Endo Flashcards
insulin (Normal BM, from what cell type and structure + half life, 3 places it’s broken down; 2 things that stim release and 2 that potentiate, something that inhibs; receptor type and what it does in muscles x4, adipose tissue x4, in liver x3; so overall insulin effect x3 and electrolyte effect)
plasma glucose is 5mmol (4-7); from beta cells, A and B chains connected by disulphide bridges, circulating free in blood with half life of under 10 mins, broken down by liver/kidney and inside target cells
cephalic phase PS driven release, also beta cells sense blood glucose by GLUT2; incretins (GIP, GLP-1) potentiate insulin release in response to oral glucose; S stimulation of alpha2 receptors inhibits insulin release to increase glucose levels during exercise;
insulin receptor is RTK with activity on beta subunits
in muscles translocates GLUT4 to muscle membrane, promotes glucose oxidation/storage as glycogen, inhibits uptake/oxidation of fats, stimulates aa uptake and protein synthesis
adipose tissue recruits GLUT4 to PM, encourages conversion of glucose to fatty acids, fatty acid uptake and inhibits lipase activity to reduce amount of FFAs
in liver promotes glucose oxidation, glyocen/triglyceride synthesis, inhibits fat oxidation
so overall promotes uptake and use of glucose, synthesis and storage of fat and protein; also affects K (decreases amount)
insulin and incretins (insulin vs glucagon broad function, 2 main incretins and 2 functions plus link of first to BM)
insulin promotes energy storage and glucagon decreases; incretin hormones glucagon like peptide and gastric inhibitory peptide act on pancreas to increase insulin release even before blood glucose levels rise though in a blood glucose dependent fashion; they also (poss) slow gastric emptying
insulin 6 functions, consequent effects of insulin deficiency x5, and insulin antagonists x4
insulin causes: uptake of glucose, promotes its storage as glycogen, as well as aa uptake, and production of proteins and fats, and suppressess beta oxidation
when insulin is lacking these go into reverse: hyperglyc causes osmotic diuresis, muscles waste and breakdown to aa, fats breakdown to glycerol and fatty acids, and beta oxidation occurs making ketones
anti-insulin hormones inc glucagon, adrenaline, cortisol, and GH
diabetes cutoff thresholds (inc how to get fasting sample, how to diagnose x3, OGTT how and when done, HbA1c how to use to diagnose and x2 not used for diagnosis; how IGT and IFG relate to DM risk; DM criteria, T1DM BM targets x2)
fasting sample is preferred, and if results from this (or random sample if needed) inconclusive can give oral glucose tolerance test
fasting (venous) blood glucose of >7mmol/L regarded as diagnostic of diabetes, fast overnight (at least 10 hours) - if between 6-6.9mmol/L then patient has impaired fasting glycaemia; note if asymptomatic need to repeat before diagnosis
random measurement (done in eg patient presenting with hyperglycaemic symptoms, and if >11.1mmol/L suggests, if no sx must repeat with fasting sample)
for the oral test, give glucose and measure plasma conc at start and 2hrs after; see if it increases to >11.1mmol/L from a raised baseline (though not usually done, only if discrepancy eg between random and fasted results or if repeat fasting alone not diagnostic); IGT if at 2 hrs >7 but <11.1)
HbA1c also needs to be repeated once to confirm if asymp, not used to diagnose T1 or children but can monitor their control
IGT can only be diagnosed after oral glucose challenge
these peeps have elevated risk of getting diabetes
IFG diagnosed from single fasted sample, with risks etc less well defined
DM criteria: fasting glucose greater than or equal to 7.0 mmol/l
random glucose greater than or equal to 11.1 mmol/l
T1DM blood glucose targets: Blood glucose targets
5-7 mmol/l on waking and
4-7 mmol/l before meals at other times of the day
note: SGLT2 in kidney is saturated with a BM around 10mmol/L so presence of glycosuria implies a higher concentration than that -> may be slightly higher or lower than this due to varying function of nephrons
note regarding HbA1c: average over last 2-3mo, and is 42 is BMs around 7 on average, if 75 is 11.8 on average, if 108 is 16.5 on average
hyperglycaemia (non-DM causes 4:4:2:1:1:1:3, main risk/sx, 4 main osmotically active particles)
causes inc pancreatic disease (CF, HH, pancreatectomy, chronic panc), endocrine disease (inc cushings, GH secreting tumour, thyrotoxicosis, phaeochromocytoma), drugs (steroids, thiazide diuretics), inherited disorders (friedreich ataxia), infections, stress, intracranial tumour/infection/seizure
it will be oft accompanied by osmotic diuresis so polyuria
note: if high osmolality w normal na, k, and urea then the remaining osmotically active particle is glucose
impaired glucose tolerance causes in kids (8)
friedriech ataxia, CF, DMD, cushing syndrome, ataxia telangiectasia, PW, down syndrome, turner syndrome
t1dm (4 sx, 2 main ix and confirmatory test, 4 stage progression, how is medical insulin duration of action or onset time increased)
polyuria, polydipsia, weight loss, tiredness -> CBG, urinalysis
autoantibodies to beta cell antigens can confim diagnosis as T1DM
not all beta cell autoimmunity progresses to T1DM but the earlier you dev autoig the higher your risk of T1DM
4 stage progression to clinical onset: stage 0 with 0/1 autoig, no dysglycaemia, 100% beta cell mass, maybe prim prevention poss; stage 1 >
/=2 autoig and otherwise same, secondary prevention target; stage 2 same but with dysglycaemia and beta cell mass begins to decrease ~6mo
before stage 3; stage 3 has hyperglycaemia, symptoms, and beta cell mass 10-20% - tertiary prevention trials
slowing rates of absorption or other techniques to prolong duration of action; eg insulin glargine is engineered to have increased
isoelectric point and so reduced solubility at physiological pH (add glycine to alpha chain and 2x arg to beta chain); others may add eg
fatty acids so bind to albumin to form reservoir or self associate to hexamers subcut
rapid acting insulin reduce tendency for molecules to self associate so more rapid absorption from subcut eg novorapid adds asp to beta
chain, humalog adds one lys and one pro to beta chain
then diff admin strats eg once daily, basal bolus, twice daily mix
pancreas embryology and T1DM pathophysiology
pancreas first appears at approximately 5 weeks of gestation as two outpouchings of the endodermal lining of the duodenum just distal to the forming stomach. The outpouchings are the ventral and dorsal pancreas. The dorsal pancreas grows more rapidly than the ventral pancreas. In addition, the ventral pancreas rotates toward the dorsal pancreas as it is “carried” by the common bile duct. Finally, the ventral and dorsal pancreas join and the ductal systems fuse so that secretions from the ventral pancreas enter the shared ductal system of the ventral pancreas and common bile duct. In the final anatomic arrangement, the head of the pancreas originates from both the dorsal pancreas and the ventral pancreas
majority of current conventional wisdom portrays type 1 diabetes as a T cell–mediated autoimmune disease involving the specific destruction of insulin-producing pancreatic β-cells.
In this model, persons destined to develop type 1 diabetes are assumed to begin life with a full cadre of β-cells. However, a “triggering” insult, likely environmental, initiates a process involving the recruitment of antigen-presenting cells. Antigen-presenting cells sequester self-antigens released by injured β-cells, followed by their transport to pancreatic lymph nodes where they are subsequently presented to autoreactive T cells followed by migration of self-reactive T cells to islets, mediating β-cell killing and promoting further inflammation; hen 85–90% of pancreatic β-cells meet their demise, symptoms of the disease occur
younger age of onset is associated with higher levels of CD20+ B cells, CD45+ cells, and CD8+ T cells in insulitis lesions, with fewer insulin-positive islets, infiltrates with fewer CD20+ cells were observed in patients with type 1 diabetes who were older at onset and were associated with lower levels of CD45+ cells and CD8+ T cells, as well as more insulin-positive islets
2 major stages: Seroconversion to positivity for islet autoantibodies (to insulin, glutamic acid decarboxylase [GAD], insulinoma antigen 2 [IA-2], or zinc transporter 8 [ZnT8]) marks the development of islet autoimmunity, and the presence of two or more type 1 diabetes-associated islet autoantibodies and normoglycemia define Stage 1 of the disease. Stage 2 is defined as the additional presence of dysglycemia and is presymptomatic. The risk of progression to clinical type 1 diabetes (Stage 3) is particularly high for children who develop two or more islet autoantibodies. most children persistently positive for only one islet autoantibody do not progress to diabetes during childhood
part genetic with inc’d risk if family also have: strongest genetic association for type 1 diabetes is with certain alleles of the HLA class II genes (odds ratio [OR] >6). Population-based association studies have shown that the odds ratio of type 1 diabetes when comparing those with the highest risk HLA-DR4-DQ8/DR3-DQ2 genotype to those with at least one dominantly protective HLA-DQ6 haplotype is approximately 200
believed to also have an environmental factor inc diet, vitamin D exposure, obesity, early-life exposure to viruses associated with islet inflammation (such as enteroviruses), and decreased gut-microbiome diversity
t1dm ix initial and monitoring
WHO Diagnostic criteria for diabetes based on blood glucose measurements and the
presence or absence of symptoms as detailed below.
1. Symptoms of diabetes plus casual plasma glucose concentration≥11.1mmol/l
(Casual is defined as any time of the day without regard to time since last meal)
2. Fasting plasma glucose ≥7mmol/l ( fasting is defined as no caloric intake for 8 hours)
3. 2 hour post load glucose≥11.1 mmol/l during an OGTT
ix at diagnosis:
Glucose, U&E, HCO3. (Orange tube Lithium heparin)
HbA1C. (EDTA tube, pink)
Anti thyroid antibodies. (Green gel tube) and TSH (orange tube)
Tissue transglutaminase antibodies. (Green gel tube)
Islet cell antibodies and GAD antibodies (green gel tube)
C-peptide (lithium heparin).
Blood gas and blood ketones
Start insulin:
A new patient will need approximately 0.5 unit/kg/day if <25 kgs and 0.7 unit/kg/day if >
25 kgs. Please make sure weight on admission is used when prescribing insulin
offer children and young people with type 1 diabetes monitoring for:
thyroid disease, at diagnosis and then annually until transfer to adult services
moderately increased albuminuria (albumin to creatinine ratio [ACR] 3 mg/mmol to 30 mg/mmol) to detect diabetic kidney disease, annually from 12 years, using the first urine sample of the day; If the initial ACR is above 3 mg/mmol but below 30 mg/mmol, confirm the result by repeating the test on 2 further occasions using the first urine samples of the day (‘early morning urine’) before starting further investigation and therapy
hypertension, annually from 12 years
Refer children and young people with type 1 diabetes for diabetic retinopathy screening from 12 years
basal-bolus insulin concept (how much insulin is basal and its 3 main roles, how much prandial, and how that restes to calculating doses for basal bolus regime), why BM rises in absence of insulin and how quickly and what would happen to cellular metabolism (hence x2 reasons to give basal even when not eating), what about bolus insulin when not eating? Initial total daily dosing per mass and whether to titrate basal or bolus, how to titrate if premixed; how many units to change by based on how many units already taking; what if not eating and taking premixed insulin? Correction dose assumption if unknown correction factor inc max to give, target to aim for, 2 times to check after correction, 4 common reasons for it to be high, 3 step plan if bleeped about hyperglycaemia, what if ketones also raised but not DKA level, inc monitoring and how long to continue)
In non-diabetic individuals, approximately 50% of the total daily insulin is secreted during basal periods, suppressing lipolysis, proteolysis, and glycogenolysis and other 50% is prandial, hence why you give half the total daily insulin requirement as basal and the other half in boluses
Because the liver is secreting glucose into the bloodstream continuously, a complete lack of insulin, even for just an hour or two, would result in a sharp rise in blood glucose level (2.5 mmol/L/h) but cells won’t take this up.
Without basal insulin, cells would resort to burning only fat for energy, and produce ketones
Thus you give basal even when not eating to match the endogenous hepatic glucose production
If unwell basal may or may not need to be higher, if not eating won’t need bolus insulin but will need correction doses that should be worked out and not PRN
Acute presentation with hyperglycaemia means you need insulin and hyperglycaemia and ketonaemia means you neeven more insulin ?DKA
TDD is 0.5 units/kg, half basal and half bolus; then this can be adjusted to get good control - titrate bolus based on postprandial readings up to 2 hours, if high persistently outside of this titrate basal; premixed is same maths, then 50% in morning and 50% in evening (with meals), evening dose up if hyper overnight and morning dose up if hyper pre-meal
change by 1-2 units if taking up to 10, if 11-30 change by 3 or 4, if >30 change by 4-6; increasing if hypers and decreasing if hypos
if not eating and take premixed insulin (ie 2 doses a day of mixed) then halve TDD or do basal only at 50% TDD
for correction doses: if you can;t work out the correction factor/find it in notes then assume 1 unit will drop BM by 2mmol/L and give up to max of 10 units aiming for BM of 8mmol/L and recheck at 2 hours (peak lowering effect) and 4 hours (starting to wear off, can make next mx decision); consider why hyperglyc (sepsis, steroids, too many carbs, missed/delayed/incorrect insulin dose)
when bleeped about hyperglyc plan is: consider above causes, r/v last 3 days, if >50% BM >14 may need to change long-term regime, give a correction dose and monitor CBGs hourly, rpt correction dose after 4 hours if needed
if BM >10 and ketones 0.6-3 then risk of DKA, give correction dose and IV or oral fluids at 500ml/hr with CBG hourly and ketones 2-hourly, continuing to give correction doses until ketones <0.6 when you can also stop fluids
if BM >10 and ketones >3 then manage as DKA
(note check ketones if T2DM with BM >10 and sx of DKA)
VRII (what type of insulin and what 3 other things is it with, what rate is it run at and how often is BM checked, why are the other solutes given; what does and doesn’t determine when to start VRII, basal insulin and VRII; 4 indications for it in T1DM and when to consider for T2DM generally; 5 specific indications, what to do in IDDM T2DM with good control having minor op?)
A VRIII regime consists IV short-acting insulin (50u of actrapid in 50ml of NaCl 0.9%) + 5% glucose +/- 0.3% KCL (40mmol) run at variable rate depending on BG (faster if higher, slower if lower). BG is monitored hourly to maintain tight control. The added glucose is to avoid hypoglycemia (though can rarely still happen) and the added KCL is to prevent hypokalemia (insulin shifts K+ into cells). VRIII is used irrespective of the BG level (may or may not be normo/hypo/hyperglycemic, but not used in DM emergencies i.e. DKA/HHS), it is more dependent on the patient’s current condition (e.g. T1DM not eating).
never omit long-acting insulin when on a VRII; however note that mixed insulin is given with meals, so if pt on twice a day mixed insulin like some humulin then omit this
Therefore in ITU, pre & peri-operative or nil by mouth for any other reason. We also use it as a bridge before we start a definitive insulin plan in a new type 1 diabetic. For type 2 diabetes, it’s usually used if a patient’s on more than Metformin or diet to control their diabetes
Here are some of the indications for sliding:
- Type 1s - for obvious reasons - they need insulin -> more than 1 meal or long acting stopped prior to surgery.
- T2DM missing 1 meal (aka if they are NBM sunday for a procedure upcoming morning/ afternoon assume they miss breakfast AND they drive into hyperglycemia (>11/12/13 different trusts different limits). Otherwise do not routinely put them on vrii. The purpose of vrii in these patients is to limit uncontrolled hyperglycemia which we know causes worse patient outcomes. also the new “ketotic prone t2dms” have to be on sliding scales.
- decomp -> post fixed rate DKA when stable/ stepped down
- those who might need emergency procedures
- poorly controlled diabetes (high hbA1c) needing urgent surgery.
If someone is t2dm and has good glycemic control, and is due a minor op, the day before give them their usual dose and on the day give them 80% (eg 10 units knock off 2 units for 8 units) their usual dose of insulin. otherwise do not need to start sliding scale.
variable rate infusion guidelines for adults (who for x2, what referral needed, how long to use, 4 indications, who to consult before starting (if you can), 2 things that influence what fluid to give and based on that which fluids should you give) what insulin to give x2
formerly known as sliding scale
for acutely unwell patients, including those with a pre-existing diagnosis of diabetes and those who present with hyperglycaemia for the first time
should be used for a short duration period as possible, with plans for a safe and effective step-down to other agents as soon as the clinical situation allows. Referral to the diabetes team as soon as possible after
admission is required
indications:
Patients with known diabetes or with hospital related hyperglycaemia unable to take oral fluid/food and for whom adjustments of their own insulin regime is not possible.
Vomiting (exclude DKA).
Nil by mouth and will miss more than one meal, for example surgery (refer to pre and post op guidelines).
Severe illness and the need to achieve good glycaemic control e.g. sepsis.
Consult the diabetes team who may be able to adjust the patient’s own insulin regime
need to know fluid status and serum K to select fluid: hypo/euvol give 1L over 10 hours as rate of 4% glucose + 0.18% NaCl if K >5, if K normal aka 3.5-5 then add 20mmol KCl, add 40mmol if <3.5
if hypervol give 500ml over 10 hours of 10% glucose, supplementing with K as above, and if hypervol but Na <135 then 5% gluc + 0.9% NaCl and supplement with K as above
when on fluid can also be on infusion of insulin, actrapid is most commonly used; if pt has basal subcut insulin this should continue alongside it, but don’t continue biphasic insulin as this should be given with meals
stop VRII 60 minutes after basal and meal time insulin has been given eg in morning
inpatient hyperglycemia - 3 patient groups, 4 ix when first picked up (if not known DM), targets for inpatients, best insulin approach in ICU and on wards, how to mx of steroid induced and not previous DM (+ how long to monitor BMs), how to mx if steroid induced and T2DM x3, and for T1DM x3, how often to check BM while on steroids, when to review metformin dose and when to stop it x3, metformin monitoring ix
inpatient hyperglycemia: three groups of patients to consider are the following:
- Known diabetes mellitus before admission - in which case consider administering correction dose.
- New diagnosis of diabetes mellitus made on admission to the hospital: in these cases patients are not aware they have diabetes but present with hyperglycemia, and diabetes is diagnosed subsequently.
- Transient hyperglycemia: this may be related to stress, infection (esp sepsis), drug therapy such as corticosteroids, or parenteral and enteral nutrition, and resolves when the inciting factor is removed
order random BM, HbA1c, urine ACR, U&Es; consider if any of the above are possible causes
consensus based uk guidelines are acceptable inpatient range is 6-12, but 6-10 is recommended and what you should aim for; in ICU continuous insulin therapy is best way
to manage, once out of ICU can transition to subcut regime; basal bolus approach
if steroid induced and not prev diabetic then start gliclazide and titrate for control, keep testing CBG after steroids stopped until <12
if steroid induced and type 2 DM but no hypos or on sulphonylurea then start gliclazide, otherwise once daily night time insulin and if doesnt reach targets consider basal bolus; or can do twice daily insulin from the start
t1dm basal bolus or twice daily if steroid once daily, if multiple times eg oral dex or iv hydrocort then subcut insulin better using once daily, then twice daily, then basal bolus as required to get control
CBG should be checked once a day if on steroids and at risk of hypers
if confused you can look up the guidelines that british diabetic society made
more generally: In adults with type 2 diabetes, review the dose of metformin if the estimated glomerular filtration rate (eGFR) is below 45 ml/minute/1.73m2:
Stop metformin if the eGFR is below 30 ml/minute/ 1.73m2.
also stop if any acute metabolic acidosis (inc DKA), if dehydrated or aki setting in; pt on metformin
should have renal function monitored before start and at least annually, at least 2x a yr if additional risk factor for renal impairment
managing high blood glucose without ketones in diabetics (when to check for ketones and what if >0.6, target BM (not inpatients: on waking, before meals, 2 hrs after meals, before bed), isf (inc how to work out and 2 times it needs recalculating), how long to wait between correction doses, how to work out correction does and when to recheck BM, what if premeal BM above target, working out premeal bolus dose, and variation in basal and bolus requirement)
If the blood glucose level is above 13mmol/L you need to check for blood ketones. If ketones are greater than 0.6mmol/L follow sick day rules and give fluids
recommended that blood glucose levels should be
4-6mmol/L on waking
4-7mmol/l before meals
Below 9mmol/L 2 hours after meals
Below 7 mmol/L before bed
If blood glucose level is above target administer some extra fast acting insulin (Novorapid, Humalog or Apidra) as a correction dose
first need to know insulin sensitivity factor - might be plan from diabetes team already, if not then work out total daily insulin units on average, divide 100 by that amount, and that gives amount 1 unit will lower blood glucose; needs recalculating if long-acting dose changes, or insulin to carbohydrate ratio changes
don’t give a correction dose within 2 hours of previous injection as might have some fast acting insulin in system still (unless has smart blood glucose meter working out correction dose)
to work out correction dose: current blood glucose minus target, then divide that by insulin sens factor to get units of fast-acting to give; check BM 2 hours after correction dose and if still high can give new correction dose
can also add correction dose to mealtime amount if premeal BM above target
you can calculate bolus amount by carb counting and using the insulin:carb ratio (bespoke for each pt) to work out how much insulin they will need for that meal, then adding a correction dose if premeal BM is above target; to first guess insulin:carb ratio you can use assumption like 1:10 or else 500/TDD = ICR, but will need lots of tinkering to get the pts actual requirement
also note that basal requirement is different at different times, eg may need to be higher in morning than in evening (for CSII and VRII) due to dawn phenomenon; also that if lower carb diet basal may need to be >50% TDD and if high carb diet bolus may need to be >50%
glucose emergencies - DKA (7 sx, 15ix; 6 severe criteria, hypokal from what; first mx step then 2nd step, first step if sysBP <90; mx monitoring x4; fluid replacement regime (and fluid choice depending on K level), what if delay in setting up insulin pump; when to insert catheter, when to insert NGT x2, what if sats fall, what other med to give; target rate for ketone reduction and what if below this rate; 2 criteria to stop FRII and when to start adding glucose (+ how to ideally give it); how long should it take to resolve and how to transition from FRII x3, what if GCS drops acutely
DKA - hypervent, nausea, vomiting, sometimes abdo pain that can be severe; confusion/stupor, up to 5% present in coma; marked signs of dehydration possible; hypergly and ketonaemia/ketonuria
take bloods: BM, ketones, vbg, lab glucose, U&Es, FBC, CRP, cultures, bone profile, urine dip (inc pregnancy test in women as this can be a trigger), urine MC&S and CXR if indicated, covid and flu swabs
is severe if GCS<12, sats <92%, BP sys <90, pulse >100 <40, pH <7.1, blood ketones >6
pt may have hypokalaemia from renal K wasting
as soon as diagnosed start 1L IV sodium 0.9% and run it over an hour, then once started you can start fixed rate insulin infusion at 0.1units/kg; if sysBP <90 first give 500ml bag over 10-15 mins which you can repeat while awaiting senior input, if after 2nd bag BP still not improving you need ITU and to consider other reasons for hypotension
then:
hourly BM and ketones, 2-hourly VBG for K and bicarb levels (but get one at 60mins, 2 hours, then 2hrly); cardiac monitoring if replacing K; discuss with HDU
fluid replacement regime will be 1L 0.9% saline over 1 hour, then 2, 2, 4, 4, 6; if K >5.5 then no addition, if 3.5-5.5 add 40mmol/L to each 1L bag and make sure to keep a close eye on the K and start cardiac monitoring, if <3.5 will need even more K which means senior review
you can give a stat dose of insulin 0.1 units/kg IM if delay in setting up the pump and continue their basal insulin regime as they would normally have it
if no urine passed by 60 mins then catheterise them, insert NG tube if GCS low or vomiting persistently, if sats fall then ABG and repeat CXR, give prophylactic heparin
target rate for ketones to fall is 0.5mmol/L/hr - if not then increase FRII by 1 unit/hr each hour until falling at target rate - also make sure to check pump is actually working
keep insulin running until ketones <0.6mmol/L and pH >7.3; if glucose falls <14 before this point reached then run 10% glucose at 125ml/hr alongside the sodium 0.9% giving the insulin and dextrose/glucose bag through the same cannula via a Y connector
should be resolved by 24 hours, you can then have them start eating and drinking and transition to subcut (should be on subcut insulin before you stop the IV) - specialist diabetes team can manage this in most trusts, but basically you work out total daily dose as weight in kg x 0.5 (0.75 if obese/teen) then give half as basal at night and split the other half 3 ways and give before each meal; only start subcut with breakfast or lunch, not overnight; if already diabetic then switch back to their previous bolus regime; if CSII then start pump at normal rate and stop IV insulin once a meal bolus has been given
if GCS drops at any point then urgent head imaging
DKA (inc 7 sx, 5 causes, how it might affect brain, diagnostic criteria x3, sick day rules x4)
DKA: vomiting, central abdo pain, deep/gasping breaths, polyuria, weakness, confusion, thirsty; onset generally quite rapid; may be initial presentation of t1 DM
infection, stroke, not taking insulin properly, steroids, MI and you should look for cause inc consider sepsis; oft signs of dehydration, ketotic odour, rarely may lead to cerebral oedema; hyperglycaemia 11/mmol or known DM, ketones in blood or urine 3mmol/L or ++, and acidosis pH <7.3
when unwell should check BM more often (4 hourly at least), check ketones if BM >14, keep hydrated, and try and get calories in even if eating little and often
child DKA criteria x3, severity scoring x3; if fluids needed but not shocked then give what first? what if shocked (inc 4 criteria for shock) and second step for these pts (inc when to consider inotropes) (Ix 9:7 and when to suspect sepsis), o/e 3 things esp looking for (inc 6 features of first), 3 steps if GCS reduced and why the second (inc max of this category); following this how to work out fluid deficit and how to work out what fluids to give over the first 48hrs; fluid choice x2 and when to add glucose (2 types and changing insulin) and what if hypo occurs, oral fluids allowed when x2 and NGT given when x2, how to modify fluids if oral intake starts; 2 times additional fluids needed inc what fluid type for second situation; 2 options if moderate+ hypokalemia occurs; when to start IV insulin (and why), inc rate and what to do about CSII/basal insulin; bicarb given x2 criteria; VTE proph x3 reasons; 10 monitoring ix (and x2 reasons to give more freq neuro obs), how to work out and use corrected Na to adjust fluid rates; what to do if clinically/biochem not improving (inc 5 reasons), phosphate replacement (inc monitoring), what if ketones not falling in 6-8hrs x2, when to switch to usual insulin regime inc timing of CSII restart
criteria:
acidosis (indicated by blood pH below 7.3 or plasma bicarbonate below 15mmol/litre) and
ketonaemia (indicated by blood beta-hydroxybutyrate above 3 mmol/litre)
Blood glucose levels are generally high (above 11 mmol/l) but children and young people with known diabetes may develop DKA with normal blood glucose levels
Children and young people with a pH 7.2- 7.29 &/or bicarb < 15 have MILD DKA
Children and young people with a pH less than 7.1-7.19 &/or bicarb < 10 have MODERATE DKA
Children and young people with a pH less than 7.1 &/or bicarb < 5 have SEVERE DKA
All children and young people with mild, moderate or severe DKA who are not shocked and are felt to require IV fluids should receive a 10 ml/kg 0.9% sodium chloride bolus over 60 minutes. (PlasmaLyte 148 is also suitable)
Shocked patients should receive a 20 ml/kg bolus of 0.9% saline over 15 minutes. Shock is
defined by the APLS definition of tachycardia, prolonged central capillary refill, poor peripheral pulses and hypotension - Following the initial 20 ml/kg bolus shocked patients should be reassessed and further
boluses of 10 ml/kg may be given if required to restore adequate circulation up to a total of 40ml/kg at which stage inotropes should be considered (these patients need early discussion with ITU)
ix: VBG, lab glucose, FBC, CRP, U&Es, ketones, and if you can get enough blood then HbA1c, TFTs, coeliac screen)
if indicated: CXR, swabs, blood and urine cultures, urinalysis +/- pregnancy test, CSF; suspect sepsis if hyper/hypotherm, raised lactate
o/e: full A-E, especially looking for cerebral oedema (headache, irritability, slowing pulse, rising blood pressure, reducing conscious level N.B. papilloedema is a late sign), infection, ileus
if GCS reduced then urgent anaesthetic, paeds consultant +/- critical care specialist + weigh child and transfer for PICU if required, but all will need 1:1 nursing in HDU setting; also weigh the child for accurate fluid admin (if >80kg then stick with 75kg as your weight so don’t over hydrate)
then work out fluid deficit based on initial VBG (ie not clinical estimate) - 5% if mild, 7% if mod, 10% if severe; add this deficit to maintenance requirements for a 48 hour period, subtract the initial 10 ml/kg bolus (but not any volume used for resus of shocked pts), then give remained over 48 hours
use sodium chloride 0.9% with 40mmol/L K or plasmalyte (with K supplement of 35mmol/L as it contains 5mmol/L) until BM <14 when you also add glucose 5% (and reduce insulin to 0.05, if it continues at 0.1 then add glucose 10%), also inc conc if glucose falls <6 and if falls <4 give 2ml/kg bolus
no oral fluids until nausea gone and ketosis resolving, NG tube if persistent vomiting or gastroparesis, reduce IV infusion if oral intake starts in first 48 hours; note no K in first bag
if massive diuresis ongoing then additional fluid needed to replace this; if ongoing large gastric aspirates may need additional 0.45% saline with KCl
if K <3mmol/L may need central venous catheter for K >40mmol/L, or may need to reduce insulin rate - discuss with critical care specialist
start IV insulin 1-2hrs after fluids started as this reduces risk of cerebral oedema; 0.05 units/kg/hr unless severe or adolescent, then do 0.1 units/kg/hr; stop CSII if theyre on one but continue long acting insulin injections
bicarb only given by intensivists if pH <7.1 and cardiac contractility being affected
VTE proph if >16yo, if on COCP, or if femoral line inserted
strict fluid balance charts, hourly BM and ketones, hourly obs, hourly neuro obs (every 30 mins if <2yo or pH <7.1 due to inc’d oedema risk), any headache or slowing pulse nurses need to immediately alert doctors, twice daily weights
need 2 hourly VBG, U&Es, lab glucose and doctor r/v every 2 hours including looking at ECG for hypokal signs
every 4 hours work out corrected sodium (lab sodium + (glucose-5.6)/3.5; if it is >5mmol/L higher than 4 hours ago increase fluid rate, if falls by >5 then reduce fluid rate; in both cases discuss with on-call consultant
if clinically or biochemically not improving then calculate anion gap and if >35 suggests concomitant lactic acidosis ?sepsis/poor perfusion; persistent acidosis may also be hyperchlor acidosis, some other cause of metabolic acidosis, incorrect fluid calculation/admin, or insulin not being given correctly (check pump); base excess due to Cl is Na - Cl - 32, base excess due to albumin is 0.25x(42-albumin) and can also contribute to ongoing acidosis
serum phophate often low but as with adults dont need to replace unless severe with sx in which case give but watch for hypocalc
if ketones not falling within 6-8 hrs then sr help, inc insulin rate ; once <1mmol/L can switch to subcut, or restart their CSII (at least 60mins before stopping IV insulin)
child DKA - cerebral oedema (4sx, 2 mx options, 5 red flags and 3 mx (inc 3dd), how long does mannitol take to work and what if not), continuing abdo pain (5 poss causes)
early manifestations to make you assess for it (but doesnt have to mean it’s this):
headache
agitation or irritability
unexpected fall in heart rate
increased blood pressure.
If cerebral oedema is suspected in these children or young people, treat immediately with the most readily available of
hypertonic saline (2.7% or 3% 2.5-5 ml/kg over 10-15 minutes) or
mannitol (20% 0.5-1 g/kg over 10-15 minutes)
hypertonic saline better but dont delay if mannitol easier to get
If a child or young person develops any of these signs –
deterioration in level of consciousness
abnormalities of breathing pattern, for example respiratory pauses &/or drop in SaO2.
oculomotor palsies
abnormal posturing
pupillary inequality or dilatation.
then treat immediately as above
restrict fluids to 50% maintenance and inform seniors immediately
exclude other diagnoses by CT scan - other intracerebral events may occur (thrombosis, haemorrhage or infarction) and present similarly
mannitol should have effect within 15 mins, if not after 30 then can repeat or give hypernat saline
Continuing abdominal pain is common and may be due to liver swelling, gastritis, bladder retention,
ileus. However, beware of appendicitis and ask for a surgical opinion once DKA is stable
HHS in children - 5sx/biochem, 2 risk factors; initial bolus to give, what fluid deficit to assume, how many boluses to give, then how to replace deficit, what to monitor and what if this doesn’t respond as it should (what rate to aim for), when to add glucose to rehydration fluid and when to give insulin, what should be in all fluids)
Hypovolaemia
Marked hyperglycaemia (40 mmol/L or more)
No significant hyperketonaemia (<3 mmol/L) or acidosis (pH>7.3, bicarbonate >15 mmol/L)
Osmolality usually 320 mosmol/kg or more
Often altered consciousness
This picture usually occurs in Type 2 diabetes, especially where there are learning difficulties or other
factors preventing proper hydration
Give an initial bolus should be of 20 mL/kg of isotonic saline (0.9% NaCl)
Assume a fluid deficit of approximately 12–15% of body weight.
Additional fluid boluses should be given, if necessary, to restore peripheral perfusion.
Thereafter, 0.45–0.75% NaCl with potassium should be administered to replace the deficit over 24–48 hours.
The goal is to promote a gradual decline in serum sodium concentration and osmolality.
As isotonic fluids are more effective in maintaining circulatory volume, isotonic saline should be restarted if perfusion and hemodynamic status appear inadequate as serum osmolality declines.
Serum sodium concentrations should be measured frequently and the sodium concentration in fluids adjusted to promote a gradual decline in corrected serum sodium concentration.
Mortality has been associated with failure of the corrected serum sodium concentration to decline with treatment, which may be an indication for haemodialysis.
Although there are no data to indicate an optimal rate of decline in serum sodium, 0.5 mmol/L per hour has been recommended for hypernatraemic dehydration
If there is a continued rapid fall in serum glucose (>5 mmol/l per hour) after the first few hours, consider adding 2.5 or 5% glucose to the rehydration fluid. Failure of the expected decrease of plasma glucose
concentration should prompt reassessment and evaluation of renal function
Unlike treatment of DKA, replacement of urinary losses is recommended
insulin not needed for BMs to fall initially; Insulin administration should be initiated when serum glucose concentration is no longer declining at a rate of at least 3 mmol/l per hour with fluid administration alone
K should be in ALL fluids
somogyi and dawn phenomena (what former is and difference from latter, evidence base for both and what an alternative might be, when to possibly suspect somogyi and 2 ways to confirm, what should first assumption be for morning hyperglycemia)
rebound high blood glucose in response to low blood glucose, in diabetics using insulin injections this can take form of high blood glucose in morning due to excess insulin at night - theory is hypo causes stress causes mobilisation of glucose
different from dawn phenomenon which is a morning rise in blood glucose due to waning insulin and surging GH
note somogyi is widely reported and known but this theory hasnt got good scientific evidence behind it and some studies have refuted - it may in fact simply be insufficient night time insulin (not lasting long enough) failing to prevent hyperglyc in morning - t1Ds having hypos at night tend to also by hypo in the morning not hyper
Somogyi rebound should be suspected when blood glucose numbers seem higher after the insulin dosage has been raised, particularly in the morning. One simple way to determine if nocturnal hypoglycemia may be causing morning hyperglycemia is to have the patient have a high protein snack with a small amount of carbohydrates at bedtime. This will help keep the blood sugar up overnight and prevent the Somogyi effect. If the morning blood sugar decreases, this is indicative of the Somogyi effect and the daily insulin should be decreased
can also wake and test blood glucose around 2-3am, if high and morning hypergly then dawn phenomenon and if low and morning hypergly then somogyi
note dawn phenomenon significance has also been questioned - if pt has rec morning hyperglyc first assumption should be night time insulin isn’t lasting long enough
4 causes of early morning hyperglyc inc which is most likely
rarely may be somogyi phenomenon, for which consider longer acting insulin; but also consider: non-compliance with insulin regimen, dawn phenomenon, or most likely inadequate insulin admin (inc the dose)
mauriac syndrome (results from what, 5sx, 2 possibly co-existing causes of similar phenotype and what the phenotype is)
resulting from poor diabetic control over long time
short, delayed bone age, obese (but short height means low weight on centile charts), delayed sexual maturation, oft hepatomegaly also
dont forget coexisting cause of short stature and obesity eg cushing syndrome (on steroids?), or hypothyroidism
infants of diabetic mothers (what hormonal change occurs in foetus and why, how this affects foetus and 2 risks this poses to labour, 2 other things might get from poorly controlled maternal DM; complication after birth inc x3 mx, 11 other neonatal conditions may have (and 2dd for the last of these), generally consider this with what 4 clinical findings)
maternal hyperglyc -> fetal hyperglyc via placental diffusion -> fetal hypeins -> insulin is anabolic so macrosomia and visceromegaly (head smaller than body though); this may lead to obstructed labour, birth injury/asphyxia
poorly controlled DM may also cause placental vascular disease so IUGR; also look for hairy ears
after birth may get a hypogly lasting for a few hours, try early feeds and maybe iv dextrose and look for hypocalc
babies may have resp distress, persistent fetal circulation, polycythaemia, or TTN (due to inc’d c-section rate); polycythaemia incs levels of jaundice, risk of thrombosis, and of NEC
may get transient hypertrophic cardiomyopathy (asym septal and LV) as well as other CHD more common; sacral agenesis inc microcolon more common (this also seen in CF and meconium ileus)
consider in eg macrosomic infant w iv dextrose, plethoric facies, and forceps marks
hyperinsulinism
Katp mutation (and multiple other receptor mutations)
Beckwith wiedemann, sotos, mosaic turner and a few rarer syndromic causes
transient (up to 3-4mo): infant of diabetic mother, SGA, stress induced
acquired: insulin overdose, insulinoma, post gastric bypass or fundoplication
Medical treatment for CHI includes nutritional support by hypertonic glucose infusion, continuous feeding through gastrostomy or nasogastric tube, or the use of cornstarch or formula for glycogen storage diseases. Furthermore, oral administration of diazoxide, a pancreatic β cells KATP channel opener, has been approved for the treatment of CHI. For patients with diazoxide unresponsive CHI, the following therapies have been attempted: off-label use of octreotide, as multiple daily injections or continuous infusion; glucagon, as a continuous infusion; intravenous injection of glucocorticoids; or oral administration of nifedipine
Diazoxide is a KATP channel opener and is effective against the causes of CHI, except for those mutations in the KATP channel genes, glucokinase gene, and SLC16A1 gene. Unfortunately, the majority of cases of neonatal onset persistent CHI are caused by mutations in the KATP channel genes; therefore, diazoxide is often ineffective
When euglycemia cannot be maintained by medical treatment, pancreatectomy has been performed to avoid neurological sequelae. However, the majority of patients who underwent subtotal pancreatectomy developed postsurgical insulin-dependent diabetes mellitus
hypoglyc (sx 8:6 and causes 9:8)
sx inc neuroglycopenic (headache, irritability, confusion, seizures, coma, jitteriness, apnoea, hypotonia) and adrenergic (tremor, tachy, sweating, hunger, pallor, visual changes)
causes inc ketotic and non-ketotic
ketotic: reduced gluc so reduced ins so more lipolysis inc malnut (inc poor feeding), birth asphyxia, prematurity or IGUR, malabsorpt, infection; liver disease eg reye, enzyme defectes eg galactosaemia, reduced levels of anti-insulins (inc hypopitu), ingestions of alcohols or salicylates
non-ketotic - excess insulin eg over-admin, infant born to diabetic mother, nesidioblastosis (b cell hyperplasia in pancreas needing removal), islet cell adeoma, rhesus isoimmunisation, BW syndrome, islet cell insulinoma, munchsausen by proxy (maternal admin)
managing hypoglycemia (if sx but BM >4, if BM <4 w or w/o sx (what shouldn’t be given to pt on low K diet, what should generally be avoided), how many times can you rpt that rx, what to give once BM >4, what if BM doesn’t respond to above (inc dose) x2 options and how many times to repeat, what else to do in alcoholics; emergency community mx inc what if glucagon not effective; 3 criteria which makes it an emergency and how to mx on ward x3; how does glucagon effect long acting carb need; what if sc insulin due? what if insulin infusion ongoing inc when to restart; how long for freq BM monitoring
Adults with symptoms of hypoglycaemia who have a blood-glucose concentration greater than 4 mmol/litre, should be treated with a small carbohydrate snack such as a slice of bread or a normal meal, if due.
Any patient with a blood-glucose concentration less than 4 mmol/litre, with or without symptoms, and who is conscious and able to swallow, should be treated with a fast-acting carbohydrate by mouth. Fast-acting carbohydrates include Lift® glucose liquid (previously Glucojuice®), glucose tablets, glucose 40% gels (e.g. Glucogel®, Dextrogel®, or Rapilose®), pure fruit juice, and sugar (sucrose) dissolved in an appropriate volume of water. Orange juice should not be given to patients following a low-potassium diet due to chronic kidney disease, and sugar dissolved in water is not effective for patients taking acarbose which prevents the breakdown of sucrose to glucose. Chocolates and biscuits should be avoided if possible, as they have a lower sugar content and their high fat content may delay stomach emptying.
If necessary, repeat treatment after 10–15 minutes, up to a maximum of 3 treatments in total. Once blood-glucose concentration is above 4 mmol/litre and the patient has recovered, a snack providing a long-acting carbohydrate should be given to prevent blood glucose from falling again (e.g. two biscuits, one slice of bread, 200–300 mL of milk (not soya or other forms of ‘alternative’ milk, e.g. almond or coconut), or a normal carbohydrate-containing meal if due). Insulin should not be omitted if due, but the dose regimen may need review.
Hypoglycaemia which does not respond (blood-glucose concentration remains below 4 mmol/litre after 30–45 minutes or after 3 treatment cycles), should be treated with 1mg intramuscular glucagon (only if no IV access) or 200ml glucose 10% intravenous infusion over 15 minutes (or 100ml glucose 20%). You can repeat this up to 3 times (150ml 105 in repeats though) In alcoholic patients, thiamine supplementation should be given with, or following, the administration of intravenous glucose to minimise the risk of Wernicke’s encephalopathy
In an emergency, if the patient has a decreased level of consciousness caused by hypoglycaemia, intramuscular glucagon can be given by a family member or friend who has been shown how to use it. (note in paeds glucogel is still first choice, rub in cheek etc) If glucagon is not effective after 10 minutes, glucose 10% intravenous infusion should be given.
Hypoglycaemia which causes unconsciousness is an emergency. Patients who are unconscious, having seizures, or who are very aggressive, should have any intravenous insulin stopped, and be treated initially with glucagon. If glucagon is unsuitable, you already have IV access, or there is no response after 10 minutes, 200ml glucose 10% intravenous infusion, or alternatively 100ml glucose 20% intravenous infusion should be given then when recovered a long acting carb meal
Patients who have received glucagon require a larger portion of long-acting carbohydrate to replenish glycogen stores (e.g. four biscuits, two slices of bread, 400–600 mL of milk
If an insulin injection is due, it should not be omitted; however, a review of the usual insulin regimen may be required
If the patient was on intravenous insulin, continue to check blood-glucose concentration every 15 minutes until above 3.5 mmol/litre, then re-start intravenous insulin after review of the dose regimen. Concurrent glucose 10% intravenous infusion 100ml/hr should be considered once restarting the IV insulin.
BM monitoring continue for at least 24-48 hrs
neonatal hypoglycaemia - definition, how common, 8 things causing persistent/severe, sx 4:5:2; asymp mx x2; symp or v low mx x2
Normal term babies often have hypoglycaemia especially in the first 24 hrs of life but without any sequelae, as they can utilise alternate fuels like ketones and lactate. There is no agreed definition of neonatal hypoglycaemia but a figure of < 2.6 mmol/L is used in many guidelines.
Transient hypoglycaemia in the first hours after birth is common.
Persistent/severe hypoglycaemia may be caused by:
preterm birth (< 37 weeks)
maternal diabetes mellitus
IUGR
hypothermia
neonatal sepsis
inborn errors of metabolism
nesidioblastosis
Beckwith-Wiedemann syndrome
Features
may be asymptomatic
autonomic (hypoglycaemia → changes in neural sympathetic discharge)
‘jitteriness’
irritable
tachypnoea
pallor
neuroglycopenic
poor feeding/sucking
weak cry
drowsy
hypotonia
seizures
other features may include
apnoea
hypothermia
Management depends on the severity of the hypoglycaemia and if the newborn is symptomatic
asymptomatic
encourage normal feeding (breast or bottle)
monitor blood glucose
symptomatic or very low blood glucose
admit to the neonatal unit
intravenous infusion of 10% dextrose
hypoglycemia 12 causes, 11sx; 5 reasons glucagon wouldn’t work; how tumours present; c peptide and insulin high x3, insulin high and c peptide low c1; 3 types of DM giving high c peptide, 2 giving normal, 1 giving low
hypoglycaemia - when hepatic glucose output falls below rate of glucose uptake by periph tissues; caused by inhib of glycogenolysis/gluconeogen by insulin (exogenous or tumour), sulphonylureas, depletion of glycogen reserves by malnut/fasting/exercise/liver disease, impaired gluconeogenesis (eg alcohol ingestion), adrenal insufficiency; acute hepatic failure, terminal renal failure, hypopitu or ACTH def, factitious
pt may be sweating, palps, diplopia, weak, tired, dizzy, appear inebriated, confused, blurred vision, maybe lowered GCS, maybe seizures; 4 is the floor!
glucagon doesn’t work if: depleted or gluconeogenesis suppressed inc malnut/fasting, adrenal insuff, chronic or alcohol induced hypo, also in those taking sulphonylureas
nb insulinomas present with fasting hypos that are recurrent (so usually in morning or when working hard)
c pep and insulin high if insulinoma, renal failure, T2DM; if insulin high and c pep low then factitious
high c pep: T2DM, maybe MODY, can occur in T1DM in first 3 years
normal: consider MODY in young person 3+ years from T1DM
low: T1DM
DM new technologies - insulin pump (risk if malfunction is what and 3 reasons this might happen); CGM inc current brand, delay relative to plasma; closed loop system; 2 forms of artificial pancreas
insulin pump: alt to multiple daily injections, deliver insulin from reservoir on continuous basis; qol higher than injections, more precise dosing, programmable basal rates, reported better Hba1c, sexual performance, reduced neuropathic pain in t2 DM pts; expensive, higher risk of DKA if malfunction (battery flat, heat exposures inactivates insulin, damage during sport etc), scar buildup decreases efficacy over time; note can be unclipped so you can go in MRI if have one
CGM: cont glucose monitoring, sensory under skin worn for a few days then needs replacement, provides additional data for blood glucose changes in response to food/exercise etc so better insulin dosages can be calculated and eg overnight blood glucose so basal insulin levels can be adjusted, alarms also for hypers/hypos and helps reduce HbA1c; fingerstick testing needed a couple of times a day to calibrate, tests from interstitial fluid so 5 min delay relative to plasma; freestyle libre 2 is current CGM, can tell you time in range etc and doctor can view remotely
closed loop: CGM results processed by software then info sent to insulin pump to deliver correct insulin, basically functions as artificial pancreas; evidence for efficacy and guidelines currently lacking but emerging technology; maybe good for eg kids with t1 DM
other artificial pancreases: bionic or implanted artificial (latter is gel that releases diff amount of insulin based on blood glucose)
insulin pump guidelines
Continuous subcutaneous insulin infusion (CSII or ‘insulin pump’) therapy is recommended as a treatment option for adults and children 12 years and older with type 1 diabetes mellitus or non-type 1, non-type 2 diabetes caused primarily by (near-) absence of insulin production provided that:
* Attempts to achieve target haemoglobin A1c (HbA1c) levels with multiple daily injections (MDIs) result in the person experiencing
disabling hypoglycaemia. For the purpose of this guidance, disabling hypoglycaemia is defined as the repeated and unpredictable
occurrence of hypoglycaemia that result in persistent anxiety about recurrence and is associated with a significant adverse effect on quality of life;
OR
* HbA1c levels have remained high (that is, at 8.5% [69 mmol/mol] or above) on MDI therapy (including, if appropriate, the use of long-acting insulin analogues) despite a high level of care
for children under 12:
parents/child very keen to start, risk explained, parents competent to manage it and willing to engage in training +/- needle phobia in child and behavioural interventions failed
CSII involves a continuous basal infusion of short acting insulin (the hourly rate typically varies over a 24 hour period), in combination with meal-time boluses of the same insulin. Both basal and bolus insulin are delivered by CSI
Any short acting insulin can be used; basal rates can be temporarily
increased/decreased to accommodate fluctuations in blood glucose levels e.g. as a consequence of increased activity, or ill health. Boluses are delivered under the patient’s direction, to cover carbohydrate intake
and to correct for high blood glucose levels
People on CSII do NOT take any long acting insulin so if there is any interruption to insulin delivery (e.g. if the cannula is blocked/dislodged/removed) hyperglycaemia
and then ketoacidosis can develop very quickly.
In these situations, the problem has to be identified and rectified, e.g. by re-siting the cannula, changing the tubing, or starting alternative insulin such as an intravenous infusion
Unless incapacitated, most people using CSII are safest remaining on CSII if admitted to hospital; they should only be adjusted by the patient or a member of the diabetes team
stop CSII in DKA or if pt incapacitated; also take it off temporarily while getting XR/CT/MRI; wait 60 minutes before discontinuing IV insulin once CSII restarted
diabetes annual review for kids
height, weight (plot on centiles as poorly controlled -> poor growth)
BP and UMA (urinary microalb)
foot check
bloods for coeliac, thyroid, cholest, HbA1c (aim for <48mmol/mol)
retinal screening from age 12
diabetic eye disease (mech; NPDR (1 mild, 5 mod, 3 severe), 2 PR (more common in which kind?), maculopathy (what and more common in which kind?)
Diabetic retinopathy is the most common cause of blindness in adults aged 35-65 years-old. Hyperglycaemia is thought to cause increased retinal blood flow and abnormal metabolism in the retinal vessel walls. This precipitates damage
Mild NPDR
1 or more microaneurysm
Moderate NPDR
microaneurysms
blot haemorrhages
hard exudates
cotton wool spots (retinal infarction), venous beading/looping and intraretinal microvascular abnormalities (IRMA) less severe than in severe NPDR
Severe NPDR aka preprolif
blot haemorrhages and microaneurysms in 4 quadrants
venous beading in at least 2 quadrants
IRMA in at least 1 quadrant
Proliferative retinopathy
retinal neovascularisation - may lead to vitrous haemorrhage
fibrous tissue forming anterior to retinal disc
more common in Type I DM,
Maculopathy
based on location rather than severity, anything is potentially serious
hard exudates and other ‘background’ changes on macula
check visual acuity
more common in Type II DM
Chronic hyperglycaemia causes blood vessels, including those supplying the retina, to weaken and rupture; the vessel walls may dilate resulting in microaneurysms or small haemorrhages.
The damaged pericytes and erythrocytes increase vascular permeability. Lipoproteins, lipids and other products carried by blood are therefore able to leak out and cluster onto the retina as hard exudates.
As blood flow becomes increasingly compromised, regions of the retina are starved of oxygen. This hypoxia is thought to stimulate the release of mediators such as vascular endothelial growth factor (VEGF) which promotes neovascularization. However, these new vessels are poorly formed and easily rupture resulting in bleeding.
Neovascularization into the vitreous humour may culminate in widespread vitreous haemorrhage causing sudden and complete visual loss. Fibrovascular bundles can lead to fibrosis and, in turn, retinal traction. This can result in retinal detachment and recurrent vitreous haemorrhage.
visual acuity assessed, slit-lamp or fundus photography to classify severity; fluorescein angiography can help you see unclear ischaemia, optical coherence tomography if diabetic macular oedema
lifestyle, glycemic, and BP control; photocoagulation if proliferative or severe nonprolif and high risk eg one eye, pregnant, frequent flyer
In focal photocoagulation, a specific point of leakage is identified and targeted with the laser. comps include worse central vision or scotoma
Pan-retinal photocoagulation (PRP)
The periphery of the retina is targeted with the aim of achieving a global reduction in oxygen demand. so less VEGF; Complications of PRP include a restricted peripheral vision, reduced quality of night vision, ocular pain, worsening macular oedema
Anti-VEGF injections focus on minimising neovascularization and thus are used in proliferative diabetic retinopathy. Aflibercept (Eylea) and Ranibizumab (Lucentis) are two commonly used anti-VEGF agents in the treatment of DR.
Although the mechanism of action is not completely understood, trials have shown intravitreal corticosteroids can also be effective in improving visual acuity and reducing maculopathy.
anti-vegf contra’d if stroke or MI in last 3mo
A potential complication of proliferative DR is bleeding into the vitreous humour, which further increases the risk of retinal detachment. In many cases, waiting for the haemorrhage to settle can allow sufficient view to perform laser therapy.
However, in persistent haemorrhage or in central, sight-threatening tractional retinal detachment a vitrectomy may be performed. This allows for the removal of the vitreous and repair of any scarring/detachment of the retina. Photocoagulation may be used intra-operatively
annual screening once >12yo
retinal detachment/vitreous h+ are main complications, also neovascular glaucoma: Neovascularization can occur within the iris and its trabecular meshwork (rubeosis) causing a narrowing and closure of the drainage angle and therefore increased intraocular pressure.
The typical presentation may include a patient complaining of an acutely painful, red eye
If left untreated, approximately 50% of patients with proliferative DR will lose their vision in 2 years.
Around 90% of affected patients will have lost most of their vision within 10 years.
Those with proliferative DR that undergo treatment can reduce their risk of severe vision loss by 50%
also get cataracts
Ca hom intro (core mechanism behind how sx arise form hypo/hyper, distribution)
Ca has structural role in bones, roles in signalling, exocytosis, ECC, stability of excitable cell membranes; hypocalcaemia lowers AP threshold both as less pos charge outside cell depolarises it and through interaction with channel proteins increasing Na permeability, giving spontaneous activity, motor nerves especially vulnerable and may give tetany with death resulting from tetanic contraction of muscles in larynx; hypercalcaemia raises AP threshold giving sluggish CNS function, muscle weakness, arrhythmia, kidney stones from precipitating calcium phosphates but not dangerous in short term
~99% in bones, relatively stable; 1kg of Ca in bones locked up as hydroxyapatite, 1g lines surfaces of canals in bone with fluid available for exchange, another gram in the ECF; plasma [Ca] is 2.5mM, around half bound to proteins, just under half free and the remainder complexed with anions; further 10g in cells, most sequestered with [Ca]cell of 50 to 100 nM; mass balance is the key regulatory feature with amount ingested = amount in faeces/urine, achieved via bone remodelling, inc Ca output by kidneys and balancing distribution between gut and ECF
parathyroid hormone (secreted from what cells, function and mechanism by which it achieves this)
secreted by chief cells in parathyroid gland, single chain 84 aa polypeptide released to raise [Ca] in ECF and essential for life; Ca binds low affinity GPCR to inhibit PTH secretion/synthesis; osteoblasts lay down new bone, requiring Ca/Pi, and are inhibited by PTH; osteoclasts don’t have PTH receptors but stimulated by cytokines released by osteoblasts (RANKL up, osteoprotegerin down) in response to PTH, bone lining cells decrease in size and retract to expose matrix to osteoclasts; PTH stimulates cytokine release to trigger differentiation into osteoclasts (calcitonin inhibits); osteocytes linked by cytoplasmic extensions to bone lining cells, rapidly transfer Ca through bone fluid by raised PTH, osteoclast numbers raised indirectly and activity increased; slower deposition by osteoblasts
calcitriol (how made, 3 things it does, synthesis regulated by what 2 hormones)
vit D is group of closely related compounds, D3 made by UV on cholesterol derivative in skin, with similar form in plant matter that people tend to rely on due to clothing and indoors; D3 metabolised by -OH additions in liver, then in kidney to give calcitriol which is a hormone that aids Ca mobilization from bone, facilitates Ca and phosphate renal reabsorption and increases Ca uptake from gut; synthesis at kidney regulated by PTH, so low plasma [Ca] gives PTH gives calcitriol; prolactin (hormone for milk production) stimulates calcitriol synthesis for max [Ca] when demand high
calcitonin (made by what cell type, secreted in response to what 2 things, does what, purpose is?)
parafollicular/C cells of thyroid make this single 33aa peptide which inhibits osteoclast activity to favour osteoblasts, more for preventing hypercalcaemia than causing hypocalcaemia
secreted in response to raised [Ca] which acts on C cells directly, and gastrin stimulates a feed forward mechanism to direct newly absorbed Ca to bone
protects maternal bone against excessive demineralisation in pregnancy (high Ca flux to foetus), or lactation, or birds during egg laying; the osteoclast suppression ensures Ca demands met by increased absorption in gut, not from bone resorption
hypocalc signs, sx, and 3 most common causes
Trousseau’s sign (sustained wrist spasm after sphygmomanometer on arm) Chvostek’s sign (contraction of facial muscles after tapping just below zygomatic bone) support diagnosis of hypocalcaemia as it causes increased excitability; prolonged QT interval possible and death from asphyxiation
most commonly CKD giving sec hyperpara
also due to decreased parathyroid gland activity (hypoparathyroidism > PTH deficiency) eg post surgery, Mg def
also from calcitriol insufficiency with abnormal bone demineralisation giving rickett’s/osteomalacia; severe vit D def common cause in kids/babies, esp in developing countries or BAME ppl
hypocalc ix (and ca albumin relationship)
healthy serum calcium is approx 2.4mmol/L, half bound to plasma proteins (less in acidosis and more in alkalosis)
if albumin falls, total serum Ca will also fall but will have normal unbound Ca levels as this is the regulated part, thus not hypocalcaemic
many labs thus reported a calcium figure adjusted for this, reporting what the total would be if normal albumin present; it is also worth looking at pH -> alkalosis displaces protons from albumin so more Ca binds, ionised down, thus hypocalc and can get sx of this; if acidosis then can get hypercalc via similar mechanism
after the initial test for ca ask: renal disease? measure urea and creatinine, and if fine then measure Mg and phosphate - > low suggests vit D deficiency and high hypopara; vit D def even more likely if PTH levels appropriately elevated, other rare causes and pseudohypopara; if PTH is inappropriately low may be due to post-surgery, Mg deficiency, or else idiopathic
chronic renal failure affects synthesis of vit D metabolites giving hypocalcaemia quite commonly, and from that bone disease and hyperparathyroidism
hyperparathyroidism 5 causes, 13 causes of hypercalc (inc MAS details: biochem picture, 10 sx, 3 causes)
Primary – caused by parathyroid gland adenoma, cancer or hyperplasia; inc MEN
Secondary – increased secretion due to low Ca (CKD or low vitamin D)
Tertiary – hypertrophied gland tissue due to prolonged secondary (hyperphosphataemia), but cause of secondary hyperparathyroisim is treated (renal transplant)
hypercalc due to to prim/tert hyperpara, PTHrP release from NSCLC, kidney cancer, or else from bone mets or multiple myeloma; from lymphoma or leukaemia, from vit D toxicity, pagets disease, thiazide diuretics, milk-alkali syndrome, prolonged immobilization increasing bone turnover
milk alkali syndrome: excessive intake of ca + alkali; hypochloraemic hypokalemic met alk + hypercalc giving nausea, vomiting, headache, polyur/polydip etc, over time mem loss, personality changes, lethargy, coma; often get AKI; milk over-ingestion can cause but most common is ca carbonate for osteoporosis or CKD, esp if also take antacids; pregnancy a risk due to vomiting + prolactin
effects of vitamin D and PTH
vit D - inc ca and phos reabsorption in gut/kidney, stimulates osteoclasts
PTH: rapid ca release plus long term osteoclasts up; incs ca reabsorpt, decs phos reabsorpt, and stimulates 1-alpha-hydroxylase in kidney (enzyme that activates vit D)
psuedohypoparathyroidism (what it is, biochem diff from hypopara, 5 signs/sx), pseudopseudohypoparathyroidism
hereditary end-organ resistance to PTH
will have v high PTH levels; short stature, rounded face, mental retardation, calcified choroid plexus, short 4th +/- 5th metacarpal
pseudopseudo has normal bone profile results but phenotypical appearance as above, reason is imprinting: kidneys will selectively activate the (functional) maternal copy while keeping the (defective) paternally-derived gene imprinted and inactive. Since the maternally-derived GNAS1 gene is functional, renal handling of calcium and phosphate is normal, and homeostasis is maintained
sx of hypercalc (9 sx, 4 things you might get) and hypocalc (7sx, how alkalosis causes these sx)
hyper: anorexia, nausea, abdo pain, constipation, polyuria/dipsia, muscle weakness, depression, poor conc, maybe renal stones, chondrocalcinosis, pancreatitis, peptic ulcers
hypo: weakness, tetany/twitches/cramps (trousseaus/chvostek), stridor, paraesthesiae, cataracts, short stature, depression/anxiety(alkalosis can make tetany/paraesthesia even if ca normal as less active ionised ca - it displaces protons from albumin and so more is bound there)
hypo-pitu system (6 hormones released by hypothal for ant pitu, 2 hormones from post pitu and the region of hypothal where post pitu neuron cell bodies are)
portal system between hypo/ant pitu; nerves fibres from PVN/SON to post pitu
releases stimulating hormones to ant pitu: corticotrophin (ACTH release), thyrotrophin (TSH/prolactin release), gondaotrophin (LH/FSH), growth hormone releasing hormones (GH), growth hormone inhibiting hormone aka somatostatin (inhibits GH, TSH, prolactin) and dopamine (inhibits PRL release), all peptide hormones except monoamine dopamine
post pituitary does oxytocin/vasopressin, fibres from SON/PVN with hormones made in cell body in hypothalamus
cortisol (and best ways to assess if high)
cortisol main glucocorticoid in humans, highest in morning and decline in day, probably due to low blood glucose after overnight fasting, shows circadian rhythm; released as acute phase response: in response to stress, amyg activates initial symp response from brainstem then HPA response by signalling the hypothal to release more CRH, cort levels rising within 15 mins and staying high for hours after
Cortisol is a potent insulin-antagonistic hormone inhibiting insulin/GLP1 secretion, stimulating glucagon secretion, and decreasing GLUT4 translocation to PM; it causes redistribution of fat giving truncal obesity, moon face, and buffalo hump in cushing disease/syndrome
aimed at dealing with stress, particularly enhancing catabolism to supply more energy to the body
cortisol stimulates gluconeogenesis (the synthesis of ‘new’ glucose from non-carbohydrate sources, which occurs mainly in the liver, but also in the kidneys and small intestine under certain circumstances). The net effect is an increase in the concentration of glucose in the blood, further complemented by a decrease in the sensitivity of peripheral tissue to insulin, thus preventing this tissue from taking the glucose from the blood. Cortisol has a permissive effect on the actions of hormones that increase glucose production, such as glucagon and adrenaline; Elevated levels of cortisol, if prolonged, can lead to proteolysis (breakdown of proteins) and muscle wasting as aa mobilised for gluconeogenesis
Cortisol inhibits production of interleukin 12 (IL-12), interferon gamma (IFN-gamma), IFN-alpha, and tumor necrosis factor alpha (TNF-alpha) by antigen-presenting cells (APCs) and T helper cells (Th1 cells), but upregulates interleukin 4, interleukin 10, and interleukin 13 by Th2 cells. This results in a shift toward a Th2 immune response rather than general immunosuppression. The activation of the stress system (and resulting increase in cortisol and Th2 shift) seen during an infection is believed to be a protective mechanism which prevents an over-activation of the inflammatory response; t prevents proliferation of T-cells by rendering the interleukin-2 producer T-cells unresponsive to interleukin-1, and unable to produce the T-cell growth factor IL-2
cortisol stimulates the production of RANKL by osteoblasts which stimulates, through binding to RANK receptors, the activity of osteoclasts – cells responsible for calcium resorption from bone – and also inhibits the production of osteoprotegerin (OPG) which acts as a decoy receptor and captures some RANKL before it can activate the osteoclasts
it stimulates gastric acid secretion, and elevated levels can stimulate mineralocort receptors giving Na/fluid retention and K loss
cortisol inhibits TSH, GHRH, and ADH
can cross blood-brain barrier, affect mood, jet-lag caused by circadian cortisol production being out of sync with real time
helps maintain blood pressure as permissive for catecholamine vasoconstriction; Glucocorticoids regulate vascular reactivity by acting on both endothelial and vascular smooth muscle cells; In endothelial cells. glucocorticoids suppress the production of vasodilators. such as prostacyclin and nitric oxide, and cause endothelin release. In vascular smooth muscle cells. glucocorticoids enhance agonist-mediated pharmacomechanical coupling at multiple levels inc Gi/Gs expression, and Ca handling proteins; also enhances the vasoconstrict effect of angII (uprg AT1r expression)
trigger erythropoietin synthesis to inc RBC production
increases procoag factor transcription and decs fibrinolytic activity thus get hypercoag in cushings
best ways to assess if level high is 24 hour urinary free cortisol, or morning cortisol after overnight low dose dex supp test
adrenal insufficiency (prim, sec, tert causes; sx/findings; mx inc sick day rules and when they apply, mx of crisis, dd for weight loss + fatigue, ix)
not enough cortisol, oft also not enough aldosterone
primary due to addisons (other autoimmune may be present), adrenal adenoma or congenital hyperplasia, or other (TB, sarcoidosis, haemochromatosis, amyloidosis, idiopathic); secondary due to hypopitu (eg adenoma compromising function); tertiary due to dec’d release of CRH from hypothal due to tumour or, most commonly of all causes overall, corticosteroid withdrawal
hypoglycaemia, dehydration, disorientation, (orthostatic) hypotension, fatigue, nausea, vomiting, aches, weight loss; hyponat, hyperkal, hypercalc; met acidosis; addisons may also have tanning esp of skin creases and buccal mucosa
note stress, esp from illness, can precipitate acute adrenal insufficiency in patients who underlying but minor insufficiency from eg recently stopped steroids or another cause from above but just a minor case
note adrenal crisis often comes from an acute decompensation of the insufficiency due to infection, trauma, adrenal H+ and main problem is hypotension resistant to fluid resus and catecholamines; iv hydrocortisone may be needed; pt may also collapse, vomit, have hypoglycaemia, confusion/slurred speech, lethargy, other u&e disturbances as above; endocrinologists usually manage these patients
long term: hydrocortisone or prednisone to replace glucocort, fludrocortisone to replace aldosterone, androgen DHEA replacement (off license)
if crisis occurs out of hospital, emerg hospital admission and immediate iv or im hydrocort and fluids if poss
sick day rules: extra glucocort cover may be needed to prevent crisis if they have surgery inc dentistry, likewise during illness or strenuous exercise (should double dose for 48hrs min)
crisis may have abdo pain and fever; nausea and vomiting key features too
consider addisons in T1 DM pts having rec unexplained hypos; weight loss, fatigue etc may also be DM, eating disorders, chronic fatigue
serum cortisol taken at 8-9am; specialist advice (maybe synacthen test) if shift work/irregular sleep, acutely unwell/chronic stressful illness, ppl on long term steroid treatment, on oestrogen treatment; if suspect after this test refer to secondary care for diagnosis to be confirmed (synacthen test)
cortisol excess tests (2 initial, 2 more to localise), pseudocushings cause, cushing effect on diurnal rhythm
urinary free cortisol assessed over 24 hours or overnight low dose dex then morning cortisol another way to tell; if low dose doesnt suppress then cushings syndrome ->then give high dose, if suppresses then cushing disease (ie from pitu), if doesnt then measure ACTH to see if high (ectopic ACTH production) or low (adrenal cause)
excessive alcohol intake can manifest as pseudocushings syndrome which will resolve after 2-3 weeks abstinence
cortisol diurnal rhythm is absent in cushings
aldosterone excess (prim 2 main causes and 2 rarer causes, blood test that suggests, main imaging, definitive ix, mx for both main causes; secondary 4 causes, mx)
primary hypraldosteronism aka Conns syndrome, single adenoma (conn’s disease) in 33% cases and rest bilat adrenal hyperplasia; rarely is adrenal cancer or familial form
suggested by high aldosterone:renin ratio
CT/MRI abdo, but as might miss small sources and incidentalomas so adrenal vein sampling for aldos levels to see if unilat or bilat; unilat surg, bilat spironolactone
secondary hyperaldosteronism associated with renal/heart/liver disease, renal artery stenosis/atheroma - hence need for renal artery US; managed with treatment of underlying cause, spironolactone also poss
adrenal insuff (5 prim causes, 4 sec, 1 tert, 5 sx + addisons specific sign, 5ix, mx inc sick day, crisis - 4 sx, 3mx, 3 triggers)
addisons: Autoimmunity e.g. 21-hydroxylase (most common)
TB
Malignancy
Adrenal haemorrhagic infarction due to anticoagulant use
Anti-adrenal drugs
Secondary adrenal insufficiency: surgery, RT, tumour, Sheehan’s syndrome…
Tertiary adrenal insufficiency: hypothalamic suppression from steroids
Classically mysterious and difficult to diagnose
Fatigue, tiredness, weight loss, salt craving (uncommon), nausea, hypotensive
May become hyperpigmented in palmar creases or scars (due to aMSH and ACTH produced from POMC) – only in Addison’s disease
Confirm:
Short Synacthen test
Morning cortisol (9am)
Localise by measuring ACTH levels (in adrenal insufficiency not Addison’s)
21-hydroxylase (sensitive but not specific)
Electrolyte changes
Secondary to low aldosterone: low sodium and high potassium
Hydrocortisone/prednisolone
Fludrocortisone
Remember sick day rules for steroids = 2x
addisonian crisis: Very unwell and present with hypoglycaemia, hypotensive/shocked, dehydrated, high fever
Need IV/IM hydrocortisone
Fluid and glucose replacement too
most often in patients with chronic adrenal insufficiency when subject to an intercurrent illness or stress
common cause of adrenal crisis is abrupt withdrawal of steroids. This is because secondary adrenocortical insufficiency develops when
steroids given
sudden loss of adrenal function such as bilateral adrenal gland haemorrhage can also produce adrenal crisis
cushings syndrome - electrolyte picture, BM, BP, 4 other signs, 3 ways to diagnose, test to localise, imaging once localised, general mx
cushings: hypernat hypokalaemic alkalosis, hyperglyc, hypertension; biggest sx inc weight gain, red/round face, easy bruising, weak limbs
Cortisol has a circadian rhythm – highest in the morning
To diagnose:
Check morning cortisol levels
Also can do a dexamethasone suppression test (low dose)
24 hour urinary cortisol
Localise w dex suppression: check ACTH 🡪 ACTH dependent (MRI head) or independent (CT abdomen)
surgical removal of whatever is making too much ie pitu adenoma or adrenal nodule/tumor/hyperplasia, or ectopic source
cushings clues in the blood, adrenal layers and need for each layer in adrenal insuff (inc what if hypopitu cause, why you don’t need to give fludro with hydro), synacthen test problem if infection or on steroids
cushings -> diabetes/hypertension, hypercoaguable, adrenal nodule
no need to give fludro if hypopitu as mineralocorticoid governed by renin not pitu, so can just give pred for its gluco action; also not
in crisis as that is deficiency of gluco action; hydrocort has fludro and gluco action so iv hydrocort can manage addisons, if oral then
pred (gluco) and fludro (mineralo) no point doing short synacthen or testing for cushings during infection or while patient is on steroids bc acth will be raised or suppressed
respectively and so inaccurate; go find rex, make good sex: zona glomerulosa, fasciulata, reticularis; mineralo, gluco, sex/androgens
cushing disease paediatric
most frequent presenting manifestations in child cohorts include weight gain (76.6%), hirsutism (56.6%) and acne (50%) with striae in up to 60%. For pituitary CD, growth retardation was the second commonest sign; hypertension also seen in 50%; early or delayed puberty is possible depending on the cause of the CD; also consider if pt may have mccune albright syndrome or carney complex
initial tests may show advanced bone age (in CD due to related to obesity, insulin resistance and elevated levels of adrenal androgens and their aromatization); however equally bone age can be within normal range as although androgens
accelerate bone maturation, hypercortisolaemia delays it
tests to confirm diagnosis: midnight cortisol, urine free cortisol, or low dose dex suppression test
at some stage of workup, depending on local expertise, you’ll need to refer to paeds endo
ix to localise: 8am plasma [ACTH], high dose dex suppression test, CRH test, MRI of pitu + USS/CT/MRI of adrenals; inferior petrosal sinus sampling IPSS before and after CRH injection if MRI inconclusive, and if this also inconclusive then CT thorax and somatostatin receptor PET scan; adrenal vein sampling alternative to IPSS if MRI inconclusive and adrenal cause suspected
HDDST and CRH test can reliably distinguish between pituitary and adrenal disease but perform less well in cases of ectopic ACTH secretion. IPSS is considered to be the gold standard to distinguish CD from ectopic and is a safe procedure in children under expert hands
mx generally surgery - to pitu, adrenals, or wherever ectopic source is (eg carcinoid tumour in bronchus); hydrocortisone may then be required post op but may be able to wean this down
steroidogenesis
cholesterol is base, then follows 1 of three pathways (one occurs in each layer of the adrenal gland); majority of these steps occur in smooth endoplasmic reticulum, except initial cholesterol to preg step and 11bh steps which happen in mito (as does final aldos synthesis)
cholesterol always becomes pregnenolone,
then in glomeulosa: preg -> progesterone, 21-hydroxylase turns this into deoxycorticosterone, 11 beta hydroxylase turns this into corticosterone which then becomes aldosterone
in fasciculata preg becomes 17-OH preg, becomes 17-OH prog (17 alpha hydroxylase is enxyme that makes preg and/or prog into 17-OH form ie can enter this path from either molecule), then 21-hydroxy and 11 beta hydrox as above make 17 OH prog into 11-deoxycortisol then cortisol
in reticularis 17,20 lyase makes 17-OH preg into DHEA and 17-OH prog into androstenedione (so again can enter sequence from either molecule and DHEA becomes androstenedione), andros then becomes testos; 5ar makes this into dihydrotestosterone in the testis, prostate, skin, brain etc and DHT is much more potent agonist of androgen receptor
aromatase turns testos into oestradiol and androstenedione into oestrone, and both of these then become oestriol; aromatase is in ovaries, adipose, brain, placenta, skin, bone, blood vessels and in cancers and fibroids
note the production of testos/oestrogen occurs in testes (leydig cells)/ovaries with the adrenal gland releasing DHEA and andros (a small amount of the later hormones may be released from the adrenals ~5%)
10 corticosteroid side effects, whats given to minimise (inc ind)
opportunistic infection due to suppressed immune system, despite this neutrophilia (more neuts enter blood from endothelium, less migrate into tissues, so total number not changed but distribution is) thinning of skin and impaired wound healing, oral thrush due to local anti-infection mechanisms suppressed when taken orally, osteoporosis due to several reasons including inc osteoclast and dec osteoblast activity, hyperglycaemia, muscle wasting, stomach ulcer, avascular necrosis of femoral head (rare, need hip replacement); other drugs given to reduce eg PPI and a bisphosphonate to protect bone; long term use can get cushings syndrome with pot-belly, body hair loss, polydipsia/uria; suppression of HPA so sudden withdrawal after >1week of use can result in acute adrenal insufficiency, poor growth in children due to GH suppression
for bisphos: (In all men and women aged > 65 years who take corticosteroids of any dose for more than 3 months, including high dose inhaled corticosteroids or patients on 3/4 courses of prednisolone in a year.)
for PPI: if older, pmh of GI ulcer/bleed, or other meds/risk factors for upper GI problems present (antigoags/plats, SSRIs, NSAIDs, cav blockers)
T3 vs T4, synthesis of both, 2 things deiodinases can make from T4, 3 things that TSH stimulates, how most T3 is made, 3 types of deiodinases, 3 reasons for sick eutthyroid, thyroid hormone effects (12) + cortisol/TSH link
T4/3 attached to thyroglobulin and stored in colloid; TRH stimulates TSH release which increases T4/3 release, T3 most potent and target tissues have deiodinase enzyme to convert T4 to T3, as does the pitu
iodine attached to tyrosine to make mono-iodotyrosine and di-iodotyrosine which are coupled to produce T3/4; removal of iodine can convert T4 into active T3 or inactive T3r; iodide taken up from blood by Na/I symporter and added to Tyr residues of thyroglobulin in follicles, internalized into follicular cells by endocytosis and broken down in lysosome to release T3/4; TSH stimulates I- uptake, oxidation to I and T3/4 secretion
most T3 made by deiodination in periph tissues from T4; T4 can also be made into T3r; T3r maybe inhibitory; type 1 deiod makes both, type 2 make T3 breaks down T3r, type 3 makes T3r breaks down T3; in sickness T1/2 are down and type 3 is up, part of how you get sick euthyroid along with changes in TSH release; also albumin down, FFAs cant bind to it so bind to thyroid binding globulin instead displacing T4
hormones do: permissive effect on catecholamines. It increases the expression of beta-receptors to increase heart rate, stroke volume, cardiac output, and contractility; increases BMR by increasing the gene expression of Na+/K+ ATPase leading to increased oxygen consumption, respiration rate, and body temperature, as well as directly stimulating thermogenesis by stimulating symp nerve input centres to BAT. Depending on the metabolic status, it can induce lipolysis or lipid synthesis. Thyroid hormones stimulate the metabolism of carbohydrates and anabolism of proteins. Thyroid hormones can also induce catabolism of proteins in high doses; In children, thyroid hormones act synergistically with growth hormone to stimulate bone growth. It induces chondrocytes, osteoblasts, and osteoclasts. Thyroid hormone also helps with brain maturation by axonal growth and the formation of the myelin sheath; meanwhile, cortisol suppresses TSH release
TRH neurons (where they are, 4 neuropeptides released onto them and what they promote, what happens during fasting)
in PVN, projections received from 2 diff leptin sensitive areas in arcuate nucleus containing either alpha-melanocyte-stimulating hormone (alpha-MSH) and cocaine- and amphetamine-regulated transcript (CART), peptides that promote weight loss and increase energy expenditure, or neuropeptide Y (NPY) and agouti-related protein (AGRP), peptides that promote weight gain and reduce energy expenditure
During fasting, the reduction in TRH mRNA in hypophysiotropic neurons mediated by suppression of alpha-MSH/CART simultaneously with an increase in NPY/AGRP gene expression in arcuate nucleus neurons contributes to the fall in circulating thyroid hormone levels, presumably by increasing the sensitivity of the TRH gene to negative feedback inhibition by thyroid hormone
hypothyroidism - BMR and SNS effect, link to prolactin and LH/FSH, myxoedema why and what else it affects,17 sx, 9 causes (2 of which are drugs, ix findings)
BMR down, decreased symp nerve activity, hyperprolactinaemia if TRH high enough suppressing androgens, LH/FSH (so affecting period, giving ED and lower libido) and can get breast growth, myxoedema due to decreased glycoasminoglycan clearance from dermis which also effects voice + tendons inc causing carpal tunnel syndrome
underactive/hypothyroidism: often no or mild symptoms but tiredness, feeling cold, poor memory, constipation or dyspepsia, weight gain, heavy or irregular periods, cool extremities, dry skin/hair, slow pulse, swelling of limbs, delayed ankle jerk and other reflexes, myoxedema, depression, muscle aches, reduced libido, carpal tunnel, hoarse voice, hyperlipidaemia; tendonitis or carpal tunnel can be the presenting complaint as glycosaminoglycans accumulate in the ECM - the tendinitis can affect any, causing eg rotator cuff problems, achilles tendonitis, bicepts tendon rupture etc
iodine deficiency most common cause worldwide, if area of world like uk with enough iodine then hashimotos thyroiditis (painless goitre, other autoimmune conditions eg t1 DM, coeliac, vitiligo enlarged firm thyroid but not always palpable) most common cause but also acute infectious thyroiditis (painful swollen neck, fever, dysphagia, TFTs may be normal), radioiodine or thyroidectomy, lithium, amiodarone, interferons, pituitary dysfunction, congenital; radiotherapy or other high doses of radiation to thyroid can also lead to hypothyroidism
TFTs, thyroid antibody test after to rule out hashimotos if hypothyroid present
hypothyroidism tests (inc for sick euthyroid)
if suspect then measure TSH and free T4
TSH elevated, T4 normal: it is hypothyroidism early (T4 low in established disease), give replacement T4
TSH elevated, T4 not quite normal but within reference limits: hypothyroidism may be developing, measure autoantibodies and repeat analysis after 2-3 months
TSH normal/low, T4 low, T3 low, T3r high: sick euthyroid
TSH low, T4 low: central problem so check cortisol/FSH/LH/prolactin
