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1 Chapter 13 Endocrine diseases These diseases arise as a result of malfunction of the endocrine glands, structures that secrete hormones. The endocrine glands do not have excretory ducts as do other glands such as the salivary and sweat glands. Their secretions are passed directly into veins. As a result of this mechanism the endocrine glands are extremely vascular. The endocrine glands, together with the hormones they secrete are listed below. Small foci of endocrine tissue are found in other organs, e.g. the gastrointestinal tract the placenta and the respiratory tract. Only the main endocrine glands will be discussed in this chapter. Hormones govern most of the main functions of the body – metabolism, maintenance of blood pressure, maintenance of fluid and electrolyte balance, growth, and sexual development and differentiation of the body. When the body is functioning normally there are feedback mechanisms that control the amount of hormone secreted so that the body responds appropriately to the ever changing stresses placed upon it during every day life. They also influence the psyche as shown by the fact that a number of endocrine diseases result in reversible psychiatric conditions. Not surprisingly, therefore, many endocrine diseases produce changes in bodily appearance and function that can be recognized both by the patients and their medical attendants. These changes come on slowly and it is useful to look at family photographs to appreciate the changes, and when they first began to appear. Endocrine glands and the hormones they secrete: Pituitary Anterior lobe ACTH (adrenocorticotrophic hormone) GH (growth hormone) FSH (follicle stimulating hormone) LH (Leuteinizing hormone) TSH (thyroid stimulating hormone) Lactogenic hormone (prolactin) MSH (melanocyte stimulating hormone) Posterior lobe ADH (antidiuretic hormone) Oxytocin Thyroid Thyroxin Calcitonin Parathyroid Parathormone Pancreas Islet cells Insulin Glucagon Adrenal Cortex Cortisol Sex hormones Aldosterone Medulla Adrenalin Noradrenalin Gonads Female Oestrogen Progesterone Male Testosterone Laboratory tests are done to clarify the biochemical abnormalities. Some of the tests in use in 2008 are listed in the appendix. 2 These test results are for information only. They are intended for reference and not for committing to memory. Imaging techniques are used to make an exact anatomical diagnosis. Treatment may be medical, to counteract the effects of the excessive hormone secretion, or therapy to replace the hormone deficiency. Many of the endocrine diseases are caused by secretions that come from tumours that develop in the glands. These tumours are removed by surgeons, and the gross and microscopic features of the tumours are assessed by pathologists. In general terms the main diseases of the endocrine glands result from overproduction or underproduction of one or more of the hormones normally secreted by the glands. In this chapter clinical and pathological features of many of these diseases will be illustrated. Pituitary The pituitary gland is an organ approximately 10 mms in diameter. It is connected to the undersurface of the brain, below the hypothalamus by a pituitary stalk. The gland itself is housed in a bony aperture called the pituitary fossa. 1 This is a view looking down into the base of the skull with the brain removed. The green arrow indicates the pituitary stalk that has been cut from the hypothalamus at the base of the brain when the brain was removed. It connects to the pituitary gland that can just be seen in the bony pituitary fossa. carotid artery and cranial nerves, 111, 1V, V and VI. These nerves may be damaged when the pituitary fossa is expanded by a tumour of the pituitary gland, or by an aneurysm of one of the arteries that form the circle of Willis which surrounds the stalk of the pituitary. On its anterior aspect the pituitary lies just posterior to the optic chiasm. Enlargement of the pituitary can cause pressure on the posterior aspect of the chiasm with symptoms of visual field defects for example, bitemporal hemianopia. The blue arrows indicate the two internal carotid arteries. The nerves in the hypothalamus react to the electrical and hormonal activity of the body by activating the secretion of hormones by the various cells in the pituitary. (a) x1 2(a) The pituitary gland is divided into 3 parts as can be seen in this horizontal section. Anterior lobe (A) Posterior lobe or the pars nervosa (P) Pars intermedia. (black arrow) The blood supply comes from two different sources. The main supply comes from the hypothalamus to the main mass of the pituitary. A second supply comes from the connective tissue that surrounds the pituitary (red arrow). This supplies the rim of cells on the periphery of the gland. Some of the connective tissue can be seen on the right hand side of the section. (b) x20 (c) x20 (PAS + Orange G) The outer sides of the lateral walls of the pituitary fossa are lined by layers of dura mater in which pass cavernous sinus, 2(b) and (c) Three types of cells can be distinguished in the anterior lobe according to their affinity for special stains. 3 Chromophobes (white arrow), Basophils (blue arrow) Acidophils (red arrow). These cells are not easy to distinguish in the H&E stain 2(b). They are more easily seen in a special stain called a PAS + Orange G. 2(c).The acidophils stain a yellow colour with this stain. The posterior clinoid processes of the pituitary fossa are clearly seen. 4 Slice of brain showing a large pituitary tumour. (blue arrows) Death occurred from haemorrhage into the tumour. This was a common end result in these tumours before the availability of modern imaging techniques and neurosurgery. (d) x10 2(d) The pars intermedia (black arrow) consists of fluid filled spaces lined by cuboidal epithelial cells. This part of the pituitary arises from the epithelium of the roof of the mouth. With the introduction of immunological staining methods it has become possible to identify the cell types in the anterior lobe of the pituitary according to the hormone they secrete rather than by their staining affinities. Hyperpituitarism Cells in the anterior pituitary may produce a tumour which grows slowly. In so doing it causes enlargement of the pituitary fossa and pressure on adjacent brain tissue. When the tumour reaches a size big enough to cause symptoms, the enlarged pituitary fossa can be seen on a lateral X ray of the skull. (a) 3(a) and (b) (a) This skull X ray of a patient with a pituitary tumour has an enormously enlarged pituitary fossa. (black arrows). The posterior clinoid processes of the pituitary fossa have been eroded. (b) (b) skull X-ray showing the presence of a claficied meningioma (blue and red arrows) And a normal sized pituitary fossa for comparison (black arrows) Some pituitary tumours secrete excess amounts of either GH (growth hormone) or ACTH (adrenocorticotrophic hormone). Some do not secrete excess hormone and cause symptoms because of pressure effects on adjacent structures. The tumours are benign. Occasionally a tumour may produce an excess of prolactin – (a prolactinoma) (a) x20 5(a) This is a microscopic section from a pituitary adenoma removed from a patient who had symptoms of over secretion of GH. All pituitary tumours have a similar pattern on H&E stained sections, as shown here. The pattern of packeting of the tumour cells surrounded by connective tissue strands is a feature common to most endocrine tumours. (b) x20 5(b) An immunostain for GH on this tumour shows positive staining by the tumour cells. Acromegaly When a pituitary adenoma arises during adult life, the clinical condition of acromegaly occurs. It is characterized by the presence of large lips, prominent frontal sinuses, enlargement of the mandible so the lower jaw over rides the upper jaw resulting in mal occlusion of the teeth. The hands and feet become larger than normal, and there is organomegaly seen best in the enlargement of the heart. These changes occur slowly over time and the patient is usually not aware of them. 4 It is usually a medical attendant or a relative who has not seen them for some time who recognizes the changes. A review of family photographs usually reveals the subtle changes. (a) 6(a) This young woman has acromegaly. Her lips and nose are enlarged and her orbital ridges are prominent. long bones have fused, the GH causes the bones to continue to grow. The patient is much taller than his or her siblings. The hands, feet and organs increase in size and the facial features of acromegaly occur as well. Even though the patient is a giant, the muscles are weak. (a) (b) (b) 6(b) This lateral X ray shows elongation of the ramus of her mandible. This caused trouble with her bite because her upper and lower teeth did not occlude correctly. 8(a) and (b) This young man is seen with his mother. His gigantism is obvious and his hands are greatly enlarged. The enlarged hands are often described as being ‘spade like.’ 6(c) Family photographs from the age of 16 to 31 show that the changes began to occur from her early twenties. The changes of gigantism can also be followed by examining family photographs as in the following example. (a) (a) (b) (b) 7(a) and (b) This woman, too has acromegaly. Note her large lips and supra orbital ridges and her enlarged hands (b). She has both neurological and endocrine symptoms of her pituitary adenoma. She has been asked to look to her left while keeping her head still. Only the right eye has moved. The lateral rectus muscle of her left eye is paralysed because the VIth cranial nerve that supplies that muscle has been compressed by the pituitary adenoma expanding laterally from the confines of the pituitary fossa. This nerve runs along the base of the brain from the lower border of the pons to the orbit via the dura mater that covers the lateral side of the pituitary fossa. (c) 9(a), (b), (c) This is a series of family photographs of a woman who presented for medical attention when she was 23 years old. In (a) and (b) she is seen with her non identical twin. In (c) she is with her mother and sister at the baptism of her niece. Throughout her life she had been the tallest girl in the country town in which she lived. She had gigantism as confirmed by the presence of increased GH in her plasma and an enlarged pituitary. She had a GH producing pituitary tumour removed. Hypopituitarism Gigantism Gigantism results when the adenoma develops before puberty and before the epiphyses of the Primary hypopituitarism Primary failure of the pituitary results in the non development of secondary sexual 5 characteristics, and the patients may be of normal stature or be shorter than normal. (a) and (b) (c) and (d) 10(a), (b), (c), (d) This young adult man has no facial, and only minimal body hair. His body habitus is not as muscular as would be expected in comparison with his siblings and contemporaries. His voice was relatively high pitched. He was diagnosed as having hypopituitarism. Acquired hypopituitarism This occurs when the pituitary is destroyed by some pathological process. Two such processes will be demonstrated Infarction from excessive blood loss during the birth of a baby Destruction by a secondary tumour. Excessive post partum haemorrhage sometimes results in infarction of the anterior lobe of the pituitary. This may result in death during the first week following the delivery. Alternatively the changes are more insidious and the woman fails to lactate develops lack of energy, increase in weight and loss of body hair caused by deficiencies of thyroid and adrenal cortical hormones. This is called Sheehan’s syndrome after the pathologist Harold Sheehan (1900 – 1988) who identified the condition when he was working in the Womens’ hospital in Glasgow, Scotland, in the 1930’s. (a) x1 11(a) This pituitary was obtained from a post mortem performed on a 24 year old woman who had a difficult delivery with excessive blood loss. A few days after delivery she lapsed into coma and died soon after being admitted to a specialist referral hospital. A is the anterior lobe and it is almost completely infarcted. It was soft to feel, and it when it was cut to make a microscopic section it fragmented. P is the posterior lobe and it is normal, because it has a different blood supply from that of the anterior lobe. The black arrow is the pars intermedia. The blue arrow indicates an area of neutrophil infiltration into the dead tissue. The red arrow indicates an area of haemorrhage. The brown arrow indicates the capsule of the pituitary which is preserved and stains red. The green arrow indicates a small peripheral zone that contains some still viable pituitary tissue that is supplied by blood from the capsule. (b) x10 11(b) This view shows the infarcted cells in the anterior lobe of the pituitary. (The small dots are staining artifacts and not cell nuclei.) (c) x10 11(c) This view shows the infarcted anterior lobe (A), the pars intermedia (I) and the posterior lobe (P). Both I and P are not infarcted because they have a different blood supply from the anterior lobe. (d) x2 11(d) This is a view from the area marked by a green arrow in 11(a). This small area of anterior lobe is situated just beneath the capsule of the pituitary and is supplied with blood from the capsule. These cells have thus managed to survive. (e)x20 11(e) Surviving cells at the area marked by the green arrow. 6 (f) x20 Normal thyroid 11(f) The tissue just a little deeper in the gland is completely necrotic. Destruction of the pituitary by a secondary tumour. (a) (b) 12(a) and (b) A 23 year old male noticed loss of libido, loss of body hair and atrophy of his genitalia over a period of 2years before presentation. Investigations showed the presence of a tumour that was destroying his pituitary. (a) (b) 13(a) and (b) This brain from another patient shows what had happened to the man illustrated in 12. A tumour of the pineal gland (green arrow on the left) had extended into his pituitary (green arrow on the right) destroying it. 14 Anterior view of a larynx with a normal thyroid gripping the trachea (brown arrow) It consists of two lateral lobes (red arrows), an isthmus (dark blue arrow) and a pyramidal lobe (light blue arrow) The green arrows mark the two cartilage laminae of the thyroid cartilage. The yellow arrow is the epiglottis. Iodine deficiency goitre Iodine deficiency causes multinodular goitres, and this is by far the most common form of goitre. Such goitres are most prevalent in parts of the world where there are high mountains where iodine has been leeched from the soil. The prevalence of iodine deficient goitres can be greatly decreased by adding iodine to the salt in these countries. Untreated iodine deficiency goitres become very large, and the women with them readily seek treatment that removes the unsightly goitre. (a) Thyroid (b) The commonest abnormality of the thyroid is a goitre which is defined as a palpable enlargement of the thyroid gland. Thyroid diseases occur predominantly in women. Types of goitre Physiological In women at puberty and during pregnancy. Pathological Iodine deficiency Tumours (benign and malignant) Thyroid hyperplasia. Immunological Thyroxicosis (toxic goitre) Hashimoto’s thyroiditis Unusual causes For example, amyloid goitre 15(a) and (b) (a) This woman was photographed in 1954 in the highlands of Papua New Guinea, when the Stone Age people of this area were having their first contact with 20th century medicine. (b) This is a very large goitre (600 grams weight) from an indigenous woman who lived in the southern highland area of South India. It is a surgical specimen from the early 1950’s. In areas of iodine deficiency, the goitrous women have marginally normal thyroid function as demonstrated by tests conducted during epidemiological investigations. 7 A significant number of children born to such goitrous women are endemic cretins. Endemic cretins This is an iodine embryopathy resulting from iodine deficiency in the mother. They do have thyroid tissue and occasionally they have a goitre. Clinical features of endemic cretins fairly characteristic facial features mental deficiency short stature a stiff back a gait in which they walk with bent knees. (a) and (b) 16(a) Two endemic cretins with their mothers in PNG in 1966. The one in the foreground illustrates the characteristic stance. 16(b) An endemic cretin in the highlands of PNG with the mountains behind. In this Stone Age culture it was possible for a severely handicapped person like this to be nurtured and to survive. Sporadic cretins In this condition the baby is born with no thyroid tissue, is severely mentally defective and fails to develop normally. Most of the goitres in countries with well funded medical services are also caused by iodine deficiency, but the goitres are much smaller than those seen in poorer iodine deficient areas. 18 This middle aged Australian woman illustrates the size of non neoplastic goitres encountered in countries with well funded medical services. Complications of goitres Unacceptable appearance They may extend behind the sternum and cause pressure symptoms, particularly shortness of breath and cyanosis from compression of the neck veins at the thoracic outlet when the woman lifts her arms above her head. 19 Chest X ray showing a retrosternal extension of a multinodular goitre that contains areas of calcification. (white arrow). Multinodular goitres 20 A lateral lobe of thyroid removed as treatment of a multinodular goitre. The cut surface shows a nodular pattern and follicles and small cystic areas filled with colloid. (a) x1 (a) and (b) (b) x2 17(a) A sporadic cretin in Australia. She had been mentally defective since birth and at 2 years of age she cannot stand unaided. (c) x4 17(b) A 67 year old female sporadic cretin in Australia. She had been in institutional care almost since birth. Thyroxin treatment had had no effect on her profound mental deficiency. 21(a), (b), (c), (d) Microscopic section of this goitre shows follicles which vary in size, and contain a variable amount of colloid (thyroglobulin) stored in each follicle. The thyroid follicles are lined by a single layer of cuboidal cells with a regular nuclear pattern. Goitres in relatively affluent countries Follicular adenomas (d) x10 8 Some nodules in a multinodular goitre are more cellular than those in the previous example, and sometimes the thyroid enlargement is due to an apparently single nodule. Such nodules may be called follicular adenomas. 22. A follicular adenoma. As part of the pre surgical workup of a goitre, an FNA (fine needle aspiration) for cytological examination is done to try to assess the likelihood of its being a carcinoma. In this specimen a needle track made by the FNA examination can be seen (red arrow). (a) x1 (b) x2 (c) x10 23(a), (b), (c) Microscopic sections of this follicular adenoma of the thyroid. Blood in the FNA track can be seen in (a) (red arrow). Thyrotoxicosis This is a condition in which the thyroid gland secretes an excess of thyroxin. It occurs predominantly in middle aged women, but as shown here, men may be affected. It has an autoimmune pathogenesis. The clinical features include, hyperactivity, excessive protrusion of the eyes (exophthalmos) rapid pulse and cardiac arrhythmias, heat intolerance, diarrhoea, and sometimes psychiatric disorders. The thyroid is usually mildly enlarged, feels warm and a bruit can be heard with a stethoscope placed on it. 24 This man has bilateral exophthalmos from thyrotoxicosis. His thyroid is not easily visible. He had other symptoms of this condition and his thyroid function tests supported the diagnosis. Hashimoto’s thyroiditis This is an autoimmune disease of the thyroid characterized by the development of a goitre of moderate size in middle aged women. (It is very rare in men) They have mild hypothyroidism and have circulating antithyroid antibodies. Treatment with replacement thyroid hormone is effective. 25 A female aged 53 presented with a goitre. Thyroid function tests showed a mild degree of hypothyroidism and positive thyroid antibodies. A diagnosis of Hashimoto’s thyroiditis was made and she responded to thyroid supplementation therapy. 26 This is a thyroid surgically removed from a different patient with Hashimoto’s thyroiditis. (Surgery is not always performed because medical treatment with replacement thyroxin is usually effective.) The cut surface shows a rather ‘meaty’ looking nodular appearance and reduction in thyroid colloid. (a) x1 (b) x2 (c) x10 27(a), (b), (c) (a) and (b) The microscopic section shows blue staining areas of cellular lymphoid infiltrations and a reduced number of colloid filled follicles. (c) There are areas of follicular epithelial cell proliferation in which the follicle cells are enlarged and have pink staining cytoplasm. These microscopic features are typical of Hashimoto’s thyroiditis. Amyloid goitre This is one of the unusual causes of goitre. 9 28 This teenage girl from Papua New Guinea presented with a goitre that felt very hard. The surgeon thought it was a thyroid cancer and he proceeded to remove it. Grossly the thyroid felt hard and rubbery. Its cut surface showed virtually no colloid and it was a cream colour. These symptoms were reversed by treatment with thyroid replacement therapy. Thyoid cyst. Cysts result from necrosis of thyroid tissue in multinodular goitres. (a) (a) x1 (b) x1 29(a) This section taken from the amyloid goitre shows homogeneous areas of pink staining along the lower right side. This is all amyloid. The paler areas consist of destroyed thyroid follicles with amyloid infiltrating the thyroid and compressing the follicles. (b) x2 (c) x10 29(a) and (b) A 45 year old female presented with an enlargement of the left lateral lobe of the thyroid. Ultrasound examination revealed the presence of a cyst which was excised. Gross examination (a) showed a cyst filled with clear fluid with a dense fibrous capsule surrounded by normal thyroid tissue. The cyst wall and the adjacent normal thyroid can be seen in the microscopic section. (b). (d) x20 Thyroid malignancies 29(b), (c), (d) These views show the thyroid follicles being compressed and destroyed by pink staining amyloid that gave a green birefringence when stained with congo red stain. Further investigations revealed that the patient had disseminated primary amyloidosis. Primary amyloidosis is relatively common in PNG. Myxoedema This is a condition of hypothyroidism which usually affects middle aged women. Clinical features The patients become lethargic unable to tolerate cold they become obese, develop puffiness around the eyes menstruation ceases and they suffer from constipation. 30 This middle aged woman has myxoedema. She had become moderately obese, her mentation had decreased and she was fatigued. Papillary carcinoma This is the commonest type of thyroid cancer. It occurs in younger patients usually less than 40 years, mostly women. It presents either as a single nodule, multiple nodules throughout the whole gland, or as enlarged cervical lymph nodes resulting from secondary metastases. It is slowly progressive with secondaries particularly in lymph nodes, bone and lung. Microscopically it has a papillary pattern and focal areas of calcification are scattered through the tumour. Frequently the tumour cells have a distinctive vacuolation of their nuclei. 32 A male 18 years presented with unilateral enlargement of the thyroid. Hemithyroidectomy was performed. When the specimen was sliced, a well circumscribed nodule of firm tissue was seen. (red arrow) Microscopic examination showed that it was a papillary carcinoma. 10 Completion thyroidectomy was performed, but no further areas of tumour were found. (a) x1 33(a) The section taken from the tumour shows a papillary tumour (red arrow) with a fibrous capsule (blue arrow) that separated it from the normal thyroid. (green arrow) Microscopically the tumours closely resemble normal thyroid tissue. Invasion of veins in the capsule of the tumour, and metastases are the indications of malignancy. 35 A follicular carcinoma removed as a single nodular enlargement of one lobe of the thyroid. (a) x1 (b) x4 (b) x2 (c) x10 (c) x20 33(b) and (c) show the fibrous capsule in which there is infiltrating tumour. The blue arrow in (c) shows another microscopic feature of papillary carcinoma small calcified areas that are called ‘psammoma bodies.’ (d) x10 (e) x20 33(d) and (e) These images show the cytological pattern of the papillary tumour. The cells are small and regular. Some of the nuclei are vacuolated in their centres. This feature is very prominent in many papillary carcinomas of the thyroid. 34 An enlarged cervical lymph node when cut across showed the presence of a nodule of colloid material. On microscopic section it showed the presence of secondary papillary carcinoma of the thyroid. Follicular carcinoma This is the second most common type of thyroid carcinoma. It occurs in older people, mainly women. It presents as a single nodule or as a result of metastases, most commonly in bone and lungs. Secondary deposits may occur many years after the original tumour has been removed. (d) x10 (e) x20 36(a), (b), (c), (d), (e) Microscopic appearances of a follicular carcinoma of the thyroid. The follicles and the epithelial cells that line them are not different from those of a normal thyroid. However, one needs to examine the capsule of the tumour - black arrow in (a) and (d) to look for the presence of venous invasion to make a diagnosis of malignancy. Invasion of a vein can be seen in (d) and (e). 37(a) A woman aged about 40 years presented with a mass above the forehead. Her primary thyroid lesion is just noticeable as a mild enlargement of the left lobe of her thyroid. 37(b) The plain X-ray of the skull showed a lytic lesion at the site of the tumour. (red arrow) Biopsy confirmed it as being a secondary carcinoma of the thyroid. The metastatic deposit looked like normal thyroid tissue, as is usually the case in secondary deposits of follicular carcinoma of the thyroid. Medullary carcinoma This is a rare tumour of the thyroid and it occurs in older people mainly women. Microscopically it consists of groups of poorly differentiated cells which are derived from C 11 cells which are dispersed among the epithelial cells that line the thyroid follicles. It is further characterized by the presence of amyloid deposited throughout the tumour. It progresses slowly with metastases occurring many years after excision of the original tumour Mostly the tumour presents as a solitary mass in the thyroid. Other associated features may accompany medullary carcinoma Some tumours secrete ACTH which results in the production of Cushing’s syndrome. This presentation is also often associated with diarrhoea. Less frequently, but interestingly, it tends to occur in families, and to be associated with one of the recognized multiple familial endocrine adenoma syndromes. Its most common manifestation in this regard is with the presence of a phaeochromocytoma which is frequently bilateral. (a) x1 (b) x10 (c) x20 38(a) (b), (c) Microscopic views of a medullary carcinoma of the thyroid showing undifferentiated tumour cells with occasional multinucleated cells. Large deposits of pink staining amyloid can be seen throughout the tumour. Multiple familial endocrine adenoma syndrome One example of this is illustrated in Fig. 39. 39 In this montage, one sees a thyroidectomy specimen (green arrow) and a cut surface of the medullary carcinoma (blue arrow). The patient also had bilateral adrenal phaeochromocytomas. (red arrows). Parathyroids There are four small normal parathyroid glands attached to the posterior surface of the thyroid, two upper and two lower. They secrete parathyroid hormone, which controls calcium levels in the blood by increasing phosphate excretion from the kidney and Ca absorption from the renal tubules and from the bowel. The PAH also helps to control bone turnover in the skeleton. Clinical conditions that occur excessive secretion of PAH (hyperparathyroidism) decreased secretion (hypoparathyroidism) Hyperparathyroidism is by far the more common clinical problem. Causes of hyperparathyroidism The formation of a tumour in one of the glands - parathyroid adenoma. Enlargement and hypersecretion of all 4 glands – parathyroid hyperplasia. Types of hyperparathyroidism Primary hyperparathyroidism when there is no recognizable cause for this. Secondary hyperparathyroidism which results from chronic renal failure. Tertiary hyperparathyroidism occurs when one or more of the hyperplastic glands becomes autonomous in its secretion of PAH. Clinical presentations The commonest presentation is with an elevated Calcium (Ca) which is asymptomatic, and detected on a routine biochemical screening for some other reason. Advanced cases present with either bone lesions or with renal calculi. Other symptoms are much less frequent. Treatment Surgical removal of the adenoma, or most of the hyperplastic glandular tissue if it is a hyperplasia. 12 40 Larynx viewed from the posterior aspect. Red arrows - the two lateral lobes of the thyroid gland wrapping around the trachea (brown arrow) The parathyroid glands are found on the posterior surface of the larynx beneath a layer of soft fascia on the most medial border of the posterior lobes of the thyroid gland. They are not easy to dissect, and the upper pair are more easily identified than are the lower pair. (black arrows). The sites where the lower pair can be found are marked by green arrows. The epiglottis is marked by a yellow arrow. Usually one finds a small amount of normal parathyroid tissue adjacent to the surgically removed adenoma. Parathyroid adenoma (d) x4 41 Thyroid viewed from the anterior aspect. There is a parathyroid adenoma replacing the left lower parathyroid gland. (green arrow). The red arrow shows a pyramidal lobe of the thyroid gland. (e) x10 42 Male 62. Operative photograph showing the removal of a parathyroid adenoma. (green arrow) The lateral lobe of the thyroid (black arrow) has been reflected upwards to reveal the adenoma. The adenoma is still attached by a blood vessel. Parathyroid hyperplasia (b) x2 (c) x10 45(b) and (c) show the microscopic appearances of the normal gland. It consists of chief cells and a few clusters of oxyphil cells with pink cytoplasm. There is a considerable amount of fat between the cell clusters. 45(d) and (e) show the microscopic features of the adenoma. It consists of chief cells and a few clusters of oxyphil cells, best seen in (e). 46 Parathyroid hyperplasia. All 4 glands are markedly enlarged and most of the tissue from each gland has been removed by the surgeon. Bone changes in hyperparathyroidism 43 In this case the surgeon has done a total thyroidectomy with removal of a right lower parathyroid gland adenoma (red arrow) and portions of the other 3 normal parathyroid glands. The surgeon aims to leave enough parathyroid tissue to maintain a normal level of PAH post operatively. If too much parathyroid tissue is removed, the patient develops tetany because the Ca level is too low. x1 45 Microscopic sections of the four glands for comparison with the surgical specimen. (a) x4 (b) x10 47(a) and (b) A section of bone from a patient with chronic renal disease and secondary hyperparathyroid hyperplasia. It shows the changes of renal osteodystrophy. The bone trabeculae are thickened, there is an increase in fibrous tissue in the marrow space. There is also increased bone turnover as shown by the presence of osteoclasts (black arrows) which are actively causing bone resorption, and osteoblasts (green arrow) which are actively causing bone formation. (a) x1 (c) x10 Von Kossa stain 45(a) Parathyroid adenoma on the right with a remnant of the normal gland on the left. 13 47(c) In renal osteodystrophy there is also an element of osteomalacia present, as shown by the prominence of osteoid seams lining the surfaces of the bone trabeculae. (black arrows) The bone, which contains calcium, stains black in this stain. Note the anatomical positions of the adrenal glands. The right one is triangular in shape and the left one is oval. (a) x2 Adrenal glands (b) x4 There are two adrenal glands each situated on the upper poles of the right and left kidneys. The right adrenal is triangular in shape and the left one is oval. When cut across, they demonstrate the presence of two layers, an outer cortex and an inner medulla. Macroscopically the cortex is yellow because of the lipid in the cells, and the medulla is a grey colour (See Fig. 61) Microscopically the cortical layer is further divided into 3 layers, from outer to inner - the glomerular, fascicular and reticular layers. The cells of the glomerular layer secrete aldosterone which is involved in the control of salt and blood pressure. Its secretion is controlled by the angiotensin renin hormones from the juxtaglomerular apparatus in the kidneys. The cells of the reticular layer secrete cortisone and sex hormones. The cells of the fascicular layer are reserve cells for the reticular layer. The medulla is related to the autonomic system and it secretes adrenalin and noradrenalin. (c) x10 (d) x20 (e) x10 (f) x20 49(a), (b), (c), (d),(e), (f) Microscopic section showing the morphology of the various layers of the adrenal gland. Black arrow capsule. Blue arrow glomerular layer Yellow arrow facicular layer. Green arrow reticular layer. Red arrow adrenal medulla. Note in (d) the reticular layer cells contain a large amount of brown lipofuscin pigment. In adrenal hyperplasia the glands are enlarged and the cut surface shows a homogeneous brown colour due to the hyperplasia of the reticular layer cells. Note in (e) and (f) that the cells of the glomerular layer are arranged in small groups and they have small nuclei. The layer is not a continuous one. (a) (b) 48(a) and (b) Anterior and posterior views of the kidneys of a 3 year old child who died from adrenal failure caused by bilateral adrenal haemorrhage as a result of meningococcal septicaemia. This is an uncommon complication of septicaemia that results from a number of different bacterial infections, the commonest being meningococcal meningitis. Diseases of the adrenal glands are associated with the overproduction or underproduction of hormones that are normally secreted by them. The main diseases are as follows: Cushing’s syndrome Is caused by an overproduction of corticosteroids (mainly cortisone). This may result from 14 a primary tumour or primary hyperplasia of the adrenal cortical cells. Secondary hyperplasia caused by endogenous increase in ACTH from a pituitary tumour, from iatrogenic administration of ACTH, or from secretion by a non endocrine tumour such as a small cell carcinoma of the lung and a medullary carcinoma of the thyroid. Addison’s disease Caused by an undersecretion of adrenal cortical hormones. This may be caused by an immunological abnormality or By destruction of the adrenal substance by such lesions as tuberculosis or secondary tumour. (Secondary lung cancer being the commonest. tumour to do this.) Phaeochromocytoma is a tumour of the adrenal medulla. It secretes adrenalin and noradrenalin. Adrenocortical tumours that secrete abnormal amounts of sex hormones, either male or female hormones. Hyper aldosteronism This is a very unusual condition caused by secretion of aldosterone by a tumour of the adrenal cortex - a small benign adenoma. Depression of immunological defence mechanisms and lowered resistance to infection. Other symptoms such as psychiatric reactions and osteoporosis may also occur. (a) 50(a) A 45 year old female with Cushing’s syndrome. She shows the truncal obesity and abdominal striae of this condition. (b) 50(b) The photograph on the left was taken 14 months before she presented for investigation. (c) 50(c) Seven months after removal of an adrenal cortical adenoma. She has lost the clinical abnormalities caused by the adrenal tumour. (a) 51(a) This is a 4 year old female child with Cushing’s syndrome. (b) 51(b) The same child aged 3 years. Another important tumour of the adrenal gland is the neuroblastoma, a tumour which arises from the adrenal medulla in very young children with a mean age of about 3 years. This does not secrete hormonal substances but it is one of the commoner tumours of childhood. (c) Cushing’s syndrome This occurs in both sexes at all ages. It presents with changes in bodily appearance Truncal obesity Stretch marks (striae) on the abdomen, Red cheeks with a round face. Hirsutism (increased facial hair in females) Hypertension This is the name given to the disease that results from loss of all the hormones secreted by both the cortex and the medulla of the adrenal gland. Those affected complain of weakness and tiredness. They may be dehydrated and they notice an increased pigmentation of the skin, and buccal mucosa. The investigations are listed in the appendix. 51(c) The same child aged 5 years one year after removal of one adrenal gland that was the site of adrenal cortical hyperplasia. Addison’s disease 15 Untreated it leads to death, but it can be controlled by adequate hormone replacement therapy. The causes are An auto immune reaction Replacement of the adrenal glands by infection (tuberculosis or fungus) and by secondary tumour. These features are illustrated in the following cases. (a) adrenal failure which is accompanied by an excessive pigmentation of the skin. Adreno cortical tumours that secrete sex hormones. (a) 56(a) An 11month old male with a lump in the right upper quadrant of the abdomen and an enlarged left lobe of liver. These are marked on his abdomen. Investigations revealed that the lump was an adrenal tumour. (b) (b) 52(a) and (b) A male aged 21 years. He worked as a builder’s labourer and was suffering from progressive weakness and lethargy. He had been hyperpigmented for 2 years. Hyper pigmentation of the palmar creases of his right hand can be seen. He also had pigmentation of his buccal mucosa. A diagnosis of auto immune Addison’s disease was made. Following hormone replacement therapy, his pigmentation and other symptoms of tiredness regressed. This type of Addison’s disease results in atrophy of both adrenal glands. 54(b) Close up of the genitalia showing abnormally precocious development. (c) 56(c) An operative photograph showing the adrenal tumour (black arrow), normal left lobe of the liver that was pushed aside by the adrenal tumour (white arrow). The red arrow indicates the right kidney. The tumour was removed and his symptoms and signs regressed. He was alive and well at 10 year follow up. Tumours of the adrenal medulla 53 The adrenal gland on the right is of normal size while that on the left is from a patient who died from Addison’s disease. It is small and atrophic. 54 Both adrenal glands from this patient who died from disseminated tuberculosis are almost completely destroyed by infiltration by the tuberculous granulation tissue. 55 Both of these adrenal glands contain secondary deposits from a primary lung cancer. (green arrows) This is a common site of secondaries from lung cancer. Sometimes the tumour deposit is so extensive that the adrenals are virtually destroyed, and in the few weeks before death the patient develops Neuroblastoma Phaeochromocytoma Neuroblastoma Neuroblastoma is one of the more common tumours that occur in childhood. It may be present at birth but its average age of onset is 3 years. It does not secrete any hormonal substance but, untreated it is a highly aggressive tumour metastasising to para aortic lymph nodes, liver and lung. 57 The mother of this 6 year old male child felt a lump in the right upper quadrant of his abdomen. The tumour was removed surgically. 16 No metastatic disease was found during this admission. (a) 58(a) This child died a few days after birth. The post mortem examination revealed a tumour replacing the left adrenal gland (green arrow). The right adrenal gland is normal. Lungs, liver and other organs had metastatic tumour deposits in them. (b) 58(b) The left adrenal and kidney were removed together, and the whole specimen was sliced vertically. The cut surface of the tumour (red arrows) is black from haemorrhage, but white homogeneous areas of tumour can be seen. It may be difficult at macroscopic examination to distinguish adrenal haemorrhage from haemorrhage into an adrenal tumour. 59 This is a post mortem specimen from a female aged 1 year who died from disseminated neuroblastoma. It is viewed from its posterior aspect. The specimen has been sliced to show the primary tumour in the left adrenal (blue arrow) and the extensive metastatic spread to the paraaortic lymph nodes. (yellow arrows). The haemorrhagic nature of the tumour can be seen by the black coloured blood within the tumour. Black arrows kidneys. Red arrow aorta. Green arrow normal right adrenal gland. x 20 60 This is a microscopic section of the preceding neuroblastoma. It consists of sheets of small cells with little cytoplasm and regular, deeply staining nuclei. Phaeochromocytoma These tumours arise from the tissue of the adrenal medulla. They nearly always secrete hormone – adrenalin and noradrenalin. This causes hypertension which characteristically occurs intermittently. The patient recognizes the presence of hypertension by the occurrence of headaches, palpitations and shortness of breath from incipient heart failure. In modern hypertension clinics, investigations are revealing the presence of phaeochromocytomas at an earlier stage of development, and the treatment is instituted earlier than before. Operation used to be fraught with some difficulty because it was not possible to ascertain beforehand which side the tumour was on. Palpation of the tumour during operation results in a surge of adrenalin and a high blood pressure which causes problems for the anaesthetists and risk for the patient. Modern imaging techniques are more sensitive and make it possible to be more accurate in identifying the side of the tumour. As mentioned already in this chapter, phaeochromocytomas may arise in association with some of the so called multiple endocrine adenoma syndromes. 61 Adrenalectomy for a phaeochromocytoma in a female aged 25 years. The tumour (black arrow) can be seen arising from the medulla. She presented with the usual symptoms of intermittent episodes of headache and tachycardia with incipient heart failure. Her symptoms disappeared after removal of the tumour. Note the remaining normal adrenal gland (red arrow). The yellow cortex and grey medulla are clearly shown. Endocrine diseases of the gonads. The gonads may fail to mature and this results in failure of the secondary sex characteristics to develop – a condition called primary hypogonadism. 17 Tumours of the gonads may secrete excessive amounts of either of the sex hormones. (a) (b) 62(a) and (b) A female aged 8 years presented because her mother noticed a lump in her lower abdomen. (a) She did not notice the precocious breast (a) and vulval (b) development of precocious puberty. (a) 63(a) Operation revealed a large tumour replacing the left ovary. (red arrow) Its surface was smooth and no other tumour was identified. The uterus, (yellow arrow) the right ovary (blue arrow) and both Fallopian tubes (black arrows) were normal, as can be seen in the operative photograph. (b) 63(b) The tumour was a granulosa cell tumour and this image shows its cut surface which is partially solid and partially cystic. These tumours frequently secrete oestrogen. When they occur before puberty they cause precocious puberty as in this case. When they occur during reproductive life they cause menorrhagia. After menopause they cause post menopausal bleeding. They may be benign or malignant. 64 At follow up 6 years after operation the patient was well and her symptoms and signs had resolved. x1 65 Orchidectomy for a testicular tumour which on histological examination was seen to be composed of Leydig cells. These cells are normal constituents of the testis and they secrete testosterone. Sometimes the tumour secretes excess testosterone, with symptoms of precocious puberty in children, or increased libido in adults Sometimes it secretes oestrogen and this causes gynaecomastia.. The blue arrow indicates the tumour. The red arrow indicates the tunica albuginea which covers the testis. The green arrow indicates the seminiferous tubules which are being compressed by the tumour, and at higher magnification it was seen that the tubules were undergoing pressure atrophy. Teratomas of the testis may also secrete sex hormones. Pancreas The pancreas has two main functions, an exocrine one in which it is a source of digestive enzymes. And an endocrine one in which it secretes insulin and glucagon. The digestive enzymes are produced by the glandular (acinar) portion of the gland, and the hormones are secreted by the cells of the islets of Langerhans. (a) x2 (b) x4 (c) x10 66(a), (b), (c) show the microscopic appearances of the pancreas. The islets of Langerhans (black arrows) are surrounded by the glandular acinar tissue of the exocrine pancreas. Within the islets, two types of cell can be identified, one of which secretes insulin and the other secretes glucagon. 18 Tumours of the islet cells are rare, but when they are encountered they may secrete either insulin or gastrin. Patients with an islet cell tumour may present with symptoms of hypoglycaemia or intractable peptic (stomach) ulcers depending on whether the tumour is secreting insulin or gastrin. Diabetes mellitus is the endocrine disease that occurs when the islet cells fail to secrete enough insulin. This failure is most commonly of immunological origin. Insulin plays an essential role in carbohydrate metabolism as well as in other aspects of energy metabolism, growth and development of the body. The main presenting symptoms of diabetes are polydypsia, (excessive drinking) polyphagia (excessive eating) and polyuria (excessive passing of urine.) In spite of the excessive eating, the patient loses weight. Patients are more susceptible to infections than are normal people. The metabolic upset causes hyperlipidaemia which results in a high incidence of atherosclerotic vascular disease and all its complications. Diabetes is divided into two types Type 1 Juvenile onset which begins in children and young adults, and requires daily insulin injections for life. Type 2. Adult onset which occurs after middle age and is associated with obesity. It can be controlled by weight reduction and oral insulin. Peripheral vascular disease is a frequent cause of occlusion of small arteries in the toes. This results in ischaemia and later, gangrene of the toes. In later stages, gangrene of the foot and the leg occurs. (a) and (b) 67(a) and (b) (a) is the right foot of a 40 year old female diabetic patient. All her toes are ischaemic. (b) A 60 year old male diabetic patient with gangrene of the fourth toe of the left foot. 19 Biochemical tests for endocrine diseases Acromegaly/Gigantism 1. Serum oestradiol Investigations 1. IGF-1 (insulin-like growth factor 1) Normal reference range Varies with age, gender, pubertal status Adult 5-30nmol/L Sample positive result IGF-1 84nmol/L 2. Oral glucose tolerance test Normal reference ranges for adults Early follicular phase 100-200pmol/L, Preovulatory phase 500-1700pmol/L, Luteal phase 500-900pmol/L, Postmenopausal 70-200pmol/L 2. FSH, LH Normal reference ranges for adults Premenopausal FSH 1-8U/L, LH 2-15U/L, Postmenopausal FSH >18U/L, LH 15-100U/L Normal reference range Growth hormone (GH) suppresses to <2mU/L after glucose load Sample positive result Nadir of GH 15mU/L after 75g oral glucose Sample positive results Male Hypogonadism Secondary hypogonadism Serum oestradiol 80pmol/L FSH 8 U/L, LH 4 U/L Investigations Primary hypogonadism Serum oestradiol 80pmol/L FSH 55U/L, LH 64 U/L Total testosterone FSH (follicle stimulating hormone) LH (luteinising hormone) Cushing’s syndrome Normal reference ranges for adults Testosterone: 8-35nmol/L FSH 1-5 U/L LH 2-10 U/L 1. 24 hour urinary free cortisol Normal reference range for adults <150nmol/24 hours Sample positive result 4000nmol/24 hours Investigations Sample positive results Primary hypogonadism Total testosterone 2.4nmol/L FSH 58 U/L, LH 39 U/L Secondary hypogonadism Total testosterone 5nmol/L FSH 5 U/L, LH 8 U/L Female Hypogonadism Investigations 0800h serum cortisol 324nmol/L Sample positive result 2. 1mg overnight dexamethasone suppression test Normal reference ranges for adults 0800h serum cortisol suppresses to <100nmol/L after 1mg dexamethasone 2300h the night before Sample positive result 0800h serum cortisol 324nmol/L 20 3. Sleeping midnight plasma cortisol Normal reference ranges for adults <50nmol/L Sample positive result Loss of circadian rhythm Precocious puberty 1. Diagnosis is made on clinical grounds. 2. Serum FSH, LH and response to GnRH (Gonadotrophin releasing hormone) will assist in differential diagnosis. Normal reference ranges Prepubertal – flat response Pubertal – LH >15U/L, FSH >7.5U/L Sample positive results GnRH dependent eg. Pituitary tumour Post pubertal levels sex steroids, gonadotrophins not suppressed GnRH independent eg. Gonadal tumour Post pubertal levels sex steroids, gonadotrophins suppressed, and response to exogenous GnRH suppressed 3. The following may be useful in determining aetiology of GnRH independent precocious puberty: Total testosterone Normal reference range Prepubertal <0.5nmol/L Serum oestradiol Normal reference ranges Prepubertal <100pmol/L Adult male 60-180pmol/L Androstenedione Prepubertal : <3nmol/L Adult female premenopausal 3.5-9.0nmol/L, Postmenopausal <6nmol/L, Male 1-8nmol/L DHEAS (dehydroepiandrosterone sulphate) Normal reference ranges Prepubertal : <4µmol/L (varies with age) Adult : varies with age and gender Serum hCG (human chorionic gonadotrophin) Non-pregnant : <5mU/L Primary Hyperaldosteronism (Conn’s syndrome) 1. Aldosterone/renin ratio (ARR) Results are affected by sodium intake, posture and many drugs Normal reference ranges Aldosterone – Adult ambulatory 100900pmol/L, supine 30-450pmol/L Plasma renin activity – Adult ambulatory 14ng/ml/h, supine <2ng/ml/h ARR 80 / 530 Sample positive results Aldosterone 1200pmol/L Plasma renin activity 1ng/ml/h ARR 1200 2. Fludrocortisone suppression test Normal reference range Aldosterone should suppress to <160pmol/L by day 5 Sample positive result Aldosterone 320pmol/l after 4 days fludrocortisone (day 5) Congenital Adrenal Hyperplasia Serum 17-hydroxyprogesterone (17-OHP) (+/synacthen stimulation) Normal reference range <6nmol/L Sample positive result 17-OHP 32nmol/L Addison’s disease 1. Short synacthen test Normal reference range Rise in plasma cortisol of >200nmol/L to peak of >500nmol/L Sample positive result Serum cortisol : basal 90nmol/l, +30min 100nmol/L +60min 200nmol/L 21 2. ACTH (adrenocorticotrophic hormone) Normal reference range 10-50ng/L Sample positive result ACTH 110ng/L 3. Anti-adrenal antibodies Normal reference range Not detectable Sample positive result Detectable Phaeochromocytoma and Neuroblastoma 1. 24 hour urinary catecholamines and metabolites Normal reference range Adults Noradrenaline <750nmol/d Adrenaline <80nmol/d Normetadrenalines <2.3µmol/d Metadrenalines <1.7µmol/d HMMA (hydroxymethoxymandelic acid) <28µmol/d Sample positive result Raised urinary excretion of catecholamines and metabolites, Raised plasma catecholamines and metabolites, Non-suppressibility on clonidine suppression test. Further dynamic testing eg. Phentolamine test and glucagon stimulation are not routine 2. Plasma catecholamines Normal reference range Adults Noradrenaline 0.1-6.3nmol/L Adrenaline 0.1-1.5nmol/L 3. Plasma metadrenalines Normal reference range Adults Metadrenaline 0.06-0.31nmol/L Normetradrenaline 0.1-0.61nmol/L 4. Clonidine suppression test Normal reference range Plasma total catecholamines suppress to <3nmol/L within 3 hours of 0.3mg oral clonidine Hyperparathyroidism 1. PTH (parathyroid hormone) Normal reference range 1-7pmol/L 2. Ionised calcium Normal reference range 1.25-1.35 mmol/L 3. Serum phosphate Normal reference range 0.8-1.5mmol/L 4. Serum creatinine Normal Child : 0.04-0.08mmol/L Normal Adult : female 0.05-0.11mmol/L Normal Adult male 0.06-0.12mmol/L 5. 24 hour urinary calcium:creatinine Normal 2.5-7.5mmol/24hrs 6. 1,25 (OH)2 Vitamin D Normal reference range 35-120pmol/l Sample positive results Primary hyperparathyroidism PTH elevated Ionised calcium elevated Serum phosphate low Normal renal function Normal to raised urinary calcium (if low consider familial hypocalciuric hypercalcaemia) Secondary Hyperparathyroidism PTH elevated Ionised calcium normal to low Serum phosphate normal to elevated Renal impairment 1,25 (OH)2 Vitamin D low Tertiary Hyperparathyroidism PTH elevated 22 Ionised calcium elevated Serum phosphate elevated Renal impairment 1,25 (OH)2 Vitamin D low 2.Anti-thyroid antibodies (microsomal, thyroid peroxidase, thyroglobulin) Normal reference range Not detected Thyrotoxicosis Sample positive results Primary hypothyroidism TSH elevated Free T4 and T3 low Anti-thyroid antibodies may be detected in autoimmune hypothyroidism eg. Hashimoto’s disease Thyroid function tests 1. TSH (thyroid stimulating hormone) Normal reference range 0.3-5.0mU/L 2. Free T4 Normal reference range 9-23pmol/L 3. Free T3 Normal reference range 3.5-5.5pmol/L 4. TSH receptor antibodies Not detected 5. ESR (erythrocyte sedimentation rate) Normal reference range Child: 2-15mm/h Adult : female 17-50y 3-12mm/h, >50y 5-20mm/h Male 17-50y 1-10mm/h, >50y 2-14mm/h Secondary hypothyroidism Free T4 and T3 low with TSH normal to low Diabetes Mellitus 1. Fasting plasma glucose (FPG) Normal reference range FPG >6mmol/L 2. 75g oral glucose tolerance test Normal reference range FPG >6mmol/L 2 hour glucose <7.8mmol/L Sample positive results Diabetes mellitus: FPG >7.0mmol/L and/or 2 hour glucose >11.1mmol/L Sample positive results Primary hyperthyroidism eg. Graves’ disease, thyroiditis TSH <0.05mU/L Free T4 and T3 elevated TSH receptor antibodies and ESR may assist with determining the aetiology Secondary hyperthyroidism eg. TSH secreting pituitary tumour Free T4 and T3 elevated with TSH normal to high Hypothyroidism 1. Thyroid function tests As listed under thyrotoxicosis Impaired fasting glycaemia FPG 6.1-6.9mmol/L, 2 hour glucose <7.8mmol/L Impaired glucose tolerance FPG >7mmol/L, 2 hour glucose 7.811.0mmol/L