1. Cushing’s syndrome

2. Cushing’s syndrome
Hypersecretion of cortisol caused by endogenous production of corticosteroids is known as Cushing’s syndrome.
It can be either ACTH-dependent or ACTH-independent in origin.
85 per cent of ACTH-dependent Cushing’s syndrome :
Pituitary adenoma that secretes an excessive amount of ACTH(CUSHING DISEASE)
Ectopic ACTH-producing tumours (small cell lung cancer, foregut carcinoid)
CRH-producing tumours (medullary thyroid carcinoma, neuroendocrine pancreatic tumour)

3. 15 per cent of patients, an ACTH-independent Cushing’s syndrome (low ACTH levels) is caused by a
unilateral adrenocortical adenoma.
Adrenocortical carcinoma
bilat- eral macronodular or micronodular hyperplasia represent rare causes of hypercortisolism.

4. Clinical symptoms

5. Diagnosis
 Morning and midnight plasma cortisol levels are elevated, possibly with loss of diurnal rhythm.
 Dexamethasone fails to suppress 24-hour urinary cortisol excretion.
 Serum ACTH levels discriminate ACTH- dependent from ACTH-independent disease.

6. Elevated or normal ACTH levels provide evidence for an ACTH-producing pituitary tumour (85 per cent) or ectopic ACTH production. Therefore, in patients with elevated ACTH,
MRI of the pituitary gland must be performed. If MRI is nega- tive and additional venous sampling from the inferior petrosal sinus has excluded a pituitary microadenoma,
a CT scan of the chest and abdomen is warranted to detect an ectopic ACTH- producing tumour.

7. In patients with suppressed ACTH levels, a
CT or MRI scan is performed to assess the adrenal glands.
Subclinical Cushing’s syndrome is diagnosed if clinical symp toms are absent in the face of abnormal cortisol secretion.

8. Treatment
Medical therapy with metyrapone or ketoconazole reduces steroid synthesis and secretion and can be used to prepare patients with severe hypercortisolism preoperatively or if surgery is not possible.
ACTH-producing pituitary tumours are treated by transsphenoidal resection or radiotherapy.
If an ectopic ACTH source is localised, resection will correct hypercortisolism.

9. A unilateral adenoma is treated by adrenalectomy.
In cases of bilateral ACTH-independent disease bilat- eral adrenalectomy is the primary treatment.
Patients with an ectopic ACTH-dependent Cushing’s syndrome and an irresectable or unlocalised primary tumour should be considered for bilateral adrenalectomy as this controls hormone excess.
Subclinical Cushing’s syndrome caused by unilateral adenoma is treated by unilateral adrenalectomy.

10. Preoperative management
Patients with Cushing’s syndrome are at an increased risk of hospital- acquired infection, thromboembolic and myocardial complications.
Therefore, prophylactic anticoagulation and the use of prophylactic antibiotics are essential.
Cushing-associated diseases (diabetes, hypertension) must be controlled by medical therapy preoperatively.

11. Postoperative management
After unilateral adrenalectomy supplemental cortisol should be given postoperatively because the contralateral gland will be suppressed.
In total, 15 mg/hour is required parenterally for the first 12 hours followed by a daily dose of 100 mg for 3 days, which is gradually reduced thereafter. .

12. After unilateral adrenalectomy, the contralateral suppressed gland needs up to one year to recover adequate function.
In 10 per cent of patients with Cushing’s disease who undergo a bilateral adrenalectomy after failed pituitary surgery, the pituitary adenoma causes Nelson’s syndrome due to continued ACTH secretion at high levels, causing hyperpigmentation as a result of chemical synergies between ACTH and melanocyte-stimulating hormone

13. Primary hyperaldosteronism – Conn’s syndrome
Defined by hypertension, as a result of hypersecretion of aldosterone
Patients with hypertension the incidence of PHA is approximately 2 per cent.

14. PATHOLOGY
The most frequent cause of PHA with hypokalaemia is a unilateral adrenocortical adenoma .
In 20–40 per cent of cases, bilateral micronodular hyperplasia is present.
Rare causes of PHA are bilateral macronodular hyperplasia, glucocorticoid- suppressible hyperaldosteronism or adrenocortical carcinoma.

15. Clinical features 30 and 50 years of age Female predominance
Hypertension
Non-specific symptoms: headache, muscle weakness, cramps, intermittent paralysis, polyuria, polydypsia and nocturia.

16. Diagnosis
Assessment of potassium level and the aldosterone to plasma renin activity ratio.
MRI or CT should be performed to distinguish unilateral from bilateral disease.
Micronodular changes and small adenomas are often underdiagnosed.

17. Selective adrenal vein cath- eterisation can help before a decision on non-surgical or surgical treatment is made
During selective adrenal vein catheterisation, samples are obtained from the vena cava and from both adrenal veins and the aldosterone to cortisol ratio (ACR) is determined in each sample. A significant difference in the ACR ratio on one side indicates unilateral disease.

18. Treatment
The first-line therapy for PHA with bilateral hyperplasia is medi- cal treatment with spironolactone. In most cases supplemental antihypertensive medication is necessary.
Unilateral laparoscopic adrenalectomy is an effective therapy in patients with clear evidence of unilateral or asymmetrical bilateral disease
A subtotal resection can be considered in the case of a typical single Conn’s adenoma.

19. PARATHYROID GLAND

20. PTH activates osteoclasts to resorb bone, and increases calcium reabsorption from urine and renal activation of vitamin D with subsequent increased gut absorption of calcium. Renal excretion of phosphate is also increased.

21. Primary hyperparathyroidism
Primary hyperparathyroidism is commonly a sporadic rather than familial condition associated with hypercalcaemia and inappropriately raised serum PTH levels due to enlargement of one or more glands and hypersecretion of PTH.

22. Epidemiology
The prevalence of sporadic primary hyperparathyroidism increases with age and affects women more than men.

23. Familial hyperparathyroidism occurs as part of the following genetically determined conditions:
MEN1 (multiple endocrine neoplasia type 1: Werner’s syndrome);
MEN2A (Sipple syndrome), rarely in MEN2B; Familial hyperparathyroidism

24. Pathology
The majority (85 per cent) of patients with sporadic primary hyperparathyroidism have a single adenoma,
approximately 13 per cent have hyperplasia affecting all four glands and about
1 per cent will have more than one adenoma or a carcinoma.
In familial disease, multiple gland enlargement is usual.

25. A single enlarged gland with three small normal glands is characteristic of a single adenoma regardless of the histology which may show considerable overlap between a hyperplastic and adenomatous gland.
Multiple adenomas occur more frequently in older patients.
Parathyroid hyperplasia by definition affects all four glands.

26. parathyroid carcinomas are large tumours and typically much more adherent or even frankly invasive than large adenomas.
Histology demonstrates a florid desmoplastic reaction with dense fibrosis and capsular and vascular invasion.

27. Clinical presentation
The classic quartet of ‘stones, bones, abdominal groans and psychic moans’ is rarely observed in developed countries when the diagnosis is usually detected on serum calcium estimation well before the full picture of severe bone disease (von Recklinghausen’s disease), renal calculi and calcinosis, pancreatitis and psychiatric disorder.

28. Diagnosis
Although ionised calcium is the physiologically active circu lating element, total serum calcium is a satisfactory measure.
The effect of binding to serum proteins must be corrected by upward or downward correction to a serum albumin level of 40 g/L.
Inappropriate, i.e. elevated or normal PTH levels in the presence of high serum calcium is diagnostic of primary HPT.
Hypophosphataemia and elevated urine calcium excretion are confirmatory.

29. Other causes of hypercalcaemia must be considered and excluded
Advanced malignancy is the most common cause of hypercalcaemia in hospitalised patients, due to parathyroid hormone-related peptide (PTHrP) or bone metastases. The PTH level is suppressed.

30. Familial hypocalciuric hypercalcaemia is an autosomal domi nant disorder characterised by mild elevation of calcium and PTH levels secondary to a missense mutation in the cell membrane calcium receptor.
The low urinary excretion of calcium will discriminate this from HPT. Parathyroidectomy is not required.

31. Treatment of primary hyperparathyroidism
At present surgery is the only curative option and should be offered to all patients with significant hypercalcaemia provided they are otherwise fit for the procedure.
There are a number of medical strategies and therapies, particularly in mild hyperparathyroidism, which include simple expectant treatment until the calcium level or symptoms reach a level at which surgery becomes more attractive, low calcium diet, withdrawal of drugs (diuretics and lithium) which aggravate hypercalcaemia and, more recently, calcium reducing agents such as bisphosphanates and the calcium receptor agonist cinacalcet.

32. Occasionally, patients present with a parathyroid crisis and severe hypercalcaemia (serum calcium greater than 3.5 mmol/L).
This results in confusion, nausea, abdominal pain, cardiac arrhythmias and hypotension with acute renal failure.
Intravenous saline and bisphosphonate therapy (pamidronate) are required to correct the dehydration and hypercalcaemia.
This is best done in a high-dependency unit or even intensive therapy unit setting to monitor the major physiological fluxes which result.

33. Indications for operation
Indications for parathyroidectomy in primary hyperparathyroidism.
Urinary tract calculi.
Reduced bone density.
High serum calciuma.
All in younger age group <50 years.
Deteriorating renal function
Symptomatic hypercalcaemia .

34. Preoperative localisation
High frequency neck ultrasound is non-invasive and should identify 75 per cent of enlarged glands. It gives better resolution but reduced penetration and cannot visualise the mediastinum Nodular thyroid disease is a confounding factor.
Technetium-99m (99mTc)-labelled sestamibi (MIBI) isotope scans (also identify 75 per cent of abnormal parathyroid glands. The area scanned must include the mediastinum to detect ectopic glands

35. Technetium-99m (99mTc)-labelled sestamibi (MIBI) isotope scans

36. Single-photon emission computed tomography (SPECT) gives a three- dimensional image which may influence the surgical approach.
Concordance between ultrasound and sestamibi scan permits a targeted approach with confidence.
However, the size of the adenoma is important and imaging and concordance decline with glands weighing less than 500 mg.

37. SPECT

38. Consent for surgery
Preoperative discussion must include the possibilities of:
persistent hyperparathyroidism (5 per cent);
recurrent laryngeal nerve injury (1 per cent);
postoperative haemorrhage (1 per cent);
permanent hypoparathyroidism;
recurrent hyperparathyroidism.

39. Operation for primary hyperparathyroidism
Targeted small incision approach and
bilateral exploration using a conventional ‘thyroidectomy’ incision are the most frequently performed.
Video-assisted (in which a video endoscope is used to reduce the size of incision and permit bilateral exploration) and totally endoscopic techniques with multiple punctures have not achieved much popularity.

40. Methylene blue infusion to assist in gland identification has largely been abandoned
A gamma probe can be used to guide exploration following preoperative injection of technetium-labelled sestamibi.
The short serum half-life of PTH means that intraoperative measurement can be used to confirm that the source of excess PTH production has been excised.

41. Serum levels of PTH are measured pre-incision, pre-removal, 5 minutes after removal and 10 minutes after removal.
The assay takes 30 minutes and if the percentage drop is not >50 per cent then further exploration is indicated.

42. Operation for primary hyperparathyroidism
Targeted approach
Confident preoperative localisation permits a 2–3 cm incision located over the site of the adenoma
Conventional approach
The glands are identified in a systematic manner commencing with the common sites and working sequentially through to the rare locations.

43. All abnormal glands are excised and, in the event of sporadic four- gland disease, subtotal parathyroidectomy is carried out, preserving approximately 50 mg of one gland.
This must be marked with a non-absorbable suture to facilitate any possible future re-exploration.

44. In patients with four-gland disease, transcervical thymectomy is recommended to reduce the risk of persistent or recurrent hyperparathyroidism.
In patients with MEN-1, total parathyroidectomy reduces the risk of recurrence.
Preoperative imaging will identify the 1 per cent of patients with a mediastinal adenoma and allow a single curative operation .

45. Parathyroid carcinoma
Cancer of the parathyroid is rare accounting for 1 per cent of cases of hyperparathyroidism.
Typical features are very high calcium and PTH levels often with a palpable neck swelling or occasionally lymphadenopathy.
Scanning may support the diagnosis.
The diagnosis is rarely known at the time of exploration but, if suspected, operation should include excision of the tumour mass with en bloc thyroid lobectomy and node dissection when indicated.

46. The diagnosis is difficult to make histologically and may only become apparent when recurrent disease presents with hypercalcaemia, increased serum PTH and evidence of local recurrence.
Adjuvant or palliative radiotherapy may be indicated and overall survival as in most endocrine can cers is reasonable with 85 per cent five-year survival.

47. Management of postoperative hypocalcaemia
Check serum calcium within 24 hours of total thyroidectomy or earlier if symptomatic
Medical emergency if the level is <1.90 mmol/L: correct with 10 mL of 10 per cent calcium gluconate intravenously; 10 mL of 10 per cent magnesium sulphate intravenously may also be required
Give 1 g of oral calcium three or four times daily
Give 1–3 μg daily of oral 1-alpha-vitamin D if necessary