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5 Endocrinology
Screen the following for abnormalities in thyroid function
https://t.me/med1917
• Patient s with atri al fibrilla tion.
• Pati ents with h yperli pidaem ia (4– 14% have hypothyroidism).
• Diabetes mellitus— on annual review.
• Wom en wi th typ e 1 DM during 1st trimester and post delivery (3- fold rise in inci-
dence of postpartum thyroid dysfunction).
• Pati ents on ami odaron e or lit hium (6- monthly).
• Pati ents with D own’s or Turn er’s syn drome, or Ad dison’s disea se (yea rly).
• Pregnant women/ women planning a pregnancy if >30 years, have a history of
goitre, family history of thyroid disease, or other autoimmune disease.
• As part of a dementia screen.
Table 5.
3
Interpreting
TFT
S
Hormone profile Diagnosis
TSH
,
T
4
TSH
, normal
TSH
,
T
4
TSH
,
T
, and
4
TSH
,
T
or
T
4
TSH
, normal
TSH
,
T
4
TSH
,
T
, and
4
Normal
TSH
,
T
abnormal
* In ‘consumptive hypothyroidism’ deiodinase activity is ; suspect if thyroxine doses have to be .
4
Hypothyroidism
T
Tre at ed hy po th yr oi di sm or s ub cl in ic al hy po th yr oi di sm (p
4
Poor compliance with levothyroxine;
or thyroid hormone resistance
T
Slow conversion of
3
hyperthyroxinaemia
Hyperthyroidism
3
Subclinical hyperthyroidism
T
and
T
4
3
T
to
T
(deiodinase deficiency; euthyroid
4
3
*
) or thyroid hormone antibody artefact
Central hypothyroidism (hypothalamic or pituitary disorder)
Sick euthyroidism or pituitary disease
T
3
Consider changes in thyroid- binding globulin, assay interference, amiodarone, or pituitary
TSH
TSH
- secreting tumour
tumour
215
211
)
Fig 5.
13
The images are from an isotope scan, with and without markers placed over the sternal
notch. We can see on the left that the nodule is metabolically inactive (‘cold’). The hot nodule (right
pair) is a very avid nodule causing background thyroid suppression.
Image courtesy of Dr Y.T. Huang.
5 Endocrinology
Thyrotoxicosis
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212
The clinical eect of excess thyroid hormone, usually from gland hyperfunction.
Symptoms Diarrhoea; weight; appetite (if , paradoxical weight gain in 10%);
overactive; sweats; heat intolerance; palpitations; tremor; irritability; labile emotions;
oligomenorrhoea ±
infertility. Rarely psychosis; chorea; panic; itch; alopecia; urticaria.
Signs Pulse fast/ irregular (AF or
erythema; thin hair; lid lag; lid retraction (exposure of sclera above iris; causing ‘stare’)
fig
5.14
; eyelid lags behind eye’s descent as patient watches your finger descend slowly).
(
There m ay be goitre (
of Graves’ disease
thalmoplegia.
1 Eye disease (see
2
Pretibial myxoedema: oedematous swellings above lateral malleoli: the
term myxoedema is confusing here.
clubbing, painful finger and toe swelling, and periosteal reaction in limb bones.
Tests
TSH
(suppressed),
neutropenia (in Graves’),
receptor antibody). If antibody negative, and cause of hyperthyroidism unclear—
consider thyroid uptake scan. If ophthalmopathy, test visual fields, acuity, and eye
movements (see
BOX
Causes Graves’ disease Prevalence: 0.5% (⅔ of cases of hyperthyroidism). :
40– 60
Typ ic a l ag e:
yrs (younger if maternal family history). Cause: circulating IgG autoantibodies binding to and activating
cause smooth thyroid enlargement and hormone production (esp.
orbital autoantigens. Triggers: stress; infection; childbirth. Patients are often hyperthyroid but may be, or become, hypo- or euthyroid. It is associated with other autoimmune
diseases: vitiligo, type
elderly and in iodine- deficient areas. There are nodules that secrete thyroid hormones.
Surgery is indicated for compressive symptoms from the enlarged thyroid (dysphagia
or dyspnoea).
tope scan, the nodule is ‘hot’ (
thyroid tissue
with thyroid tissue.
thyroid storm, p
(
thyroglobulin.
painful goitre,
p
214
(
(rare).
Tox i c a d e n om a Th ere is a solit ary nodule prod ucing
Metastatic follicular thyroid cancer, or struma ovarii: ovarian teratoma
Exogenous Iodine excess, eg food contamination, contrast media
820
Others 1 Subacute de Quervain’s thyroiditis: self - limiting post- viral with
T
° ±
), lithium (hypothyroidism more common), immunotherapy. 3 Postpartum. 4 TB
5
Hydatidifo rm mol e (con sider if hy peremesis).
Treatment Varies depending on cause.
1
Drugs - blockers (eg propranolol 40mg/ 6h) for rapid control of symptoms.
Anti- thyroid medication: two strategies (equally eective):
carbimazole
20– 40
in range, monitor
simultaneously (less risk of iatrogenic hypothyroidism). In Graves’, maintain on
either regimen for
radioiodine or surgery. Carbimazole
to dangerous sepsis; rare (
of infection, eg
2
Radioiodine (
dence for cancer, birth defects, or infertility in women.
T
131
I
tion. Caution in active hyperthyroidism as risk of thyroid storm, and avoid if
active thyroid eye disease (
3
Thyroidectomy (usually total) Carries a risk of damage to recurrent laryngeal
nerve (hoarse voice) and hypoparathyroidism (transient/ permanent). Patients
will become hypothyroid, so thyroid replacement needed.
4
In pregnancy and infancy Get expert help. See
Complications Heart failure (thyrotoxic cardiomyopathy, in elderly), angina, AF
10– 25
(seen in
osteoporosis, ophthalmopathy, gynaecomastia.
%: control hyperthyroidism and warfarinize if no contraindication),
SVT; VT
rare); warm moist skin; fine tremor; palmar
fig
5.15
); thyroid nodules; or bruit depending on the cause. Signs
BOX
‘Thyroid eye disease’): exophthalmos, oph-
3
Thyroid acropachy: extreme manifestation, with
T
, and
T
. There may be mild normocytic anaemia, mild
4
3
2
+
ESR
, Ca
,
LFT
. Also Check thyroid autoantibodies (
‘Thyroid eye disease’).
G
- protein- coupled thyrotropin receptors, which
1
DM,
Addison’s (table
p
210
5.4
). Tox i c m u l t in o d u l ar g oi t r e Seen in the
), and the rest of the gland is suppressed. Ectopic
, if already hyperthyroid). Levothyroxine excess causes
ESR
. Low isotope uptake on scan.
mg/ 24h PO; check
3
- monthly. B Block- replace: give carbimazole + levothyroxine
12– 18
months then withdraw. ~50% will relapse, requiring
°, sore throat/ mouth ulcers.
) Most become hypothyroid post- treatment. There is no evi-
TFT
S every
6
wks and adjust dose; once
SE
0.03
: agranulocytosis (neutrophils, can lead
%)); warn to stop and get an urgent
p
821
).
OHCS
Thyroid storm (p
NSAID
p28 &
S.
2
CI
T
), and react with
3
T
and
T
. On iso-
3
4
T
,
4
Drugs: amiodarone
13
A Titration, eg
FBC
if signs
: pregnancy, lacta-
OHCS
p
251
.
821
).
≈
TFT
TSH
9
:1.
T
,
3
S
5 Endocrinology
Thyroid eye disease
https://t.me/med1917
Seen in 25– 50% of people with Graves’ disease. The main known risk factor is
smoking. The eye disease may not correlate with thyroid disease and the patient
can be euthyroid, hypothyroid, or hyperthyroid at presentation. Eye disease may
be the first presenting sign of Graves’ disease, and can also be worsened by treatment, typically with radioiodine (usually a transient eect). Retro- orbital inflammation and lymphocyte infiltration results in swelling of the orbit.
Symptoms Eye discomfort, grittiness, tear production, photophobia, diplopia,
acuity, aerent pupillary defect (
p68) may mean optic nerve compression: seek
expert advice at once as decompression may be needed. Nerve damage does not
necessarily go hand- in- hand with protrusion. Indeed, if the eye cannot protrude
for anatomical reasons, optic nerve compression is more likely— a paradox!
Signs Exophthalmos— appearance of protruding eye; proptosis— eyes protrude
beyond the orbit (look from above in the same plane as the forehead); conjunctival
oedema; corneal ulceration; papilloedema; loss of colour vision. Ophthalmoplegia
(especially of upward gaze) occurs due to muscle swelling and fibrosis.
Tests Diagnosis is clinical. CT/
MRI
of the orbits may reveal enlarged eye muscles.
Management Get specialist help. Treat hyper- or hypothyroidism. Advise to stop
smoking (worse prognosis). Most have mild disease that can be treated symptomatically (artificial tears, sunglasses, avoid dust, elevate bed when sleeping to
periorbital oedema). Diplopia may be managed with a Fresnel prism stuck to one
lens of a spectacle (aids easy changing as the exophthalmos changes). Oral selenium
supplementation at
disease, try high- dose steroids (
200
mcg daily may be beneficial in mild disease. In more severe
IV
methylprednisolone) and mycophenolate mofetil.
Surgical decompression is used for severe sight- threatening disease, or for cosmetic
reasons once the activity of eye disease has reduced (via an inferior orbital approach, using space in the ethmoidal, sphenoidal, and maxillary sinuses). Eyelid surgery may improve cosmesis and function. Orbital radiotherapy can be used to treat
ophthalmoplegia but has little eect on proptosis.
2
nd line: rituximab, tocilizumab.
Causes of goitre
Diuse
• Physiological
• Graves’ disease
• Hashimoto’s thyroiditis
• Subacute (de Quervain’s)
Fig 5.
14
Thyroid eye disease: lid retraction causing a
‘staring’ appearance.
Fig 5.
15
Goitre.
thyroiditis (painful).
Nodular
• Multinodular goitre
• Adenoma
• Carcinoma.
213
Table 5.
4
Manifestations of Graves’ disease— and pathophysiology
Pituitary
Heart Rate; contractility
Liver
Bone Bone turnover; osteoporosis
Genital Libido; erectile dysfunction Sex hormone globulin; testosterone
Genital Irregular menses Oestrogen antagonism
Metabolic
White fat Fa t m a ss Adrenergic- mediated lipolysis
CNS
Muscle Proximal myopathy
Thyro id
* Emotional or tactile stimuli cause spasms; seen in any autoimmune state (eg type 1 DM); : baclofen± IV Ig.
Suppressed
Perip heral
Ther mogene sis; O2 use Fat ty ac id o xi da ti on ; Na- K
Sti perso n syndrome ( rare )
Secretion of
TSH
T
;
3
T
LDL
(p
682
) Ty pe 1 5’- deiodinase;
*
and
T
3
4
Expression of thyrotropin subunit
Serum atrial natriuretic peptide
Osteocalcin;
Antibodies to glutamic acid decarboxylase
Sarcoplasmic reticulum Ca
Typ e 2 5’- deiodinase activity in thyroid
LDL
recept ors
ALP
; urinary N- telopeptide
ATP
2
+
- activated
ase
ATP
ase
5 Endocrinology
Hypothyroidism (myxoedema)
BRADYCARDIC
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214
The clinical eect of lack of thyroid hormone. It is common (4/
prognosis is excellent; untreated it is disastrous (eg heart disease, dementia).
it is insidious, both you and your patient may not realize anything is wrong, so be
alert to subtle, non- specific symptoms, esp. in women
Symptoms Tiredness; sleepy, lethargic; mood; cold- disliking; weight; constipation;
menorrhagia; hoarse voice; memory/ cognition; dementia; myalgia; cramps; weakness.
Signs
; Reflexes relax slowly; Ataxia (cerebellar); Dry thin hair/ skin;
Yawning/ drowsy/ coma (p
hands; feet) ± pericardial or pleural eusion;
Defeated demeanour; Immobile ± i leus ; CCF. Also: neuropathy; myopathy; goitre (fig
Diagnosis (p
210
) Have a low threshold for doing
secondary hypothyroidism:
Cholesterol and triglyceride ; macrocytosis (less often normochromic anaemia too).
Causes of primary autoimmune hypothyroidism
• Primary atrophic hypothyroidism : ≈ 6:1. Common. Diuse lymphocytic infil-
tration of the thyroid, leading to atrophy, hence no goitre.
• Hashimoto’s thyroiditis Goitre due to lymphocytic and plasma cell infiltration.
Commoner in women aged
tial period of hyperthyroid (‘Hashitoxicosis’). Autoantibody titres are very high.
Other causes of primary hypothyroidism
Worldwide the chief cause is iodine deficiency.
• Post- thyroidectomy or radioiodine treatment.
• Drug- induced: antithyroid drugs, amiodarone, lithium, iodine, immunotherapy.
• Subacute thyroiditis: temporary hypothyroidism after hyperthyroid phase.
Secondary hypothyroidism Not enough
Hypothyroidism’s associations Autoimmune is seen with other autoimmune dis-
1
eases (type
DM, Addison’s, and PA, p
primary biliary cholangitis, ovarian hyperstimulation (
polyneuropathy, organomegaly, endocrinopathy,
skin pigmentation/ tethering.
recessive) defect in hormone synthesis, eg Pendred’s syndrome (with deafness): there is
uptake on isotope scan, which is displaced by potassium perchlorate.
Pregnancy problems Poorly treated hypothyroidism may be associated with pre-
eclampsia, preterm delivery, low birth weight, postpartum haemorrhage, cognitive
impairment in the child. Often needs increased dose of levothyroxine in pregnancy.
Treatment
• Healthy and young Start levothyroxine (
TSH
in the lower half of the reference range. Consider measuring
for
3
months and titrating levothyroxine as needed— until
TSH
monitor
• Elderly or ischaemic heart disease Start with 25mcg/ 24h; dose by 25mcg/ 4wks
according to
• If diagnosis is in question and T4 already given Stop
onc e a year. Enzyme induce rs (p
TSH
(cautiously, as levothyroxine may precipitate angina or MI).
Amiodarone An iodine- rich drug structurally like
thyroid problems from it. Hypothyroidism can be caused by toxicity from iodine ex-
T
release is inhibited). Thyrotoxicosis may be caused by a destructive thyroiditis
cess (
4
or due to thyroid hormone synthesis from the excess iodine content of amiodarone.
Radioiodine uptake scans or gland vascularity on thyroid ultrasound may help distinguish the causes and strategy of treatment. Seek expert help. Patients are often
treated with a combination of antithyroid medications and steroids whilst the cause is
identified. Thyroidectomy may be needed if resistant to medical therapy.
Myxoedema coma The ultimate hypothyroid state before death. See p
2
Treat the patient not the blood level! No exact cut- o in
from heart disease mirrors
2.5– 3.5
. If
TSH
>3.65 and possibly symptomatic, a low dose of levothyroxine may be tried. Monitor symptoms,
TSH,
and
T
carefully. Overexposure to thyroxine may cause osteoporosis ± AF.
4
1000
40
yrs old (: ≈ 6:1).
820
); Cold hands ± T°; Ascites ± non- pitting oedema (lids;
Round puy face/ double chin/ obese;
TFT
S!
TSH
T
and
TSH
or due to lack from the pituitary, p
4
60– 70
yrs. May be hypothyroid or euthyroid; rarely ini-
TSH
(due to hypopituitarism); very rare.
330
). Turner’s and Down’s syndromes, cystic fibrosis,
Genetic Dyshormonogenesis: genetic (often autosomal
T
) at 1.6mcg/ kg
4
681
TSH
even when in the normal range in women. Risk ≈ 1.4 if
TSH
(eg ≥4mU/ L);2
OHCS
p
146
);
M
- protein band (plasmacytoma) +
POEMS
PO;
review at 12wks. Aim
TSH
is on target— thereafter
) metabolism of levothyrox ine.
T
; recheck
TSH
4
T
; 2% of users will get significant
4
can be given partly because risk of death
TSH
/ yr). If treated,
As
5.16
T
(in rare
4
226
syndrome—
TSH
every
in 6 weeks.
820
.
1.5– 2.4 vs 1.7 if
TSH
).
).
5 Endocrinology
Why are symptoms of thyroid disease so various, and so subtle?
https://t.me/med1917
Almost all our cell nuclei have receptors showing a high anity for
TR
- 1 is abundant in muscle and fat; TR- 2 is abundant in brain; and TR
as
T
: that known
3
abundant in brain, liver, and kidney. These receptors, via their influence on various
enzymes, aect the following processes:
• The metabolism of substrates, vitamins, and minerals.
• Modulation of all other hormones and their target- tissue responses.
• Stimulation of O2 consumption and generation of metabolic heat.
• Regulation of protein synthesis, and carbohydrate and lipid metabolism.
• Stimulation of demand for co- enzymes and related vitamins.
Subclinical thyroid disease
Subclinical hypothyroidism Defined by a raised
10
is common: ~
thyroidism is ~
% of those >55yrs have
2
%, and increases as
TSH
TSH
TSH
with normal
. Risk of progression to frank hypo-
T
and
4
T
; risk doubles if thyroid peroxidase anti-
bodies are present, and is also increased in men.
Management:
• Confirm that raised
• Recheck the history: if any non- specific features (eg depression), discuss benefits of
treating (
• Have a low threshold for carefully supervised treatment as your patient may not be so
asymptomatic after all, and cardiac deaths may be prevente d. Treat if :
2
+ ve thyroid autoantibodies. 3 Past (treated) Graves’. 4 Other organ- specific auto-
immunity (type
to progress to clinical hypothyroidism. If
months— only continue if symptoms improve (or the patient is trying to conceive). If
the patient does not fall into any of these categories, monitor
• Risks from well- monitored treatment of subclinical hypothyroidism are small (but
TSH
is p ersis tent (r echec k in 2– 4 mon ths).
p
214
) with the patient— maybe they will function better.
1
DM, myasthenia, pernicious anaemia, vitiligo), as they are more likely
TSH
4– 10, and vague symptoms, treat for 6
TSH
yea rly.
1
TSH
≥10mu/ L.
there is an risk of atrial fibrillation and osteoporosis if overtreated).
Subclinical hyperthyroidism Occurs when
AF
an increased risk of
, heart failure, and osteoporosis.
TSH
, with normal
T
and
4
T
. There is
3
Management:
• Confirm that suppressed
• Check for a non- thyroidal cause: illness, pregnancy, pituitary or hypothalamic in-
suciency (suspect if
TSH
- suppressing medication, eg thyroxine, steroids.
• If
TSH
<0.1, treat on an individual basis, eg if aged >65 years, concurrent cardiovas-
cular disease or osteoporosis, symptoms of hyperthyroidism, or a toxic nodule.
• Options are carbimazole or propylthiouracil— or radioiodine therapy.
• If no symptoms, recheck 6- monthly.
TSH
is p ersis tent (r echec k in 2– 4 mon ths).
T
or
T
are at the lower end of the reference range), use of
4
3
215
- 1
is
. It
3
Fig 5.
16
Facial appearance in hypothyroidism.
Look for: pallor; coarse, brittle, diminished hair
(scalp, axillary, and pubic); dull or blank expression
lacking sparkle; coarse features; puy lids. These
signs are subtle:
uring
Reproduced from Cox and Roper, Clinical Skills,
have a low threshold for meas-
TSH
.
with permission from Oxford University Press.
2005
,
5 Endocrinology
Parathyroid hormone and hyperparathyroidism
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216
Parathyroid h ormone
by four parathyroid glands situated posterior to the thyroid (
controlled by −ve feedback via Ca
2
+
leasing Ca
active
and PO
1,25
dihydroxy- vitamin
4
Primary hyperparathyroidism Causes ~80% solitary adenoma, ~20% hyperplasia
0.5
of all glands, <
% parathyroid cancer. Presentation Often ‘asymptomatic’ (not in
retrospect!), with Ca
depressed, thirsty, dehydrated- but- polyuric; also renal stones, abdominal pain, pancreatitis, and ulcers (duodenal:gastric
cause pain, fractures, and osteopenia/ osteoporosis.
with hypertension. Association:
neoplasia’).
normal vit
hypocalciuric hypercalcaemia, tertiary hyperparathyroidism).
Also PO
urinary Ca
Tests Ca
D
(other causes of this: thiazides, lithium, familial
−
3
(unless in renal failure),
4
2
+
. Imaging: osteitis fibrosa cystica (due to severe resorption; rare) may show up as subperiosteal erosions, cysts, or
brown tumours of phalanges ± acro- osteolysis (
DEXA
(p
pot’ skull.
675
fluid intake to prevent stones; avoid thiazides + high Ca
Indications for parathyroidectomy: symptomatic hypercalcaemia,
2
+
serum Ca
>2.85, osteoporosis, renal calculi, renal function, age
50
yrs, hypercalciuria. Complications: hypoparathyroidism, recurrent laryngeal nerve damage ( hoarse), symptomatic Ca
(hungry bones syndrome). Pre- op
an adenoma; intra- op
moval. Recurrence: ~
sensitivity of parathyroid cells to Ca
indicated for management of symptomatic hyperparathyroidism
in those not fit for surgical intervention; monitor Ca
week of dose changes;
Secondary hyperparathyroidism Ca
take, chronic renal failure.
PTH
≥85pmol/ L and parathyroidectomy tricky.
Tertiary hyperparathyroidism Ca
longed secondary hyperparathyroidism, causing glands to act autonomously having
undergone hyperplastic or adenomatous change. This causes Ca
PTH
unlimited by feedback control. Seen in chronic renal failure.
of
Malignant hyperparathyroidism Parathyroid- related protein (
by some squamous cell lung cancers & breast and renal cell carcinomas. This mimics
PTH
resulting in Ca
2
+
Hypoparathyroidism
Primary hypoparathyroidism
with or inappropriately normal
p
670
, ± autoimmune comorbidities (see
Causes Autoimmune; congenital (Di George syn.,
(calcitriol/ alfacalcidol) combined with Ca
Daily recombinant synthetic
Secondary hypoparathyroidism Radiation, surgery (thyroidectomy, parathyroid-
ectomy), hypomagnesaemia (magnesium is required for
Pseudohypoparathyroidism Failure of target cell response to
metacarpals (esp.
ganglia (
fig
5.19
), IQ. Tests Ca
4
th and 5th, fig
(PTH)
is normally secreted in response to low ionized Ca
2
+
levels.
PTH
−
3
from bones • Ca
D
production is . Overall eect is Ca
3
2
+
on routine tests. Signs relate to: 1 Ca
acts by: • osteoclast activity re-
2
+
and PO
≈
7:1). 2 Bone resorption eects of
3
MEN-
1 (see
BOX
2
+
&
PTH
or inappropriately normal with
; for osteoporosis, p
PTH
8
% over 10yrs.14 Cinacalcet (a ‘calcimimetic’)
SE
US
sampling may be used to confirm re-
: gastrointestinal, myalgia.
‘Multiple endocrine
ALP
from bone activity, 24h
fig
5.17
674
). If mild: advise
and
MIBI
scan may localize
2
+
(
PTH
secretion); mainly
2
+
,
PTH
(appropriately). Causes Vit D in-
p
593
). The glands are
−
3
reabsorption in the kidney •
4
2
+
(p
2
+
and PO
668
BP: so check Ca
) ± ‘pepper-
2
+
intake.
2
+
Fig 5.
2
+
within 1
osteolysis.
Correct causes. Phosphate binders; vit D; cinacalcet if
2
+
,
PTH (
inappropriately). Occurs after pro-
2
+
from secretion
PTHrP
(
PTH
is , as
PTHrP
is not detected in the assay).
PTH
se cre tio n is due to g lan d fa ilu re. Tes t s Ca
−
3
PTH
; PO
or ,
ALP
4
BOX
2
+
PTH
inj ectio ns are av ailable— emerging treatment option.
2
supplements. Aim for a low– normal Ca
5.18
), round face, short stature, calcified basal
+
,
PTH
, or
. Signs Those of hypocalcaemia,
‘Autoimmune polyendocrine syndromes’).
OHCS
p
846
). Activated vitamin D
PTH
secretion).
PTH
ALP
. As for 1° hypoparathyroidism.
2
+
levels,
−
3
.
4
): weak, tired,
PTH
can
2
+
in everyone
17
Acro-
© Dr I Maddison
myweb.lsbu.ac.uk
) is produced
2
+
, usually
. Signs Short
2
+
.
5 Endocrinology
AIRE
Multiple endocrine neoplasia (
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In
MEN
syndromes there are functioning hormone- producing tumours in multiple or-
gans (they are inherited as autosomal dominants).
• Neurofibromatosis (p
p
698
& p
694
(
510
). • Carney complex (spotty skin pigmentation, schwannomas, myxoma
MEN
types 1, 2a, and 2b)
15
They comprise: •
MEN- 1
and - 2
). • Von Hippel– Lindau and Peutz– Jeghers syndromes
of skin, mucosa, or heart, especially atrial myxoma), and endocrine tumours: eg pituitary adenoma, adrenal hyperplasia, and testicular tumour.
MEN- 1
• Parathyro id hype rplasia/ adenoma (~95%; most Ca
• Pancreas endocrin e tumours (70%)— gastrinoma (p
rarely, somatosta tinoma (
p
255
), or glucagonomas (±glucagon syndrome: migrating rash; glossitis; cheilitis,
(
fig
8.21
, p
327
• Pituitary prolactinoma (~50%) or GH secreting tumour (acromegaly,16 p
; anaemia; weight; plasma glucagon; glucose).
DM
+ steatorrhoea + gallstones/ cholangitis),
2
+
).
267
) or insulinoma (p
232
209
VIP
); also,
), or,
oma
adrenal and carcinoid tumours are associated.
MEN- 1
gene is a tumour suppressor gene. Menin, its protein, alters transcrip-
The
tion activation. Many are sporadic, presenting in the
MEN- 2a
• Thyroid : medu llary thyroi d carci noma ( seen i n ~
• Adrenal: phaeochromocytoma (~50%, usually benign and bilateral).
• Parat hyroid hy perpla sia (~80%, but less than 20% have Ca
MEN- 2b
Has similar features to
MEN- 2
a plus mucosal neuromas and Marfanoid
3
rd– 5th decades.
100
%, p
592
).
2
+
).
appearance, but no hyperparathyroidism. Mucosal neuromas consist of ‘bumps’
on: lips, cheeks, tongue, glottis, eyelids, and visible corneal nerves.
MEN- 2
The gene involved in
kinase. Tests for ret mutations are revolutionizing
a prophylactic thyroidectomy to be done before neoplasia occurs, usually before
3
yrs of age. NB: ret mutations rarely contribute to sporadic parathyroid tumours.
a and b is the ret proto- oncogene, a receptor tyrosine
MEN- 2
treatment by enabling
Autoimmune polyendocrine syndromes
Autoimmune disorders cluster into two defined syndromes:
Type 1 Autosomal recessive, rare.
Cause Mutations of
(Auto ImmuneREgulator) gene on chromosome 21.
Fea ture s • Addison’s disease. • Chronic mucocutaneous candidiasis. • Hypo-
parathyroidism.
Also associated with hypogonadism, pernicious anaemia, autoimmune primary
hypothyroidism, chronic active hepatitis, vitiligo, alopecia.
Type 2
HLA D3
and D4 linked, common.
Cause Polygenic.
Features • Addison’s disease. • Type 1 diabetes mellitus (in 20%).
• Autoimmune thyroid disease— hypothyroidism or Graves’ disease.
Also associated with primary hypogonadism, vitiligo, alopecia, pernicious anaemia,
chronic atrophic gastritis, coeliac disease, dermatitis herpetiformis.
217
.
Fig 5.
18
Pseudohypoparathy-
4
roidism: short
metacarpals.
th and 5th
Fig 5.
19
Cerebral calcification in pseudohypopara thy-
roi dism: periventricular (left) and basal ganglia (right).
Courtesy of Professor Peter Scally.
5 Endocrinology
Adrenal cortex and Cushing’s syndrome
ACTH
CRF
ACTH
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218
Physiology The adrenal cortex produces steroids: 1 Glucocorticoids (eg cortisol), which
aect carbohydrate, lipid, and protein metabolism.
sodium and potassium balance (eg aldosterone,
have weak eect until peripheral conversion to testosterone and dihydrotestosterone.
Corticotropin- releasing factor (
from the pituitary, which in turn stimulates cortisol and androgen production by the adrenal cortex. Cortisol is excreted as urinary free cortisol and various
Cushing’s syndrome This is the clinical state produced by chronic glucocorticoid
excess + loss of the normal feedback mechanisms of the hypothalamic– pituitary–
adrenal axis and loss of circadian rhythm of cortisol secretion (normally highest on
waking). The chief cause is oral steroids. Endogenous causes are rare:
ACTH
; of these a pituitary adenoma (Cushing’s disease) is the commonest cause.
to
1
ACTH-
dependent causes (
• Cushing’s disease Bi lat eral adre nal hype rpl asi a fro m an
adenoma (usually a microadenoma,
dose dexamethasone test (see
leads to no change in plasma cortisol, but
morning cortisol (as occurs in normals).
• Ectopic
p
266
production Especially small cell lung cancer and carcinoid tumours,
. Specific features: pigmentation (due to
alkalosis (cortisol leads to mineralocorticoid activity), weight loss, hyperglycaemia. Classical features of Cushing’s are often absent. Dexamethasone even in
high doses (
• Rarely, ectopic
2
ACTH-
• Iatrogenic Pharmacological doses of steroids (common).
• Adrenal adenoma/ cancer (May cause abdo pain ± virilization in , p
the tumour is autonomous, dexamethasone in any dose won’t suppress cortisol.
• Adrenal nodular hyperplasia (As for adrenal adenoma, no dexamethasone
suppression.)
• Rarely Carney complex, p
8
mg) fails to suppress cortisol production.
independent causes (
Symptoms Weight; mood change (depression, lethargy, irritability, psychosis);
proximal weakness; gonadal dysfunction (irregular menses; hirsutism; erectile dysfunction); acne; recurrent Achilles tendon rupture; occasionally virilization if .
Signs Central obesity; plethoric, moon face; bualo hump; supraclavicular fat distri-
&
bution; skin
BP
mus cle at rophy; bruises ; purp le abd omina l stri ae (fig
; glucose; infection- prone; poor healing. Signs of the cause (eg abdo mass).
Te st s Random plasma cortisols may mislead, as illness, time of day, and stress (eg
venepuncture) influence results. Also, don’t rely on imaging to localize the cause: nonfunctioning ‘incidentalomas’ occur in ~
detects only ~
70
% of pituitary tumours causing Cushing’s (many are too small).
Treatment Depends on the cause.
• Iatrogenic Stop medications if possible.
• Cushing’s disease Selective removal of pituitary adenoma (trans- sphenoidally).
Bilateral adrenalectomy if source unlocatable, or recurrence post- op (complication: Nelson’s syndrome: skin pigmentation due to
tumour, as adrenalectomy removes −ve feedback; responds to pituitary radiation).
• Adrenal adenoma or carcinoma Adrenalectomy: ‘cures’ adenomas but rarely
cures cancer. Radiotherapy
• Ectopic
Surgery if tumour is located and hasn’t spread. Metyrapone, ketoconazole, and fluconazole cortisol secretion pre- op or if awaiting eects of radiation. Intubation + mifepristone (competes with cortisol at receptors) + etomidate
(blocks cortisol synthesis) may be needed, eg in severe
Prognosis Untreated Cushing’s has vascular mortality.17 Treated, prognosis is
good (but myopathy, obesity, menstrual irregularity,
changes and
DM
often remain— so follow up carefully, and manage individually).
2
Mineralocorticoids, which control
p
660
). 3 Androgens, sex hormones which
CRF
) from the hypothalamus stimulates
ACTH
)
p
228
). : >1:1. Peak age: 30– 50yrs. A low-
BOX
‘Investigating suspected Cushing’s disease’)
8
mg may be enough to more than halve
ACTH
), hypokalaemic metabolic
ACTH
17
- oxoge nic steroids .
80
ACTH
- secreting pituitary
secretion
% are due
production Some thyroid (medullary) and prostate cancers.
ACTH
due to −ve feedback
217
. McCune– Albright syndrome, see
5
% on adrenal CT an d ~10% on pituitary
&
adrenolytic drugs (mitotane) follow if carcinoma.
)
224
.) Because
OHCS
p
5.20
); osteoporosis;
ACTH
from an enlarging pituitary
ACTH
- associated psychosis.
BP
, osteoporosis, subtle mood
854
.
MRI. MRI
5 Endocrinology
Investigating suspected Cushing’s syndrome
ACTH
CRH
https://t.me/med1917
First, confirm the diagnosis (a raised plasma cortisol), then localize the source on
the basis of laboratory testing. Use imaging studies to confirm the likely source.
1
st- line tests Overnight dexamethasone suppression test: a good outpatient test.
Dexamethasone
suppresses to <
2
%; false + ves: 2% normal, 13% obese, and 23% of inpatients. NB: false + ves
<
1
mg PO at midnight; do serum cortisol at
50
nmol/ L; no suppression in Cushing’s syndrome. False −ve rate:
9AM. Normally, cortisol
(pseudo- Cushing’s) are seen in depression, obesity, alcohol excess, and inducers
of liver enzymes (rate of dexamethasone metabolism, eg phenytoin, phenobarbital, rifampicin,
alternative.
2
nd- line tests If 1st- line tests abnormal: 48h dexamethasone suppression test:
give dexamethasone
6
h after last dose). Again, in Cushing’s syndrome, there is a failure to suppress
at
cortisol.
pituitary (suppression) from other causes (no/ part suppression).
p
681
). 24h urinary free cortisol: (normal: <
0.5
mg/ 6h PO for 2d. Measure cortisol at 0 and 48h (last test
48
h high- dose dexamethasone suppression test: (2mg/ 6h) may distinguish
280
nmol/ 24h) is an
Midnight cortisol:
admit (unless salivary cortisol used). Often inaccurate due to measurement issues.
Normal circadian rhythm (cortisol lowest at midnight, highest early morning) is lost
in Cushing’s syndrome. Midnight blood, via a cannula during sleep, shows cortisol in
Cushing’s. Late night salivary cortisol can also be used as a
2
nd- line test.
Localization tests (Where is the lesion?) If the 1st- and 2nd- line tests are + ve—
plasma
. If
ACTH
is undetectable, an adrenal tumour is likely
glands. If no mass, proceed to
guish a pituitary cause from ectopic
corticotropin- releasing hormone (
test or
. Measure cortisol at
IV
ACTH
ectopic
production.
If tests indicate that cortisol responds to manipulation, Cushing’s disease is likely.
Image the pituitary (
.
sampling
If tests indicate that cortisol does not respond to manipulation, hunt for the
source of ectopic
neck, thorax, and abdomen, eg for small
ACTH
adrenal vein sampling. If
ACTH
production by high- dose suppression
) test:
120
min. Cortisol rises with pituitary disease but not with
MRI
) and consider bilateral inferior petrosal sinus blood
100
— eg IV contrast CT of chest, abdomen, and pelvis ±
ACTH-
secreting carcinoid tumours.
CT/ MRI
ACTH
is detectable, distin-
adrenal
mcg ovine or human
MRI
CRH
of
219
Fig 5.
20
Hypercortisolism weakens skin; even
normal stretching (or the pressure of obesity,
as here) can make its elastin break— on
healing we see these depressed purple scars
(striae). Cortisone or rapid growth contributes
to striae in other contexts: pregnancy, adolescence, weight lifting, sudden- onset obesity,
or from strong steroid creams. Striae mature
into silvery crescents looking like the underside of willow leaves. Unsightly immature
striae may be improved by
YAG
la ser s.
5 Endocrinology
Addison’s disease (adrenal insuciency)
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220
Primary adrenocortical insuciency (Addison’s disease) is rare (~0.8/
but can be fatal. Destruction of the adrenal cortex leads to glucocorticoid (cortisol)
and mineralocorticoid (aldosterone) deficiency (
unforgiving master of non- specificity and disguise’.
tion or anorexia nervosa in error (K
Physiology See fig
Fig 5.
21
Pathways involved in adrenal function.
5.21
.
+
is in the latter but in A ddison’s).
fig
5.21
). Signs are capricious: it is ‘the
18
You may diagnose a viral infec-
100 000
),
Causes 80% are due to autoimmunity in the UK. Other causes
)
worldwide
opportunistic infections in
haemorrhage (
drome;
, adrenal metastases (eg from lung, breast, renal cancer), lymphoma,
Waterhouse– Friderichsen syndrome, p
SLE
), congenital (late- onset congenital adrenal hyperplasia).
Secondary adrenal insuciency The commonest cause is iatrogenic, due to long-
term steroid therapy leading to suppression of the pituitary– adrenal axis. This only
becomes apparent on withdrawal of the steroids. Other causes are rare and include
hypothalamic– pituitary disease leading to
duction remains intact, and there is no hyperpigmentation as
Symptoms Often diagnosed late: lean, tanned, tired, tearful ± weakness, anorexia,
dizzy, faints, flu- like myalgias/ arthralgias. Mood: depression, psychosis.
vomiting, abdominal pain, diarrhoea/ constipation. Think of Addison’s in all with un-
explained abdominal pain or vomiting. Pigmented palmar creases
(ACTH
; cross- reacts with melanin receptors). Postural hypotension. Vitiligo. Signs
of critical deterioration (
Tests Na+ & K+ (due to mineralocorticoid), glucose (due to cortisol). Also: ur-
aemia, Ca
do plasma cortisol before and ½h after tetracosactide (Synacthen®)
IV
2
+
, eosinophilia, anaemia. Short
. Addison’s is excluded if 30min cortisol >~
depending on laboratory assay). Steroid drugs may interfere with assays: ask lab.
in pregnancy and contraceptive pill, cortisol levels may be reassuring but falsely ,
due to cortisol- binding globulin.
inappropriately high). It is low in secondary causes.
antibodies: + ve in autoimmune disease in >
assess mineralocorticoid status.
antibodies are negative— eg to look for
Treatment See p
hydrocortisone daily, in
819
in late afternoon. Avoid giving late (may cause insomnia). Mineralocorticoids to
correct postural hypotension, Na
Adjust both on clinical grounds. If there is a poor response, suspect an associated
autoimmune disease (check thyroid, do coeliac serology:
TB (
commonest cause
HIV
(eg
CMV
, Mycobacterium avium, p
ACTH
production. Mineralocorticoid pro-
p
819
): shock (BP, tachycardia), T°, coma.
ACTH
stimulation test (Synacthen® test):
550
nmol/ L (but exact threshold varies
Also •
ACTH
: in Addison’s,
698
9AM
396
); adrenal
; antiphospholipid syn-
ACTH
.
GI:
nausea/
&
buccal mucosa
250
mcg
IM/
NB:
ACTH
is (>
300
ng/ L:
• 21- Hydroxylase adrenal auto-
80
Adrenal CT/
for Addisonian crisis (shocked). Replace steroids: ~15– 25mg
2– 3
doses, eg 10mg on waking, 5mg at lunchtime, and 5mg
+
, K+ : fludrocortisone PO from 50–
%. • Plasma renin & aldosterone: to
MRI
consider adrenal imaging if auto-
TB
or metastatic disease.
p
262
).
200
mcg daily.
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