Endocrine pathology Flashcards
DDx: insulin inj OD or insulinoma
- Investigations: C-peptide
Classification of diabetes mellitus
- Type 1 DM
- Type 2 DM
- Other causes of DM:
- Pancreatic disease
- Hormonal antagonists to insulin (eg, cortisol, GH, catecholamines)
- Drug - & chemical-induced
- Genetic syndromes: Down’s, turner’s
- Gestational DM (is typically resolved after delivery)
Etiology of Type I DM
- Most cases of type 1 diabetes are caused by immune- mediated destruction of the pancreas -> insulitis
- The reason for the autoimmune attack on the pancreatic beta-cells is unknown but genetic and environmental factors are important:
- Genetic susceptibility:
- concordance between monozygotic twins is 40%
- association with HLA-DR3 & DR4/DQA1& DQB1
- Environmental factors:
- Association with viruses: coxsackie B4, Rubella, Mumps and some drugs and toxins
Autoimmunity:
- Characterized by islet cell antibodies (ICA), other antibodies against pancreatic components and infiltration of the pancreatic islets by T-cells
- There is a long pre-diabetic phase during which the destruction of cells continues
- The autoimmune system which destroys the pancreas is triggered by viral or chemical attack on beta cells, leading to exposing new proteins or due to molecular mimicry between viral and cell structures. The HLA system is relevant because it is involved in antigen presentation.
Etiology and Pathogenesis: Type 2 DM
- caused by a combination of cell failure and Insulin resistance
Genetic Factors:
- stronger than Type 1 (80 % concordance in identical twins).
- no HLA associations
- typically a polygenic disorder: depends on the simultaneous presence of several genes but environmental factors (eg obesity) are involved
Environmental factors:
- Obesity is associated with around 80% of patients with Type 2 DM.
- More than half of patients with diabetes have BMI between 25 – 29 kg/m2
- Relative risk (RR) for DM for BMI >35kg/m2 100- fold than BMI <22 kg/m2
- DM type II is rare at BMI 21-22
- Increased FA and TNF in pathological state oppose action of insulin
Pancreatic pathology in DM
Type 1 DM (left):
- selective destruction of insulin-secreting beta cells surrounding Germinal Centre (GC); presence of GC makes it look like a LN.
- insulitis, a chronic inflammatory infiltrate of the islets affecting primarily insulin containing islets.
Type 2 DM (right):
- Moderate reduction islet tissue;
- Fibrosis on periphery
- Variable degrees of deposition of amyloid called amylin
Clinical symptoms in DM
- prominent in uncontrolled Type 1
- Polyuria: osmotic diuresis
- Nocturia
- Thirst: dehydration
- Weight loss: catabolic state
- Tiredness: muscular weakness due to proteolysis and lack of glucose
- Blurred vision: reversible dehydration of lens, and of aqueous and vitreous humour
- Vomiting: ketones stimulate the area postrema
- Hyperventilation (Kussmaul breathing): respiratory compensation to metabolic acidosis
Diagnosis of DM
- HbA1c > 6.5% (but A1c also elevated in other hemoglobinopathies)
- Fasting plasma glucose (FPG) level > 126 mg/dL (7 mmol/L)
- Best test for diabetes
- Two-hour plasma glucose > 200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test (OGTT)
- Good test for pre-diabetics:
- Patient fasts overnight
- Take basal glucose level
- Give 75 gram glucose and measure blood glucose level at 120 minutes
- Classical signs and symptoms (polyuria, polydipsia and unexplained weight loss), plus random glucose level > 200 mg/dL (11.1 mmol/L)
Prediabetic states
- Impaired fasting glycaemia (IFG):
- fasting plasma glucose above normal and below the diabetic range i.e. FPG > 100mg/dl but < 126 mg/dl (between 5.6 mmol/L and 6.9 mmol/L)
- Impaired glucose tolerance (IGT):
- 2-h value in the OGTT of > 140 mg/dl but < 20 mg/dl (between 7.8 and 11.1 mmol/L, during an OGTT)
- A1c 5.7–6.4%
Acute complications of DM
- Hypoglycemia: complication of diabetes treatment
- Diabetic ketoacidosis
- Hyperosmolar nonketotic coma (HSS)
- Lactic acidosis
PPt factors of DKA
- Infection or acute illness
- Trauma
- Emotional disturbance
- Missed insulin dose
Pathophysiology of DKA:
- vicious cycle of progressive metabolic disruption
- Acute insulin deficiency, and the rise in stress hormones levels lead to progressive hyperglycaemia; severe hyperglycemia cause a huge osmotic diuresis and gross dehydration.
- Acute insulin deficiency and the rise in levels of stress hormones (due to cellular starvation and hypovolemia) lead to development of ketosis. Ketosis cause vomiting.
- Electrolyte disturbance is caused by (i) insulin deficiency (ii) osmotic diuresis (iii)vomiting
- Acidosis is caused by (i) ketosis (ii) lactic acidosis, caused by dehydration and vasoconstriction by stress hormones.
Management of DKA
- Saline infusion to replace fluids
- Restore metabolic control
- Insulin
- potassium supplements
- Bicarbonate “sometimes”
Hyperosmolar hyperglycemic state (HSS)
- Occurs in elderly patients with type 2 DM taking sweetened solutions (due to feeling hypoglycemic) leading to hypergycemic state
- Relative insulin deficiency-sufficient to prevent ketosis but cannot suppress hyperglycaemia
- Usually very high glucose levels causing dehydration.
- Treatment: fluid replacement and insulin
Long-term complications of DM
Are caused by vascular complications which are divided into:
- Microangiopathy:
– affects capillaries, arterioles and small blood vessels
– Characterized by thickening of basement membranes, which causes leakiness
– manifestation: retinopathy, nephropathy, neuropathy
- Macroangiopathy
– atherosclerosis in large-to-medium-size arteries that manifests as: ischemic heart disease, Stroke, peripheral vascular disease
Diabetic nephropathy from Nodular glomerulosclerosis -> pathomnemonic of DM
- Note: hyaline arteriolosclerosis also seen in lower right portion of image; macrovascular change
- important cause of end-stage renal failure (ESRF)
Morphology: see renal FC for details
- thickening of BM
- leaky membrane
- Kimmelstein-Wilson nodule
Diabetic retinopathy
- commonest cause of blindness in adults between 30 and 65 years of age.
Morphology
- microaneurysms
- dot-blot spots -> retinal hemorrhages
- advanced proliferative retinopathy with, exudates, neovascularization, and tractional retinal detachment
- lost of pericytes
Causes of hypopituitarism
- Tumors: adenoma, craniopharyngioma, cerebral and secondary tumors
- Vascular: Sheehan’s syndrome (delivery causes state of shock & hemorrhage), severe hypotension
- Infection: meningitis, TB, syphilis, HIV/AIDS
- Hypothalamic disorders: tumors, functional disorders, isolated deficiency of GHRH and LH/FSH-RH (GnRH secretion)
- Iatrogenic: irradiation, hypophysectomy
- Miscellaneous: sarcoidosis, hemochromatosis
- Note: Panhypopituitarism may cause coma due to hypoglycemia or electrolyte imbalances
Hyperprolactinemia
Causes
- Physiological stress
- Drugs: e.g. antipsychotics, oral contraceptive pill, antidopamine drugs
- Tumors: Prolactinoma, Stalk section which removes inhibitory signal on prolactin secretion
- Renal failure
- Ectopic source
Clinical features and investigation
- Gonadal dysfunction:
- amenorrhea or anovulation, infertility
- decreased libido, erectile impotence in men
- Galactorrhea
- Investigations:
- Blood levels of prolactin
- MRI or CT scanning
- Treatment: initially medications but surgery may be needed
Hyperthyroidism (thyrotoxicosis)
Histo
- scalloped colloids w a lot empty spaces in bw -> glands are more active
- decreased colloid due to consumption in the formation of papillary projections lined by tall columnar cells and INCREASED TH production
Causes
- Grave’s disease: the most common cause:
- – is an autoimmune disease with HLA associations
- – Causes goiter with diffuse enlargement
- – Characterized by ophthalmopathy and pretibial myxedema
- – thyroid stimulating immunoglobulins which bind TSH receptors
- toxicadenoma
- toxic multinodular goiter
- thyroiditis: inflammation destroys acini and causes TH release (gland is not hyperactive)
- – Subacute (De Quervain’s) thyroiditis: pain, tenderness, fever
- – Postpartum thyroiditis due to natural immunosupression during pregnancy
- Functional thyroid cancer (produces thyroid hormones)
Sx (partial list)
- diffuse goitre
- proximal myopathy
- Lid-lag
- Menstrual disorders and infertility
- Effects on heart (arrhythmias) and bone (osteoporosis)
- Diarrhea
- Characteristic sx to Graves and due to deposition of mucopolysacchrides
- Pretibial myxdema -> hyperthyroidism; (Genereal myxdema -> hypo)
- Exophthalmos
- Acropachy: tenderness and clubbing in wrists
Dx: Thyroid stimulating immunoglobulins (TSI) occur in Grave’s disease
C&C
- thyroid storm: arrhythmia, pyrexia, heart failure
- TH sensitizes effects of catecholamines on CVS and CNS via increase catecholamine receptors
Thyroid adenoma
Gross: solitary thyroid nodule, spherical lesion that compresses the adjacent non-neoplastic thyroid
Histo:
- variable sized follicles
- acellular collagenous area -> capsule
- upper image -> normal tissue
- lower image -> well-differentiated neoplasm
Etiopath:
- somatic mutations in the TSH receptor signaling pathway
- mutations of RAS; genetic alterations shared with follicular carcinomas.
Sx: functional (toxic nodule is rare) or non-functional
Hashimoto’s disease
- *Microscopic**
- Mononuclear lymphocytes surrounding Germinal centres; follicles in bw
- oxyphil (PTH producing) & Hurthle cells (associated with Hashimoto’s thyroiditis[1] as well asfollicular thyroid cancer)
- Type IV Hypersensitivity
Sx: weight gain, hoarseness of voice changes, depressed, apathetic, bradycardia, cold intolerance, slowed reflex, alopecia, galactorrhea, infertility, generalised myxdema, hypoPrl, CTS, psychosis
Cretinism: protruberant abdomen, characterstic cry, short stature, coarse dry skin, lack of teeth, protruding tongue, mental retardation
Dx: antimicrosomal and antithyroglobulin antibodies are present in
high titres in Hashimoto’s disease
C&C: lymphoma
Follicular carcinoma
Histo:
- Invade the capsules and spread into blood vessels
- smaller and scalloped follicles; variable sized
- Herthle cells
- Well differentiated follicles, which can be difficult to tell apart from normal thryoid tissue
Etiopath:
- cause: iodine deficiency
- RAS mutation
- hematogenous spread
Sx: functional carcinomas rare so more important to check for hematogenous spread to lungs
Papillary carcinoma of thyroid
Gross image: multifocal papillary masses
Histo (left):
- papillary shape of follicles
- psammoma bodies
Histo (right):
- Large thyrocytes w dense nucleus & clear cytoplasmaaka “Orphan Annie eyes” due to dispersion of chromatin
Etiopath:
- most common thyroid carcinoma
- cause: radiation
- spread: lymphatic
Sx: functional nodule are -> check for cervical LN enlargement
Medullary carcinoma of the thyroid
Gross
- Solitary or multifocal
- Multicentricity in familial type
Microscopic
- Tumour cells surrounded by extracellular deposition of amyloid.
- polygonal to spindle-shaped cells, which may form nests, trabeculae, and even follicles
- originates from the parafollicular cells (also called C cells) of the thyroid; they produce calcitonin
Etiopath
- Occurs in the following clinical Settings:
- Sporadic- accounts for 80% of all cases of medullary thyroid cancer.
- Part of Multiple Endocrine Neoplasia Syndromes (MEN 2A or MEN 2B)
- inherited medullary carcinoma not associated with endocrine disorders.
Sx:
- Cervical lymphadenopathy (LAD)
- Voice hoarseness
- Dysphagia
- Watery diarrhea
- Paraneoplastic syndrome
Dx
- total thyroidectomy; Calcitonin measurement is useful in monitoring of treatment
Cushing’s syndrome: Hypercortisol (Hyperadrenal)
Causes
– Exogenous steroids
– Pituitary dependent
– Adrenal adenoma
– Ectopic ACTH
Sx (Selected list)
- Hypertension
- Thin limbs and muscular weakness due to proteolysis
- Impaired glucose tolerance
- Psychiatric disturbances
- Menstrual disturbances
- osteoporosis, kyphosis, fractures -> hypercalcemia
- Edema
Dx
- 24 hour urinary free cortisol: commonly used screening test
- DST: 1 mg Overnight DEX
* Normal individuals typically have very low levels of cortisol in these samples (<50 nmol/L), indicating that ACTH secretion is suppressed, while cortisol level is not suppressed in patients with Cushing’s disease - Late-night salivary cortisol: new test
- Low-dose DST: 2 mg DEX/day for 2 d: To exclude hypercortisolism caused by depression, obesity and alcoholism.
After the diagnosis of Cushing’s syndrome is established, the source of excess cortisol needs to be determined:
- high-dose DST: 8 mg DEX overnight or 2 day 8 mg DEX
* Plasma ACTH
* Localization: MRI or CT scan
Adrenal cortical adenoma
Gross
- small tumour (1 to 2 cm)
- usually non-functional
- elder, obese, women
- can result in hyperaldosteronism (Conn syndrome) -> -ve feedback on RAS -> low renin
- Adenoma (benign, most of the cases), hyperplasia, carcinoma
Sx: sodium retention leading to hypertension, hypokalemia and metabolic alkalosis
Dx
A. Case detection: Aldosterone: renin ratio (ARR)
B. Confirmatory tests:
- Oral Na+ loading test
- Fludrocortisone Suppression test (FST)
C. CT scan: Unilateral or bilateral micro-or macro-adenoma or bilateral hyperplasia
D. Adrenal venous sampling: For lateralizing the source of excess aldosterone
Pheochromatocytoma
Morphology
- hyperplasia of chromaffin
- nest of cells aka “Zellballen bodies (pathomnemonic)
- *Etiopath:**
- NF & RET
- Rule of 10: 10% familial, 10% bilateral, 10% extra-adrenal (sympathetic chains), 10% malignant
- tumor of Chromaffincells.
- Secretes mostly adrenaline and noradrenaline and rarely dopamine
- The 10% rule (approximate rule): 10% extraadrenal; 10% inherited; 10% malignant; 10% bilateral; 10 in childhood;10% component of multiple endocrine neoplasia, MEN2a and MEN2b.
- *Sx:**
- neurofibroma
- sympathomimetic sx (DDx w thyrotoxicosis)
Dx:
- Measure catecholamines and their metabolites in a 24- hour urine collection
- MRI or CT scanning: for localization of tumor
- I-123-metaiodobenzylguanidine (MIBG) scintigraphy:
- *C&C:**
- renal injury & nephrosclerosis
- sudden cardiac deaths
- stroke
