There was an interesting article the other day in the New York Times Magazine section of the newspaper (Sunday, October 14, 2007). the article was entitled “Addicted to Water” and written by Lisa Sanders. The article was typical of those medical “whodunnits” that are found fairly frequently in the New York Times and in other publications, most notably, the New Yorker magazine- more or less the literary equivalent of an episode of “House” on TV (refering to Dr. House, the mean and nasty brilliant medical diagnostician).

The Medical History

The case concerns a 38 year old woman with a history of excessive thirst and urination for many years. The woman had been evaluated many times for her symptoms, primarily with tests for diabetes mellitus, which invariably turned out negative. To make a long story short, the woman was in the hospital having just given birth (by C-section) to a healthy baby. The OB-GYN intern had noted the woman had consumed a large amount of water overnight, over 3 gallons, and was concerned. The intern had the good sense to look into the situation and eventually the diagnosis, diabetes insipidus was made and appropriate treatment initiated.

Thinking About Excessive Thirst and Urination

When a patient complains about whatever to their doctor, it would seem logical that the doctor would carefully consider the complaint. Patients complain about lots of things and part of the doctor’s job is to figure out which complaints require investigation, which to ignore, and which to monitor for a while (i.e.,”if it doesn’t get better, let me know”). Often what happens is that the complaint is more or less ignored or evaluated in a cursory manner, particularly if the patient does not present the complaint as being vey important. In my opinion, all complaints about excessive thirst and/or urination should be taken seriously and evaluated. First, a good medical history, a physical examination, and then laboratory studies if indicated. As the magazine article mentioned, the first thing one tends to think about is whether the patient’s symptoms are a sign of diabetes mellitus. The patient in the story had, in fact, been tested many times over the years for diabetes mellitus and tests had always been “negative.”

Where Does Urine Come From?

The body works hard to keep itself clean, inside and out. The blood is kept “clean” in a number of ways. The lymphatic system helps filter out nasty things such as viruses and bacteria. The kidneys clean the blood by filtering out excessive water, minerals (e.g., sodium and potassium), and waste products, mostly generated by processes that use foods for energy production. Anyway, the kidneys are remarkably efficient in keeping the composition of the blood very constant; it filters the blood on a continual basis, removing waste products and retaining “the good stuff.” With respect to water (most of the blood is water, right?), the kidneys usually know just how much water to excrete and how much to retain (i.e., reabsorb after filtering). Key to this process is the hormone vasopressin (also called anti-diuretic hormone or ADH), produced in the hypothalamus and stored in the posterior part of the pituitary gland. Vasopressin acts on the kidneys to tell them how much water from the filtered blood to excrete and how much to reabsorb. If the kidneys do not get a vasopressin “message,” they do not allow reabsorption of water, leading to lots of urine production. Sometimes this is appropriate, as after a fraternity party, but at other times it is not. If a person takes a hike in the desert and forgets to take enough water along, enough vasopressin is secreted to tell the kidneys to conserve as much water as possible (if the kidneys are woring properly, some water is always being excreted to carry wastes away). It’s a great system.

The Differential Diagnosis of Excessive Thirst and/or Urination

So, if things do not seem to be working properly, what might be the cause? First, any substance in the blood that requires water to be eliminated, can lead to excessive urination (leading to thirst, right?) if present in excess. For example, excessive sugar in the blood “spills” into the urine and requires water to be excreted. Thus, patients with diabetes mellitus typically complain of excessive thirst and urination (polydipsia and polyuria. The blood sugar level has to get above about 180-200 mg/dl for sugar to “spill” into the urine, leading to excesive urination production- below that level, the sugar is reabsorbed after being filtered by the kidneys. So, it’s easy to tell if a person’s excessive thirst and/or urination is caused by diabetes mellitus- the urine will show sugar and the blood sugar level will be elevated. Why doctors kept testing the patient in the article for diabetes over and over, I can’t say, but they should have considered other possibilities when the diabetes mellitus tests were negative.

Other possibilities include psychgenic water drinking, diabetes insipidus, and kidney disease. Some people just drink and drink. Sometimes it’s just a habit and sometimes it reflects a psychological disorder. It’s generally easy to diagnose from the medical history, and if necessary, laboratory testing. Simply withholding water (under strict medical supervision) will show that before becoming dehydrated a patient with psychogenic water drinking will secrete vasopressin and concentrate his urine.

Kidney disease generally does not cause a striking increase in urine output, but the ability to concentrate urine can be conmpromised. Simple laboratory tests can determine wheter the kidneys are filtering properly.

Diabetes insipidus can be caused by actual insufficient vasopressin secretion or secretion of an abnormal form of vasopressin or kidneys that are not responsive to vasopressin (called nephrogenic diabetes insipidus). Some medications and electrolyte abnormalities can prevent the kidneys from responding to vasopressin, mimicking diabetes insipidus (e.g., high blood levels of calcium, low blood levels of potassium). “Real” diabetes insipidus is generally called central diabetes insipidus and can be idiopathic or caused by a brain disorder, generally involving the hypothalamus or the pituitary gland. Trauma is certainly a well known cause. The possibility of a serious brain disorder is a very good reason for evaluating all complaints of excessive thirst and/or urination.

Making a Diagnosis and Initiating therapy

It is generally not very difficult to make a diagnosis of diabetes insipidus but the key is to determine the mechanism if possibe- obviously, the approach is quite different depending on whether the cause is unknown (“idiopathic”) or a brain tumor. Treatment is generally easy using synthetic vasopressin, which is available in tablet form (for mild cases and for enuresis) and as a nasal spray.

What Should We Take Away From the New York Times Magazine Article?

I’m glad the patient in the article finally got diagnosed and treated but it shouldn’t have taken years and years. It was inappropriate for her to have been tested over and over fro diabetes mellitus- once should have been enough. Patients need to be sure their doctors take their complaints seriously and investigate them properly. Of course, this is where the art of medicine comes in (as opposed to the science). Not every complaint requires a ten gallon of blood and ten million dollar workup. It’s not always easy.

In an upcomoing entry, I will discuss the exact opposite sitiuation- too much vasopressin, commonly called the syndrome of inappropriate ADH or SIADH for short.

First, I apologize for not having written an entry for quite some time. I just haven’t been properly inspired by anything in particular. I was tempted to write about the SCHIP fight- President Bush vs. most of the rest of the country. I assume that anyone reading this website is quite familiar with SCHIP (you know, the program to fund medicaid for children). Anyway, there was really nothing I could add to the debates other than what I have discussed in earlier entries. Well, maybe I could add a bit more? The fight over SCHIP really has nothing to do with fiscal responsibility, which is one of the main arguments against the current bill which President Bush vetoed. The other argument is that the current bill is sort of creeping socialism- down the slippery slope to a single government-sponsored health insurance plan. Both arguments are frankly ridiculous. The costs for the current bill are like pocket change for the government. Also, the government already pays for about 60% of all health care costs. We are already way down the “slippery slope.” It is also important to remember that although the disucssions are centered aroiund the dear little children, more than 50% of total Medicaid costs are for nursing home care of the elderly who cannot get the care under Medicare as it is currently structured (a topic for a future entry?).

In my opinion, the best argument against SCHIP is that as it is admnistered in most of the U.S., participants are really “second-class citizens” and often can’t even get access to adequate health care. I love the idea of making sure all children can get high quality health care without regard to ability to pay, but SCHIP is not the way (I am encouraged a bit by some of the individual State proposals to use the SCHIP money to buy private insurance for children- that at least, moves us away from the wide-spread problem of poor access to medical care for children with Mediciaid).

Generics vs. Brand Name Drugs

Now, to what I had intended to address in this entry- drugs. I heard part of a piece on NPR the other day about problems with the generic form of the brand name drug Wellbutrin (GlaxoSmithKline). The chemical name for the drug is ibupropion hydrochloride. The drug is widely used for the treatment of depression. It has had its share of controversy, most recently because of concerns that the drug is associated with sucicidal ideation in children and adolescents. Anyway, the current issue is about whether the generic form of the drug is less effective than the brand name, which surely costs much more than the generic “equivalent.”

Pharmacokinetics 101

How can 2 tablets with the same amount of active ingredient (in this case, ibupropion hydrochloride) have different bioactivity (i.e., one drug preparation is more effective than the other)? The answer is in the details. It is well known that the inert ingredients in medications (usually called “filler”) can affect a drug’s absorption rate. Thus, the term “generic equivalent” may be a nisnomer in many cases. The only way true equivalence can be established is to perform rigorous studies comparing the brand name drug and the generic preparation. With respect to antidepressant drugs, the studies would need to address the question of whether or not the two preparations were equivalent in effectiveness and with no significant differences in side effects.

The Data

Apparently there had been quite a number of anecdotal reports of less effective control of depression with the generic form of Wellbutrin. I think many of these reports were ignored given the fact that it was people with psychological problems complaining- just the psychologically impaired patient thinking that the generic was not as good as the brand name. Even when it comes to buying dishwashing detergent, brand name loyalty is strong.

As it turns out, maybe the crazy people aren’t so crazy? Apparently, recent studies have shown that the active ingredient in the generic form of Wellbutrin is released from the tablet much more quickly after being swallowed than from the brand name tablet and thus is excreted/degraded much more quickly than with the brand name tablet. Who’d have thunk it? Actually, lots of people- the manufacturers of the generic drug, the FDA, psychologisyts and psychiatrists, and many others should have thought about it.

What does this have to do with endocrinology?

This website is obstensibly about endocrinologic matters, so what’s the relevance of antidepressant drug matters? Good question. We endocrinologist use drugs and the Wellbutrin story is very relevant to many of the medications we prescribe. For example, there has been a longstanding fight between the manufacturer of the brand name thyroid medication Synthroid (Abbott Pharmaceuticals) and the FDA about the bio-equivalence of various generic forms of the drug (the chemical name is levo-thyroxine). The generics are a bit less expensive than the brand name but a variety of studies have shown big differences in the lot-to-lot potency of some generic forms of the drug vs. the brand name. So, it is not too surprising that many endocrinologists strongly favor Synthroid over any of the generic forms of the drug. When I treat patients with generic forms of L-Thyroxine, I tend to order thyroid function tests more often than if the patient is being treated with Synthroid. I bet it ends up costing the patient (or the insurer) more to use the generic than brand name form of the medication?

A second example is a medication for treatment of diabetes insipidus, a condition that is associated with inability to control urine output. The medication is called vasopressin. It is available in tablet form for mild cases (or for treating enuresis) but patients often require a nasal spray which they typically use 1-3 times daily. There is a generic form of the drug which is quite a bit less expensive than the brand name drug (Desmopressin). Unfortunately, the generic requires refrigeration and is associated with much more nasal irritation than the brand name which can be left at room temperature and seems to cause very little nasal irritation. Same active ingredient but …………

I could list quite a few more examples, but you probably get my point. I am not necesssarily trying to defend manufacturers of brand name products which are often far more pricey than they should be. I only want to point out that before the term “generic equivalent” is given to a medication, rigorous studies need to be performed which include not only studies of bioactivity, but also of side effects and inconveniences (e.g., requiring refrigeration or not).