Category Archives: Endocrinology

Prolactin

Secreted from the pituitary, but also a stress hormone (can be used to distinguish pseudo seizures from epileptic seizures). So can go up to 1000 in healthy people. Always worth repeating a high result at least 24hrs hours later, after a 20 minute rest.

Important because of prolactinomas, which can cause:

  • gynaecomastia
  • galactorrhoea
  • delayed puberty
  • space occupying lesion effects – headaches, visual field defects

Any lesion in the vicinity of the pituitary may also cause raised prolactin so not specific.

In children, high levels can be due to presence of macroprotein isoforms, which are not considered pathological – lab can check.

Hypertension

In children under 10, high BP is usually secondary to an underlying disease or condition. Primary hypertension increasingly recognised in older, obese children.

Do repeated measurements, ideally automated home BP monitoring, before diagnosing hypertension. Check manually as well as with automated device. Beware “white coat effect”, even if not clearly anxious.

Use appropriate cuff size – cuff should cover at least 75% of the upper arm from the acromion to the olecranon (should be sufficient space at the antecubital fossa to apply stethoscope!) .  An inappropriately small cuff will overestimate BP.

Long list of causes, so follow the clues.

Family history important, of course.

Examination

So needs thorough history and examination, including:

  • Fundi
  • Bruits, radiofemoral delay
  • Neck for goitre

Complications

Consider then end organ effects –

  • Proteinuria, high creatinine
  • Retinopathy
  • Left ventricular hypertrophy, cardiac failure
  • Abnormal tone and reflexes, cranial nerve deficits if severe

Management

Depends on how high, whether other risk factors (diabetes, chronic kidney disease), symptoms and evidence of end organ damage.

Initially low salt diet, weight loss (if obese).  Remember other morbidities related to obesity.

Acute hypertension might need frusomide and/or nifedipine.

Long term treatment is only going to be started if no improvement with lifestyle measures. Target BP depends on risk factors, as above.

[2016 European Society for Hypertension guidelines]

Short Stature

Are they really? Plot height and weight, and check figures if in doubt!

Investigate if:

  • More than 2 standard deviations below mean worthy of investigation,
  • more than 2 standard deviations below mean parental height.
  • Height velocity less than 5cm per year

Is there evidence of chronic disease? Needs full history and examination, including urine dip. Common things would be renal failure, coeliac disease, IBD, hypothyroidism. Endocrine causes tend to produce relatively heavy children, other chronic diseases tend to produce relatively slight children.

Are they dysmorphic? Main syndromes to look out for:

  • Turners – besides short stature, webbed neck, characteristic facies, short metacarpals, broad chest with widely spaced nipples, hyperconvex fingernails and toenails (but can be missed); decreased growth velocity and delayed puberty

Bone age will be delayed in all except familial and idiopathic. Progressively falls behind in endocrine disorders.

Causes

Constitutional delay – good weight at birth, then “catch down” growth, dropping through centiles in infancy. Growth velocity is then normal, but with delayed bone age and delayed puberty.

Small for gestational age babies tend to catch up in first few years of life with their genetic potential, but can take up 4 years or more. 10% however remain small (more than 2 SDs below MPH) through life. Consider other causes if no catch up in first 6 months of life or still small at 2 years.

Growth hormone deficiency – can be congenital or acquired (head injury, meningitis etc). Early growth tends to be normal (growth hormone doesn’t contribute much in first few years of life). Look for microphallus and midline facial abnormalities.

Investigations

  • Karyotype if dysmorphic or if girl
  • TFTs
  • IGF1 – screening test for Growth hormone problems, but may need GH stimulation testing
  • U&Es, LFTs, CRP/ESR
  • Urinalysis
  • Bone age

Thyroid

Thyroid issues can be congenital, neonatal, autoimmune, or related to syndromes eg Downs, Digeorge.

Note that thyroid function tests can be affected by intercurrent illness, there is also viral thyroiditis where you might get transient (usually mild) abnormalities.  So borderline results (especially if asymptomatic or other medical issues) usually just need repeated.  If results confusing, do T3.  If normal then abnormal T4 likely to be transient.  If suspicion of evolving problem, do autoantibodies (TPO antibody, Thyroid Receptor Ab (TRab)).  If progressive decline then likely to be emerging autoimmune condition.

All kinds of unusual clinical presentations in thyroid disease, for example:

  • Effusions in hypothyroidism, including pericardial effusions – capillary dysfunction!? Impaired lymphatic drainage?
  • Body pain
  • Precocious puberty (although delayed more typical)

Congenital Hypothyroidism

Isolated TSH elevation >20 is usually treated.

True congenital hypothyroidism mostly dysgenesis, ie poorly formed gland, of which <2% have identified mutations (mostly thyroid peroxidise, thyroglobulin and TSH receptor proteins – EDTA sample, Dr Therese Bradley at SGH Genetics).  May be due to dyshormonogenesis (10%, autosomal dominant, gland looks normal on scan), TSH Receptor defect. Do a Family History.

Mostly found on newborn screening now.  Life long.

Placental thyroxine important, iodine too, on neonatal thyroid function.  In the first 14/7 of life, high TSH/T4/T3 seen.  Transient neonatal hypothyroidism seen, 25% of +ve guthrie tests!

Symptoms

If missed or untreated, classic signs are umbilical hernia, goitre, hoarse cry, coarse facies, Developmental Dysplasia of Hip!

Imaging

SPEG recommend that all families should be given the opportunity for imaging, subject to availability, because more informative than blood tests alone, will aid in genetic counselling, likelihood of lifelong treatment if proven permanent CH, provides a useful guide as to thyroxine dose.

Combined isotope and ultrasound imaging (dual scanning) is preferred. Isotope scans should be performed by day 5 of start of treatment to ensure avoidance of false negatives due to TSH suppression (advisable to take thyroid function sample on day of scans to confirm reliability of results). Ultrasound may show an abnormal gland (dyshormonogenesis) or else agenesis (no gland).   But in agenesis may be remnants of embryonic structural elements which can be mistaken for a gland – can persist into teenage years but max 5mm x 5mm!. Hence importance of supporting radio-isotope imaging.  Experience of ultrasonographer important.

Management

Some concern that thyroxine liquid not as consistent levels?  Automatic script request from pharmacy, patient then notified when ready.

Follow up

  1. Scottish guideline suggests typical doses at different ages, up to age 3, to encourage dose changes with growth rather than waiting till dose insufficient and hypothyroidism emerges (see table).  Use TFTs to confirm compliance.
  2. Assess growth: weight, length until 2 years, then height, head circumference until 3 years
  3. Assess development – consider pre-school audiology (for subtle hearing impairment due to CH)
  4. Transition – patient education. Boys to GP (unless problems with control), girls – to adult endocrinology (for pre-pregnancy counselling).

Aim for fT4 > 15 pmol/l and TSH <5.0 mU/l

Age LT4 dose (ug daily) LT4 dose (ug/kg/day)
Female Male Female Male
3 months 41.3 43.3 7.2 6.9
6 months 45.8 50.0 6.1 6.2
9 months 47.9 53.1 5.6 5.7
12 months 55.0 53.1 5.8 5.2
18 months 62.5 61.1 5.8 5.3
24 months 70.3 58.3 5.9 4.6
36 months 75.0 62.5 5.3 4.25

Insulin pumps

Pumps particularly good for recurrent hypoglycaemia, suboptimal control, under 5s, better QOL.

Good for sport.

Parents report loss of control!

Continuous blood glucose monitoring – 6 days, twice daily calibration bloods. Not Prescribable. Some link to pumps, others diagnostic only. Newest pumps can auto-adjust rate but only downwards. Esp normal pre-prandial bloods but Suspected hyperglycaemic between meals.

Ketones cause insulin resistance so higher doses acceptable. Blood ketone over 3 must come to hospital, but no fixed need for IV therapy.

Tight glucose from diagnosis seems to give best results in long term – “metabolic memory”? Prolonged honeymoon phase? Better education?

ADAPT study starting, prevention.

Only 15g snack allowed if on pen eg half apple! Else low carb eg cheese, pepperoni. Pumps allowed snacks of any size, tend to calm down after first couple of weeks!

Digestion v variable. High fat, high carb? Glycemic index ie fibre. Chewing!

Pump can bolus with individual courses! Slow bolus for cinema or buffet meal eg over 30 mins.

Non-waterproof pumps disconnected for bath etc, shower cap applies to cannula site, leave pump running to avoid air space.

 

 

Diabetic Ketoacidosis

DKA – Updated NICE guidance 2016.

The potentially serious acute complication of diabetes.  In the absence of adequate insulin, glucose levels start to rise in the blood, spilling over the threshold for kidney resorption and causing a diuresis.  Metabolism switches to ketone bodies, causing acidosis.

There is no fixed definition. One guideline says pH <7.11 (about 73), bicarbonate under 18.

Beware can develop with normal glucose levels IN THOSE TAKING INSULIN.  Suspect if blood ketones above 3 in known diabetic, refer to hospital.  Between 0.5 and 3, follow sick day rules.

Rehydration should only be attempted by experienced paediatric teams!  Estimate fluid deficit on basis of blood pH – 7.1 or above, assume 5%, below 7.1 then 10%.

For maintenance, use 2ml/kg/hr for under 10kg; 1ml/kg/hr for 10-40kg; 40ml/hr for above that.

See graphic in BMJ 2016.

BSPED 2015 – Changes from previous guideline are as follows:

  1. Change in the degree of dehydration to be used to calculate fluids; 5% for mild to moderate DKA and 10% for severe DKA, based on pH
  2. De-emphasise sodium chloride bolus at the start of treatment apart from the sickest children
  3. No more than one 10ml/kg fluid bolus to be given without discussion with a senior doctor
  4. Further reduction in maintenance fluid rates, and simpler calculation of fluid rates
  5. No longer to subtract any boluses given up to 20 ml/kg from the fluid calculation (as the rate is already reduced significantly from previous guidelines)
  6. Continuation of 0.9% sodium chloride (instead of changing to 0.45% sodium chloride) for the full duration of rehydration
  7. Option for using an intravenous insulin infusion rate of 0.05 Units//kg/hour OR 0.1 Units/kg/hour

Diabetes

Updated NICE guidance 2016.  Characteristics:

  • random glucose >11,
  • polyuria, polydipsia,
  • excessive tiredness,
  • weight loss.

WHO 1999 criteria – fasting normally <5.6, >7 diagnostic.  Random >11 diagnostic (assuming there’s nothing sticky on the finger tested!!!).  Glucose tolerance test (starts with fasting level) 2hr level >11.1 diagnostic, 7.8-11.1 is impaired glucose tolerance.

False positives – infection, recent surgery, uncontrolled thyroid disorder, starvation.

Epidemiology

Increasing rates in Europe. Scotland rate second only to Scandinavia.  Marked increase in under 5s. Aiming for routine pump therapy within a few months.

Subtypes

Type 2 more often in S Asian, Hispanic, Afro-Caribbean.  Clue is raised c-peptide – as this is co-produced with insulin, it means there is still endogenous insulin being produced (and cleared at more consistent rate than insulin, so more reliable, esp if on exogenous insulin).  C-peptide also used to look for insulinoma or factitious hypoglycaemia.  May also predict glycaemia control, complications and response to hypoglycaemic agents.

LADY – latent autoimmune diabetes of the young. More common? Different HLA type. Antibody positive but insulin sensitive and slow progress.

MODY – inability to produce insulin but normal beta cells.  Eg KIR 6.2 mutations, within months of birth.

Management

Reduced ideal HbA1c target – 48mmol/l (6.5%).  

No DAPHNE for kids.

Multiple daily injections from diagnosis, with level 3 carbohydrate (CHO) counting education, blood ketone testing strips.  Other regimens eg BD, TDS only for where problems with compliance.  See also pumps.

NICE guidance now includes Type 2 – suspect if strong FH, obesity, black/Asian origin, minimal insulin requirements (<0.5u/kg after “partial remission phase”), evidence of insulin resistance (viz acanthosis nigricans).

BMJ NICE diabetes infographic

Optimal blood glucose range is 4-7 on waking and between meals; 5-9 after meals; 5+ when driving.  At least 5 tests per day recommended, more frequently during physical activity and illness.But take into account:

  • risk of hypoglycaemia;
  • competitive sports;
  • need to lose weight;
  • life goals (careers, exams, foreign travel);
  • any relevant co-morbidity.

Monitoring

Annual thyroid, hypertension, albuminuria checks from diagnosis; retinopathy testing from age 12.  Type 2 don’t need thyroid but do need dyslipidaemia.

School

Most schools happy to give insulin. But no legal requirement. Lancets for school retract into cartridge.

Self-Efficacy

Encourage ownership of meters etc, downloading at home. Over 14 to get access to SCI-DC, as adults.

Hypoglycaemia

Glucose levels are maintained after a meal by release from glycogen stores (glycogenolysis), driven by Glucagon. When glycogen stores are low, then glucose can be produced from fat stores by fatty acid oxidation (via ketones) and from protein by gluconeogenesis. The switching over is moderated by cortisol, and growth hormone also important.  Insulin is the only hormone that lowers blood sugar levels.

Hypoglycaemia makes you grumpy, sweaty, pale. It can cause a wide range of acute, transient neurological symptoms including tremor, confusion, ataxia, weakness.  If severe, it causes seizures, which causes release of glucose from muscles. Some cases of sudden unexpected death are thought to be due to inborn errors of metabolism causing hypoglycaemia.

Recurrent severe episodes in infancy can lead to permanent neurodisability.

There is debate about what level of blood sugar is abnormal, or whether it is only symptomatic low blood sugar that is important.  Less than 2.6mmol/l is uncontroversial (note that near patient tests are not very accurate at low levels, which they are not really designed for, so lab confirmation is always required).

Usual cause is acute viral illness with reduced oral intake and vomiting.  But this can also be a trigger that reveals an underlying metabolic disorder…

  • Neonate? If big liver, remember Galactosaemia and Fructosaemia (reducing sugars in urine). Else Beckwith Wiedemann Syndrome.
  • High glucose requirement (see below)? =Hyperinsulinism
  • Signs of adrenal insufficiency? Abdominal/back pain, low Na, high K/Ca! Hyperpigmentation.
  • Signs of hypopituitarism? Growth failure, midline defects, micropenis.
  • Encephalopathy (esp vomiting)? Consider organic aciduria
  • Odour? Consider Maple syrup urine disease etc
  • Ketones present? If not then Fatty acid oxidation disorder eg MCAD.
  • Hepatomegaly? Glycogen storage disorders, also galactosaemia, acute liver failure eg Reyes syndrome (this may also be the mechanism in respiratory chain disorders).
  • Overdose? Propranolol, alcohol, salicylates in particular.
  • Consanguinity?
  • Time of last meal? Endocrine problems can cause symptoms at any time, as can hyperinsulinism. Glycogen storage/synthase problems cause early hypoglycaemia (ie within 3-8 hours).

Investigations

Get 1 ml lactate & 6 ml lithium heparin, bloodspots on neonatal screening card during hypo, and first urine (freeze).

Glucose requirement (mg/kg/minute) can be calculated from the following formula:

  • from IV fluids = Infusion rate (ml/hr) x % of glucose infusion x 0.1677/weight.
  • from oral feed: glucose content of standard infant formula is 7.2g/ 100ml, and of LBW formula is 8.6g/ 100ml.

Normal is 4-6 mg/kg/min, over 8 is suspicious of hyperinsulinism.

  • Insulin and C-peptide. Insulin should be undetectable, C-peptide 0.3-1.12 if hypoglycaemic with appropriate insulin response. Else hyperinsulinism (exogenous, or congenital)
  • Blood Glucose – below 2.6 considered true hypoglycaemia.  Note that BM sticks are not really designed for low sugars, and are not reliable.
  • Lactate – should be normal, otherwise high (with ketones) suggests glycogen storage disorder (with notable exception of Glycogen synthase defect)
  • TFTs – hypopituitarism
  • Cortisol – hypoadrenalism (cortisol should be high as part of stress response eg over 400 – else consider hypoadrenalism (Addison’s)
  • LFTs – beware primary liver problem
  • U&Es, Calcium – Low sodium, high potassium/Ca seen in hypoadrenalism
  • Ammonia – for organic acidaemias etc, or primary liver problem
  • Amino acids – for Maple Syrup Urine Disease etc
  • Carnitine, hydroxybutyrate – for Fatty Acid Oxidation (FAO) disorders
  • Acylcarnitines (blood spot) – for FAO disorders
  • Free Fatty acids – for FAO disorders, esp FFA/3OH-butyrate ratio (ketones are made from FFA so should be higher or not much lower, else block)
  • Blood gas – ?Acidosis
  • Urine for reducing sugars (Galactosaemia etc),
  • Urine/blood for organic acids

Prognosis

Mostly ketotic hypoglycaemia, due to starvation/vomiting. Adequate history?  Beware encephalopathy, raised ammonia, hepatomegaly.

75 LGA newborns with hypoglycaemia followed up to age 4 – no late effects. [Archives of Disease in Childhood 2005;90]