Course Authors
Eli Ipp, M.D.
In the past three years, Dr. Ipp has received grant/research support from Pfizer, Inc., R.W. Johnson, and Novo-Nordisk. He has served as a consultant for Novo-Nordisk, SmithKline Beecham Pharmaceutical and Hoechst Marion Roussel. Dr Ipp has also served on the Speakers' Bureau for Novo-Nordisk.
Estimated course time: 1 hour(s).
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Upon completion of this Cyberounds®, you should be able to:
A 67 year-old woman presents to her physician with a history of constipation and weakness. The physician further elicits a history of bipolar depression, for which the patient is receiving lithium therapy. Otherwise, the patient has no significant past medical or surgical history. Her family history is likewise not contributory.
What other information would be useful at this stage?
Clearly, there is a large differential diagnosis for constipation in the elderly. Similarly, weakness is also a non-specific symptom that should be considered on its own merits. However, this evaluation will focus on the endocrine aspects of the patient. On further questioning, it turns out that the patient also has polyuria. She is a lean Caucasian female without any obvious abnormalities on physical examination.
Which of the following endocrine diagnoses are appropriate considerations? Place them in order of likelihood ( "1" is most likely) as the primary diagnosis. You have five chances to get the correct sequence. At the end of the conference you will find my sequence of diagnostic priorities.
We will now consider each of these possibilities. Go straight to the discussion of the diagnoses you have chosen. You may ignore those endocrine diagnoses that you think are unlikely. If you have missed something, it will become clear later and you can return to the choices you decided to skip over at this time. Clicking on highlighted words will bring up screens with additional information on certain subjects.
Diabetes Mellitus
This disease can obviously cause nocturia, due to an osmotic diuresis, result in constipation, due to fluid losses, and explain weakness as a result of volume depletion or electrolyte abnormality. At the age of 67, Type 2 diabetes is common (10% of the U.S. population at that age) and explains all of the patient's symptoms and could, therefore, be considered as the primary diagnosis. However, diabetes mellitus is not the first choice in this patient. She does not have any risk factors for diabetes. These include a history of gestational diabetes, a positive family history for diabetes in siblings or parents or ethnic origin that might predispose her to diabetes (e.g., Mexican-American, Japanese-American or Native-American). Although obesity is also a risk factor, keep in mind that although she is not obese, even a normal BMI (body mass index) may be associated with the presence of an abnormality of fat distribution. Intra-abdominal fat accumulation (that may be diagnosed by imaging only) can theoretically increase the risk of diabetes in this patient (see previous conference). However, we have no further information to suspect this is the case. A fasting plasma glucose equal to, or greater than, 126 mg/dl on two occasions (according to the new American Diabetes Association criteria) will diagnose diabetes.(1)
Adrenal Insufficiency
This disease is also an unlikely cause of the patient's symptoms. Although women tend to develop idiopathic Addison's disease more commonly than men do (female-to male ratio may be as high as 2.6), it is a distinctly unusual diagnosis at the extremes of life. Sixty to seventy percent of cases are diagnosed in the third to fifth decade - so this would be a rather late presentation for our patient. Furthermore, although weakness is certainly one of the important symptoms of this disorder and gastrointestinal manifestations are a frequent occurrence in Addison's disease, anorexia, nausea and, less often, diarrhea are more common gastrointestinal manifestations. Hyperpigmentation and hypotension are also absent in this case. Evaluation of serum sodium and potassium for hyponatremia or hyperkalemia and a cortrosyn (ACTH) stimulation test will diagnose this disorder, if seriously considered. They are not necessary in this patient.
Hypothyroidism
This is one of three endocrine side effects of lithium that we will address. Lithium is concentrated in the thyroid and inhibits both formation and secretion of thyroid hormone. As many as 36% of patients receiving lithium have biochemical evidence of hypothyroidism.(4) Clinically overt hypothyroidism is less common and tends to occur in patients treated for long periods. Patients with thyroid antibodies may be more susceptible to the hypothyroid effects of lithium. Hypothyroidism is not likely to be the primary diagnosis in this patient, however. Although constipation and weakness may be explained by diminished thyroid function, the diuresis cannot. On the contrary, hypothyroidism is associated with a tendency to retain free water. Of course, the absence of obvious physical signs suggestive of hypothyroidism does not help to rule this out in an elderly, possibly depressed woman, because overlap may occur in the clinical manifestations. A TSH measurement would help to rule out the diagnosis of primary hypothyroidism.
Hypercalcemia
Lithium has three major effects on calcium metabolism: hypercalcemia, hypocalciuria and elevated parathormone (PTH). Hypercalcemia is a well recognized phenomenon that we will discuss in some detail because it is not often considered in patients with vague complaints but should be taken into account in any patient being treated with this medication. Furthermore, the pathophysiology of lithium-induced elevation of serum calcium raises important issues that can be better understood if one considers some of the new concepts we have learned from the recently described calcium sensor and its disorders. Clinical studies suggest that as many as 25% of patients receiving lithium have elevated serum calcium concentrations.(4),(5) This may not be reflected in total serum calcium concentrations; ionized calcium is more likely to be abnormal.(5),(6) About 10% of patients have frank hypercalcemia. The mechanism for hypercalcemia involves a direct effect of lithium on the parathyroid glands. This has been confirmed in vitro and in vivo; both lithium-treated subjects and in vitro parathyroid tissue have an altered set-point for calcium-induced PTH secretion, with a shift to the right in the dose-response curve.(7),(8) Lithium appears to induce a state of resistance to the effect of increasing serum calcium so that the calcium concentrations required to inhibit PTH secretion are significantly higher in lithium-treated patients.
Parathormone (PTH) levels may also be elevated; cross-sectional studies indicate that this is most likely to occur in patients who are on lithium in excess of ten years or are over 60 years of age, where 34% have increased serum PTH concentrations.(4) Prospective studies have also shown that serum calcium and parathormone levels increase with lithium treatment.(6) Thirdly, lithium has also been shown to reduce calcium concentrations in the urine despite hypercalcemia.(9) Decreased renal excretion of calcium, thus, also contributes to the development of hypercalcemia.
Hypercalcemia in other clinical situations is almost always associated with hypercalciuria, so the association of elevated serum calcium during lithium treatment with low urine calcium excretion is quite unusual. There is, however, a rare clinical disorder in which this clinical picture is also observed -- benign familial hypocalciuric hypercalcemia (BFHH). Indeed, on closer inspection, lithium-induced hypercalcemia (LIH) and BFHH have a number of features in common. BFHH is a rare, autosomal dominant genetic disorder with 90% penetrance, in which patients present with asymptomatic hypercalcemia and hypocalciuria. Affected persons usually have mild to moderate hypercalcemia associated with abnormal recognition of calcium ions by the parathyroid glands and kidneys.(10) Before recognition of this disorder, it was confused with hyperparathyroidism. However, removal of a parathyroid gland does not cure this form of hypercalcemia, which is due to mutations in the newly described calcium-sensing receptor.(10)
In evaluating this patient, the issue of nocturia now needs to be addressed. Polyuria is a recognized symptom of hypercalcemia and, thus, LIH could ostensibly be the primary diagnosis. But, first, we should examine the physiology of calcium-induced polyuria. After filtration, calcium is first reabsorbed in the proximal tubule and then the thick ascending limb (TAL) of Henle. The renal calcium receptor, now also demonstrated in the kidney, senses serum Ca++ concentrations in peritubular vessels; if serum Ca++ levels increase, calcium absorption in the TAL is reduced and calciuria is enhanced. In this way, serum calcium can directly regulate urine calcium excretion by a mechanism that is independent of PTH. Hypercalcemia induces calciuria, tending to reinstate homeostasis.
Another important step in this process occurs downstream in the nephron, where increased luminal Ca++ results from diminished TAL Ca++ absorption. This increase in Ca++ concentrations is detected in the inner medullary collecting duct (IMCD) where vasopressin (AVP)-dependent water reabsorption occurs. In the presence of vasopressin, water channels (aquaporin 2) are inserted into the IMCD apical membranes and water is reabsorbed, following the osmotic gradient. It is well known that an increase of luminal calcium concentrations reduces water permeability in the IMCD, producing a vasopressin-resistant water diuresis. The mechanism for this effect is now explained by the finding of the calcium sensor in the apical epithelium of the IMCD.(11) The calcium receptor in this site is associated with aquaporin water channels -- thus providing a mechanism for luminal calcium to induce a diuresis. When luminal Ca++ increases, reduced water permeability prevents high concentrations of calcium from precipitating in the distal nephron.
An increase in serum calcium concentrations, therefore, ordinarily induces an increase urine output by this two-step mechanism (decreased Ca++ absorption in the TAL and decreased permeability to water in the IMCD - both due to normal sensing of Ca++ by the calcium receptor in these two different sites in the kidney). However, one of the features of lithium hypercalcemia, like BFHH, is hypocalciuria. How might this be explained? It appears that, with lithium treatment, the calcium sensing mechanism in the kidney, like in the parathyroid, may be resistant to ambient Ca++ concentrations. Although there is no evidence that lithium has a direct effect on the calcium receptor per se, the drug appears to have the same effect as a functional, heterozygous inactivating mutation in the calcium receptor seen in BFHH - i.e., despite elevated serum Ca++ levels, absorption at the TAL is not reduced. There is no increased delivery of Ca++ to the IMCD, thus, the IMCD calcium receptor is not activated and a diuresis does not develop. Lithium-induced hypercalcemia, like BFHH, is not associated with hypercalciuria and, thus, polyuria will not be a consequence.
Hypercalcemia is, therefore, not the best diagnosis in this case because it fails to explain all the patient's symptoms. Constipation and weakness can be explained but polyuria is not a manifestation. Although we do not yet know the precise mechanisms involved in lithium hypocalciuria, the rapid progress being made in understanding the calcium receptor and its signal transduction pathways; and parallels with BFHH are instructive in explaining the absence of polyuria in LIH.
Diabetes Insipidus
The polyuria observed by this patient could be due to diabetes insipidus. A renal concentrating defect has been well-described in patients receiving lithium therapy. Serum lithium concentrations in the therapeutic range for affective disorders can produce diabetes insipidus in as many as 12-30% of patients receiving the drug.(12) This effect of lithium is an example of drug-induced nephrogenic diabetes insipidus, which typically is not responsive to vasopressin therapy, and is not a consequence of calciuria - as discussed above. Fortunately, it is a transient phenomenon and, in most patients, it will remit once lithium therapy is discontinued, when urine concentrating ability usually returns towards normal. In this patient, constipation and weakness may be explained by the development of volume depletion from the patient's excessive diuresis.
The diagnosis of diabetes insipidus can be made in a series of steps after confirming the presence of polyuria with a 24-hour urine collection. A serum electrolyte measurement in an otherwise healthy, elderly woman will probably show a serum sodium in the upper range of normal or mild hypernatremia. If fasting serum osmolality is <295 mosmol/L or serum sodium <143 mEq/L, urine osmolality and specific gravity should be measured during a water deprivation test. Failure to concentrate urine, despite an active diuresis, will provide a diagnosis of diabetes insipidus. Failure to respond to the vasopressin analogue, dDAVP (with an increase in urinary concentration and a decrease in urine output) once serum osmolality or sodium have exceeded the above cut-off points, will confirm a nephrogenic rather than a central mechanism. Treatment consists of stopping lithium, using single daily or lowest effective dosing or concomitant thiazide therapy. The decision to stop lithium requires a careful evaluation of the relative risks and morbidity of continuing polyuria versus the availability and efficacy of alternative drugs for her affective disorder.
In summary, this patient raised some interesting issues. An elderly woman presents with relatively innocuous, non-specific symptoms of constipation and mild weakness. Her physician did not ignore her symptoms or pass them off as old age or depression; rather the possibility of lithium effects was considered and a diagnosis of diabetes insipidus confirmed. Diabetes mellitus, hypercalcemia and hypothyroidism were excluded by a single blood draw in the fasting state (for serum glucose, calcium and TSH). Adrenal insufficiency was not considered further on clinical grounds alone. A clinical diagnosis was made possible by analyzing the patient's symptoms carefully and applying some basic physiological concepts to the differential diagnosis. This case illustrates how understanding the mechanisms of a rare genetic disorder can help to comprehend an apparently related side effect of a commonly used drug.
My order of diagnostic priorities that would most likely explain this clinical picture:
- Diabetes insipidus
- diabetes mellitus
- hypercalcemia
- hypothyroidism
- adrenal insufficiency