grand round 06/10/2009 martin o. weickert and colleagues warwickshire institute for the study of...

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…