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Grand Round 06/10/2009 Martin O. Weickert and colleagues

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1 Grand Round 06/10/2009 Martin O. Weickert and colleagues
Neck & Hormones Grand Round 06/10/2009 Martin O. Weickert and colleagues Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism

2 Endocrine active organs in the neck
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) Prevalences UK, depending on definitions, Yu et al. Clin Endocrinol 2009; Franklyn ESE abstracts 2009

3 Steph Horne House Officer
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 Chest clear HS I + II + 0 CNS intact

8 Impression….. perforated ulcer gallstones GORD pancreatitis

9 The blood results… electrolytes: NAD WCC: 14.42, Hb: 11.8, Plts: 417
alk Phos: 227, ALT: 36, Amylase: 33

10 Impression: Acute abdomen AXR/CXR: NAD A&E: Abdo pain and diarrhoea
Gastro referral TIMELINE Surgical team referral Admitted to SAU OGD and Colonoscopy Discussions re; Laparotomy

11 Then along came…. Thyrotoxicosis 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 Prevalence ca 2.7% UK in females, ca 0.3% in males. Overall ca 1 : 1000 in females

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 With globalization and immigration, TPP is no longer confined to certain geographic areas and has been increasingly reported throughout the world. 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 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

22 Further changes... normocytic anaemia increased LFTs increased bone AP
hypercalcaemia, hyperphosphataemia low albumin mild leukopenia low cholesterol

23 Sleep-wake homeostasis
24-hour variation of TSH Hormone Circadian Sleep-wake homeostasis Cortisol +++ + Testosterone - GH PRL ++ Increase of TSH with metoclopramide (Scanlon JCEM 1980) adapted from McDermott: Sleep and Endocrinology 2009

24 Sleep-wake homeostasis
24-hour variation of TSH Hormone Circadian Sleep-wake homeostasis Cortisol +++ + Testosterone - GH PRL ++ TSH tonic inhibitory role for DA in the control of TSH secretion adapted from McDermott: Sleep and Endocrinology 2009; Patel Clin Sci 1972

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 PTU: also fulminant hepatitis But evl smaller risk of XXX

28 An orthopaedic outlier !

29 No orthopaedic intervention needed!
History 59 year old lady attended A&E at 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 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 PTH results came back later, hence initially thought to have multiple myeloma

34 Further investigations
myeloma screen negative PTH (NR ), Vitamin D (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 Ca2+ and PTH trends post op
Date Calcium( ) PTH( ) 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 2.35 0.8 437 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
patient with pHPT control Biopsy specimens from iliac crest thin cortices contrasting maintenance of trabecular bone Parisien et al. JCEM 1990

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 distal clavicular resorption subperiostal bone resorption
radiological disappearance of some bones subperiostal bone resorption along the radial aspects of the middle phalanges 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

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 Moosgaard Denmark 81% vs 60% in controls Ca 20% (McDermott p 136) Subjects with primary hyperparathyroidism were 3.34 kg (95% confidence interval, ; P < ) 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.

53 Cholecalciferol tablets 1.25 mg (50000 units)
Grey et al. JCEM 2005

54 Cholecalciferol tablets 1.25 mg (50000 units) weekly for 4 weeks,
thereafter 1 tablet per month for 12 month Grey et al. JCEM 2005

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)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) Eastell JCEM 2009, Holick NEJM 2007, Tucci EJE 2009

57 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 1,25(OH)2D Calcitriol; 25(OH)D Vit D

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 Unless homozygous, in newborns CHECK pHPT Ca/Crea Cl > 0.02 CHECK

61 FHH usually benign and asymptomatic family history?
urinary calcium/creatinine clearance < 0.01 surgery in FHH patients without benefit! Grandmother had the same association, age 55 years don’t make the diagnosis without family screening


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
untreated after starting treatment with L-Thyroxine

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… Addisons, ketoacidosis

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