Phaeochromocytoma is a neuroendocrine tumour of the medulla of the adrenal glands. It secretes large quantities of  the catecholamines noradrenaline, and to a lesser extent, adrenaline.

Epidemiology

Rule of 10: 10% familial, 10% bilateral, 10% extra-renal, 10% malignant

Presentation

• Severe headaches
• Severe hypertension (eg 210/100) and orthostatic hypotension, both fluctuating
• Cardiac tachyarrythmias (eg SVTs)
• A plethora of other symptoms, including flushing+unwell+wt loss (like in hyperthyroid), panic/anxiety, sweating, pallor, hyperglycaemia, pyrexia, abdominal pain …
• May be worsened by TCA (if you thought it was ps-somatic), beta-blockers, IV contrast

Complications

MI, heart failure, dilated cardiomyopathy, arrhythmias, stroke, coma, death

Associations

MEN 2a,2b; neurofibromatosis; Von Hippel-Lindau syndrome.

Diagnosis

• Initial best test to rule out phaeochromocytoma: metadrenaline from blood.
• Confirmed by 3x 24-hour collection of urine catecholamines.
• CT abdo.
• Nuclear imaging: MIBG: chrommafin-seeking isotope scan, for extra-renal tumours

Management

Medical

• Stabilise patient: ALPHA-blockers (phenoxybenzamine) BEFORE beta-blockers, to prevent hypertensive crisis from unopposed alpha-stimulation.

Surgery

• Definitive Rx: surgical resection of adrenal gland.

Life-long follow up

• Malignant recurrence may present late

References

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• Spontaneous forms of the syndrome are very rare – it generally occurs as a result of administered ACTH or glucocorticoid.
• Spontaneous disease usually occurs as a result of various tumours:
  • Excessive ACTH from the pituitary gland
  • ACTH producing tumours (e.g. in pituitary or from lung cancer)
    • Cushing’s disease is a particularly form of Cushing’s syndrome due to a pituitary adenoma
  • Adrenal tumours (non-ACTH dependent pathway)

Diagnosis can be tricky and there a several types special investigations that can be used in different combinations to confirm a diagnosis. After the diagnosis has been confirmed, imaging is typically required to define (and sometimes to locate) the tumour.

Prognosis without treatment is poor – there is a 50% 5-year mortality. Treatment involves destruction (either surgically or with radiotherapy) of the tumour. Medical treatment may be used to lower the cortisol levels in the interim.

Epidemiology

• The incidence of spontaneous Cushing’s syndrome is 10 per 1,000,000 per year
• Peak incidence is between age of 25 and 40 – when associated with an adrenal or pituitary tumour
• Risk factors:
  • Female (F:M 5:1)
  • Diabetes – especially if poor glycemic control
    • Prevalence fo 2-5% amongst patients with T2DM
  • Obesity
• Cushing’s is often divided in ACTH (corticotropin) dependent, and corticotrophin independent causes
• ACTH dependent
  • 80% due to pituitary adenomas
  • 20% due to small cell lung ca, or carcinoid tumours, or any other endocrine tumour
• ACTH independent
  • Adrenal adenoma – 60%
  • Adrenal carcinoma – 40%
• Note that pigmentation can only occur with ACTH dependent causes (due to POMC), and that impaired glucose tolerance (leading to diabetes) and hypokalemia both occur, but only with the ectopic ACTH type of the disease. This is because, unlike an excess pituitary secretion (probably due to a pituitary tumour), the ectopic tissue does not respond to feedback from excess cortisol in the blood, and as a result, ACTH levels are likely to be higher with this type of the condition.

Pathology

Clinical features

The clinical features of Cushing’s syndrome are varied, and as spontaneous disease is rare, the diagnostic ability of any one factor is weak.
It is also possible to confuse diagnosis with other conditions, such as depression and obesity, because many of the diagnostic factors are non-specific.
The clinical features are those of glucocorticoid excess:
Symptoms:

• Weight gain
• Change of appearance
• Depression
• Insomnia
• Amenorrhoea / oligomenorrhoea
• Poor libido
• Thin skin / easy bruising
• Hair growth
• Acne
• Slow growth in children
• Back pain
• Reduced libido
• Polyuria
• Dyspepsia

Signs:

• “Moon face”
• Frontal balding (female)
• Pigmentation
• Skin infections
• Hypertension
• Osteoporosis / osteopenia
• Pathological fractures – particularly vertebrae and ribs
• “Buffalo hump” – a dorsal fat pad
• Kyphosis – hunch back
• Striae – stretch marks – can be purple or red- occur mainly on the abdomen
• Supraclavicular fat pads
• Oedema
• Proximal myopathy
• Glycosuria
• Diabetes / impaired glucose tolerance

Differentials

• Anxiety or depression
• Chronic excessive alcohol consumption
• Obesity
• Poor controlled T2DM
• HIV

Investigations

Investigations to diagnosed Cushing’s Syndrome

• It is very important to rule out other differentials or an iatrogenic cause (exogenous corticosteroids) first. Take a very detailed drug history.
• Confirming diagnosis is difficult. Often obese and depressed patients will have abnormal abnormal cortisol values. Taking a random cortisol value is of no benefit whatsoever, due to daily variations, and variations caused by stress and illness. Investigations used to confirm the diagnosis of Cushing’s include:
• 48-hour low dose dexamethasone test – administration of cortisol in disease-free individuals will result in a reduced secretion of CRH, thus reduced ACTH, and thus reduced cortisol release. Patients with ACTH-dependent Cushing’s will fail to suppress their cortisol level to less than 50nmol/L. This is the most reliable test – but also the most inconvenient as it requires testing and administration of medications over a 48 hour period.
  • There is a variation of this test – the 1mg overnight dexamethasone suppression test
    • 1mg of dexamethasone is given at 11pm and an 8am cortisol level is measured
• 24-hour urinary free cortisol measurements – this is often repeated twice to confirm the diagnosis. Two normal values are unlikely to be Cushing’s, but it is still possible. The test involves measuring the complete urinary output for 24 hours, which when tested for cortisol – gives an indication of the cortisol output over a 24 hour period.
  • Cortisol should not exceed 280nmol/L.
  • The test is invalid if creatinine excretion varies by >10% between collections and needs to be repeated
  • False positives are seen with: strenuous exercise, anorexia, psychosis, alcoholism, depression
• Circadian rhythm – patients in hospital have values of blood cortisol take at 0900 and 2400 without warning. Normal patients will show considerable variation, whilst Cushing’s patients are likely to have a high 2400 level, although probably a normal 0900 level – i.e. they have lost their normal diurnal variation.
• FBC – may show raised WCC
• U+E – hypokalaemia is common but not always present

Clinical differentiation between pituitary and ectopic disease is difficult, and not perhaps even necessary, as the disease is so similar clinically. Often the ectopic tumours are benign.
It does however have implications for treatment.
If ACTH is very low or even undetectable, then this suggest an adrenal tumour – the ACTH has been suppressed so much that it is no longer detectable – this can only occur in ACTH independent disease.
In differentiating ectopic from pituitary disease, you should remember that pituitary disease tends to retain some features of suppression, whilst ectopic disease will not.

Investigations to identify the cause fo Cushing’s Syndrome

• Plasma ACTH
  • Pulsatile secretion
  • Highest at 8am
  • Lowest at midnight
  • Increased by stress
• ↓ACTH (undetectable) and ↑cortisol = ACTH-independent Cushing’s syndrome
  • Follow up with imaging to discover the underlying cause – as long as exogenous steroids have been excluded
• ↑ACTH and ↑cortisol = ACTH dependent Cushing’s Syndrome
  • Consider an 8mg dexamethasone suppression test or the 48 hours dexamethasone test to confirm the diagnosis

Other investigations

• MRI / CT – in the case of adrenal adenomas and carcinomas (ACTH-independent Cushing’s), then the tumours are nearly always large and can be spotted on CT. Chest + abdomen CT is often performed when ACTH-indepednet Cushing’s is suspected and the location needs to be identified. Carcinomas can be distinguished by their irregular outline and possible metastasis. Often there is also adrenal hyperplasia in ACTH-dependent causes.
• Pituitary MRI can show a pituitary tumour, but it is often very small, and in many cases may be missed.
• Potassium levels – hypokalaemia is common ectopic disease.
• High-dose dexamethasone test – lack of any suppression suggests an adrenal tumour or an ectopic source of ACTH.
• Chest x-ray – should always be performed to check for a carcinoma of the bronchi. However, if ectopic disease is suspected, then full CT of the lungs should be performed.

Treatment

• There is a 50% 5-year mortality if the disease is left untreated.

The two main options of treatment are surgery and radiotherapy. In both cases, the hypersecretion of cortisol should be controlled medically before the definitive treatment begins.

• If this preparatory medication is not given, then there is a much higher mortality once treatment begins.
• The usual drug for treatment is metyrapone which is an 11β-hydrolase blocker.
• Sometimes ketoconazole is used. When this is given, levels of cortisol in the urine should be measured, and amounts of the drug titrated against these values. Levels of cortisol in the urine should be kept between 150-300nmol/L.
• Medical treatment only may be used if the patient is unfit or unwell to undergo surgery

• Trans-sphenoidal removal of the tumour is the treatment of choice. This will result in a cure in 75-80% of cases – however this is dependent on the surgeon.
• External pituitary irradiation – this is slow! It is effective in 50-60% of cases, but requires a lot of follow up. It tends to be used when pituitary surgery has failed.
  • In children, 80% of cases are cured this way.
• Medical therapy – to reduce ACTH secretion is rarely effective. Examples of drugs include bromocryptine and cyproheptadine.
• Bilateral adrenalectomy – this is an effective last resort if other treatments have failed.

• Should be resected after remission with drug treatment has been achieved. Contralateral adrenal suppression may last for years.

• These are very aggressive and the prognosis is poor.
  • 30% of patients survive to 5 years
• Generally, if there are not widespread metastasis, then the primary tumour should be treated surgically. There is a drug call op’DDD (mitotane) which is adrenolytic, and this can slow progression of the disease considerably. Radiotherapy may be beneficial to some patients.

• These should be removed wherever possible, and if not, then chemo and radiotherapy can be beneficial.
• Drug control of the disease will help manage symptoms, and in patients where the tumours are thought benign, the patient can often benefit from adrenalectomy.

References

• Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
• Cushing’s Syndrome – patient.info
• Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.

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• As opposed to Cushing’s Syndrome – which is an excess of glucocorticoids, and as opposed to Addison’s disease which is a lack of both glucocorticoids and aldosterone

Causes

• About 80% of cases are due to a solitary mineralocorticoid producing adrenal adenoma.
  • Classically this is “Conn’s Syndrome” and other causes technically are not. In reality, the terms hyperaldosteronism and Conn’s syndrome are often used interchangeably
• About 20% of cases are due to adrenal hyperplasia.
  • 15% of cases are bilateral
  • <5% of cases are unilateral
• Adrenal carcinoma can also cause hyperaldosteronism

Pathology

 

Presentation

• Hypertension
• Hypokalaemia
  • 70% of patients have normal potassium
  • May cause weakness
• Hypernatraemia
  • Most patients have sodium in the normal range
• Metabolic alkalosis
• Polyuria and polydipsia

Investigations

• U+E – may show hypernatraemia and hypokalaemia – but often not
• Renin and aldosterone levels
  • Increased aldosterone
  • Decreased renin – if renin is normal then primary aldosteronism is excluded
  • Aldosterone/renin ratio is the usual way that diagnosis is confirmed
  • Ratio >800 confirms diagnosis and prompts need to investigate for the cause
  • Results can be altered by antihypertensives
    • False positives – B-blockers
    • False negatives – ACE-inhibitors, ARBs, calcium channel blockers
• ECG – signs of hypokalaemia
• CT / MRI
  • To look for adrenal mass or hyperplasia
• Salt loading and renin and aldosterone levels
  • Patients are loaded with salt tablets and high salt diet for two weeks
  • In the normal physiological state, this should suppress plasma aldosterone
  • In primary hyperaldosteronism, aldosterone is not suppressed
  • Rarely used – doesn’t seem to enhance diagnostic rate and is fiddly and time-consuming
• Lying and standing aldosterone and renin levels
  • Can differentiate between adrenal hyperplasia and adrenal adenoma
  • Samples taken after lying down for several hours and repeated after standing for several hours
  • Need careful interpretation by a specialist
  • In adrenal hyperplasia – aldosterone increases after 4 hours of standing by >30%
  • In adrenal adenoma – there is not change in postural results

Differentials

There are many possible differentials, although clinically the most important is renal artery stenosis (RAS) which often presents with a similarly hypertensive patient. In these circumstances, performing an USS of the renal tract is important to exclude RAS as a differential. Other findings in RAS include:

• Raised renin AND aldosterone
• Renal arteriogram is the gold standard of diagnosis
• U+E may show hypokalaemia and impaired renal function

Other differentials include:

• Cushing’s disease
  • Aldosterone and renin levees are low
• Congenital adrenal hyperplasia
• Nephrotic syndrome

Management

• Adrenal adenoma (Conn’s Syndrome)
  • Surgical removal of the adenoma
  • In the meantime, medical management may be required:
    • Spironolactone (aldosterone antagonist)
  • Hypertension may persist after removal of tumour due to secondary effects of hypertension on the vasculature
• Bilateral adrenal hyperplasia
  • Medical management with aldosterone antagonists
    • Spironolactone – blocks both aldosterone and testosterone receptors, which can cause gynaecomastia, menstrual irregularities and erectile dysfunction
    • Amiloride – another potassium sparing diuretic, although its effects are generally weaker than spironolactone
    • Eplerenone – selective aldosterone antagonist and thus does not suffer from the same testosterone effects as spironolactone. More evidence is needed to evaluate its effectiveness in adrenal hyperplasia

References

• Hyperaldosteronism – patient.info
• Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
• Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.

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