The Medical Detectives Volume I

by Berton Roueche

  "Mack came into the N.I.H. clinical center on October 18. He was forty-six years old, and a big, powerful man. He said he had lost some weight in recent months, but he still weighed a good two hundred pounds. We gave him the usual workup, including neurological and ear-nose-and-throat evaluations, and the results were, as we say, uneventful. He was a little hard of hearing from working around airplanes, but that was all. He was, in general, in excellent health. I sat down with him and we had a long talk. His trouble had come on gradually. Back in June, he said, he began to notice that onions had a peculiar taste. In July, he began to notice that meats of all kind also tasted peculiar—tasted as if they had been cooked in rancid grease. Then other foods began to taste bad. Vegetables had an 'iron and tinny' taste. Cigarettes smelled like Vicks Vapo-Rub. For the past three or four months, he had been living on lettuce, cottage cheese, milk, and ice cream. It was weird—fantastic. I wondered if he might be crazy. I'd never heard of such a thing except as a manifestation of some other and demonstrable disease. I took him down to the hospital kitchen. I got out a cold roast of beef and cut off a beautiful slice and asked him just to taste it. I've never seen such a look of revulsion. He said he wouldn't, he couldn't—he would vomit. Just the smell of it made him feel sick. I took him back to his room. I had to believe him—but I certainly had something to think about. And I thought about it. I knew from a study I'd been involved in a couple of years before that a substance called D-penicillamine can diminish taste acuity, and even distort taste. This has happened a number of times to patients being treated with that drug for various diseases —rheumatoid arthritis, idiopathic pulmonary fibrosis, scleroderma. When D-penicillamine was discontinued, normal taste returned. Our study also showed that the administration of D- penicillamine was usually followed by a drop in the concentration of copper in the blood. We treated those patients with supplemental copper, in the form of copper sulphate, and normal taste returned. That certainly suggested that copper might play a role in the physiology of taste. We then began to wonder about the possibility of a similar role for other metals that are minutely present in the body—zinc, for example. We tried the same experiment again, only this time using zinc sulphate instead of copper. We got the same result. Normal taste returned. Well, with that in mind, I arranged to measure the levels of copper and zinc in Mack's blood serum. Which was done. And the results were normal. There was no decrease at all.

  "That was rather a shock. I had been all set to start him on one of those metals—probably zinc. It has a very low toxicity. So now what? But I still wanted to do something. And I thought, What's the harm—why not try it anyway? So I wrote out an order for oral zinc sulphate—four hundred milligrams a day. And what happened? It was really quite dramatic. Two days later, he said things didn't seem to smell as bad as they had. The next day, there was more improvement, and the day after that I dragged him down to the kitchen again and offered him another slice of roast beef. He ate a couple of bites, and said it didn't taste too bad. A few more days, and his taste was back to normal. He was well. It was a gratifying recovery, and it raised an interesting point. Mack's serum-zinc level was never less than normal, and yet he had—or seemed to have—a certain zinc deficiency. I wondered if something could happen to deplete the supply of zinc in a specific area —as in the taste buds on the tongue. In any event, the zinc had seemed to work. Mack was discharged on November 4, with a good supply of pills, and that was the end of him as far as I was concerned. I never heard of him again.

  "I didn't forget him, though. That wouldn't have been possible. And for several reasons. One was this. I have an old friend, an English colleague, and about a week after Mack went back to Texas my friend—I'll call him Wilson—turned up in Washington on his way out West somewhere. I hadn't seen him for a couple of years, and I picked him up at his hotel and drove him home to dinner. On the way, I happened to mention that my wife was cooking a leg of lamb. I thought Wilson acted a little strange. He cleared his throat and looked embarrassed. Finally, he said some thing about not eating much these days. He wondered if he might have something very light—a little cottage cheese, perhaps, and some lettuce. The truth was, he said, he couldn't eat meat anymore. He couldn't stand the smell of it. As a matter of fact, there were very few foods that didn't have a most unpleasant smell. It was like talking to Sergeant Mack. I asked him how long this had been going on. A couple of years, he said. It was a nuisance, but he had learned to live with it. I felt—it's hard to say how I felt. But I said I thought I might be able to help him. He gave me a hopeless look. I asked him if he would let me try. Would he come into the hospital for a week or two? He shrugged. He didn't see much point in it, but—all right. I made the arrangements, and he came in, and we worked him up very thoroughly to exclude any other possibilities—liver disease, a tumor, all the rest. We found nothing. He was normal in every way but one. His serum-zinc level was down. I put him on placebos for three days. If he improved on placebos, which are nothing but sugar pills, that would strongly suggest that his problem was functional—was rooted in some emotional disturbance. There was, however, no change. Then I started him on oral zinc. It wasn't like Sergeant Mack—it wasn't in the least dramatic. But after four or five days his serum zinc began to rise. His sense of smell improved. He could eat a little something—an egg, a slice of meat. But then he had to leave. He couldn't postpone his engagements any longer. I discharged him on November 17. I gave him a supply of zinc- sulphate pills. Zinc sulphate is not a prescription drug, you know. We were using it in an entirely experimental setting. The official view is spelled out in the standard text 'The Pharmacological Basis of Therapeutics,' which says, The systemic actions of zinc have no therapeutic application. . . . All drugs must by law have a specific use. Zinc is not recognized as having any usefulness internally except as an emetic.' Well, Wilson went on his way, but he called me a few weeks later, just before flying back to England. He had continued to improve. He wasn't all the way back to normal, but he felt enormously better.

  "And that was when I heard about Rudy Coniglio. A friend and colleague named Wilbur James Gould made the arrangements, and I went up to New York and saw him. It sounded like the same sort of thing. I gave him a drop of relatively concentrated hydrochloric acid. This is a compound that normal people find extremely sour. But Rudy didn't bat an eye. He couldn't even taste it. That didn't immediately rank him with Sergeant Mack and Dr. Wilson, but it was more than a little suggestive. I certainly wanted to know a bit more. Those first two cases had merely whetted my curiosity. I was really interested now. So I got Rudy into the Bethesda clinical center as soon as I could—on January 11. We started with a very comprehensive workup—all the routine tests, plus a skull series, EEG, brain scan, sinus series, a neurological examination, an ophthalmological study, copper and zinc evaluations, and a tongue biopsy. An examination of tongue tissue could tell me if there had been any anatomical changes in the area of the taste buds. The test results were essentially normal—all but the trace-metal evaluations and the tongue biopsy. Zinc and copper— serum and urinary both—were low. On the fifth hospital day, I started Rudy on oral zinc sulphate: four hundred milligrams a day. There was some improvement by the end of the first week, and it was marked by the end of the second week. That was when I saw the results of the tongue biopsy. They were quite impressive —startling, even. The normal structure of the taste buds was almost totally absent. I was looking at the pictures—the photographic enlargements of the electron-microscope examination— and you 'couldn't miss it. The taste buds looked frayed, worn down, moth-eaten. But now it was two weeks later. So I made another tongue biopsy. And waited with some impatience for the results. They were very interesting indeed. They looked like a normal tongue. Very close to it, anyway. Rudy had left by then. I had discharged him on January 31, with the usual supply of pills. I asked him to call me in a couple of months to keep me posted on his progress, and I also arranged for him to come back to the center in July for another checkup. He called me
in March. He was taking his four hundred milligrams of zinc sulphate every day, and he was fine—he was all the way back to normal. On July 12, he came into the clinical center again, and he stayed a little over a week, until July 21. His trouble seemed to be completely under control. But I wanted to follow him—I had lost track of Mack, and Wilson was back in England. I wanted to be sure, so I made arrangements to see him again in another three months or so."

  Mr. Coniglio says: "I wonder how many people went into the crazy house with this thing I had. I mean, years back—before Dr. Henkin. I bet plenty. I was almost there myself. But Dr. Henkin fixed me up. I came back home that second time from the hospital, and I never felt better in my life. It was even better than the first. I felt better in my mind. For almost a year now, I could eat and drink and smoke and work at my place. I had a normal life. But I think it was around the beginning of October that I noticed something different. It starts very gradual, very slow. At first, I don't believe it. But things are beginning to smell again. They stink. I'm taking the pills, but I'm losing. They don't do any good. Oh, my God—I'm scared. It wasn't as bad as before, thank God, but I know that smell and that garbage taste. I know I'm going backward. I can still work, but my nerves are bad, and I think maybe I better sell out—get rid of the place before I get worse. So I did. I sold Rudy's. I did all right—I got a good price. But the way I'm feeling, I don't really care too much. Because it is getting close to time for me to go back to the hospital. I got to go back, and I don't know what I'm going to say to Dr. Henkin. He thinks I'm cured. He thinks he made me well, and I'm not. I almost don't want to see him. You know, I'm embarrassed. But the time came, and I got the appointment letter and I went down to Bethesda and Dr. Henkin came in and I told him. And he laughed."

  Dr. Henkin says: "Laughed? I don't know—maybe I did. But it wasn't because I was amused. If I laughed, it could only have been from relief. I was pleased. Rudy had confirmed an important hypothesis. Maybe / was a little embarrassed, too. Rudy's suffering those past few weeks was all my fault. He should, of course, have called me when the first symptoms returned. That's what I told him to do. I realize now why he didn't—he didn't want to disappoint me. Which tells you a lot about Rudy. It was terrible that he didn't call. I could have helped him right away. Because the pills I sent him off with in July were not zinc-sulphate pills. They were placebos. That was something I had to do. This is a research hospital. My work is clinical research. Sergeant Mack had dropped out of sight, and Dr. Wilson was way to hell and gone in England. But I still had Rudy. He gave me an opportunity I had to take. I had to see if the recoveries I had seen were truly in response to medication—if it wasn't a matter of spontaneous remission or a psychosomatic response to a sympathetic hospital and medical situation. And now I was sure—reasonably sure. It was only necessary to put Rudy back on the old regime. Which I did. And then I was sure. In Rudy's case, at any rate, oral zinc- sulphate, at four hundred milligrams a day, was genuinely therapeutic."

  Adolph (Rudy) Coniglio has the distinction of being the first victim of idiopathic hypogeusia whose experience has been recorded in definitive detail. He thus is classically commemorated in the infant annals of the disease. He is, however, no longer alone in affliction. Others—many others—have since followed in his enigmatic footsteps. More than ten thousand cases of taste and smell dysfunctions are now known to Dr. Henkin from correspondence with colleagues throughout the United States, and some fifteen hundred more have been diagnosed, attended, and treated by him and his associates in Bethesda and Georgetown.

  "Call it ten thousand," Dr. Henkin says. "But I'm inclined to think that those cases we have on record are only a fraction of the real total. I'll tell you why. Fifty-five of the cases we saw at the clinical center were our own people—National Institutes of Health employees. There were around ten thousand men and women working in one or another of the several institutes, and fifty-five cases gave us an incidence rate of roughly one in one hundred and eighty. Now, let's project that on a national population of over two hundred million. And what do we get? It suggests that more than one million Americans are suffering from hypo- geusia or its related disorders. That really is a lot of cases. I think it's a reasonable figure, though. Hypogeusia isn't a new disease, of course. It's been around for a long, long time. It's merely a newly discovered disease. I think loss of taste is probably just as historical an affliction as loss of sight or hearing. But we don't know much about it, because it's only just been recognized. Remember all those doctors who thought Rudy Coniglio's trouble was psychosomatic?

  "So we're beginning to get somewhere. I think zinc sulphate is therapeutic. It works—not always, less often than we would like, but often enough to prove its worth. We're beginning to understand that problem. We understand, at any rate, that it is an immensely complicated one. But treatment isn't all. We've also been learning something about the nature of the disease. One thing we know is this: As a group, the victims of hypogeusia are measurably deficient in zinc. There are a number of conditions that can bring about hypogeusia. We know it can happen in pregnancy— perhaps because a portion of the mother's zinc is transferred to the baby. We know it can be brought about by head injury, by a fall or a blow. We know it occurs in cancer—I've seen it in my own experience. About ten per cent of the patients we've studied who were found to have hypogeusia have later been found to have cancer. Which raises an interesting question. Is hypogeusia a disease? Or a symptom? Hypogeusia and its related disorders occur in a variety of infectious diseases. Hepatitis is one. Flu is another. About half the people in whom we have confirmed a loss and distortion of taste and smell developed the disorder following an attack of flu. Like Rudy—Rudy is our model case. Another group of our patients developed aberrations of taste and smell after some surgical procedure. I don't know why. Maybe stress is a factor. That casts some possible light on a rather familiar phenomenon. Postoperative patients are always complaining about the quality of hospital food. Can all hospital kitchens be that bad? Or could it be the patients' sense of taste? I wonder. And then we have a third group. These are the patients whose hypogeusia is truly idiopathic. We can't find any precipitating insult. I think we will in time, possibly in the area of nutrition.

  "A team of pediatricians at the University of Colorado Medical Center, in Denver, has reported some interesting findings. They examined a group of a hundred and thirty-two boys and girls with ages ranging from four to sixteen. Zinc concentrations were normal for all but nine of the group. Seven of the nine were found to be below normal in both height and weight, and they also reported poor appetite. They were then tested for taste acuity. All were found to be suffering from hypogeusia. They then were treated with oral zinc sulphate. Normal taste acuity returned. Other studies, here and elsewhere, have confirmed our conviction that zinc can be a crucial factor. One of our studies involved a group of normal people—volunteers. We biochemically depleted their body zinc. We used an essential amino acid called L-histidine, which has the power to strip zinc from its binding proteins and excrete it through the urine. The immediate effect of depletion was appetite loss. That was followed by a loss of taste and smell. Then distortions of taste and smell appeared. Oral zinc therapy reversed the condition, even in the face of continued administration of L-histidine. So once more zinc emerged as a major marker for normal taste acuity.

  "Much of what we feel we have learned has come from a double-blind test that we staged in 1973 at the N.I.H. The true effectiveness of a drug can best be established in a double-blind test. The test we did on Rudy was a single-blind: the patient didn't know the nature of the drug he was given, but the doctor did. In a double-blind test, the true drug and the placebo are delivered to the clinician in containers labelled in a code known only to the investigator who prepared the medication. The doctor is as blind as the patient—he can't anticipate results. Our double-blind test involved a group of one hundred and six patients. Half of them were given placebos, and the other half got zinc sulphate. The
results were a shock. Some of the people on placebos got better. Some didn't. Some people on zinc got better. And some didn't.

  Statistically, we could not distinguish between the group that got placebos and the group that got the zinc. We couldn't believe our eyes. What was going on here? We thought we had been put back to zero. Then we calmed down and took a closer look at the data and we got a clue. In a single-blind test, we give the patient the placebo first, and if there is no response we then try zinc. If, however, he responds to the placebo, we drop him from the study. A placebo response suggests that other factors are involved— maybe a functional debility, maybe a psychosomatic problem. In any event, when we dropped the placebo responders from the double-blind study we ended up with results much like those of our single-blind tests. So we had another confirmation. But the study actually gave us something more than that. It encouraged us to reconsider, to rethink. We realized that there is a great diversity of taste and smell disorders, with a great variety of causes, and we were forced to conclude that zinc is no magic bullet. That is to say, it is a drug like other drugs. Magic bullets are rarer than people like to think. There are, for example, insulin- resistant diabetics. And the famous antibiotics are far from being comprehensively effective.

  "We were also encouraged by the study to reconsider some of our criteria. We had been using serum-zinc levels—the concentration of zinc in the blood—to measure both zinc deficiency and the response to zinc therapy. We decided that there might be a more definitive approach. We had plenty of room to maneuver in. The phenomenon of taste has never been of very great interest to medicine. The reason probably is that its pathology had never seemed to have much diagnostic value. Not like vision, for example, or hearing. Consequently, very little is known about the mechanics of taste. The conventional explanation supposes it to be entirely a neural process. Our studies have suggested a different explanation. We now think the perception of taste is initiated chemically. We don't know just how this chemical information is then translated into electric signals to the brain, or how those signals are coded to define the basic qualities of salt, sweet, sour, and bitter. But we do know that taste is initiated at the taste buds, of which there are more than a thousand in the oral cavity. We thought that zinc must be present in the bud. But then the question arose: How does the zinc get there? Well, the first possibility that came to mind was the obvious one—the saliva. Saliva serves the oral cavity as blood serves the rest of the body. We decided that our next move would be a study of the saliva.