Perspectives on Medicine

An introduction to epigenetics

2010-05-20T10:44:00.043-04:00

Epigenetics?

You very likely remember from high school biology the story of Gregor Mendel, the monk who in the mid 1800s observed that the inheritance of traits among pea plants in his garden was not random but seemed to follow certain patterns or laws. Despite his discovery, however, he knew nothing about the mechanism by which his pea plants transferred this information, their genetic code. We now know it is as the molecule DNA, deoxyribonucleic acid.

(Your other memory from biology class likely is this famous black and white picture of Francis Crick and James Watson standing next to a model of DNA, representing their discovery of the structure of DNA in 1953.)

Photo courtesy of UCSB

Science has rapidly progressed and within the last ten years the Human Genome Project has unraveled the full sequence or code of human DNA; yet, despite knowing the full sequence of DNA there is a lot in humans we still can't explain, predict, etc. We haven't licked human disease. Why is that? What more to the puzzle could there be?

Let me address one aspect of this puzzle: epigenetics.

How is it that in your body the exact same DNA, or code, is present in your liver cells as in your brain cells and yet the two cell types are very different? Or that identical twins share the exact same DNA and yet are different individuals, even if subtly so? Clearly, the answer to these questions is not simply DNA.

The answer instead partly lies in how the DNA is read or expressed in cells. One mechanism: regions of the DNA are made more or less accessible to being read. Two people allowed to read different sections of an encyclopedia will walk away with different knowledge.

For instance, a cell may attach or associate certain chemical groups or molecules (such as methyl groups) to certain regions of DNA and, thus, alter the structure or reading of those regions but in no way change the DNA sequence itself. These modifications are not part of the DNA (or genome) itself, but 'outside' or 'above' the DNA, and make up what is called the epigenome (from the Greek meaning literally above the genome or DNA).

In this way the epigenome, despite not being the actual code or DNA sequence, plays an important role in cells. Knowing the DNA sequence is not sufficient. What is also important is how the DNA is expressed.

Two prominent examples of the epigenome's effect on the human body include X-chromosome inactivation and genomic imprinting.

X-chromosome inactivation

Quick review: In general the cells of our body have two copies of DNA, one copy inherited from our mother and the other from our father. In order to fit into our cells, the DNA is packed up and organized as chromosomes, and human DNA consists of 23 pairs of chromosomes (again, one pair from each parent). The sex chromosomes (denoted as either X or Y) are the chromosomes that determine our sex, whether we'll be male or female. A person born with two X chromosomes is born as a female.

For years scientists have known that in any given cell of a woman, only one of the two X chromosomes (either from her mother or father) is generally expressed while the other is inactivated (not expressed). This inactivation (X-chromosome inactivation) appears to occur randomly, such that in one cell the mother's X chromosome may be inactivated and in another cell the father's X chromosome. It occurs as a result of changes to the epigenome, which allow only one X chromosome in each cell to be read despite both X chromosomes being present. Once set this inactivation and epigenetic changes are passed along as the cell divides.

Genomic imprinting

Another exception to the idea that we are essentially the expression of both our mother's and father's DNA, because each cell contains a copy of DNA from each parent, is genomic imprinting. For some locations on the DNA, who we are is determined not by both the mother's and father's DNA but by either the mother's or father's DNA. The DNA from one parent is silenced, not read or expressed due to genomic imprinting, parent-specific epigenetic changes of that DNA location.

Angelman syndrome and Prader-Willi syndrome are two examples in which genomic imprinting manifests in humans. Prader-Willi syndrome has captured some attention as many patients suffer from truly insatiable appetites that require their families to lock the refrigerators and remove all other food from the house.

Imprinting may play a role in other more complex disorders, including bipolar disorder.

Epigenome and the environment

What scientists are trying to understand now is to what extent the epigenome plays a greater role in humans.

The epigenome in our bodies is not permanent and, in contrast to our DNA sequence, is more malleable to change. One theory posits that this ability of the epigenome to change developed as a mechanism to assist us in adapting to our environment. For instance, if a child were born into a period of drought and starvation, there would be a benefit if the child were adapted to such an environment. Evolution, which occurs over many years and generations, however, would be of little use to this child.

Animal studies and human epidemiological (population) studies suggest that the environment during our time in the womb and shortly after birth affect our risk of developing various diseases later in life, leading some scientists to question whether the epigenome is to blame. Does the environment alter our epigenome and thus affect the long term expression of various parts of our DNA with repercussions later in life? To return to our example, changes made early on to adapt to starvation could be detrimental if the child is later exposed to plentiful food.

A well-known experiment in mice involves a location on the DNA in mice (called the Agouti gene) that plays a role in the color of their coat. In certain mice who have a variation of the Agouti gene, A^vy, the color of the coat is related to the degree of epigenetic changes (methyl groups) that have been added in variable fashion during pregnancy, allowing mice born with identical DNA to have different coat colors, from yellow to brown. The extent of added methyl groups affects the expression of the DNA. Mice with few methyl groups added to this portion of DNA have yellow coats (and appear predisposed to obesity) while those with numerous methyl groups have brown coats.

What scientists discovered is that if they fed the mothers vitamins and other supplements considered “methyl-donors” (thought to promote the addition of methyl groups) during pregnancy, that they increased the number of brown mice born. This finding was true as well when the mothers were fed a phytoestrogen (a component of some plant foods that act like estrogen in parts of the body) called genistein, which at levels seen with high soy diets is also known to increase the amount of methyl groups added to DNA.

Epigenome and cancer

The epigenome may also have a role in cancer. There are certain parts of the DNA in every cell that promote growth (oncogenes) and that inhibit growth (tumor suppressor genes). In a well regulated cell there is a proper balance between these forces, but a tip in the balance of expression or lack of expression of certain genes can produce unregulated growth in a cell, or cancer.

Epigenome and behavior?

One mouse study suggests the potential inheritance of certain behaviors via the epigenome. In mice the mother's nurturing of her offspring (maternal instincts such as licking and grooming), is learned early after birth. (Mice that have been nurtured also appear as adults less fearful and better able to respond to stress.) Studies suggest that this nurturing occurs and is passed along due to epigenetic changes in the offspring during nurturing; the offspring grow up to be mothers and nurture their own offspring and continue the cycle.

In conclusion

The possibilities of epigenetics are eye-opening although a lot of questions still remain. To what degree is epigenetics, beyond a few examples, actually relevant in humans? If to a significant degree, then what in our environment affects the epigenome? Can we take advantage of this knowledge to prevent or treat disease? Eat certain foods or take certain vitamins? Or would such treatments be too indiscriminate and while addressing one disease possibly promote another?

For those interested in more detail:

Jirtle, Randy L and Michael K Skinner. "Environmental epigenomics and disease susceptibility," Nature Reviews Genetics, Vol 8 (April 2007), 253-262.

Arsenic, our friend? Arsenic as chemotherapy.

2010-01-05T09:57:00.017-05:00

Recently, in the process of caring for a patient with leukemia, I was reminded by the oncologist of arsenic as a treatment option for certain leukemias. That's right, arsenic...

ar·se·nic (ärs-nk)
n.

Symbol As, A highly poisonous metallic element having three allotropic forms, yellow, black, and gray, of which the brittle, crystalline gray is the most common. Arsenic and its compounds are used in insecticides, weed killers, solid-state doping agents, and various alloys.

The Free Dictionary (http://www.thefreedictionary.com/arsenic)

Chemotherapy in today's age is to a large degree still poison - potentially effective poison in extending patients lives but poison nevertheless. Therefore, to be receiving arsenic, in the eyes of you and your oncologist the benefits outweigh known toxicity and risks. However, the idea of arsenic as a chemotherapy can be a tough one to swallow.

As far as medicine has come over the years (and it has become quite advanced in certain regards), medicine still has a long way further to advance – an idea that can be forgotten by the lay population. Our expectations in a society now with ubiquitous iPhones and Wifi internet on airplanes may not carry over well to medicine. Certain successes in medicine, such as pacemakers or heart transplants, may have helped create this impression. The reporting of medical news by the lay press often reinforces it, feeding unrealistic expectations by its tendency or bias towards portraying miraculous success stories, early technological breakthroughs, or early, intriguing but unconfirmed experimental results.

And then there is arsenic as an addition to standard chemotherapy or a second or third line agent in the treatment of various leukemias.

Arsenic in our environment is found in both natural and industrial sources but as it can be poisonous, particularly with chronic exposure (arsenic poisoning is a serious health problem in various part of the world), our exposure is regulated by the government. For example, the Maximum Contaminant Level (MCL) of arsenic in drinking water is currently set by the EPA at 10 micrograms per liter of water.

On a given day we may ingest up to a few hundred micrograms from our water or food. The amount of arsenic given with each daily infusion of chemotherapy to the average male (~70 kg in weight) might equal 10.5 milligrams (mg) – on the order of 100 times more than our daily intake.

Which is not to say I wouldn't take arsenic if it were indicated or recommended by my doctor given my medical condition. I merely think people might appreciate this perspective on medicine.

A similar example in cardiology and primary care

A similar example would be Warfarin - initially marketed as rodent poison but used in medicine since the 1950s and remains today the most prescribed anticoagulant in the United States with increasing numbers of prescriptions written to treat various blood clotting disorders, such as atrial fibrillation (a type of irregular heart beat), pulmonary emboli (clots in the lungs), and deep vein thrombosis (clots in the legs).

Can you think of other examples?

Cancer screening

2009-10-22T10:40:00.009-04:00

Finally... For those who haven't yet read this article in the NY Times, worthwhile reading.

Cancer Society, in Shift, Has Concerns on Screenings

By GINA KOLATA

Published: October 20, 2009

Guest entry: Domestic violence and narcissist personality disorder

2009-04-19T21:28:00.013-04:00

posted by Antigone Kostas, MD (psychiatry resident)

The cycle of violence in domestic abuse: The abusive husband hits his wife and, while the wife may then leave, after many pleas from the husband that he’ll never do it again and that he truly loves her, she’s back with him, for a period of relative peacefulness (the honeymoon phase) - only to be hit again and for the cycle to repeat.

Why does the wife go back to the abusing husband? And who is the abusing husband? In his paper, “Dyadic Violence, Shame, and Narcissism,” Stewart Hockenberry, a psychologist, explores who these people may be and why this happens. He claims that in many situations it is the play between two different narcissistic characters—the Grandiose Narcissist and the Symbiotic Narcissist.

A narcissist is often a person "who is full of him/herself." Narcissists have grandiose views of themselves, often to oddly enough buoy themselves against feelings of low self-esteem. Characteristics of narcissists include using other people for their own gains and lacking empathy.

So, first, how does a narcissist develop? Hockenberry finds that, “Early childhoods are variously characterized by narcissistic injuries linked to abandonment, separation, lack of parent-child attunement, neglect, impingement, and abuse; each shares a unifying theme of profound, inescapable, and self-negating shame.” Thus the narcissist is very much the shamed, wounded child.

The grandiose narcissist hides his shame and feelings of inadequacy by “playing the big man.” Moreover, the grandiose narcissist, because of his shame and self-hatred, finds someone else upon whom he can “project his own frustration and thus dissociate from these feelings of self-hatred. By projecting these feelings onto someone else, the grandiose narcissist can triumph over his internal shame by ‘revenge.’”

In an abusive relationship this plays out usually after the honeymoon phase. During the honeymoon phase, the other person is “loved and idealized as long as domination and complete control of their responses can be assured.” However, when things do not go according to plan, the narcissist feels attacked and strikes back.

The example Hockenberry gives is that of a doting man on a woman who soaks up all the adoration and makes no complaints. As the story goes, this cannot go on forever and when the woman starts to point out needs of her own or to have a few complaints, the grandiose narcissist goes into a narcissistic rage—feeling attacked-- and is ballistic.

But who pairs up with the grandiose narcissist? Hockenberry counters that it is often a narcissist as well - a symbiotic narcissist. The symbiotic narcissist also has shame, but is instead self-deprecating, turning her anger/aggression inward and living by martyrdom. She often feels responsible for other people’s pain and anger - suffering becomes familiar and even natural.

The symbiotic narcissist was “raised in control-oriented, oppressive environments, in which at least one of the parents was intrusive or invasive of personal boundaries, [and] the individual attachments are tenuously maintained, often at the cost of considerable pain and suffering. Because of overwhelming needs for attachment and bonding, actual abuse and suffering are frequently denied or are seen in themselves as signs of attachment.”

So the grandiose narcissist seeks out those he can degrade when the situation feels out of hand, while the symbiotic narcissist eats up the suffering. Hence the cycle of attack/revenge and victimization/suffering continues.

Bibliography

Hockenberry, Stewart L., “Dyadic Violance, Shame, and Narcissism,” Contemporary Psychoanalysis, Vol 31, No.2 (1995).

Alzheimer's, dysphagia, and PEG tubes – a conversation

2009-03-16T09:53:00.028-04:00

Grandpa had been gradually declining from Alzheimer's dementia for years (he was confined to bed and he could no longer communicate with his family), but on this visit, after he was admitted to the hospital with pneumonia for the second time in a few months, it was clear he was now also having difficulty swallowing (dysphagia in medical terms). Grandpa was choking on the simplest of foods, including liquids and pureed foods, when he was tested by the speech therapist. Even when slowly fed small spoonfuls he wasn't safe to eat.

(image of pneumonia by Tim Snell, http://www.flickr.com/photos/timsnell/2347749472/)

“How will he get food?” the family asked.

“We have a couple of options,” the doctor began. “One is to entirely bypass his mouth and throat, where all the difficulty is, by placing a tube, a PEG tube through the skin of his abdomen directly into his stomach. The tube can then be used to feed him, give him medicines, etc.”

“Is that major surgery?” the family asked.

“Although not without risks, it's a relatively simple procedure. The gastroenterologists place PEG tubes relatively often and serious complications are rare. The procedure is performed by passing a camera through the mouth down into the stomach, in the same way that upper endoscopies (EGDs) to view the esophagus and stomach are performed. There the gastroenterologists shine a light up at the skin and where that light is seen on the skin is where they place the tube.”

“Sounds worth doing,” the family said.

“From what I've told you so far I'd have to agree, except as usual nothing is quite so straightforward. For instance, there is some controversy as to how effective the PEG tube truly is in patients like Grandpa, whether the tube truly prevents aspiration (food going into the lungs) any more than merely trying to carefully feed him by mouth slowly and with small spoonfuls.

Despite all of us having a sphincter or valve at the lower part of our esophagus to keep stomach contents from coming back up, we all at some point during the day, usually at night, likely allow some stomach contents into our lungs. We aspirate. Similarly, even with the PEG tube some of the contents from Grandpa's stomach will find their way into his lungs. The difference between us and Grandpa, though, is that we are able to protect our lungs. If food or stomach contents go the wrong way, we quickly cough them up. Grandpa can't as I'm sure you've noticed by his really weak cough.”

“So if we don't place a PEG tube?” the family asked.

“The other option is to merely let Grandpa eat and accept the fact that some food will likely go the wrong way and into his lungs with all the risks that entails, including more pneumonias and potentially death.^¹

Sounds terrible, I know, but where we are now with Grandpa, with dysphagia and food going into his lungs, is part of the natural progression of Alzheimer's. It is common and generally signifies that the Alzheimer's patient is severely impaired and that life expectancy is short. And the benefit of placing a PEG tube in a terminally ill patient, sadly, is unclear.

Knowing that, not everyone would want an artificial feeding tube.^² In fact, letting Grandpa eat and take those risks is a reasonable option, and one that many families choose.^³

The question in the end is what would Grandpa have wanted? If Grandpa were able to be here today and tell us, what would he say?

“I have a question,” one family member asked, “If we place the tube, can he still eat?”

“While he can still eat with the PEG tube, the main reason for us to place the tube, would be to try to minimize his risks. It would make less sense in Grandpa's case to both place the tube and let him eat.

If we do choose to allow Grandpa to eat, however, knowing that Grandpa will continue to develop pneumonias, I would suggest that the next time he does that we don't actually transfer him back to the hospital. Rather than us at the hospital trying to help him recover from that pneumonia in order to be healthy enough to go through the process all over again, I would leave these issues to his regular doctor to manage and, if necessary, to make Grandpa comfortable. It is another difficult decision but one worth considering...

Another way to think about these issues is what do we really want to accomplish? PEG tubes, for instance, make for easier delivery of medications, but if we are trying to have Grandpa live longer or have a better quality of life, that may be unrealistic.”^⁴

1We all pass at some point and pneumonias are a common way in which we pass.

2You would think that swallowing is as hardwired as anything else in our body, like a reflex or our heart beating, something that requires no thought and would never go, but that isn't true. It actually requires a level of brain function to effectively coordinate all the movements of swallowing: to chew, push food to the back of the pharynx, initiate the swallow, etc.

3Nutrition is seen as a symbol of life and withholding full nutrition, in some way letting a family member go, letting them pass, even if naturally, can be difficult for families; yet, in many ways this dilemma developed only as a result of modern technology, our ability to place feeding tubes, give antibiotics, etc.

4An unintended consequence which people don't usually consider is that every time Grandpa returns to the hospital and is treated for pneumonia with antibiotics, the risk of creating more and more drug resistant bacteria increases. The fear from a medical and societal perspective is the development of bacteria potentially resistant to all known antibiotics.

(Brief) Reaction to Article: "Percutaneous Coronary Intervention versus Coronary-Artery Bypass Grafting for Severe Coronary Artery Disease"

2009-02-19T20:35:00.030-05:00

"Percutaneous Coronary Intervention versus Coronary-Artery Bypass Grafting for Severe Coronary Artery Disease" by Patrick W. Serruys, M.D., et. al. (New England Journal of Medicine (NEJM), March 5, 2009)

I was drawn tonight to the above NEJM article by an article posted on the New York Times (NYT) website, "Heart Stents Found as Effective as Bypass for Many Patients" by Roni Caryn Rabin. This NEJM article has yet to be published in print but was published in advance online.

My first two reactions to the study (and there were many others but these I feel are the most important) :

(i) The follow up of patients was only for one year. I suspect the majority of us are hoping to live much longer than one year after our procedure... Follow up at, let's say, 5 years would be much more valuable, and I think much more revealing. There are usually two periods of divergence between patient groups that we see when evaluating vascular surgeries - such as evaluating the benefits of placing stents versus performing surgery with carotid stenosis (blockages of the arteries that supply blood to the brain and increase people's risk of strokes): early on and long term. Surgeries typically have higher risks early on but lower long term, and with stents the reverse is typically true. Thus, a further divergence between patient groups after one year would not be a surprise to the medical community.

(ii) There are significant differences between the medicines the two groups received after their procedure (even simple medicines like aspirin and cholesterol lowering medicines like statins - drugs that we know reduce strokes, heart attacks, etc.) I encourage you to look at Table 2 of the article and compare the two columns, PCI (patients receiving stents) and CABG (patients receiving surgical bypasses). The patients who had bypass surgery consistently, in regard to each of the medicines listed, were less like to receive the medical standard of care. Those differences make the comparison between the groups of patients much more difficult. Rather than comparing apples and apples, the study is forced to compare more apples and oranges. One wonders at how the two groups would have differed if they had both received the general standard of medical care after their procedures. Perhaps the surgical bypass patients would have done even better. One would expect so.

By the way for the women out there, 78% of the study participants were men - a flaw that continues to plague studies, even today.

If you are interested, I encourage you to attempt to read the article - you will understand more than you think and be able to make your own opinions. If not, I encourage you to read the editorial accompanying the article, Coronary Revascularization in Context by Richard A. Lange, M.D., and L. David Hillis, M.D. (NEJM, March 5, 2009).

Consumers should be aware of the limitations of what they read and are told. For those interested, previous entries on related subjects: The almighty cardiac stent and Reaction to Article: "Communicating Medical News -- Pitfalls of Health Care Journalism".

Placebos, doctors, and fibromyalgia (Addendum)

2009-02-08T18:08:00.008-05:00

As discussed in the last entry, one of the problems with surveying doctors' prescribing habits in treating fibromyalgia is that it disregards the controversy surrounding the diagnosis. Therefore, does doctors' use of placebos in treating fibromyalgia really represent their general use of placebos? Published online today is an article that elucidates further the skepticism that surrounds this diagnosis.

For those interested: "Drugmakers' push boosts 'murky' ailment" written by Matthew Perrone, AP Business Writer.

Placebos, doctors, and fibromyalgia

2009-02-01T23:46:00.015-05:00

A placebo, according to the American Heritage Dictionary, is “a substance containing no medication and prescribed or given to reinforce a patient's expectation to get well.”

When we think of placebos, we generally think of sugar pills; however, the concept of placebos has evolved to include pills with active ingredients and more broadly any “treatment whose benefits (in the opinion of the clinician) derive from positive patient expectations and not from the physiological mechanism of the treatment itself.” (BMJ 2008;337:a1938; Prescribing "placebo treatments": results of national survey of US internists and rheumatologists).

Using this broad definition, a group of researchers set forth to study the current practices of U.S. doctors in prescribing placebos. Its study results, published in the British Medical Journal (BMJ) in October 2008, were reported in all the major newspapers, including an article in the New York Times.

The study, as it was reported, found that approximately half of the American internists and rheumatologists surveyed regularly prescribe placebos.

While the general public likely was surprised by these results, as some doctors might have been, anyone reading the actual study likely was not. Despite the suggestion that the study surveyed the general attitudes and behaviors of physicians in prescribing placebos, the study actually asked the questions specifically in the framework of fibromyalgia.

Fibromyalgia

Fibromyalgia is a poorly understood condition of chronic pain over multiple muscle and soft tissue areas of the body often accompanied by nonspecific symptoms, such as fatigue, headache, and sensation of joint or tissue swelling. The symptoms of fibromyalgia occur with varying severity and can be aggravated by various factors, such as stress or poor sleep.

While a physical exam reveals tender points located symmetrically on both sides of the body, the patients look healthy and have no other real findings on exam, labs, or x-rays. Once other potential diagnoses are excluded, the diagnosis of fibromyalgia is made.

What causes fibromyalgia? We don't know. How best to treat it? We don't know.

Some studies suggest that prolonged sleep deprivation can cause symptoms similar to fibromyalgia, but many patients with fibromyalgia do not have sleep disturbances. An association of fibromyalgia with mood disorders has led some doctors to attribute the symptoms to psychiatric causes, but again the majority of patients with fibromyalgia do not have psychiatric disorders. In part because co-existing illnesses can confound the diagnosis, a clear explanation for fibromyalgia does not yet exist.

The current explanation for fibromyalgia is that the brains of patients with fibromyalgia are overly sensitive to the nerve signals emanating from the patients' muscle and soft tissues and, as well, over-interpret these inputs as pain. (There are parallels here with irritable bowel syndrome.)

Despite this knowledge and the knowledge that patients with fibromyalgia suffer from real pain, doctors in general, without any objective findings in their patient, have a hard time understanding the disorder and treating it. They tend to see fibromyalgia as in their patients' heads and can become as frustrated as the patients in trying to treat the chronic pain.

Treatments for fibromyalgia

The available treatments for fibromyalgia include patient education, aerobic exercise, muscle strengthening, cognitive behavioral therapy, and, of course, medications. The medications are of varying but limited benefit and include some tricyclic antidepressants, serotonin reuptake inhibitors (SSRIs), anticonvulsants, and muscle relaxants in combination with acetaminophen (Tylenol). Consistent with a lack of evidence for muscle or tissue inflammation in fibromyalgia, there is generally no benefit from anti-inflammatory agents, such as NSAIDs (a group of pain relievers that include over the counter medications such as ibuprofen and naproxen) or prednisone. The prescribing of narcotics other than tramadol are usually avoided due to a lack of evidence and a concern for long-term abuse.

A look back now at the BMJ study

The study surveyed doctors to explore current practices in prescribing placebos. Despite how the study was reported in the lay press, the questions were asked in the framework of treating fibromyalgia. Given what you now know about fibromyalgia (a condition of chronic pain with an unknown cause that is difficult to treat) are you as surprised by the study results? Clearly, if the study asked the questions in the framework of other diagnoses, such as rheumatoid arthritis or heart disease, you would not expect half of doctors surveyed to report regularly using placebos.

The study revealed the use of the following placebos: over the counter pain relievers (41%), vitamins (38%), sedatives (13%; usually implies benzodiazepines or 'valium-like' medicines - drugs that soothe or calm and can induce sleep), antibiotics (13%), saline (3%, salt water), and sugar pills (2%). Saline and sugars pills, in not containing active ingredients, were the only two placebos in the traditional sense of the word and made up 5% of cases in which placebos were used (not 5% of doctor-patient encounters for fibromyalgia).

Risk-benefit analysis

As observed in the study, the placebos of today are generally not sugar pills but pills with active ingredients. In fact, obtaining sugar pills from pharmacies is now extremely difficult as very few pharmacies will, and only on special request, make them – it requires time and know-how. I suspect doctors' fear of being sued also plays a role in the prescribing of more active than inactive placebos, as a medicine with an active ingredient appears more easy to justify.

The beauty of sugar pills, of course, is that they carry little risk to the patient. If ultimately the patient and doctor want the patient to feel better and if a pill, whether a placebo or not, can be effective with little risk to the patient, then the risk-benefit analysis would seem to favor giving it.

There are obvious risks, however, in prescribing medicines with active ingredients: side effects, allergic reactions, interactions with other medicines the person is taking, etc. The use of antibiotics in the study as a purported placebo in treating fibromyalgia is, therefore, of a bit more concern. The antibiotics were presumably prescribed to allay patients' fears of Lyme disease or other chronic bacterial infections, reflecting unfortunately already known inappropriate use of antibiotics (see past entry: Antibiotics and the common cold). Without evidence of a clear bacterial infection, a risk-benefit analysis, particularly in fibromyalgia, would of course generally not favor antibiotics as they may lead to real, potentially serious medical problems.

A placebo effect for doctors?

Placebos are not only for patients, though. They can be for patients' families and even the doctors themselves. While doctors in the study may have justified the use of antibiotics as placebos for their patients, they very well may have been treating themselves - perhaps their own concerns about missing a diagnosis behind persistent, nonspecific complaints or a desire to discover a fortunate, effective and sufficient treatment for the patients' problems.

Less discussed is this idea that sometimes in prescribing specific treatments to patients, doctors are actually, in essence, treating themselves or treating themselves in addition to the patient – when, to rework the earlier definition of placebo, positive doctor expectations may outstrip the known benefits from the physiological mechanism of the treatment itself. The doctor's desire to help the patient get better or be more comfortable may at times be too great.

Of course, not for naught, positive doctor expectations may lead to positive patient expectations and treatment benefits via the placebo effect.

A few more thoughts from the study

The authors of the BMJ study on placebos bring up two additional interesting and unanswered questions for discussion: the ethical considerations of prescribing placebos and whether placebos work if patients know they are taking placebos.

Thoughts?

Guest entry: Suicide, psychiatry, and fiction

2009-01-26T12:51:00.013-05:00

posted by Antigone Kostas, MD (psychiatry resident)

It's been insidious. Having been on vacation from psychiatry residency for a week with more time to peruse fiction selections, I have noticed a change.

At one point in a story I was reading the narrator noted that he and another guy "just ended up" peeing together behind a tree. He mentioned this detail in passing, as a segue to the conversation they had while peeing, but whoa! How does something like that happen? What happened to personal space and the fact that a whole field (without a mention of a paucity of trees) does not necessarily situate these urinals naturally next to each other? Suddenly, a major red flag appears. Details I would have normally glossed over, I now can't.

Way too much Freud.

In addition, since working in the psychiatric ER, I have learned not to dismiss things. I have learned to ask very specific questions and not to leave things to vague feelings. At first, I admit, I didn't see the point ("They're suicidal, they swallowed a bottle of pills, for god's sake hospitalize them!!"), but we can't hospitalize all the suicidal patients

^¹, especially those with borderline personality disorder^² when the events were just an acting out.

People with borderline personality disorder don't have a strong sense of 'wholeness.' Much of what they feel internally comes from what is going on externally, and as a result they cannot regulate their own emotions very well. They don't tolerate frustration well so they may jump from the extremes of being very angry to being okay. While they were in the throes of a very strong emotion when they tried to commit suicide, they just don't feel that way anymore. Borderlines often have multiple suicide attempts in their history and some actually do die, usually because they misjudged the lethality of their attempt, but more often the attempts are a cry for help or an acting out.

In the course of examining suicide attempts, innumerable questions arise. How serious was the attempt? How many pills did they take? What was it? For example, Benadryl is less serious. Did they take it in front of someone in a melodramatic gesture? Who found them? How were they found? Did they leave a note? A note is more serious and suggests they were not just acting in the heat of the moment. Have they attempted suicide before? What were their other suicide attempts like? Are they repetitive incidences of acting out or are they all serious attempts? Can they keep it together now in the psychiatric ER?

In the ER, as psychiatrists, we have to probe the patients' motivations at each step, study their current affect and decide whether we think they're serious about making another attempt. It can be tricky (and there's no guarantee that someone might not act unpredictably and try suicide again...), which is why we really have to make sure we probe every detail and make sure we don't miss something the patients are trying to hide.

This is the reason why now, reading fiction, if I read an odd description and the author does not explain the context or motivations of the characters, I feel like I am being duped. I cannot easily go on, gloss over for the sake of fiction, because the whole premise is false. It would never happen! There needs to be context... Instead of location location location, it's now context context context!

.....

1We can't hospitalize all the suicidal patients in part because there are too many of them.

2Borderline personality disorder is a complex syndrome and includes some of the following diagnostic criteria:

"– dramatic efforts to avoid being alone
– a pattern of intense unstable relationships
– disturbances of self-image
– self-damaging acts
– suicidal threats or gestures
– marked emotional instability
– persistent feelings of emptiness
– difficulties with controlling anger
– thoughts of persecution or episodes of dissociation”

(Robinson, David, J. Disordered personalities. Rapid Psychler Press, Michigan: 2005)

Reaction to Article: "Communicating Medical News -- Pitfalls of Health Care Journalism"

2009-01-11T20:16:00.022-05:00

Communicating Medical News -- Pitfalls of Health Care Journalism by Susan Dentzer (New England Journal of Medicine; January 1, 2009)

The article above, printed in the “Perspectives” column in a recent issue of The New England Journal of Medicine, reviews the failings of heath care news and challenges journalists to offer a more complete picture and resist the urge to sensationalize and oversimplify the news. I recommend that every consumer of health care news read the article as it provides an important perspective.

The article will also give readers a better appreciation for the frustration that doctors experience reading health care news in the lay press, realizing the misinformation that readers digest, and knowing the time and energy they then must spend attempting to correct mistaken notions.

The bottom line: read health care news with a good degree of skepticism. (Despite journalism's best intentions, the media industry is ultimately in the business of making money. Health care news, whether fully accurate or not, sells and increased sales bring more money.)

Turns out our mothers were right: why we should eat slowly and fully chew our food

2009-01-01T19:17:00.013-05:00

In talking with gastroenterologist friends about being on call this holiday season, they humorously note the number of times they inevitably are called by the Emergency Room to see patients in whom food has become lodged in their esophagus.

Swallowing

In the normal act of eating, after chewing our food, a bolus is transferred from the back of our mouth to our pharynx and then to our esophagus. Once in our esophagus the food is pushed along to our stomach by peristalsis, organized contractions of the muscles of the esophagus. (a graphic illustration of the swallowing process, www.hopkins-gi.org/multimedia/database/intro_250_Swallow.swf)

Holiday hiccups

In our holiday zeal on seeing all the delicious, prepared goodies (after starving all day in anticipation), we inhale our holiday meals, but several unlucky individuals among us will get a large piece of food stuck in their esophagus (the size of the food bolus overwhelming the muscles of the esophagus) and be found by a gasroenterologist uncomfortable, lying on a stretcher in the ER in search of relief.

The remedy

The patients are brought to the Endoscopy Suite where the gastroenterologist passes a flexible tube with a camera at its end (an endoscope) through the mouth and down the esophagus to where the food is lodged. Once there, typically, the gastroenterologist simply pushes the food through the rest of the esophagus to the stomach where digestion will aid it's transit through the remainder of the digestive tract...

Not always a laughing matter

On a more serious note the procedure, an esophagogastroduodenoscopy (EGD), like any other procedure has its own risks, including the potential for rupture of the esophagus – a steep price to pay for time otherwise spent eating slowly and enjoying a meal.

Guest entry: Multiple personality disorders, a theory

2008-12-28T22:49:00.018-05:00

posted by Antigone Kostas, MD (psychiatry resident)

Key Thoughts After Reading Richard Gottlieb's "Does the Mind Fall Apart in Multiple Personality Disorder? Some Proposals Based on a Psychoanalytic Case"

In one of our case conferences, a resident presented a patient with a diagnosis of multiple personality disorder (MPD) to open discussion. However, what we residents very quickly learned from our supervising attendings is that no credible psychiatrist really BELIEVES in multiple personality disorder. Instead MPD is a figment of very suggestible, most often sexually or physically abused people. Therefore when a friend who is not in psychiatry asked to learn more about MPD, I groaned. Nonetheless, I gathered some articles on the subject and was actually surprised to find one that offered an interesting perspective in understanding MPD. Gottlieb takes a psychoanalytic approach to MPD rather than one looking to hypnotize the patient and fuse the multiple selves. Below is his explanation of how MPD evolves.

Gottlieb argues that MPD is not a problem of a disintegrating mind or multiple selves. Rather it is multiple behavioral states (not selves) stemming from fantasies of being multiple people. First he says the person must believe that multiple personalities are possible. This is not a far leap when one considers what happens during trauma and when one dissociates. The dissociating person thinks, "This terrible thing is not happening to me, but rather I am over here as an observer of a different me who is the unfortunate participant, victim...." (Gottlieb 1997) etc. Hence the multiple view points. Also, these people are often victims of sexual/physical trauma who have had their "bodies forcibly intruded upon, entered, filled, and emptied." Implicitly, Gottlieb argues that if someone has had control over someone else's body, someone else could likewise have control over his/her mind. Thus, the emergence of MPD.

Gottlieb, Richard M. "Does the Mind Fall Apart in Multiple Personality Disorder? Some Proposals Based on a Psychoanalytic Case." Journal of American Psychoanalytic Association, 45: 907-932.

Kidney stones (and obesity)

2008-12-19T23:00:00.015-05:00

(continued from a previous entry, The excesses of modern life and kidney stones)

4. Weight

The NY Times article “A Rise in Kidney Stones Is Seen in U.S. Children” alludes to the rise in obesity as a likely contributor to an increase in kidney stones but neglects to provide an explanation.

A simple argument, of course, would implicate known risk factors, such as a higher intake of salt and protein and insufficient intake of water, but the assertion of the article and many experts is that obesity increases the risk of kidney stones independent of typical risk factors.

How might that be? The link is insulin resistance.

Insulin resistance

Insulin resistance is the insufficient response of the body to the insulin that the pancreas secretes. That is, normally, in proportion to our meals the pancreas (to assist in regulating our metabolism of food) secretes insulin that initiates important chains of events in our muscle, liver, and fat tissues. In the setting of insulin resistance, the pancreas secretes the insulin, but the body's tissue, rather than jumping to attention and reacting appropriately, merely shrugs. Again, the body is resistant to the insulin the pancreas is secreting. To overcome this indifference, the pancreas must secrete more insulin.

There are several causes of insulin resistance, including genetic, but a growing cause is obesity. (Not all obese individuals develop insulin resistance, and proper diet, exercise and weight loss can lower insulin resistance.)

The problem with insulin resistance is that it is associated with multiple medical problems, such as diabetes mellitus (often the first step on the road to diabetes, developing even decades before diabetes is diagnosed), hypertension, and cardiovascular disease.

Uric acid

Less well known is the association between insulin resistance and high uric acid levels in the body. High levels of uric acid in the blood can lead to the infamous gout, a painful, inflammatory arthritis.

In the urine high levels predispose to kidney stones - not only to uric acid stones but also to almost all other types of kidney stones. Microscopic crystals of uric acid can act as the tiny seed or nucleus around which other minerals are able to amass, thereby provoking the formation of other types of kidney stones.

Bottom line

Obesity is linked to insulin resistance and its association with high levels of uric acid in the urine, which contribute to kidney stones.

(More on insulin resistance in a future entry.)

Kidney stones (and high protein diets)

2008-12-01T21:41:00.009-05:00

(continued from a previous entry, The excesses of modern life and kidney stones)

3. Protein

The New York Times article “A Rise in Kidney Stones Is Seen in U.S. Children” implicates recent high-protein fad diets as contributing to the increased incidence of kidney stones.

Specialists of kidney stones and calcium metabolism have long derided the high level of protein in the typical Western diet as contributing to not only kidney stones but likely also to osteoporosis. (Osteoporosis is more prevalent in Western societies - including in immigrants to the West relative to the inhabitants of their native-born lands – suggesting environmental causes.)

Protein as an acid

In the same way that the body functions best with a certain amount of water, at a certain temperature, etc., the body functions best at a certain acid-base level, a certain pH (7.4). As a result the body works hard to maintain this optimal acid-base state.

Proteins, however, are acidic. They are made of amino acids, and therefore eating protein requires the body to buffer these amino acids to maintain the proper pH - a task which it does using buffers in the blood.

The effects of high protein diets

Eating high amounts of protein, however, overwhelms these buffers in the blood, and the body is forced to find other ways to buffer the extra acid. One of the ways it does so is to break down bone. As expected when bone is broken down, calcium is also released, and extra calcium inevitably spills into the urine.

The kidneys, in attempts to rid the body of the extra acid, acidify the urine, but this makes the aggregation of crystals in the urine easier and further predisposes a person to kidney stones. In addition, the extra acid in the body (this metabolic acidosis) lowers the levels of urinary citrate, a molecule that normally attempts to inhibit kidney stone formation.

Bottom line

With high protein diets the resultant acidic urine, low levels of urinary citrate, and extra calcium in the urine all contribute to the increased risk of kidney stones.

The excesses of modern life and kidney stones

2008-11-17T21:03:00.013-05:00

The article “A Rise in Kidney Stones Is Seen in U.S. Children” was recently featured in the New York Times.

The article reported what is a perceived increase in kidney stones in children and attempted to explain the phenomenon based on changes in lifestyle. The idea is that, as the genetics of the population have not changed significantly, increases in kidney stones can be attributed to changes in the environment.

Generalizing from what is known about kidney stones in adults, I will briefly expand on the points made in the article so that the reader has a fuller view of how our lifestyle today (a life of excess, if I may) contributes to kidney stones.

Below is a brief list outlining the topics to be discussed over a series of entries:

(Water)
Salt
Protein
Weight
Colas
Exercise

Be aware: while for many people kidney stones are preventable, there are, however, underlying metabolic and medical causes of kidney stones, and kidney stones are a reason for evaluation by your physician.

Kidney stones are the aggregation of crystals in the urine

One way to conceptualize how kidney stones are formed is to think back to the experiment you did in grade school in which while stirring water you slowly added more and more salt. Initially, the additional salt fully dissolved in the water, but a point arose when the water could no longer hold any more salt, when the sodium suddenly precipitated out and crystals developed. While this is an overly simplistic analogy for how kidney stones form (the urine, for instance, contains molecules such as citrate that attempt to prevent the formation of crystals or kidney stones), it can be a useful one.

1. Water

The analogy clearly is useful in understanding how a lack of sufficient water intake predisposes people to the formation of kidney stones and how drinking more water is the best way to prevent kidney stones. The more water we drink, the more we dilute our urine and the greater difficulty crystals have in aggregating.

How much fluid to drink?

The more important question, of course, is how much should people urinate or how dilute should the urine be. The recommendation is that people with kidney stones should pass a little over 2 liters (~1/2 gallon) of urine per day, which amounts to drinking ~ 3 liters of fluid per day. Also, because a concentrated urine at any time of the day still predisposes to kidney stones, the fluid intake should be spaced throughout the day, including at night. Those living in hotter climates or engaged in heavy exercise likely need to drink more, as they are losing much of the water in ways other than through the kidneys, such as through the skin by sweating.

A rule of thumb: if the urine of a person with kidney stones looks like water (clear, not yellow) throughout the day than that person is drinking enough water.

Caution: there are dangers to drinking too much water (please consult with your doctor), and those of us not predisposed to kidney stones do not need to meet those amounts.

(the discussion of other lifestyle elements contributing to kidney stones to be continued in future entries...)

Nasal spray decongestants, underrecognized limitations

2008-11-11T10:19:00.014-05:00

Mr. Jones came into the office complaining of ongoing nasal congestion since his most recent cold. "Doc, it's been weeks, and I can't get my nose to clear up. The only relief I get is from this nasal spray, and it doesn't seem to do much anymore." He pulled the bottle of nasal spray from his pocket to show me. "But if I don't use it, I can't breathe."

In the throes of an illness, we reach for any and all potential remedies for a little relief, including the nasal spray decongestants conveniently found over the counter at our local pharmacy. Nasal spray decongestants, such as Afrin, work by constricting the blood vessels in the inflamed lining or mucosa of our nose and in so doing attempt to shrink the mucosa, open the passages and help us breathe.

In studies, however, the benefit after a single dose compared to placebo (the placebo always has some benefit, often significant) is only about a ten to fifteen percent improvement in reported symptoms, and this benefit quickly wanes with each subsequent dose. The nasal congestion returns, and after continued use of the spray for a few days, there is no benefit.

Of course, most illnesses last longer than three days, and therefore people find themselves continuing to use the spray. (To compensate and find some relief, people often then increase the frequency of sprays.) Unfortunately, after using the nasal spray for more than a few days, people suddenly discover on trying to stop that they can't.

Rebound Congestion

The mucosa in their nose is even more inflamed and their congestion is even more severe than if they had never used the spray. They have what is called rebound congestion.

People using nasal spray decongestants for prolonged periods of time essentially become addicted to the spray and not because of any 'high," but a stuffed nose from which a person struggles to breathe is truly frustrating.

Do not use this product for more than 3 days.

Many people believe that the warning labels on over the counter medications are meant to be taken with a grain of salt, if not ignored altogether, but that is short-sighted. The warning on the nasal spray decongestant labels can't be written in large enough letters. The sprays are simple over the counter (OTC) medications, but one of the greatest difficulties ENT (ear, nose & throat) doctors face in their practice is getting people off of them.

Names of nasal spray decongestants

The list below is a non-exhaustive list of over the counter nasal spray decongestants in this class and their active ingredients.

Active ingredients:

oxymetazoline - Afrin, Vicks Sinex
phenylephrine - Dristan, Neo Synephrine

What this class of sprays have in common is that they are adrenergic (like adrenaline - what is released into the blood on seeing a bear). While they are topical nasal sprays, there is always a degree of absorption, even if small, across the mucosa of the nose. As a result those with high blood pressure or otherwise predisposed to heart attacks or strokes are also instructed by the label not to use these nasal sprays.

Alternative OTC nasal sprays

Often forgotten saline (salt water) nasal sprays can be quite effective in relieving symptoms of nasal congestion and potentially decreasing the risk of sinus infections, as they moisten the mucus and allow the sinuses to keep draining. (A draining sinus is generally not an infected sinus.) A runny nose is merely a nuisance.

The truth about cold medicines

Despite the commercials for nasal spray decongestants and other cold medications and despite the fact that we live in a world of the internet, high definition TVs and portable telephones, there really is no great over the counter medication for a cold. None are tremendously better than placebo and none are without the potential for side effects. There is something to be said for being on some level accepting of a cold and the stuffy or runny nose that comes with it. If only we always have the luxury to be that patient.

More about cold medicines in a future entry..

Strep, antibiotics, and acute rheumatic fever

2008-11-04T18:37:00.013-05:00

“My throat is killing me” was the first thing Mr. Jones said on seeing me in the office on Monday. He had developed a sore throat on Friday of the past week, and after suffering through the weekend and not improving, he broke down and made an appointment. While he wasn't sure what I could offer him – he didn't think he had strep throat^¹ - he was miserable and subconsciously hoped I might give him an antibiotic anyway and he would get better sooner. He wanted relief. Swallowing was still exceptionally painful and, while he admitted loving ice cream, he was clearly tired of eating only ice cream.

I could sense his frustration, but before falsely raising his expectations for antibiotics and disappointing him further I felt compelled to tell him that, while I would do the best I could to help him feel better, antibiotics at that point would unlikely shorten the course even if he had strep throat.

“Thanks Doc,” Mr. Jones joked, feigning for the door before sitting back down.

I explained that strep throat generally resolves on its own within five days (more than a week is unusual), and in the few studies suggesting that antibiotics can shorten the course (only by a day or two), antibiotics were started within the first forty-eight hours of symptoms.

I reassured Mr. Jones, though, that all hope was not lost and that there are in fact potential benefits to being diagnosed late with strep throat and delaying the start of antibiotics. Studies suggest that starting antibiotics late, at least two days after the onset of symptoms, is actually associated with a much lower risk of its recurrence during the same strep season.

“So I'm better off not having started antibiotics?” Mr. Jones asked.

While guidelines do not recommend delaying antibiotics in strep throat, the theory behind doing so is to provide the body the time to better develop antibodies to the bacteria, a stronger immune reaction, and memory for protection the next time the person is exposed.

“Why bother then to take antibiotics at all?”

As discussed, antibiotics started early have the ability to shorten the course of strep throat. Antibiotics also decrease the transmission of strep throat to close contacts, including family members. Studies performed with penicillin (still considered the first line treatment for strep throat), show that patients are minimally contagious within twenty-four hours of starting antibiotics.

“Sure, but...”

The main reason for administering antibiotics in strep throat, however, is to prevent acute rheumatic fever. Acute rheumatic fever is an inflammatory, autoimmune (the body attacking itself) reaction that can develop in untreated strep throat. “…the immune system [normally] works by recognizing constant and variable patterns on ‘foreign’ materials and microbes that don’t originate in the host and targeting these invaders and the cells that harbor them for destruction and elimination.” (from A.B.’s entry “Biology of a Cure for HIV,”) In acute rheumatic fever the immune system confuses the patterns on the bacteria with those on tissues in the body, including the heart. Long term damage to the heart and heart valves are potential, severe complications of acute rheumatic fever. (The fear with a vaccine against strep throat, that the body will attack itself, is a large reason why such a vaccine is not yet available.)

Acute rheumatic fever is thankfully rare in the United States although it is more common worldwide. It primarily affects children between 5 and 15 years of age, but can infrequently strike adults, particularly those previously affected. Some people, due to the genetics of their immune systems, are more predisposed to rheumatic fever in the setting of certain ‘rheumatogenic’ strains of strep bacteria. (The reason for the age discrimination, therefore, may be that most adults predisposed to acute rheumatic fever have already revealed themselves as such as children.)

“Sounds scary, but you just said acute rheumatic fever is rare in the U.S., especially for an adult, and that strep throat will go away in a few days anyway. Again, I'm confused, why should I bother with antibiotics?”

Given the severity of potential complications of acute rheumatic fever, the benefits of antibiotics are thought to outweigh the risks. Amazingly, starting the antibiotics even up to nine days after the onset of symptoms (and by then the sore throat has likely already resolved) still prevents acute rheumatic fever. A study conducted on military recruits discovered the phenomenon.

There is the potential for other rare complications of strep throat in adults, such as an extension of the infection, scarlet fever and streptococcal toxic shock syndrome.

“Yes, but don't forget I'm not so sure I have strep,” Mr Jones added.

After discussing further with Mr. Jones his symptoms, examining him and ruling out potential complications, I had to agree that I didn't think he had strep throat. Not unexpectedly most sore throats are viral, and strep throat makes up maybe less than 10% (one in ten) of sore throats that present to doctors. Do we give antibiotics to everyone? (for further reading on the forces at play in administering antibiotics, "Antibiotics and the common cold")

Mr. Jones, however, had enough symptoms that I couldn't be sure that he didn't have strep throat, and I recommended we evaluate further. Even the most experienced doctors are notoriously unable to reliably diagnose who has strep throat by only history and exam.

How then do doctors evaluate sore throats and determine who has strep and who needs antibiotics? A blog entry for another day, but Mr. Jones ended up on throat culture having strep throat.

.....

1Strep throat (streptococcal pharyngitis): an infection of the throat by a particular type of bacteria, Group A streptococcus.

Biology of a Cure for HIV

2008-10-29T22:59:00.008-04:00

“When are they going to find a cure, doc?”

HIV is epidemic, infecting 2.5 million people a year, and 33 million people worldwide and has been responsible for more than 25 million deaths. During the early days of the epidemic, many people who were infected died within a matter of months. We have crossed significant hurdles since then. Therapy for HIV started with just one drug – zidovudine, or AZT – and has evolved into combination therapy with several potent drugs. Today standard treatment for HIV is called Highly Active Anti-Retroviral Therapy, or HAART. Patients who take HAART can mitigate most of the fatal complications of HIV infection, although many people still do not have access to these life-saving medications. Despite the success of HAART, recipients are committed to lifelong therapy which can be costly, toxic, and complicated. The risk for someone who stops HAART is that the disease can come back, putting the sufferer at constant risk of a poor outcome. Understandably, many HIV-infected persons wonder why there hasn’t been a cure. Some patients have even expressed concern that there are doctors, pharmaceutical companies, and even governments who are suppressing a cure. Before such human failures are blamed for HIV, we still have the difficult challenge of HIV itself.

Some of the reasons why HIV has proven so tenacious lie deep within the biology of the virus...

Taking a fast hold…

From the earliest time points after transmission, HIV quickly insinuates itself into an unsuspecting host patient, like a parasite. HIV is primarily acquired by blood and body fluid exchange through sexual transmission (heterosexual or homosexual) or via the bloodstream directly (in the case of an improperly screened blood supply or intravenous drug use). No matter how it is acquired, once introduced into the body swarms of HIV virus particles (called virions) quickly spread to the body’s lymph nodes – the transit locations for most immune cells. HIV then multiples vigorously and from the lymph nodes disseminates widely throughout the body. Since HIV infection is not localized to one discrete area of the body, therapy, in order to be effective, must penetrate all of the nooks and crannies in which HIV may be hiding. At the current time not all of the drug constituents of HAART pervade into the various HIV-hosting compartments in the body. An example of this is HIV and the brain. Although HIV infects the brain and can lead to significant dementia, some drugs penetrate the fluid around the brain very poorly. People who take those drugs have undetectable viral quantities in routine blood tests, but may still have detectable HIV in the brain fluid, making control of the virus more challenging.

Another reason why a cure is not forthcoming is because of the concerted attack HIV poses to our immune system. The hallmark of HIV infection is the rapid, progressive loss of important cells of the body’s immune organs, the infected person’s CD4 T cells, leading to the Acquired Immunodeficiency Syndrome or, the more familiar moniker, AIDS. The CD4 T cell is critical for guiding various aspects of the body’s immune responses towards the many microbes to which we are exposed, including HIV itself. Even antibiotics require our immune system to do the majority of the work in cleaning up infections. The loss of CD4 T cells not only makes us vulnerable to opportunistic infections but also limits our ability to eradicate HIV from our system, even with HAART. The remaining immune cells are stymied by the propensity of HIV to mutate rapidly, making it challenging for consistent patterns to be recognized by the host. (At the risk of oversimplification, the immune system works by recognizing constant and variable patterns on ‘foreign’ materials and microbes that don’t originate in the host and targeting these invaders and the cells that harbor them for destruction and elimination.)

“But doesn’t HIV therapy improve the CD4 T cell counts?”

It’s true that the CD4 T cells in the blood are replenished when patients consistently take HAART. But despite the best available therapy, HIV-infected persons retain residual defects in their immune system. For instance, the majority of CD4 T cells are, in fact, found in the intestinal wall, and these are not fully replenished by HAART. Though it is difficult to predict the significance of these residual intestinal immune defects, one can envision that HIV could take advantage of holes in the immune system in order to persist in the host.

The Persistence (Despite) Time

The reduction of circulating HIV virus, or viremia, by HAART is the best predictor of a patient’s long-term outcome. A relatively common scenario is to see a patient’s quantity of virus start at more than 750,000 copies per milliliter and then rapidly drop to undetectable levels with the initiation of HAART. However, studies have shown that stopping HAART is detrimental. No matter how long the patient has been taking HAART, an interruption in therapy results in the virus recovering its numbers. Where, then, does HIV hide when people are on HAART?

In addition to the widespread dissemination of HIV early on in the infection, some HIV virions also infect a smaller population of cells and that allow the virus to remain in a latent state, not multiplying the way other virions do. In this situation, the genetic material of HIV is integrated stably in between stretches of the patient’s own DNA. This population of integrated HIV virus resting within cells is called the latent reservoir. Although the virus in the latent reservoir doesn’t harm the body (as far as we know), it is sufficiently hidden from the immune system to resist eradication. In addition, currently available antiretroviral drugs are predominantly active against multiplying virus. Because this latent state of HIV is characterized by a general lack of multiplicationfar fewer multiplying virions, the virus is safe even when patients are on HAART.

“Most cells in the body must die at some point. Why not wait for these reservoir cells to die, then allow HAART to finish off the virus?

In fact, the latent reservoir itself is a long-lasting population of cells infected with HIV. The lifespan of the latent reservoir has been estimated in years to decades, and only very few are thought to die during a person’s life. It is hypothesized that it would take 40 years or more for HIV within this reservoir to be eradicated entirely with HAART – an impractical amount of time for a cure.

“So is there any hope for a cure?”

Although some scientists feel that HIV eradication is impossible, the past 20 years has seen an explosion in new therapies for HIV, and there are newer agents in the pipeline. Never in the history of medicine have such large strides been made against a disease in such a short period. We still have much to learn about the virus, but with knowledge will come further answers as to how to better treat HIV. As a hopeful example, there are a number of people who were found to be resistant to HIV infection altogether. Through careful genetic studies, it was learned that cells from these individuals lacked a molecule on their surface called CCR5. CCR5 is normally manipulated by HIV to gain entry into host cells. So, the people who were CCR5 deficient were actually protected from HIV. Scientists used this knowledge to design drugs that block CCR5, thereby helping to control the ability of HIV to infect new cells. This class of drugs, CCR5 inhibitors, has recently been approved for the treatment of difficult to control HIV.

In 2008 we have crossed many important milestones in HIV research and treatment, some of which have been explored here. But we have many more milestones to come. Further investigation will reveal new ways to control HIV, until one day a cure will finally be in our grasp.

Surrogate endpoints in medical trials

2008-10-16T23:56:00.025-04:00

What if I tell you that, in those who survive heart attacks, the presence of abnormal electrical conductions from the lower chambers of the heart (ventricular arrhythmias¹) is a risk factor for sudden death? That the risk of dying is in fact two to threefold higher in those patients after heart attacks with ventricular arrhythmias and no or mild symptoms? You’d insist we find a way to reduce those ventricular arrhythmias. And if I tell you that we already have two drugs, anti-arrhythmics called encainide and flecainide, that are quite good at doing just that, suppressing those arrhythmias? Perfect, you’d say.

You’d prescribe the medications to your patients and be reassured shortly afterwards on observing a reduction in their ventricular arrhythmias. Admittedly, small studies have not yet shown an increase in survival, but you’d accept that as a limitation of small studies. The reduction in ventricular arrhythmias is real, and larger studies collaborating your view that the drugs thus must also improve survival seem inevitable.

Such was the scenario in late 1989, and for the reasons above doctors regularly gave the anti-arrhythmic drugs encainide and flecainide to patients with ventricular arrhythmias after heart attacks. Then, the preliminary results of the Cardiac Arrhythmia Suppression Trial (CAST) trial were published in the New England Journal of Medicine (NEJM), and the medical community was stunned.

(The vertical line (y-axis) represents survival, and the horizontal line (x-axis) the passage of time.)

N Engl J Med. 1989;321:406-412.

CAST trial

As you would expect, in viewing the graphs, the CAST trial as it was initially designed had to be stopped early.

In the trial, patients after heart attacks with ventricular arrhythmias and no or mild symptoms whose arrhythmias would suppress with encainide or flecainide were given either the anti-arrhythmic agents or a placebo (a sugar pill). They were then followed for an extended period of time. The purpose of the study was to finally answer whether the suppression of these ventricular arrhythmias would truly increase survival.

Although the CAST trial was groundbreaking in this regard - the first well-designed trial to study the question of whether antiarrhythmic drugs safely and effectively reduce the risk of sudden death - the outcome for many physicians seemed to be a foregone conclusion. At the time a few probably even flinched at the idea of giving some of the patients a placebo.

Instead, those patients given encainide and flecainide had about a three-fold increase in overall mortality. They clearly did worse no matter how you analyzed the data: deaths from arrhythmias, nonfatal cardiac arrests, deaths from non-arrhythmic cardiac causes, death from any cause, etc. As Dr. Jeremy Ruskin wrote in an editorial that accompanied the results of the CAST trial, the “results … astounded most observers and challenge[d] much of the conventional wisdom about antiarrhythmic drugs and some of the arrhythmias they have been used to treat.”

Where had doctors’ thinking gone wrong?

Doctors began to equate the indisputable clinical endpoint of survival with the surrogate endpoint, the presence or absence of ventricular arrhythmias. Rather than studying survival of patients as the endpoint in their trials, doctors used the surrogate endpoint, ventricular arrhythmias, and then began in their minds to blur the distinction between reductions in ventricular arrhythmias and survival.

Simply put, the lessons of the CAST trial are that studies are still essential to answering clinical questions, despite what the medical community may believe on faith or common sense may tell you, and you shouldn’t rely heavily on surrogate endpoints.

Next up, Zetia and Vytorin?

A similar scenario potentially exists today with the cholesterol medication Zetia or ezetimibe. Zetia was approved in 2002 by the FDA and is sold both alone and in combination with a statin (the current standard in cholesterol medications), as Vytorin. Zetia works via a novel mechanism and as a result allows for further reductions in cholesterol in patients already on statins. It also is available for people who don’t tolerate statins.

Historically, drugs that lower cholesterol have been proven to prevent heart attacks and save lives, but will that necessarily always be true? Zetia received its FDA approval in large part based on its ability to lower cholesterol, the surrogate endpoint, but does Zetia prevent heart attacks and saves lives? There is no data to prove that. Despite FDA approval of Zetia six years ago, that data is not expected for at least another few years when a large trial called the IMPROVE-IT trial (critics argue that Merck and Schering-Plough were slow to initiate such a trial) studying about 10,000 patients is finally expected to be completed. Until then what should doctors recommend to their patients?

Could we discover that lowering cholesterol is not a sufficient surrogate? That Zetia does not in fact prevent heart attacks or save lives? Could the medical community find itself again with its pants down as it did when the results of the CAST trial were revealed? Possibly. Estimated sales of Zetia and Vytorin in 2007 close to $5 billion suggest that the lessons of the CAST trial perhaps no longer ring loudly. Growing uncertainty, however, has led guidelines to recommend more and more that Zetia not be used as a first line agent in lowering cholesterol.

How much should we rely on surrogate endpoints?

Despite historical failures of surrogate endpoints, such as with the CAST trial, surrogate endpoints have an important use in medical research, particularly with clinical endpoints that are rare or do not occur for protracted periods of time. For example, approximately a quarter of patients with chronic hepatitis C go on to develop cirrhosis (the replacement of the liver by scar tissue), but the process occurs over several decades. Imagine evaluating medications for preventing cirrhosis in hepatitis C and waiting over thirty years to determine whether the drugs are effective. Instead, most trials today look for the eradication of the hepatitis C virus from patients, a surrogate endpoint which has been shown to be associated with the lack of progression to cirrhosis.

Satisfying public demand for new medications and public demand for shortened approval processes for drugs require the use of surrogate endpoints; however, with a shortened approval process, post-marketing surveillance for key clinical endpoints and adverse events become even more crucial.

Our better understanding of science and medicine at the molecular level continually generates surrogate endpoints, but these surrogate endpoints must be meticulously and vigilantly selected. In addition, the medical community must always underscore the distinction between clinical and surrogate endpoints. The lessons of the CAST trial should not be forgotten.

.....

¹The heart is made of four chambers, two small chambers on the top (atria) and two large chambers on the bottom (ventricles). The atria merely feed the ventricles extra blood at the end of the filling cycle, but the ventricles are the workhorses of the heart sending blood to the lungs and the rest of the body. The normal electrical conduction of the heart begins in a node of the atria and spreads to the rest of the heart in a systematic fashion. Ventricular arrhythmias are abnormal spontaneous electrical conductions originating from the ventricles (six or more per hour).

High blood pressure (hypertension), in short

2008-10-07T23:12:00.019-04:00

Mr. Jones, a fifty-four year old man, had been into the office several times in the last year. He was reasonably thin, walked regularly, and felt great. Each time his blood pressure was slightly elevated, around 142/84. Each time I reminded him of the importance of blood pressure control.

He was already on blood pressure medications, but he was resistant to the idea of taking more medication. I knew though that, despite his protests, his diet (as he was a bachelor) was loaded with salt and that he could possibly control his blood pressure simply by lowering the salt in his diet. Each visit we discussed the sources of sodium in his diet, and I encouraged changes.

Otherwise, I told him, we needed to increase his blood pressure medications. A mild elevation in his blood pressure would unlikely kill him in the near future, but an increased risk of a stroke or a heart attack over time was real. Each time he reassured me that he would start watching the sodium in his diet and get his blood pressure under control.

In the end the decision on what to do was his, but short of twisting his arm I strongly pushed for changes. How important to him was the salt in his meals? While life is not only about quantity (years lived) but also the quality of those years, perhaps he was able and willing to make a few simple lifestyle changes. I couldn’t say that better blood pressure control would necessarily prevent a heart attack or stroke (we all have to die of something), but it would certainly lower his risk and potentially delay the possibility.

Several months later at his next appointment Mr. Jones, a statistician, returned with excitement. To my surprise and admittedly even to his own surprise, he finally decided to heed my advice.

Statistically significant

He started looking at the labels of foods, and he was amazed by how much sodium was in just about everything he ate. He then didn’t just reduce his sodium intake, but he decided to test the hypothesis and followed his blood pressure over several months with the same care and exactness with which he had done everything in his life. Once he had collected enough blood pressure readings, he performed a full statistical analysis and was surprised to discover, as he said, that not only was his doctor right but how much cutting down on sodium lowered his blood pressure.

Hypertension as a silent killer

While hypertension occurs in over half of people over sixty-five years of age, it is actually quite prevalent in the population as a whole. Population data from the United States around the year 2000 suggest that hypertension is present in about one third of people eighteen years and older.

What are the symptoms of high blood pressure? None. How do patients with high blood pressure feel? Great.

Because there are no symptoms, people often don’t know that they have hypertension, and once diagnosed the lack of symptoms and lack of immediate risks add to people’s poor compliance with treatment. The problem is that blood pressure elevations, even mild elevations, are associated with significant medical problems: heart disease (such as thickening of the heart, heart attacks, and heart failure), strokes, bleeding strokes, and kidney failure.

The risks of high blood pressure, including death, are correlated with the degree of elevation. The risk lies as a continuum on blood pressure readings. There is no magical blood pressure; the body doesn’t know numbers. The risks are also not immediate, except in special circumstances, but cumulative over time.

What is the number one risk of death to man or woman in the United States? Prostate cancer? Breast cancer? Colon cancer? By far, heart attacks and strokes.

“So my blood pressure is elevated. I’ve had high blood pressure all my life. That’s just the way my body is...”

That nothing has happened to you does not mean you are healthy and that something won’t happen. High blood pressure is a high-stakes numbers game. That you’ve walked into the middle of traffic without looking and weren’t killed doesn’t mean that it’s safe or that if you continue to do so that you won’t be hit and killed the next time you venture out.

Things worse than death…

In fact, getting killed instantly is not necessarily a bad way to pass, but as in motor vehicle accidents that’s not usually what happens with high blood pressure. Living with a disability the rest of your life (such as not being able to move the right side of your body and needing someone to feed you and wipe you, not being able to talk, or not being able to walk three feet without stopping due to shortness of breath) – feeling terrible and not being able to do the activities you want to do with your friends and family – that is the typical consequence and misery of poorly controlled hypertension.

Causes of blood pressure

There are numerous causes of hypertension. The most common by far, the one most people think about when hypertension is mentioned, is called essential or primary hypertension (high blood pressure not due to other identifiable causes), and is the focus of this entry. Other explanations for high blood pressure include white coat hypertension (being in the doctor’s office), medicines such as oral contraceptives, kidney diseases, sleep apnea, and thyroid and other endocrine abnormalities. Ruling out these secondary causes is part of a doctor’s initial evaluation of a patient’s hypertension.

Am I doomed?

Thankfully there are therapies to lower blood pressure, and plenty of studies show that lowering blood pressure significantly reduces risks. Clinical trials suggest mean reductions of a quarter to a third of strokes or heart attacks with control of blood pressure. The benefits are generally seen with long-term reductions in blood pressure; however, the elderly, given their overall greater risk, are more likely to benefit even from short term reductions in blood pressure.

Many medications are available to lower blood pressure (including various diuretics, ACE inhibitors, angiotensin receptor blockers - ARBs, calcium channel blockers and beta blockers), but lifestyle changes, such as Mr. Jones’ reduction in dietary sodium, can have significant effects on blood pressure. Lifestyle changes, in fact, are recommended as the first treatment option in people with mild hypertension. Only when a patient has failed lifestyle changes are medications recommended, according to national guidelines.

Despite doctors being well aware of these guidelines and the importance of lifestyle changes for their patients, doctors find themselves over time reaching more often and sooner for medications. Doctors, after seeing many failed attempts at lifestyle changes, may come to expect the next patient to fail as well. They may fear patients will not follow-up in a timely way and instead be left with poorly controlled blood pressure. Then, not only is the patient exposed to health risks, but the doctor fears his own malpractice risks. In addition, to counsel a patient on diet and exercise and changing habits is time consuming. In the age of insurance-imposed short visits, doctor usually don’t have the time to properly or effectively do so. Giving a pill is much easier. Patients faced with their own monetary and time constraints often cannot make the frequent visits to the doctor needed for this approach.

Lifestyle changes are not easy to make. Losing weight or getting used to lower levels of salt requires a focus and commitment. Patients are typically motivated to improve their health and make changes on first being diagnosed with high blood pressure, but the commitment tends to wane. Taking a pill is much easier.

Lifestyle changes, however, are key. Possible lifestyle changes include but are not limited to cutting down on dietary sodium, losing weight, aerobic exercise, avoiding excessive alcohol intake, and better handling stress. While each have an impact on blood pressure and your health, together they have a much greater impact.

Doctors treat high blood pressure because doctors can easily measure it and treat it. Taking a medicine to lower your blood pressure may be effective in lowering your blood pressure, but it does nothing for the other chemical changes occurring in your body that doctors do not routinely measure and that are detrimental to your health. Hypertension for many people is merely a sign of more significant underlying health issues developing from a poor diet, little exercise, and excess weight. The analogy frequently used is that of the tip of the iceberg with the remainder of the massive iceberg underwater and out of view.

Dietary sodium

Sodium clearly plays a role in high blood pressure as hypertension is mainly seen in societies in which people eat more than 2.3 g of sodium per day. The excess sodium intake over many years is thought to play a role. In societies in which people take in less than 1.2 g sodium per day, hypertension is actually rare.

Lowering dietary sodium intake lowers blood pressure. Some people are more sensitive to changes in dietary sodium intake, but on average the drop in blood pressure is about 5 points (mm Hg). The full effect is generally seen within a month, with other further benefits over the long term.

Where is the sodium in your diet? Everywhere. Any food you haven’t made yourself is loaded with salt. Virtually all prepared foods, frozen dinners, soups, restaurant meals, condiments, and sauces for instance are loaded with sodium. Even foods labeled “low sodium” have excessive amounts of sodium. Even food in the local hospital cafeteria has way too much sodium. (Beware: any food that is truly low in sodium is probably high in sugar or fat.) Food companies are in the business of selling food, and salt enhances flavor.

To all those that love salt in their meals and can’t imagine living without it, the taste of salt is a habit. The more salt you regularly have in your meals the more you’ll want and vice versa. You have to be willing to let your taste buds adjust over time.

Just a little overweight

Being overweight is thought to contribute to about a quarter to a third of cases of high blood pressure, and being overweight not only increases your risk of high blood pressure but also your risk of diabetes mellitus, high LDL cholesterol, low HDL cholesterol, and a thickened heart among other medical issues.

Not unexpectedly there are benefits to your blood pressure from losing weight. In those with high blood pressure, one study showed that a 10 percent reduction in weight resulted in a 4 point (mm Hg) drop in blood pressure. Other studies demonstrate 5-20 mm Hg drops in blood pressure for each 10 kg of weight loss. In overweight individuals a sustained loss of weight results in a lower risk of developing hypertension down the road.

Note that even by eating less you will be reducing your sodium content, but the benefits of weight loss are independent of the reduction in sodium intake.

Exercise

Regular, continued aerobic exercise lowers blood pressure about 5 mm Hg, and certainly exercise has other benefits, including weight loss, a lower cholesterol, an increase in HDL (good cholesterol), and a decrease in overall mortality. (All the benefits of exercise, countless – a discussion for another entry.)

Alcohol

Although there appears to be a health benefit from small amounts of alcohol, alcohol consumption is another example of when more is not necessarily better. There is a clear association between excess alcohol intake and health risks including hypertension, independent of its extra calories and the associated extra weight. A maximum of one drink per day is recommended for women, two drinks per day for men.

Personality traits and stress

Stress and personality traits have been implicated in high blood pressure but a direct link is difficult to prove. There is a concern, however, that while their effects on blood pressure and the body in the short term may be reversible, that over time they may result in chronic, physiological changes.

And to those without high blood pressure, are there benefits from lifestyle changes?

In people with normal blood pressure, the decrease in blood pressure from lifestyle changes are small, but even small changes could over long periods possibly have benefits as well. To the degree that people are able and willing to make changes, there is no reason for them not to do so.

So…

So while there is clearly more to be said about high blood pressure, hopefully this will induce people to have their blood pressure checked and managed – not only with medications but also with lifestyle changes. How to make change (changing habits) is also a discussion for another entry…

What other questions about high blood pressure do people have that perhaps their doctors haven’t discussed with them?

Dr. Who? Hospitalist medicine.

2008-09-24T23:28:00.005-04:00

Last week when Mr. Jones went to his local emergency room with chest pain and was told he would require admission to the hospital for further evaluation, he expected at some point in the ER to be comforted by the sight of his own doctor, Dr. Gupta. Dr. Gupta, his primary care doctor, had been his doctor for over the last twenty years, had seen him through his first heart attack, had successfully gotten him to quit smoking, and had cared for his wife.

Mr. Jones was surprised to hear, though, that Dr. Gupta no longer saw patients at the hospital and that instead another doctor he had never met before, a hospitalist named Dr. Stevens, would be taking care of him at the hospital.

Hospitalists are doctors employed by hospitals or by groups that contract with hospitals to care for patients in the hospital. They are typically specialists in general internal medicine who practice only inpatient medicine. Because of financial pressures on hospitals and financial, lifestyle, and time pressures on outpatient physicians, the hospitalist system is a growing trend in U.S. healthcare.

Advantages to the patient?

Despite patients’ general resistance to change and Mr. Jones’ initial anger and sense of abandonment on not seeing Dr. Gupta, there are advantages to care by a hospitalist physician.

Availability

A hospitalist by definition only works at the hospital and therefore is generally able to both more quickly evaluate a patient and transfer him upstairs from the emergency room to a regular room. If a patient’s condition deteriorates, a hospitalist is already present at the hospital. In contrast, a patient’s regular physician may have to wait until a break in the day, such as lunchtime or after work, to leave the office and drive to the hospital. In an emergency, the physician must drop everything to rush to the hospital.

Focus on inpatient medicine

A hospitalist focuses on inpatient care and as a result hones these skills while a primary care doctor, at a time when more medical care is being performed in an outpatient setting, may have fewer patients in the hospital and greater difficulty in keeping up those skills.

Fresh look

By having a fresh set of eyes and ears, the hospitalist may pick up on details that a patient’s regular doctor may have overlooked. Changes that occur to a patient slowly over time also may be imperceptible to the patient’s primary care doctor who sees him regularly.

Shorter hospital stays

By spending their day at the hospital, hospitalists tend to shorten patients’ stays. Even paperwork, ordering of tests, or calls to specialists that might otherwise be pushed to later that day or the following day when the primary care doctor has a window of free time, may get done sooner by the hospitalist and thus facilitate a patient’s evaluation and stay.

Disadvantages to the patient?

There is no substitute for knowing a patient

A patient’s regular doctor knows his patient better than a hospitalist meeting the patient for the first time. While hospitalists attempt to communicate with patients’ primary care doctors, all of the subtleties about a patient cannot be transmitted in a simple five or ten minute conversation or in papers faxed from a chart.

How a patient complains of chest pain – the words used, the tone of voice, the look on the face - may be as important as what is said. Abnormal findings on physical examination may be present for many years and not warrant concern or further studies.

The primary care doctor may know that a given patient is not one to complain or go to the ER and may, therefore, be even more suspicious that something is truly wrong. On the other hand, the doctor may know that a given patient has complained about this same chest pain for the last fifteen years, the quality or severity of the chest pain is the same, and it has been evaluated already numerous times. The doctor may instead recognize that the patient’s visit to the ER may have as much to do with the patient’s recent strained relationship with his wife as it does chest pain.

Loss or distortion of information

There is also inevitably the potential for a loss or distortion of information whenever a patient’s care changes doctors’ hands. The greatest risk is at the time of admission and discharge between the hospitalist and primary care doctor. There is also a risk between hospitalists changing shifts as the same doctor is not necessarily always seeing the patient. Hospitalists faced with the details of many patients who they have met for the first time, may also overlook or under emphasize important details of a patient’s history.

…and consequences of the game of telephone

A doctor with a lack of information may make wrong diagnoses and make changes to a patient’s care that are unnecessary or not warranted, such as order additional tests, repeat tests, or change medicines.

The consequences can be quite serious. An article in the New York Times six years ago described the story of a patient recently released from prison who was brought to a New York City ER. Several different doctors saw the patient over several shift changes. The patient who originally went to the ER for an exacerbation of her asthma was later errantly diagnosed by new doctors with worsening of her psychiatric disease.

(http://query.nytimes.com/gst/fullpage.html?sec=health&res=9A01E0DB1E3CF93BA25755C0A9649C8B63)

The new doctor

A patient may spend a fair amount of time choosing his regular doctor, but he has little choice in the hospitalist who takes care of him. A patient is seen by the hospitalist working that shift. While hospitalists are usually specialists in internal medicine, as are the primary care doctors, due to the shift work nature and the high burnout rate, hospitalists are often hired soon out of residency and therefore may initially be long on training but short on experience. That situation may change as more doctors decide to become hospitalists.

Emotional aspects

A patient’s emotional response to a doctor can play an important role in the healing process. Patients get to know their primary care doctors over time. End of life issues are much easier to discuss and implement by a doctor who has an ongoing relationship with a patient. In addition, a patient who doesn’t have confidence in their doctor would not receive the highest level of care.

In the end

Hospitalist medicine is a growing trend in U.S. healthcare and is here to stay. The question is how the system of hospitalist medicine will evolve to meet our needs and to minimize its shortcomings.

The almighty cardiac stent

2008-09-15T00:58:00.023-04:00

Mr. Jones had the scare of his life. At only fifty-six years of age he never expected to have significant build-up of cholesterol in his arteries, let alone chest pain. He first noticed the chest pain while mowing his lawn and then again whenever he over-exerted himself. Eventually, although not noticing a change in the chest pain, Mr. Jones could no longer ignore it. He met with his primary care doctor who, concerned that it was related to his heart, referred him to a cardiologist.

The cardiologist shared the concern and, given the high suspicion, promptly ordered a cardiac catheterization – a procedure in which a wire is traversed, usually from the right groin, up to the heart to inject the arteries with dye and evaluate for blockages. Mr. Jones’ catheterization showed various small build-ups of cholesterol but also one blocking over 70% of an artery.

Judging this blockage as the likely cause of Mr. Jones’ symptoms, the interventional cardiologist by inflating a balloon opened the artery and then expanded a stent (a wire mesh) in place to help keep it open.

(http://www.youtube.com/v/9FPapBbbS4o&hl=en&fs=1)

Afterwards the cardiologist shared with Mr. Jones the pictures of what he had done. The significantly blocked artery, now with a stent, looked quite good.

On leaving the hospital that day, Mr. Jones exhaled a sigh of relief feeling better, reassured and grateful that a significant blockage in his artery had been fixed, opened up, and that he had bought himself more time to enjoy with his family. The cardiologist left work feeling good for having helped a patient and for a job well done.

Of course, the real story is missing. The cardiologist had helped the patient, but Mr. Jones and the cardiologist may have lost the big picture that day and perhaps perpetuated a myth.

Dispelling the myth

Data from studies investigating stents for heart disease do no prove that patients with stable blockages in the arteries of their heart do better in the long term with early placement of stents than merely management by medications. That is, studies do not show that stents allow people to live longer or have fewer heart attacks than those treated with medications.

The real benefit of stents is their ability to improve symptoms, chest pain or shortness of breath, shortly after they are placed. This benefit over medications too dissipates with time. One study that looked at patients five years after either initial placement of stents or management by medications showed similar amounts of chest pain between the two groups.

Why then does the information get lost and the myth perpetuated?

Part of the reason that the myth is perpetuated is psychological - we as patients want stents to solve the problem. On being diagnosed with blockages in our arteries, faced with heart disease and our own mortality, we, like Mr. Jones, want to think actions can be taken to quickly reduce our risk of heart attacks and prolong our life. We want to sleep better. The stent that quickly and visually opens an artery and makes us feel better reinforces the idea.

The before and after pictures of the clogged artery are also visually quite compelling to doctors. Doctors want to believe. They are familiar with studies, but doctors only see real people in their office, individuals like Mr. Jones. They don’t want their patients only on average to do better, but they want Mr. Jones to do well, not have heart attacks and live longer. Placing stents and seeing a quick relief of chest pain and shortness of breath reinforces that idea to doctors as well, even if it’s inaccurate.

The interventional cardiologist on inserting the dye and diagnosing the blockage is there with a wire in Mr. Jones’ groin ready and able to open the blockage. Does he ignore the prominent blockage, not act, and remove the wire? How does Mr. Jones react? Patients appreciate feeling better right away and generally equate that with a better level of care. Imagine explaining to Mr. Jones that he will instead be only started on medications and that, despite the significant blockage in his artery, he should do just as well as his friends with stents.

The idea in medicine of not “doing something just because you can do something” can be one of the most difficult lessons for doctors to learn and for a patient to accept. As a patient who presents to a doctor with a problem and as a doctor in charge of making this person better, there is always a pressure to do something, anything. The pressure to do something, anything, however can cause people to neglect the associated risks.

Cardiologists as specialists

Specialists like cardiologists feel this pressure more than anyone. As a specialist, the expert, the cardiologist is expected to offer solutions others can’t and make everything better. If the cardiologist does nothing and/or merely adjusts medications patients may wonder why they are seeing the specialist. The patients may stop seeing the cardiologist.

Mr. Jones was referred to the cardiologist by another doctor (likely one who also specialized in internal medicine but decided not to specialize further). The cardiologist therefore may interpret the internist’s referral of Mr. Jones as an interest in doing more, seeing an intervention performed. The internist may just want assistance in adjusting medications or a second opinion but that idea may not be transmitted. An internist can adjust medications and not put in a stent just as a cardiologist can. The cardiologist may fear that if he doesn’t place a stent and merely adjusts medications, that the internist will send patients to a different cardiologist who will do more and intervene further.

What is a cardiologist without patients? The salary of an interventional cardiologist may also indirectly be tied to the number of procedures he does and the stents he places. (As an aside, I in no way want to diminish the role that cardiologists play in the care of patients.)

Stents have no role?

Does that mean patients with a blockage over 70% and stable chest pain shouldn’t have a stent placed? Clearly that is a discussion patients can only have with their doctors, but it means that if people are relying on stents to open their arteries and keep them from having fewer heart attacks and living longer, they may need to rethink their assumptions.

For future discussion: the theoretical reasons as to why stents don’t necessarily save lives or prevent heart attacks, why stress tests in asymptomatic patients are generally not recommended, and what do we know that prevents heart attacks and saves lives.

A first look at end of life issues

2008-09-08T19:37:00.010-04:00

We have to die eventually, a fact of which we are all sufficiently aware; yet we rarely, if ever, think about how it might unfold and we certainly don’t talk about it. The lack of discussion as individuals and as a society about end of life issues adds to emotional distress and to increasing health care costs.

Imagine Grandpa of one hundred years of age whose heart has stopped. Miraculously the event is witnessed, he is resuscitated, pacemaker pads are quickly placed on his chest to keep him alive, and he is rushed to the hospital. On arrival he is in critical condition and sedated on a mechanical ventilator, and he is transferred to the intensive care unit. Grandpa can’t communicate his wishes, but if he is to survive long-term he will need an implantable pacemaker. Do we place the pacemaker?

You, as the next of kin, are now in charge of the decisions regarding Grandpa’s care. Unfortunately, Grandpa never discussed his wishes with you about what he would want done in these circumstances and never drafted a living will. Faced with the life and death decision, determining the fate of Grandpa, the decision seems clear: uphold life above all else and place the pacemaker. However, is that the best decision?

For the last five years he has suffered from worsening Alzheimer’s dementia. He no longer knows who he is or where he is. He spends his days confused, and someone feeds him, changes his diapers, and turns him so he doesn’t develop bedsores. Do we still place the pacemaker?

Are we doing Grandpa a service by placing it? He has lived a good number of years, more than many of us can dream of, and at one hundred years of age one day in the near future, whether a pacemaker is placed or not, he will likely pass on. What if he believed that he had had a great life, that his wife, friends, and neighbors had already passed and that he would one day pass from something?

Remember Grandpa already died once. His heart stopped. Modern technology merely brought him back to life, and only for this reason are we faced with these questions. His mental function and lifestyle prior to the cardiac arrest were poor, but as a result of the cardiac arrest and resuscitation efforts his mental function will likely be even worse, if he is not already neurologically devastated.

You finally decide to not place a pacemaker and, in so doing, believe that you are fulfilling what Grandpa would’ve wanted. You then discover that your younger brother Jimmy, who only now has arrived at the hospital, disagrees with you and the rest of the family and believes Grandpa would’ve wanted the pacemaker. A family debate ensues. Without truly knowing Grandpa’s wishes there is no right or wrong answer. How does the family resolve this issue? How do the doctors resolve this issue? You as the next of kin are legally empowered with making the decision, but for obvious reasons doctors, like families, prefer unanimity in these situations.

Meanwhile days pass with Grandpa still in the intensive care unit lying in bed, staring at the ceiling unresponsive, and awaiting a decision. The doctors pepper you with other questions. What would you like done if Grandpa were to go into cardiac arrest in the hospital? Would you want him to receive an electrical shock in attempts to disrupt an abnormal rhythm and rescue him? Would you want for him to again undergo chest compressions (in which, yes, if done properly ribs are cracked) in attempts to maintain circulation as he is resuscitated? Would you want a tube placed in his stomach to feed him as he is no longer able to eat on his own? Would you want to continue drawing daily blood tests?

Is this how Grandpa imagined passing away? What if instead for the last five years rather than dementia he merely suffered from severe arthritic pain that confined him to a wheelchair and about which he complained incessantly? What if instead he had been a healthy one hundred year old man? Lots of questions arise.

The lack of discussion as a society of end of life issues (hoping instead for others to address or for the issues to go away) negatively impacts us and (to be addressed further) also leads to higher health care costs and to a skewed distribution of society’s health care expenditures.

Risk by the numbers: absolute vs relative risk

2008-09-03T08:59:00.020-04:00

“Doc, I can’t take the pain anymore,” Mrs. Wiedner said as she hobbled with a cane back to the examining room in the office. “I’ve had enough!” At eighty-six years of age she had suffered from severe arthritis in her knees for many years. “What about this Celebrex I keep hearing about? My neighbor says it works like a charm, but I hear it causes heart attacks.”

Celebrex is a pain reliever in the family of medications called COX-2 inhibitors and part of the broader group of pain relievers called non-steroidal anti-inflammatory drugs (NSAIDs) that include over the counter medications such as ibuprofen and naproxen. These medications have received widespread attention for their potential to increase the risk of heart attacks and strokes, and Vioxx, a COX-2 inhibitor, has been removed from the market.

Unfortunately all medicines (even over the counter medicines) have risks, but to understand the risks associated with a medication you first have to understand something about the numbers behind risk - a topic often neglected by patients and their doctors.

What if I told you that I have secretly developed a new drug, a potion that after only one dose insures perfect physical health. Would you be interested? Of course. Would I be rich? Probably. What if I told you that taking the drug, unfortunately, also doubles your risk of developing Alzheimer’s disease at an early age. Would you take the drug?

I assume you’re not too keen on getting early Alzheimer’s, let alone doubling your risk, but what if before taking the drug your risk of developing early Alzheimer’s is only one in a billion. Would you then be willing to double your risk of early Alzheimer’s to insure perfect health? I probably would. Sure, your risk relative to someone who didn’t take the drug would be double, but your absolute risk would only be two in a billion – a trivial number or risk to insure perfect physical health.

In selling the drug I would for full disclosure mention the increased risk of early Alzheimer’s. Though unless I wanted to scare you, rather than stating that the drug doubles a patient’s risk of early Alzheimer’s, I would state simply that it increases your risk by one in a billion. Either way I would be accurate, but why scare you?

What if, however, your risk of developing early Alzheimer’s before taking the drug is instead one in five or 20%. If the drug that guarantees perfect physical health doubles your risk of early Alzheimer’s (that is, the relative risk is again doubled), your absolute risk of developing early Alzheimer’s after taking the drug would now be two in five, 40%. With that risk for early Alzheimer’s, would you still want to take the drug? Maybe, but those odds are clearly less favorable.

Therefore understanding relative risk, knowing whether something doubles or halves your risk, is often insufficient. It is important to ask what the initial risk is and think about what the change in absolute risk really is. Never going outside may decrease your risk of being hit by a meteor or being robbed, but what is your risk to begin with? Most people would probably still decide to walk outside.

Another way to look at the numbers is to calculate the number needed to treat, the number of patients needing to take the drug to affect one person. The number needed to treat (NNT) is equal to 100 divided by the difference in absolute risk expressed as a percent. In the last example, the NNT for one additional person to develop early Alzheimer’s is 5 (100 divided by 20). In contrast, in the first example the NNT for one additional person to develop early Alzheimer’s is 10 million (100 divided by 0.00001).

Drug companies, the media, and others have their reasons for either magnifying or diminishing the perception of medications’ risks. In reading numbers it is always helpful to question what the vested interests are of those who quote you the numbers. Then you can look objectively and evaluate the numbers.

Celebrex is, therefore, an excellent example. The media has certainly stressed the potential increased risk of heart attacks from COX-2 inhibitors, but for many people the absolute risk may be low. What is Mrs. Wiedner’s risk of a heart attack to begin with? Are there other more common risks from Celebrex she should worry about? How much is the pain really bothering her? Are there alternative medications that she might consider taking? Are the risks of Celebrex to her worth the benefits? These are questions that only she can answer with the help of her doctor and understanding what the numbers really mean. Once a person understands risk, however, they can make their own decision.

Hopefully this look at the numbers behind risk assists you in having informed discussions with your doctor about medications and medical treatments.

Antibiotics and the common cold

2008-08-25T14:08:00.007-04:00

While everyone knows that antibiotics are over-prescribed for the common cold, and doctors are regularly reminded to limit their use, the practice continues. Why are doctors habits slow to change? Why do patients frequently request antibiotics from their physicians? The lack of a real discussion in society about the forces in play is a significant reason for the ongoing problem.

Everyone has had the common cold. It’s miserable. Fatigue, aches and pains, a runny nose, a post nasal drip, a cough, pressure over the sinuses, a sore throat… On top of all that, you can’t sleep, you’ve been up half the night caring for your child who is also sick, work is as busy as ever, and you have a critical meeting later in the week a few time zones away.

“I can’t afford to be sick.”

The pressures at home and at work are enormous. Doctors, realizing these pressures and faced with ill patients, everyday scour their brains for answers to the common cold but only come up with ways to relieve symptoms. Simple measures like fluids, rest, saline rinses, acetaminophen as needed and a tincture of time are generally all that doctors have to offer.

“Doc, you’re telling me I can put my hard drive on my keychain, but there isn’t anything for the common cold?”

Despite all the advances of modern medicine, there is still nothing to cure the common cold. Antibiotics kill bacteria, but they don’t kill viruses like the common cold. Unlike bacteria, viruses are not living things or cells. Viruses are merely particles that hijack the body’s cells. Bacteria and viruses are separate entities, and taking an antibiotic to kill the common cold is analogous to using cooked pasta to hammer a nail – humorous but ineffective.

“But I’m sure what I have is bacterial.”

Unlikely but possible. Nothing in medicine is absolute and doctors are sometimes wrong. Ascertaining as to when, even if rarely, antibiotics might be indicated can be difficult. Because even a simple illness can change, doctors always insist on being called if symptoms are worsening or the illness is not resolving.

While patients may understand this complexity and uncertainty, patients are also the ones feeling miserable and under pressure to return to their busy lives. It’s a very difficult position in which to find themselves and increases the chance that they might consider their illness to be bacterial or consider antibiotics.

Fear of being wrong, however, also drives a doctor’s prescription habits. Gradually, without a doctor realizing what is happening, the range of signs and symptoms for which he prescribes antibiotics begins to expand.

“Are you sure I don’t have a sinus infection?”

Possibly, but determining whether a sinus infection is viral or bacterial is difficult, and guidelines generally recommend that doctors (once they have ruled out anything serious) wait at least 7-10 days before prescribing antibiotics. Unfortunately, also, no symptom or test clearly distinguishes those who need antibiotics. Doctors, however, often deem one-sided facial pain with dark mucus, a toothache, or pain on bending, or a two-staged illness in which the symptoms are worsening after initially improving, as considerations to treat with antibiotics.

“Yet antibiotics have always worked for me in the past.”

Patients who have frequently taken antibiotics for the common cold may understandably develop a false association between improving and taking antibiotics. Patients usually wait a few days before calling the doctor, and when they then start the antibiotics and improve they relate the two events. Unknown is whether they would have otherwise improved had they not taken the antibiotics. A common understanding among doctors is that patients generally improve in a week with antibiotics or seven days without. It is also one reason for the importance of randomized, controlled trials in medicine.

Analogous to falsely associating antibiotics with improvement is to observe that every morning when the rooster crows the sun rises and then to attribute the sun rising to the rooster crowing. Similarly college students have been known to misattribute feeling sick after a long night of drinking to the nuts at the bar rather than to the excess number of drinks they consumed.

“I never had problems with antibiotics in the past.”

The reasons to minimize antibiotic use are often undervalued. One is simply that side effects from antibiotics are common and unpredictable, including nausea, vomiting, diarrhea, rash, and others that can compound a patient’s misery. There is also the potential for interactions with other medications that are being taken. An increase in antibiotic resistance with the liberal use of antibiotics is a serious problem both for individual patients and the rest of society. One day available antibiotics may not even be effective in treating simple conditions. More serious side effects from antibiotics are less common, but if they happen to you, particularly when they are life threatening, they suddenly don’t seem so uncommon and antibiotics don’t seem so benign.

“My other doctor always gave me antibiotics.”

Often even the best intentioned doctor after being asked multiple times for antibiotics will relent. Again, doctors are human. It takes a strong will to resist a patient’s repeated entreaties in the face of the possibility, even if remote, that the doctor is wrong. Being wrong, despite part of being a doctor, opens the doctor up to emotional tumult of his own, finger-pointing by others, and malpractice lawsuits. In addition, doctors rationalize that the patient will just see another doctor who will prescribe the antibiotics anyway.

This idea of not losing a patient to another doctor is one of the financial pressures to prescribe antibiotics that a doctor faces. Unintentionally, insurance companies also indirectly pressure doctors to use antibiotics by limiting visits to fifteen minutes, including writing the note. Explaining to patients and reassuring them why antibiotics are not needed is time consuming, and a doctor will sometimes choose to give a patient antibiotics rather than spend the time as the waiting room quietly fills with the next patients. Patients, of course, fear the financial impact of missing work, and doctors understand that as well.

Hopefully this look at the over-prescribing of antibiotics clouds the picture enough to open the discussion.