Pituitary Disease Viva

Long Case Viva Defence

Candidate's opening statement (model answer)

"Mr David Thompson is a 54-year-old man, a truck driver, who presents with progressive enlargement of his hands and feet over 2 years, recent-onset type 2 diabetes, and newly diagnosed hypertension. His wife reports heavy snoring with witnessed apnoeas and excessive daytime somnolence. He has also noticed bilateral hand paraesthesia and weakness consistent with carpal tunnel syndrome. [1]

On examination he has the classic acromegalic phenotype — frontal bossing, prognathism with interdental spaces, a large nose, oily sweaty skin, multiple skin tags over the neck and axillae, and large hands and feet. Blood pressure is 158 over 96. He has a positive Tinel sign at both wrists. [1]

His IGF-1 is 3 times the upper limit of normal for his age. His OGTT growth hormone nadir is 8 micrograms per litre — failure of suppression confirms acromegaly. His MRI shows a 16 mm pituitary macroadenoma with suprasellar extension abutting but not elevating the optic chiasm, and mild cavernous sinus invasion. His visual fields are full. His full anterior pituitary panel is otherwise normal apart from a borderline low testosterone consistent with mild gonadotropin deficiency. [1]

His main problems are:

1. Acromegaly from a somatotroph macroadenoma — biochemically active with mass effect
2. Obstructive sleep apnoea — from macroglossia and pharyngeal soft tissue thickening
3. Cardiomyopathy screen pending — acromegalic concentric LVH is a major cause of mortality
4. Type 2 diabetes and hypertension — metabolic consequences of growth hormone excess
5. Bilateral carpal tunnel syndrome — from soft tissue proliferation
6. Colonic polyp and cancer risk — requires colonoscopy at diagnosis
7. Mild hypogonadism — may improve with biochemical control [1]

My immediate priorities are: transsphenoidal surgery as first-line definitive treatment; pre-operative colonoscopy, echocardiogram, and sleep study to address the comorbidities that contribute to acromegaly mortality; and lifelong surveillance for biochemical control and tumour recurrence." [1]

Examiner probing questions and model answers

Q1: "Why did you choose IGF-1 rather than random growth hormone as your screening test?" [1]

"Growth hormone is secreted in pulses — it varies minute to minute, with peaks after meals, exercise, and stress, and troughs between. A single random GH level is uninterpretable. IGF-1, by contrast, is produced by the liver in response to GH stimulation and has a long half-life of 12 to 15 hours. It integrates the GH signal over days to weeks, giving a stable measure of average GH exposure. The Endocrine Society acromegaly guideline, published by Katznelson in JCEM in 2014, recommends age- and sex-matched IGF-1 as the initial screening test because a normal IGF-1 effectively excludes acromegaly. Only if IGF-1 is elevated or equivocal do I proceed to the confirmatory test — the 75-gram oral glucose tolerance test with GH measurement. In health, glucose suppresses GH to below 1.0 microgram per litre. Mr Thompson's failure to suppress to 8 micrograms per litre confirms autonomous somatotroph secretion." [1]

Q2: "His tumour abuts the chiasm. How does a pituitary tumour cause a bitemporal hemianopia?" [1]

"The optic chiasm sits directly above the pituitary gland in the sella turcica. The central decussating fibres — those carrying the temporal visual field from the nasal retina — pass through the inferior and central portion of the chiasm, directly in the path of a tumour expanding superiorly. When a macroadenoma grows upward through the diaphragma sellae, it compresses these inferior chiasmal fibres first, causing loss of the temporal field in each eye — a bitemporal hemianopia. The superior chiasmal fibres, representing the nasal fields, are more posterior and are affected later. This is why the visual field defect often starts in the superior temporal quadrants and progresses inferiorly. In Mr Thompson's case, the tumour abuts but does not elevate the chiasm, so his fields are preserved — but I will monitor them closely with serial Humphrey perimetry." [1]

Q3: "After surgery his IGF-1 is still elevated. What medical therapy do you choose and why?" [1]

"If Mr Thompson has persistent acromegaly after transsphenoidal surgery — which is likely given the cavernous sinus invasion, which the surgeon cannot safely resect — I start a first-generation somatostatin analogue. Octreotide LAR at 20 to 30 milligrams intramuscularly every 4 weeks, or lanreotide autogel at 90 to 120 milligrams subcutaneously every 4 weeks, are equivalent first choices. These bind somatostatin receptor subtype 2 on the somatotroph adenoma and suppress GH secretion, normalising IGF-1 in about 50 to 60% of patients and shrinking residual tumour in 40 to 60%. [1]

If his IGF-1 is not controlled on a first-generation SSA, I escalate. The PAOLA trial, published by Colao in JCEM in 2014, compared pasireotide LAR with continued octreotide or lanreotide in patients inadequately controlled on first-generation SSA. Pasireotide achieved superior biochemical control. However, pasireotide causes significant hyperglycaemia — it inhibits insulin and incretin secretion, causing new or worsened diabetes in 50 to 60% of patients. Mr Thompson already has type 2 diabetes, so I would monitor his glucose very closely if I switch to pasireotide. [1]

The alternative is pegvisomant — a genetically engineered growth hormone receptor antagonist. The Trainer trial, published in NEJM in 2000, showed that pegvisomant at 20 milligrams daily normalised IGF-1 in 89% of patients. Because it blocks the receptor rather than reducing GH secretion, serum GH rises — this is expected and does not indicate tumour growth. I use pegvisomant as monotherapy or in combination with an SSA for SSA-resistant disease, monitoring liver function for transaminitis." [1]

Q4: "Why is cardiovascular disease the leading cause of death in acromegaly, and what do you do about it?" [1]

"Acromegaly increases all-cause mortality with a standardised mortality ratio of approximately 1.7. The leading cause of death is cardiovascular disease, driven by several mechanisms: first, acromegalic cardiomyopathy — concentric left ventricular hypertrophy with diastolic then systolic dysfunction, which is directly caused by GH and IGF-1 excess acting on cardiac myocytes. Second, hypertension — present in 30 to 40% of acromegaly patients. Third, the metabolic consequences — insulin resistance, type 2 diabetes, and dyslipidaemia. Fourth, obstructive sleep apnoea, which independently increases cardiovascular mortality. [1]

My management is: achieve biochemical control — normalising IGF-1 and GH restores mortality to population norms. I screen for cardiomyopathy with an echocardiogram at diagnosis and periodically. I treat hypertension aggressively — ACE inhibitor or ARB first-line. I manage diabetes — metformin first-line, and glucose often improves as GH is controlled. I perform a sleep study and start CPAP if sleep apnoea is confirmed — this is mandatory pre-operatively to reduce anaesthetic risk. And I assess cardiovascular risk factors comprehensively and treat them to target. The key message is: acromegaly is a multisystem disease, and treating the GH excess alone is not sufficient — I must manage the cardiovascular comorbidities to normalise mortality." [1]

Q5: "He has a prolactin of 250 mU/L. Is this a prolactinoma?" [1]

"No. This is the stalk effect, not a prolactinoma. The prolactin is only mildly elevated — 250 mU/L is within the range of stalk effect. The stalk effect occurs when a non-functioning macroadenoma — or any sellar mass — compresses the pituitary stalk, removing tonic dopamine inhibition of prolactin secretion from normal lactotrophs. Dopamine is the physiological inhibitor of prolactin; when the stalk is compressed, prolactin rises moderately, typically up to 2000 to 3000 mU/L. A true macroprolactinoma of Mr Thompson's size — 16 mm — would have a prolactin well above 4000 mU/L, roughly 700 mU/L per millimetre of maximal tumour diameter. His prolactin of 250 is far too low for a prolactinoma. This distinction is critical because the management is different: a prolactinoma is treated with cabergoline, but a non-functioning adenoma — which this is — is treated with surgery. If I mistakenly treated him with cabergoline, the tumour would not shrink and the diagnosis would be delayed." [1]

Q6: "What is the cortisol-first rule and why does it matter?" [1]

"The cortisol-first rule is: when replacing pituitary hormones in a patient with hypopituitarism, always start hydrocortisone before levothyroxine. Giving levothyroxine to a patient with untreated ACTH deficiency is dangerous — the increased thyroid hormone upregulates hepatic 11-beta-hydroxysteroid dehydrogenase type 2, which accelerates cortisol clearance. In a patient who already has inadequate cortisol production, this precipitates acute adrenal crisis — hypotension, hyponatraemia, hypoglycaemia, and potentially death. This is the single most dangerous pituitary prescribing error. [1]

For Mr Thompson, if he develops hypopituitarism after surgery — which is possible, particularly ACTH deficiency from manipulation of the normal gland — I replace hydrocortisone first, at 15 to 25 milligrams daily in divided doses. Only after cortisol is established do I start levothyroxine. And when monitoring his thyroid replacement, I use free T4, not TSH — TSH is unreliable in central hypothyroidism and will be low or inappropriately normal regardless of the adequacy of replacement." [1]

Q7: "Tell me about the Tomlinson study and why it changed your practice in hypopituitarism." [1]

"The West Midlands Prospective Hypopituitary Study, published by Tomlinson in JCEM in 2001, followed 1014 patients with hypopituitarism and demonstrated a standardised mortality ratio of 1.87 — nearly double the expected mortality. The excess deaths were from cardiovascular, respiratory, and cerebrovascular causes. This study, confirmed by the Pappachan meta-analysis in 2015 showing an overall SMR of 1.99, established that hypopituitarism is a condition with significant excess mortality. [1]

The modifiable contributors include: over-replacement of glucocorticoids — the Murad meta-analysis in 2016 showed that higher hydrocortisone replacement doses are associated with increased mortality, supporting a lower-dose strategy, aiming for 15 to 20 milligrams daily rather than the traditional 25 to 30. Untreated growth hormone deficiency — which contributes to adverse body composition and cardiovascular risk. And undertreated gonadal failure — hypogonadism contributes to osteoporosis and cardiovascular risk. [1]

For Mr Thompson, if he develops post-surgical hypopituitarism, I would: use the lowest effective hydrocortisone dose, replace testosterone if deficient, monitor bone density, and assess for GH deficiency once stable — somatropin replacement improves quality of life, body composition, and bone density in confirmed GH-deficient adults, provided there is no active malignancy." [1]

Short Case Discussion

Scenario: "Examine this patient's face and hands, then present your findings"

Candidate presentation (model): [1]

"On general inspection, the patient is a middle-aged man with coarse facial features. The face is elongated with frontal bossing, prominent supraorbital ridges, a large fleshy nose, macrognathia with a pronounced underbite, and widened interdental spaces. The skin is oily with multiple skin tags over the neck and axillae. There is frontal balding. [1]

Examining the hands: the hands are enlarged and spade-like, with thickened fingers. The skin is oily and sweaty. There is a surgical scar over the left wrist consistent with a previous carpal tunnel release, and a similar scar on the right wrist. Tinel sign is positive at the right wrist. There is no synovitis or joint deformity, but there is reduced range of movement at the metacarpophalangeal joints consistent with acromegalic arthropathy. The feet show similarly enlarged shoes size. [1]

In summary, these findings are consistent with acromegaly — growth hormone excess causing acral enlargement, prognathism, hyperhidrosis, skin tags, and carpal tunnel syndrome. I would like to take a full history including asking about changes in ring, shoe, and glove size, snoring and daytime somnolence, headaches, visual symptoms, and sweating. I would screen for type 2 diabetes, hypertension, and cardiac symptoms. I would confirm the diagnosis with serum IGF-1 and an oral glucose tolerance test, and image the pituitary with MRI." [1]

Examiner: "Why does acromegaly cause carpal tunnel syndrome?" [1]

"Carpal tunnel syndrome in acromegaly is caused by soft tissue proliferation and oedema in the flexor compartment of the wrist. Growth hormone and IGF-1 excess stimulate proliferation of connective tissue, tendons, and synovium. The median nerve becomes compressed as the carpal tunnel narrows from this tissue overgrowth. It is typically bilateral and is one of the most common presentations of acromegaly, often preceding the diagnosis by years. It may improve with biochemical control of the acromegaly, but established nerve damage may not fully recover." [1]

Examiner: "What is the significance of the skin tags?" [1]

"Multiple skin tags, also called acrochordons, are a common feature of acromegaly and are thought to reflect the trophic effects of growth hormone on skin. They are also associated with insulin resistance and may indicate an increased risk of colonic polyps — several studies have shown a correlation between the number of skin tags and the presence of colonic neoplasia in acromegaly patients. This is why I would perform a colonoscopy at diagnosis in any patient with acromegaly." [1]

Examiner: "How would you perform a visual field examination on this patient?" [1]

"I would examine each eye separately. First, I check visual acuity with a Snellen chart, with and without correction and with a pinhole if reduced. Then I test visual fields by confrontation — sitting opposite the patient at arm's length, asking them to cover one eye and fixate on my nose, while I present a target — typically a red pin or my wiggling finger — in each of the four quadrants. I compare their field to mine. For a patient with a pituitary tumour, I specifically look for a bitemporal defect — loss of the temporal field in each eye. If I find one, the defect should respect the vertical midline, distinguishing a chiasmal lesion from a retinal or optic nerve lesion. I would then check eye movements for cranial nerve palsies from cavernous sinus involvement, and examine the fundus for optic atrophy from chronic chiasm compression. I would confirm any field defect with formal Humphrey perimetry." [1]

Examiner: "What hormone must you check before offering surgery for a pituitary macroadenoma?" [1]

"Prolactin. This is the single most important pre-operative hormone test. If the prolactin is markedly elevated — above 4000 mU/L and proportional to tumour size — the diagnosis is a macroprolactinoma, and the treatment is a dopamine agonist such as cabergoline, NOT surgery. Cabergoline shrinks macroprolactinomas within weeks, often resolving visual field defects. Surgery is reserved for dopamine agonist resistance or intolerance. If I operate on a macroprolactinoma without checking prolactin, I have subjected the patient to unnecessary surgery when medical therapy would have been curative. If the prolactin is low or only mildly elevated — as in the stalk effect of a non-functioning adenoma — surgery is appropriate." [1]