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

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Presentation on theme: "Grand Round 06/10/2009 Martin O. Weickert and colleagues Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism Neck & Hormones."— Presentation transcript:

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

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: 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

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)

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 HormoneCircadianSleep-wake homeostasis Cortisol ++++ Testosterone +++- GH ++++ PRL adapted from McDermott: Sleep and Endocrinology 2009

24 24-hour variation of TSH HormoneCircadianSleep-wake homeostasis Cortisol ++++ Testosterone +++- GH ++++ PRL TSH 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

28 An orthopaedic outlier ! Noushad

29 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 patients 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 TSH 2.71 CRP <3

34 Further investigations myeloma screen negative PTH (NR ), 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 DateCalcium( ) PTH( ) ALP( ) 16/7/ /8/ /8/ /8/ /8/ /8/ /8/ /8/ /8/ /8/ /9/ /9/ /10/ Ca 2+ and PTH trends post op

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 patient with pHPTcontrol Biopsy specimens from iliac crest 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 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 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 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 Interactions with magnesium 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!


63 Patient with adynamia and dizziness bradycardia first degree AV block low voltage in all leads flat or negative T- waves QT interval

64 after starting treatment with L-Thyroxine untreated ECG in severe hypothyroidism

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…

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