Monday, September 06, 2004

Surgery of Parathyroid

THE PARATHYROID GLANDS
The four parathyroid glands are located posterior to the thyroid gland. They produce parathyroid hormone (PTH), which is the primary regulator of calcium physiology. PTH acts directly on bone, where it induces calcium resorption, and on the kidney, where it stimulates calcium reabsorption and Reabsorption of phosphates by the renal tubules. Serum PTH levels are tightly regulated by a negative feedback loop. Calcium, acting through the calcium-sensing receptor, and vitamin D, acting through its nuclear receptor, inhibit PTH synthesis and release.

Surgical Anatomy

These endocrine glands, usually two pairs- superior and inferior, but exact no. of parathyroid may vary .(88% 4 glands,6% 5 glands and in remaining 6% 3 Glands)


Position and embryology: The superior parathyroid, on each side, develops from the fourth pouch (hence called parathyroid IV). Superior parathyroid glands fairly constant in position closely embedded in thyroid postero Lateral border of thyroid Gland immediately above entry of inf. thyroid artery.Rarely it might vary above and within substance of thyroid gland along the of thyroid gland.
Paradoxically , the inferior parathyroid develop from the third pharyngeal pouch (Parathyroid III). The inferior parathyroids develop together with the –thymus and, since the thymus descends low down, the glands come down to a lower level than their counterparts developing from the fourth pouch . They are usually situated at the lower pole of thyroid gland.and may be found any where in this situation downwards to the upper pole Thymus.5% found in upper anterior Mediastinum
di- George Syndrome –( Congenital absence of parathyroid gland,Thymus and pharyngeal derivatives ) is a rare congenital anamoly

The glands are oval in shape, about the size of small peas ,the inferior glands being larger than the superiors. Their color varies from red or pink to yellow depending on the amount of fat deposition as age advances. They have, however, a distinctly different colour from the thyroid and this factor is of great help in their identification either at thyroidectomy or at parathyroidectomy. Small fat lobules usually bruised on operation table may look like parathyroid but Sink it in water parathyroid will sink – fat lobule will float ( Sink test)

Histology
The gland contains rich sinusoidal capillary net work with islands of secretary cells.
Microscopically, the parathyroids contain three types of cells :-
A. Basophilic or chief cells ( Principle cells) They have Small, vasicular nuclei and poorly staining cytoplasm
B. Eosinophilic cells (their number increases as age advances)
C. Water – clear cells. Usually found in hyperplastic parathyroid or neoplastic tumour

Surgical Physiology : - The hormone of the parathyroid is parathromone, which is polypeptide. It regulates the calcium and phosphorous metabolism of the body, maintaining a balanced ratio between the two. The normal level of serum calcium is 9 tp 11 mg per 100 ml and that of serum phosphorus is 3 to 4.5 mg per 100 ml (4,5 to 5.5 and 1.8 to 2.7 mEq. per liter respectively). The product between calcium and phosphorus in mg i.e. Ca x P is about 40 in a normal subject.

The control on the calcium and the phosphorus metabolism is maintained by the effect of parathormone on two organs, viz, bone and kidney. As to the exact mode of control, there are two views :-
1. Parathormone stimulates osteoclasts to bone destruction; thus mobilizing calcium and phosphate from bone to blood. This theory fails to explain why the serum phosphorus level should be low when the calcium level rises in hyperparathyroidism.
2. Parathormone controls Reabsorption of phosphates by the renal tubules. Since there is a reciprocal relationship between phosphorus and calcium, any change in the serum phosphate level brings in a compensatory change in the calcium level by mobilization from the bone. This view is more commonly accepted.
In addition Parathormone augments absorption of Ca from gut and controle GIT limb of Calcium metabolism

One important point about the serum calcium is to how it is held in solution in the blood plasma. From this point of view, the calcium may be divided into three parts: -
(a)About one-third is held adsorbed on plasma proteins; this is non-ionised and is physiologically inactive.
(b) A small part is in close attachment with organic acids; this also is non-ionised and, hence, physiologically inactive.
© The remainder is held in solution by Parathormone. It is only this part which is ionized and is physiologically active i.e. dynamic. The rise or fall of serum calcium, as seen in hyper and hypo-parathyroidism respectively, is only with respect to this part.


HYPERPARATHYROIDISM ( HPT)


It is clinical syndrome where in there is an excess of parathormone secretionthat is acting on all the target organs of Parathormone
Aetiology
Primary Hyperthyroidism
A)Primary Hyperplasia
a) Chief Cell Hyperplasia alone or part of MEA IIA and IIB
b) Water Clear Cell Hyperplasia(WCCH)
Hyperplasia involving all the parathyroids –
these account for about 20% of the cases
B) Neoplasia :
a)Adenoma which might exist alone or as part of Multiple endocrine adenoma syndrome(MEN II A Medullary carcinoma of thyroid, Parathyroid Adenoma or Hyperplasia and Pheochromocytoma )
Solitary adenoma in a parathyroid, obviously hormone-secreting- these account for 80% of the cases
b) Carcinoma in a parathyroid – extremely rare.

Secondary Hyperthyroidism
a)Chronic renal failure with Renal osteodystrophy
b) Malabsorption syndrome
In both the cases Serum Ca is low leading to Compensatory parathyroid Hyperplasia of all 4 glands.

Tertiary Hyperthyroidism
: Persistant HPT after Renal Transplantation in Renal osteodystrophy exists in about
20% of cases of Renal osteodystrophy



Biochemical Changes of HPT
(1)Elevation of the Serum Calcium Level – In the majority of cases there is considerable rise in the level of serum calcium. There are two views to explain this rise:-
(a)That parathormone directly mobilizes calcium from the bone by stimulating the osteoclasts to bone destruction.
(b) That parathormone diminishes tubular Reabsorption of phosphate in the kidney so that there is increased phosphate excretion in the urine. The serum phosphate level, therefore, falls. Since there is a reciprocal relationship between the phosphate and calcium levels in the serum, the serum calcium level is elevated.
The serum calcium level often rises to 12 to 16 mg (sometimes 20mg) from the normal level of 9 to 11 mg per 100 ml.
As has already been stated, this elevation is only in respect to that part of the serum calcium which is held in solution by parathormone and is ionized and physiologically active; i.e. dynamic. The actual level, to which the serum calcium rises, depends on four factors: -
(a) Rate of mobilization from the bones.
(b) Rate of absorption from the gut (i.e. food)
© Rate of excretion by the kidneys.
(d) Rate of Excretion from the gut.

(2) Increased Excretion of Calcium in the Urine – There are two routes of excretion of calcium from the body viz. the stool and the urine. In a normal individual most of the calcium is eliminated in the stool and only 10 to 30% in the urine. In hyperparathyroidism this ratio is reversed and the urine is supersaturated with calcium. This calcium is excreted: -
(a) as calcium phosphate, if the urine is alkaline.
(b) as calcium oxalate if the urine is acid.

3. Increased Excretion of Phosphorus in the Urine : As has been stated, this is the prime factor in the biochemical disturbances. However, when gross renal damage sets in, in the late stage of the disease (see below), the phosphorus excretion may fall.
4. Diminished Level of Serum Phosphorus : As phosphorus is excreted in high quantities in the urine, its level in the serum falls ( normal 3 to 4.5 mg/100ml)
5. Elevation of Serum Alkaline Phosphatase Level: - As in all bone dystrophies, there is an elevation in the level of serum alkaline phosphatase (normal 3 to 13 KA units/100ml)


Clinical Features:
The clinical features of HPT can be described in one statement bones, stones, abdominal groans and psychic moans
A. The Bone Lesions – In early case vague bony pain and joint pains may be presenting features (D/D Rheumatism ) Lesions in bones, i.e. parathyroid, osteodystrophy, is the most well recognized manifestation of hyperparathyroidism but it is not invariable. In at least some cases, the bones may be spared by increased utilization of dietary calcium. The changes may involve the entire skeleton and are as follows:
(1)Generalized demineralization with subperiosteal bone resorption (voRecklinghausen’s disease of bone)
(2) In some areas there may be complete replacement of osseous structure by fibrous tissue ( i.e. osteitis fibrosa) in which there is an abundance of osteoclast giant cells ( the so-called brown tumour of hyperparathyroidism_. Such areas of fibrous replacement may become cystic (osteitis fibrosa cystica). Some bones are commonly affected viz. the metaphysis of long bones, mandible, maxilla, and phalanges.
(3) Softening of bones may lead to deformities.
(4) Pathological fractures may occur through the cystic areas.

(B) Stones (The Kidney Lesions)
The increased urinary output of calcium may lead to the following changes:
(1)Formation of urinary calculi (hyperparathyroidism should be excluded especially in cases of multiple and recurrent calculi)
(2) Nephrocalcinosis: Radiologically seen as streaks of calcification in the line of renal tubules. Calcific foci block the renal tubules and cause fibrosis and obliteration of the corresponding nephrons.
(3) Widespread obliteration of nephrons, resulting in renal damage, may cause polyuria, hypertension and renal failure. Renal failure is often the cause of death in these cases.

C) The Abdominal Groans
(1) Dyspeptic cases :Anorexia, nausea and vomiting may be the presenting features.
(2) Peptic ulcer may occur in 15% of cases. The pain is worsened by alkalis. Recurrent bleeding may occur. The ulcer may not be demonstrable radiologically.
(3) Acute, subacute or chronic pancreatitis may occur in some cases
4) Persistent Irritable GIT may be seen in some cases

D)Psychic Moans :
Uncommon presentation , present with lethargy, Tiredness, Listlessness or irrational behavior and some may be wrongly Labeled as Neurotic

E) Hypercalcemic Syndrome
These patients present with minor mental changes, Lethargy,polydypsia, polyurea
and Dehydration,

F) Acute Hypercalcemic Syndrome is rapidly deteriorating clinical condition where in patients present initially with nausea, vomiting followed by abdominal pain and land up in oliguria and deteriorate fast to be in Coma

G) Asymptomatic: some of the patients may be detected during biochemical check up/.




Special Investigations:
(A)Biochemistry:
(1)Elevation of serum calcium
(2) Increased urinary excretion of calcium.
(3) Increased urinary excretion of phosphorus
(4) Diminished serum phosphorus
(5) Elevation of serum alkaline phosphatase.
(6) Elevation of serum parathormone (upper limit of normal is 0.5 microgram per litre of serum). The hormone is always detectable in hyperparathyroidism patients while it may be undetectable in many normal subjects.
(7) Sulkowitch Test: The patient is given a diet containing 125 mg of calcium daily, for three successive days. In hyperparathyroidism more than 200mg of calcium is excreted in the urine daily ( in a normal subject this level will be less than 100 mg).

B. X-Ray of the Bones:
(1) Generalized decalcification, often with cyst formation.
(2) Subperiosteal resorption, best seen in the middle phalanges. There is often an associated Reabsorption of the tufts of the terminal phalanges.
(3) Pathological fractures.
(4) The skull may have a ‘ground glass’ appearance due to decreased density.

C. X-Ray of the Kidneys may show stones or nephrocalcinosis.
D.Metastatic Calcification in soft tissues may be occasionally seen
Localization of Parathyroid Pathology:
Preoperative:MinimumInvasive
n Ultra Sound :operator dependant
n Computed tomography – usefull for localization outside neck
n Barium swallow, and Cine oesophagogram can partly help
n Neck massage PTH, urinary cyclic AMP
n Technetium Tc 99m Sestamibi radionuclide 91% to100% accuracy
n Thallium Technicium isotope Substraction scanning: useful for Adenoma but not for Hyperplasia
n MRI : 64% detection rate
Low signal is obtained on T1 weighted images,
T2 weighed images give contrast resolution
Preoperative:Invasive:
n Selective venous sampling of PTH
n Selective Angiography
n Arterial injection of selenomethionine 15
n Needle aspiration
Intra operative:
n Methylene blue
n 0-Toludine blue,
n Urinary Cyclic AMP
n Intraoperative assessment of PTH
n Intraoperative gamma probes for nuclear mapping




.

Parathyroidectomy:
Indications
1) Primary HPT
Hyperplasia – 3.1/2 gland is removed
Adenoma --- one
Carcinoma – Local Radical Diss.
2) Secondary HPT
– If bone decalcifation
- Severe pain.
3) Tertiary HPT
4) Re operative.

History
n Felix Mandl in Vienna, Austria performed the first successful Parathyroidectomy in 1925.
n Endoscopic Parathyroidectomy was pioneered by Dr Michel Gagner at the Cleveland Clinic in 1996
Surgical techniques

n Open Parathyroidectomy
n Minimally invasive Radioguided Parathyoidectomy
n Endoscopic Parathyroidectomy
The actual type of surgery depends on the pathology, and may be as follows: -
(1)If there is a parathyroid adenoma, it should be excised. However, after excising the tumour, all the other three parathyroids are to be explored and examined. This is because multiple adenoma may occur, involving more than one parathyroid. The operation is performed with a colar incision, as for subtotal thyroidectomy. While the parathyroids may be found in their normal positions behind the thyroid lobes, they may be located in abnormal situations as well, e;g.
(a)embedded in the substance of the thyroid.
(b) in the tracheo-oesophageal groove.

(2) If no adenoma is detectable and all or several parathyroids are found to be larger than normal, parathyroid hyperplasia is the diagnosis ( had there been a hidden adenoma, the parathyroids would be smaller in size due to disuse atrophy). In such cases, three or three and a half of the parathyroid glands are removed.

(3) When the parathyroids appear normal or smaller in size, adenoma in am ectopic parathyroid is the likely pathology. In these cases, after careful search of the thyroid lobes and the tracheo-oesophageal grooves, the Mediastinum has to be explored. For this purpose, a sternal split is done. An ectopic parathyroid may be located:
(a)retrosternal
(b) on the pericardium
© in relation to the thymus ( a thymectomy may have to be done).

4. If some of the parathyroids ( particularly the inferior glands) are not traceable in the neck, the Mediastinum has to be explored, as above, in order to find out the glands.

Auto Transplantation of Parathyroid
Indications
– Primary Thyroid hyperplasia
– Secondary HPT
– Re operative HPT
– Total Thyroidectomy for Ca Thyroid
This technique is useful to avoid Hypoparathyroidism I cases of hyperplasia Where after the surgery if hypo functioning is seen it can be avoided by auto transplantation

Deferred parathyroid Autotransplantation
n Immediately placed in to sterile saline or tissue culture
n Sliced into 1x1x3mm silvers.
n 3ml Glass vials will accommodate 10 silvers 1 to 1.5 ml
– 10% DMSO dimethyl sulfoxide
– 10% autologus serum
– 80% Tissue culture media
n Frozen after immersion at rate of 1degree centigrade per minute
n Till you reach -80degree Centigrade
n -190 o C Vapour phase Liquid nitrogen freezer
n Linde BF 4/6 biological freezing system
n Thawing rapidly to 57oC
n Implant in Thigh subcutaneously



HYPOPARATHYROIDISM
Causes:

(1)Post Operative: These account for the majority of the cases. They occur after thyroidectomies, but only in about one percent of the cases. The features appear in one to five days after the operation, but if the symptoms are mild, the condition may remain unrecognized for weeks (see complications of thyroidectomy, Chapter 30).

(2) Insidious: These occur spontaneously in some people. The condition is characterized by weakness, opacity of the lenses, brittlessness of the nails, loss of dental enamel, loss of hair, and a low serum calcium level.

(3) Idiopathic: This occurs in children, usually in the active stages of rickets.

(4) Secondary: These cases occur secondary to alkalosis and may be found in:
(a) Long continued vomiting- Pyloric stenosis, high intestinal obstruction.
(b) Prolonged administration of alkalis – peptic ulcer.

Clinical Features: The features of tetany set in when the blood calcium level comes down to the ‘tetany level’ which is usually below 6 mg /100ml of serum. It takes a few days for this level to be reached, so post-operative tetany (the commonest form) takes about 2 to 5 days to appear. The milder forms may be missed clinically for longer periods. The earlier the features appear, the delayed is the recovery.

The clinical features are all motor, resulting from muscular irritability:
(1)Widespread fibrillation of the muscle fibers may give the patient a sensation of tingling and numbness of the lips, nose and extremities, there may be a typical circum-oral pallor.
(2) The muscles of the forearms and legs go into spasm, resulting in what is called the ‘carpo-pedal spasm’. The characteristic features are: -
(a)The foot assumes an equines position 9i.e. plantar-flexion)
(b) The hand assumes the ‘obstetrical position’ – the fingers are extended except at the metacarpophalangeal joints (which are flexed), and the thumb is adducted.

(3) In latent cases, muscle spasms which are not ordinarily seen, may be induced as follows:-
(a)Trousseau’s Sign: - A sphygmomanometer cuff is applied round the arm and the pressure is raised to above the systolic level- the hand assumes the ‘obstetrical position’.
(b) Chvostek’s sign:- Tapping the facial nerve, just in front of the ear, with a percussion hammer, provokes twitching of the facial muscles.


(4) In severe cases, the spasms may be more pronounced e.g.

(a)Generalized fits
(b) Spasm of the muscles of respiration – dyspnoea.
© Spasm of intra-ocular muscles- blurring of vision.

(5) The insidious cases may present with weakness, cataracts, brittle nails, lack of dental enamel and loss of hair.

Special Investigations:
(1)Estimation of Serum Calcium- This is always low, usually below 6 mg. per 100 ml in frank cases of tetany.
(2) Erb’s Sign- A hyper excitability of the muscles can be seen on galvanic stimulation.

Treatment: .


Thursday, June 17, 2004

THE ADRENAL CORTEX

Embryology: Unlike the medulla, which is of ectodermal origin, the cortex of the adrenal is mesodermal in origin. It arises in a ridge, which appears just by the side of the mesonephros (Wolffian body).

Structure: The adrenal cortex is composed of large polyhedral cells, rich in lipoids, and the cells are arranged in three different layers, which, from outside inwards are named:-
1.Zona glomerulosa which produces Aldosterone
2.Zona fasciculate which is store house of Steroids
3.Zona reticularis.which manufactures rest of coricoid hormones

Adrenal Cortical Hormones: The hormones of the adrenal cortex are all esters of cholesterol; the polycylic nucleus of cholesterol is modified by the addition of O2, OH2, or other complex groups, by the action of different enzymes. More than fifty such compounds have been isolated. The more important of these are divided into three groups:
1.Glucocorticoids.
(2)Mineralocorticoids or salt-regulating hormones.
3.Sex hormones.’

Glucocorticoids: These hormones are so named because they favor neoglucogenesis. The are concerned in the metabolism of protein and carbohydrate., favoring formation of glucose from non-carbohydrate sources. Hydrocortisone (cortisol) is the chief of these hormones. It is so called because it possesses a hydroxyl (OH) group at the 11-position- it thus belongs to the class of 11-oxysteroids. It is essential for life because it has an overall effect on general metabolism and also some effect on water and electrolyte balance. Cortisone is a synthetic preparation and converted into hydrocortisone in the body, exerting same effects.
Hydrocortisone, after metabolism is excreted in the urine chiefly as 17-hydroxycorticoids.
Hyperplasia or tumours of those cells which produce Glucocorticoids, results in what is known as Cushing’s syndrome. The Glucocorticoids are chiefly produced in zona fasciculate and zona reticularis.

Mineralocorticoids: These are concerned in the maintenance of water and electrolyte balance. Aldosterone is the most important of these hormones. It is also known as 11-desoxycorticoid because it possesses neither an oxygen atom nor a hydroxyl group at the 11 position (e.f. hydrocortisone). The control on water and electrolyte balance is effected mainly by the agency of the cells in the renal tubules. Excess of the hormones causes increased tubular Reabsorption of sodium and chloride, which are retained along with water in the blood (oedema, hypertension); there is loss of potassium in the urine resulting in hypopotassaemia. Conversely, a deficiency of the hormones results in loss of sodium in the urine and retention of potassium. The excess loss of sodium causes a fall in the osmotic tension of plasma and extracellular fluid; water now leaks into the cells and a dehydration (extra-cellular) results.
The synthetic mineralocorticoid is desoxycorticosterone (D.O.C.A.) and it has the same effects as Aldosterone.
Hyperpl;asia r neoplasm of those cells, which produce Aldosterone, results in what is known as Conn’s syndrome ( primary aldosteronism). Aldosterone is produced in the zona glomerulosa.

Sex Hormones: Both androgenic and oestrogenic hormones are produced in the adrenal cortex. The sex hormones are known as 17-ketosteroids or 17 oxosteroids because they possess an oxygen atom at the 17 position.
The male (androgenic) hormone is androsterone.
The female (oestrogenic) hormones are oestrone, oestriol and oestradiol-17B.
Excess of the Oestrogens may (very rarely) cause effeminancy in the males.

Control of Cortical Function: The adrenal cortex is under control of anterior pituitary through agency of A.C.T.H. i.e. adrenocorticotrophic hormone (corticotrophin) which stimulates the adrenal cortex. Conversely hydrocortisone of the adrenal cortex inhibits the secretion of ACTH (feed back mechanism).

Role of Adrenal Cortex in ‘Stress’: The adrenal cortex quickly responds to all types of stress (trauma, haemorrhage, burn, acute infection, acute perforations etc) and this is well demonstrated by the microscopical appearance of the gland. The cells of the adrenal cortex are normally laden with lipid materials, which represent the storehouse of the hormones of the gland. Under conditions of stress, there is a depletion of this lipid storage (as the hormones are discharged into circulation). Thereafter, there is a phase of cellular overgrowth, associated with re-accumulation of the lipid materials (suggesting return of normalcy).

Tests for Adrenal Cortical Function:
A. By measuring the blood level of the hormone directly:-
1.Plasma cortisol (hydrocortisone) level.- Normally 8 to 28 micrograms per 100 ml.
2.Other cortical hormones- Using radio-activation techniques, it is now possible to estimate the levels of the other cortical hormones individually.
B.By measuring the urinary output (24 hours) of the metabolites of individual cortical hormones or of the hormones themselves:
1.17- Hydroxycorticoid ( for hydrocortisone)
(2) 17=oxosteroid i.e. 17=ketosteroid (for androgens and Oestrogens)
3.Aldosterole itself
4. The three Oestrogens themselves.(1 & 2 are usually measured for testing cortical function)
C.Similar estimations made after stimulating the adrenal cortex by administering A.C.T.H. (A.C.T.H. stimulation tests):-
-- These are done with the idea that patients with adrenal hyperplasia respond much more than persons with normal cortical function.
--The urinary output of the 17-hydroxycorticoid and 17-ketosteroid in 24 hours are measured first. Thereafter, the cortex is stimulated by ACTH gel ( 40 units given intramuscularly, twice, in a span of 24 hours). The urinary output of the two metabolites are measured in the urine of the next 24 hours.
D.Similar estimation made after suppressing the adrenals by inhibiting A.C.T.H.
A.C.T.H. suppression is usually done by injecting hydrocortisone, or more commonly, dexamethasone (which suppresses the pituitary by the same feedback mechanism as hydrocortisone). The urinary excretion of 17-hydroxycorticoid and 17 ketasteroid in 24 hours prior and after the injection is measured. It is found that there is a far more severe depression in the excretion of the metabolites in patients with adrenal hyperplasia than in normal subjects. Curiously, however, in patients of adrenal tumours with over activity, this depression is not noticed. This is explained by the fact that the secretion of the cortical hormones from adrenal tumours is autonomous, i.e. not under control of ACTH. Thus the ACTH suppression test is valuable not only in diagnosing cortical over-activity but also making a differential diagnosis between adrenal hyperplasia and neoplasm.
Therapeutic Uses of Hydrocortisone (and Cortisone):
1. In Endocrine (adrenocortical) Deficiency:
a. After bilateral adrenalectomy.
b.Adrenocortical insufficiency i.e. hypocorticism- acute or chronic (Addison’s disease)
2.In Non-endocrine Conditions:
a. Allergic conditions.
b.Blood dyscrasias
c. Collagenoses
d. Granulomatous disorders
e.Rheumatoid arthritis
f.Different skin and eye conditions, acting as an anti-allergic agent (applied locally).


CUSHING’s SYNDROME
This is the commonest form of hypercorticism and is due to an excessive production of the Glucocorticoids, chiefly hydrocortisone. It occurs in the adults and is, therefore, also known as post-pubertal or adult hypercorticism.
The other types of hypercorticism are:-
1.Infantile
2.Pre-pubertal
3.Post-menopausal.

Pathology:
The excessive production of the hydrocortisone (cortisol) may be brought about by one of the following conditions:
 Primary:
 Cushing disease: Pituitary Tumors : 30% (Basophil adenoma or invasive carcinoma of the anterior pituitary )
 Hyperplasia of adrenal gland: 60%
 Ectopic ACTH producing Tumour
 (Ulcerogenic islet-cell tumour of the pancreas, . Bronchial carcinoma ,Small cell carcinoma of lung and thymic carcinoma
 Tumor of adrenal cortex(35%)
 Adenoma
 Carcinoma
 In some of these cases there may be a tumour of the thymus or of the pineal glands (located between the posterior parts of the thalamus of the two sides).

 Secondary:
Excessive steroid Therapy for long time can induce clinical picture of Cushing Syndrome. Thae therapy may be for
 Rheumatoid arthritis
 Transplants Patients receiving Steroid therapy
 Auto immune disorders

Clinical Features: Females suffer more commonly than males (3:1). A typical patient is a female between 15 and 30 years of age (excepting the cases where the condition is drug-induced).
The clinical features may be divided into 5 broad groups:-
1.Those due to metabolic disorders.
2.Those due to fluid and electrolyte disturbances.
3.Sexual disorders.
4. Mental changes
5. Other features.




A.Those due to Metabolic Disturbances:
Disturbances releted to fat, protein, sugar and calcium metabolism: -
1.Obesity: Although overall weight is not increased
Deposition of fat in certain areas There is an excessive deposit of fat over
 Protuberant abdomen
 Buffalo lump (fatty pads over the scapulae)
 Moon face with pursed lips
 Obliteration of supraclavicular fossae.

2.Protein breakdown::
 Thinning of arms and legs due to muscle breakdown
 (the swollen abdomen with the thinned-out legs may be compared to
‘a lemon on the match-sticks’).
 Increasing muscular weakness.

3.Atrophy of the dermis and inhibitory effect on fibrous tissue:
 Skin gets inelastic and assumes a tissue-paper consistency; on the abdomen :
striae gravidarum.
 Purpura and bruising to minimal trauma

4. Diabetes, due to increased neoglucogenesis.

5. Negative calcium balance causing gross osteoporosis and, sometimes, pathological fractures (particularly of the vertebrae)
These disturbances are releted to fat, protein, sugar and calcium metabolism: -
1.Obesity: There is an excessive deposit of fat over some particular parts, resulting in:
a. Protuberant abdomen
b.Buffalo lump (fatty pads over the scapulae)
c. Moon face with pursed lips
d. Obliteration of supraclavicular fossae.
e.Increased body weight.

2.Protein breakdown::
a.Thinning of arms and legs due to muscle breakdown (the swollen abdomen with the thinned-out legs may be compared to ‘a ,lemon on the match-sticks’).
b.Increasing muscular weakness.
3.Atrophy of the dermis and inhibitory effect on fibrous tissue:
a.Skin gets inelastic and assumes a tissue-paper consistency; on the abdomen this gives the same pattern as striae gravidarum.
b.There is a high-colored complexion due to transparency of the skin.
c. Purpura and bruising to minimal trauma (due to atrophy of capillary walls).
4. Diabetes, due to increased neoglucogenesis.
5. negative calcium balance causing gross osteoporosis and, sometimes, pathological fractures (particularly of the vertebrae)

B Those due to Fluid and Electrolyte Imbalance: These occur because hydrocortisone has a weak Aldosterone effect. There is retention of sodium and water with excessive loss of potassium. This results in:
1)Hypertension, may lead to cardiac hypertrophy, myocardial ischaemia, cerebro-vascular accidents, and congestive heart failure.
2.)Hypokalaemic alkalosis.

C)Sexual Disorders:
1)Common types:
(a)Sterility and impotency in the males.
(b) Sterility and menstrual disorders in the females (oligomenorrhoea, amenorrhoea or menorrhagia).
(2)Uncommon type i.e. Adreno-genital Syndrome: These are the cases where sexual disorders are more predominant than the metabolic disorders:
a) Most commonly it occurs in females due to excessive secretion of androsterone. The condition usually starts at about the age of 20. There is oligomenorrhoea, atrophy of the breasts, enlargement of the clitoris, deepening of the voice, and a change of body structure to a manly build.
b) Very rarely it may occur in young males due to excessive seceretion of Oestrogens. There is gynaecomastia, atrophy of the testes, change in voice etc.

A. Mental Changes: Various types of psychosis may set in ( more than half of the cases).
B. Other Features:
(1)Increased growth of lanugo hairs, sometimes frank hirsutims.
(2) Acne and skin infections (due to suppressed inflammatory reaction).
(3) Recurrent itntercurrent infections (due to same reason)
(4) Excessive pigmentation of the skin (this is not due to excess of hydrocortisone but because of increased A,.C.T.H.)

Special Investigations:
(1)Blood Count – Polycythemia and leucocytosis (with lymphopaenia and cosinopaenia).
(2) Urine Examination
(a)Glycosuria
(b) Hypercalciuria
(3) Blood Biochemistry:
(a)Hyperglycaemia
(b) Hypercholesterolaemia.
4. B.M.R. – Low.
5. X-Ray:
(a)Skeleton- There may be gross osteoporosis, particularly in the vertebrae and pelvis.
(b) Pituitary fossa (sella turcica)- An enlargement may sometimes be seen if the condition is due to a pituitary tumour.
(c) Lungs- Rarely presence of stones and nephrocalcinosis.
(d) Kidneys- Rarely presence of stones or nephrocalcinosis.
(e) X-rays to demonstrate adrenal tumours ( see under phaeochromocytoma)
6. Hormone Assays:
(a)Estimation of Plasma cortisol level.
(b) Estimation of urinary 17-hydroxycorticoid and 17-ketosteroid.
© A.C.T.H. stimulation test.
(d) A.C.T.H. suppression test. (see tests for adrenal cortical function)

Treatment:
(1)When the pathology is primarily in the adrenal:
(a)In cases of adrenal hyperplasia ( which is bilateral)- Total adrenalectomy on one side and resection of seven-eighth of the adrenal gland on the other side.
(b) In cases of adrenal neoplasm) adenoma or carcinoma)- Excision of the adrenal gland that contains the tumour.
If the diagnosis is a tumour and the side is ascertained, an extraperitoneal approach by the lumbar route (as for the kidney) is done; the twelfth rib (sometimes also the eleventh) is excised to expose the adrenal. In other cases, a Tran peritoneal approach has to be made, so that both the adrenals can be examined.

(2)When the adrenal condition is secondary to a pituitary tumour: Two forms of treatment are available:
(a)Surgical removal of the pituitary (hypophysectomy)
(b) Radiation=ablation of the pituitary by implanting Ytrrium –90 pellets into the gland.

Cortisone Replacement in Adrenalectomy: The daily output of hydrocortisone from the adrenals, in a normal subject, is about 25 mg. After bilateral adrenalectomy, this amount has tobe supplied from outside throughout the life time of the patient. Following subtotal adrenalectomy, however, the remnant of the adrenal tissue gradually picks up function and the external supply may be withdrawn after sometime. Similarly, even after bilateral adrenalectomy, the adrenal cortical rests in the body may be geared into action in some cases and the external supply may be discontinued.

Again the stress of the operation and anaesthesia, for adrenalectomy, requires a high supplement during and after the operation. It is desirable that the higher supplement is instituted from one or two days prior to the date of operation.

The following is a tentative routine of cortisone replacement in cases of adrenalectomy- A)Before Operation : For 1 or 2 days- Cortisone acetate, intramuscularly, 100 mg daily
(B)On the day of Operation:
(1)1 to 2 hours before operation- Cortisone acetate, intramuscularly,100mg
(2) During Operation – Hydrocortisone hemisuccinate, 100 mg in the intravenous drip. Alternatively, the hydrocortisone is pushed directly intravenous just after extirpation of the adrenals.
(3) After Operation: Cortisone acetate, intramuscularly, every 6 hours.

C. Until 5th Post-Operative Day: Cortisone Acetate, 100 mg, intramuscularly or orally, according to the patient’s condition.
(D)After 5th Day : Cortisone acetate is given, but the dose is gradually reduced to 25 to 50 mg in cases of total adrenalectomy and to nil in subtotal adrenalectomy (the remaining adrenal tissue picks up function).

Notes on Endocrine Surgery : Adrenal Medula

My Dear Students,
You can down load these notes and pay more attention on understanding the problems during lecture
yours with knowledge base
Dr Arun Jamkar
THE ADRENAL GLANDS

The adrenal gland, one on each side, is enclosed, together with the kidney, within the renal fascia but a lamina of fibroareolar tissue separates the two structures, so that they occupy separate compartments.
The adrenal gland because of its anatomical position has been a fascinating area for surgeons and now with advent of minimum invasive surgery the fascination has further increased. In addition it is one of the rare field where a combined team efforts by surgeon, physician . and anesthetist have shown miracle results
The right adrenal is triangular in shape and the left is semi lunar.
Each gland has usually three arteries, but a single vein. The arteries are:
1 The Superior adrenal artery, branch of Inferior phrenic Artery
2. The Middle adrenal artery, branch of abdominal aorta direct.
3,.The Inferior adrenal artery, branch of Renal.artery
The veins on the two sides differ from each other:-
a) The right adrenal vein is very short and drains directly into the inferior vena cava, distal to the hepatic vein. The vein is so short that the gland actually sits on the inferior vena cava.
b) The left adrenal vein is longer and it drains into the left renal vein. Anatomical communications exist between the renal vein and the Azygos vein, so that the venous blood from the left adrenal has direct access into the vertebral, intercostals, and internal mammary veins of the left side.

These differences in the veins of the two sides are important in two ways:
1.Adrenalectomy is a little more difficult on the right side because the vein is so short that it may tear even with mild traction on the gland, and as the tear is practically on the inferior vena cava, the bleeding may prove very difficult to be controlled.
2) Metastatic lesions from malignant tumours of the adrenal (e.g. Neuroblastoma) may show differences in their distribution. With growths on the right side, hepatic metastasis is commoner; with tumours on the left side, bone metastasis is commoner (especially the skull, by way of vertebral veins).

The adrenal gland ( like the pituitary) consists of two different tissues , the cortex and the medulla. Except for the fact that these two parts are in so intimate anatomical relationship as to deserve description together, there is every reason to consider the two parts separately, because developmentally, structurally, as well as functionally, the two behave as separate endocrine organs.They only share blood supply and anatomical location.





THE ADRENAL MEDULLA
Embryology: The adrenal medulla is ectodermal in origin. It is developed together with the sympathetic nervous system, from the neuroectoderm. Hence, it is in close functional relationship with the sympathetic nerves, its secretions acting on the sympathetic nerve endings.Chromafin cells from neuro ectoderm migrate towards the primitive cortex and enter inside to form the medulla.

Histology:
The adrenal medulla consists of :-
The medulla is below the inner most layer of zona Reticularis .mainly chromaffin tissue, an aggregation of chromaffin cells. These are large polyhedral cells and are so named because they contain granules which stain yellow with chromic acid. These granules are actually the secretions of the adrenal medulla and they are found as such, inside the small radicals of the adrenal vein.
2)Some nerve cells of the sympathetic nervous system.

Functions: The secretion of the adrenal medulla consists of different catecholamines, of which only two are important:
1.Adrenaline.
2. Noradrenaline: This is the unmethylated precursor of adrenaline.
In health, 80% of the secretion of adrenal medulla is adrenaline and only 20% nor-adrenaline.

Adrenaline causes peripheral vasoconstriction but muscular vasodilatation.
Nor adrenaline causes an over-all vasoconstriction. However, the actions of nor-adrenaline is short lived. These effects are produced by the action of adrenaline and nor-adrenaline on the sympathetic nerve-endings. In conditions like fear, anger and pain ( i.e. when the body is subjected to noxious stimuli), the adrenal medulla is stimulated by way of the splanchnic nerve and it quickly liberates its hormones in the blood to make a rapid response . Adrenaline has an additional effect of glycogenolysis.
















TUMOURS OF THE ADRENAL MEDULLA

There are three common tumours-
Phaeochromocytoma, Ganglioneuroma and Neuroblastoma.
Classification:
A) According to Origin:
l. Those :arising from the chromaffin cells- Phaeochromocytoma.
2. Those arising from the nerve cells (mature or immature) of the sympathetic nervous system:
a) Arising from and reproducing nerve cells of very immature type-Neuroblastoma.
b) Arising from and reproducing ganglion nerve cells of adult type-Ganglioneuroma.
B)According to Pathology:
1.Benign:
a,. Ganglioneuroma
b,. Phaeochromocytoma ( 90%)
2.Malignant
a) Neuroblastoma
b) Phaeochromocytoma (10%)



PHAEOCHROMOCYTOMA
Phaeochromocytomas are tumours composed of chromafin tissue derived from nervous system ,It is a functionally active catecholamine secreting tumor.
It produces an excess of adranaline especially noradranaline 20:1 ratio
It occurs in 4th and 5th decade of life,with higher preponderance in the female
Only 0.5 % of all hypertensives have their hypertension due to pheochromocytoma
Yet all Patients with sustained hypertension under 60 years should be evaluated for Pheochromocytoma.
Origin: These tumours originate in the chromaffin cells of the adrenal medulla. 90% arises from chromafin cells in adrenal medula
10% occasions tumour may originate from extra-adrenal chromaffin tissue (i.e. at ectopic sites) e.g.
a). ) Most common extra adrenal site is Oragn of Zuckerkandle,
b) Para ganglia of sympathetic nervous system-coeliac, mesenteric,
renal, hypogastric, testicular
c) Sympathetic ganglia.
A tumour in an ectopic site is more likely to produce nor-adrenaline

• Phaeochromocytoma. Can be a part of autosomal dominant multiple endocrine neoplastic syndrome
 Multilple endocrine adenomatosis type IIB (Parathyroid adenoma/hyperplasia, Medulary carcinoma of thyroid,Phaeochromocytoma)

 Multiple endocrine adenomatosis type IIA ( Sippel’s syndrome)
Medularry carcinoma of thyroid,mucosal adenoma,Marfanoid app., Phaeo.

 Von Hippel- Lindau syndrome (Haemangioplastoma of cerebellum,retina or brain and Phaeochromocytoma.


Pathology: Pheochromocytoma is called as 10 % tumour as
10% are extra adrenergic
10% are Multiple
10% are malignant
10% are in Children
10% are Bilateral

1.The tumour is usually benign, but may be malignant (10%). Metastasis may occur from a malignant growth.
2.In about 10% of cases the tumour is bilateral. Sometimes there are multiple tumours.
3.The tumour is usually small ( less than 5 cm). It has a thin but definite capsule. It is soft and is brownish in colour.
4. Microscopically, it consists of phaeochromocytes in large numbers. these are large, well-differentiated round cells, which characteristically stain black with chromium salts.
.

Pathological Effects:
This tumour is important because it secretes the adrenal medullary hormones in excess- both adrenaline and nor-adrenaline. The proportion between the two differs from case to case, but in a vast majority it is the nor-adrenaline which preponderates. The normal ratio of adrenaline to nor adrenaline (80:20) may just be reserved. A tumour in an ectopic site and one in a child is more likely to produce nor-adrenaline These hormones, released into the blood stream, cause hypertension. In all the cases, to start with, the hypertension is paroxysmal, the systolic blood pressure rising to alarmingly high levels during the attacks. in at least 50% of the cases the hypertension becomes persistent, though paroxysms may be superadded even on such cases. As the hypertension becomes persistent all its complications may set in.

A similar type of paroxysmal hypertension may occur in the rare condition of hyperplasia of the adrenal medulla, in which both the adrenalins share.

Clinical Features: Almost always the patient is an adult, both the sexes being equally affected. The presenting features are :
1. Paroxysms of hypertension, or hypertensive attacks are very characteristics pheochromocytoma, They are predisposed by Bending, twisting,Change of
emotions and Post-prandial hypoglycemia. During the attacks there is increased catecholamines in circulation producing both alpha and beta adrenergic effects
Due to alpha adrenergic effect The systolic blood pressure is raised enormously during attacks,Tachycardia,Excessive head ache, sweating unrelated to Temperature Palpitation.Nervousness,Circumoral Pallor.
The patients during the attak are frightened , have feeling of Doom, and say “ I am going to Die” .Weakness, hypotension follows the attack which is severe enough to produce gangrene especially at periphery like Toes and fingers.

2. Other associated symptoms, which in order of frequency are – headache (35%), palpitation, vomiting,(26%) sweating (27%), dyspnoea,(19%) weakness and pallor.(17%)
Nevousness 10%. Abdominal pain 12% .Persistent hypertension in about 50% of cases. Even in these cases, attacks of paroxysmal increase may occur from time to time. Cardiovascular changes may set in, and Hypertensive retinopathy may occur.
3. Cholelithiasis
4 .Abnormal glucose tolerance test,10% of cases develop diabetes mellitus
5 Bleeding may be presentation in form of Epistaxis,Hematemesis,and Haematuria
.4. A phaeochromocytoma may originate or may be switched into activity during pregnancy.


Special Investigations:
A. Radiography;
1 .A straight X-ray may very occasionally show a soft tissue shadow in the adrenal
re gion. Usually, however, the tumour is too small to cast such a shadow.
2 I.V.P. may show displacement of the pelvi-calyceal system at the upper pole
of the kidney. This may sometimes be mistaken for a renal tumour.
3. Paracoccygeal air insufflation into the Retroperitoneal tissues:-
Due to better modalities of investigation ,this modality is no more used
B Aortography – As the tumours are usually vascular, the increased vascularity may be well demonstrated.
C Retrograde venous catheterization and injection of a contrast medium.
4. CAT Scan may be of great help in the diagnosis.

B.Hormone Tests:
1.Urine Tests:
(a)Estimation of V.M.A.( vanillyl mandelic acid), which is a metabolite of the catecholamines i.e. nor-adrenaline and adrenaline. A colorimetric examination is done. The normal output is 2 to 8 microg in 24 hours. In phaeochromocytoma this level is significantly raised.
(b)Direct estimation of catecholamines in the urine by flourimetric method. This may be done as an alternative to (a).
© Animal Test: Extracts from the patient’s urine, containing the catecholamines, are injected into a cat to find if there is arise in blood pressure.
2. Blood Examination: A retrograde venous catheterization is done and blood from the inferior vena cava is directly drawn for estimation of nor-adrenaline.
3.Pharmacological Tests: These are done by administration of drugs, which either
Provoke or diminish the hypertension, and their effects are studied:
(a)Drugs provoking hypertension: Histamine or mecholyl is injected intravenously and an attack of hypertension is provoked for confirmation of diagnosis. The procedure is dangerous for the patient, and is therefore condemned.
(b)Drugs diminishing hypertension: Adrenaline-antagonist drugs are administered and the blood pressure is reduced; this confirms the diagnosis. This procedure is safe and therefore standard. Piperoxane or dibenamine may be used, but the most commonly used drug is Rogitine (phentolamine), 5mg given intravenously.



Treatment: The only available treatment is removal of the adrenal gland on the affected side. If the side is certain, an extra-peritoneal approach by the lumbar route (as for the kidney) is done. The twelfth (sometimes also the eleventh) rib is excised to expose the adrenal. If the side of the tumour is uncertain, a transperitoneal approach has to be made, so that both the adrenals can be examined.
Surgery for Pheochromocytoma
Open Adrenalectomy
1. Lateral Retroperitoneal
2. Transabdominal
Laparoscopic Adrenalectomy
1. Retroperitoneal
2. Transpertitoneal
Intra operative Control of Catecholamine Release
Combination of regional + G.A. provides satisfactory condition till tumour exposure
During Manipulation of tumour –brisk Presser response :
1. Control of hypertension
with potent I V vasodilator eg Sodium NitroPurusoid
2. Control of Tachycardia - with Beta blockers

Special Precautions at Operation: During anaesthesia and while manipulating the adrenal, there is every possibility of rise in blood pressure to serious levels. After removal of the adrenal, with the tumour, there is again the possibility of sudden fall of blood pressure. These may be combated by the following procedures:-
1.Regitine, 20 to 40 mg thrice daily, is given orally for a few days prior to the date of operation.
(2) Before induction of anaesthesia, Regitine 5 mg is administered intravenously.
(3)While manipulating the adrenal, Regitine 5 mg is again given intravenously, and repeated if required.
(4) As soon as the adrenal gland is removed (or the vein ligated), nor-adrenaline is given intravenously to combat hypo tension. A nor-adrenaline drip may have to be continued for the first forty eight hours and then the drug is gradually tailed off over a week.