194 PHYSIOLOGY CASES AND PROBLEMS
Case 33
Syndrome of Inappropriate Antidiuretic Hormone
Krishna Sharma is a 68-year-old mechanical engineer who retired 1 year ago, when he was diagnosed with oat cell carcinoma of the lung. Always an active person, he has tried to stay busy at
home with consulting work, but the disease has sapped his energy. After dinner one evening,
his wife noticed that he seemed confused and lethargic. While he was sitting in his recliner
watching television, he had a grand mal seizure. His wife called the paramedics, who took him
to the emergency department of the local hospital. In the emergency department, the information shown in Table 4-8 was obtained.
TABLE 4-8
Mr. Sharma's Laboratory Values
Plasma Na•
Plasma osmolarity
Urine osmolarity
112 mEq/L (normal, 140 mEq/1.)
230 mOsm/L (normal, 290 mOsm/L)
950 mOsm/L
Mr. Sharma's blood pressure was normal, both supine (lying) and upright. He was treated immediately with an infusion of hypertonic (3%) NaCl. He was released from the hospital a few days
later, with strict instructions to limit his water intake.
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QUESTIONS
1. Oat cell carcinomas of the lung may secrete antidiuretic hormone (ADH). Unlike ADH secretion
from the posterior pituitary, ectopic hormone secretion from the cancer cells is not feedbackregulated. As a result, blood levels of ADH can become extraordinarily high. What is the major
effect of these high levels of ADH on the kidney? In light of this effect, explain Mr. Sharma's
urine osmolarity.
2. Why was Mr. Sharma's plasma NW- concentration so low? Why was his plasma osmolarity so low?
3. Mr. Sharma's disease is called syndrome of inappropriate antidiuretic hormone (SIADH). What
is "inappropriate" about SIADH?
4. Why did Mr. Sharma have a grand mal seizure?
5. Was Mr. Sharma's total body water increased, decreased, or normal? Why was his blood pressure normal?
6. Hypertonic NaCI is 3% NaCI, which corresponds to an NaC1 concentration of 517 mEq/L. How
did infusion of hypertonic NaCI help to correct Mr. Sharma's low plasma Na' concentration?
7. Why was it so important that Mr. Sharma restrict his water intake when he went home? What
would happen if he did not limit his water intake?
8. If Mr. Sharma found water restriction too difficult, his physician planned to treat him with
demeclocycline, an ADH antagonist. How would this drug have helped him?
196 PHYSIOLOGY CASES AND PROBLEMS
ANSWERS AND EXPLANATIONS
1. The major action of ADH is to increase the water permeability of the principal cells of
the late distal tubule and collecting ducts. As a result, the tubular fluid equilibrates osmotically with the interstitial fluid surrounding the nephron. Because the collecting ducts pass
through the corticopapillary osmotic gradient of the medulla and papilla, the tubular fluid
becomes hyperosmotic (see Figure 4-8). In the presence of high levels of ADH, the final urine
osmolarity is equilibrated with the osmolarity at the tip of the papilla, which can be as high
as 1200 mOsm/L.
A urine osmolarity of 950 mOsm/L indicates that Mr. Sharma was, most definitely, concentrating his urine. To concentrate his urine, he needed both a corticopapillary osmotic gradient
(for the urine to equilibrate with) and ADH (to increase water permeability and permit that
osmotic equilibration). You may wonder why his urine osmolarity was only 950 mOsm/L (rather
than 1200 mOsm/L, as shown in the ideal nephron in Figure 4-8). In all likelihood, at the time
of measurement, the osmolarity at the tip of his renal papilla happened to be 950 mOsm/L. In
the presence of high ADH, his collecting ducts equilibrated with that osmolarity.
2.
It is tempting to say that Mr. Sharma's plasma Na concentration was low (hyponatremia)
because he lost Na* from his body. However, loss of Na* is not the only possible reason for a low
plasma Na* concentration. Remember, the question is about Na* concentration, which is the
amount of Na* divided by the volume. Thus, plasma Mr' concentration can be decreased if the
amount of Na* in plasma is decreased or if the amount of water in plasma is increased. In fact,
decreased plasma Na* concentration is almost always the result of water excess, not Mr' loss.
In Mr. Sharma's case, SIADH, with its high circulating levels of ADH, caused increased water
reabsorption by the collecting ducts. This excess water was retained in the body and diluted the
plasma Na* concentration. Mr. Sharma's plasma osmolarity was low for the same reason that his
plasma Na* concentration was low: reabsorption of too much water by the collecting ducts led
to dilution of solutes in the plasma.
3. The "inappropriate" aspect of SIADH refers to an inappropriately high ADH level and high
water reabsorption when there is already too much water in the body. (Evidence of too much
water in the body is provided by the low plasma Na' concentration and osmolarity.) For example, Mr. Sharma's very low plasma osmolarity (230 mOsm/L) should have completely inhibited
ADH secretion by his posterior pituitary. No doubt, it did! However, Mr. Sharma's lung cancer
cells secreted their own ADH autonomously, without any feedback control or regulation. This
autonomous secretion by the cancer cells was not inhibited by his low plasma osmolarity and
was inappropriate for his plasma osmolarity.
4.
Mr. Sharma had a seizure because of swelling of his brain cells. As discussed earlier, high levels
of ADH stimulated water reabsorption by his kidneys. This excess water diluted his extracellular
osmolarity, as reflected in his decreased plasma osmolarity. As a result, extracellular osmolarity
became transiently lower than intracellular osmolarity. Extracellular osmolarity was lower only
transiently, however, because water shifted from extracellular fluid (ECF) to intracellular fluid
(ICF) to reestablish osmotic equilibrium. This shift of water caused swelling of all cells. Because
the brain is contained in a fixed structure (the skull), swelling of brain cells caused a seizure.
5. Mr. Sharma's total body water was increased. High levels of ADH caused increased water reabsorption and net addition of water to the body. This additional water distributed between ECF
and ICF in the usual proportions (i.e., one-third to the ECF and two-thirds to the ICF).
One of the puzzling features of SIADH (and one exhibited by Mr. Sharma) is that this addition of water to the body does not usually cause an increase in blood pressure. (One might
expect increased ECF volume to be associated with increased blood volume and increased
blood pressure.) In SIADH, blood pressure usually does not increase for two reasons. (1) Most
RENAL AND ACID-BASE PHYSIOLOGY
197
(two-thirds) of the excess water retained in the body goes to the ICF rather than to the ECF; thus,
ECF volume, blood volume, and blood pressure are not affected as much as you might initially
think. (2) The initial increase in ECF volume activates atrial volume receptors that stimulate
secretion of atrial natriuretic peptide (ANP). ANP causes increased Na excretion, which
decreases the Na content and volume of the ECF toward normal. In essence, there is an
"escape" from the effects of high ADH on ECF volume.
+
+
6.
+
Hypertonic NaC1 has an Na concentration of 517 mEq/L. Mr. Sharma's ECF (which includes
plasma) had an Na concentration of 112 mEq/L. Thus, the infused solution, with its much
higher Na - concentration, increased Mr. Sharma's plasma Na concentration and osmolarity.
l
+
+
7. The primary treatment for chronic SIADH is water restriction. Mr. Sharma's cancer cells are
likely to continue their unrelenting secretion of ADH, which will continue to "force" his urine
to be concentrated. If Mr. Sharma restricts his water intake, then hyperosmotic urine is "appropriate." However, if he drinks large quantities of water, his kidneys will not be able to make
appropriately dilute urine (because of his permanently high ADH state) and he will become
hyponatremic and hyposmolar again.
8.
Demeclocycline, an ADH antagonist, would be expected to block the action of ADH on the
collecting ducts and inhibit ADH-stimulated water reabsorption. Therefore, it is possible that
Mr. Sharma would not have to restrict his water intake while taking this drug.
O . Key topics
Antidiuretic hormone (ADH)
Atrial natriuretic peptide, or atrialpeptin (ANPI
Corticopapillary osmotic gradient
Demeclocycline
Hyperosmotic urine
Hyponatremia
Hyposmolarity
Principal cells
Syndrome of inappropriate antidiuretic hormone ISIADH)