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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
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• 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
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An interesting case….
Steph Horne
House Officer
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Demographics
• 35 year old Caucasian Female
• self admission to A&E
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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
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And the rest…
• PMHX:– appendix removed 6
years ago– hyperthyroidism– anxiety
• SHX:– smoker 4-5 per day– mild alcohol intake– on methadone treatment
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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
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Impression…..
• perforated ulcer• gallstones• GORD• pancreatitis• gastroenteritis
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The blood results…
• electrolytes: NAD• WCC: 14.42, Hb: 11.8, Plts: 417• alk Phos: 227, ALT: 36, Amylase: 33
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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
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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)
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Treatment…
• symptomatic relief : beta blockers
• carbimazole• USS thyroid gland• thyroid autoantibodies
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The result…
• diarrhoea resolved
• tremor/anxiety improved
• discharged with endocrine follow up
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Common causes of thyrotoxicosis
• Graves` disease
• toxic adenomas
• toxic multinodular goitre
• thyroiditis
• ingestion of excessive exogenous thyroid hormone– iatrogenic, inadvertent, or surreptitious
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Some rarer causes
• TSH-secreting pituitary adenoma
• struma ovarii– ectopic production in ovarian teratomas
• extremly high levels of hCG– choriocarcinomas, germ cell tumours
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“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
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unspecific in aged patients...
• tiredness, apathy, depression
• „dementia“, confusion, psychosis
• GI symptoms
• AF, worsening of angina pectoris, or congestive heart failure
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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
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Biochemical findings in thyrotoxicosis
• low TSH
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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
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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
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Further changes...
• normocytic anaemia
• increased LFTs
• increased bone AP
• hypercalcaemia, hyperphosphataemia
• low albumin
• mild leukopenia
• low cholesterol
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24-hour variation of TSH
Hormone Circadian Sleep-wake homeostasis
Cortisol +++ +Testosterone +++ -GH + +++PRL ++ +++
adapted from McDermott: Sleep and Endocrinology 2009
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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
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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
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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
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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
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An orthopaedic outlier !
Noushad
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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
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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
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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’
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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
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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
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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
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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
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Management
• IV N.Saline 4L/day
• IV pamidronate
• pain relief
• traction for fracture femur
• cast for fracture humerus
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Other x-rays
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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
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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
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Current management
• sandocal 1gram TDS
• alfacalcidol 1microgram/day
• traction down
• still an inpatient
• not yet weight bearing
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Follow up x-rays- 30/9/09
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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
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Primary hyperparathyroidism (pHPT)
• „stones, bones, abdominal groans …“
• depression
• „stones, bones, abdominal groans, and psychic moans …“
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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
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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)
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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
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Band keratopathy
• calcium-phosphate precipitation in medial and limbic margins of cornea
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Parathyroid bone disease
• thin cortices
• contrasting maintenance of trabecular bone
patient with pHPT control
Biopsy specimens from iliac crest
Parisien et al. JCEM 1990
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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
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salt-and-pepper appearance of the calvarium
trabecular bone resorption with loss of definition of cortices
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subperiostal bone resorption
along the radial aspects of themiddle phalanges
distal clavicular resorption
radiological disappearance of some bones
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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
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Grey et al. JCEM 2005
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Grey et al. JCEM 2005
Cholecalciferol tablets 1.25 mg (50000 units) weekly for 4 weeks,thereafter 1 tablet per month for 12 month
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„…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
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? 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)
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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
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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
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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
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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
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FHH
• usually benign and asymptomatic
• family history? • urinary
calcium/creatinine clearance < 0.01
• surgery in FHH patients without benefit!
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Patient with adynamia and dizziness
• bradycardia
• first degree AV block
• low voltage in all leads
• flat or negative T-waves
• ↑ QT interval
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after starting treatment with L-Thyroxine
untreated
ECG in severe hypothyroidism
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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…