What Does a “Normal Range” Mean?

I do not want to get all technical here, but what goes into establishing a normal range (really called ” reference interval) is rather complicated and is heavy into statistics.  I will try to keep it simple.  Basically, every laboratory is supposed to establish its own  reference interval for every laboratory test it performs.  Every pathologist and clinical chemist knows how this is supposed to be done.  One takes x number  of people (usually 50-100) who are presumably normal with respect to the test in question, and performs the test on them.  A mean value is calculated as is the normal range (usually the mean +/- 2 standard deviations or SD).  If the test values follow a “normal” distribution (you know the familiar bell-shaped curve), then the mean +/- 2 SD comprises about 95% of values in a healthy population.  In statistical terms, this means that out of 100 normal people, 5 individuals are likely to have their test results either above or below the 2 SD reference interval.  I told you this was complicated.  All you need to know is that people who are entirely normal have a reasonable chance of having a laboratory test result that is outside the reference interval.

Do All Laboratories Calculate Their Own  Reference Intervals?

Many laboratories actually do not calculate their own  reference intervals although as far as I know, all large commercial laboratories do this.  It is quite a bit of work and a small laboratory in a hospital or in doctor’s office is not going to want to mess with it.  Instead, they use either the  reference interval that comes in the packaging with the test kit they use or use some published reference interval.  Unfortunately, even if the laboratory does a great job in performing the test, the test results may not fit so well with the reference interval the laboratory uses.  For example, if the published serum free thyroxine level normal reference interval is 1.1 ng/dl +/- 0.5 (mean +/- 2 SD) but if the laboratory normal reference interval is actually 1.3 ng/dl +/- 0.5, many reports will be interpreted by the ordering physician as either normal or abnormal when the opposite is true.  Another important example is HbA1c, the test that quantifies average plasma glucose over the previous 2-3 months and is now widely used to screen for/diagnose diabetes or glucose intolerance.  A level 6.5% or greater is considered diagnostic for diabetes but only if the test is performed in a laboratory that has test results aligned (basically standardized) to those in the Diabetes Control and Complications Trial (DCCT) Reference Laboratory.  That approach obviates the need for the laboratory to establish its own reference interval (I still think it is a good idea for the laboratory to do that if it is at all practical).  I didn’t even mention the fact that for many laboratory tests there are age and sex differences in the  reference interval.  If this is not appreciated by the physician, serious errors in interpretation of the test result can be made.  For example, serum alkaline phosphatase is much higher in growing children than in adults.  In a child, a serum alkaline phosphatase of 300 U/L might be just fine, while in an adult it likely means either liver or bone disease.

Back to the Slightly Elevated Serum Calcium and the Slightly Low serum Sodium

In the “real” world, not the world of medical student tests, physicians must frequently figure out what do do with a test result that is outside the reference interval.  First, as I discussed in my earlier entry, no test should be ordered without a good reason.  Second, the test result must be reviewed and interpreted; some physicians are so busy that they often do not even look over the tests they have ordered or just scan them, looking for the test results listed as “out of range.”  Sometimes a test result is abnormal yet it falls just inside the reference interval.  Remember, just because a test result is outside the reference interval it is not always abnormal, that is, related to some medical problem.  In much the same way, just because a test result is inside the reference interval, that does not mean all is well.  Borderline low and high test results need to be scrutinized.  Maybe they mean something and maybe not.  That is more of the art and science of medicine.  How do medical students learn about these things?  I am not sure.  Based on the test I just graded, maybe we do not do such a good job in teaching them either how to order tests in an artful and scientific way and in figuring out what to do with the test results.

The Most Important Part of Sorting Out Test Results

In my opinion, arguably the most important part of interpreting laboratory test results is sharing the information with the patient and discussing what the results might or might not mean.  In this age of electronic medical records, e-mail, etc., I am amazed at how many otherwise excellent physicians do not have a systematic method of keeping track of what tests they have ordered for their patients and what the test results turn out to be.  Worst of all, they do not have a systematic way of getting in touch with their patients to let them know what the test results are and what it all means.  All patients deserve to be “in the loop.”

Do Physicians Order Unnecessary Laboratory Tests and Procedures?

There are endless data, especially in the past few years, to show that as a group, physicians order far too many laboratory tests and procedures.  The recent interest in this phenomenon is to a great extent related to efforts to bring some measure of control to U.S. health care costs.  For example, a recent report in the New York Times  addressed the question of laboratory tests and procedures, focusing on a report by 9 major medical specialty groups in which 45 tests and procedures that have no proven benefit to patients were  listed.   The newspaper article was entitled “Endless screenings don’t bring everlasting health,” and was written by Lisa Schwartz and Steven Woloshin.  There has also been a measure of pressure brought to the question of whether physicians who own a stake in a laboratory, order more tests (performed in the physician-owned laboratory) than those who have no financial interest in ordering the test other than, perhaps, a charge for interpreting the test result (see “Doctor’s stake in a lab affects biopsy rate, ” written by Mitchell, JM., in Health Affairs, April 2012).  To me, the most interesting data are those from a study carried out a few years ago in which the investigators studied whether physicians ordered fewer tests when the prices of the test were listed on the order form.  As it turned out, when the prices were listed, doctors actually ordered about 20% fewer tests.  Clearly they didn’t “need” those tests, but just wanted them.  That’s the good news.  The bad news is that after a year, when the prices were taken off the ordering form, the docs, reverted to their original ordering behavior.  Recent studies have found very similar results.  For example,  hospitalists at the Johns Hopkins Hospital in Baltimore studied how often common but expensive laboratory tests were ordered with or without the cost of the test listed (“Knowing costs affects lab test ordering“).  They found that over a 6-month period November 2009-May 2010, there was an average decrease of about $16,000 billing per test when costs were displayed on the order form compared with a 6-month period 1 year earlier.  This was just for one hospital.  The investigators, led by Dr. Leonard Feldman, concluded that much of the reason for the excessive test ordering was simply a lack of awareness of how much tests cost.  The investigators acknowledged that they did not have any data to show that patients’ outcomes were not affected adversely by stingy testing.   So, the excessive ordering is not always related to to either personal financial benefit or other factors such as medico-legal concerns.  What is it due to?  Beats me, but I think it is to a great extent a “reflex” action and one of convenience- if I order everything I might need right now, I will know what’s what sooner. That’s just my theory.  It might be mostly a question of personality- those docs who require immediate gratification vs. those who can tolerate waiting for answers?  We can gain some insights from a recent study entitled, “Why do physicians order unnecessary preoperative tests? A qualitative study,” written by SR Brown and J Brown (Family Medicine 2011;43:338-43).  the investigators interviewed 23 physicians and nurse administrators and found that the main reasons for ordering unnecessary tests were as follows: practice tradition, belief that physicians wanted the tests performed, concern about medicolegal issues, concern about possible surgical delays, and lack of awareness of evidence and guidelines.

How Should Physicians Order Laboratory Test and Procedures?

I do not believe most medical students and resident physicians are taught the “art” of ordering laboratory studies and procedures.  That gap in training is to some extent, related to the fact that many of the patients seen by students and resident physicians have either acute illnesses where time is of the essence or are patients for which reliable follow-up is quite uncertain.  So, it’s sort of “catch while catch can.”  In the real world, physicians are generally not in such a rush and they would do well to stage their testing unless the situation is urgent.  Why order every test you might need at the first encounter when starting with a few simple basic tests would suffice?  Sometimes, I hear that the blitz is performed because it causes less inconvenience for the patient- they won’t need to come back for a test that is needed based on the initial basic testing.  In my opinion, that argument is nonsense.  It certainly makes no economic sense.  If one is worried about the possible need for another venipuncture, extra blood can be drawn initially and stored, to be assayed as needed.  Laboratories do it all they time.  That’s what freezers are for.

Another side of the question of what to order, is the importance of explaining to the patient exactly what tests were ordered and why.  Many physicians just do not take the time to explain this to their patients.  Maybe, sometime the docs just don’t know exactly why they ordered what they ordered?

Finally, there is the question of letting the patient know what the tests showed and what it all means.  I am astonished how many physicians have no organized way to communicate test results with their patients.  It is really shameful.  Have any of them ever heard of e-mail or even the U.S. postal service?  In my view, if a physician takes the time and trouble (for the physician and patient) to order a laboratory test or procedure, the least the doc can do is get back to the patient with the test result and interpretation/plan in timely fashion.  Some physicians are super at this task and some are horrible.

The Future

It will be interesting to see how much pressure is put on physicians various “expert panels,” insurers, and governmental agencies (e.g., Medicare, Medicaid) to cut back on ordering tests?  It is already happening, particularly for various screening studies.  I do worry that some of our patients will suffer because of ill-advised recommendations based on epidemiological data (the kind that look at how many people we need to screen for this or that disease to save 1 life or to detect 1 cancer.  Good medical care is not always about maximum cost effectiveness.  But, there is no question that we as physicians could do better in the way we order laboratory tests and how we use the results to guide our therapies.

Basically, the Raum and Boffey articles opine on the fact that U.S. health care costs are extraordinary and that if we do not find a way to bring costs down quite a bit, we will have very difficult decisions about what other things we hold near and dear (e.g., education, infrastructure, national defense) that we will need to cut back on.  The Rattner article focuses on the long-term dangers of high U.S. debt.  I found the data in the Bossey piece on comparative costs for various medial services in Britain, Canada, France, Germany, and the U.S., particularly interesting.  For example, the average cost for cataract surgery in the U.S. (public and private sector) at $14,764 beats the closest competitor by $11,412.  It is truly breathtaking how much we in the U.S. (physicians, hospitals, and clinics) charge for routine medical services relative to the rest of the world, particularly since our outcomes are not generally superior to outcomes elsewhere.

In my opinion, based on my reading of the 3 articles in the NYT, at some point, the U.S. will have to go on a health care cost diet.  I predict the diet will be very difficult for us (the general public and the health care providers) to start and to follow.  How in the world will we be able to keep all the stakeholders reasonably happy with the process and the result?  This is scary stuff.

The Diethylstilbesterol (DES) story

DES is a synthetic nonsteroidal estrogen that was developed in the late 1930s.  It was widely used as a supplement to cattle feed (to fatten them up) and in humans as estrogen replacement therapy and for treatment of prostate and breast cancers. In the late 1940s, one study showed that DES could prevent miscarriage if given early in pregnancy. Other studies had shown no benefit, yet DES was widely used for quite a long time despite very convincing data that accumulated showing no benefit with respect to miscarriages.  Eventually, doctors got the message and use of DES faded away.  Then, in 1971, the NEJM published results from a very scary study performed by Herbst et al., showing an association between DES use during pregnancy and development of a rare vaginal cancer (clear-cell adenocarcinoma) many years later in female offspring of these mothers.  I still remember when the news hit.  I was a pediatric resident physician and doing my pediatric endocrinology rotation.  Even back then I was reading the NEJM regularly (I have been a regular subscriber since 1965). I remember the many discussions we all had about the data. As it turned out, by the early 1990s, 431 cases of the rare cancer had been identified in young women exposed to DES in utero. The median age of cancer diagnosis was 19 years.  We now know that the mechanism for the development of the cancer was probably drug-induced abnormal development of the Mullerian ducts (these ducts develop into the uterus, fallopian tubes,  and a bit of the vagina).  It was all a nightmare for the mothers, the young women, and the physicians involved in their care.

What did we learn from the DES catastrophe?

I am not certain what the collective “we” learned from the DES story.  I do know what I learned- that all medical treatments, be they procedures or medications, have risks and benefits.  Many times we know what the potential benefits are for a given treatment, but do not know what the risks might be.  Thus, it is always important to consider and to weight unknown risks vs. the potential benefits.  This is no easy task but it needs to be done and physicians who do not do this, do a disservice to their patients.  The potential benefit of a given treatment must be compelling enough to counter the unknown risks of the therapy, whatever the therapy might be.  We (here I mean the collective “we”), keep learning this lesson over and over.  Just this week, I read an article (and two accompanying editorials) in the NEJM entitled ” Stenting versus aggressive medical therapy  for intracranial arterial stenosis.”  In summary, the study showed that stenting was associated with many more deaths than the medical therapy.  As it turned out, the stenting procedure was approved by the FDA in 2005 after a small non-randomized study showed benefit from the stenting vs. medical therapy.  Now the “experts” are moaning and groaning about the fact that FDA approval for the stenting procedure was probably inappropriate given the very limited data and that a large randomized trial should have been performed, which as it turns out was the substance of the current NEJM article.  Then there is the story about the “metal-on-metal” hip replacement devices that is turning out to be another medical therapy catastrophe (see “Medical Devices-balancing regulation and innovation, ” written by Curfman GD and Redberg RF in this week’s NEJM).  I could go on and on.  We as caregivers all need to go back and review the DES story and understand why we need to learn as much as possible about risks and benefits of any given therapy/device before we “jump in.”  Obviously, if a patient faces certain death and a new therapy comes along, it would not be appropriate to “sit on one’s hands.”  But, few new medical treatments meet that urgency standard.  Pressures from device manufacturers and pharmaceutical companies and the researchers who either developed or tested the treatments, should not trump the need for careful unbiased assessment of the risks and benefits of the proposed treatment.

A brief medical history

My mother lived in Columbia, Missouri, not far from me.  She was born in 1919 and had been generally quite healthy.  A few years earlier, she developed a peripheral neuropathy (etiology unknown) and had to use a walker to get around.  She stayed active, swimming 2-3 times a week.  She had a primary care doctor, a general internist,who was on the faculty at the University of Missouri and whose office was only a few blocks from her home.  She had a good relationship with the doctor and the nurse who worked with him and everything was fine and dandy.  Then, all of a sudden, the doctor closed his practice and  my mother did not have a primary care doctor.  The doctor she had been seeing contacted my mother and told her that he was leaving the clinic, wished her well, and  and he suggested another physician who he had taken the liberty of speaking with, and who had agreed to accept my mother into her practice.  So far so good.

In January of this year (just after her original doctor left the clinic), my mother developed some vascular problems with her legs.  She was seen in the internal medicine clinic by the “new” physician who took a brief medical history and referred my mother to a vascular surgeon for a consultation.  From the time of the first visit with the new physician, my mother was not pleased.  I felt the problem was mostly that my mother had gotten used to the previous doctor and that over time she would warm to the new doctor.  Oh was I wrong.

As it turned out, my mother had an arterial thrombosis in her right leg and had vascular surgery at the end of January of this year.  The surgery was not easy for her (at age 90 years, I don’t think any surgery is easy); she spent a week in the surgical intensive care unit but things improved steadily.  Once out of intensive care, she was transferred to a medical/surgical ward and was cared for by the vascular surgeons and by the internal medicine hospitalists.  Every day she was seen by a different internal medicine doctor and not once did she see or even hear from her new primary care doctor.

After discharge from hospital, my mother was scheduled to be seen by her primary care doctor.  As it turned out, after the appointment was made, the doctor’s schedule changed and my mother was seen by an internist who was just “covering.”  The clinic had known for a week that the primary care doctor would not be in clinic for my mother’s appointment, but did not inform my mother.  The “covering doctor” knew nothing about my mother’s case history and I would describe the clinic visit as a disaster.  My mother swore that she would never go back to that clinic again and she didn’t.  She insisted that I find her a new doctor, someone like her previous doctor.  I decided that my mother might do better with a family practice doctor.  I twisted a few arms and the Chairman of the Department of Family and Community Medicine, and also a geriatrics expert,  said he would be pleased  to see my mother.  An appointment was made for late April of this year.

Is it gall-bladder disease?

In mid-April, my mother developed intense itching and then her urine turned dark.  Remember, my mother was in-between primary care doctors at this time.  I ordered some basic lab tests (I was forced to order the tests since my mother did not have a doctor) and had the results sent to the new primary care doctor explaining in an e-mail that he was to see my mother for the first time in about a week for what was to be routine clinic visit.  The test results were consistent with biliary obstruction but there was also anemia and the platelet count was very high.  I as a pediatric endocrinologist was way out of my comfort zone.  Within an hour after I e-mailed the lab test results to the new doctor, he called me and told me that he wanted to see my mother the next day if she was willing.  She reluctantly agreed to the clinic visit (by this time she was tired of all doctors, nurses, hospitals, and clinics).

The first clinic visit with the new doctor

The next day, I drove my mother to the new doctor’s office and from the beginning, I knew things were going to be different.  Starting with the receptionist then the nurse, and finally the doctor, it was a completely different atmosphere than at the internal medicine clinic where it was “all business.”  First, all of the personnel acted as if they were actually happy to see my mother and made her feel comfortable.  The doctor had already reviewed my mother’s chart (we have excellent electronic medical records at my university medical center ) and the visit didn’t start out as if the doctor didn’t know anything about my mother, which had been the case every time at the internal medicine clinic after my mother’s first doctor left the clinic.  The new doctor’s demeanor was excellent.  He spoke to my mother, not to me as had been the case previously and made her think she was his only patient.  He didn’t rush and he explained things to my mother and told her what he wanted to do, why, and asked her it she was willing.  When we left the clinic my mother was the happiest woman on earth- she had found a doctor just like her first one and she had complete faith in his recommendations.

The bad news

Unfortunately, as it turned out, my mother did have biliary obstruction, not from a gall-stone but from inoperable pancreatic cancer, diagnosed in mid-May of this year.  To make a long story, a bit shorter, every step of the way from the work-up to the diagnosis and until my mother’s death on August 20, her primary care doctor “ran the show.”  He took charge and made sure she saw whatever specialists she needed to see (e.g., oncological surgeon) but he maintained control of the treatment plan.  He arranged for hospice care and was able to persuade her to do it even though I hadn’t been able to.  He worked closely with the hospice team throughout.

At the very end of April, the new doctor went out of town for 2 weeks (on a cruise with his wife), but he had informed my mother of his upcoming trip and made arrangements for another colleague to manage her case while he was away, and called her immediately on his return.  He even made a house call the afternoon before my mother died.  Remember, this is the Chairman of the Department, a very, very busy man.  But, once he agreed to see my mother, he made clear in everything he said and did that he had taken “ownership, ” something her previous doctor had not.  For me it was a wonderful experience, considering the circumstances.

My mother certainly had enough to deal with given her diagnosis and the last thing she needed was to have a lack of confidence in her health care provider.  But, my mother had complete faith in her doctor and it made all the difference in the world.  Her doctor was not an expert in pancreatic cancer and maybe not expert in anything except the most important thing, expertise in knowing what it means to be a patient’s doctor.

Ownership and Medical Homes

These days there is considerable discussion about the need for each patient to have a “medical home.”  The idea is that all patients, particularly those with chronic diseases, need to be part of a medical care system that can meet all of the patient’s care needs and that the patient care is provided in a organized and efficient fashion.  Who can argue with such a concept?  With my mother’s illness, I learned that having a medical home is not enough; it is also necessary that one person, be it a physician, nurse, social worker or whomever, needs to take ownership of the patient and do everything possible to be certain the patient’s medical care needs are being met within the medical home.  For my mother, getting excellent health care could not keep her cancer from taking her life, but it made the final days and weeks of her life far better than they would have otherwise been.  There is a lesson here for all of us.

One last thing.  For those of you who are particularly interested in end-of-life issues, I highly recommend a recent article in the New Yorker, entitled “Letting Go.  Rethinking end-of-life treatment,” written by our old friend, Atul Gwande.  I warn you in advance- the article is long- but very well done.

In my opinion, this is a very tricky issue.  For example, as I have discussed in previous entries, for many people who are overweight genetics plays a very important role; their obesity is not just the result of willful unhealthy behaviors.  As employers and insurers pursue the idea of promoting desirable behaviors, they need to be very careful not to place an unreasonable burden on people whose health problems are more the result of “bad” genes and bad luck than bad behaviors.

My Westminster College Lecture

As long as I’m writing about health care, I might as well tell you that the other day, I gave a lecture at Westminster College in Fulton, Missouri.  Fulton is only about 25 miles from my home town, Columbia, Missouri, and the county seat of Callaway County, named for James Callaway,the grandson of Daniel Boone.  Fulton (population 13,000) is  known mostly for having 2 excellent colleges, Westminster and William Woods, and for the Winston Churchill Memorial and Library(WCML).  The WCML is located on the campus of Westminster College and is the site of Churchill’s famous “Iron Curtain” speech.  Many world leaders have visited the site and have given important speeches, including the one by then Soviet President Mikhail Gorbachev who announced the end of the Cold War and the fall of the “Iron Curtain.”  My not yet famous speech in Fulton was entitled “Chaos theory in action: The U.S. health care system.”

I spoke to a class of about 35 students in a course that examined a wide range of controversial contemporary issues.  I have no idea why the course director, Professor Margot McMillen thought U.S. health care might be a controversial issue.  Anyway, I tried my best to provide the students with a framework for understanding the current U.S. health care reform debates rather than focusing on my opinion on how to fix the problems.  I tried to keep the discussion apolitical which, I have learned, is the best way to get people on both sides of the debate to listen.  I focused primarily on describing the cost-generating components of the system.  I divided those components into 2 large categories, government and non-government.  On the government side was Medicare, Medicaid, U.S. Public Health Service (Indian Health, Etc.), Veteran’s Administration, Military (active duty members and their families), and miscellaneous (e.g., Community Health Centers).  On the other side was private insurance and self-pay (this included out-of-pocket health care expenses for even people with insurance or Medicare or Medicaid).

For each  component I tried to describe its history and current status, including costs and my take on its weaknesses (e.g., difficulties that many people on Medicaid have in finding physicians willing to see them).  I then tried to address what most experts feel are the 2 most important problems with the current U.S. health care system, lack of access and high and ever increasing costs.   By the end of the hour, I think most of the students understood enough about the issues to critically critique the various health care proposals that  bombard us if we read newspapers, watch television, or listen to the radio.  Apparently, each student will be required to write a paper about the lecture.  If Professor McMillen will give me permission, I want to read the students’ papers.  Did I actually teach them anything or do I need to “go back to the drawing board” to find a better way to educate people about the U.S. health care system?  Maybe, as the title of my lecture suggested, I should just give up trying to bring order to chaos?

I would only add to the discussion that in some instances, hair loss is on an auto-immune basis (called alopecia areata if the hair loss is spotty or alopecia totalis if the loss is big time) and is strongly associated with certain other auto-immune disorders, particularly chronic lymphocytic thyroiditis (aka Hashimoto’s thyroiditis) and adrenal insufficiency.  If the hair loss is considerable and sustained over weeks-to-months, I would strongly recommend a visit to a dermatologist before embarking on potential therapeutic misadventures.

The second article which appeared in the New York Times Magazine on Sunday January 17, 2010 was written by Tom Dunkel and was entitled “Vigor Quest.” The article was a very interesting and surprisingly balanced discussion of the attempts by what appears to be an increasing number of people obsessed with prolonging their youth, or at least, their youthful performance in a variety of activities.  My interest in the subject is, of course, as an endocrinologist (not as an aging endocrinologist).  Much of the discussion in the article focused on testosterone and growth hormone, drugs about which much has been written in both the medical and non-medical literature.  The subject has been in the news quite a bit recently with the controversy surrounding use of these drugs in professional athletes.  There is no question that deficiency of either testosterone or growth hormone can impair athletic performance and affect overall vigor.  The still unanswered questions are whether taking one or both of these substances when there is no apparent deficiency can be helpful and if there are potentially serious side-effects.  It is good that the National Institutes of Health has embarked on a long-term (6 years) study of the potential mental and physical benefits of testosterone therapy in elderly men.  They should also consider a companion study of growth hormone.  I for one strongly recommend that until we have much more scientific information, use of these biological agents be limited to patients who have definite deficiencies and symptoms and signs to match the laboratory findings.  But, I just wonder how fast I could swim if………?