Endocrinology Flashcards
regulation of thyroid axis
TRH
- released from hypothalamus
- increases TSH production and secretion
TSH
- released from anterior pituitary
- stimulates thyroid hormone synthesis
- > via TSH-receptor
- > G protein coupled
- > increases cAMP
thyroid hormones
- high levels
- > inhibit TRH and TSH
- low levels
- > increase basal TSH and responsiveness to TRH
other
- cold
- > increased TRH secretion
- emotions
- > excitement/anxiety = increase in TRH
- smoking
- > decreases action of thyroid hormones
- estrogen
- > increases thyroxine binding protein
- > increases total thyroid hormone
- androgen
- > do the opposite
- drugs (eg. phenytoin)
- > interfere with thyroid hormone protein binding
thyroid hormone synthesis
iodine
- source
- > fish, seaweed and seafood
- > diary products
- > iodised salt
- blood transport
- > bound to albumin
- basolateral transport
- > Na Iodide Symporter (NIS)
- > increased expression in deficiency
- > decreased expression in excess
- apical transport
- > pendrin
in lumen (colloid)
- organification
- > oxidation by thyroid peroxidase
- > iodide -> iodine
- bind to tyrosine residues of thyroglobulin
- > monoiodotyrosine
- > diiodotyrosine
- ester bonds join iodotyrosines
- > catalysed by thyroid peroxidase
- > MIT + DIT = T3
- > DIT + DIT = T4
- thyroglobulin transported by into follicular cell
inside follicular cell
- T3/T4 released from thyroglobulin within lysosomes
- > MIT and DIT recycled
transported into blood
- serum binding proteins
- > thyroxine binding protein
- > albumin
- 99% protein bound
- > higher proportion of T3 free
- T4 produced 20x more than T3
- > T3 binds to receptor with higher affinity
- T3 is more potent hormone
- > T4 converted to T3 by deiodinases
- > types I, II, III
thyroid hormone action
predominately gene transcription
- T3/4 binds to nuclear thyroid hormone receptors
- > alpha and beta
- bind to thyroid response elements
- > promoter region of target genes
- > increase or decrease gene expression
metabolism
- greatly increased by thyroid hormones
- > food utilisation
- > protein synthesis and catabolism
- mitochondria
- > increase in number and size of
- > increase in ATP formation
- ion transport
- > increases activity of Na/K ATPase ->generates heat
- > leaky membranes to Na drives Na/K ATPase further
- carbohydrates
- > increased insulin secretion and glucose uptake
- > increase glycolysis/gluconeogenesis
- lipids
- > increased lipolysis
- > increased fatty acid oxidation
- > increased free fatty acids, but decreased cholesterol, triglycerides and phospholipids
- > increases LDL receptor on liver
- > hypo results in fatty liver and atherosclerosis
- weight
- > increase and decrease with hormone level
cardiac
- production of metabolic waste and consumption of O2
- > vasodilation and peripheral blood flow
- > increases CO
- heart rate
- > increases excitability of the heart -> increase HR
- contractility
- > initially increased
- > in chronicity leads to decompensation and failure
- blood pressure
- > mean pressure remains normal
- > pulse pressure widened
resp
- increased O2 consumption with metabolism
- > tachypnea
- > increased tidal volume
GI
- increased appetite
- increased motility and gastric secretions
- > diarrhoea
Muscles
- hyper = initially increased reflexes
- > weakened with chronicity due to catabolism
- hypo = weak and sluggish reflexes
Neuro
- racing thoughts
- anxiety, paranoia, worry
- tremor
- > due to excitability
sleep
- increased metabolism = tiredness
- increased excitability = insomnia
sexual function
- men
- > hypo = loss of libido
- > hyper = impotence
- women
- > hypo = menorrhagia/amenorrhea, irregularity
- > hypo = loss of libido
growth
- skeletal growth in children
- brain development in neonate and fetus
high/low TSH causes
High TSH
- hypothyroidism
- TSH secreting pituitary tumour
- thyroid hormone resistance
Low TSH
- thyrotoxicosis
- first trimester pregnancy
- > suppression by hCG
- after treatment for hyperthyroid
- medications
- > glucocorticoids
causes of hyperthyroidism
IGNITE
- Inflammation (thyroiditis)
- > infection
- > radiation
- > amiodarone
- > occasionally early silent or subacute thyroiditis
-Graves
- Neoplasia
- > hydatiform mole
- > chorciocarcinoma
- Iodine induced
- > jod basedow phenomenon in autonomous nodules
- > contrast
- > amiodarone
- Toxic nodules and adenoma
- > gain of function mutations giving autonomy
- > TSH receptor
- > alpha subunit of stimulating G protein
- Exogenous
- > thyroxine replacement
causes hypothyroidism
II CHRIST
- Iodine
- > deficiency most common
- > excess (wolff chaikoff effect)
- Infiltration
- > reidells thyroiditis (fibrous)
- > sarcoid/amyloid/haemochromatosis
- Central (rare)
- > secondary = anterior pituitary
- > tertiary = hypothalamus
- Hashimotos
- Resistance (rare)
- > mutation in nuclear receptor for T3
- Iatrogenic
- > radiation
- > surgery
-Subacute/silent thyroiditis
- Transient
- > ->withdrawal of exogenous
symptoms of hyperthyroidism
SWEATTIIINGG
- skin
- > sweaty
- > warm
- > onycholysis
- > alopecia
- > thyroid acropatchy in graves
- weight loss
- eyes
- > staring
- > lid lag
- > exophthalmos in graves
- appetite increased
- tachycardia
- tremor
- insomnia
- intolerance of heat
- irregular menstruation
- neuro
- > nervous
- > emotional lability
- GI
- > diarrhoea and malabsorption
- goitre
symptoms hypothyroidism
MOM’S SO TIRED
- memory loss
- obesity
- menstrual irregularity
- slowness (speech/mental and physical)
- skin
- > dry, coarse (including hair)
- > cool
- > dry
- > myxedema
- output (cardiac) decreased
- > reduced exercise tolerance
- > SOB
- tiredness
- intolerance of cold
- reflexes sluggish
- eyes
- > periorbital oedema
- depression
thyroid storm aetiology, manifestations, management
cause
- usually in patients with longstanding hyperthyroidism
- > graves
- > toxic nodules or adenoma
- thyroid surgery
- trauma
- infection
- acute iodine load
- parturition
clinical manifestations
- exaggerated presentation of thyrotoxicosis
- cardiovascular
- > tachycardia
- > arrhythmias
- > cardioresp failure
- fever
- altered mental status
- > anxiety
- > delirium/psychosis
- > coma
lab manifestations
- TSH and thyroid hormone levels are not greatly altered
- free T3 and T4 greatly increased
management
- in ICU
- same as usual thyrotoxicosis treatment but larger doses
- > beta blockers
- > glucocorticoids
- > iodine solution
what is sick euthyroid syndrome
any acute illness can cause abnormalities in circulating TSH or thyroid hormones in the absence of thyroid disease
-thought to be due to release of cytokines such as IL-6
low T3 syndrome
- most common
- features
- > normal TSH and T4
- > decrease in total and unbound T3
- cause
- > impaired deiodination of T4 in the periphery
- > decreased clearance of reverse T3
low T4 syndrome
- very sick patients
- type 3 deiodinase
- > increased expression in muscle and liver with decreased tissue perfusion
- accelerates T3 and 4 metabolism
Graves aetiology and autoimmunity
Aetiology
- genetic
- > eg. HLA-DR polymorphism
- environmental
- > smoking
- > stress
- > post partum
- > iodine (amiodarone, contrast)
Autoimmunity
- anti bodies to TSH receptor
- > thyroid stimulating Ig (TSI)
- > activate receptor
- also antibodies to
- > thyroid peroxidase
- > thyroglobulin
- spectrum
- > graves, hashimotos, silent thyroiditis
Graves pathophys and path
Pathophys
- insult or infection to thyroid epithelial cell
- infiltrating T cells
- > produce interferon gamma
- expression of HLA class II molecule
- > initiates autoimmune cascade
- TSI
- > hormone over production
- > follicular cell hypertrophy and hyperplasia
pathology
- thyroid diffusely englarged
- > follicular hyperplasia
- > intracellular colloid
- > reduced follicular colloid
- lymphocytic infiltration
- > predominately T cells
- > some B cells
pathophys of pretibial myxoedema and orbitopathy
fibroblasts
- express TSH receptor
- > stimulation by TSI
- also activated by local cytokines from lymphocytes
- produces GAGs
- > in mucinous oedema
- > dermis = myxedema
- > retro-orbital = proptosis
also in orbitopathy
- invasion of muscles
- > lymphocytes
- > mast cell
- > macrophages
- causing
- > impaired venous return
- > pressure on optic nerve
- > ulceration
also in myxedema
- non pitting oedema
- > fragmentation of dermal collagen
- > compression of lymphatics
aetiology, pathophys and path of hashimotos
aetiology
- genetic
- > HLADR polymorphisms
- > CTLA-4 polymorphisms
- environmental
- > pregnancy
- > smoking
- > excessive iodine intake
pathophys
- antibodies
- > TPO/Tg = secondary role fix complement/membrane attack complex
- > TSH-R = blocking antibody
- lymphocytes
- > CD8 cytotoxic t cells destruction
- > cytokines, interferon gamma = apoptosis
path
- profuse lymphocytic infiltration
- > both T and B cell
- > within follicle = peripolesis
- lymphoid germinal centers
- destruction of thyroid follicles
- > absence of colloid
- > varying degrees of fibrosis
- progression to atrophic in chronicity
- > more extensive fibrosis
autoimmune associations thyroid disease
CRASHPADS
- coeliac
- rheumatoid
- alopecia areata
- srojens
- hepatitis (chronic)
- pernicious anaemia
- addisons
- diabetes (type I)
- SLE
+vitiligo
myxoedema aetiology and clinical manifestations
Cause
- can occur in any disease causing hypothyroidism
- trigger
- > acute infection
- > surgery
- > cold exposure
Clinical manifestations
- neuro
- > confusion, lethargy, obtunted
- > (can be myxedema madness with psychosis)
- > seizures
- hyponatraemia
- > contributes to neuro effects
- hypothermia
- hypoventilation
- > resp acidosis
- hypoglycaemia
- cardiac
- > bradycardia
- > narrowed pulse pressure with diastolic HTN
Graves investigation findings
Graves
- low TSH
- T3/4
- > elevated free
- > total may be misleading
- > high T3:T4 or FT3:T4 (low in thyroiditis)
- antibody immunoassay
- > presence of TSH receptor antibodies
- > 80% have TPO antibodies
- > most have Tg antibodies
- radioiodine uptake
- > homogenous uptake
- scintigraphy
- > diffuse uptake
- ultrasound
- > highly vascular
- MRI orbit
- > thickening intra-orbital muscles
Hashimotos investigation findings
Hashimotos
- high TSH
- T3/T4
- > T4 down
- > T3 often normal due to increased deiodination
- antibodies (present in >95%)
- > TPO
- > Tg
investigations thyroid disease
ECG
glucose
FBC -graves = microcytic + thrombocytopaenia -hashimotos = normocytic or macrocytic Iron studies LFTs -bili elevated in graves Lipids -hypo = elevated triglycerides/cholesterol Coags
Thyroid function tests
- TSH as screener
- > unbound T4 and follow up with T3
- antibodies
- > TPO
- Tg
- TSH-R
Consider
- nodules
- > ultrasound
- goiter
- > radioiodine uptake
- > scintigraphy
- MRI orbit in graves
treatment hypothyroidism
- levothyroxine
- > prohormone (T4)
- > deoidinated in periphery to T3
- > 70-80% of dose is absorbed
- > long half life (one week) -> once daily = allows steady state
- adverse effects
- > rare
- > allergy to capsule filler
treatment hyperthyroidism
- beta blockers
- thionamides
- > block oxidation of iodine in thyroid
- > rash, urticaria, arthralgias
- > granulocytopenia/agranulocytosis
- radioiodine ablation
- > capsule or oral solution
- > extensive tissue damage within 4 months
- > can cause permanent hypothyroidism
- surgery
- > permanent hypothyroidism
- > iatrogenic hypoparathyroidism
- > recurrent laryngeal nerve damage
complications diabetes
Microvascular:
- nephrology
- retinopathy
- neuropathy
Macrovascular:
- CAD
- CCF
- PAD
- CVD
Non Vascular (FUDGIE):
- Foot (amputation, ulceration, claw/hammer toes, charcot, callous)
- Urological (cystopathy, UTIs, sexual dysfunction, retrograde ejaculation)
- Dermatological (xerosis, pruitis, poor healing, bullosis diabeticorum, diabetic dermopathy)
- Gastrointestinal (gastroparesis, diarrhoea, constipation)
- Infection (all infections, skin, pulmonary, fungal)
- Eye (glaucoma, cataracts)
ddx diabetes
Type 1
- younger
- underweight
- ketotic
- low C peptide
- antibodies
LADA (>30, non obese, respond to glucose therapy but decline, low c peptide, antibodies)
Type 2
- picked up in screening
- overweight
- non ketotic
- initial response to glucose lowering drugs
- normal C peptide
- no antibodies
HHS or DKA
Monogenic:
-MODY maturation onset diabetes of the young (strong fam hx, non obese, non ketotic, responds to glucose therapy, c peptide normal, no antibodies, confirmed by genetics)
Exocrine pancreas
- cystic fibrosis
- hereditary haemochromatosis
- chronic pancreatitis
Other (CVD GAPS)
- Cushings
- Viral (unlikely, HVC)
- Drugs (many, glucocorticoids, anti-HTN like thiazides)
- glucagonoma
- acromegaly
- pheochromocytoma
- somatostatinoma
investigations diabetes
Need to repeat:
- Random plasma glucose
- Fasting (8hrs) plasma glucose
- HbA1c
- 2hr glucose tolerance test (75g oral glucose)
Islet Cell Antibodies (2 of):
- insulin
- glutamic acid decarboxylase 65 (GAD65)
- zinc transporter (ZnT8)
- Islet antigens (IA2, IA2beta)
C peptide
Urinary ketones
Other
- LFTs
- Lipids
- EUCs
- urinalysis and urine albumin:creatinine
- ECG
diabetes targets
Individualise targets and avoid hypoglycaemia
HbA1c:
- general = <7%
- short duration without medication = <6%
- with complications = 8%
Blood glucose:
- fasting = 4-8mmol/L
- post prandial = <10mmol/L
type 2 diabetes glucose monitoring
Glycaemic control usually assessed by HbA1c.
Ketone monitoring is usually unnecessary, save SGLT-2 inhibitors when sick.
Blood glucose self monitoring (with a glucose strip and blood glucose monitor)
- used when treated with insulin or sulfonylureas.
- can be used in absence of these medications to educate about effect of dietary intake and exercise, to assist with reinforcement and motivation, when sick or pre-surgery, when taking drugs (eg. corticosteroids) or with major lifestyle changes
Continuous glucose monitoring can be used in patients using insulin.
DKA pathophys
Decrease in insulin, increase in counter-regulatory hormones (glucogon, cortisol, catecholamines, growth hormone). Particularly balance between insulin and glucagon.
Low insulin and high glucagon decreases hepatic level of fructose-2, 6-bisphosphate, thus increasing the activity of fructose-1, 6-bisphosphatase and decreasing the activity of phosphofructokinase-1.
In addition, the ratio glucagon to insulin increases the activity of phosphoenolpyruvate carboxykinase and decreases the activity of pyruvate kinase. This shifts the handling of pyruvate towards gluconeogenesis and away from glycolysis.
There is also an increase in glycogenolysis and the low levels of insulin reduces expression of the Glut-4 glucose transporter, which decrease glucose uptake.
At the same time, there is an increase in lipolysis and beta oxidation, forming Acetyl Coa, available as an energy substrate. Overtime there is a buildup in ATP, decreasing flux through the electron transport chain and increasing available NADH which inhibits the krebs cycle and increases levels of acetyl coa. Acetyl CoA does not inhibit beta oxidation, so it continues to build up and is diverted towards ketogenesis, with the formation of acetoacetate, which can be converted to D-beta-hydroxybutyrate or acetone. At physiological pH, these ketone bodies exist as keto acids and are neutralised by bicarbonate. As bicarb is depleted, ketoacidosis develops.
HHS ddx
Provisional:
- HHS or DKA due to polydypsia, polyuria
- HHS favoured due to absence of nausea, vom, abo pain and most prominent feature is drowsiness
Encephalopathies
- hypernatraemic
- hypogylcaemic (insulin)
- septic
- electrolyte deficiency
Encephalitis
Meningitis
Drugs and alcohol
- intoxication
- withdrawal (wernicke’s)
- anticholinergic effects
Unlikely:
- sagittal sinus thrombosis
- subacute subdural
- brain tumour
- non-dominant hemisphere stroke
- depression
- dementia
investigations pituitary mass
- FBC (anaemia in hypothyroid, hypocortisol, hypogonadism)
- EUC (hyponatraemia in ACTH deficiency)
- serum prolactin
- insulin like growth factor 1
- 24 hour urinary free cortisol
- late-night salivary cortisol
Consider
- LH, FSH (gonadotroph)
- TSH and T4
- beta HcG for suspected germ cell tumour
Imaging
MRI (with gadolinium enhancement)
- causes of pituitary mass usually take up gadolinium more than surrounding tissue but less than normal.
- If mass is seen as seperate from rest of pituitary it is unlikely to be adenoma.
- cysts may be enhanced in T2 and hypointense T1.
- meningioma = homogeneous uptake
- craniopharyngioma = solid and cystic with enhancement of solid
diagnostic criteria diabetes
Symptomatic (polyuria, polydypsia, impaired vision, DKA HHS) with random >11.1
HbA1c 6.5%
Fasting plasma glucose >7.0
2hr glucose tolerance >11.1
Impaired:
- fasting plasma 5.6-6.9
- glucose tolerance 7.8-11
- HbA1c 5.7-6.4
Results need to be repeated
risk factors diabetes
For both:
-family hx
Type 2:
- older age
- overweight
- physical inactivity
- HTN
- dyslipidaemia
- CVD
- racial
- gestational diabetes
- pre diabetes
- polycystic ovary syndrome
hx diabetes
Typical symptoms
-polyuria, polydypsia, fatigue, weakness, nocturia
Acute complications
- DKA (nausea, vom, abdo pain)
- HHS (significant fatigue)
Chronic complications (Type 2) -blurry vision, paresthaesias, infections (skin, UTI), weight loss
Risk factors
Past MHx
- hospitalisation (DKA, HHS)
- presence of complications
- hypoglycaemic episodes
- CVD
Medications
-use, compliance, efficacy, side effects
Psychosocial
- smoking
- diet
- functional impairment, distress
Exam diabetes
Exam
- full cardiovascular including peripheral vascular
- examination of the feet, including assessment of ankle reflexes, pulses, vibratory sensation, and monofilament touch sensation
- dilated retinal examination
- skin for infections and acanthosis nigricans
treatment DKA
Goals
- restore circulating blood volume
- inhibit lipolysis, gluconeogenesis and ketogenesis
- address precipitating factors
- re-establish normal physiology and electrolyte balance
Issues
- acidosis
- dehydration
- hypokalaemia (hyper)
Fluids IV
- start early
- resuscitate, restore, maintain
Insulin IV
- infusion @ o.1unit/kg/hr
- don’t drop BG >5mmol/L (cerebral oedema)
- aim for 10-15mmol/L
- begin 5% glucose infusion, maintain insulin infusion
- goal is to address acidosis, not hyperglycaemia
- hyperglycaemia corrected in 4-8hrs but acidosis may take 24
Potassium
- total body depletion
- insulin and correction of acidosis drives K into cells
- need to provide K once urinary flow is established
Monitoring -hourly BG, ketones, VBG (pH), electrolytes (Na, K) until -patient alert -ketoacidosis reversed -tolerating oral fluids
Education -review precipitating events -symptoms and triggers of DKA -self management during illness or reduce fluid intake check BG and ketones often maintain hydration present to medical attention early
Prognosis and complications DKA
approx 1% mortality
-usually due to precipitant
DKA related
- gastrointestinal bleeding
- oedema (pulmonary)
Treatment related
- oedema (cerebral)
- Thrombosis (venous)
- Hypoglycaemia, hypokalaemia
pathophys HHS
Decrease in insulin, increase in glucagon and other counter-regulatory hormones (cortisol, catecholamines, growth hormone). Decrease in insulin is less than DKA. Insulins inhibition of lipolysis is far greater than inhibition of gluconeogenesis, which is thought to explain absence of ketogenesis in HHS.
Decrease in hepatic fructose 2, 6-bisphosphate, which increases the activity of fructose-1, 6-bisphosphatase and decreases the activity of phosphofructokinase-1. Likewise, there is an increase in activity of phosphoenolpyruvate carboxykinase, and decrease for pyruvate kinase. Overall there is a shift in the handling of pyruvate towards gluconeogenesis and away from glycolysis.
At the same time, there is decrease expression GLUT-4, decrease glucose uptake, and an increase in glycogenolysis. Overall, marked increase in blood glucose, increasing plasma osmolality.
This draws water out of cells and increases ECF volume. Initially, this dilutes the electrolyte concentration in the blood. There is an osmotic diuresis of relatively electrolyte deficient water, thus increasing plasma osmolality.
investigations HHS
Bedside: glucose -elevated (>45 mmol/L) ABG/VBG -mild acidosis (normal anion gap) -bicarb may be marginally low Dipstick -glucosuria -ketones may be present Capillary ketones -prefered -may be present (but low)
Bloods FBC -leukocytosis EUC and CMP -elevated urea and creatinine (dehydration) -Na low (1.5 for every 5.6) -K normal or increased -Ca, Ph, Mg low -Lactate (normal) -Lipids may be elevated -LFTs (baseline, encephalopathy)
Consider:
- blood, sputum, stool culture
- urinalysis
- chest xray
- ECG and trops
- tox screen
- thiamine
- EEG
compare DKA and HHS
Note that they are thought to exist along a continuum
Demographic:
- DKA = Type 1, younger, first presentation
- HHS = elderly, Type 2
Triggers:
- same
- Dehydration and unable to tolerate oral fluids in elderly HHS
Symptoms:
- onset more acute for DKA
- both polyuria, polydypsia, weakness
- DKA has nausea, vom, abdo pain
- HHS notable lethargy, confusion, stupor
Signs:
- dehydration for both
- DKA = fruity breath, Kussmaul breathing
- HHS = focal neuro signs and seizures
Investigations:
- glucose >45 HHS, <35 DKA
- pOsm variable in DKA, >320 mmol/kg in HHS
- high anion gap acidosis more typical of DKA
- ketones may be present in both, but higher level in DKA
Treatment:
-almost identical
Prognosis:
- 1% mortality DKA
- significantly higher for HHS (5-15%)
- for both, usually due to underlying condition
- higher rate in HHS may be related to older demographic
diabetes monitoring/complication screening
Every 3-4 months
- HbA1c
- SMBG results
- hyperglycaemia symptoms
- hypoglycaemic episodes
- dietary intake
- exercise
- weight
- blood pressure
- foot exam
- injection sites
- diabetes distress
Every 12 months
- vitamin B12 (if on metformin)
- peripheral neuropathy
- retinopathy (may be 2 years)
- UACR
- lipid levels
- smoking
