Endocrinology, therapeutic drug monitoring, and toxicology

Endocrine, drug, and poison questions look scattered, but they share one skill: reading a result against a feedback loop or a threshold. Know that a low pituitary hormone with a high target hormone means the gland is overactive, that a trough is drawn just before the next dose, and that carbon monoxide poisons by grabbing hemoglobin, and you can answer this whole cluster from principles. These are reliable points because the physiology does not change year to year.

Thyroid function and feedback

The thyroid runs on a feedback loop: the hypothalamus releases TRH, the pituitary releases TSH (thyroid-stimulating hormone), and the thyroid releases T4 and T3. When thyroid hormone is high, it suppresses TSH; when it is low, TSH climbs. That inverse relationship is the key to interpretation.

• Primary hypothyroidism (the thyroid itself is failing): TSH is high, T4 is low. The pituitary shouts louder at a deaf gland.
• Primary hyperthyroidism (the thyroid is overactive): TSH is low, T4 is high. The pituitary goes quiet because there is plenty of hormone.

TSH is the best first-line screening test for thyroid dysfunction because it changes early and sensitively. Free hormone measurements (free T4) reflect the active, unbound fraction better than total T4, which is affected by binding-protein changes.

The adrenal cortex and cortisol

Cortisol follows a strong diurnal rhythm: highest in the early morning and lowest late at night. That is why collection time matters, and why a lost nighttime low is an early clue to cortisol excess.

• Cushing syndrome is cortisol excess (truncal obesity, moon face, hyperglycemia). Overnight dexamethasone suppression testing probes whether cortisol can be turned off.
• Addison disease is cortisol deficiency (fatigue, low sodium, high potassium, low blood pressure).

The pituitary partner here is ACTH, which drives cortisol release, so measuring ACTH alongside cortisol localizes the problem to the pituitary or the adrenal gland.

Reproductive hormones and tumor markers

The pituitary gonadotropins FSH and LH drive the ovaries and testes to make estrogen, progesterone, and testosterone, again under feedback control. Human chorionic gonadotropin (hCG) is the hormone of pregnancy and the basis of pregnancy testing; it also serves as a tumor marker for trophoblastic and germ-cell tumors.

Tumor markers are substances that rise with certain cancers. They are mainly used to monitor known disease and detect recurrence, not to screen the general population, because they lack the specificity for screening. Anchor each marker to its organ:

Tumor marker	Chiefly associated with
PSA (prostate-specific antigen)	Prostate
AFP (alpha-fetoprotein)	Liver (hepatocellular) and germ-cell tumors
CEA (carcinoembryonic antigen)	Colorectal cancer
CA-125	Ovarian cancer
CA 19-9	Pancreatic cancer
hCG	Trophoblastic and germ-cell tumors

Therapeutic drug monitoring

Some drugs have a narrow therapeutic index: the gap between an effective level and a toxic one is small, so the lab measures blood levels to keep the patient in the safe window. Classic monitored drugs include digoxin, lithium, the aminoglycoside antibiotics, phenytoin, theophylline, and valproate.

Timing is everything, and the board tests it directly:

• The trough is the lowest level, drawn just before the next dose. It confirms the drug has not fallen below the effective range.
• The peak is the highest level, drawn after absorption and distribution are complete. It checks for a level high enough to be toxic.
• Meaningful monitoring waits for steady state, reached after about five half-lives of regular dosing, when intake and elimination balance.

A trough drawn at the wrong time (say, soon after a dose) reads falsely high and can trigger a wrong dose change, so the sampling time is part of the result.

Toxicology: four classics

Carbon monoxide (CO) binds hemoglobin with an affinity roughly 200 times that of oxygen, forming carboxyhemoglobin and blocking oxygen transport. The skin can look cherry-red, and standard pulse oximetry is misleading; the lab measures carboxyhemoglobin by co-oximetry.

Lead poisons heme synthesis by inhibiting the enzymes that build heme, so it causes anemia with basophilic stippling of red cells. Children are especially vulnerable through ingestion of old paint and dust.

Alcohols raise the osmolal gap. Ethanol is the common one; methanol and ethylene glycol are dangerous because they add both an osmolal gap and a high-anion-gap metabolic acidosis from their acid metabolites.

Acetaminophen (paracetamol) in overdose is hepatotoxic; its specific antidote is N-acetylcysteine, which replenishes glutathione and limits liver injury.

Worked example: the osmolal gap

Calculated osmolality (SI) is about 2 × sodium + glucose + urea, all in mmol/L. With sodium 140, glucose 5, and urea 5: 2 × 140 + 5 + 5 = 290 mmol/kg. If the measured osmolality is 320, the osmolal gap is 320 − 290 = 30 mmol/kg, which is high. A gap that large signals an unmeasured osmotically active substance in the blood, such as ethanol or another alcohol.

Common traps

• Reading a high TSH as hyperthyroidism. A high TSH with low T4 is primary hypothyroidism.
• Ignoring the collection time for cortisol, which has a strong morning-high, night-low rhythm.
• Using a tumor marker to screen healthy people; markers are for monitoring known disease.
• Drawing a trough after the dose instead of just before it, which falsely raises the level.
• Interpreting a level before steady state (five half-lives) as if it were final.
• Forgetting that carbon monoxide makes pulse oximetry unreliable, so carboxyhemoglobin must be measured directly.

Recap

Thyroid and adrenal results read against feedback: primary hypothyroidism gives high TSH and low T4, primary hyperthyroidism low TSH and high T4, and cortisol peaks in the early morning. Tumor markers monitor known cancers rather than screen, each tied to an organ (PSA prostate, AFP liver, CEA colon, CA-125 ovary). For drug monitoring, draw the trough just before the next dose, wait five half-lives for steady state, and remember the four toxins: carbon monoxide forms carboxyhemoglobin, lead blocks heme synthesis, alcohols raise the osmolal gap, and acetaminophen is treated with N-acetylcysteine.