neck and hormones
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Grand Round 06/10/2009
Martin O. Weickertand colleagues
Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism
Neck & Hormones
• thyroid– thyrotoxicosis (2% of UK population)
– hypothyroidism (9.3% (w), >60 yrs up to 16%; 1.35% (m))
• parathyroid glands– hyperparathyroidism
(prim HPT < 0.1 – 3.4%, ↑ with age;
sec HPT i.e. 80% in chronic haemodialysispatients )
– hypoparathyroidism(most common post-surgery;
otherwise rare)
Endocrine active organs in the neck
Yu et al. Clin Endocrinol 2009; Franklyn ESE abstracts 2009
An interesting case….
Steph Horne
House Officer
Demographics
• 35 year old Caucasian Female
• self admission to A&E
Presenting complaint
• upper abdominal pain
• epigastric area: burning/sharp in nature
• bloody diarrhoea
• vomited 15 times, diarrhoea for 5 days
• not able to tolerate any oral food/fluids
• similar episode 6 months ago
• OP endoscopy booked but DNA
And the rest…
• PMHX:– appendix removed 6
years ago– hyperthyroidism– anxiety
• SHX:– smoker 4-5 per day– mild alcohol intake– on methadone treatment
On examination:
Temperature: 36.3
BP: 174/112
PR: 99
RR: 24
O2 Sats: 99% OA
Mews: 2
Pain score: 3 (0-3)
Chest clear
HS I + II + 0
CNS intact
Epigastric pain
No Organomegaly
BS +
Unable to demonstrate guarding
PR: Empty Rectum
Impression…..
• perforated ulcer• gallstones• GORD• pancreatitis• gastroenteritis
The blood results…
• electrolytes: NAD• WCC: 14.42, Hb: 11.8, Plts: 417• alk Phos: 227, ALT: 36, Amylase: 33
TIMELINE
Surgical team referral
Admitted to SAU
OGD and Colonoscopy
Discussions re; Laparotomy
A&E: Abdo pain and diarrhoea
Impression: Acute
abdomen
AXR/CXR:
NAD Gastro referral
Then along came….
• TSH < 0.02 mU/L (0.35 – 6 mU/L)• free T3 – 36.3 pmol/L (2.8 – 7.1 pmol/L)• free T4 – > 100 pmol/L (9 – 26 pmol/L)
Treatment…
• symptomatic relief : beta blockers
• carbimazole• USS thyroid gland• thyroid autoantibodies
The result…
• diarrhoea resolved
• tremor/anxiety improved
• discharged with endocrine follow up
Common causes of thyrotoxicosis
• Graves` disease
• toxic adenomas
• toxic multinodular goitre
• thyroiditis
• ingestion of excessive exogenous thyroid hormone– iatrogenic, inadvertent, or surreptitious
Some rarer causes
• TSH-secreting pituitary adenoma
• struma ovarii– ectopic production in ovarian teratomas
• extremly high levels of hCG– choriocarcinomas, germ cell tumours
“Classical” symptoms of thyrotoxicosis
• hyperactivity, irritability, altered mood
• sleep disturbances
• sweating, heat intolerance
• palpitations
• weight loss, occasionally weight gain (polyphagia)
• oligo-/amenorrhoea, loss of libido
unspecific in aged patients...
• tiredness, apathy, depression
• „dementia“, confusion, psychosis
• GI symptoms
• AF, worsening of angina pectoris, or congestive heart failure
Thyrotoxic periodic paralysis (TPP)
• 2% in Asians, rare in Caucasians (0.15%)
• hyperthyroidism-related hypokalaemia
• sudden shift of K+ into cells– associated with exercise– inducible by carbohydrate + insulin challenge
• presentation in ED with – acute muscle weakness – systolic hypertension, tachycardia, high QRS
voltage, first degree AV block
McFadzean BMJ 1967, Lin Mayo Clin Proc 2005
Biochemical findings in thyrotoxicosis
• low TSH
Other states with low TSH
• secondary hypothyroidism– low normal or normal TSH– low fT4– usually associated with deficiencies of other pituitary
hormones
• thyroid sick syndrome– ? aquired transient central hypothyroidism (Chopra JCEM
1997)
– low TSH (but not completely suppressed)– low fT4 and fT3
Biochemical findings in thyrotoxicosis
• low or suppressed TSH
• increased fT4 and/or fT3 in overt thyrotoxicosis– check for isolated fT3 thyrotoxicosis
• normal fT4 and/or fT3 in „subclinical“ thyrotoxicosis– increased risk of osteoporosis; evtl symptomatic
• frequently increased auto-Abs level in AIT
Further changes...
• normocytic anaemia
• increased LFTs
• increased bone AP
• hypercalcaemia, hyperphosphataemia
• low albumin
• mild leukopenia
• low cholesterol
24-hour variation of TSH
Hormone Circadian Sleep-wake homeostasis
Cortisol +++ +Testosterone +++ -GH + +++PRL ++ +++
adapted from McDermott: Sleep and Endocrinology 2009
24-hour variation of TSH
Hormone Circadian Sleep-wake homeostasis
Cortisol +++ +Testosterone +++ -GH + +++PRL ++ +++TSH +++ ++
adapted from McDermott: Sleep and Endocrinology 2009; Patel Clin Sci 1972
Circadian rhythm of TSH
• ? less bioactive and differently glycosylated TSH molecules secreted during the night(Persani et al JCEM 1995)
Russell et al. JCEM 2009
Circadian rhythm of TSH and fT3
• circadian rhythm of fT3
• delayed by 90 min
• clinical relevance?• drug induced
increase of TSH, e.g. metoclopramide (Scanlon JCEM 1980))
Russell et al. JCEM 2009
Interaction with SHBG
• oral contraceptives may not be fully protective in thyrotoxicosis – ↑ SHBG (Ford Clin End 1992)
– ↑ clearance of contraceptives
• caution in fertile female patients after radioiodine therapy
An orthopaedic outlier !
Noushad
History
• 59 year old lady• attended A&E at
01.42 am, 16/7/09• fell down in the toilet• injury to left arm• deformity of left arm
No orthopaedic intervention
needed!
W20
History
• increasing confusion- 16 weeks
• weight loss and bilateral leg pains for the same period
• was not mobilising, just stayed in bed!
• no medical help sought until the fall
• fracture of right olecranon in 2006 after a trivial fall
Further story
• left humerus was painful and deformed
• X-ray showed• referred to ortho• ‘no ortho intervention
needed, can go home with fracture clinic appointment’
Further story
• patient’s daughters mentioned the poor physical and mental state, refuses to take her home
• 04.45- patient c/o of right thigh pain
• X-ray ordered
Blood investigations
• urea 9.0, creatinine 64, Na 143, K 4.0
• adjusted Ca 3.68, ALP 606, Alb 41
• Hb 11.0, WCC 17.36, Neuts 15.29
• TSH 2.71
• CRP <3
Further investigations
• myeloma screen negative• PTH 114.2 (NR1.1-4.2), Vitamin D 11.0
(NR 10-60)• in the meanwhile patient was reviewed by
T&O team• ‘pathological fractures due to likely
malignancy’, • admitted to medical ward (20), for joint
care
Management
• final diagnosis- primary hyperparathyroidism with pathological fractures
• patient transferred to orthopaedic ward
• close input from endocrine team
• MIBI scan and USS neck- Left inferior parathyroid adenoma
Management
• IV N.Saline 4L/day
• IV pamidronate
• pain relief
• traction for fracture femur
• cast for fracture humerus
Other x-rays
Management
• left inferior parathyroidectomy 17/8/09
• severe hypocalcaemia expected
• ergocalciferol (Vitamin D2) 300,000 units i.m. given after parathyroidectomy
• sandocal 1gram TDS started
Date Calcium(2.1-2.58)
PTH(1.1-4.2)
ALP(30-120)
16/7/09 3.68 114.2 606
16/8/09 2.76 450
17/8/09 2.61
18/8/09 2.41
18/8/09 2.35 0.8 437
18/8/09 2.26 0.6 405
19/8/09 2.28 452
21/8/09 1.99 5.6
26/8/09 1.93 16.5 711
30/8/09 1.92 36.4 658
1/9/09 1.87 45.4 574
18/9/09 2.13 24.9 325
3/10/09 2.18 223
Ca2+ and PTH trends post op
Current management
• sandocal 1gram TDS
• alfacalcidol 1microgram/day
• traction down
• still an inpatient
• not yet weight bearing
Follow up x-rays- 30/9/09
Hungry bone syndrome
• excessive skeletal remineralization once skeleton released from PTH excess
• ongoing ↑ALP, ↓Ca, ↓Ph, ↓Mg
• hypocalcaemia in pre-existing VitD deficiency
• may require large doses of VitD/derivates and calcium for weeks to month
Primary hyperparathyroidism (pHPT)
• „stones, bones, abdominal groans …“
• depression
• „stones, bones, abdominal groans, and psychic moans …“
Modern vs classical pHPT
• abrupt increase in annual incidence since the early 1970s – 0.15 (1965 – 1974) to 1.12 (1975) per 1000
persons (Wermers Ann Int Med 1997)
– introduction of screening
• > 85% of modern pHPT patients are asymptomatic or have unspecific symptoms
Modern vs classical pHPT
• kidney stones only in 15-20% of patients with „modern“ pHPT
• reduced BMD
• far subtler abnormalities in bone
• often radiographics NAD • routine skeletal x-rays are no longer
recommended (Bilezikian et al. JCEM 2002)
Biochemical findings in pHPT
• increased PTH
• increased (or normal) calcium
• low normal fasting serum phosphate
• other associated findings may include– increased chloride, Cl/phosphate ratio ≥ 33,
elevated urinary pH (> 6), increased alkaline phosphatase
Band keratopathy
• calcium-phosphate precipitation in medial and limbic margins of cornea
Parathyroid bone disease
• thin cortices
• contrasting maintenance of trabecular bone
patient with pHPT control
Biopsy specimens from iliac crest
Parisien et al. JCEM 1990
Osteitis fibrosa cystica
• striking and generalised increase in osteoclastic bone resorption
• osteoclastomas (brown tumours) with osteous expansion and lucency
• fibrovascular marrow replacement
• increased osteoblastic activity
salt-and-pepper appearance of the calvarium
trabecular bone resorption with loss of definition of cortices
subperiostal bone resorption
along the radial aspects of themiddle phalanges
distal clavicular resorption
radiological disappearance of some bones
pHPT and vitamin D deficiency
• modern pHPT: bone disease mainly in patients with severe vitamin D deficiency
• however• co-existing pHPT and vitamin D deficiency is
very common! (Mossgaard Clin End 2005, Eastell JCEM 2009)
– association with ↑ PTH, Ca, ALP, accelerated bone turnover, larger parathyroid glands/tumours, greater likelihood of abnormal bones (Tucci Eur J Endocrinol 2009)
– calcium levels can also be normal
Grey et al. JCEM 2005
Grey et al. JCEM 2005
Cholecalciferol tablets 1.25 mg (50000 units) weekly for 4 weeks,thereafter 1 tablet per month for 12 month
„…suggest that vitamin D repletion in patients with PHPT does not exacerbate hypercalcemia and may decrease levels of PTH and bone turnover“.
Grey et al. JCEM 2005
? Mechanisms
• PTH-induced increase in 1-alpha hydroxylase
• ↑ 1,25(OH)2D (calcitriol)
• inhibition of PTH gene transcription, protein production and parathyroid gland proliferation (Beckermann Am J Med Sci 1999)
• no association between change in 1,25(OH)2D
and PTH levels (Grey JCEM 2005)
• no decrease of PTH with active Vit D metabolites (Lind Acta Endocrinol 1989)
• no relation 25(OH)D with 1,25(OH)2D in cross-sectional studies (Silverberg Am J Med 1999, Rao JCEM 2000)
Mechanisms
• ? non-1,25(OH)2D induced effects of 25(OH)D and other metabolites on PTH production
• ? stimulation of VitD receptor in parathyroid tissue by VitD deficiency
• ? intracrine action of parathyroid-derived 1,25(OH)2D to reduce PTH
low magnesium levels blunt the stimulation of parathyroid glandsinduced by low Vit D levels
often normal PTH levels even when 25-OH VitD below 20 ng/mL
unknown effects of hypomagnesia in patients with pHPT
Interactions with magnesium
Sahota et al. Osteoporos Int 2006
Further secrets parathyroid
• PTH levels normally decrease with age
• association pHPT with metabolic syndrome– increased body weight in patients with pHPT
(Bolland JCEM 2005, Meta-analysis)
– increased leptin and decreased adiponectin (Delfini et al Metabolism 2007)
• consider co-existing disorders in patients with pHPT– drugs (thiazides, lithium), malabsorption, renal
failure, tumours
Familiar hypocalciuric hypercalcaemia (FHH)
• 2% of all asymptomatic hypercalcaemia
• dominantly inherited
• usually heterozygous loss of function mutation in the CaSR
• PTH inappropriately normal or high, lifelong Ca++ ↑ and Mg++ ↑, both of variable degree
• enlarged glands and mild parathyroid hyperplasia can occur
FHH
• usually benign and asymptomatic
• family history? • urinary
calcium/creatinine clearance < 0.01
• surgery in FHH patients without benefit!
Patient with adynamia and dizziness
• bradycardia
• first degree AV block
• low voltage in all leads
• flat or negative T-waves
• ↑ QT interval
after starting treatment with L-Thyroxine
untreated
ECG in severe hypothyroidism
Conclusions
• patients with neck hormonal derangements may primarily present in other Specialties– e.g. Gastroenterology, Orthopaedics, ED, Cardiology,
Psychiatry
• being unaware of hormonal derangements can expose the patient to unnessecary procedures– e.g. EGD, coloscopy, intracardiac catheter, surgery…
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