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Neck and Hormones

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  • Prevalences UK, depending on definitions,
  • Prevalence ca 2.7% UK in females, ca 0.3% in males. Overall ca 1 : 1000 in females
  • With globalization and immigration, TPP is no longer confined to certain geographic areas and has been increasingly reported throughout the world.
  • T3 thyrotoxicosis mainly seen in XXX US scan helps to differentiate between AIT, Graves`, and toxic adenoma adenomas that produce overt hyperthyroidism generally are ≥ 3 cm
  • Increase of TSH with metoclopramide (Scanlon JCEM 1980)
  • tonic inhibitory role for DA in the control of TSH secretion
  • PTU: also fulminant hepatitis But evl smaller risk of XXX
  • PTH results came back later, hence initially thought to have multiple myeloma
  • Clinical correlates may include bone pain and tenderness, bowing of the shoulders, kyphosis and loss of height, collapse of lateral ribs and pelvis with pigeon breast and triradiate deformities, respectively
  • Moosgaard Denmark 81% vs 60% in controls Ca 20% (McDermott p 136) Subjects with primary hyperparathyroidism were 3.34 kg (95% confidence interval, 1.97-4.71; P < 0.00001) heavier than controls in 13 studies reporting body weight. In four studies reporting body mass index, subjects with primary hyperparathyroidism had an increased body mass index of 1.13 kg/m(2) (-0.29 to 2.55; P = 0.12) compared with controls.
  • Cholecalciferol tablets 1.25 mg (50000 units)
  • Eastell JCEM 2009, Holick NEJM 2007, Tucci EJE 2009
  • 1,25(OH) 2 D Calcitriol; 25(OH)D Vit D
  • Unless homozygous, in newborns CHECK pHPT Ca/Crea Cl > 0.02 CHECK
  • Grandmother had the same association, age 55 years don’t make the diagnosis without family screening
  • Addisons, ketoacidosis
  • Transcript

    • 1. Grand Round 06/10/2009 Martin O. Weickert and colleagues Neck & Hormones Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism
    • 2.
      • 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 haemodialysis
        • patients )
        • hypoparathyroidism
        • (most common post-surgery;
        • otherwise rare)
      Endocrine active organs in the neck Yu et al. Clin Endocrinol 2009; Franklyn ESE abstracts 2009
    • 3. An interesting case…. Steph Horne House Officer
    • 4. Demographics
      • 35 year old Caucasian Female
      • self admission to A&E
    • 5. 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
    • 6. And the rest…
      • PMHX:
        • appendix removed 6 years ago
        • hyperthyroidism
        • anxiety
      • SHX:
        • smoker 4-5 per day
        • mild alcohol intake
        • on methadone treatment
    • 7. On examination: Chest clear HS I + II + 0 CNS intact Temperature: 36.3 BP: 174/112 PR: 99 RR: 24 O2 Sats: 99% OA Mews: 2 Pain score: 3 (0-3) Epigastric pain No Organomegaly BS + Unable to demonstrate guarding PR: Empty Rectum
    • 8. Impression…..
      • perforated ulcer
      • gallstones
      • GORD
      • pancreatitis
      • gastroenteritis
    • 9. The blood results…
      • electrolytes: NAD
      • WCC: 14.42, Hb: 11.8, Plts: 417
      • alk Phos: 227, ALT: 36, Amylase: 33
    • 10. 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
    • 11. 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)
      Thyrotoxicosis
    • 12. Treatment…
      • symptomatic relief : beta blockers
      • carbimazole
      • USS thyroid gland
      • thyroid autoantibodies
    • 13. The result…
      • diarrhoea resolved
      • tremor/anxiety improved
      • discharged with endocrine follow up
    • 14. Common causes of thyrotoxicosis
      • Graves` disease
      • toxic adenomas
      • toxic multinodular goitre
      • thyroiditis
      • ingestion of excessive exogenous thyroid hormone
        • iatrogenic, inadvertent, or surreptitious
    • 15. Some rarer causes
      • TSH-secreting pituitary adenoma
      • struma ovarii
        • ectopic production in ovarian teratomas
      • extremly high levels of hCG
        • choriocarcinomas, germ cell tumours
    • 16. “ 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
    • 17. unspecific in aged patients...
      • tiredness, apathy, depression
      • „ dementia“, confusion, psychosis
      • GI symptoms
      • AF, worsening of angina pectoris, or congestive heart failure
    • 18. 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
    • 19. Biochemical findings in thyrotoxicosis
      • low TSH
    • 20. 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
    • 21. 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
    • 22. Further changes...
      • normocytic anaemia
      • increased LFTs
      • increased bone AP
      • hypercalcaemia, hyperphosphataemia
      • low albumin
      • mild leukopenia
      • low cholesterol
    • 23. 24-hour variation of TSH adapted from McDermott: Sleep and Endocrinology 2009 Hormone Circadian Sleep-wake homeostasis Cortisol +++ + Testosterone +++ - GH + +++ PRL ++ +++
    • 24. 24-hour variation of TSH adapted from McDermott: Sleep and Endocrinology 2009; Patel Clin Sci 1972 Hormone Circadian Sleep-wake homeostasis Cortisol +++ + Testosterone +++ - GH + +++ PRL ++ +++ TSH +++ ++
    • 25. 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
    • 26. 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
    • 27. 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
    • 28. An orthopaedic outlier ! Noushad
    • 29. 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
    • 30. 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
    • 31. 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’
    • 32. 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
    • 33. 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
    • 34. 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
    • 35. 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
    • 36. Management
      • IV N.Saline 4L/day
      • IV pamidronate
      • pain relief
      • traction for fracture femur
      • cast for fracture humerus
    • 37. Other x-rays
    • 38. 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
    • 39. Ca 2+ and PTH trends post op 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
    • 40. Current management
      • sandocal 1gram TDS
      • alfacalcidol 1microgram/day
      • traction down
      • still an inpatient
      • not yet weight bearing
    • 41. Follow up x-rays- 30/9/09
    • 42. 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
    • 43. Primary hyperparathyroidism (pHPT)
      • „ stones, bones, abdominal groans …“
      • depression
      • „ stones, bones, abdominal groans, and psychic moans …“
    • 44. 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
    • 45. 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)
    • 46. 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
    • 47. Band keratopathy
      • calcium-phosphate precipitation in medial and limbic margins of cornea
    • 48. Parathyroid bone disease
      • thin cortices
      • contrasting maintenance of trabecular bone
      Parisien et al. JCEM 1990 patient with pHPT control Biopsy specimens from iliac crest
    • 49. 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
    • 50. salt-and-pepper appearance of the calvarium trabecular bone resorption with loss of definition of cortices
    • 51. subperiostal bone resorption along the radial aspects of the middle phalanges distal clavicular resorption radiological disappearance of some bones
    • 52. 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
    • 53. Grey et al. JCEM 2005
    • 54. Grey et al. JCEM 2005 Cholecalciferol tablets 1.25 mg (50000 units) weekly for 4 weeks, thereafter 1 tablet per month for 12 month
    • 55. „… 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
    • 56. ? Mechanisms
      • PTH-induced increase in 1-alpha hydroxylase
      • ↑ 1,25(OH) 2 D (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) 2 D 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) 2 D in cross-sectional studies (Silverberg Am J Med 1999, Rao JCEM 2000)
    • 57. Mechanisms
      • ? non- 1,25(OH) 2 D 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) 2 D to reduce PTH
    • 58. Interactions with magnesium low magnesium levels blunt the stimulation of parathyroid glands induced 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 Sahota et al. Osteoporos Int 2006
    • 59. 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
    • 60. 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
    • 61. FHH
      • usually benign and asymptomatic
      • family history?
      • urinary calcium/creatinine clearance < 0.01
      • surgery in FHH patients without benefit!
    • 62.  
    • 63. Patient with adynamia and dizziness
      • bradycardia
      • first degree AV block
      • low voltage in all leads
      • flat or negative T-waves
      • ↑ QT interval
    • 64. ECG in severe hypothyroidism after starting treatment with L-Thyroxine untreated
    • 65. 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…