CHAPTER 38

PARATHYROID GLANDS
HYPOPARATHYROIDISM
HYPERPARATHYROIDISM
ADRENAL GLANDS
ADRENAL CORTEX
DISORDERS OF ADRENOCORTICAL FUNCTION
ADRENAL MEDULLA
TUMOURS OF THE ADRENAL MEDULLA

PARATHYROID GLANDS
Anatomy. The parathyroid glands, four in number, axe small, oval in shape,
commonly about 0.5 cm in size, soft, mobile, yellowish brown in colour and
arranged in pairs most often closely applied to the thyroid gland, either within
or closely applied to its capsule. The upper pair are more constant in position than
the lower: 80 per cent are found ott the posterolateral aspect of the thyroid,
immediately above the termination of the inferior thyroid artery, close to the
cricothyroid articulation. Most of the remaining 20 per cent are posterolateral to
the upper pole of the thyroid lobe. The lower pair are more variable in position: 40
per cent are found at the lower pole of the thyroid and 40 per cent are within the
thymic tongue (Fig. 38.1). The remaining 20 per cent are variable in site, most
often some distance lateral to the thyroid, and less often in the mediastinal thymus
a few centimetres below the sternal notch or, very occasionally, ectopically situated
near the carotid sheath, sometimes as high as the carotid bifurcation. On rare
occasions, a parathyroid, usually the upper gland, may be retrophaiyngeal, retrooesophageal or actually within the thyroid substance and, in 12 per cent of
individuals, there is one or more supernumeray gland usually associated with a

lobule of thymic tissue. Each gland has a delicate capsule and is supplied by a
single leash of blood vessels clearly seen running in the subcapsular plane (Fig.
382). Very often, parathyroid glands are associated with or embedded within a pad
of fat, which gives a useful due to identification.
Histology. The stroma consists of a rich sinusoidal capillary network with islands
of secretory cells interspersed with fat cells. The glandular cells are of two types.
The chief or principal cells are small with vesicular nuclei and poorly staining
cytoplasm. Waterclear cells, derived from the chief cells, are found itt
hyperplastic and neoplastic glands. The oxyphil cells are less numerous and
larger, with granular cytoplasm and deeply staining nuclei.
Physiology. The chief cells of the parathyroids produce parsthormone, the
hormone being released directly into the bloodstream. The circulating level of
parathormone can be measured by radioimmunoassay, which is sufficiently reliable
to distinguish between high and low levels. Facilities for obtaining the estimation
are available everywhere in the UK through the Supra-Regional
Assay Service.
Parathormone:
stimulates osteoclastic activity, thereby increasing bone resorption by
mobilising calcium and phosphate
increases the reabsorption of calcium by the renal tubules, thus reducing the
urinary excretion of calcium;
augments the absorption of calcium from the gut;
reduces the renal tubular reabsorption of phosphate, thus promoting
phosphaturia.
FIg. 38.1 Parathyroid gland. Normal and uncommon sites.
Fig. 38.2 The blood supply of a parathyroid gland.
Parathyroid hormone is an 84-amino acid peptide which has a short half life
before degradation into amino-terminal and carboxyterminal fragments, with the
amino-terminal fragment having biological activity. Available assays measure
either the intact hormone, the amino- or carboxy-terminal or mid-portion fragments.
Calcftonin (Copp) is secreted by the parafollicular cells of the thyroid
(thvrocalcitonin). It lowers the serum calcium and effects calcium storage in bones,
quite the opposite action from parathormono.
Parathyroid hormone-related protein (PTH-rP) is a hypercalcaemic factor with
similar bioactivity to that of parathyroid hormone. Since its recent isolation from
cancer cell lines and carcinoma of the breast, strong evidence has emerged that it is
an important hormonal mediator of cancer-associated hypercalcaemia in patients

with solid turnouts. Plasma lTH-rP 1-86 concentrations may be measured by a

two-site immunoradiometrtc assay.

HYPOPARATHYROIDISM
Parathyroid tetany, due to hypocalcaemia, is a rare complication of subtotal
thyroidectomy (less than 1 per cent) but a more common complication of total
thyroidectomy. At these operations, some of the parathyroid glands may be
removed or have their blood supply temporarily embarrassed. It may also occur
after surgery to the parathyroids themselves. Symptoms usually appear on the
second or third postoperative day, and are temporary. Milder forms of
hypoparathyroidism have been described in the follow-up of thyroidectomised
patients. Permanent hypoparathyroidism, most commonly encountered following
radical thyroidedomy for cancer, requires constant supervision and treatment.
Tetany in the newborn may occur within the first few days of life in the child born
of a mother with undiagnosed hypoparathyroidism.
Spontaneous hypoparathyroidism is an unusual form of autoimmune disease.
Clinical features. The first symptoms are tingling and numbness in the face,
fingers and toes. In extreme cases, cramps in the hands and feet are very painful;
the extended fingers are flexed at their metacarpophalangeal joints, with the thumb
strongly adducted (Fig. 38.3); the toes are plantarflexed and the ankle joints
extended the so-called carpopedal spasm. Spasm of the muscles of respiration
not only results in pain and stridor, but dread of suffocation. In infancy, the
symptoms of tetany may be mistaken for epilepsy, although there is no loss of
consciousness.
Fig. 38.3 The obstetricians hand seen in parathyroid tetany.
Latent tetany may be demonstrated by:
Chvosteks sign. Tapping over the branches of the facial nerve at the angle of
the jaw will produce twitching at the corner of the mouth, the ala of the nose and
the eyelids.
Trousseaus sign. A sphygmomanometer cuff applied to the arm and inflated
above the systolic blood pressure for not more than 2 minutes will produce carpal
spasm.
Treatment. In acute cases the symptoms may be relieved speedily by the slow

intravenous injection of 1020 ml of a 10 per cent solution of calcium ghiconate.

This may be repeated until the patients circulating calcium level has been
stabilised. For longer-term management, the absorption of calcium is enhanced by
oral administration of the most active metabolite of vitamin D 1,25
dihydroxycholecalciferol (1,25(OH)2D3). Its major action is on the gut, promoting
active absorption of calcium and phosphorus, raising calcium levels to normal
within a week. Magnesium supplements may occasionally be needed. Serum
calcium levels must be estimated daily and the dosage adjusted as appropriate.

HYPERPARATHYROIDISM
Hyperparathyroidism is associated with an increased secretion of parathyroid
hormone. This occurs in:
Primary hyperparathyroidism, which is an unstinsulated and inappropriately
high parathyroid hormone secretion for the concentration of plasma ionised
calcium and is due to adenoma or hyperplasia, and very rarely carcinoma.
A single adenoma is the commonest finding (multiple in 6 per cent). The whole
gland is usually considerably enlarged, darker in colour, firmer and more vascular
than normal; in some a rim of normal parathyroid tissue may be seen surrounding
the adenoma. The histological appearances are the same as in hyperplasia, with a
predominance of chief and water-dear cells. ABO (H) cell surface antigens are lost
from the parathyroid cell surface in adenoma and carcinoma, but not in
hyperplasia. Carcinoma of the parathyroids is extremely rare, less than I per cent. It
tends to invade locally and recur after operation. Blood-borne metastases have
burn aescribed.
Secondary hyperparathyroidism is associated with chronic renal failure or
malabsorption syndromes. The stimulus for the hyperplasm is chronic
hypocalcaemia. All four glands are involved.
Tertiary hyperparathyroidism is a further stage in the development of reactive
hyperplasia where autonomy occurs as the parathyroids no longer respond to
physiological stimuli.
Franhse( Chzustek, 183584. Physician, Josefsakadetnie, Vienna, Austria.
Arrnand Trousseau, 180267. Physician. Hotel Dies. Paris, France.
531
IllS ~SUIU P,I~U MuI-irisu-SL LaLMINUO

Clinical features. Hyperparathyroidism, rarely found in the first decade of life, is

commoner in women than men, and most commonly found between the ages of 20
and 60 years. The clinical features vary enormously, even when the biochemical
changes are similar.
Asymptomatic cases. The most common presentation is the detection of
unsuspected and asymptomatic hypercalcaemia by routine biochemical screening.
Bones, stones, abdominal groans and psychic moans. Only 50 per cent of
patients suffer from any of these.
Nonspecific symptoms include muscle weakness, thirst, polyuria, anorexia, and
weight loss a challenge to the astute clinician!
Bone disease. There may be generalised decalcification of the skeleton, as in
osteitis fibrosa cystica (von Recklinghausens disease), single or multiple cysts, or
pseudotumours of any bone. The latter are particularly common in the jaw bones.
Early radiological changes first appear in the skull and in the phalanges (Fig. 38.4),
with loss of density and subperiosteal erosions. Many patients presenting with
vague pains in the bones and joints are mistakenly diagnosed as rheumatic.
Fig. 38.4 Loss of density and subperiasteal resorption of the
phalanges ins case of primary hypetparathyroidism. (Mr Anthony W
Goode.)
Renal stones. Hyperparathyroidism must be considered in every patient
presenting with renal tract stone or nephrocalcinosis (Fig. 38.5), and even in those
cases of renal colic where no stone can be demonstrated.
Dyspeptic cases. Patients with nausea, vomiting and anorexia are relatively
common. Peptic ulcer and pancreatitis are not infrequently found in association
with hyperparathyroidism, but the relationship is not as yet fully understood.
Psychiatric cases are not uncommon; women, complaining of tiredness,
listlessness and with obvious personality changes, are often wrongly labelled
neuro
Fig. 38.5 Nephrocalcinosis.
tic or menopausal. Patients have been admitted to mental institutions because of
irrational behaviour.
Acute hyperparathyroidism. This diagnosis is difficult and only too often made
after death. Nausea and abdominal pain is followed by severe vomiting,
dehydration, oliguria, and finally coma. The serum calcium is very high. Treatment
is urgent after rehydration, which is vital. Biphosphonates (disodium etidronate and

pamidronate) are specific inhibitors of bone resorption. They are highly effective
given parenterally and may also be used in the preoperative, short-term medical
management of severe hypercalcaemia in primary hyperparathyroidism.
Clinical examination and investigation. Clinical examination may be unrewarding
but the cause of dehydration or confusion may be found in the eyes. Corneal
calcification may be detected. It begins on the lateral and medial borders of the
limbus (which distinguishes it from arcus senilis) and is best seen through a hand
lens by the light of a bright torch reflected off the iris. Less common is band
keratopathy in which a transverse band of calcification forms across the front of
the cornea, and conjunctival calcification where redness of the eye also occurs.
Hypertension may be present in up to 50 per cent of cases. There may be
electrocardiographic changes with a shortened QT interval, primarily by an effect
on the length of the S.T segment. A parathyroid adenoma is very seldom
palpable in the neck. The diagnosis is confirmed with the following biochemical
findings:
elevation of serum calcium (upper limit of normal 2.6 mmolll). Serum calcium
occurs as calcium ions complexed to citrate and bound to albumin. Therefore the
serum albumin concentration should be known in order to apply a correction
factor: corrected serum calcium (mmolll) = measured serum Ca (mmolll) + (40

A) x 0.02, where A = serum albumin (gil);

diminution of serum phosphorus (lower limit of normal 0.8 mmolll);
increased excretion of calcium in the urine (upper limit of normal 62 mmol per
24 hours for females, 75 mmol for males);
elevation of the serum alkaline phosphatase in cases with bone disease;
elevation of serum parathormone concentration.
The diagnosis of hyperparathyroidism largely depends on confirmed
hypercalcaemia, exclusion of other causes of hypercalcaemia (see below) and a
532
Fried ridi Daniel von Recklin,hauses. 1833-2920. Professor of Pathology,
Strasboug. France.
raised parathormone level. Present-day immunoradiometric assays (upper limit of
normal varies according to the laboratory) for biologically active intact parathormone are highly reliable and a raised level is even more reliable. Detectable
levels of parathormone within the normal range, in the presence of hypercalcaemia,
are suggestive of the diagnosis.
Preoperative localisation. Provided the surgeon is experienced in parathyroid
surgery, preoperative localisation tests may do little to enhance the ability to detect
95 per cent of abnormal glands at surgery. However, a multimodal approach

combining thallium technetium isotope scanning, neck ultrasonography and

magnetic resonance imaging may yield precise information which will clearly
facilitate surger, and reduce unnecessary dissection of tissue. Localisation tests are
particularly indicated before re-exploration when the initial operation has failed,
but may also be helpful to less experienced surgeons.
The simplest localisation test is an ultrasonic scan but results vary according to
the skill and experience of the investigator.
Computed tomography is of most value in localising a lesion in the mediastinum
rather than the neck.
Thallium-technetium isotope subtraction imaging may locate up to 90 per cent of
parathyroid adenomas before surgery (Fig. 38.6). Like ultrasonography. subtraction
scintigraphy is more accurate the larger the adenoma, and is inaccurate in
parathyroid hyperplasia
Magnetic resonance imaging is improving rapidly with some centres reporting
up to 64 per cent detection prospectively. A low signal is obtained from the
parathyroid glands on a T1-weighted image while a T2-weighted image appears in
early studies to produce good contrast resolution from the surrounding tissues.
Invasive techniques such as selective angiography and selective venous
sampling may be helpful in locating an abnormally situated gland after a failed
initial exploration.
3 ~S
Fig. 38.6 The preoperative localisation of a parathyroid adenoma by 201T1 and
se~lTc subtraction scintigraphy. The technique is first to outline the thyroid with
w~~~Tc and then to administer an isotope such as 201T1 which is taken up by both
thyroid and parathyroid tissue. The two images are captured by a gamma camera
and, by computer subtraction of the two images, the enlarged parathyroid remains
as a hot spot. (TI thallium; Tc = technetium.)

Differential diagnosis. Other causes of hypercalcaemia must be remembered and

excluded. They are:
secondary cancer in bone (breast, prostate, bronchus, kidney and thyroid);
carcinoma with endocrine secretion (bronchus, kidney and ovary);
multiple myeloma;
vitamin D intoxication;
sarcoidosis;
thyrotoxicosis.

The differential diagnosis presents no problem if the parathormone level is

estimated. In none of the above-mentioned conditions will parathormorte be
detectable in the blood.
Treatment. The only corrective treatment is surgical removal of the overactive
gland or glands. In symptomatic patients, the indications for operation are clear
cut. Many patients, however, in whom hypercalcaemia has been discovered
incidentally, are not overtly symptomatic and a decision in favour of operation is
more difficult.
Preoperative treatment is not usually necessary except in acute cases, when rapid
correction of dehydration and electrolyte imbalance is necessary, with a careful
daily check on the serum calcium. Drugs used would have been discussed earlier.
A recent international survey of operative strategy shows that the approach is
changing. Removal of the adenoma with biopsy of the other glands has been
supplanted by removal of the adenoma, a peroperative histological diagnosis and
then biopsy of one normal gland. If the peroperative biopsy is that of a hyperplastic
gland, then removal of all four glands with autotransplantation is indicated.
Approximately 90 per cent of cases of primary hyperparathyroidism are associated
with single-gland disease (adenoma). Ten per cent of cases are associated with
multiple-gland disease, either hyperplasia or more than one adenoma. Adenomas,
single or multiple, are removed.
In approximately 10 per cent of cases even the most experienced surgeon in this
field may find difficulty in locating a parathyroid adenoma.
Parathyroid tissue can be successfully autotransplanted into the arm, a useful
technique to avoid repeated potentially difficult explorations of the neck. The
indications are tertiary hyperparathyroidism in patients undergoing chronic renal
dialysis, and recurrent hvperparathyroidism. The technique is to excise all the
parathyroid tissue from the neck and to implant eight 1-mm 3 fragments into a
pocket in the forearm muscle mass marking the site with nonabsorbable sutures.
Postoperative vitamin I) and calcium replacement therapy is required for varying
periods. Recurrent hyperca!caemia is an indication for exploration of the
implantation site and to further excise parathyroid tissue.
Prognosis. With successful surgery in severe cases, bones will recalcify and
pseudotumours resolve. Renal stones i~ill not disappear, but the incidence of
recurrence after surgical removal is reduced, and deterioration in renal function is
prevented. Psychiatric patients show an early and often remarkable recovery. Many
patients who are not overtly symptomatic beforehand are aware of improvement in
wellbeing after correction of hypercalcaemia. In a small minority of cases,

hyperparathyroidism recurs alter several years, and may warrant further surgery. In
533
THE PARATI-IYROID AND ADRENAL GLANDS
some of these, autotransplantation (above) offers reasonable prospects of control;
Wells has reported excellent results when autotransplantation has been used for
recurrent and familial hyperparathyroidism.
Hypertension associated with hyperparathyroidism is common, but the
mechanism is unclear.
Long-term survival has been studied in 900 patients in Sweden. Despite
successful surgery for primary hyperparathyroidism, the risk of premature death
from cardiovascular and malignant diseases remained significant. Thus long-term
follow up is important as this indicates that primary hyperparathyroidism causes
damage that is not reversed by surgery.
Patients with persistent and recurrent primary hyperparathyroidism are a difficult
management problem. For patients in whom initial exploration fails, reoperation is
associated with a higher morbidity and a greater chance of failure. Accurate
diagnosis and review of the initial pathology are essential, a family history of
multiple endocrine neoplasia should be excluded, together with occult malignancy.
Preoperative venous sampling of the neck and thorax is particularly valuable in
localising a missed adenoma which is the most common cause of failure at the first
operation.
Mild asymptomatic hypercalcaemia is a relative contraindication to further
surgery but regular follow up is mandatory. With an experienced surgeon, up to 90
per cent of missed lesions may be found but persistent postoperative
hypocalcaemia may occur in up to 10 per cent of patients and recurrent laryngeal
nerve injury is seen in about 6 per cent.
Parathyroid carcinoma. Parathyroid carcinoma is a rare condition to be considered
when a high serum calcium is associated with a palpable lump in the neck. At
operation it has a characteristic grey-white colour and is adherent because of local
invasion of adjacent soft tissue. The best results are obtained by early recognition,
avoiding rupture of the tumour capsule and aggressive surgical management
including ipsilateral thyroid lobectomy. Surgical clips should be used to outline the
tumour bed for postoperative radiotherapy.
Multiple endocrine neoplasia syndrome APUD cells

Always consider that a patient with hyperparathyroidism may also have multiple
endocrine adenomas. The cells involved, irrespective of the site, have the common
chemical characteristics of amine precursor uptake and decarboxylation and are
thus known as APUD cells. The disorder is inherited as an autosomal dominant, the
manifestations in any one family tend to be similar and all members of the family
should be investigated.
Type I. This most common variant involves the parathyroid glands (90 per cent),
pancreatic islets (80 per cent), pituitary (65 per cent), thyroid and adrenal
cortex. There is hyperplasia of the parathyroid glands and a chromophobe adenoma
of the pituitary which may result in increased prolactin production or acromegaly.
The pancreatic tumour may produce gastrin (the Zollinger-Ellison syndrome) or
insulin, glucagon, somatosta tin or vasoactive intestinal peptide (VIP) causing
watery diarrhoea. Treatment is surgical excision.
Type ha. Fifty per cent have parathyroid hyperplasia. The associated lesions may
be a medullary carcinoma of thyroid, which produces calcitonin, and a
phaeochromocytoma. The latter should be excluded or be the first priority for
treatment before exploration of the neck (see also Chapter 37).
Type Jib. This is differentiated from Type ha because of additional neurological
abnormalities. Mucosal neuromas produce lumpy and bumpy lips (Fig. 37.42) or
eyelids and there is a characteristic Marfanoid facial appearance. Megacolon and
ganglioneuromatosis are also found (see also Chapter 37).
ADRENAL GLANDS
Surgical anatomy. At birth, the adrenal glands have attained nearly adult
proportions. Fully developed, each weighs about 4 g, but the left is a little larger
than the right. A deeper yellow colour and a firmer consistency enables the gland to
be distinguished from the adjacent fat. Each rests on the superior, anterior, and
medial aspects of the superior pole of the corresponding kidney, and presents the
appearance of a French Liberty cap wom at a rakish angle.
Although intimately related anatomically, the adrenal cortex and the adrenal
medulla are quite separate internal secretory glands.
The adrenal glands are supplied by several adrenal arteries, rendering them
remarkably vascular, but only one vein drains each gland. On the right side the
adrenal vein is short and enters the inferior vena cava, while on the left it empties
into the left renal vein (which communicates through the azygos vein with the left
intercostal, internal mammary, and vertebral veins (Anson)). This dissimilarity of
the right and left venous flow determines, to some extent, the location of
metastases from malignant tumours of these glands.

Dia8nostic investigations
Computed tomography (CT) has been a significant advance in imaging the adrenal
glands and in the detection of adrenal masses with an accuracy of 90 per cent (Fig.
38.7). tJltrasonography can detect most adrenal masses larger than 2 cm in
diameter, but is operator and machine dependent and less accurate, especially in
obese patients. Computed tomography has made invasive techniques, such as
selective retrograde venography and selective arteriographv, almost obsolete. In
those cases where computed tomography findings are inconclusive and functional
information is required, isotope scanning (see below) and differential venous
sampling for hormone levels may be indicated.
A radiograph or computed tomography- scan of the pituitary fossa showing an
enlarged pituitary fossa is suggestive of a basophil adenoma of the pituitary gland
with excess adrenocorticotrophic hormone (ACTH I pituitary secretion.
Robert Milton Zol!inger, 6.1903. FormerlyProfessorof Surgery, Ohio State
University, Columbus, Ohio, USA.
Edwin Holmcr Ellison, 19181970. Professor of Surgery, Marquette University,
Milwaukee, Wisconsin, USA.
Anlonin Berna,d Joan Ma, fan, 28581942. Professor otPaediatrics. Paris,
France.
Barry J. Asses, Conte,nporary. Reseani2 Profcoss~, Deportment of
Otolaryng,sis~y ~nd Maxillofscial Surgsrv, College of Medicine, Umiiversitm1 ot
kwj, lena City, lows. USA
534
Sa,m. i .4. WoEs, Jr.. Contimporan. Br!xby Professor of Surgery and Chciirma,s,
Department of Surgery, Washington Unizersity School of Mcd join,. St. Louis,
Missouri, LISA.
Fig. 38.7 Computed tomooraphy scan of adrenal glands showing a 1.5cm left
adrenal adenorna. (Mr Anthony W. Goode.)
Adrenal gland scintigraphy using NP-59 (311-613-iodomethyl-19 Norchest5(l0)EN-313-ol) is of value in addition to computed tomographv. In a benign
functioning adrenal tumour there is uptake with
suppression of the contralateral gland. By contrast adrenocortical carcinoma does
001 usually concentrate the isotope and, as a result of conttalateral gland
suppression, there is little uptake. Bilateral adrenal hyperplasia produces the

opposite result with a prominent bilateral image.

Magnetic resonance imaging is of value particularly for small lesions.
ADRENAL CORTEX
The adrenal cortex is made up of the following layers from without inwards: the
zoos glomerulosa, the zoos fasciculata, and the zona reticularis.
Physiology. At least 50 steroid compounds have been isolated from the adrenal
cortex. These hormones exhibit various types of activity which, for practical
purposes, can be arranged in three groups.
Mineraiocorticoids which are concerned in the maintenance of water and
electrolytic balance. A deficiency of these hormones produces sodium diuresis,
potassium retention and dehydration; an excess results in hypertension. oedema,
cardiac dilatation, and hypokalaemia. Aldo~tero,me is the most important of these
salt regulating hormones (see Coons syndrome, later).
Glucocorticoids are concerned with the metabolism of proteins and
carbohydrates, favouring the formation of the latter from the bodys storehouse of
the former. This conversion is known as gluconeogenesis. The best knos.en of
these are hydrocortisone (also known as carlisol), and cortisone (which is
converted in the body to hydrocortisone). The therapeutic application of these
hormones falls under tu-o headings.
In endocrine deficiencies. Hvdrocortisone is the logical need in adrenocortical
insufficiency and after bilateral adrenalectomy.
hi nonendocrine diseas,. Hydrocortisone or synthetic analogues, such as
prednisone and betamethasone, are used in the treatment of a diversity of diseases,
including allergic conditions, granulomatous disorders, blood diseases and the
collagenoses. Hydrocortisone is used in the treatment of hvpocorticism and shock
(Chapter 4) and is an effective antiallergic agent in a number of skin diseases and
eye conditions.
Sex hormones. Androgenic and oestrogenic hormones are produced by the
adrenal cortex. Excessive secretion of androgens due to adrenal enzyme
deficiencies or tumours causes virilism in females or, rarely, excessive secretion of
005trogens brings about effeminacy in males.
lnterhomionic action. The anterior lobe of the pituitary gland secretes ACTH
which stimulates the adrenal cortex, whereas the corhso of the adrensl cortex
inhibits the secretion of ACTH. ACTH secretion is also controlled by highcr
cerebrol centres and the hypothalamic corticotrophin releasing hormone (CRI11.
Tests of adrenocortical activity

The tests are of two types, those that confirm the presence of a change in cortisol
production and those that indicate a cause. No tests should be interpreted in
isolation but all the results of the investigations should be considered together.
Plasma electrolytes. Sodium levels are raised and potassium low in a
hvperfunctioning adrenocortical lesion with the opposite in Addisons disease but
changes in Addisons disease may not occur until the patient is approaching crisis.
Plasma cortisol levels. Diurnal variation with a maximum value at 8.00 am. may
be lost in both Cushings syndrome where all levels are high and in insufficiency
when levels are low.
Plasma ACTII levels. Low plasma levels are found with adrenal tumours and high
levels with a pituitary lesion or ectopic ACTH production. The ratio of ACTH to
related peptides such as ~-lipotrophin may facilitate the distinction between
pituitary Cushings and ectopic ACTH production.
Plasma aldosterone levels. The concentration of aldosterone is only one
thousandth that of cortisol, and both dietary sodium and posture may change the
value. Plasma renin levels should be measured along with aldostecone to
differentiate between primary and secondary hyperaldosteronism.
Urinary steroid excretion. Cortisol secretion rate. The daily output of cortisol is a
precise measure of adrenocortical activity, but is routinely performed in only a few
centres. Adult levels are reached bn- lB years of age and after 40 years fall
gradually, to be halved by 70 years of age. The average excretion is higher in
Caucasian males. The daily output may be determined by the administration of a
small amount of radioactive labelled cortisol, which is metabolised and excreted,
and the urinary radioactivity measured. The normal range is 5-28 mg per 24 hours,
with high levels in Cushings syndrome and low levels in adrenal insufficiency.
Urinary cortisol excretion. The cortisol excretion in a 24-hour urine sample is
probably the best screening test for adrenocortical oversecretion.
17-cxosteroids or kef asteroids. These reflect androgen output, and excretion is
increased in many women with virilising syndromes.
Dexamethasone suppression test. Dexamethasone is 25 times more potent than
cortis~l. Dexamethasone 0.5 mg is administered 6-hourly for 2 days and causes a
marked decrease in urinary steroid excretion by inhibiting ACTH production, and
thus cortisol, without contributing greatly to the total urinary steroid output. In
Cushings syndrome, no effect is produced by the dose. Larger doses of up 102 mg
6-hourly will, over several days, reduce urinary steroid excretion if the overactivity
is secondary to bilateral adrenal hyperplasia, but not with an adrenal tumour, which
is autonomous. Measurement of the plasma cortisol at 9 am, after the
administration of 2 mg dexamcthasone the previous midnight serves as a
convenient screening test for Cushings syndrome.
Metyrapone test. This differentiates between excess ACTH production and a

lesion in the adrenal cortex causing Cushings syndrome. Metyrapone inhibits the
biosynthesis of cortisol so plasma levels fall, lithe pituitary adrenal axis is intact,
this results in an increase in ACTH production and stimulation of the adrenal
cortex. The basal levels of 17-oxosteroids and ketosteroids in the urine are
measured for 2 days, 750 mg of metyrapone is given per 4 hours and a 24-hour
urine collection completed. A normal response is a two to fourfold increase in the
urinary steroids over basal levels. A diminished response in Cushings syndrome
indicates a primary adrenal lesion.
Synacthen test. Tetracosactrtn (Synacthen) 250 ag is given intramuscularly and
blood cortisol measured at 30 and 60 minutes. In normal subjects the basal plasma
cortisol should be greater than 60 icgiitre and be at least 70 ag/litre after
stimulation. In Addisons disease the response is impaired
DiSORDERS OF ADRENOCORTICAL FUNCTION
Acute hypocorticism
1. Adrenal apoplexy in the newborn. Extensive haemorrhage into one or both
adrenals may be a cause of death in infants within the
535
hC AKA I HYHUIU ANt) AL)HIrNAL (.iLANIJ~
first few days of birth. The condition may occur after long and difficult labour, and
particularly when resuscitative procedures have to be employed to combat
asphyxia neonatorum. The haemorrhage into the adrenals follows necrosis of the
innermost layer of the cortex, which always occurs at birth, possibly as a result of
sudden withdrawal of the female sex hormone (oestrogen). Adrenal crisis in the
newborn produces signs of profound shock. A mass may be palpable in one or both
renal regions. Intravenous fluid therapy with hydrocortisone, or failing the latter,
cortisone intramuscularly, offers the only hope.
2. Waterhouse-Priderichsen syndrome. Massive bilateral adrenal cortical
haemorrhage occurs in cases of fulminating meningococcal septicaemta and in
some cases of streptococcal, staphylococcal. or pneumococcal septicaemia. Most
cases occur in infants and young children, hut it can happen in adults with severe
haemorrhage or burns. The Onset is catastrophic, with rigors, hyperpyrexia,
cyanosis, and vomiting. Petechial haemorrhages into the skin which coalesce
rapidly into purpuric blotches are a constant feature. Profound shock follows, and
before long the patient passes into coma. The condition is one of overwhelming
sepsis that pursues a galloping course, death occurring in most cases WIthin 48

hours of the onset of symptoms unless correct treatment is given without delay.
Unilateral haemorrhage causing a lesser degree of systemic upset and not
associated with infections has been described. This type of case resembles a
perinephric abscess or other upper abdominal acute condition.
Confirming the diagnosis. It is futile to await the result of a blood culture.
Bilateral tenderness 5 cm below the costal margin, clear urine (oliguna is often
present), and an absence of signs in the lungs help to call attention to the adrenal
glands. In meningococcal infection the diplococcus may be demonstrated by
smears obtained from a punctured petechial spot in the skin.
Treatment. Antibiotic therapy must be given intensively by the intravenous
route. Hydrocortisone 100 mg is given iv., or i.m. if venous access is difficult. Up
to 400 mg hydrocortisone may be required in the first 24 hours. No
mineralocorticoid is needed as the weak intrinsic salt-retaining action of
hydrocortisone suffices at this dosage. Oral medication may be commenced after
the first day and then over about 4 days reduced to a maintenance level. Oxygen
should also be administered. Following such treatment, improvement often sets in
within 3 hours, and a number of patients have recovered.
3. Crises of infantile hypercorticism (see later).
4. Following bilateral adrenalectomy. If precautions are taken, acute
hypoeorticism is unusual in the postoperative period. Treatment is to give 300 mg
hydrocortisone on the first day. Moat patients achieve a maintenance dose of 30
mg/day. After about 3 weeks fludrocortisone 0.1 mg may be given.
5. Postoperative adrenal lsaemorrhage. Adrenal haemorrhage is a rare unexpected
cause of deterioration and sudden death in the postoperative period. In some cases
the left adrenal gland is damaged during radical gastrectomy for carcinoma (Fox).
In other cases, when adrenal haemorrhage is bilateral, there is no evidence of
operative injury, they are usually associated with intra-abdominal sepsis,
pneumonia, coagulation defects and cancer. Thrombosis of the adrenal veins is the
cause of infarction of glands.
Chronic hypocorticism (Addisons disease)
This is due to adrenocortical insufficiency consequent upon progressive destruction
with lymphocytic infslRupert VVatcrhouse, 18731958. Clinical Pathologist and
Physician, Royal
United Hospital, Bath, England. Described this syndrome in 1911.
Carl Frideri. horn, b. 1886. Formerly Medical Superintendent, Childrens
Department, Sundbt1 Hospital. Copenhagen. Wrote his account of this syndromm
in 1918.
Brrnord Scm Comrtrmporars. Pathologist. Clueing Cross Hospital, London, i

.Thu
Those,.. Aa,i:..:m, 1793-186/I PJIySIC*OmI, Gut1s Hospital, London, England.
Drscrib./ rhc rlf5-cls of diseasc of thc suprarrna! capsules in 1849.
tration of the zona reticularis, the zona fasciculata, the zona glomerulosa, and the
medulla of the adrenal glands, in that order. In about 60 per cent of cases the
condition is believed to be due to an autoimmune disease, sometimes in association
with autoimmune thyroiditis (Chapter 37) and pernicious anaemia. Tuberculosis,
metastatic carcinoma and amyloidosis account for the remaining 40 per cent.
Clinical features. Addisons disease usually commences in the third or fourth
decade. Sometimes it is the terminal event in cases of adrenogenital hyperplasia.
The sex distribution is about equal. The leading features are muscular weakness
and a low blood pressure. Irregular dusky pigmentation of the skin, due to deposits
of melanin, appears at points of pressure, e.g. garter or belt, and in the flexion
creases. Pigmentation of mucous membranes, particularly of the mouth, is often
striking. When fully established, the course of the disease is punctuated by crises
of acute adrenocortical insufficiency (see above).
Treatment is medical. In long-term management, most patients require 2030
mg hydrocortisone in divided doses, with fludrocortisone 0.1 mg daily as
mineralocorticoid replacement. Signs of overtreatment include hypertension,
hypokalaemia and oedema; those of undertreatment, fatigue and hypotension.
Where relevant, chemotherapy is mandatory for tuberculosis (Chapter 7).
Prognosis. By the use of replacement corticosteroids, the expectation of life of a
patient suffering from Addisons disease has been extended from up to 3 years to
many years.
Hypercorticism
The various forms of adrenal cortical hyperfunction are classified according to the
age of onset:
infantile;
prepubertal;
adult, otherwise known as Cushings syndrome the commonest type;
postmenopausal;
primary aldosteronism (Conns syndrome) can occur at any age.
Infantile hypercorticism. Androgenic excess during intrauterine life is one form of
pseudohermaphroditism in the ftmale child. The condition is present at birth;
sometimes the enlarged clitoris and a varying degree of hypospadias make it
difficult to determine the infants sex. The 17-ketosteroid content of the urine may
be sufficiently elevated to substantiate a diagnosis of a female with adrenal
hyperfunction. If this is not tIme case, it is justifiable to perform sex determination

by a skin biopsy before the age of 1 year. Female pseudohermaphroditism with

sirilism is invariably associated with disease of the adrenal cortex, usually bilateral
hyperplasia of the cortex. Hormonal studies have shown that there is a congenital
failure of the adrenal glands to synthesmssi glucocorticoids. Due to this lack, these
infantt are liable to acute phases of
jteorn tV. Cm: 1 1 9P~ A ,r.einm. ,m~ <.~mb. woe PwYeom ~ Intrrnal
Alcdhm:, at the Uniecrsols hest;w. Aims ..4rho, Michigan, USA.
536
adrenal insufficiency during stress or infection, or to suffer from periodic
hypoglycaemic attacks. They need corticosteroid replacement, not only in the
emergency, but as long-term therapy, thereby inhibiting the secretion of excessive
androgens. In the absence of such treatment, the epiphyses join early, the patients
are dwarfed, menstruation does not occur, and the breasts do not develop. These
tendencies are corrected by hydrocortisone given orally, 23 mg or more daily, the
dose being determined by 17-ketosteroid estimations (Simpson). Hirsutism is
moderated, but not necessarily abolished. The treatment should be commenced
early if good results are to be obtained.
Prepubertal hypercorticism. There is never any doubt as to the sex of the infant at
birth, and during the very early years of life the child is normal. The symptoms
commence about the age of 5 or 6 years.
In the female. Pubic and axillarv hair appear, but there is no gross enlargement of
the clitoris. The child is short in stature, the legs being especiall~ stunted, but she
looks much older than she is. Puberty is often precocious, menstruation, if it
occurs, being scanty. There is a deepening of the voice at this time.
In the male. The term infant Hercules is descriptive. He is extremely short,
muscular, and hirsute. The genitalia assume adult proportions, and spermatozoa are
often present in the seminal fluid.
In both sexes, 17-ketosteroid content of the urine is increased. A very high
reading supports the diagnosis of an adrenocortical tumour, which must always be
excluded. In both males and females, with a later onset or the passage of time, the
features of Cushings syndrome become superadded.
Treatment. This is identical with that of Cushings syndrome.
Postpubertal or adult hypercorticism (Cushings syndrome) is due to an excessive
endogenous production of glucocorticoids, mainly hydrocortisone. It is an
uncommon condition, often suspected but seldom confirmed. Pituitary-dependent
Cushings syndrome is the commonest form of endogenous hypercorticism

accounting for up to two-thirds of all cases. An adrenal adenoma accounts for 20

per cent and carcinoma (which may be bilateral) 5 per cent. In the remainder there
is no discernible structural alteration in the glands and the condition is due to an
ectopic source of an ACTH-llke substance being secreted, either by a benign
tumour (e.g. bronchial carcinoid) or a malignant tumour of bronchus, mediastinum,
or pancreas. Non-ACTH-dependent primary adrenocortical hyperplasia is a rare
cause of Cushings syndrome. Alcoholism also must be considered.
In its most typical form, Cushings syndrome is exogenous and is seen in patients
treated with large doses of cortisone over long periods for nonendocrine diseases,
particularly rheumatoid arthritis, and in patients receiving transplants.
Clinical features. The female to male ratio is at least 3:1. The great majority of
cases (excluding those induced by cortisone therapy) occur in females between 15
and 30 years of age, in whom it produces highly characteristic features. Although
the patients weight is not necessarily increased, there is a deposition
Samuel Loonard Simpson, 190083. Consulting Endocrinologist, St Marys
Hospital, London, Englarj.
Hercules, one of the most famous of the heroes of Greek mythology, was noted for
his prodigious strength.
Haney Cushing. 18691939 Professor of Surgery, Harvard University, Boston.
Massachusetts US.4. (191232). Described this syndrome in 1932
(I
Fig. 38.8 GushingS syndrome contour lemon on match-sticks.
Fig. 38.9 Gushings syndrome in a woman aged 23 years. Adrenal hyperplasia.
(Di- Leonard Simpson, London.)
of fat in certain situations. The face becomes rubicund, rounded like a full moon,
and the lips are pursed. The abdomen becomes protuberant, the neck thick, the
supraclavicular fossae obliterated, and a roll of fat appears over the region of the
vertebra prominens (buffalo hump). The arms, and especially the legs, are
relatively thin, the muscular development is poor, and the patient complains of
increasing weakness. As the disease progresses, so the general contour becomes
more and more that of a lemon on match-sticks (Fig. 38.8). Consequent upon the
inhibitory effect of the hypercorticism on fibrous tissue, the skin becomes of
tissue-paper consistency, and inelastic. Exceedingly characteristic are purple-red
striae distentiae,mostly on the abdomen (Fig. 38.9), of a texture that can be
likened to an overstretched garter. Ecchymoses are frequent and bruising occurs on
the slightest trauma. Acne is common and there is a low resistance to skin
infections. Often there is increased growth of lanugo hair, but hirsutism is usually

absent. Amenorrhoea is usual or, in the male, impotence. Due to a negative calcium
balance, the matrix of bone becomes thin, and
537
It~ frAHAIt-IYHUID AND AL)HLNAL (3LANVS
severe osteoporosis results. Pathological fractures, particularly compression
fracture of a vertebra, are common, and this is sometimes the first reason for the
patient seeking advice. Mild glycosuria is often present. Hypertension is frequent,
and eventually congestive heart failure supenenes. In about 60 per cent of cases,
various psychoses occur.
Cushings syndrome is rare in children; when it occurs, the patient is nearly
always a female and an adrenal tumour is usually the cause.
A subgroup, probably due to an excessive secretion of adrenal androgens
(adrenogenital syndrome), commences between the ages of 15 and 25 and is
confined to females. One of the first indications of its onset is amenorrhoea or
oligomenorrhoea. There follows an excessive growth of hair on the face (Fig.
38.10), acne, atrophy of the breasts, alteration in bodily contour and muscular
development, deepening of the voice, and enlargement of the ditoris. Jewish and
Spanish women are more prone to this affliction than those of other races.

FIg. 38.10 Adrenogenital syndrome in a woman of 28. (Dr Leonard

Simpson, London.)
Arrhenohlastoma of the ovary. This rare condition occurs between puberty and
the menopause and also causes hirsutism. It may also arise in a suprarenal rest.
Screening tests. There are three simple tests (see above) which may be used to
screen patients suspected to have Cushings syndrome:
plasma cortisol levels and diurnal rhythm;

 24-hour urinary free cortisol excretion;

overnight dexamethasone suppression test.
Each of these tests is highly discriminating with false positive and false negative
results in only about 5 per cent of cases. However, patients with severe or chronic
illness or alcoholism may have elevated midnight plasma cortisol levels and ma;
fail to show overnight suppression after dexamethasone.
Definitive diagnosis. Suspected Cushings syndrome may be confirmed by the
low-dose dexamethasone suppression test (see above), which is highly reliable.
Differential diagnosis. After the diagnosis of Cushings syndrome has been
established, it is necessary to deterrninc the cause of adrenocortical hyperfunction.
In general, adrenal hyperfunctioning tumours and ectopic ACTFl-s~crc-ting tu
mours function autonomously and
are unaffected by hormonal manipulation. In contrast, the feedback mechanism in
pituitary Cushings is functioning although it is abnormal. Thus appropriate
investigations (see above) are the high-dose dexamethasone suppression test,
measurement of plasma ACTH levels and the metyrapone test, which has largely
been replaced by plasma ACTH assay. Nearly all patients with adrenal tumours and
with the ectopic ACTH syndrome, in contrast to pituitary Cushings, fail to
suppress with a high dose of dexamethasone and suppression is indicative of
Cushings disease. In addition, patients with Cushings disease or the ectopic
ACTH syndrome have detectable or elevated plasma ACTH levels, whereas
cortisol-producing adrenal tumours suppress pituitary ACTH secretion and plasma
levels are extremely low. A high plasma ACTH level after high-dose
dexamethasone indicates autonomous ACTH secretion by a nonpituitarv tumour,
whereas if the ACTH level is low it indicates the presence of an adrenocortical
tumour that has suppressed ACTH secretion by the normal pituitary.
Localisation studies. Computed tomography accurately identifies virtually all
adrenal tumours in patients with Cushings syndrome and has replaced other
techniques. It is also the most reliable method of detecting nodules in the lungs,
mediastinum and pancreas, which are potential sites of ectopic ACTH production.
Pituitary computed tomography has also replaced other techniques for the
detection of pituitary microadenomas in Cushings disease, although only 50 per
cent of such adenomas are identified. Bilateral selective inferior petrosal venous
sampling for ACTH levels is a valuable but technically difficult method of
confirming and localising pituitary-dependent Cushings disease if computed
tomography is unhelpful.
Treatment. Trans-sphenoidal pituitary adenectomy in skilled hands is now the
treatment of choice for pituitary lesions. External pituitary irradiation is less
reliable in terms of long-term remission but is more successful in children.

Yttrium-90 implantation is an alternative form of pituitary irradiation. Bilateral

total adrenalectomy is a reliable procedure for patients with Cushings disease in
whom pituitary treatment has failed.
The treatment of an adrenal tumour is surgical resection and resection of benign
ectopic ACTHsecreting tumour is curative. Many, however, are malignant and
widely disseminated when Cushings syndrome becomes clinically apparent.
Nelsons syndrome. Hyperpigmentation and pituitary enlargement occurs in
about 20 per cent of cases after bilateral adrenalectomy and is avoided by selective
pituitary microsurgery.
Prognosis. Most patients are alive 20 years after successful resection of an
adrenal adenoma, but survival beyond 5 years is rare with a carcinoma
Dsn H. Ne2ss; b.1923. American in5crs~
AUH~NAL
(jLANUS
(Welbourn). Pituitary microadenectomy in expert hands results in cure in about 80
per cent of patients.
Very rarely, the adrenogenital syndrome appears in youths and men. Owing to
excessive production of oestrogenic hormones by the adrenal cortex.
gynaecomastia, atrophy of the testicles, and psychic signs of effeminacy appear
(adrenal feminism).
Postmenopausal hypercorticism is usually characterised by the growth of a beard
(the bearded woman of the circus), and is often accompanied by mental aberration.
A lesser degree of hirsutism is almost a natural accompaniment of the ageing
process, particularly in dark-haired females, and it is difficult to draw the line
between the normal and the pathological. Thus it is that operative treatment is
usually disappointing.
Primary aldosteronism (Coons syndrome) is a surgically correctable type of
hypertension found in 12 per cent of all hypertensive patients. It is characterised
by autonomous excessive aldosterone secretion which leads to sodium retention
and a fall in serum potassium. The latter causes the typical associated features of
the syndrome, namely episodes of muscular weakness associated with polyuria and
polydipsia. The plasma sodium is high and the potassium is low, but simple
administration of potassium does not relieve the condition. Renin and angiotensin
levels are depressed. The cause is either an aldosterone-secreting adrenal adenoma
or bilateral adrenocortical hyperplasia (less common). Computed tomography and
adrenal scanning with radioactive-labelled cholesterol are the appropriate

localisation tests to distinguish between them. When these fail, adrenal venous
sampling with measurement of aldosterone to cortisol ratios is the next step.
Unilateral adrenalectomy is the treatment for an aldosterone-producing adenoma
and has a high cure rate, whereas surgery has been disappointing in adrenocortical
hyperplasia and these patients are generally managed medically.
Secondary aldostetonism is associated with cirrhosis of the liver, and renal artery
stenosis with high levels of renin and angiotensin.
The incidental adrenal mass - incidentaloma. Computed tomography and
magnetic resonance imaging have resulted in increasing numbers (up to I per cent)
of adrenal tumours being identified in the course of abdominal imaging for the
investigation of other Conditions. The finding may represent an adrenal tumour but
more probably a benign lesion. Opinion is divided about management but
essentially functioning lesions are excised whereas nonfunctioning lesions are
managed according to size. Lesions less than 3 cm in size should be followed 3monthly for a time by computed tomography and excised if they enlarge, whereas
those larger than 3 cm should be excised to exclude malignancy.
Adrenalectomy for hypercorticism
It is essential that all patients who are to be subjected to adrenalectomy are
supported intra- and postoperatively by adrenocortical hormone replacement
therapy, irrespective of the extent of adrenal resection.
Corticosteroid therapy. Corticosteroids are started when anaesthesia is induced.
There is no advantage of one steroid over another except for their different
durations of action. Hydrocortisone is very short acting, prednisolone intermediate
and dexamethasone long acting. Each may be given intravenously or
intramuscularly.
During the first 24 hours after induction of anaesthesia, the patient should receive
no more than 300 mg hydrocortisone, 60 mg prednisolone or 6 mg dexamethasone.
The dosage should be halved each day until a maintenance dose orally
(hydrocortisone 30 mg. prednisolone 5 mg or dexamethasone 0.5 mg) is reached.
Fludrocortisone 0.1 mg daily (replacing aldosterone) is usually added to the
maintenance dose of corticosteroid to regulate fluid and salt balance.
After total adrenalectomy the patient should always carry a card stating the
dosage of corticosteroid she is receiving. Any stress (e.g.
further operation or infection) is an indication to increase the dosage.
Operation. When an adrenal tumour has been demonstrated preoperatively,

excision of that adrenal gland alone is carried out.

Posterior approach. An ample posterolateral incision, such as is used for
nephrectomy (Chapter 57), is used. After subperiosteal resection of the 12th rib, the
lower border of the pleura is defined and protected. The incision is extended
through the bed of the 12th rib to reveal the perinephrw fat, within which the
adrenal gland is identified, as described below. Sometimes an approach through the
bed of the 11th rib, reflecting the pleura upwards, is preferred. (See also the
anterior approach, below.)
On the right side the suprarenal vein is short and may be tom from the rena cana
if it is not identified and ligated at an earls stage of the dissection. By finger and
gauze dissection, keeping close to the gland, the gland is freed from below and
behind, upwards, ligating and dividing bleeding sessels as they are encountered,
until it is suspended only by its main vascular pedicle near its apex.
Anterior approach. The adrenal glands are approached through either a curved
transverse incision or a long midline incision. The left adrenal gland is approached
first by cutting along the lateral leaf of the lienorenal ligament and then curving
downwards and medially, so as to enable a wide peritoneal flap to be reflected. By
retracting the spleen downwards and medially, the adrenal gland comes into view.
The fascsa over its lateral border is incised, and by gauze dissection the blood
vessels of the gland are defined, ligated, and divided, thus freeing the gland, which
is removed. Alternative approaches can be made by an up and under dissection of
the mesocolon and pancreas, or through the lesser sac. The right adrenal gland is
more deeply situated. The peritoneum is incised lateral to the duodenum and above
the upper pole of the kidney. The flap of peritoneum is raised to expose the anterior
surface of the adrenal gland as it lies against the bare surface of the liver. The
fascia covering the lateral surface of the gland is incised. A finger can then be
inserted above the upper pole of the gland into the space between the two layers of
fascia enclosing the gland (Fig. 38.11). This prevents the gland from becoming
displaced upwards, which otherwise it is prone to do. The anterior fascial layer is
then incised transversely and the gland can be dissected under vision, as on the left
side. After removal, each gland should be inspected to check its completeness, and
each adrenal bed must be searched for the presence of accessory adrenal tissue,
which is present in 32 per cent of cases. If this important step is omitted, failure of
the operation is not unlikely.
Thoracoabdominal approach. For removal of a large adrenal
tumour (>10-15 cm in diameter) a thoracoabdominal incision gives the wide
exposure necessary for radical resection en bloc which may
fer
triG -

FIg. 38.11 Incision in the fascia lateral to the right adrenal gland. Insertion of the
finger into the space above the gland prevents its upward displacement. (After J. C.
McKeown and A. Ganguli.)
539
Richard Burkewced Welbourn. Formerly Professor of Surgical Endocrinology.
Royal Postgraduate Mcdictl School. London, England.
THE PAPIATHYROID AND ADRENAL GLANDS
involve removal of the ipsilateral kidney or spleen and tail of the pancreas.
ADRENAL MEDULLA
Physiology. The medulla of the adrenal glands (chromaffin tissue), which is
developed, together with sympathetic nerves, from edoderm, is grey in colour and
connected intimately, both anatomically and functionally, with splanchnic nerves.
Chromaffin tissue is so called because the large polyhedral cells of which it is
composed contain granules that stain yellow with chromic acid. These granules are
the intemal secretion of the adrenal medulla itself, for they can be observed being
extruded in tote into radicles of the adrenal vein. The secretion consists of the
catecholamines, adrenaline and noradrenaline. In health, 80 per cent of the output
is adrenaline, and 20 per cent is noradrenaline. However, in hypertunctioning
medullaxy tumour (phaeochromocytoma) this ratio is completely reversed. Fear,
anger, pain, and effort give rise to an increased output in response to the stimuli
received via the splanchnic nerves.
Effects of catecholamines mediated by alpha- and betaadrenergic receptors
Actions of ctatecholamines. Catecholamines exert their effects through specific
cell surface receptors: alpha-receptors and beta-receptors (Table 38.1). These
mediate the actions of the endogenously released catecholamines, noradrenaline
and adrenaline, and some of the actions of dopamine. The receptors have quite
different pharmacological properties and an organ may have more than one type.
The complex actions of catecholamines include altering enzyme activity, metabolic
pathways, and the permeability of cell membranes to ions.
Pharmacological inhibitors of alpha stimulation (alpha-blockers) include the longacting phenoxybenzamine (Dibenyline) and short-acting phentolamine (Rogitine).
Beta-blockers include propranolol (lnderal) and practolol (Eraldin).

Table 38.1 Effects of catecholamines mediated by alpha-and b.ta-adrenerglc

receptors
Alpha Beta
Effect on
receptor receptor
Cardiac output
Nil
Increase
Heart rate
Nil
Increase
Force of myocardial contraction
Nil increase
Myocardial excitability Increase lncrease+ +
Blood pressure systolic Increase Nil
Blood pressure diastolic Increase
Decrease
Blood vessels in skin Constrict Dilate
Blood vessels in muscle
Constrict Dilate
Smooth muscle in bronchi Nil Relax
Smooth muscle in intestine Relax Relax
Smooth muscle in bladder Relax Relax
Smooth muscle in sphincters
Constrict Constrict
TUMOURS OF THE ADRENAL MEDULLA
Tumours of the adrenal medulla are dassified as follows:
a Neoplasms of the sympathetic neurones
ganglioneuroma
neuroblastoma (sympatheticoblastoma)
a Neoplasm of chromaffin cells = phaeochromocytoma.
Those occurring at any age
A ganglioneuroma is relatively benign. This neoplasm is symptom-less, grows to a
large size, and constitutes one of the varieties of retroperitoneal sarcoma (Chapter
49). Only 15 per cent involve the adrenal, the remainder occurring in any position
along the sympathetic chain. If removed completely at a comparatively early stage,
a cure may be expected.
Those occurring in infants and children
Neuroblastoma is a malignant tumour of neural crest origin arising from
sympathetic nervous tissue from the orbit to the pelvis. Three-quarters arise in the
abdomen and half of these from the adrenal gland. It is the most common solid
tumour of infancy and childhood, and by far the most common in the newborn. The
incidence is approximately I per 10000 live births. Ninety per cent of cases of
neuroblastoma occur under the age of 8; over half occur in children under 2 years.

Clinical fratures. Three-quarters of patients present with an abdominal mass.

Metastatic spread, via lymphatics and bloodstream, occurs at an early stage, and
approximately 70 per cent of cases have metastases at the time of initial diagnosis
(Fig. 38.12). Weight loss, failure to thrive, abdominal pain and distension, fever
and anaemia may be present. Excessive catecholamine production may cause
hypertension, flushing, sweating and general irritability. Some of these tumours
produce vasoactive intestinal polypeptide (VIP), which results in watery diarrhoea
and hypokalaemia. Acute cerebellar ataxia charaderised by opsomyodonus and
chaotic nystagmus or the dancing eye syndrome is an unusual manifestation of
neuroblastoma of unknown cause.
Diagnosis. Over 80 per cent of patients excrete catecholamine metabolites in the
urine. The most common byproducts assayed in the urine are vanffiylmandelic acid
(VMA) and homovanillic acid (HVA) and such measurements may be useful in
monitoring the course of the disease.
Plain radiography show fine, stippled calcification in 50 per cent of cases.
Abdominal ultrasound examination shows the anatomical margins and extent of the
disease, and is particularly helpful in evaluating the results of treatment.
Fig. 38.12 The common sites for metastases from neuroblastoma of the adrenal.
Bones are involved more frequently than the liver. Synthesis of catecholamines:
tyrosine -~ 3,4-dihydrophenylaminc (DOPA1 3.4-dihydroxyphenylethylamine
(dopamine) noradrenaline .-.. adrenaline.
Computed tomography demonstrates calcium in 80 per cent of cases and
accurately evaluates intraspinal extension as well as hepatic and renal metastatic
disease. Magnetic resonance imaging is a promising technique which may
supersede computed tomography in many patients. It will also evaluate bone
marrow metastases.
Meta-iodobenzyl-guanidine (MIBG, see below) is metabolised by neuroblastoma
cells and may be used for imaging, especially in small residual tumours not evident
on other conventional imaging studies.
Bone-seeking isotope (eemTc), as well as demonstrating bone involvement, is also
concentrated by 60 per cent of adrenal lesions.
Treatment. Although surgical excision is the mainstay of cure in localised
disease, widespread disease at presentation often makes surgery inappropriate as
the primary form of treatment. Multidrug chemotherapy and radiotherapy are
instituted in advanced disease. Surgical excision is appropriate in disease confined
to one side of the midline, or as a delayed treatment following control by
chemotherapy and radiotherapy. However, the cure rate remains low with an
overall survival rate of 3035 per cent. Age has an important favourable influence

on prognosis the younger the patient the better the prognosis, and children in the
first year of life have a long-term survival rate of 70 per cent.
Phaeochromocytoma has been called the 10 per cent tumour because
approximately 10 per cent are bilateral, malignant, extra-adrenal, multiple, familial
and occur in children. Although 90 per cent of phaeochromocytomas arise in the
adrenal medulla, they may be found anywhere along the paraganglionic system.
The most common extra-adrenal site is the organ of Zuckerkandl at the aortic
bifurcation and less common sites are the urinary bladder, renal hilum, chest and
neck. Extra-adrenal tumours have a higher incidence of malignancy of 2540 per
cent. A phaeochromocytoma is a soft, vascular tumour usually less than 5 cm in
diameter but occasionally very much larger. It is usually pink-tan in colour and is
composed of large, differentiated, sympathetic ganglion cells, and a few fibres,
enclosed in a delicate capsule. It owes its name to the presence of chromaffin
granules. This tumour occurs in both sexes, usually during early adult life or
middle age. It produces, either intermittently or continuously, an excess of
adrenaline, and especially of noradrenaline: the ratio of the latter to the former
often being as high as 20:1 causing hypertension which is either paroxysmal or
persistent. The latter predominates statistically and probably indicates a late stage
of the disease. Consequently all patients under 60 years of age who suffer from
sustained arterial hypertension deserve routine tests to confirm or exclude a
phaeochromocytoma. Although not more than 0.5 per cent of cases of hypertension
are caused by a phaeochromocytoma, at the Mayo Clinic, where routine diagnostic
procedures are undertaken to confirm or exclude the presence of this tumour in all
cases of hypertension, the percentage has been stated to be nearly 3 per cent.
Untreated, it progresses to a fatal termination from cardiac dysrhythmia or cerebral
haemorrhage.
The importance of phaeochromocytoma as a component of the multiple
endocrine neoplasia syndromes MENIIa and MENIIb should be remembered (see
earlier and Chapter 37).
Clinicalfeatures. A typical complaint is that of fear I thought I was going to
die. The most common symptoms, in order of frequency, are: headache (55 per
cent), palpitation, vomiting, sweating, dyspnoea, weakness and pallor i.e. the
symptoms of adrenal overdosage. The paroxysmal attack may vary from a few
minutes to some hours. The blood pressure may be very high and hyperglycaemia
present. The symptoms may be mistaken for hyperthyroidism, hypocalcaemia, an
acute anxiety state, paroxysmal atrial tachycardia and carcinoid syndrome. The
main obstacle to the diagnosis of a phaeochromocytoma is the failure to think of it
as a cause of the observed symptoms.
Diagnostic tests. The basis of the laboratory diagnosis is measurement of elevated

catecholamines and their metabolites in urine and blood.

Urine studies. Confirmation of the diagnosis is usually readily made by
measurement of free catecholamines, vanillylmandelic acid (VMA) and
metadrenalines (metanephrines) in 24-hour collections of urine. Patients with
phaeochromocytoma usually excrete free catecholamines in excess of 100 lLg/ 24
hours, VMA in excess of 7 mg~24 hours and metadrenalines in excess of 1.3
mg/24 hours. Laboratories vaty in the reliance they place on these various
estimations; at the Mayo Clinic, for example, most reliance is placed on urinary
metadrenalines. False positive elevations of metsdrenaline excretion may occur in
patients taking monoamine oxidase inhibiting drugs, and in those who have
recently had angiographic contrast studies.
Plasma cafechoitzmines. Sensitive assays are now available for plasma
catecholamines and patients with phaeochromocytoma usually have total plasma
catecholamines in excess of 1000 ~~.gIm1. Such assays may be highiy accurate in
confirming the diagnosis, but plasma catecholamines may not be continuously
elesated and many factors, including exercise, severe illness and the drug
methyldopa, may influence the levels.
Localisation tests.

Computed tomography (Fig. 38.13) is the method of choice for localisation

with an accuracy of 9095 per cent and has largely replaced more invasive and
hazardous techniques such as arteriography and selective venous sampling.
Because of their size, most adrenal phaeochromocytomas are also visible on
ultrasound scan-rung.
Radjonuclide imaging. The development of a specific radionuclide for
catecholamine precursors. iodine-labelled MIBG, has been a significant recent
advance in the localisation of adrenal and ectopic phaeochromocytomas. Only
abnormal areas of adrenergic tissue show uptake of MIBG and normal adrenals do
not visualise. MIBG scanning may be particularly valuable in locating an ectopic
phaeochromocytoma when computed tomography shows normal adrenals (Fig.
38.14).
Fig. 38.13 Computed tomography scan of upper thorax showIng a solid
mediastirial mass compressing the left lung and displacing the trachea to the right.
A case of ectopiC phaeochromocytOma.
FIg. 38.14 Same case as Fig. 38.13. An 131l-meta-iodobenzyl-guanidine (?silBG)
scan confirming the presence of an ectopic phaeochromocytoma of the adrenal.
Preoperative preparation. Catecholamine-seaeting tumours are a challenge to
both the surgeon and anaesthetist. A patient with phaeochromocytoma is

hypovolaemic because of the contraction of the vascular bed by excess circulating

catecholamines. During surgery handling of the tumour may increase circulating
catecholamine levels up to 6(X)-fold causing large swings in blood pressure and
cardiac arrhythmias. Severe hypotension may follow removal of the tumour. These
dangers may be minimised by careful preoperative preparation. Effective blockade
of the effects of high circulating catecholamines has significantly reduced the
operative mortality and is mandatory. The alpha-adrenergic blocking drug
phenoxybenzamine in an initial dose of 20-40 mg/day is increased until
hypertension is controlled and mild orthostatic hypotension induced. Such
preparation takes 13 weeks. In most centres a beta-blocking drug such as
propranolol is added for 3-7 days before operation to control tachycardia and
axsythmias. Extra fluids should be given iv. to occupy the sudden expansion of the
vascular bed when the tumour is removed, and a preoperative fluid overload is
advisable.
Operation. During surgery-, intravenous infusions of alpha- and beta-blocking
drugs are given, if required, as determined by the blood pressure, pulse rate and
central venous pressure. The hazardous phases in the operation are during the
induction of anaesthesia, positioning of the patient on the operating table, when the
tumour is manipulated, and immediately after removal of the tumour. Sodium
nitroprusside, a direct peripheral vasodilator. is the drug of choice for the
management of significant intraoperalive hypertension.
Even though preoperative localisation is highly accurate, the possible multiplicity
of tumours (intra- and extra-adrenal) and the need to avoid excessive tumour
manipulation necessitate a generous transabdominal approach. The tumour should
be manipulated as little as possible and the main adrenal vein ligated as a first step.
Inadvertent rupture of the tumour should be avoided as this may result in local
spread and recurrence of even apparently benign tumours.