Endo

Question 1

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)

Answer 1

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)

Question 2

insulin and incretins (insulin vs glucagon broad function, 2 main incretins and 2 functions plus link of first to BM)

Answer 2

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

Question 3

insulin 6 functions, consequent effects of insulin deficiency x5, and insulin antagonists x4

Answer 3

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

Question 4

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)

Answer 4

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

Question 5

hyperglycaemia (non-DM causes 4:4:2:1:1:1:3, main risk/sx, 4 main osmotically active particles)

Answer 5

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

Question 6

impaired glucose tolerance causes in kids (8)

Answer 6

friedriech ataxia, CF, DMD, cushing syndrome, ataxia telangiectasia, PW, down syndrome, turner syndrome

Question 7

t1dm (4 sx, 2 main ix and confirmatory test, 4 stage progression, how is medical insulin duration of action or onset time increased)

Answer 7

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

Question 8

pancreas embryology and T1DM pathophysiology

Answer 8

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

Question 9

t1dm ix initial and monitoring

Answer 9

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

Question 10

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)

Answer 10

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)

Question 11

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?)

Answer 11

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.

Question 12

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

Answer 12

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

Question 13

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

Answer 13

inpatient hyperglycemia: three groups of patients to consider are the following:

1. Known diabetes mellitus before admission - in which case consider administering correction dose.
2. 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.
3. 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

Question 14

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)

Answer 14

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%

Question 15

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

Answer 15

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

Question 16

DKA (inc 7 sx, 5 causes, how it might affect brain, diagnostic criteria x3, sick day rules x4)

Answer 16

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

Question 17

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

Answer 17

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)

Question 18

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)

Answer 18

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

Question 19

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)

Answer 19

 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

Question 20

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)

Answer 20

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

Question 21

4 causes of early morning hyperglyc inc which is most likely

Answer 21

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)

Question 22

mauriac syndrome (results from what, 5sx, 2 possibly co-existing causes of similar phenotype and what the phenotype is)

Answer 22

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

Question 23

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)

Answer 23

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

Question 24

hyperinsulinism

Answer 24

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

Question 25

hypoglyc (sx 8:6 and causes 9:8)

Answer 25

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)

Question 26

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

Answer 26

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

Question 27

neonatal hypoglycaemia - definition, how common, 8 things causing persistent/severe, sx 4:5:2; asymp mx x2; symp or v low mx x2

Answer 27

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

Question 28

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

Answer 28

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

Question 29

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

Answer 29

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)

Question 30

insulin pump guidelines

Answer 30

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

Question 31

diabetes annual review for kids

Answer 31

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

Question 32

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?)

Answer 32

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

Question 33

Ca hom intro (core mechanism behind how sx arise form hypo/hyper, distribution)

Answer 33

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

Question 34

parathyroid hormone (secreted from what cells, function and mechanism by which it achieves this)

Answer 34

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

Question 35

calcitriol (how made, 3 things it does, synthesis regulated by what 2 hormones)

Answer 35

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

Question 36

calcitonin (made by what cell type, secreted in response to what 2 things, does what, purpose is?)

Answer 36

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

Question 37

hypocalc signs, sx, and 3 most common causes

Answer 37

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

Question 38

hypocalc ix (and ca albumin relationship)

Answer 38

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

Question 39

hyperparathyroidism 5 causes, 13 causes of hypercalc (inc MAS details: biochem picture, 10 sx, 3 causes)

Answer 39

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

Question 40

effects of vitamin D and PTH

Answer 40

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)

Question 41

psuedohypoparathyroidism (what it is, biochem diff from hypopara, 5 signs/sx), pseudopseudohypoparathyroidism

Answer 41

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

Question 42

sx of hypercalc (9 sx, 4 things you might get) and hypocalc (7sx, how alkalosis causes these sx)

Answer 42

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)

Question 43

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)

Answer 43

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

Question 44

cortisol (and best ways to assess if high)

Answer 44

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

Question 45

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)

Answer 45

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)

Question 46

cortisol excess tests (2 initial, 2 more to localise), pseudocushings cause, cushing effect on diurnal rhythm

Answer 46

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

Question 47

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)

Answer 47

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

Question 48

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)

Answer 48

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

Question 49

cushings syndrome - electrolyte picture, BM, BP, 4 other signs, 3 ways to diagnose, test to localise, imaging once localised, general mx

Answer 49

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

Question 50

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

Answer 50

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

Question 51

cushing disease paediatric

Answer 51

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

Question 52

steroidogenesis

Answer 52

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%)

Question 53

10 corticosteroid side effects, whats given to minimise (inc ind)

Answer 53

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)

Question 54

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

Answer 54

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

Question 55

TRH neurons (where they are, 4 neuropeptides released onto them and what they promote, what happens during fasting)

Answer 55

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

Question 56

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)

Answer 56

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

Question 57

hypothyroidism tests (inc for sick euthyroid)

Answer 57

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

Question 58

hypothyrodism causes (inc drugs) and myx coma (inc mx)

Answer 58

Iodine deficiency – rare in the UK, most common cause over the world Hashimotos thyroiditis – very brief hyper, longer hypo; antithyroid peroxidase (anti-TPO) antibodies and antithyroglobulin antibodies. Initially it causes a goitre after which there is atrophy Post-partum thyroiditis – brief hyper (weeks), longer hypo (months), mostly self-resolving De Quervain’s thyroiditis – as above, high ESR, tender thyroid, self-resolving; viral infection with fever, neck pain and tenderness, dysphagia and features of hyperthyroidism. There is a hyperthyroid phase followed by a hypothyroid phase as the TSH level falls due to negative feedback. It is a self-limiting condition and supportive treatment with NSAIDs for pain and inflammation and beta-blockers Riedels thyroiditis - hard, firm thyroid, fibrous tissue lithium, amiodarone myxoedema coma: Undiagnosed/inadequately treated hypothyroidism May be precipitated by infections, medications, surgery etc Presentation: it is a misnomer Usually present with: hypothermia, hypotensive, bradycardic and confusion Almost always >60 and 90% in winter Treatment: IV thyroid replacement, as GI absorption compromised Corticosteroids, as may have hypopituitarism

Question 59

thyroid physiology + what happens at birth

Answer 59

outpuching of floor of pharynx, migrates caudally to lower neck w thyroglossal duct running from foramen caecum down to gland iodide from food concentrated in thyroid, peroxidase turns it into iodine which then is incorporated into tyrosine in thyroglobulin using peroxidase tyr residues iodinated at one or both ends (mono or diiodothyronine) which then couple with MIT + DIT making triiodithyronine T3 or DIT + DIT to make T4 this thyroglobulin secreted into colloid for storage. TSH causes endocytosis of thyroglobulin which is hydrolysed to liberate free t3 and t4, which are bound to thyroxine binding globulin and albumin, but free component is active thyroid hormones control BMR, growth, mental dev, sexual maturation, and inc beta receptor sensitivity to catecholamines

Question 60

congen hypothyroidism (inc structure vs functional, when to consider more)

Answer 60

hard to diff from down syndrome baby sometimes usually agenesis or dysgenesis, usually sporadic; rarely dyshormonogenesis in which case a goitre will be present coarse facial features, dryk skin, prolonged jaundice, large fontanelles, cutis marmorata, bradycardia, hypotherm, hoarse cry, cold extremities, hypotonia, lethargy/poor feeding, constipation, umbilical hernia, macroglossia, oedema if left untreated can get irreversible mental retardation screening for serum TSH at 7 days (after postnatal surge), and will find it is v high if also hypoglyc, small phallus, or midline defects consider generalised hypopitu problem

Question 61

childhood hypothyroidism

Answer 61

congen, 1 in 4000, 2x common in girls; poorly devd thyroid in 75% cases, thyroid hormone metab problems in 10%, hypo-pitu dysfunction in 5%, transient in 5% due to maternal thyroid disease or carbimazole usually clinically normal at birth, then feeding difficulties, lethargy, low freq of crying, constipation; macroglossia, large fontanelle, myxoedema, low temp, bradycardia, hypotonia, pericard effusion, short stature, maybe goitre; usually no other endo abnorms, no neonate jaundice, no association with low birth weight part of heel prick screening (looks at TSH and T4 - high former and low latter confirms); thyroxine replacement started early to stop neurodev problems, titrated to TFTs which are monitored regularly, as is growth and achievement of milestones hashimotos is most common acquired, usually in adolescence; slowing growth, low energy, cold sensitivity, sleepiness, usually delayed puberty but can be precocious; de quervains also poss, and iatrogenic during treatment for hyperthyroid subclin hypothyroid also common in kids

Question 62

hyperthyroidism (effect on BMR, effect on SNS x2, 19 symptoms inc how an older pt might present, thyroid storm (6 sx, how might die, 7 triggers), 2 reasons might dev hypothyroid, 9 causes, 2 ix, 3 mx)

Answer 62

BMR up, inc'd symp nerve activity and beta receptor expression may be asympt or nervousness, irritability, inc perspiration, raised HR, tremor, thin skin, brittle hair, insomnia, weakness in arms and thighs, weight loss, tiredness, lighter or more irregular periods, hair loss (inc outer eyebrows), heat intolerance, anxiety, nausea, palpitations, atrial fib, also T3 can cause osteoporosis in excess, thus older pt may present with fracture thyroid storm: rare but severe complication with high fever, fast and oft irreg heartbeat, BP up, vomiting, diarrhoea, agitation or even psychosis; acute onset, risk of acute heart failure then shock and death; usually if hyperthyroid and treatment stopped or undiagnosed/controlled and concurrent big illness eg sepsis, MI, DKA, dehydration, PE, stroke, trauma etc damage to gland over time from condition or radioiodine can eventually lead to hypothy grave's diseases (pretibial myx giving thick shin that is non-pitting, bulging eyes, goitre) toxic thyroid adenoma, toxic multinodular goitre, eating ground pork or beef contaminated with thyroid (rare), amiodarone, too much iodine after eating eg kelp, pitu problems, thyroid nodules or cancer; thyroiditis measure TSH, then after eg anti-TSHr antibodies (graves) beta blockers, carbimazole, radioiodine (and iv fluid resus if storm); (last 2 only after specialist, 1st can be started in prim care to bridge gap after referral made to specialists)

Question 63

hyperthyroidism biochem

Answer 63

TSH low, T4 raised confirms diagnosis in pregnancy, oestrogen stimulates thyroid binding globulin synthesis in liver so total T4 raised, although free T4 will be normal binding proteins also altered in eg women on the pill, patients with nephrotic syndrome some patients will have normal T4 but elevated T3 if suspect, measure TSH and T4 TSH undetectable, T4 raised: thyrotoxicosis TSH detectable, T4 raised: repeat the analysis or immunoassay interference TSH undetectable, T4 normal: likely find T3 elevated elderly thyrotoxic patients often dont show the usual sign of hyperthyroidism, some will only present with atrial fibrilliation, or else weight loss leading to anxiety and a futile search for malignant disease

Question 64

hyperthyrodism- graves disease signs, treatment (inc s/e) and investigation/scan focus, 3 surgery complications, thyrotoxic storm

Answer 64

exophthalmos, pretibial myxoedema and thyroid acropachy Solitary adenoma Toxic multinodular goitre = may feel nodular goitre in neck Amiodarone = Lots of side effects beta blockers inhib effects, carbimazole inhibs synthesis (but agranulocytosis), radio iodine destruction, Thyroidectomy – RLN palsy, hypoCa (hypopara) and haematoma carbim: dose is sufficient to block all production and the patient takes levothyroxine radioiodine: Must not be pregnant and are not allowed to get pregnant within 6 months Must avoid close contact with children and pregnant women for 3 weeks (depending on the dose) Limit contact with anyone for several days after receiving the dose Radioactive iodine is given orally or intravenously and travels to the thyroid where it is taken up by the cells. The more active the thyroid cells, the faster the radioactive iodine is taken up. A gamma camera is used to detect gamma rays emitted from the radioactive iodine. The more gamma rays that are emitted from an area the more radioactive iodine has been taken up. Diffuse high uptake is found in Grave’s Disease Focal high uptake is found in toxic multinodular goitre and adenomas “Cold” areas (i.e. abnormally low uptake) can indicate thyroid cancer Uptake is decreased in thyroiditis, so in the hyperthyroid phase this is one way to tell it from graves thyrotoxic storm: Complication of hyperthyroidism – 50% mortality if untreated Usually due to: contrast injection, trauma, surgery, infection, DKA, MI High fever (usually over 40), confusion, agitated and vomiting/diarrhoea Treatment Thyroid blocking agent - Carbimazole or propylthiouracil Iodine B blockers Steroids should be given due to increased metabolism, and also as reduces T4->T3 conversion

Question 65

neonatal hyperthyroidism

Answer 65

in 1-2% of mums with Graves disease due to transplacental transfer of TSIs (aka immunoglobulins, not thyroid hormones, so mum neednt be thyrotoxic at birth) baby presents within 1 week w irritability, diarrhoea, tempinstability, tachycardia (may be svt), weight loss; may have features of heart failure disappears when the antibodies do, usually in 2-3 weeks

Question 66

managing babies born to mothers with thyroid disease

Answer 66

thyroid gland in the fetus develops at 3 to 4 week of gestation but produces little thyroid hormone until 12 weeks. The fetus is dependent on the small amounts of T4 that can cross the placenta during the first trimester. During the second trimester the hypothalamic-pituitary axis becomes functional by 25 week of gestation and the TSH rises along with T3 from the thyroid gland. The full maturation of the hypothalamo-pituitary-thyroid feedback system happens in the third trimester. Therefore when babies are born the thyroid levels are a reflection of the fetal thyroid production. At birth there is a TSH surge which results in high T4 and T3 levels. TSH should return to normal within 2-3 days of birth, followed by T3 and T4. TFTs should be interpreted within the clinical context and with caution, particularly within the first 3 days of life.  Maternal TSH & T3 do not cross the placenta (poor permeability and placenta deiodinases)  T4 crosses the placenta during the first trimester but this reduces significantly with increasing gestational age. At term only if the fetus is athyroid, a small amount of T4 can cross the placenta.  Carbimazole, propythiouracil, thyroid stimulating immunoglobulins (TSIs) and thyroid inhibitory antibodies cross the placenta maternal hypothyroidism: Secondary to congenital aplasia/ hypoplasia, There is only a slightly increased risk of hypothyroidism to the baby. Blood spot test will suffice. 2. Secondary to Hashimoto thyroiditis Maternal inhibiting antibodies (& rarely stimulating antibodies) can cross the placenta. Infant can develop transient hypothyroidism and rarely hyperthyroidism Clinical review (Face to face/Telephone consultation) / TFTs on day 10-14 3. Secondary to treatment for Graves’ disease Maternal Thyroid stimulating immunoglobulins (TSIs) continue to be produced even after ablation or radioiodine and cross the placenta. Infant is at risk of thyrotoxicosis and should be managed as other card

Question 67

children born to mothers with thyroid disease - hyperthyroidism

Answer 67

Neonatal Graves’ disease develops in approximately 1 to 5 % of infants born to mothers with Graves hyperthyroidism and is caused by transplacental passage of maternal stimulatory thyrotropin receptor antibodies (TRAbs).  In babies who are exposed to high titres of TRAbs, hyperthyroid symptoms typically present at birth.  However, the infant may instead have hypothyroidism following delivery, depending on the balance of the maternal stimulatory TRAbs and maternal antithyroid drug Neonatal Graves’ hyperthyroidism resolves spontaneously within 3-12 weeks after birth as the maternal TRAbs disappears from the infant’s circulation measuring cord TRAbs level is worthwhile as cord TRAbs levels correlates with the risk of developing hyperthyroidism in the neonatal period.  Negative or undetectable TRAbs conversely indicate an extremely low risk of developing neonatal Graves disease Measuring cord TFTs at birth however does not correlate with thyroid function in the neonatal period, therefore it is not recommended to monitor TFTS before day 3 of life. sx of neonatal thyrotoxicosis Background history of foetal tachycardia, advanced bone age, foetal goitre  Irritability, jitteriness and restlessness  Small fontanelle, warm/moist skin, hyperthermia  Poor feeding, poor weight gain, increased frequency of bowel movements  Tachycardia and arrhythmia (can lead to cardiac failure)  IUGR, goitre and non- immune hydrops.  Systemic and pulmonary hypertension  Eye signs (staring, lid retraction) may be present if infant at high risk (Positive maternal TRAbs in pregnancy  Hyperthyroidism with unknown TRAbs (mother currently hypo/hyper/euthyroid)  Family history of TSH receptor mutation  Current or previous antenatal Graves disease  Signs of neonatal thyrotoxicosis ) then: At birth:  Cord blood should be sent for TRAbs after delivery.  If negative, infant is considered low risk and routine newborn care is advised On day 1 of life:  If cord blood for TRAbs was not sent, then send infant TRAbs  Assess the infant to look for signs/symptoms of hyperthyroidism.  At-risk babies who are well can be discharge home after 48 hours of observation including HR, temperature, RR and feeding.  Parents must be advised of the signs and symptoms of thyrotoxicosis and an information leaflet should be given to parents and following follow up plan put in place.  Consider a face-to-face review on D3-5 if felt to be clinically required. On day 10-14 of life:  In babies with positive TRAbs: TFTs on day 10-14.  This should be followed by a face-to-face review in clinic If the infant tests positive for TRAbs with normal TFTs:  They will need further review at 2-3 months If TFTs demonstrate hyperthyroidism admit for CV monitoring and temp support, and discuss starting carbimazole with paeds endo breastfeeding should be recommended and supported for women on thyroxine or any antithyroid medication. Women may safely breastfeed on doses of carbimazole below 15 mg/day or PTU below 150 mg/ day. Discuss if they are on higher doses

Question 68

4 complications of anti-thyroid drugs

Answer 68

All patients should be warned to stop therapy and have a blood test if they develop a fever, sore throat or mouth ulcers neuts 1-1.5 continue but closely monitor, <1 stop and monitor daily - may need sepsis algorithm if unwell + discuss with haem to consider G-CSF drug rashes are also common with anti-thyroid drugs and usually respond to topical treatments, antihistamines or switching to an alternative anti-thyroid drug Arthralgia and vasculitis are very rare with carbimazole but are seen more frequently with propylthiouracil treatment. Stop the anti-thryoid drug. Perform an autoantibody screen, particularly a full ANCA screen, for drug-induced lupus and discuss with rheumatology Mild hepatitis with an increase in transaminases to 1.6x upper limit of normal also commonly occurs after around 3 months treatment with propylthiouracil. This is usually transient and requires no treatment - but v rarely get allergic hepatitis; can get cholestatic picture with carbimazole

Question 69

management of thyroid emergencies

Answer 69

hypothyroid coma - Patients will usually look classically hypothyroid with non pitting oedema, facial coarsening, loss of hair, cool dry skin, altered mental status; hypothermia, bradycardia, slow reflexes, possibly T2RF, hyponat, hypoglyc, macrocytosis and maybe elevated CK get ABG, TFTs, cortisol, FBC, U&Es, glucose, CK; septic screen, ECG hydrocort IV start regularly; liothyronine 5-10mcg oral or via NG (IV only as a last resort as higher risk of cardiac s/e); continuous cardiac monitor, rewarm with blanket; monitor BMs 4 hourly and treat hypos; endo will guide inc in lithyronine dose and switch to levothyroxine; let CCOT and endo know; abx after septic screen sent unless pretty sure no infectious trigger general thyrotoxicosis mx: Check FBC, U+E, LFTs, calcium prior to starting treatment Start carbimazole 20mg bd orally Consider beta blocker: e.g. propranolol 40mg-80mg tds for rapid relief of symptoms in severe thyrotoxicosis Refer to endo thyroid storm: cardinal features of thyroid storm are fever above 38°C, tachycardia above 110 (+/- atrial fibrillation), heart failure and agitation. If none of these features are present, the patient does not have thyroid storm. Burch & Wartofsky >45 confirms diagnosis, 25-45 are impending storm so manage as if it is a storm bloods as above and septic screen; ECG, continuous cardiac monitor Propranolol 80mg tds PO to reduce heart rate and block effects of thyroid hormones. Alternatively, propranolol 2mg iv over 10 minutes can be used in a very unstable patient or one who cannot take oral medication; CCB is alt if asthma Propylthiouracil 200mg tds PO / NG / PR to stop release and production of thyroid hormones. This is more suitable than carbimazole in emergency situations as it also prevents peripheral T4 - T3 interconversion IV Hydrocortisone 200mg, followed by prednisolone 20mg tds PO. This prevents peripheral conversion of T4 to T3 Chlorpromazine 50-100mg im may be given if emergency sedation is required Cholestyramine 3g po tds may also be given to aid clearance of thyroid hormones by blocking their enterohepatic circulation 60 minutes following the first dose of propyl-thiouracil give Lugol’s iodine 5 drops qds PO - after propylthiouracil treatment, iodide will prevent further release of pre-formed thyroid hormones active colling, fluid resus, BMs 4hrly and treat if abnorm; treat precipitant eg abx until screen negative, rehydrate etc

Question 70

thyrotoxic periodic paralysis

Answer 70

sporadic form of hypokalemic periodic paralysis, which most commonly presents as sudden onset weakness in the proximal muscles. It is a reversible condition that can be treated with quick replacement of potassium and normalization of thyroid hormones often confused with familial periodic paralysis (FPP) due to the similarity in presentation but can be differentiated based on the presence of thyrotoxic features and biochemical testing; Any cause of hyperthyroidism can lead to thyrotoxic periodic paralysis Thyrotoxicity can contribute to hypokalemia by a direct increase in the genetic transcription of genes coding for the Na-K ATPase pump as well as an increase in the pump's intrinsic activity; also cause Beta-2 adrenergic stimulation and a rise in sensitivity to circulating catecholamines, resulting in an increase in Na-K pump activity Genetic mutations in the L-type calcium channel α1-subunit (Cav1.1) have been described in Southern Chinese with TPP. The mutations are located in a different part of the gene from those described in the related condition familial periodic paralysis. In TPP, the mutations described are single-nucleotide polymorphisms located in the hormone response element responsive to thyroid hormone; Of people with TPP, 33% from various populations were demonstrated to have mutations in KCNJ18, the gene coding for Kir2.6, an inward-rectifier potassium ion channel. This gene, too, harbors a thyroid response element. Non-selective beta-blockers have been shown to improve neuromuscular symptoms by reducing the intracellular shift of phosphate and potassium - eg IV propranolol Other muscular disorders like myasthenia gravis, Guillain Barre syndrome, transverse myelitis, botulism, tick paralysis, and other familial periodic paralysis syndromes should be ruled out when patients present with acute muscle weakness long term mx is pt education to avoid triggers, eg carbohydrate-rich foods, strenuous physical activity, high salt/sodium intake, stresses (surgical, infectious, psychological), trauma, and drugs

Question 71

human growth hormone levels through life, regulation, direct/indirect effects, investigation

Answer 71

greatest between weeks 16-20 and continuous after birth until adulthood with late divergence between sexes; growth velocity declines after birth until growth spurt, and earlier the growth spurt, shorter the final height; genetic, environmental (nutrition) and physiological (GH) all affect; GH has 2 disulphide bridges, is closely related to prolactin regulated through several complex feedback mechanisms in response to stress, exercise, nutrition, sleep, and growth hormone itself. The primary regulation factors are growth hormone-releasing hormone (GHRH), somatostatin, and ghrelin. GHRH functions to promote HGH production and release. Somatostatin inhibits the release of GHRH as well as the HGH release response to GHRH stimulus; ghrelin binds to somatotrophs to stimulate HGH secretion. Insulin-like growth factor-1 also acts to inhibit HGH by both directly inhibiting somatotrophic HGH release and indirectly through synergistically increasing the release of somatostatin. Additionally, HGH will negatively feedback into the hypothalamus, thus decreasing GHRH production. The net effect of this regulatory mechanism produces a pulsatile release of HGH into circulation that varies hourly hyperglycemia also inhibits GH release, and hypoglyc stims; androgens and oestrogens stim, hence it reaching highest levels during puberty, sleep and exercise also inc its release and insulin/cortisol decrease its release direct effects of HGH on the body are through its action on binding to target cells to stimulate a response. The indirect effects occur primarily by the action of insulin-like growth factor-1, which hepatocytes primarily secrete in response to elevated HGH growth: Chondrocytes and osteoblasts receive signals to increase replication and sarcomeres hypertrophy as well as other organs growing to thus allow for growth in size via HGH’s activation directly, T4 is also converted more to T3, IGF1 increases anabolism, cell rep/div, and inhibs apoptosis metabolic: mainly through IGF1,cells enter an anabolic protein state with increased amino acid uptake, protein synthesis, and decreased catabolism of proteins. Fats are processed and consumed by stimulating triglyceride breakdown and oxidation in adipocytes, thus raising FFAs. Additionally, HGH suppresses the ability of insulin to stimulate the uptake of glucose in peripheral tissues and causes an increased rate of gluconeogenesis in the liver, leading to an overall hyperglycemic state Due to the pulsatile nature of HGH levels found in the blood, conventional measurements of serum HGH are almost useless because the values may vary from undetectable to extremely high depending on environmental stressors and conditions. If a clinician suspects HGH deficiency, it is best to evaluate IGF1

Question 72

acromegaly (17 sx, 7 complications, most common causes and misc other causes (how to tell these from main cause), initial screen and test to further suggest it + 5 other ixwhich organs need to be checked/monitored?), 3 mx options)

Answer 72

high GH exposure leading to enlarged hands, feet, nose, lips, ears and general thicker skin; swollen vocal cords giving deeper voice and slower speech; macroglossia and pronounced jaw and brow; headaches which may be severe; hyperhidrosis, carpal tunnel, skin tags; spacing of teeth; hyperpigmentation, more hair growth complications: cardiomyopathy then heart failure; hypertension, sleep apnoea, DM 2; thyroid nodules, colonic polyps, arthropathy usually results from a pituitary adenoma, which may develop over many years or quite rapidly; tumours of pancreas, lungs, ovaries, and adrenal glands can also cause (but 98% of cases are pitu adenoma) and in these cases GHRH often raised unlike if pitu cause (though rarely the other tumours can make GH itself); pitu can still enlarge in these cases, so analyse the removed specimen in case there's another tumour present IGF1 pos as initial screen and then GH suppression test with oral glucose and GH levels still normal/high suggests acromeg assess other pitu hormones, and MRI to image adenoma; CT scan if indicated to look for other tumour causing ectopic GH/GHRH; echo and ecg to check on heart, and test visual fields inc'd risk of thyroid and CR cancer so regular colonoscopy transsphenoidal surgery, radiotherapy as adjunct or if surgery not poss; somatostatin eg octreotide are viable alt to surgery

Question 73

acromegaly signs/symps, investigations, management

Answer 73

MSK Arthralgia/arthritis Cardiac Hypertension, cardiomyopathy Respiratory OSA Endocrine Diabetes mellitus, hyperprolactinaemia Physical Prognathism, acromegaly, macroglossia Hyperhydrosis, frontal bossing Serum IGF-1 & prolactin OGTT Pituitary MRI Trans-sphenoidal surgery Octreotide

Question 74

hormonal control of growth at different ages - growth velocity

Answer 74

growth rate of a child varies being highest during fetal life (fastest growth occurs in utero and especially between gestational weeks 20 and 24 when the growth rate is 2.5 cm per week) and infancy, slowing down during childhood, accelerating during puberty, and then ultimately ending when adult height has been reached by the end of the adolescent period During the first year of life, growth rate is still high averaging 25 cm per year. Thereafter, growth rate slows down to about half in the second year - nutrition is biggest influencer of growth at this point age 2 to puberty more steady and nutrition has less influence on growth during this period whereas hormonal regulators more important height velocity is usually 6–8 cm per year from 2 to 6 years, after which it slows down somewhat. Between 6 and 8 years, adrenarche occurs. There is an increase in anabolic hormones released by the adrenal glands leading to a small transient growth spurt Growth during Puberty During puberty, a growth spurt occurs when girls and boys increase their heights by 20–25 and 25–30 cm, respectively. In boys, signs of puberty appear somewhat before this growth spurt begins whereas in girls it starts in parallel. The growth starts distally in the extremities with hands and feet. Then arms and legs will grow and lastly the spine. The maximum growth rate, the so-called peak height velocity (PHV), occurs during later stages of puberty at around 12 years in girls and 14 years in boys After PHV, there is a steep decline. Typically menarche occurs in girls after PHV, and they grow for approximately 2 more years. However, there is a large individual as well as ethnic variation in the timing and tempo of pubertal development and growth By the end of puberty, the growth plates become narrower and eventually close. This process is stimulated by increased levels of circulating sex steroids as normally found during puberty. When all growth plates have been closed, no further growth can take place and adult height has then been achieved.

Question 75

physiology of growth - growth plate, GH and IGF1

Answer 75

Long bones are formed through a process called endochondral ossification. It involves mesenchymal stem cell condensation and the development of a hyaline cartilage model. In the shaft of this model, a primary ossification center forms and gets vascularized, and thereafter secondary centers of ossification form in both ends of the long bones, the so-called epiphyses. After birth, further longitudinal bone growth takes place in a thin remnant of cartilage localized between the primary and secondary ossification centers called the growth plate the resting zone is made up of stem-like cells, waiting to be recruited to the proliferative zone under the influence of the growth hormone (GH) where they undergo mitosis and get stacked in columns. They then reach the hypertrophic zone where they undergo hypertrophy and secrete extracellular matrix proteins and undergo apoptosis giving rise to lacunae which are invaded by bone-forming cells. This process causes elongation of the diaphysis GH is mainly regulated by two peptides secreted by the hypothalamus, GH-releasing hormone and the inhibitory hormone somatostatin. It is also stimulated by ghrelin produced in the stomach, and insulin-like growth factor 1 (IGF-1) exerts negative feedback control GH stimulates longitudinal bone growth both via direct stimulation of the growth plate and indirectly via IGF1 - serum conc of both may be up 3x during puberty Circulating IGF-1 is mainly produced in the liver but IGF-1 is also ubiquitously expressed in many other tissues such as fat and muscle. IGF-1 is also produced in the growth plate, thereby acting in a paracrine/ autocrine fashion under the influence of GH; it stimulates linear growth in the growth plate via increased chondrogenesis (proliferation, hypertrophy, and ossification); IGF-1 is an anabolic hormone-stimulating protein synthesis through the uptake of amino acids from the circulation. It also increases bone mineral density and muscle mass and causes lipolysis GH deficiency appears to mainly affect postnatal growth whereas IGF-1 deficiency affects both prenatal and postnatal growth Insulin is important for both fetal and childhood growth - via increasing IGF1 release and via directly activating the IGF1 receptor. Insulin and IGF-1 are both strongly connected to nutrition. A high intake of protein and minerals has been found to lead to a 25% increase in serum IGF-1 concentration

Question 76

physiology of growth - thyroid, sex and misc hormones, and interaction with health state

Answer 76

thyroid hormone function involves chondrocyte maturation, cartilage matrix synthesis, mineralization, and degradation. Hypothyroidism during childhood and adolescence causes a delay in skeletal maturation and growth arrest. Thyrotoxicosis, on the other hand, advances skeletal maturation and causes growth acceleration but due to early fusion of the growth plates, the outcome will be a decreased final height Estrogens play an important role for growth in both girls and boys. In girls estrogens are mainly produced by the ovaries. There is also estrogen production in the testes although the main production in boys occurs in peripheral tissues by aromatizing androgens; Estrogens affect growth by regulating the effect of GH, and its secretion by reducing IGF-1-mediated negative feedback; they also stimulate osteoblasts and inhibit osteoclasts; although stimulating growth during puberty, they are also the factor that finally leads to growth plate fusion at the end of puberty in both females and males in boys testosterone has been found to lead to a stimulatory effect of GH on IGF-1 secretion leptin appears to stimulate GH secretion by acting on the hypothalamic level as well as having a local effect in the growth plate by stimulating chondrocyte proliferation and cell differentiation growth suppression due to chronic illness is due to: malnutrition, glucocorticoids (endogenous and exogenous) which inhibit GH secretion, and downregulate GH receptors in the liver thereby inhibiting IGF activity, as well as causing apoptosis in the growth plate and suppressing chondrocyte differentiation; cytokines, which act synergistically by decreasing chondrocyte proliferation and hypertrophy as well as increasing apoptosis as well as suppressing levels of IGF1 and sex steroids; catch up growth after stopping steroids is possible to a partial degree malnutrition reduces growth due to: less insulin, IGF1, and leptin activity + more FGF21 production which directly suppresses chondrogenesis; also possibly due to lower levels of Ca, phos, and vit D GH is important in first 6 mo - GH levels are high in mid-gestation and at birth, then fall sharply for the first few weeks and more slowly over the next few months reaching pre-pubertal levels by around the age of 6 months; nutrition is also key at this stage

Question 77

child short for age, w constipation, recently less sociable, gaining weight, poor school performance

Answer 77

may also be intolerant of cold, have a goitre it's juvenile hypothyroidism, which doesnt have affect on intellect like congen pale, dry skin; periorbital puffiness consider hashimoto (associated with down, turner, klinefelter syndromes + SLE and other autoimmune disorders) consider other causes of hypothyroid as for adults

Question 78

abnorms of growth (common causes, normal growth inc final height estimate)

Answer 78

infancy: commonly nutrition childhood: commonly GH puberty: commonly GH or sex steroids average rate is 5-7cm per year (7-12 per year around puberty); growth velocity charts detect slow-down before normal growth chart for boy: mid parental height is mothers + 13, then mark fathers, midpoint between these and 3rd to 97th percentile within 10cm of this for girl: fathers -13cm then mothers and midpoint between as above

Question 79

causes of growth abnorm (2 normal variants and how to tell apart, 2 nutritional, 6 chronic disease inc how one age is, 5 endocrinopathies inc affect on bone age and appearance [13 things for one of these], 2 related to gestation, difference in appearance for 2 kinds of dwarfism, 4 common dysmorphic syndrome causes)

Answer 79

normal variants: familial (parents are short - no delay for age, following centile), constitutional (children born with normal weight/length and during first few years rate slows then height returns to normal w bone age 1-4 yrs behind chronological age, puberty oft delayed, may have pos FH of similar (or FH of delayed menarche), diagnosis of exclusion, then normally catches up eventually) nutritional disorders (malnut or malabsorb) chronic disease (inc CKD, RTA, heart failure, chronic severe asthma, IEMs; bone age delayed, progressive deviation from chrono age as disease untreated) endocrinopathies: hypothyroid and GH def (delay in bone age), latter begins deviation after 5mo w doll like face and poss hypoglyc; cushing and precocious puberty (advanced bone age, inc'd initial growth velocity but premature fusion of physis), hypopitu (short, round face, saddle nose, short neck, small larynx w high pitched voice, small hands/feet, delayed sexual dev, microphallus, fine scalp hair and maybe loss of body hair), pallor (loss of MSH activity of ACTH), and hypoglyc - tumours here may cause bitemp hemi and hydroceph due to 3rd ventricle obstruction children born IUGR or premie dysmorphic children: turner, noonan, PW, down syndrome etc as well as achondroplasia (will see normal sized trunk but small limbs) or spondyloepiphyseal dyplasia (short trunk and normal limbs, diff is spinal irradiation)

Question 80

insulin stress/tolerance test (for what three things, 2 steps (inc 3 things measuring and how long for, how the hormone should change)

Answer 80

for GH, cortisol, prolactin problems inject insulin measure glucose/GH/cortisol at 15, 30, 45, 60, 120 mins peak GH <7 suggests def, >15 exclude cortisol levels should double

Question 81

hormone effects on bone age - excess and def of cortisol, thyroxine, GH, androgens

Answer 81

cortisol excess delays, def normal thyroxine excess advances and def delays GH excess is normal and def delayed androgen excess considerably advances, def is normal

Question 82

GH def how presents: at birth (3sx), infants/children (3 sx inc age when particularly noticeable), main ix + 3 other blood ix, imaging, genetic testing (2 egs of syndromes), one other imaging test you'd want, mx

Answer 82

Growth hormone deficiency may present at birth or in neonates with: Micropenis (in males) Hypoglycaemia Severe jaundice Older infants and children can present with: Poor growth, usually stopping or severely slowing from age 2-3 Short stature Delayed puberty give glucagon, insulin or something, see if poor GH secretion in response Test for other associated hormone deficiencies, for example thyroid, androgens, cortisol MRI brain for structural pituitary or hypothalamus abnormalities Genetic testing for associated genetic conditions such as Turner syndrome and Prader–Willi syndrome Xray (usually of the wrist) or a DEXA scan can determine bone age and help predict final height daily subcut GH injections - note GH also known as somatropin and this is what the med might well be called

Question 83

diabetes insipidus causes (inc prim poly)

Answer 83

primary polydipsia, cranial, nephro first is due to habitual or compulsive drinking, often normal MRI and due to affective disorder but can be response to dry mouth in eg sjogren syndrome and need anticholinergics, or due to structural hypothal damage from sarcoid, TB mening, head injury, tumours cranial due to relative def in ADH due to genetic/congen, head injury eg pitu surgery, craniopharyngoma, mets from breast or lung, germinoma, very rarely a pit adenoma; inflam eg sarcoid, histio, autoimmune hypophysitis; aneurysm, infarction or sheehan syndrome nephro may be genetic*, drug induced (mannitol, lithium*), amyloidosis, hypercalc* or hypokal*, PCKD, tract obstruction, pyeloneph

Question 84

water deprivation test

Answer 84

also known as the desmopressin stimulation test. This is the test of choice for diagnosing diabetes insipidus. Polyuria (excessive urine production) Polydipsia (excessive thirst) Dehydration Postural hypotension Hypernatraemia Low urine osmolality High serum osmolality

Question 85

polyuria clinical process

Answer 85

exclude metabolic cause (hypercal, hypokal, hyperglyc) exclude drugs; paired morning plasma and urine osmol; high urine osmol, normal plasma excludes DI; low urine low plasma likely prim polydip; low urine normal or high plasma possibly cranial or nephro DI water dep or desmopressin test prim DI then avoid excessive fluid intake with graded reduction, try alt measures to ease thirst, dont give desmo; if central then give desmo and treat underlying cause; if nephro treat cause, consider trial of high dose desmo or thiazide diuretic or nsaid

Question 86

polyuria/dipsia 8 diffs

Answer 86

DM, DI, RTA (hypokal causes), any other cause of hypokal, hypercalcemia, chronic kidney disease, relief of prolonged urological obstruction, and psychogenic polydipsia

Question 87

DI and AKI (inc also some central and renal causes of DI)

Answer 87

DI normally has polyuria/dipsia freq and nocturia + nocturnal enuresis in kids but if drinking not kept up with, or additional stress from eg fever or diarrhoea, then dehydration will set in; may even see dehydration sx like constipation, vomiting, even venous thrombosis, w good urine output; may dev an AKI will need fluid dep and desmopressin test note central causes inc histiocytosis X and AD familial inheritance note nepho causes inc reduction in medullary interstitium tonicity after a prolonged polyuria in ef post obstructive neph, interstitial nephritis, fanconi syndrome

Question 88

pituitary dysfunction

Answer 88

usually benign, usually curable adenoma > prolactinoma > GH > ACTH > TSH > LH/FSH; GH secretion giving gigantism or acromegaly, ACTH producing may give cushing's; non-functioning tumours cause effect only by effect on surrounding structures (bitemp hemianopia); carcinomas only 0.1-0.2%; retroorbital headache (may present like cluster headache) or bitemp, sudden catastrophic if pitu apoplexy; hydrocephalus if large; other visual field defects may occur, extension into hypothal may cause disreg of appetite, body temp, thirst; vertigo, nausea may also present with hypopitu (order LH > GH > TSH > ACTH) so infert, oligo/ameno, dec libido or ED, impaired growth or loss of muscle mass PFTs, MRI, then surgery (radiotherapy if some secretion remains after tumour) PFTs: give small amounts of TSH, GnRH, measure IGF-1 (low if GH low) or insulin tolerance test: check blood for GH, cortisol, glucose; fast acting iv insulin injection; check bloods again at 30, 45, 60, 90, 120 mins, see if GH and ACTH (so cortisol) secreted

Question 89

pituitary function tests in children

Answer 89

Dynamic tests are needed for hormones which vary through the day If growth hormone sampling is included in the test the patient should fast overnight and on the morning of the test have only water to drink and be relatively "rested" prior to admission. Other tests often do not need fasting, but check if unsure. The child is usually admitted as a day-case and should come to the ward for 08:00 hrs. A needle, (21G Butterfly or cannula) is inserted into a vein and fixed into position for the duration of the test. A three-way stopcock is attached to the needle, which is kept patent with heparinised saline. A ligature is applied proximal to the needle and fasting samples collected A meal must be eaten and retained before discharge home. may collect any or all of GH, TSH, FSH, LH, cortisol, ACTH, testosterone/oestradiol, prolactin at base; and then the first 5 also at 20 and 60 minutes, and GH also at 90, 120, and 150 minutes; after time 0 different things can be given to stimulate, in a combined ant pitu function test this could be clonidine + TRH + LHRH low dose synacthen test can be combined with above taken at t0,30,60 with synacthen given at t0; If atypical adrenal hyperplasia is suspected, in addition take blood for 17 OH progesterone, androstenedione and DHEAS at 0, 30, 60; also combine with a midnight cortisol level to give diurnal variation; note ACTH goes in chilled EDTA and needs to go straight to lab with advanced notice while others can go in lithium heparin bottle glucagon stim test taking GH levels every 30min for 3 hours after giving IM glucagon at t0 for GH deficiency; clonidine is an alternative to this, sometimes preferred because it is taken as a tablet glucose tolerance test is collect samples for glucose, insulin +/- GH at t0,30,60,90,120; test for glycosuria; oral glucose solution given at t0 (test glucose and GH for tall stature, glucose for DM, and all 3 for insulin resistance) water deprivation test: weight before and hourly during; Calculate 5% of the body weight, subtract it from the starting weight and discontinue the test if the patient's weight falls below this level. Terminate the test at any time if there are clinical signs of serious dehydration (or plasma osmolality rises) day one - Normal diet and fluid intake. Send each specimen of urine passed for measurement of volume and osmolality - at least every 4 hours. Note the collection time on the container. If the osmolality of any urine is greater than 700mmol/l, no further testing is required. day two - after first feed, no more food/fluid from 08.30; Collect blood for paired plasma osmolality and sodium and urine osmolality and sodium 2 hourly); Terminate the test as soon as any urine osmolality is greater than 700mmol/l, or if there are clinical signs of significant dehydration, or if sodium or osmolality rises significantly; If > plasma osmolarity rises more than 295 and urine osmolarity less than 300 then proceed to DDAVP test. Once 0.125micrograms DDAVP has been given slowly replace total of fluid lost from urine output during the test. Ensure the child does not have extra fluids; Do not allow off the ward until U&Es, plasma and urine osmolarity have normalised. This will happen if kidneys are functioning normally. Ensure parents/carers understand the importance of slow re-introduction of fluids, until DDAVP effect wears off – approx. 8 hours time. (Limit fluid intake to 500ml for 8 hours post IM DDAVP)

Question 90

pitu apoplexy (inc 6 sx, causes, ix, mx)

Answer 90

pitu apoplexy: usually into pitu adenoma which usually hasnt been diagnosed; sudden headache +/- worsening visual field defect or double vision, then acute panhypopitu, notably adrenal crisis; oft nausea and vomiting, sometimes meningism, may have dilated pupils due to CNIII compres adrenal crisis: hypotens, hypogly, abdo pain; seems to just happen in these tumours and others, perhaps treating prolactinoma may precipitate but generally idiopathic, though low incidence MRI, LP (rule out SAH/mening), basic bloods inc pitu tests, visual field testing; treat adrenal crisis, refer to neurosurg if seeing a sag MRI quite likely due to pitu adenoma

Question 91

hypopitu (types, causes, tests - inc basal, dynamic, and indirect - treat) and hyperpitu (types)

Answer 91

hypopituitarism: dec secretion of 1+ of the 8 pitu hormones, if most or all then panhypopitu; LH/FSH def give oligo/amen, infert in women, men lose facial/scrotal/trunk hair, muscle mass, get anemia; dec libido, osteoporosis risk, and delayed puberty in children GH def gives dec muscle mass, central obesity, impaired attention/memory, and in kids growth retardation/short stature ACTH def gives adrenal insuff (and in kids this can cause failure to thrive, delayed puberty TSH def gives hypothyroid prolactin def may give inability to breastfeed ADH def gives central diabetes insipidus, and may be masked if also ACTH def with symptoms once cortisol replaced, this is bc cortisol helps maintain blood pressure, so if its levels are low then BP falls which triggers vasopressin release (by angiotensin inc, ANP dec, and cortisol directly inhibs vasopressin release) oxytocin def has few symptoms, maybe abnormal social dev may get general symptoms from cause eg headache, visual field defects most cases due to pitu adenomas compressing normal tissue, or comp from nearby tumour like craniopharyngioma, meningioma, glioma etc may also be brain abscess, meningitis/enceph, sarcoidosis or haemochromatosis, sheehans or pitu apoplexy, radiation (mainly GH/FSH/LH), also TBI, SAH, rare congen hypoplasia; causes treated as normally would, sympto tumours get transsphenoid surgery may need hormone replacement therapy; must correct cortisol def before thyroid otherwise get adrenal crisis basal tests for TSH, FSH/LH, prolactin; dynamic tests for ACTH, GH; no adequate test for ADH but indirect; low morning cortisol or low IGF1 (esp in context of others being low) then insulin suppression test (give insulin, GH or ACTH should rise and if doesnt confirms, for ACTH do ACTH stim test with synthetic ACTH to confirm by measuring adrenal response - if primary no response, if early sec response and if late sec no response as adrenals atrophy over time, will see low basal ACTH levels); fluid dep and desmo for di insip nonsec most common and may cause hypopitu and symptoms above, or hyperprolac prolactinoma most common secretory one and treated with bromocriptine (but raised prolactin more often nonsecretory compressing pitu stalk relieving the dopamine inhibition of tumour, cabergoline alt to bromocript); GH may give acromeg or gigantism; ACTH cushings hyperprolac can give irregular, heavy periods, lactation in men and women, gynaecomastia, ED and dec libido, infertility, long term osteoporosis

Question 92

misc endocrine tumours

Answer 92

prolactinoma: type of pitu adenoma; amenorrhoea, galactorrhoea, loss of axillary/gonad hair, hypogonadism, gynaecomastia, ED; mass effect symptoms bromocriptine (DA agonist) shrinks tumour in 80% cases, if fails then surgery insulinoma: usually benign beta cell tumour, hypoglycaemia (symptoms improved for a bit by eating); headache, lethargy, diplopia or blurred vision, seizures or coma if bad; once hypoglyc confirmed, CT imaging and then surgery MEN: multiple endocrine neoplasia type 1; tumours of parathyroid glands (95% time), gastroenterohepatic tract (30-80% eg insulinoma or carcinoid tumour, may also get this in lung), ant pitu (15-90%); sometimes adrenocortical or thyroid, lipomas, meningiomas etc; autosomal dom; many benign but 1/3 pts will die from malignancy related to MEN1

Question 93

MEN features in each type (3:3:4)

Answer 93

MEN is autosomal dominant MEN1: Parathyroid (95%): hyperparathyroidism due to parathyroid hyperplasia (hypercalc commonest presentation) Pituitary (70%) Pancreas (50%): e.g. insulinoma, gastrinoma MEN2: Medullary thyroid cancer (70%) Parathyroid (60%) Phaeochromocytoma (ret oncogene mutation) MEN3: Medullary thyroid cancer Phaeochromocytoma Marfanoid body habitus Neuromas

Question 94

phaeochromocytoma (what cell type, 4 classic sx, 4ix, mx x4 inc order of meds)

Answer 94

Neoplasm of the chromaffin cells of the adrenal medulla Classically presents with: Diaphoresis Palpitations Headaches Hypertension Symptoms are classically episodic Serum and urinary metanephrines and normetanephrines CT-Abdomen Chromogranin A Medical therapy Alpha blockade (hypertension) before beta blockade (arrhythmias) - as unopposed alpha action can lead to hypertensive crisis Fluids given due to catecholamine induced volume contraction Surgical therapy – adrenalectomy

Question 95

phaeochromocytoma (derived from what embryological structure, 2 associated syndromes and how often, 13 sx, how long paroxysms last, main ix and 5 sources of false positives, what b blockers can do, 3 other ix, 2x mx options, another tumour that can secrete catecholamines, diff in secretion between adrenal and extraadrenal sites)

Answer 95

derived from neuroectoderm (hence secrete catecholamines) 10% malignant, 10% associated with syndromes like NF2 or MEN II htn (may be sustained or intermittent), weight loss, headaches, chest pain, attacks of swating/flushing, tachy/palps, polyuria/nocturia, glycosuria and impaired glucose tolerance also anixety, nausea, behavoural change, postural hypotension if chronic (symp response blunted) paroxysms usually last 15-45mins 24h urinary analysis for VMA and HMMA; FP in stress, illness, caffeine, bananas/vanilla consumption, b blocker use *b blockers can cause paradoxial rise in BP* plasma catecholamines, CT scan, MIBG surgery oft cures, alpha then beta blockade in mean time neuroblastoma can also secrete catecholamines but to lesser extenet adrenal sites make more adr, extraadrenal sites (10% of cases) more noradr

Question 96

paraneoplastic syndromes (inc l/e, polyc)

Answer 96

paraneoplastic: cushing (small cell lung cancer, pancreatic, some neural); SIADH (small cell, neuro), hypercalc (SCC lung, multi myelo, breast, renal, bladder, leukaemia/lymphoma, SCC elsewhere), lambert-eaton (small cell), acanthosis nigricans (gastric, lung, uterine), polymyositis (NHL, lung, bladder), dermatomyositis (lung, NHL, breast, stomach, colon, ovarian, pancreatic), polycythemia (renal, HCC) HPOA with SCC and ACC of lung

Question 97

genital and gonad development (dev of ridges, 2 ducts, what the gamete stem cells do, what is SRY and 2 cells it leads to [+what each of these produces and the role of each product)

Answer 97

genital system like kidney mainly from intermediate mesoderm, urogenital ridge begins ~week 4 and genital ridge on medial side ~weeks5-6, indifferent gonad stage weeks 7-8 where male/female ridges and gonads the same wolffian duct associates with genital ridge initially, then paramesonephric/mullerian ducts form by invagniation of coelomic epithelium medial to mesonephric duct with the 2 coexisting in indifferent stage in both sexes stem cells of the gametes, during week 6 migrate through dorsal mesentery into the genital ridges to initiate sex-specific gonadal differentiation; sex of gonad determined by sex of ridge, not sex of germ cells SRY on Y chromosome critical, discovered by examining XX males (1 in 20,000) where SRY locus was translocated onto X chromosome; SRY encodes DNA/RNA binding protein of 223 aa that acts as master switch in controlling battery of genes responsible for male sex determination such as Sox9, triggers dev of Sertoli and Leydig cells in testis which produce gonadal hormones MIS and androgens respectively which signal to rest of body to stimulate male sexual differentiation (androgens) and repress formation of female internal genitalia (MIS)

Question 98

genital and gonad dev - dev of female genital system inc what the paramesonephric ducts form, what gartner's duct is, where does remainder of vagina dev from, common malform that can happen here (inc 3x complications it gives), femal external genital dev, common problem with male external genitalia dev

Answer 98

paramesonephric ducts enlarge, fusing with each other inferiorly at urogenital sinus to form fallopian tubes, uterus and top of vagina; gartner's duct is remnant of wolffian duct in females, may develop a cyst uterus from medial fusion of inferior paramesonephric ducts on midline with upper 1/3 of vagina from PMD and remainder from urogenital sinus (cloaca - endoderm); failure of correct fusion generates most common malformations eg didelphyd uterus where it remains bicornate (2 vaginas kinda); higher incidence of spontaneous abortion in first trimester, infertility, preterm labour females: by 10 weeks, genital tubercle begins to bend caudally to become clitoris with side portions of genital swellings enlarging to become labia majora and urethral folds persisting to become labia minora males: requires testosterone, made from dihydrotestosterone by 5 alpha reductase with deficiency resulting in feminisation until puberty when growth spurt associated with increased testosterone provokes rapid sexual maturation: guevadoces

Question 99

errors in sex determination (primary intersex 2 causes, secondary intersex 4 presentations)

Answer 99

primary intersex: anomalies of gonad, true hermaphroditism with testis on one side and ovary on other, rare and due to early unilateral somatic mosaicism; hermaphroditism more commonly gonadal dysgenesis with mixed testicular and ovarian tissues within gonad caused by errors in genetic sex determination, usually mutation, deletion or transloation of SRY together with chromsome abnormalities secondary intersex due to breakdown in signalling between soma and gonad: testicular feminisation/androgen insensitivity syndrome: due to defects in androgen receptor, complete is testis + female soma in 0.005% births, partial if poorly developed male soma 0.01% births congenital adrenohyperplasia micropenis in 0.002% births, hypospadias (urethra opens in vental penis or in vagina) both often idiopathic or associated with low androgen levels, due to failure in urethral fold fusion

Question 100

descent of testis

Answer 100

gubernaculum is column of matrix running from indifferent gonads through inguinal region; predates myoblasts in ant abdo wall so its presence forms inguinal canal; isn't contractile but provides pathway for testes to move along; should descend around time of birth but highly retractile in neonates; as testis descends ensheathed by peritoneum, the processus vaginalis, which should obliterate to tunica vaginalis but may remain patent giving congenital inguinal hernia or, if incomplete, a hydrocele

Question 101

genetic sex determination

Answer 101

three components dependent on chromosomal constitution of individual with sperm carrying y or x and egg an x; normally XY=male, XX=female; abnormalities/imbalances alter this simple rule; determination of gonadal sex depends on genetic sex (ie chromosomes) of indifferent gonad; sex of gonad affects somatic sex through paracrine and endocrine molecules; so genetic sex (y present/absent) shapes gonadal sex (testis, ovary) shapes somatic sex (penis etc vs uterus etc) shapes brain sex (constant activity of HPG axis vs cyclical activity of HPG axis) SRY: Sex determining Region of Y, encodes DNA/RNA binding protein of 223aa, with 79aa HMG (high mobility group) box nucleic acid binding domain; by binding it affects nucleci acid stability/accessibility; found from studying of sex reversed XY mice; affects expression of other genes (eg SOX9) involved in gonad differentiation, though precise mechanisms not yet understood; handful of other genes found which cause sex reversal when mutated, many of these believed to be involved in SRY pathway; encodes testis determining factor; SP1, WT1, SF1 all bind to promoter; TDF complexes with SF1 and binds to TESCO (testis specific enhancer of SOX9 core), upstream of SOX9 start site; SOX9/FGF9 +ve feedback needed to make enough SOX9 for sertoli cell diff; Swyer syndrome if Sry to X chromosome in meiosis so XY but dev as a girl, no functional ovary though so no puberty - treated with hormones

Question 102

foetal sexual differentiation (when and how genital ridges formed, formation of primitive sex cords and what they become, role of SOX 9)

Answer 102

genital ridges form during 5th/6th weeks and are colonised by primordial germ cells migrating from extraembryonic mesoderm close to yolk sac coelomic epithelium proliferates to make primitive sex cords which are bipotential (both sets of ducts - indifferent gonad stage) - female sex cords become ovarian follicles, male become rete testis and sertoli cells SOX9 initiates FGF9 (important for sertoli cell dev - knockouts have MtF sex reversal) expression, which +ve feedback to increase SOX9; Sry only expressed transiently; SOX9 does other downstream targets too like MIS

Question 103

foetal ducts/gonads diff (3 things that arise from genital ridge under SRY influence - what 2 of these things make and how each interacts with the ducts, if no SRY what happens, persistent mullerian duct syndrome 5 sx)

Answer 103

PGCs arrive, and due to SRY expression in ridge, ridge diffs to testis, sertoli (cord cells - form seminiferous tubules) and leydig cells (stromal cells) (latter two first); sertoli cells make mullerian inhibitory substance MIS to destabilise paramesonephric ducts, and leydig cells make testosterone to stimulate formation of mesonephric ducts (form vas and associated parts) no SRY, stromal cells diff to form ovarian follicles in absence of MIS, diff'd down default pathway; mesonephros degenerates above metanephros due to absence of androgens and paramesonephric ducts form oviduct, uterus and upper part of vagina, the two ducts fusing in midline and inferiorly with urogenital sinus in persistent mullerian duct syndrome (usually from MIS mutation), small underdeveloped uterus/oviducts may be present in otherwise normal male: mullerian/wolfian ducts may intertwine leading to non-functional vas, cryptorchidism and infertility and uterus may herniate into inguinal canal

Question 104

external genitalia (what hormone + enzyme) and mental sex differentiation

Answer 104

former driven primarily by dihydrotestosterone, produce from testosterone by action of 5 alpha reductase present in local tissues, with absence of this enzyme leading to female genitalia (guevodoces people) evidence of diff between male/female brains: structural (size of some bits), chemical (levels of transmitters), physiological (cyclicity, metabolism), psychological (gender, aggression) and cognitive (verbal fluency, spatial ability); evidence from animal studies that testosterone to females within first few days of birth suppresses hypothalamic cyclicity and oestrous cycles; experiences and hormones at embryo, neonate, puberty and adult stages result in phenotypic sex differences

Question 105

AIS - chromsomes, phenotype, gonads and hormones, how androgens normally bind and affect transcription 5ar deficiency: gonads, hormone problem, appearance at birth and change over time

Answer 105

ais: XY with overtly normal sexual appearance (look like a woman), normal testes and androgen production and no uterus, fallopian tubes or upper vagina; androgens like DHT diffuse into cell, bind androgen receptor which translocates to nucleus, dimerises and binds regulatory sequences in promoters of androgen responsive genes, mutations stop this 5ar/guevedoces: normal testes but unable to make DHT as enzyme lacking in urogenital sinus/external genitalia; minimal virilisation at birth (could be girl kid) then extreme virilisation when puberty hits and androgen levels rise; urethra opens near anus; majority exhibit heterosexual male behaviour and orientation

Question 106

androgen insensitivity syndrome

Answer 106

In a female full-term infant, inguinal hernias should prompt investigation for a possible androgen insensitivity syndrome typical presentation for complete androgen insensitivity syndrome is either primary amenorrhoea in adolescence, or inguinal swellings in an infant. A female adolescent with the disorder has breast development and a pubertal growth spurt at the appropriate age, but no menses. Development of oestrogen-dependent secondary sexual characteristics occurs as the result of excess aromatisation of androgens. Pubic and axillary hair is usually absent or can be present in sparse amounts In infancy, complete androgen insensitivity syndrome presents as an inguinal hernia or labial swelling containing a testis in an apparently female infant. karyotyping or a biopsy of a gonad within the hernial sac should be done; uterus, cervix, and proximal vagina are absent in complete androgen insensitivity syndrome because of the action of antimüllerian hormone produced by Sertoli cells of the testis; vagina varies from a dimple in the perineum to normal length, but is always blind-ending Serum testosterone concentrations are either within or above the normal range for men and boys and luteinising hormone (LH) concentrations are inappropriately increased; Concentrations of follicle-stimulating hormone and inhibin are generally normal. Excess testosterone is produced and peripherally aromatised to oestrogen which, together with LH-induced direct secretion of testicular oestrogen, results in serum oestradiol concentrations higher than those noted in men and boys but lower than those reported in women without complete androgen insensitivity syndrome differential diagnosis for complete androgen insensitivity syndrome in female adolescents includes other causes of primary amenorrhoea clinical presentation of partial androgen insensitivity syndrome depends on the degree of responsiveness of the external genitalia to androgens. The typical phenotype is micropenis, severe hypospadias (perineoscrotal), and a bifid scrotum that might contain gonads. Occasionally, the appearance of the genitalia is more consistent with complete androgen insensitivity syndrome, apart from the degree of clitoromegaly; Sequencing of the androgen receptor gene to identify an abnormal receptor is needed for a firm diagnosis of partial androgen insensitivity syndrome. If possible, an in-vitro functional assay should be done to confirm pathogenicity Care needs to be individualised, flexible, and holistic. Management is dependent wholly on a multidisciplinary team. When complete androgen insensitivity presents in infancy, early gonadectomy with puberty induction later can be done, or gonadectomy can be delayed until early adulthood - if gonadectomy is done in childhood, puberty should be induced with oestrogen replacement

Question 107

gonadal mosaicism

Answer 107

Mixed gonadal dysgenesis (MGD) is a term used to describe individuals who have chromosomal mosaicism as well as dysgenetic gonads and variable internal and external reproductive anatomy 45,X/46,XY mosaicism, also known as X0/XY mosaicism and mixed gonadal dysgenesis is a mutation of sex development in humans associated with sex chromosome aneuploidy and mosaicism of the Y chromosome; clinical manifestations are highly variable, ranging from partial virilisation and ambiguous genitalia at birth, to patients with completely male or female gonads. Most individuals with this karyotype have apparently normal male genitalia, and a minority have female genitalia, with a significant number of individuals showing genital abnormalities or mixed sex characteristics Wide phenotypic variation exists for patients with a postnatal diagnosis of 45,X/46XY ranging from phenotypic males with cryptorchidism or hypospadias, phenotypic females with gonadal dysgenesis, and the more common presentation of one testis, one streak gonad and Mullerian structures. Interestingly, 90–95% of patients with a prenatal diagnosis of 45,X/46,XY will be phenotypically normal male Germ cell tumors (GCT) are at an increased prevalence in individuals with a DSD where a Y chromosome is present, and the risk may be higher depending on how much Y material is present shared decision making and MDT management is needed for these patients some management guidelines divide patients into three groups and treatment strategies: 1. Mild undervirilization where orchidopexy, biopsy and post-puberty surveillance with self-exams every three months; annual ultrasounds are performed; 2. Ambiguous genitalia for which there is a lower threshold to perform gonadectomy and; 3. Female phenotype where elective gonadectomy is recommended.

Question 108

management of a baby born with ambiguous genitalia

Answer 108

A child with a suspected DSD may present with one or more of these features: a bifid scrotum bilateral undescended testes clitoromegaly (phallus >0.8mm in an apparent female infant) micropenis (phallus <2cm stretched penile length in an apparent male infant) proximal (penoscrotal or perineal) hypospadias distal or midshaft hypospadias in combination with any of the above features If a patient has hypospadias that is not penoscrotal or perineal and no other features of concern are present, no immediate action is required. Advise the parents against circumcision until after surgical review and refer to the Urology Team; A good urinary stream should be observed prior to discharge If any of these features are detected at delivery and there is uncertainty about the sex of the baby, explain to the parents that it is not possible to tell whether their infant is a girl or a boy. Do not guess the sex, or even voice your suspicions neonatal consultant on call should be informed about the baby and they should be discussed with endo reg on call blood sample for QF-PCR for the Y chromosome and micro-array to confirm above ang vie more info on chromosomes urgent pelvic USS can identify the presence or absence of Mullerian structures and help with sex assignment 2nd line tests may include UE, glucose and cortisol after D3, 17-OH progesterone ideally taken >36 hours after birth to allow the postnatal surge to subside; AMH, FSH, LH, testosterone; ACTH, DHAS, androstenedione; urine steroid profile Sex chromosome DSD includes conditions such as 47,XXY (Klinefelter syndrome and variants), 45,X (Turner syndrome and variants), 45,X/46,XY (mixed gonadal dysgenesis) and 46,XX/46,XY (chimerism). These are often diagnosed antenatally with confirmation of the diagnosis after birth. 46,XY DSD has three broad categories: disorders of gonadal (testicular) development, disorders in androgen synthesis or action and other causes, including hypogonadotrophic hypogonadism, cryptorchidism and isolated hypospadias. They are a heterogeneous group of disorders, where the phenotype is consistent with reduced male sex hormone action 46, XX DSD encompasses disorders of gonadal (ovarian) development, such as gonadal dysgenesis and disorders secondary to androgen excess. Most commonly, the high levels of androgens responsible for virilisation in 46,XX DSD patients are secondary to production by the foetal adrenal glands and amongst them 21 hydroxylase deficiency CAH is the most common disorder. Androgen excess during pregnancy may be endogenous (secondary to an adrenal adenoma, dermoid cyst, Sertoli-Leydig tumour, sex cord stromal tumour or metastatic carcinoma) or exogenous (secondary to danazol, progestins or potassium sparing diuretics). Exogenous steroids taken during pregnancy can also cause posterior fusion of the labia, clitoral enlargement and increased degrees of androgenisation.

Question 109

stages of learning about gender

Answer 109

at 2 years old understand gender identity (man vs woman); between 2-3 develop gender role ie what gender they are; by 4-5 years realise gender is fixed: gender constancy; thereafter enforce gendered behaviour in themselves and others, gender policing; adult humans and monkeys treat babies different based on what gender they believe they are: amount/type of verbalisation, physical treatment, how they interpret responses, values attached to responses, toys and clothes provided

Question 110

CAH path - cause leading to what hormone effect, inheritance pattern, less common cause, what main enzyme normally does and how this links to hormone effect, how females present, how males/some females might present if severe (3 biochem things, 5 signs/sx), how some females may present if mild (5 sx) and boys if mild (5 sx), pigmentation

Answer 110

Congenital adrenal hyperplasia is caused by a congenital deficiency of the 21-hydroxylase enzyme. This causes underproduction of cortisol and aldosterone and overproduction of androgens from birth. It is a genetic condition that is inherited in an autosomal recessive pattern. In a small number of cases it is caused by a deficiency of 11-beta-hydroxylase rather than 21-hydroxylase 21-hydroxylase is the enzyme responsible for converting progesterone into aldosterone and cortisol. extra progesterone floating about that cannot be converted to aldosterone or cortisol, it gets converted to testosterone instead. The result is a patient with low aldosterone, low cortisol and abnormally high testosterone; due to low cortisol get excessive ACTH production and adrenal gland hyperplasia Female patients with CAH usually presents at birth with virilised genitalia, known as “ambiguous genitalia” and an enlarged clitoris due to the high testosterone levels. Patients with more severe CAH present shortly after birth with hyponatraemia, hyperkalaemia and hypoglycaemia. This leads to signs and symptoms: Poor feeding Vomiting Dehydration Failure to thrive Arrhythmias in mild cases: girls: Tall for their age Facial hair Absent periods Deep voice Early puberty boys: Tall for their age Deep voice Large penis Small testicles Early puberty pitu makes more ACTH -> MSH -> pigmentation of skin

Question 111

CAH

Answer 111

21 hydroxylase def in 95% of cases, prog and 17 OH prog not made into deoxycorticosterone and deoxycortisol respectivelt so failure to produce aldosterone and cortisol, instead the two accumulate and become andorostenedione thence testosterone so this excessive reduced cortisol means more ACTH so adrenal hyperplasia and inc'd precursor production so even more testosterone second commonest enzyme problem is 11beta hydroxylase preventing deoxycorticosterone and deoxycortisol being made into aldo/corti common presentations: genital hypertrophy (+ poss labial fusion), genitals may be pigmented after several weeks due to ACTH; 21h def get salt losing crisis from day 3 onwards so hypotension, dehydration, vomiting, shock - early sign is rising K, same biochem picture in AKI, aldos def, and DKA (tho latter also acidosis and K may be normal despite total body depletion), similar clinical picture to UTI and pyloric stenosis (biochem to differentiate); may also present with hypoglyc 11b form less often salt losing crisis as 11 deoxycorticosterone appears to protect against this and may cause hypokal (has some mineralo activity) partial defects may have no sx until puberty: amenorrhoea, hirsutism in females and precocious puberty in males; may have excessive growth, but epiphyses fuse earlier so lower final height

Question 112

ix (main things that might be raised, general biochem picture and poss difference in 11bh def, 2 other ix in babies with ambig genitalia) and mx for CAH (inc initial x3, long term x3, monitoring treatment efficacy)

Answer 112

ix finds highly raised 17OHP levels or 11 deoxycortisol, poss biochem abnorms (low na, glucose, high k, met acidosis, high urea)(maybe hypokal in 11bh due to mineralocort activity of precursors that buildup here) do other tests in female babies to exclude other causes of ambiguous genitalia - pelvic US ?uterus etc present, karyotype treatment: iv fluid resus, correct electrolytes, iv hydrocortisone, in long term hydro and fludro to prevent ACTH induced hyperplasia and retain salt; serum or salivary 17OH prog levels can monitor treatment also poss surgical correction of genitalia

Question 113

causes of growth abnorm - 2 normal variants, 16 other causes inc effect of chronic disease on bone age, 13 sx of hypopitu

Answer 113

normal variants: familial (parents are short - no delay for age, following centile), constitutional (children born with normal weight/length and during first few years rate slows then height returns to normal w bone age 1-4 yrs behind chronological age, puberty oft delayed, may have pos FH of similar (or FH of delayed menarche), diagnosis of exclusion, then normally catches up eventually) nutritional disorders (malnut or malabsorb) chronic disease (inc CKD, RTA, heart failure, chronic severe asthma; bone age delayed, progressive deviation from chrono age as disease untreated) endocrinopathies: hypothyroid and GH def (delay in bone age), latter begins deviation after 5mo w doll like face and poss hypoglyc; cushing and precocious puberty (advanced bone age, inc'd intial growth velocity but premature fusion of physis), hypopitu (short, round face, saddle nose, short neck, small larynx w high pitched voice, small hands/feet, delayed sexual dev, microphallus, fine scalp hair and maybe loss of body hair), pallor (loss of MSH activity of ACTH), and hypoglyc - tumours here may cause bitemp hemi and hydroceph due to 3rd ventricle obstruction children born IUGR or premie dysmorphic children: turner, noonan, PW, down syndrome etc as well as achondroplasia (will see normal sized trunk but small limbs) or spondyloepiphyseal dyplasia (short trunk and normal limbs, diff is spinal irradiation)

Question 114

ambiguous genitalia - differentiation starts and finishes when, female pseudoherm phenotype and 3x causes, male pseudoherm 4 causes, true hermaph, 3 main ix, 6mx

Answer 114

diff starts at 6 weeks, complete by end of first trimester female pseudoherm: normal internal ducts but masculinised ext genitalia due to inappropriate androgens eg androgen secreting tumour/medications or CAH male pseudoherma: may be due to inborn error of met of testos synth, 5ar def, testicular fem syndrome (complete or partial def of test receptors), leydig cell hypoplasia true hermaphrodism: extremely rare, due to test and ovarian tissue present; may be 46 XX, 46 XY, or mosaicism ix inc karyotype, uss of pelvis for uterus, measure 17 OH prog mx: fluid resus if salt losing crisis, psych support to parents, advise against naming until all ix complete; determine both genetic sex and what gender to rear the child (easier to reconstruct female genitalia so many genetic males reared as females), hormone replacement necessary if CAH; consider genetic counselling

Question 115

causes of micro(10), macropenis (2)

Answer 115

micro: idiopathic, hypopitu (pan or eg GH or gonadtrophin def), hypothal dysfunction eg kallman, test feminisation syndrome, PW, noonan, down syndrome, smith-lemli-opitz syndrome macro: CAH (may see scrotal pigmentation), prec puberty

Question 116

initiation of puberty - 3 main hormones that rise, trigger for this (hormone, weight - inc how weight sensed), turkish family genes affected and why this means they don't have puberty

Answer 116

FSH, LH, and sex steroids rise from pre-pubertal levels GnRH pulses precede this change with exogenous pulses able to initiate puberty and brain tumours that activate GnRH production leading to premature puberty and tumours/damage that prevent GnRH production leading to delayed puberty puberty begins consistently at 47kg for girls and 55kg for boys with candidate for weight sensing being leptin, a peptide hormone made by adipose tissue: some genetic disorders of leptin result in failure of puberty; leptin receptors are in hypothalamus and levels peak before stage 5 of puberty, then decrease to adult levels; age of puberty is decreasing families in turkey have genetic defects in TAC3 (1 family) and TACR3 (2 families) with some family members not going through puberty, having severe congenital gonadotropin deficiency; TAC3 codes for neurokinin B and TACR3 its receptor; neurokinin B is member of substance P related tachykinins and is highly expressed in hypothalamic neurons that also express kisspeptin, a recently identified regulator of GnRH secretion

Question 117

puberty - menarche/gonadarche/adrenarche, growth spurt height gain (+ dependent on which 2 hormones, dimorphism), general change in body composition, when first ovulation related to menarche, what generally happens to boys and girls

Answer 117

menarche (first menstruation) definitive sign in women but preceded by 2-4 years of other changes dependent on steroid hormones from gonads (gonadarche) and adrenal glands (adrenarche) growth spurt: boys begin about 2 years after girls so taller at point of take off than girls were, height gain similar for both during spurt so 10cm mean height difference from difference in point of take off; growth occurs in roughly every muscloskeletal dimension, though sexual variation leads to some sexual dimorphism: boys shoulders broaden more and girls hips do too; the spurt is dependent on sex steroids and growth hormone from ant pituitary lean body mass, body fat virtually identical in prepube girls/boys; adult men have 1.5x lean mass of women, women have twice as much body fat (deposited in hips and breasts); skeletal mass of adult men ~1.5x of women; greater average strength of men from greater number of muscle cells due to action of androgens; males have more body water; fat% of 12 okay for guys, in similar girl would be 28% first ovulation from months to 2 years after menarche, slight risk of pregnancy before/immediately after menarche too as sometimes occurs at same time ovaries, oviducts, uterus, vagina grow and mature; secondary sexual characteristics: pubic/axillary hair, pelvis widens, breasts grow/mature, sweat and sebaceous glands become more active (acne) and voice lowers slightly; metabolic rate, blood pressure and heart rate increase; nipple pigmented, areola darkens/widens tests/vas/seminal vesicles/prostate grow and mature; scrotum and penis grow markedly and spontaneous erections become more freq, inc to stressful/emotionally charged stimuli; nocturnal emissions (these and spontaneous erections tend to decrease after puberty); secondary sexual characteristics: pubic/axillary/chest/face/limb hair, sweat glands in axilla (odour), sebaceous glands active (acne), vocal cords lengthen and voice deepens/breaks to be an octave lower than females

Question 118

typical sequence of puberty (age 9=17 males and females) + tanner stages

Answer 118

females: age 9 growth spurt begins; 10 breasts, pubic hair, hips; 11 areola pigmented, internal repro organs mature; 12 axillary hair, menarche, breasts fill in; 13 ovulation, growth spurt stops, sweat etc; 14 voice deepens and 15 adult stature reached males: age 9 first stages of spermatogenesis; 10 fat deposition, testes enlarge; 11 growth (of everything), pubic hair, erections; 12 nocturnal emissions and hair; 13 axillary/upper lip hair and voice deepens; 14 first fertile ejaculation and breast enlargement in some; 15 adult hair pattern, loss of body fat, sweating; 16 muscle growth and shoulders broaden; 17 adult stature reached female: 1 prepubertal, 2 sparse pubic hair around labia, breast a little elevated, 3 pubic hair darken/curl/increase in amount and breast and areola enlarge, 4 pubic hair coarse and abundant, breasts similar, 5 adult spread of hair to thighs, areola part of breast contour; males: 1 prepubertal, 2 scanty long pubic hair, penis larger, scrotum larger/diff texture; 3 darker pubic hair begin to curl, penis and testes larger; 4 pubic hair coarse and curly, glans widens and testes larger; 5 adult distribution of pubic hair, testes at adult size

Question 119

thelarche and tanner staging

Answer 119

examples of use include delivering timely anticipatory guidance on menstrual hygiene needs (menarche occurs about 2 years post-thelarche/tanner 2 breasts) or targeting scoliosis exams at well-visits before and during peak height velocity (Tanner 2 to 3) Puberty in females begins with the development of breast buds under the areola, also known as thelarche, and represents entry into Tanner Stage 2. As puberty progresses, the glandular tissue of the breast increases in size and changes in contour. In females, thelarche is followed in 1 to 1.5 years by the onset of sexual hair (pubic and axillary), known as pubarche. Menarche, the onset of menses, arrives on average at age 12.5 years, regardless of ethnicity, following thelarche on average by 2.5 years (range 0.5 to 3 years). Between Tanner Stage 2 and 3 breast development, females experience peak height velocity In males, the onset of puberty ranges from 9 to 14 years of age. The first secondary sexual characteristic visible is gonadarche when the testicular volume reaches greater than or equal to 4 mL (or long axis greater than or equal to 2.5 cm) and enters tanner stage 2. During Tanner Stage 3 genital development, males undergo peak height velocity. Spermarche, the counterpart of menarche in females, is the development of sperm in males and typically occurs during genital Tanner Stage 4; It takes approximately 5-6 years for the testicles to reach the average adult volume of 18 mL Precocious puberty is defined as the onset of Tanner 2 secondary sexual characteristics before age 8 years in females or age 9 years in males if the continued progression of pubertal development occurs soon after. Delayed puberty should be considered if females have not reached Tanner 2 thelarche by age 13 years old or if males have not reached Tanner 2 gonadarche by age 14 years. Primary amenorrhea is defined as a failure to start menses within 3 years of Tanner Stage 2 (thelarche) or by age 15 years. It is important to note that some males will temporarily develop glandular breast tissue (pubertal gynecomastia) between genital tanner stage 3 and 4, which may be emotionally troubling but not physically harmful Pubic Hair Scale (both males and females) Stage 1: No hair Stage 2: Downy hair Stage 3: Scant terminal hair Stage 4: Terminal hair that fills the entire triangle overlying the pubic region Stage 5: Terminal hair that extends beyond the inguinal crease onto the thigh Female Breast Development Scale Stage 1: No glandular breast tissue palpable Stage 2: Breast bud palpable under the areola (1st pubertal sign in females) Stage 3: Breast tissue palpable outside areola; no areolar development Stage 4: Areola elevated above the contour of the breast, forming a “double scoop” appearance Stage 5: Areolar mound recedes into single breast contour with areolar hyperpigmentation, papillae development, and nipple protrusion Male External Genitalia Scale Stage 1: Testicular volume < 4 ml or long axis < 2.5 cm Stage 2: 4 ml-8 ml (or 2.5 to 3.3 cm long), 1st pubertal sign in males Stage 3: 9 ml-12 ml (or 3.4 to 4.0 cm long) Stage 4: 15-20 ml (or 4.1 to 4.5 cm long) Stage 5: > 20 ml (or > 4.5 cm long)

Question 120

hormones and puberty - what oestrogens do, what female androgens do, what testicular androgens do; LH/FSH levels from neonate to puberty, types and source of oestrogens x2, what happens to weak androgens in females, first endocrine change of puberty in both sexes, change in hormones in males (inc oestrogens), 2 other hormones that change during puberty

Answer 120

ovarian oestrogens drive breast/female genitalia, androgens from ovary/adrenal gland drive growth of hair, glands, bone, sex drive; testicular androgens drive body hair, male genitalia, enlargement of larynx and its muscles neonates: LH/FSH pulses in first 20 weeks when near adult levels, then secretion stops and levels low/undetectable through childhood, then FSH rises followed by increasingly pulsatile LH with changes regardless of if testosterone present showing GnRH output alters without -ve feedback in females: LH, FSH, oestradiol rise and at menarche and first ovulation, LH/FSH surge; oestrogens cause onset of breast maturation, pelvic fat etc; oestradiol from large growing follicles in ovary and oestrone from body fat; weak androgens released in large quantities from adrenal gland and converted into testosterone at target site; in both sexes rise in adrenal dehydroepiandrosterone (DHEA) is first endocrine change of puberty; androgens do bone growth, glands, hair etc and may increase sex drive in pubescent girls in males: rise in FSH/LH ~age 10 trigger spermatogenesis and inc androgen secretion from testes; androgens cause changes and increase sex drive/touch sensitivity of penis so spont erection freq increases; oestrogens rise slightly, probably from sertoli cells and some males exhibit gynecomastia which usually goes away within 2 years; balance of androgens/oestrogens in both males and females determines secondary sexual characteristics other hormones in puberty: growth hormone from ant pituitary in increasing amounts near puberty, responsible (along with androgens) for growth of bones/tissues with GH deficiency giving short height, delayed sexual maturation; inc TSH from ant pituitary so inc'dthyroid hormone which may account for pubertal rise in metabolic rate and is essential for body growth

Question 121

causes of puberty - 4 step general sequence, why GnRH low in children x2 reasons, links between nutrition, day length, sensory deprivation and puberty, link between stress and puberty, genetics and puberty (inc an important specific enzyme)

Answer 121

pulsatile rise in GnRH -> pulsatile rise in FSH/LH -> increased gonadal steroids -> sex structures brain may have gonadostat: androgens/oestrogens -ve feedback on GnRH production, so low GnRH, hypothalamus thought to be 6-15x more sensitive to steroidal inhib in children than in adults so even low concs exert inhib, then as puberty approaches sensitivity decreases with evidence that smaller amounts of oestrogen needed to lower LH/FSH levels in girls than in women also central inhib of GnRH pulse gen by other areas of brain with this lifted at puberty with evidence: children born without gonads have no steroids for -ve feedback but still have low FSH/LH and GnRH release occurs at normal age; also LH surge in women (hypo GnRH surge centre matures or ant pitu can make/store adequate gonadotropins in late puberty) nutrition: the whole body fat sensing thing via leptin and overweight children tend to enter puberty earlier than lean peers but still controversial - may link to BMR etc; for day length, melatonin and pineal secretions may inhib repro functions with lesions of pineal gland giving precocious puberty and secretory tumours delaying, maybe artificial light extends day length - but blind kids undergo early puberty (as do deaf kids - seems sensory deprivation accelerates sexual maturity) stress as in lab animals stressors can delay puberty, also emotional/physical stress can (maybe!) delay puberty in humans; may be due to enlarged adrenal glands/cortisol; also proposed stress in infancy can accelerate puberty with girls growing up in absence of biological father, esp if there is a stepfather, entering puberty earlier on average, or if parents fight a lot/are mean to kid; also tended to have menarche/sex earlier, kids at younger age and spent less time with kids genetic factors thought to explain 15% variation; in USA black girls tend to reach puberty 1yr before white girls; menarche tends to be similar in mothers/daughters and within 2months for identical twins; variant of CYP3A4 influences degradation of testosterone with high activity form increasing oestrogen:testosterone ratio; 2 copies 90% girls breast dev starts by age 9.5, 1 copy 56% and 0 copies 40%

Question 122

kisspeptin and puberty - gonadarche triggered by what, 2 main areas linked to GnRH regulation, what happens with kisspeptin at puberty, how does arc nuc control LH release (inc other 2 NTs), how does oestrogen regulate kisspeptin, role of leptin and AgRP

Answer 122

Gonadarche is triggered by a resurgence in a pulsatile pattern of hypothalamic GnRH secretion areas of the hypothalamus implicated in the neuroendocrine regulation of gonadotropin secretion include the anteroventral periventricular nucleus, the periventricular nucleus, and the arcuate nucleus; these areas contains kisspeptin neurons; several other neurotransmitters have been equally strongly implicated in the control of the onset of puberty inc GABA, glut etc activation of GnRH neurons by kisspeptin at puberty reflects a dual process involving an increase in kisspeptin input from the AVPV (aka preoptic area) and a post-transcriptional change in GPR54 signalling within the GnRH neuron that increases responsiveness of GnRH neurons to kisspeptin; meanwhile arc nuc provides tonic kisspeptin input to GnRH to support basal LH production; clear sexual dimorphism in POA with females expressing a lot more kisspeptin neurons than males, driven by androgen expression during dev all KiSS-1 neurons express oestrogen receptor, which is thought to mediate the predominant effects of sex steroids on GnRH secretion - ARC neurons are inhibited by oestradiol (neg feedback) and AVPV/POA are stimulated (pos feedback for eg pre-ov surge) NKB and Dynorphin are expressed by ARC neurons and much less by AVPV neurons; so in ARC, assuming that NKB stimulates and Dyn inhibits Kiss1/Dyn/NKB neurons, the recurrent collaterals constitute a potentially oscillatory feedback loop - a burst of kisspeptin, Dyn and NKB would be released, followed by a delayed inhibition of Kiss1/Dyn/NKB cells, mediated by Dyn acting through kappa opioid receptor. As this subsides, the cells would become active, restarting the entire process; GnRH pulse generator is most active when E2 levels are low leptin binds glutamatergic neurons in PMV which lead to GnRH neuron activation to provide a permissive action for puberty initiation; AgRP neurons releases GABA to inhibit POA neurons, helping to link energy status to puberty/periods - ghrelin also reduces kisspeptin release

Question 123

precocious puberty 6 causes, mx if central cause

Answer 123

hormone secreting tumour of adrenals or ovaries gonadotropin producing tumours congen adrenal hyperplasia hypothyroidism exogenous oestrogens follicular cysts of ovary GnRH agonist if central cause, leads to dec FSH/LH output by desensitising pitu

Question 124

precocious puberty

Answer 124

true: puberty occurs in normal synchronous fasion suggesting intact hypo-pitu axis, may be idiopathic or sec to trauma, tumours, h+, hydroceph, NF, prim hypothyroid (only cause of prec pub + short stature + delayed bone age) false/pseudopuberty: pitu indy/not synchronous, may be cushing syndrome, CAH, adrenal tumour, ovarian cyst/tumour, test tumour, albright-mccune syndrome (see cafe au lait spots, polostotic fibrous dysplasia and prec puberty due to prim ovarian cysts sec oestradiol), or gonadotrophin secreting tumour eg hepatoblastoma or dysgerminoma, or ingestion of exog hormones eg birth control in true precocuous puberty FSH and LH levels high, low in pseudopub- so give GnRH stim test (also check sex hormon and adrenal hormone levels inc 17 OH prog); also in boys true puberty wil have large testes, pseudo small; also consider skull MRI, bone age pubertal gynaecomastia common in tanner stages 3/4 due to inc in oest:test ratio and will resolve spont (but exclude pitu/test/hepatic tumour, hyper/hypothyroid, liver disease, klinefelter, test failure, drugs) premature adrenarche (pubic hair dev) needs f/u, if clitormeg or other signs of masculinisation consider CAH most important long term consequence is short stature

Question 125

adolescent gynaecomastia guidelines

Answer 125

Children who present with breast symptoms will need a clinical examination to exclude other pathology e.g. Klinefelter (XXY) syndrome, precocious puberty or drug-induced breast enlargement Breast development in a child under the age of 7 would be considered premature thelarche and precocious puberty should be ruled out gynaecomastia affects approximately 60% of adolescent males, with a mean onset between 12 and 14 years and typically lasting 6-12 months, with spontaneous regression in 90% of cases; treatment should be delayed until symptoms have persisted for more than two years and providing reassurance that symptoms persist in only 10% Ultrasound scan is considered to be the most appropriate and most reliable diagnostic tool for worrying breast lumps (ie any that is not a breast bud) with core biopsy if needed; most of these lumps are cysts Accessory nipples (Polythelia) or supernumerary breast (Polymastia) can occur in 1-6% of the population and reassurance alone is needed

Question 126

puberty problems

Answer 126

delayed: absence of testicular dev by 14yo, no breasts by 13 or breasts but prim amen by 15; constitutional delay by far commonest cause, diagnosed once other things eliminated; chronic illness, malnutrition, over-exercise, hypothyroidism, psychosocial deprivation, steroid therapy; tumours of/near hypothal or pitu, irradiation or trauma to that area, kallmans; peripheral causes eg bilat cryptorch, prader willi, klinefelters, irradiation, cyclophos; in girls prader willi, turner, irradiation eg total body prior to bone marrow transplant, cyclophos, CAH or androgen insensitivity, PCOS, iron overload full physical exam to inc fundoscopy and visual fields; maybe FBC, U&E, ferritin, coeliac screen, urinalysis, TFTs, FSH/LH; check bone age CDGP may need reass, monitor; maybe induct puberty with test/oest for boy/girl; in test/ov failure induce then ongoing hrt; central delay similar unless can treat cause precocious - central most common, usually normal but at one end of spectrum for girls, boys it's concerning; may be various CNS tumours, trauma, hamartomas, hydrocephalus; gonadotropin (central) indy may be CAH, hepatomas/hepablastomas, choriocarcinoma of eg gonad, exogenous oest/andro exposure, severe hypothyroid; maternal hormones may cause breast dev in girls under 3 which may regress, androgen sec in middle childhood means <7yo can have pubic hair thorough clinical assessment then sex steroid levels, random LH, TFTs, adrenal steroid precursors if CAH suspected, HCG pelvic uss essential in girls w/o central cause (detect ovarian tumour/cyst), prog central get brain MRI; hand/wrist x rays for bone age; surgery, GnRH agonists, glucocorts

Question 127

how to tell constitutional delay; hypogon hypogon and hypergon hypogon

Answer 127

Xray of the wrist to assess bone age and inform a diagnosis of constitutional delay hypogon hypogon: amage to the hypothalamus or pituitary, for example by radiotherapy or surgery for previous cancer Growth hormone deficiency Hypothyroidism Hyperprolactinaemia (high prolactin) Serious chronic conditions can temporarily delay puberty (e.g. cystic fibrosis or inflammatory bowel disease) Excessive exercise or dieting can delay the onset of menstruation in girls Constitutional delay in growth and development is a temporary delay in growth and puberty without underlying physical pathology Kallman syndrome hypergon hypogon: damage to the gonads (e.g. testicular torsion, cancer or infections, such as mumps) Congenital absence of the testes or ovaries Kleinfelter’s Syndrome (XXY) Turner’s Syndrome (XO

Question 128

neonatal breast engorgement

Answer 128

common, due to effect of maternal oestrogens on breast tissue, may even see milk like substance; rarely may get abscess here and then need abx

Question 129

delayed puberty

Answer 129

absence of enlarged testes by 14yo in boy and absent period by 15 or breast enlargement by 13 in girl constitutional: often accompanies growth delay hypogonadotrophic hypogonadism: idipathic, kallman (anosmia, microphallus, crypotorchidism), PW, hypothal/pitu damage inc trauma/infection/tumour/irradiation/surg/congen; diabetes, athletes, cushings, anorexia hyper hpoy: FSH and LH high, defective gonads eg prim ovarian failure (turner syndrome), chemo, post irradiation; prim test failure eg klinefelter, crypotorchidism, test feminisation, chemo, irradiation ix: bone age, FSH, LH, TFTs, test, oestradiol, GnRH stim test, HCG stim test (test relase measured), visual field analysis, SXR, cranial MRI if hypo hypo

Question 130

congenital hypogonadotropic hypogonadism part 1

Answer 130

Pulsatile secretion of GnRH by specialized neurons in the hypothalamus stimulates the release of FSH and LH by the pituitary, which in turn stimulate steroidogenesis and gametogenesis in the gonads. Notably, the onset of puberty is preceded by two periods of HPG axis activity: the fetal life and infancy (minipuberty) Constitutional delay of growth and puberty (CDGP) is the most frequent cause of delayed puberty (2% in the general population) and is related to a transient GnRH deficiency. In CDGP, puberty eventually begins and is completed spontaneously. In contrast, congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disease caused by GnRH deficiency. It is characterized by absent or incomplete puberty with infertility; When CHH is associated with anosmia, it is termed Kallmann syndrome; also be clear by assessing tanner stages whether this is delayed puberty, or arrested puberty (ie made it some way through before stopping) In boys, T levels start to increase after 1 week postnatally, peak between 1 and 3 months, and then decline to low prepubertal levels by ∼6 months; hese changes mirror GnRH-induced LH activation. During minipuberty, T levels correlate with penile growth, acne, and onadotropin secretion stimulates the production of inhibin B (a marker of Sertoli cell number and function); Although there are no clear clinical signs of GnRH deficiency in female infants, micropenis and cryptorchidism raise a suspicion of CHH in male infants, as these signs may reflect the lack of activation of the HPG axis during fetal and postnatal life delayed puberty: traditional clinical cut-offs applied are 14 years for boys (TV <4 mL) and 13 years for girls (absence of breast development) CDGP is commonest cause of delayed puberty but also a diagnosis of exclusion. Other underlying causes of delayed puberty should be actively investigated and ruled out, including hypergonadotropic hypogonadism [HH (e.g., Klinefelter syndrome or Turner syndrome)], permanent HH (e.g., CHH, tumors, infiltrative diseases), and functional hypogonadotropic hypogonadism (FHH; e.g., systemic illness, anorexia nervosa, excessive exercise)

Question 131

congenital hypogonadotropic hypogonadism part 2

Answer 131

male patients with CHH seek medical attention for absent or minimal virilization, low libido, and erectile dysfunction; In 75% of patients with CHH, puberty never occurs, leading to severely reduced TV (<4 mL) and the absence of secondary sexual characteristics (i.e., sparse facial and body hair, high-pitched voice). In this group (absent puberty), micropenis and/or cryptorchidism are commonly observed. In contrast, 25% of patients with CHH exhibit partial GnRH deficiency as evidenced by some spontaneous testicular growth (TV >4 mL) with little virilization; Most patients do not have any ejaculate in the setting of severe hypogonadism. Indeed, T is needed for seminal and prostatic fluid production and optimal ejaculate volume. Most patients with CHH have eunuchoidal proportions with arm spans typically exceeding height by ≥5 cm, reflecting the delayed closure of the epiphysis of long bones in the absence of gonadal steroids. The lack of increased sex steroid levels leads to steady linear growth without a growth spurt; however, final height is rarely affected and they may even be taller Typical changes of body composition in boys with CHH include decreased muscle mass and female body habitus with a gynoid pattern of fat distribution. Mild gynecomastia can be seen in untreated patients due to the imbalance of the T/E2 ratio. Bone maturation is impaired, with delayed bone age and lower bone density observed relative to peers most prevalent complaint is primary amenorrhea in nearly 90% of women with CHH; 10% may have had some bleeding before amenorrhoea sets in; absent breast development is observed in a minority of women with CHH; Pubarche also shows great variability, ranging from absent to almost normal pubic hair as adrenarche may still occur leading to adrenal androgen production some related syndromes: CHARGE, waardenburg, septo-optic dysplasia Most men and women with CHH have very low circulating gonadotropin levels and apulsatile LH secretion; Circulating E2 levels in women with CHH are usually low or in the lower end of the normal range during the follicular phase and consistently lower in males; Circulating T levels in patients with CHH are usually low and Low circulating androgen levels (androstenedione and T) are reported in women with CHH despite normal circulating dehydroepiandrosterone sulfate concentrations; men have low serum inhibin B levels indicating a reduced Sertoli cell population Brain MRI is performed at baseline to exclude hypothalamic–pituitary lesions and to assess defects in the olfactory bulbs, corpus callosum, semicircular canals (anomalous in CHARGE syndrome), cerebellum and midline testis volume tracked with orchidometer or testis USS bone mineral density should be assessed with DEXA scan genetic testing may be used to identify the precise cause ddx Structural causes affecting the hypothalamic–pituitary axis may lead to acquired HH. These causes can be classified into tumors (pituitary adenomas, craniopharyngeomas, and other central nervous system tumors), irradiation, surgery, apoplexy, or infiltrative diseases (i.e., hemochromatosis, sarcoidosis, and histiocytosis). Less commonly, head trauma or subarachnoidal hemorrhage can be associated with acquired HH Combined pituitary hormone deficiency is a rare congenital disorder characterized by impaired production of pituitary hormones affecting at least two anterior pituitary hormone lineages with variable clinical manifestations; To differentiate CPHD from CHH, biochemical assessment of pituitary function with measurements of IGF1, morning cortisol, TSH, and free T4 and prolactin is needed in addition to evaluating specific clinical manifestations of selective anterior pituitary hormone deficiency. Even subtle indications of insufficiency for one of the pituitary hormones warrants further testing with appropriate dynamic challenge tests and brain MRI CDGP vs CHH is hard to tell but remember CDGP is more common; presence of cryptorchidism and/or micropenis strongly argues in favor of CHH, reflecting the absence of gonadotropins and sexual hormones during both fetal life and minipuberty, as do CHH associated phenotypes (features of kallmans, CHARGE syndrome etc) For both sexes, malnutrition due to an organic disorder such as celiac disease, inflammatory bowel disease (e.g., Crohn disease, ulcerative colitis) or other chronic inflammatory and infectious states should be ruled out as the primary cause underlying a patient’s HH before rendering a diagnosis of CHH With appropriate HRT, patients with CHH can develop secondary sexual characteristics, maintain normal sex hormone levels and a healthy sexual life, and achieve fertility. using combinations of oestrogens, androgens, and gonadotropins

Question 132

anorexia nervosa

Answer 132

10x more common in girls, mean onset is 12 in boys and 16 in girls disturbed sense of image, morbid fer of obesity, relentless pursuit of low weight - body weight will be 25% below standard oft amenorrhoea, evidence of vomitnig or excessive exercise, or laxative abuse may see: constipation (v common), (postural) hypotension, bradycardia, hypothermia, sensitivity to cold, amenorrhoea, hypoglyc, alopecia (sparing ax/pub hair unlike hypopitu), lanugo hair, ankle oedema, leucopenia, hypokal (if vomiting), alkalosis (ditto), arrhytmias, dental erosions, knuckle calluses LSH, FSH, test, oesta, T3/4 down prolactin, GH, cort up diffs: thyrotoxicosis, DM, neoplasia, malabsotp, IBD, hypopitu 1/3 fully recover, 1/3 partially, 1/3 remain severe; male sex, late onset, bullimia, purging, unstable family relationships, greater weight loss are poorer prognosis

Question 133

obese child

Answer 133

must exclude: cushings, hypothyroid, mauriac, polycystic ovaries, PW, laurence-moon-biedl, and hypothal disorder (eg postinfection/trauma) in babies also think of BW, diabetic mothers polycystic ovaries usually obesity, acne, irregular periods, hirsutism usually from puberty and worsening over time; cysts seen on USS; andorens up, LH high and FSH normal/low

Question 134

premature adrenarche vs precocious puberty

Answer 134

Premature adrenarche (also referred to as premature pubarche) refers to the early appearance of pubic hair, axillary hair, or both in children without other signs of puberty. An adult-type axillary body odor is the other major clinical finding. Unlike precocious puberty you wont see eg breast dev/male genital enlargement Usually benign, unsure why it starts early - being overweight may be linked. Signs of severe androgen excess (eg, clitoral enlargement, growth acceleration, severe acne) should prompt further investigation to exclude a rare virilizing tumor or a variant form of congenital adrenal hyperplasia

Question 135

failure to thrive

Answer 135

weight falls across one or more weight centiles and birtheweight below 9th centile or 2 or more centiles and between 9th and 91st or falls 3+ centiles and bw >91st centile or current centile below 2nd centile for weight if weight loss >10% of bw in early days of life and/or fails to return to bw within 3 weeks then maybe feeding problems so observe feeding, otherwise normal and not to worry refer to paeds if faltering growth + rapid weight loss or undernutrition, suspect underlying condition, safeguarding concerns, unexplained short stature , primary care management fails also suspect if length or height more than 2 centile spaces below mid parent centile history should include feeding pattern (what, how much, how often - consider feeding diary), child behaviour at meals; pregnancy and birth history; any other symptoms in child; PMH, FH, SH (including any possible sources of stress) do a general examination follow up to monitor growth including up to monthly if 1yo+, fortnightly if 6-12mo, weekly if <6mo, daily if <1mo 4-8 weeks usually needed for recovery to begin but may take several months, if new symptoms reconsider need for referral otherwise advice inc regular meal times with family, age appropriate foods, dont drink too much before meal etc causes: usually a mix of diff factors; lack of available healthy food (or child neglect), feeding difficulties (breast feeding problems, cleft lip/palate etc), developmental delay, eating disorders, lack of feeding knowledge/skills, malabsorption (coeliac, ibd, chronic diarrhoea, protein losing enteropathy, food allergy), persistent vomiting (gord, obstruction, food sensitivity), excessive energy expenditure (CHD, CF, DM, hyperthyroid, inborn errors of metabolism, RTA, genetic disease eg down syndrome, malignancy, immunodef fall in growth across centiles may also be due to steroids(or cushings for non-iatrogenic reasons), hypothyrodism, chronic illness, GH def

Question 136

contraception for children <13yo

Answer 136

Children under the age of 13 years are not able to consent to sexual intercourse and hence any sexual activity would be regarded as rape under the law. This is one situation under the GMC guidelines where you are compelled to break confidentiality - you must contact the local child protection lead and refer to social services

Question 137

telogen effluvium

Answer 137

Telogen effluvium is excessive shedding of resting or telogen hair after some metabolic stress, hormonal changes, or medication, with generally an acute onset In a normal healthy person's scalp, about 85% are anagen hair and 15% are telogen hair. Anagen hair are actively growing hair while telogen hair are resting hair. A few hairs may also be in catagen. A hair follicle usually grows anagen hair for almost four years, then rests for about four months. A new anagen hair begins to grow under the resting telogen hair and pushes it out. If there is some kind of stress to the body it can cause 70% of anagen hair to precipitate into the telogen phase thus causing hair loss Common triggering events are acute febrile illness; severe infection; major surgery; severe trauma; postpartum hormonal changes, particularly a decrease in estrogen; hypothyroidism; discontinuing estrogen-containing medication; crash dieting; low protein intake; heavy metal ingestion; and iron deficiency - consider testing for these things eg haematinics and TFTs, if you're not sure or can't find a stressor or there are other sx to make you suspect generally a self-limiting condition

Question 138

menstrual cycle and dysmenorrhoea

Answer 138

follicular phase: At the beginning of the menstrual cycle, levels of FSH rise causing stimulation of a few ovarian follicles. 2. As follicles mature they compete with each other for dominance. 3. The first follicle that becomes fully mature begins to produce large amounts of oestrogen. 4. Oestrogen inhibits the growth of the other competing follicles. 5. The single follicle that reaches full maturity during this process is referred to as the Graafian follicle (the oocyte develops within this). 6. The Graafian follicle continues to secrete increasing amounts of oestrogen. 7. Increasing amounts of circulating oestrogen results in: endometrial thickening thinning of the cervical mucus to allow easier passage of sperm inhibition of LH production by the pituitary gland 8. As oestrogen levels rise, they eventually surpass a threshold level, at which point they conversely stimulate LH production, resulting in a spike in LH levels around day 12. 9. The high amounts of LH cause the membrane of the Graafian follicle to become thinner. 10. Within 24-48 hours of the LH surge, the follicle ruptures releasing a secondary oocyte. 11. The secondary oocyte quickly matures into an ootid and then into a mature ovum. 12. The mature ovum is then released into the peritoneal space and is taken into the fallopian tube via fimbriae (finger-like projections). Luteal phase Once ovulation has occurred LH and FSH stimulate the remaining Graafian follicle to develop into the corpus luteum. 14. The corpus luteum then begins to produce the hormone progesterone. 15. Increased levels of progesterone result in: the endometrium becoming receptive to implantation of the blastocyst negative feedback causing decreased LH and FSH (both needed to maintain the corpus luteum) an increase in the woman’s basal body temperature 16. As the levels of FSH and LH fall, the corpus luteum degenerates. 17. Degeneration of the corpus luteum results in loss of progesterone production. 18. The subsequent falling level of progesterone triggers menstruation and the entire cycle begins again. if fertilisation occurs: If an ovum is fertilised it produces hCG which is similar in function to LH. 20. hCG prevents degeneration of the corpus luteum (resulting in the continued production of progesterone). 21. Continued production of progesterone prevents menstruation. 22. The placenta eventually takes over the role of the corpus luteum (from 8 weeks gestation). in sync with this hormonal cycle is the uterine cycle: Proliferative phase During the proliferative phase, the endometrium is exposed to increasing levels of oestrogen as a result of FSH and LH stimulating its production. Oestrogen stimulates repair and growth of the functional endometrial layer allowing recovery from the recent menstruation (increasing endometrial thickness, vascularity and the number of secretory glands). Secretory phase The secretory phase begins once ovulation has occurred. This phase is driven by progesterone produced by the corpus luteum and results in the secretion of various substances by the endometrial glands, making the uterus a more welcoming environment for an embryo to implant. Menstrual phase At the end of the luteal phase, the corpus luteum degenerates (if no implantation occurs). The loss of the corpus luteum results in decreased progesterone production. The decreasing levels of progesterone cause the spiral arteries in the functional endometrium to contract. The loss of blood supply causes the functional endometrium to become ischaemic and necrotic. As a result, the functional endometrium is shed and exits through the vagina as menstruation.

Question 139

dysmenorrhoea and menorrhagia

Answer 139

Simple period problems are best managed in primary care. Most menstrual dysfunction in adolescence is associated with anovulatory cycles. Baseline history, exam, and ix Refer to gynaecology where they are significantly disruptive to schooling and/or extracurricular activities, not responding to primary care management or complicated by a medical or physical/learning disability. Immaturity of HPO axis in first 2 years following menarche, results in more than 50% of cycles being anovulatory * Irregular cycles – 20 to 90 days; * >90 days are 95th percentile for length – warrants investigation * After 1-2 years, capacity for oestrogen positive feedback to anterior pituitary develops with subsequent LH surge and ovulation results in more cycle regularity Anovulatory cycles result in: Heavy bleeding * Prolonged bleeding * Painful periods – if heavy; become more painful in ovulatory cycles due to circulating prostaglandins * Iron deficiency anaemia Dysmenorrhea Topical treatments e.g. heat, wheat bags Ibuprofen in addition to paracetamol is often the most useful combination of simple analgesics Consider whether endometriosis, fibroids, pelvic inflam disease possible -> O&G to further assess; normally if the onset of menstrual pain follows several years of painless periods -> this or if otherwise suspect consider pelvic USS, and swabs if at risk of STIs If the woman does not wish to conceive, consider prescribing a 3–6 month trial of a hormonal contraceptive as an alternative first-line treatment. COCP as first choice Secondary dysmenorrhoea is the most likely diagnosis when: Pain starts after several years of painless periods. Pain is not consistently related to menstruation alone and may persist after menstruation finishes or may be present throughout the menstrual cycle but is exacerbated by menstruation. Other symptoms are present, including: Other gynaecological symptoms, such as dyspareunia, vaginal discharge, menorrhagia, intermenstrual bleeding, and postcoital bleeding. Non-gynaecological symptoms, such as rectal pain and bleeding (which may be associated with endometriosis). IUD insertion may be a secondary cause of dysmenorrhoea (usually following insertion 3–6 months previously). Pain may be accompanied by longer and heavier periods, often with intermenstrual bleeding or spotting. The IUD may require removal, and an alternative form of contraception considered Primary dysmenorrhoea is the most likely diagnosis when: Menstrual pain starts 6–12 months after the menarche, once cycles are regular. Pain, usually cramping in nature, occurs in the lower abdomen but may radiate to the back and inner thigh. Pain starts shortly before the onset of menstruation and lasts for up to 72 hours, improving as the menses progresses. Non-gynaecological symptoms, such as nausea, vomiting, diarrhoea, fatigue, irritability, dizziness, bloating, headache, lower back pain, and emotional symptoms, are present. Other gynaecological symptoms are not present Menorrhagia Tranexamic acid (1g tds for up to 4 days), decreases blood loss by up to 50% and can be used in combination with analgesics. Full Blood Count (FBC), TFTs and clotting studies in severe cases; consider PCOS Consider fibroids, endometriosis, and polyps and discuss with gynae ?pelvic USS

Question 140

primary and secondary amenorrhoea

Answer 140

primary: Hypothalamic/pituitary disease * Hypog hypog * Congenital GnRH deficient * Constitutional delay of puberty * Hyperprolactinemia * Ovarian aetiologies( Gonadal dysgenesis, Turner syndrome, PCOS) * Congenital anatomic lesions (Imperforate hymen, transverse septum) secondary: * PREGNANCY * Hypothalamic causes (Idiopathic, Endocrinopathies, Stress/exercise/eating disorders, Weight loss, Chronic illness, PCOS) * Pituitary causes (Lesions, trauma) * Ovarian causes (Premature ovarian insufficiency, Ashermans syndrome) get Menstrual history – age of menarche, regularity, duration, associated pain, acne, hirsutism * Bleeding history – dental procedures, surgery, nosebleeds * Sexual history

Question 141

hirsutism

Answer 141

PCOS is 70-80% of cases consider: hypothyroid, acromegaly, hyperprolactinemia, cusghins, androgenic tumours, taking androgens, phenytoin, high dose steroids, penicillamine, non-classic CAH, idiopathic in 6-7% stage severity with ferriman-gallway score; up to 8 treat for cosmseis, >8 investigate for androgen excess mx: cosmetic inc lasers, bleaching, waxing, shaving consider OCP

Question 142

PCOS - diagnosis

Answer 142

In adolescents, suspect PCOS if the girl has the following: Clinical features of hyperandrogenism (such as severe acne and hirsutism). Irregular menstrual cycles, defined as: Normal in the first year post-menarche as part of the pubertal transition. More than 1 year to less than 3 years of irregular cycles (more than 45 days or less than 21 days) after the onset of menarche. More than 3 years of irregular cycles (more than 35 days or less than 21 days, or less than 8 cycles every year) post menarche to perimenopause. More than 1 year of irregular cycles (more than 90 days for any one cycle) post menarche. Primary amenorrhea by age 15 years or more than 3 years of irregular cycles post thelarche (breast development). also consider if indirect evidence of insulin resistance, such as obesity (especially central obesity) and acanthosis nigricans Measure total testosterone — this is normal to moderately elevated in women with PCOS. Measure sex hormone-binding globulin (SHBG) — this is normal to low in women with PCOS and provides a surrogate measurement of the degree of hyperinsulinaemia. Calculate free androgen index (100 multiplied by the total testosterone value divided by the SHBG value) to assess the amount of physiologically active testosterone present — this is normal or elevated in women with PCOS (the normal range is usually defined as lower than 5) Note that reliable assessment of biochemical hyperandrogenism is not possible in women on hormonal contraception due to effects on SHBG and altered gonadotrophin-dependent androgen production. If assessment of biochemical hyperandrogenism is indicated, hormonal contraception should be stopped for at least 3 months before the assessment Measure the following to rule out other causes of oligomenorrhoea and amenorrhoea (such as premature ovarian failure, hypothyroidism, and hyperprolactinaemia): Luteinizing hormone and follicle-stimulating hormone — may be increased in women with premature ovarian failure, and decreased in women with hypogonadotropic hypogonadism. Prolactin (normal range is less than 500 mU/L) — may be mildly elevated in women with PCOS. Thyroid-stimulating hormone USS not usually done in adolescents Exclude other causes of hyperandrogenism (such as late-onset congenital adrenal hyperplasia, Cushing's syndrome, or an androgen-secreting tumour) if: There are signs of virilization, for example, deep voice, reduced breast size, increased muscle bulk, and clitoral hypertrophy. There is rapidly progressing hirsutism (less than 1 year between hirsutism being noticed and seeking medical advice). The total testosterone level is significantly elevated (greater than 5 nmol/l or more than twice the upper limit of normal reference range). In adolescent girls, both hyperandrogenism and irregular menstrual cycles are required for a diagnosis of PCOS. Great caution should be taken before diagnosing PCOS if there are clinical features of androgen excess (such as hirsutism and biochemical hyperandrogenism) without irregular menstrual cycles. Adolescents who have features of PCOS but do not meet the diagnostic criteria should be considered to be at 'increased risk' of PCOS and reassessed at or before full reproductive maturity (that is, 8 years post-menarche)

Question 143

PCOS - management

Answer 143

Offer advice on the possible long-term complications of PCOS, including type 2 diabetes and cardiovascular disease (CVD). Encourage a healthy lifestyle to reduce the risk of these complications and to help improve the clinical features of PCOS Ask about symptoms of OSAS, such as snoring and daytime fatigue/somnolence. If symptoms are present, refer for investigation and treatment Screen for depression and anxiety and manage appropriately Consider prescribing the combined oral contraceptive (COC) pill alone for the management of clinical hyperandrogenism and/or irregular menstrual cycles, provided there are no contraindications. Metformin has been used off label to treat PCOS. However, there is uncertainty regarding the relative benefits compared with COC. if deemed 'at risk' then consider prescribing a COC for management of clinical hyperandrogenism and irregular menstrual cycles, provided there are no contraindications This will require withdrawing the COC for 3 months or longer to determine the persistence of hyperandrogenic anovulation at reassessment age

Question 144

vagina problems

Answer 144

itching/soreness: Most common cause is recurrent vulvovaginitis, common age 2-7 yrs. Simple non-invasive inspection of the vulvovaginal area. Empirical antibiotic or thrush treatment is not indicated. Swabs rarely indicated unless sexually active. Prepubertal hymen is very sensitive so perineum surface swab only if there is visible discharge or skin changes suggestive of infection. Consider threadworms, empirical treatment may be appropriate. Exclude UTI and constipation which can exacerbate vulval irritation. Most respond to reassurance and simple hygiene advice Candida infection (thrush) is rare in prepubertal girls; a confirmed infection on swab should raise the possibility of other medical conditions (e.g. diabetes, immunosuppression) or Child Sexual Abuse (CSA). Recurrent symptoms or those not responding to general advice should be referred to gynaecology White/yellow, non-offensive vaginal discharge is normal in young girls and increases as they become oestrogenised, often with cyclical variation. Discoloured or offensive discharge may indicate bacterial vulvovaginitis - swab, treat Copious, green or offensive discharge. Consider sexually transmitted disease (STD) or foreign body. Suspicion of foreign body should be discussed with the paediatric gynaecology service or on call gynaecology team. Suspicion of STD in girls who are sexually active should be referred to GUM clinic.