Pituitary and Thyroid Disorders

Anatomy

The pituitary gland (hypophysis) lies in the sella turcica and is suspended from the hypothalamus by the infundibular stalk. It is regulated by the hypothalamus and is divided into two sections. The posterior section is the neurohypophysis, which is an extension of the hypothalamus and releases vasopressin and oxytocin into the blood. The anterior section is the adenohypophysis, which is a pharyngeal derivative that secretes six trophic hormones, including GH, lactogenic hormone, adrenocorticotropic hormone, thyroid-stimulating hormone (TSH), follicle-stimulating hormone, and luteinizing hormone.

Pathology

Secretion of GH from the anterior pituitary somatotrophs is usually controlled by GHRH synthesized in the hypothalamus and transported through the pituitary stalk to the somatotrophs in the anterior pituitary gland. As soon as the GH is released into circulation, it stimulates the liver to produce insulin-like growth factor 1 (IGF-1). IGF-1 is the primary mediator of many of the growth-promoting effects of GH and is therefore responsible for most of the clinical manifestations of acromegaly and gigantism.

In the immature skeleton, in which the growth plates are still open, GH hypersecretion stimulates endochondral bone formation at the physeal growth plates, leading to excessive bone growth in both length and width, therefore resulting in the very tall but normally proportioned person seen in gigantism.

As soon as the physeal growth plates have fused, GH hypersecretion reactivates endochondral bone formation at various cartilage-bone junctions and stimulates periosteal bone formation, leading to mainly growth in bone width. The osseous as well as soft tissue hypertrophy, particularly in the acral parts of the body, such as the hands, feet, and mandible, results in the characteristic appearance of acromegaly.

Stimulation of endochondral bone formation in acromegaly at various cartilage-bone junctions results in deposition of new cartilage on preexisting cartilage and enlargement of the joint. Excessive GH stimulates articular chondrocyte proliferation and increased matrix production, leading to thickening of the articular cartilage and widening of the joint spaces. The GH also stimulates hypertrophy of periarticular tissues, resulting in ligamentous laxity and joint instability. Eventually, these processes lead to wear and fissuring of the cartilage. The repair mechanisms are impaired because of excessive GH and, consequently, allow overproliferation of regenerating fibrocartilages, which may subsequently become calcified and result in osteophyte formation. Eventual destruction and thinning of the articular cartilage lead to joint space narrowing.

Stimulation of periosteal bone formation results in many characteristic findings of acromegaly. In the skull, periosteal bone deposition leads to thickening of the calvaria, enlargement and forward protrusion of the mandible, prominence of the supraorbital ridges and facial bones, and deepening of the alveolar sockets of the teeth with separation of the teeth. In the long bones, subperiosteal and subligamentous bone formation results in thickening and irregularity of the cortex, prominence of the bony tuberosities, and osteophytosis. One characteristic finding is enlargement of the distal phalangeal tufts. In the vertebral column, there is increase in anteroposterior and transverse diameters of the vertebral bodies without proportional increase in height, giving the vertebral bodies a short appearance. There is associated increase in the size of the intervertebral disk, which is produced by marginal subperiosteal formation of cartilage. Osteophytes of the spine may be extensive.

Stimulation of soft tissue hypertrophy by excessive GH leads to thickening of the skin, enlargement of the hands and feet, organomegaly, muscular hypertrophy, and other connective tissue overgrowth that contribute to many of the clinical manifestations of acromegaly and pituitary gigantism.

Techniques and Relevant Aspects

Radiographs and MRI are the most commonly used imaging modalities in the evaluation and work-up of acromegaly and pituitary gigantism. Radiographs can demonstrate characteristic features that are often sufficient to suggest the diagnosis and prompt further evaluation.

After confirmation of GH hypersecretion by laboratory studies, pituitary MRI is often used to detect for pituitary adenoma because it is the most common etiology. If MRI is contraindicated, CT of the sella turcica may be performed.

If pituitary MRI or CT findings are negative, CT of the chest, abdomen, and pelvis is useful in the evaluation for rare ectopic secretion of GH/GHRH by tumors in the lung, pancreas, adrenal, or ovaries.

Ultrasonography is occasionally used instead of radiography to observe for response to treatments. Colao and colleagues reported the use of ultrasonography in evaluating soft tissue thickness and joint space widening for reversibility in response to treatment.

Pros and Cons

Magnetic resonance imaging has several advantages over CT, including the ability to display pathologic lesions in three orthogonal planes without loss of information and the ability to demonstrate the relationship of the pituitary lesions to the optic chiasm and cavernous sinuses. MRI provides more detailed information of the surrounding structures that may be affected by the GH- or GHRH-secreting tumors.

CT has the advantage of providing better visualization of the bony septa in the sphenoidal sinus, which may be important if a transsphenoidal surgical approach is being considered.

Radiography

Soft Tissue

Skin thickening may be observed as a result of collagen tissue response to excessive GH. Many articles have documented the utility of measuring heel pad thickness as a diagnostic aid for acromegaly. The shortest distance between the calcaneus and the plantar skin surface is usually measured ( eFig. 80-1 ). Although there are variations in heel pad thickness related to body weight, gender, and race, values greater than 25 mm in men and 23 mm in women are highly suggestive of the disease in the absence of other local causes of skin thickening, such as infection, injury, or edema.

Muscular and connective tissue hypertrophy in the extremities may cause peripheral neuropathy due to nerve compression, and this can be seen on MRI as edema around the nerve along with soft tissue hypertrophy.

Skull

The calvaria is usually thickened, but, uncommonly, it can be thinned. The sella turcica may be enlarged or destroyed. The paranasal sinuses are prominent, and there is increased pneumatization of mastoid air cells. The supraorbital ridges and zygomatic arches are prominent as well. There is enlargement of the mandible and widening of the mandibular angle, resulting in forward protrusion of the mandible, giving the “lantern jaw” appearance. Consequently, there is poor dental closure and inability to properly incise food. Anterior tilting of the teeth and interdental separation may be observed, as well as hypercementosis of the teeth and macroglossia ( eFig. 80-2 ).

Hand

The hand contains many diagnostic clues in a patient with acromegaly. Some characteristic findings include enlarged distal phalangeal tufts, widened articular spaces of the metacarpophalangeal joints, squared phalanges and metacarpal bones, thickened soft tissues of the fingers, enlarged sesamoid bone, beak-like osteophytosis at the metacarpal heads, and bone formation at insertion sites of tendons and ligaments. A distal phalangeal tuft width of more than 12 mm in men and over 10 mm in women is virtually diagnostic of acromegaly. A metacarpophalangeal joint space width of more than 2.5 mm in both men and women is suggestive of acromegaly. A soft tissue thickness measured at the proximal midphalanges of more than 27 mm in men and 26 mm in women is also suggestive of acromegaly ( eFig. 80-3 ).

Some studies have been done using the sesamoid index as a diagnostic aid for acromegaly. To determine the sesamoid index, the medial sesamoid of the first metacarpophalangeal joint is measured on a nonmagnified radiograph with a 36-in. focus-film distance. The greatest diameter of this sesamoid bone in millimeters is multiplied by the greatest diameter of the same sesamoid image perpendicular to the first measurement. The reliability of this sesamoid index approach has been challenged because of variations in measurement in normal men and women, but, generally, values greater than 40 in men and 32 in women are suggestive of acromegaly. The sesamoid index from normal men and women is generally around 20, with a range from 12 to 29. Acromegaly is less likely with values less than 30 but cannot be excluded. In addition to increased size of sesamoid bones, an increased number of sesamoids may also be seen.

Spine

In the spine, there is increased anteroposterior and transverse diameters of vertebral bodies secondary to anterior and lateral appositional bone growth. There is no change in the vertebral body height, resulting in the appearance of a short vertebral body. These findings are more often seen in the thoracic and lumbar spine and are less common in the cervical spine. There is also increased height of the intervertebral disk space, which may account for the increased spinal mobility. This is particularly evident in the lumbar region. The anterior and lateral osteophytes in the thoracic and lumbar spine may be extensive, perhaps due to excessive spinal mobility from lax paraspinal ligaments and thickened intervertebral disks. In the cervical spine, widening of the atlantoaxial joint space may be observed. Commonly, there is an increase in kyphotic curvature of the thoracic spine and lordotic curvature of the lumbar spine.

A few studies have reported the incidence of spinal stenosis in patients with acromegaly and pituitary gigantism, resulting from hypertrophy of bones and ligaments, widening of vertebral bodies, and developmental narrowing of the spinal canal.

Scalloping of the posterior margins of the vertebral bodies may be observed ( eFig. 80-4 ), and the etiology is unclear. There is a predilection for the lumbar spine. This finding is not specific for acromegaly and can be found in a number of other conditions. (See discussion on differential diagnosis.)

Acromegaly

A combination of radiographic findings would be sufficient to suggest a diagnosis of acromegaly. Some of these radiographic findings, when viewed individually, are not specific to acromegaly and may be seen in other disorders. For example, widened phalangeal tufts are seen in patients working in heavy manual labor. Scalloped vertebral bodies can result from increased intraspinal pressure from intraspinal neoplasm, cyst, or syringomyelia or from dural weakness predisposing vertebral bodies to deformity, as may be seen in Marfan syndrome, neurofibromatosis, and Ehlers-Danlos syndrome. The joint space narrowing, osteophytosis, cyst formation, and sclerosis seen in late stages of acromegalic arthropathy resemble those in degenerative disease. Soft tissue enlargement and peripheral neuropathy, such as carpal tunnel syndrome, may be seen in hypothyroidism secondary to myxedematous tissue. A prognathic jaw can also be seen in hypopituitarism.

One disorder that has been reported to have similar clinical and radiographic findings to acromegaly is familial pachydermoperiostosis, characterized by abundant periosteal new bone formation, enlargement of the distal extremities with spade-like hands, squaring of the phalanges, thickening of the skin, coarsening of facial features, and prominent paranasal sinuses. However, unlike acromegaly, there are no signs of endochondral bone formation. The sella turcica is normal, the phalangeal tufts are not widened, the mandibular size and angle are normal, and the articular joint spaces are preserved. In pachydermoperiostosis, the GH level is normal.

Another condition that can mimic acromegaly is long-term therapy with phenytoin (Dilantin), which can lead to the development of thickened calvaria, thickened heel pad, and coarse facies.

Pituitary Gigantism

Most children who present with gigantism do not have pituitary gigantism. There are many causes of tall stature that should be excluded, including chromosomal causes of tall structure (Sotos, Weaver, Marshall-Smith, and XYY syndromes), precocious puberty, hyperthyroidism, Marfan syndrome, and Beckwith-Wiedemann syndrome. Other associated disorders should be considered as well, such as McCune-Albright syndrome, multiple endocrine neoplasia type 1, neurofibromatosis, tuberous sclerosis, and Carney complex.

Medical Treatment

Surgery is usually the first-line therapy for most patients because pituitary adenoma is the most common cause of GH hypersecretion and often can be resected. If surgery fails to sufficiently reduce the GH and IGF-1 levels to normal, medical treatment is usually the first choice for secondary treatment for residual disease. Medical treatment can also be considered as a primary therapy in patients who are not surgical candidates due to unacceptable risks, patients who refuse surgery, and patients with adenomas that are surgically inaccessible. The medical treatments available include pharmacologic agents, such as somatostatin analogues, dopamine agonists, and GH receptor antagonists.

The somatostatin analogues commonly used are octreotide and lanreotide. The somatostatin analogues are effective in lowering the serum GH level, reducing the tumor size, and improving the clinical manifestations of acromegaly.

The dopamine agonists have limited effectiveness in the treatment of acromegaly. They are generally less effective than the somatostatin analogues. An exception is with tumors that cosecrete prolactin, which the tumors have a better response rate to dopamine agonists than to the somatostatin analogues. The dopamine agonists include bromocriptine and cabergoline, with the latter being somewhat more effective. These dopamine agonist agents have the advantage over other treatments in that they are taken orally.

A novel pharmacologic option when there is no response to other medical treatments is a GH receptor antagonist such as pegvisomant. This mutated GH molecule blocks the native hormone from binding and is reported to be very effective in lowering the IGF-1 level. Long-term studies are still needed, and this antagonist has not been tested in children.