraemia – elevated serum urea and creatinine ¥ Oliguria ¥ Haematuria ¥ Mild to moderate proteinuria ¥ Hypertension ¥ Usually due to glomerulonephritis
What might urinalysis show for asymptomatic urine abnormalities
¥ Microscopic proteinuria ¥ Microscopic haematuria ¥ Leucocytes ¥ Glucosuria ¥ Nitrites
Classification of glomerulonephritis
Primary - no identifiable cause
Secondary - drugs, infections, AI, malignancy
What is benign nephrosclerosis?
Chronic hypertension
BP >140/90
Primary essential HTN
Secondary HTN
What is malignant nephrosclerosis
Accelerated HTN
Malignant HTN
- BP >180/110
- Acute end organ damage
Pathogenesis of benign hypertensive nephrosclerosis?
Thickening of small arteries and arterioles. Ischaemic damage to glomeruli and tubules
Pathogenesis of malignant hypertensive nephrosclerosis
Severe damage to small arteries and arterioles, ischaemic injury to glomeruli and tubules
Medical emergency - urgent but controlled reduction in BP
What is renal artery stenosis?
Usually unilateral critical narrowing of main renal artery due to atheromatous disease in elderly
Results in ischaemic damage to glomeruli and tubules
Can be a cause of secondary hypertension
What is thrombotic microangiopathy?
Uncommon condition characterised by widespread thrombosis or arterioles and capillaries due endothelial damage or platelet activation
3 main types:
- haemolytic uraemia syndrome
- Atypical haemolytic uraemia syndrome
- Thrombotic thrombocytopenia purpura
3 phases of acute tubular necrosis
- initiation phase: mild oliguria with mild increase in serum creatinine
- Maintenance phase: sustained oliguria, rising serum creatinine with uraemia
- Recovery phase: massive diuresis with electrolyte disturbance
What is chronic pyelonephritis?
Chronic inflammation and scarring centred on renal calyces, pelvis and tubulointerstitium
Renal complications of myeloma kidney
- cast nephropathy
- amyloidosis
- light chain deposition disease
- acute tubular necrosis
- renal vein thrombosis
Clinical syndromes associated with hypo and hyper function of ACTH
Cushings disease and hyoadrenalism
Clinical syndromes associated with hypo and hyper function of FSH and LH
Hyper - often silent, maybe testicular enlargement or menstrual abnormalities, infertility
Hypo - hypogonadism
Clinical syndromes associated with hypo and hyper function of growth hormone
Hyper - acromegaly
Hypo - mild can have decreased muscle mass, severe may show dwarfism
Clinical syndromes associated with hypo and hyper function of thyroid stimulating hormone
Hyperthyroidism (rare)
Hypothyroidism
Clinical syndromes associated with hypo and hyper function of PRL
Hyperprolactinaemia
Hypo - amenorrhoea, impotence
Clinical syndromes associated with hypo and hyper function of ADH
Hyper - SIADH
Hypo - diabetes insipidus
What is diabetes insidious?
Passage of large volumes of dilute urine. The kidney is unable to resorb water from the urine. Thirst and polydipsia present and risk of dehydration. Due to reduced ADH secretion (central) or ADH resistance (nephrogenic).
What is SIADH?
Syndrome of inappropriate ADH secretion: resorption of XS amounts of water resulting in hyponatremia, cerebral edema.
Usually caused by ectopic ADH secretion from small cell lung carcinoma
3 most common causes of hyperthyroidism
Graves - diffuse hyperplasia
Hyperfunctional MNG
Hyperfunctional thyroid adenoma
How might older and younger patients present with hyperthyroidism?
Younger - sympathetic activation
Older - more cardiovascular symptoms - dyspnea, AF, weight loss
What commonly causes nodular colloid goitre (early stages)?
Iodine deficiency
What cells release which hormone in response to low calcium serum levels?
Chief cells in the parathyroid hormone release parathyroid hormone
Actions of PTH
¥ Bone resorption
¥ Renal tubular resorption of calcium
¥ Increases conversion of Vit D to active (hydroxy) form in kidney
¥ With Vitamin D, promotes calcium resorption from small intestine
¥ Increases urinary phosphate excretion causing phosphaturia
¥ Net effect is to increase serum calcium
Organs affected in MEN-1 (Wermer’s syndrome)
Parathyroid: primary hyperparathyroidism
Pancreas: NET
Pituitary: prolactinomas
Main manifestation in MEN-2 syndrome
Thyroid medullary carcinoma
Microvascular and microvascular complications of diabetes
Macro: atherosclerosis, ischaemic heart disease, cerebrovascular disease, peripheral vascular disease
Micro: retinopathy, nephropathy, neuropathy
What is crescentic glomerulonephritis and its importance?
Medical emergency
Filling of the Bowmans’s space by proliferation of parietal epithelial cells
What might be seen on LM, IF and EM in membraneous nephropathy? and how might the patient present?
LM: thickened BM with spikes
IF: capillary loop IgG + C3
EM: Subendothelial deposits with spikes
Present: nephrotic syndrome
What might be seen on LM, IF and EM in IgA nephropathy? and how might the patient present?
LM: Mesangiopathic
IF: IgA mesangial deposition
EM: mesangial immune deposits
Present: nephritic syndrome
What might be seen on LM in acute tubular necrosis? and how might the patient present?
Dehydration leading to acute renal failure
LM: tubular injury/necrosis
What might be seen on histology in benign hypertensive nephrosclerosis? and how might the patient present?
- Arteriosclerosis of intima
- hyperplasia of media
- hyalinosis of arteriole due to leakage of plasma proteins due to HTN
- Tubular atrophy and interstitial scarring
Present: chronic renal failure and hypertension
What types of glomerulonephritis might nephrotic syndrome be associated with?
Minimal change disease
Focal segmental glomerulosclerosis
Membraneous nephropathy
What types of glomerulonephritis is nephritic syndrome associated with?
Membrano proliferative/mesangiocapillary
Post infectious glomerulonephritis
IgA nephropathy
What is benign hypertensive nephrosclerosis?
BP > 140/90
Thickening/sclerosis of small arteries and arterioles
Resulting in ischaemic damage to glomeruli and tubules
Presentation: chronic renal failure
What is malignant hypertensive nephrosclerosis?
BP > 180/110
Severe damage to small arteries and arterioles requiring urgent but controlled reduction in blood pressure
Results in ischaemic injury to glomeruli and tubules
Presentation: acute renal failure
3 main types of thrombotic microangiopathy
- haemolytic uraemic syndrome - E coli
- thrombocytopenic purpura - autoantibodies to ADAMTS-3
- atypical haemolytic uraemic syndrome
What is thrombotic microangiopathy?
Widespread thrombosis of arterioles and capillaries due to endothelial damage or platelet activation
Most common cause of acute renal failure
Acute tubular necrosis: tubular injury/necrosis due to ischaemia or toxins
What is tubulointerstitial nephritis?
Tubulointerstitial inflammation due to various causes
- Acute - interstitial edema, neutrophilic infiltrate
- Chronic - lymphocyte infiltrate with tubular atrophy and fibrosis
Immune mediated
What is chronic pyelonephritis?
Chronic inflammation and scarring centred on renal calyces, pelvis and tubulointerstitium
2 Main clinical settings:
1. reflux nephropathy
2. obstructive nephropathy
What is myeloma kidney?
Medical emergency
Widespread tubular obstruction by intraluminal light chain casts causing acute renal failure
Causes of hyperprolactinaemia
Prolactinoma, hyperplasia, head trauma or mass effect
Stalk compression - due to reduced dopamine from hypothalamus
Cause of hypothyroidism in infancy/childhood
Cretinism: endemic iodine deficiency
Pathology of T1DM vs T2DM
1: insulitis infiltrate of T cells and macrophages, beta cell depletion and islet atrophy
2: no insulitis, amyloid deposition in islets, mild beta cell depletion
What are the following functional syndromes:
- Hyperinsulinism
- Zolligner Ellison syndrome
- Hyperinsulinism
Usually benign, result in episodic hypoglycaemia - Zolligner Ellison syndrome
Results in XS gastrin secretion leading to severe peptic ulceration with possible diarrhoea
Which renal stones are likely to form after infection with urea-splitting bacteria - klebsiella or proteus?
Struvite stones - magnesium ammonium phosphate
What do these terms mean in relation to glomerulonephritis: Focal Diffuse Segmental Global
Focal: <50% of ALL glomeruli
Diffuse: >50% of ALL glomeruli
Segmental: <50% of individual glomerulus
Global: >50% of individual glomerulus
Acute consequences of T1 and T2DM
Type 1
DKA: insufficient insulin leads to hyperglycaemia which causes osmotic diuresis and dehydration. This activates the ketogenic pathway whereby there is increased fat breakdown and ketone bodies as a by product. If urinary excretion is compromised = systemic ketoacidosis
Type 2
Hyperosmolar, hyperosmotic state
Severe dehydration due to severe osmotic diuresis as a result of hyperglycaemia (absence of ketosis)
Zolinger Ellison syndrome
XS gastrin secretion by gastrinoma of pancreas, duodenum, stomach
= severe peptic ulceration and diarrhoea
- half malignant
- 25% associated with MEN1 syndrome
Hyperinsulinism
Episodic hypoglycaemia may be precipitated by exercise or fasting, relived by glucose
Types of crescentic glomerulonephritis
- antiglomerular membrane disease - A/B to a3 chain of type 4 collagen in GBM
- Immune complex mediated GM (SLE) -ANA
- Paul glomeruloneprhitis - ANCA
Vasculitis associated with Pauci glomerulonephritis
- Wegener’s granulomatosis: tried of necrotising granulomatous inflammation of upper + lower resp tract and kidney
- Churg-Strauss syndrome: similar to Wegener with asthma and peripheral eosinophilia
- Microscopic polyangitis: widespread small vessel vasculitis in multiple organs
Acute tubular necrosis
Most common cause of acute renal failure
Due to: ischaemia or toxins
Causes tubular injury/necrosis - dead cells plug the tubule and raise pressure = reduced GFR and present with brown casts
Clinical course/3 phases of acute tubular necrosis
- initiation - mild oliguria with mild increase in serum creatinine
- maintenance - sustained oliguria, rising serum creatinine with uraemia
- recovery phase - massive diuresis with electrolyte disturbances
Acute vs chronic tubulointerstitial nephritis
Acute: interstitial deem with neutrophilic/eosinophilic infiltrate
Chronic: lymphocytic infiltrate with tubular atrophy and interstitial fibrosis
Aetiology of tubulointerstitial nephritis
Drugs - NSAIDS, PPI, a/b Infections Metabolic - urate, calcium, oxalate Vascular diseases Malignancy
Clinical presentation of tubulointerstitial nephritis
Fever, peripheral eosinophilia, rash, mild proteinuria, eosinophils in urine and acute renal failure
Two main clinical settings of chronic pyelonephritis
- Reflux nephropathy
2. obstructive nephropathy
Renal complications of myeloma kidney (malignant clinical proliferation of plasma cells)
Cast nephropathy Amyloidosis Light chain deposition Acute tubular necrosis Renal vein thrombosis
