THE GLUCOCORTICOID AXIS - Clinical features, Investigations

The adrenal gland consists of an outer cortex producing steroids (cortisol, aldosterone and androgens) and an inner medulla secreting catecholamines. Aldosterone secretion is under the control of the renin-angiotensin system (see later). Corticotrophin-releasing hormone (CRH) from the hypothalamus stimulates ACTH (from the anterior pituitary), which stimulates cortisol pro-duction by the adrenal cortex. Cortisol feeds back on the hypothalamus and pituitary to inhibit further CRH/ACTH release. CRH release, and hence cortisol release, is in response to a circadian rhythm (light-dark), stress and other factors. Random ‘one-off serum cortisol measurements may therefore be misleading in the diagnosis of hypoadrenalism or Cushing's syndrome. Cor-tisol has many effects, particularly on carbohydrate metabolism. It leads to increased protein catabolism, increased deposition of fat and glycogen, sodium retention, increased renal potassium loss and a diminished host response to infection.

Synthetic steroids are widely used in the treatment of a variety of inflam-matory disorders and replacement therapy in adrenal insufficiency. They differ in their structure and potency and include cortisol, prednisolone, methy-prednisolone and dexamethasone. Fludrocortisone is produced by modifica-tion of hydrocortisone. It has potent mineralocorticoid activity and is used to replace natural aldosterone in patients with primary adrenal insufficiency.

Addison’s disease: primary hypoadrenalism

This is a rare condition in which there is destruction of the entire adrenal cortex.

Aetiology

More than 90% of cases result from destruction of the entire adrenal cortex by organ-specific autoantibodies. This is associated with other autoimmune conditions, e.g. autoimmune thyroid disease, ovarian failure, pernicious anaemia and type 1 diabetes mellitus. Rarer causes are adrenal gland tuber-culosis, surgical removal, haemorrhage (in meningococcal septicaemia), and malignant infiltration. Primary hypoadrenalism must be differentiated from secondary (to pituitary disease) or tertiary (to hypothamalic disease) adreno-cortical failure or after prolonged corticosteroid treatment for non-endocrine conditions (p. 665).

Clinical features

There is an insidious presentation with non-specific symptoms of lethargy, depression, anorexia and weight loss. Postural hypotension caused by salt and water loss is an early sign. Hyperpigmentation (buccal mucosa, pressure points, skin creases and recent scars) results from stimulation of melano-cytes by excess ACTH in primary hypoadrenalism. There may be vitiligo and loss of body hair in women because of the dependence on adrenal androgens. Hypoadrenalism may also present as an emergency (Addisonian crisis), with vomiting, abdominal pain, profound weakness, hypoglycaemia and hypo-volaemic shock.

Investigations

Investigations are threefold: to demonstrate inappropriately low cortisol secretion, to determine if cortisol deficiency is independent or dependent on ACTH secretion, i.e. primary or secondary/tertiary hypoadrenalism, and to determine the specific cause of the adrenal failure:

■ Single cortisol measurements - a random daytime cortisol below 100 nmol/L is highly suggestive and above 550 nmol/L makes the diag-nosis unlikely, but single values are not usually helpful.

■ The short ACTH (tetracosactide) stimulation test is the key diagnostic investigation and demonstrates failure of exogenous ACTH to increase plasma cortisol (Table 14.9). However, it does not differentiate primary from secondary hypoadrenalism.

■ Plasma ACTH level - a high level (>80 ng/L at 0900 h) with low or low-normal cortisol confirms primary hypoadrenalism. Reduced ACTH and cortisol indicate secondary or tertiary hypoadrenalism.

■ The long ACTH stimulation test is used to a diagnose secondary hypo-adrenalism or adrenal suppression by steroids.

■ Adrenal antibodies are detected in most cases of autoimmune adrenalitis.

Table 14.9 Tetracosactide stimulation tests

Short test

1. Take blood for measurement of plasma cortisol

2. Administer tetracosactide 250 μg i.m./i.v.

3. Take blood for measurement of cortisol atter 30 minutes

4. Interpretation: adrenal insufficiency is excluded if the basal plasma cortisol exceeds 170 nmol/L and exceeds 600 nmol/L at 30 minutes. Further tests (plasma ACTH and long synacthen test) are needed to establish the cause of hypoadrenalism.

Long test

1. Take blood for measurement of plasma cortisol

2. Administer tetracosactide 1 mg i.m.

3. Take blood for cortisol at hourly intervals for 5 hours, then at 8 and 24 hours

4. Interpretation: patients with normal adrenal glands reach a plasma cortisol concentration of over 1000 nmol/L by 4 hours with a rise of >550 nmol/L over baseline. In patients with Addison’s disease the cortisol response is impaired throughout, and in secondary adrenal insufficiency a delayed but normal response is seen.

■ Other tests include hyponatraemia, hyperkalaemia. A raised urea and hypoglycaemia are occasionally seen. Serum calcium may be high.

■ Chest and abdominal X-rays may show evidence of tuberculosis, with calcified adrenals.

Addisonian crisis is a life-threatening emergency that requires immediate treatment before full investigation (Emergency Box 14.2). Treatment should begin on the basis of clinical suspicion without waiting for the results of labo-ratory tests.

Management

This is with lifelong steroid replacement taken as tablets:

■ Hydrocortisone. The usual dose is 20 mg on waking and 10 mg in the evening, which mimics the normal diurnal rhythm. The dose is best monitored by measuring a series of cortisol levels throughout the day.

■ Fludrocortisone, a synthetic mineralocorticoid, 50-300 μg daily. The dose is adequate when serum electrolytes are normal, there is no postural drop in blood pressure and plasma renin levels are suppressed to within the normal range.

Patients should wear a Medic Alert bracelet or necklace and carry the medical information card supplied with it. Both should indicate the diagnosis, daily medications and doses. They should also keep an (up-to-date) ampoule of

Emergency Box 14.2
Management of acute hypoadrenalism
Investigations
• Take blood for plasma cortisol and ACTH before administration of
hydrocortisone
• Full blood count, urea and electrolytes, blood glucose, serum calcium and blood cultures
Immediate
• Hydrocortisone 100 mg intravenously
• 0.9% saline, 1 L over 30–60 minutes
• 50 mL of 50% dextrose if hypoglycaemic
• Search for precipitating cause, e.g. infection, gastroenteritis
Subsequent
• Hydrocortisone 100 mg intramuscular 6-hourly until BP stable and vomiting ceased
• 0.9% saline 2–4 L intravenously in 12–24 hours; monitor by JVP or CVP
• Expect recovery, with normal BP, blood glucose and serum sodium, within 12–24 hours
• When stable, convert to oral maintenance treatment continued lifelong

hydrocortisone at home in case of major illness or if they are unable to take their oral medication due to vomiting. In a normal individual, stress of any type, e.g. infection, trauma and surgery, causes an immediate and marked increase in ACTH and hence in cortisol. This is a necessary response and therefore it is essential in patients on steroid replacement that the dose is increased when they are placed in any of these situations. The usual dose is 100 mg hydrocortisone intramuscularly for minor surgery and, for major surgery 100 mg hydrocortisone 6-hourly until oral medication is resumed. The dose is doubled during minor illness.

Uses and problems of therapeutic steroid therapy

In addition to their use as therapeutic replacement for deficiency states, steroids are widely used for a variety of non-endocrine conditions such as inflammatory bowel disease, asthma and rheumatological conditions. Long-term steroid use is associated with side-effects (Table 14.9) and also results in suppression of the adrenal axis if used continually for more than 3-4 weeks. All patients receiving steroids should carry a ‘Steroid Card' and should be made aware of the following points:

■ Steroid therapy must never be stopped suddenly unless treatment has been for less than 2-3 weeks. After 3 weeks doses should be reduced very gradually.

■ Doses should be doubled in times of serious intercurrent illness.

■ Other physicians, anaesthetists and dentists must be told about steroid therapy.

Patients should also be informed of potential side-effects and this information should be documented in the patient records. The clinical need for high-dose steroids should be continually and critically assessed. Steroid-sparing agents (e.g. azathioprine) should always be considered and screening and prophy-lactic therapy for osteoporosis introduced.

Secondary hypoadrenalism

This may arise from hypothalamic-pituitary disease or from long-term steroid therapy leading to hypothalamic-pituitary-adrenal suppression. The clinical features are the same as those of Addison's disease but there is no pigmenta-tion because ACTH levels are low and, in pituitary disease, there are usually features of failure of other pituitary hormones. A long ACTH test (Table 14.10) will differentiate between primary and secondary adrenal failure. Treatment is with hydrocortisone; fludrocortisone is unnecessary. If adrenal failure is secondary to long-term steroid therapy, the adrenals will recover if steroids are withdrawn very slowly.

Cushing’s syndrome

Cushing's syndrome is caused by persistently and inappropriately elevated circulating glucocorticoid levels. Most cases result from administration of synthetic steroids or ACTH for the treatment of medical conditions, e.g. asthma. Spontaneous Cushing's syndrome is rare and two-thirds of cases result from excess ACTH secretion from the pituitary gland (Table 14.11). Cushing's disease must be distinguished from Cushing's syndrome. The latter is a general term which refers to the abnormalities resulting from a chronic excess of glucocorticoids whatever the cause, whereas Cushing's disease specifically refers to excess glucocorticoids resulting from inappropriate ACTH secretion from the pituitary (usually a microadenoma, less often corti-cotrophin hyperplasia). Alcohol excess mimics Cushing's syndrome clinically and biochemically (pseudo-Cushing's syndrome). The pathogenesis is incom-pletely understood but the features resolve when alcohol is stopped.

Clinical features

Patients are obese: fat distribution is typically Central, affecting the trunk, abdomen and neck (buffalo hump). They have a plethoric complexion with a

Table 14.10 Adverse effects of corticosteroids

Physiological

Adrenal and/or pituitary suppression

Pathological

Cardiovascular

Endocrine

Increased blood pressure

Weight gain

Glycosuria, hyperglycaemia (diabetes mellitus)

Gastrointestinal

Impaired growth in children

Peptic ulceration exacerbation (possibly)

Acute pancreatitis

Bone and muscle

  Osteoporosis
Renal

Proximal myopathy and wasting

Polyuria

Aseptic necrosis of the hip

Nocturia

Pathological fractures

Central nervous

Skin

Depression

Thinning

Euphoria

Easy bruising

Psychosis

Insomnia

Eyes

Cataracts

Increased susceptibility to infection

(signs and fever are frequently masked)

Septicaemia

Reactivation of tuberculosis

Skin (e.g. fungi)

Oral candida (including with inhaled drugs)

moon face. Many of the features are the result of the protein-catabolic effects of cortisol: the skin is thin and bruises easily and there are purple striae on the abdomen, breasts and thighs (Fig. 14.9). Pigmentation occurs with ACTH-dependent cases. Patients with ectopic production of ACTH tend to have rapidly progressive symptoms and signs and have evidence of the primary tumour.

Table 14.11 Causes of Cushing's syndrome
ACTH-dependent causes
Pituitary-dependent (Cushing’s disease)
Ectopic ACTH-producing tumours (small-cell lung cancer, carcinoid tumours)
ACTH administration
Non-ACTH-dependent causes
Adrenal adenomas
Adrenal carcinomas
Glucocorticoid administration
Others
Alcohol-induced pseudo-Cushing’s syndrome

Fig. 14.9 Cushing’s syndrome - symptoms and signs. Bold type indicates signs of most value in discriminating Cushing’s syndrome from simple obesity and hirsutism.

Investigations

In a patient with suspected spontaneous Cushing’s syndrome the purpose of investigation is firstly to confirm the presence of cortisol excess, and secondly to determine the cause.

Contirm raised cortisol

■ The 48-hour low-dose dexamethasone suppression test is the most reli-able screening test. Dexamethasone 0.5 mg 6-hourly is given orally for 48 hours. Normal individuals suppress plasma cortisol to <50 nmol/L 2 hours after the last dose of dexamethasone.

■ 24-hour urinary free cortisol is raised (normal <700 nmol/24 h) in most cases.

■ Circadian rhythm studies show loss of the normal circadian fall of plasma cortisol at 2400 h in patients with Cushing's syndrome.

Establishing the cause of Cushing’s syndrome

■ Adrenal CT or MRI will detect adrenal adenomas and carcinomas, as those which produce Cushing's syndrome are usually large.

■ Pituitary MRI and CT will detect some, but not all, pituitary adenomas.

■ Plasma ACTH levels are low or undetectable in adrenal gland disease (non-ACTH dependent) and should lead to adrenal imaging. High or inap-propriately normal values suggest pituitary disease or ectopic production of ACTH.

■ High-dose dexamethasone suppression test. Dexamethasone 2 mg 6-hourly is given orally for 48 hours. Most patients with pituitary-dependent Cushing's disease suppress plasma cortisol by 48 hours. Failure of suppression suggests an ectopic source of ACTH or an adrenal tumour.

■ Corticotrophin-releasing hormone test. An exaggerated plasma ACTH response to exogenous CRH (bolus given intravenously) suggests pituitary-dependent Cushing's disease.

■ Other tests will depend on the probable cause of Cushing's syndrome, which has been established from the above tests. Chest X-ray, bronchos-copy and CT of the body may localize ectopic ACTH-producing tumours. Selective venous sampling for ACTH will localize pituitary tumours and an otherwise occult ectopic ACTH-producing tumour.

■ Radiolabelled octreotide (111In octreotide) is occasionally helpful in locat-ing ectopic ACTH sites.

Management

Surgical removal is indicated for most pituitary (usually a trans-sphenoidal approach) and adrenal tumours and may be appropriate for many cases of ectopic ACTH-producing tumours.

Drugs which inhibit cortisol synthesis (metyrapone, ketoconazole or aminoglutethimide) may be useful in cases not amenable to surgery.

External-beam irradiation of the pituitary produces a very slow response and is restricted to cases where surgery is unsuccessful, contraindicated or unacceptable to the patient.

latrogenic Cushing's syndrome responds to a reduction in steroid dosage when possible. Immunosuppressant drugs such as azathioprine are used in conjunction with steroids to enable lower steroid doses to be used to control the underlying disease.

Incidental adrenal tumours

With the advent of improved abdominal imaging, unsuspected adrenal masses have been discovered in about 4% of scans. Most are small non-secreting adenomas. Others are secreting adenomas, carcinomas or metas-tases. Metastases will usually be apparent from the previous or ongoing medical history and specific imaging phenotype. If the imaging suggests an adenoma, functional tests to exclude secretory activity are indicated: dexam-ethasone suppression test for subclinical Cushing's syndrome; 24-hour urinary specimen for measurement of catecholamines to exclude a phaeo-chromocytoma; and plasma renin and aldosterone if hypertensive. Most authorities recommend surgical removal of large (>4-5 cm) and functional tumours but observation of smaller hormonally inactive lesions.

Ebook Essentials of Kumar and Clark's Clinical Medicine, 5e

1. Ethics and communication

Ethics and communication

2. Infectious diseases

Infectious diseases

3. Gastroenterology and nutrition

Gastroenterology and nutrition

4. Liver, biliary tract and pancreatic disease

Liver, biliary tract and pancreatic disease
LIVER BIOCHEMISTRY AND LIVER FUNCTION TESTS
SYMPTOMS AND SIGNS OF LIVER DISEASE
JAUNDICE
HEPATITIS
NON - ALCOHOLIC FATTY LIVER DISEASE (NAFLD)
CIRRHOSIS
COMPLICATIONS AND EFFECTS OF CIRRHOSIS
LIVER TRANSPLANTATION
TYPES OF CHRONIC LIVER DISEASE AND CIRRHOSIS
PRIMARY SCLEROSING CHOLANGITIS
BUDD - CHIARI SYNDROME
LIVER ABSCESS
LIVER DISEASE IN PREGNANCY
LIVER TUMOURS
GALLSTONES
THE PANCREAS
CARCINOMA OF THE PANCREAS
NEUROENDOCRINE TUMOURS OF THE PANCREAS

5. Haematological disease

Haematological disease
ANAEMIA
Assessment and treatment of suspected neutropenic sepsis
HAEMOLYTIC ANAEMIA
INHERITED HAEMOLYTIC ANAEMIAS
ACQUIRED HAEMOLYTIC ANAEMIA
MYELOPROLIFERATIVE DISORDERS
THE SPLEEN
BLOOD TRANSFUSION
THE WHITE CELL
HAEMOSTASIS AND THROMBOSIS
THROMBOSIS
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Malignant disease
MYELOABLATIVE THERAPY AND HAEMOPOIETIC STEM CELL TRANSPLANTATION
THE LYMPHOMAS
THE PARAPROTEINAEMIAS
PALLIATIVE MEDICINE AND SYMPTOM CONTROL

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Rheumatology
COMMON INVESTIGATIONS IN MUSCULOSKELETAL DISEASE
COMMON REGIONAL MUSCULOSKELETAL PROBLEMS
BACK PAIN
OSTEOARTHRITIS
INFLAMMATORY ARTHRITIS
THE SERONEGATIVE SPONDYLOARTHROPATHIES
Clinical features, Investigations
INFECTION OF JOINTS AND BONES
AUTOIMMUNE RHEUMATIC DISEASES
SYSTEMIC INFLAMMATORY VASCULITIS
DISEASES OF BONE
THERAPEUTICS

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WATER AND ELECTROLYTE REQUIREMENTS
BODY FLUID COMPARTMENTS
REGULATION OF BODY FLUID HOMEOSTASIS
PLASMA OSMOLALITY AND DISORDERS OF SODIUM REGULATION
DISORDERS OF POTASSIUM REGULATION
DISORDERS OF MAGNESIUM REGULATION
DISORDERS OF ACID - BASE BALANCE
THERAPEUTICS

9. Renal disease

Renal disease
INVESTIGATION OF RENAL DISEASE
GLOMERULAR DISEASES
NEPHROTIC SYNDROME
URINARY TRACT INFECTION
TUBULOINTERSTITIAL NEPHRITIS
HYPERTENSION AND THE KIDNEY
RENAL CALCULI AND NEPHROCALCINOSIS
URINARY TRACT OBSTRUCTION
ACUTE RENAL FAILURE/ACUTE KIDNEY INJURY
CHRONIC KIDNEY DISEASE
RENAL REPLACEMENT THERAPY
CYSTIC RENAL DISEASE
TUMOURS OF THE KIDNEY AND GENITOURINARY TRACT
DISEASES OF THE PROSTATE GLAND
TESTICULAR TUMOUR
URINARY INCONTINENCE

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COMMON PRESENTING SYMPTOMS OF HEART DISEASE
INVESTIGATIONS IN CARDIAC DISEASE
CARDIAC ARRHYTHMIAS
HEART FAILURE
ISCHAEMIC HEART DISEASE
RHEUMATIC FEVER
VALVULAR HEART DISEASE
PULMONARY HEART DISEASE
MYOCARDIAL DISEASE
CARDIOMYOPATHY
PERICARDIAL DISEASE
SYSTEMIC HYPERTENSION
ARTERIAL AND VENOUS DISEASE
ELECTRICAL CARDIOVERSION
DRUGS FOR ARRHYTHMIAS
DRUGS FOR HEART FAILURE
DRUGS AFFECTING THE RENIN - ANGIOTENSIN SYSTEM
NITRATES, CALCIUM - CHANNEL BLOCKERS AND POTASSIUM - CHANNEL ACTIVATORS

11. Respiratory disease


Respiratory disease
TUBERCULOSISnd
DIFFUSE DISEASES OF THE LUNG PARENCHYMA
OCCUPATIONAL LUNG DISEASE
CARCINOMA OF THE LUNG
DISEASES OF THE CHEST WALL AND PLEURA
DISORDERS OF THE DIAPHRAGM

12. Intensive care medicine

Intensive care medicine

13. Drug therapy, poisoning, and alcohol misuse

Drug therapy, poisoning, and alcohol misuse

14. Endocrine disease

Endocrine disease
PITUITARY HYPERSECRETION SYNDROMES
THE THYROID AXIS
MALE REPRODUCTION AND SEX
FEMALE REPRODUCTION AND SEX
THE GLUCOCORTICOID AXIS
THE THIRST AXIS
DISORDERS OF CALCIUM METABOLISM
DISORDERS OF PHOSPHATE CONCENTRATION
ENDOCRINOLOGY OF BLOOD PRESSURE CONTROL
DISORDERS OF TEMPERATURE REGULATION
THERAPEUTICS

15. Diabetes mellitus and other disorders of metabolism

DIABETES MELLITUS
DIABETIC METABOLIC EMERGENCIES
COMPLICATIONS OF DIABETES
SPECIAL SITUATIONS
HYPOGLYCAEMIA IN THE NON - DIABETIC
DISORDERS OF LIPID METABOLISM
THE PORPHYRIAS

16. The special senses

THE EAR
THE NOSE AND NASAL CAVITY
THE THROAT
THE EYE

17. Neurology

COMMON NEUROLOGICAL SYMPTOMS
COORDINATION OF MOVEMENT
THE CRANIAL NERVES
COMMON INVESTIGATIONS IN NEUROLOGICAL DISEASE
UNCONSCIOUSNESS AND COMA
STROKE AND CEREBROVASCULAR DISEASE
EPILEPSY AND LOSS OF CONSCIOUSNESS
NERVOUS SYSTEM INFECTION AND INFLAMMATION
HYDROCEPHALUS
HEADACHE, MIGRAINE AND FACIAL PAIN
SPINAL CORD DISEASE
DEGENERATIVE NEURONAL DISEASES
DISEASES OF THE PERIPHERAL NERVES
MUSCLE DISEASES
MYOTONIAS
DELIRIUM
THERAPEUTICS

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Dermatology

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