Endocrine/Metabolic Complications of Advanced Cancer Flashcards
Cushing’s Syndrome in Advanced Cancer (pathophys, associated cancer types)
- Can occur as clinically overt paraneoplastic syndrome due to ectopic ACTH secretion
- Most cases of ectopic ACTH syndrome are due to lung CA (small cell or bronchial carcinoids), with the remainder due to thymomas or islet cell tumour of the pancreas
Hypercortisolism:
- Osteoporosis, hypertension, facial plethora, proximal muscle weakness, striae (>1cm wide, red/purple), easy bruising
How to diagnose Cushing’s syndrome
- Initial diagnosis of hypercortisolism requires two abnormal tests:
- 24 hour urinary cortisol (x3 ULN)
- Overnight dex suppression test (normal if next am cortisol <50)
- Late night salivary cortisol - Once hypercortisolism is confirmed, measure ACTH
- ACTH suppressed = ACTH-independent Cushing (image adrenals for possible adenoma/hyperplasia)
- ACTH Intermediate (5-20) = CRH or desmopressin test. If No ACTH response, ACTH-independent. If ACTH response, ACTH-dependent
- ACTH High or normal (>20) = ACTH-dependent Cushings (Pituitary adenoma/classic Cushing Disease vs Ectopic ACTH/CRH secretion) - To determine whether ectopic or classic Cushing Disease:
- Very high ACTH levels and no suppression following high dose dex for days suggests ectopic source.
- With a pituitary adenoma, would see partial feedback and suppression following high dose dex.
Presentation of Cushing Syndrome
- Muscle weakness or atrophy
- Edema
- Hypertension
- Mental changes
- Glucose intolerance
- Weight loss
In ectopic production from a slower growing tumour (e.g. bronchial carcinoid or thymoma), may have more classical features:
- Truncal obesity
- Moon facies
- Cutaneous striae
Treatment of Cushing’s Syndrome secondary to ectopic ACTH secretion
Optimally, tumour resection.
Alternatives: Medications to inhibit synthesis of cortisol
- Ketoconazole 200mg PO TID up to 400mg PO TID
If ineffective, add:
2. Metyrapone 250mg PO BID - TID, up to TDD 4.5g/day
If still ineffective, consider:
- Mitotane
- Octreotide (may suppress ectopic ACTH secretion)
- Mifepristone
Monitor with 24hr urinary cortisol
Will likely require hormone replacement therapy (e.g. hydrocort 20mg q8am and 10mg q6pm) for mineralocorticoid replacement - consult with endocrinology.
SIAD - definition
- Concentrated urine in conjuntion with hypo-osmolar and hyponatremic plasma - occurs due to abnormal renal free water excretion and the presence of inappropriate antiduresis
- Note that in 15% of cases, there is no ADH secretion, so SIADH is less appropriate than Syndrome of inappropriate antiduresis
Pathogenesis of SIAD
- Antidiuretic hormone acts on kidney to activate aquaporin channels in the collecting ducts, allowing the resorption of free water but not ions
- Effect is more water retention but loss of sodium in the urine
Etiology
- CNS causes (infections, bleeds, MS)
- Cancers (Small cell, mesothelioma, GI cancers, GU cancers, sarcoma, lymphoma)
- Pulmonary causes (PNA, lung abscess, asthma, CF)
- Drugs (Carbamazepine, valproic acid, SSRIs, MDMA, Morphine, amitriptyline)
- Sarcoidosis
Ectopic ADH secretion can occur in tumours, most commonly in small cell lung ca or carcinoid tumours, but also GI, GU cancers and lymphomas/sarcomas. May be a presenting symptom of cancer and precede overt presentation by up to 1 year!
Clinical features of Syndrome of inappropriate antidiuresis
- Clinically significant symptoms of hyponatremia occur at plasma sodium <120
- Confusion -> stupor -> coma -> seizures
- Nausea, vomiting
Clinical features vary with degree of hyponatremia and rate of decline (as brain cells can compensate with slower change)
Diagnosis of SIAD
SIADH
- Euvolemic hyponatremia due to ADH from posterior pituitary
- ADH secretion increases free-water reabsorption in the kidneys, resulting in a relative dilution of sodium in the body = hypoosmolar hyponatremia
Diagnosis of SIADH:
- Hypoosmolar hyponatremia (Plasma osmo <275, plasma sodium < 135)
- High urinary sodium and osmo (Urine osmo 100, urine Na+ >20mEq/L)
- Successful correction with fluid restriction (and no correction with IV NS)
- Failure of water load test (unable to excrete >90% of a 20ml/kg water load in 4 hours or dilute urine to osmo <100)
Treatment of SIAD
- Depends upon rate of onset and presence of neuro complications
- Acute hyponatremia with neuro symptoms has a mortality of 5-8%. Occurs of 48 hrs and is typically due to surgery or self-induced with polydipsia
Acute:
- hypertonic saline to correct serum sodium at a rate of 0.5 mmol/L/hr, total rise NTE 25 mmol/L and stop correction once Na >120
Chronic
- Fluid restriction limited to 500ml/day
- Target U/O of < 500ml/day
- Max correction of 8 meq/24hrs (to avoid osmotic demyelination)
May consider other measures in a palliative context as fluid restriction can impact quality of life.
- Demeclocycline (causes nephrogenic DI, lessening sensitivity of collecting tubule to ADH) and alleviates chronic SIADH
- Tolvaptan (ADH receptor antagonist)
- Urea (osmotic diuretic increasing free water excretion, can be given orally)
Non-islet cell tumour hypoglycemia: Pathogenesis/Definition
Hypoglycemia is frequent with pancreatic islet cell tumours (secrete insulin). However, can also happen with non-islet cell tumours, typically due to secretion of insulin like growth factors.
In some cases, tumours secrete an abnormal precursor to IGF-2. When levels are sufficiently high, IGF-2 will begin to bind to lower-affinity binding sites on insulin receptors and cause hypoglycemia.
These tumours are typically large (averaging 2.4 kg!), retroperitoneal or intrathoracic, often with liver invasion, and growing over several years.
Rarely, cervical CAs have been known to secrete insulin, as well as tumour production of antibodies to insulin and insulin receptors.
Clinical features of non-islet cell hypoglycemia
Hypoglycemia
- More commonly occurs with advanced disease
- Cerebral hypoglycemia (confusion, agitation, stupor, coma, seizures - usually following exercise or fasting - often occur in early AM or late afternoon)
- Secondary secretion of catecholamines (tremors, nausea, malaise)
Investigation of non-islet cell hypoglycemia
- if not obvious, consider testing for insulin levels and C-peptide levels during an episode (in patients with non-islet cell hypoglycemia, both will be suppressed)
- Review meds for other caues of hypoglycemia (e.g. sulphonylureas)
- Consider liver failure as a cause (impaired gluconeogenesis)
Treatment of non-islet cell hypoglycemia
- IV glucose infusion to correct hypoglycemia (anything in excess of 10% requires a central line)
- Debulking surgery and chemo may improve paraneoplastic hypoglycemia
- Frequent feeds
- Consider steroids, parenteral glucagon
Feature and common sites of insulinomas
Features:
- Neuroglycopenia (confusion, fits)
- Permanent neurologic deficits may occur
Sites:
- Beta islet cell tumours (pancreas)
- MEN associated
Palliative therapy for insulinomas
- Frequent feeds
- IV glucose
- Diazoxide (not useful in non-islet cell tumour hypoglycemia, but inhibits insulin release from beta islet cells) + HCTZ as sodium/water retention is a side effect
- Refractory: Octreotide (if radioactive octreotide scan positive)
Feature and common sites of gastrinomas (Zollinger-Ellison syndrome)
Features:
- Peptic ulceration
- Diarrhea, weight loss, malabsorption, gastric dumping
Sites:
- Pancreas
- Duodenum (most common)
Treatment of gastrinomas
- Gastrectomy
- PPIs
- H2 receptor antagonists
- Octreotide (may reduce symptoms)
- Debulking surgery of liver
Features and common sites of VIPoma (vasoactive intestinal polypeptide)
Features
- Watery diarrhea (without abdominal pain), tea coloured
- Hypoglycemia
- Achlorhydia
- Hypercalcemia
- Hyperglycemia
- Hypomagnesemia
Sites:
- Pancreas (most common)
- Neuroblastoma
- SCLC
- Pheo
Essentially causes secretory diarrhea, glycogenolysis
Treatment of VIPoma (vasoactive intestinal polypeptide)
- Octreotide (long acting lanreotide an option once stable)
- Glucocorticoids (if refractory to octreotide)
- Potassium, bicarb during attacks
Features, Common sites of glucagonoma
Features:
- Migratory necrolytic erythema (often presenting symptom, begins as erythematous papules or plagues on the face, perineum, and extremities, then over weeks enlarge, coalesce, and then centrally clear leaving a bronze coloured, indurated area with blistering/crusting at the borders. Often pruritic and painful and can affect mucous membranes)
- Mild DM
- Muscle wasting
- Anemia
- Diarrhea
- VTE
- Stomatitis
- Encephalitis
Sites:
- Pancreas (alpha cells)
