When Is a Disease a “Disease”?

Have you ever known anyone who you admired but found out later that there was much more to the person than you ever recognized? Such was my association with Dr Michael Burnhill, who was my colleague and friend from our first meeting in 1985 until his death at 72 years of age in 2000.

I knew many things about Michael. He had graduated magna cum laude from Syracuse University in 1949 and received his medical degree in 1955. He was board-certified in obstetrics and gynecology and had been a pioneer in women’s health. I also knew that Michael had an illustrious academic medical career at George Washington University Hospital and Johns Hopkins Hospital and School of Medicine, and that he had joined the staff at the Robert Wood Johnson Medical School and University Hospital as a professor of obstetrics and gynecology and senior attending physician from 1972 to 1999. What I didn’t know was that he and his father, Dr Charles Birnberg, had developed the popular early intrauterine device (IUD) known as the Birnberg Bow,1 and that he later became the vice president of medical affairs for the national Planned Parenthood Federation of America from 1995 to 2000; he was obviously a very strong advocate for women’s health issues and self-determinism.

One of the many things I personally learned about from Michael during the years of our friendship was the historical way in which women’s health issues were often marginalized as “all in the mind” or a “functional disorder.” He was particularly concerned about the way that medicine treated pelvic pain in women where no overt pathology could be found as a psychosomatic issue that had no “organic” pathological explanation. His clinical experience told him that this was not true. When women came to him with a presentation of pelvic pain, he found that in many cases the pain could be attributed to chronic inflammation due to low-level bacterial or fungal infection. Using this concept as the etiology for pelvic pain syndromes, he successfully treated thousands of women with this presenting symptomatology in the course of his medical career by using probiotic and prebiotic therapy to improve mucosal immune function.

My friendship with Michael coincided with my work on developing the concept of functional medicine as a systems biology approach to understanding the origin of chronic illness. Michael became more and more convinced that the solution to treating female pelvic pain of unknown origin was to understand the complex interrelationship among the patient’s microbiome, the systemic immune system, and the reproductive system. In essence, he believed that pelvic pain was a perfect example of a functional somatic disorder, the origin of which was rooted in a chronic disturbance of the urogenital immune system that was triggered by cross-infection from the gastrointestinal microbial community. He did not see unexplained urological pain syndromes as a “disease,” but rather as one of a group of functional somatic syndromes.

So when should a condition be recognized as a “disease” and how does a “disease” differ from a functional somatic syndrome? The 9th edition of the International Classification of Diseases (ICD-9), established in 1975, listed 13 000 codes for diseases. The 10th edition, which was released in 2012, listed 68 000 codes for diseases. What does this mean in terms of our understanding of the term disease? How do we account for 55 000 additional codes for disease being provided in the ICD-10 if disease is discrete and well defined? I believe the answer relates to the lens though which we view human function. That is, the definition of a pathology changes when we move from descriptive symptomatology to a more quantitative series of diagnostic tools such as X-ray assessment, blood chemistry evaluation, electron microscope identified histopathology, nuclear magnetic resonance (NMR) spectral data, and immunohistochemistry. And to this list of assessment tools, we now need to add the full complement of omics analytics including genomics, transcriptomics, proteomics, metabolomics, and epigenomics.

Many of the new diseases listed in the ICD-10 were thought of as syndromes or conditions of unknown pathology in the ICD-9. As biomedical sciences have evolved, so has our understanding of the “organic” nature of many chronic conditions rooted in functional physiological disturbances that were previously considered “syndromes.” What information indicates a disturbance in function that justifies defining the condition as a “disease?” Where do we draw the line? There are clearly no hard and fast rules that guide us in determining where a functional somatic syndrome ends and a disease begins. But there is now strong evidence that stratification of different genotypes for major diseases such as heart disease, diabetes, autoimmune diseases, and cancer results in the identification of many variants of the disease that originate from different functional genomic expression patterns, and therefore respond to different therapies.2,3,4,5 From this new understanding comes a different definition of disease and an even greater blurring of the lines. There is recognition that there is a gradient of increasing pathology moving from early stage functional changes to functional somatic syndromes and then progressing onto a specific pathology that is called a “disease.”

Functional Medicine, Functional Somatic Syndromes, and the Definition of “Disease”

Let’s return to my story about Michael. He recognized that the presentation of pelvic pain of no known origin in his female patients was not simply because the condition was “all in the mind.” Rather, he surmised that the pain was resulting from disturbances in function within the urogenital tract that were not obvious through the traditional lens of pathology. Further, he recognized that these women suffered from a disturbance that involved multiple systems that cut across the disciplinary boundaries of medical specialties. Michael was most interested in the condition of vulvodynia, which he believed was a classic example of a “functional medicine” disorder. His experience identified the condition as a result of contamination of the vulvar area with both fungal and bacterial organisms that triggered the inflammatory immune response. His approach to treatment of this functional somatic syndrome was to use pre- and probiotics to restore lactic acid producing bacteria to the microbiome of the reproductive tract.

In 2015 the identification of novel mechanisms involved in generating vulvodynia pain was published from work done at the Rochester School of Medicine and Dentistry.6 This work implicated a fibroblast-mediated proinflammatory response to the fungus Candida albicans as a major contributor to the induction of pain in women with vulvodynia. The findings of this clinical study on the origin of vulvodynia were supported by an earlier publication by a separate group of researchers. These results were from an animal model of the condition, which also demonstrated that vulvovaginal fungal infections result in persistent pain.7 This etiology of the condition confirms Michael’s advocacy 25 years ago. He recognized that vulvodynia resulted from a functional imbalance of the mucosal microbiome, triggering immune system reactivity and their associated relationship to the gastrointestinal microbiome. It was not a “disease” but rather a result of a functional disturbance among several different physiological processes.

Interstitial cystitis and chronic bladder pain as members of the disorders presenting with urogenital pain have also been defined as heterogeneous functional somatic syndromes with etiology related to disturbances in the systemic and mucosal immune systems. Supporting this systemic immune relationship to the etiology of these conditions is the recognition that both coronary heart disease and rheumatoid arthritis are inflammatory comorbidities associated with interstitial cystitis and chronic bladder pain.8

So we come back to the question I posed in the title of this article: When is a disease a “disease?” In any discussion of what constitutes a “functional somatic syndrome,” there is debate as to whether all of these syndromes that do not have a discrete pathology can be considered as derived from a singular cause or whether they derive from functional disturbances of multiple systems.9 In the medical literature, this debate has been defined as “lumpers” and “splitters.”10,11 Lumpers are those individuals who believe that functional somatic syndromes all arise from a singular psychogenic cause, whereas splitters believe that there are many different contributing features to functional somatic syndromes representing both organic and psychological factors. It is my belief that this debate is akin to the philosophical debate of “how many angels can exist on the head of a pin?”

The 21st-century explanation of the etiology of functional somatic syndromes derives from the new concept of systems biology, which is focused on understanding the underlying disturbances that give rise to complex chronic illness. These disturbances arise from the interaction of the genes of the individual with their environment, lifestyle, diet, and activity patterns. The functional medicine approach to understanding the etiology of these functional somatic syndromes is to search for the underlying imbalances in core physiological processes that result in the presenting signs and symptoms. The differentiation between a “syndrome” and a “disease” is somewhat arbitrary under the functional medicine formalism and depends on the severity, intensity, and frequency of the presenting symptoms and how the diagnosis fits into the ICD-10 classification system. Basically, we need to move beyond even asking the question. The intellectual pursuit in defining whether a specific condition that a patient presents with is a disease or a functional somatic syndrome is not as important in improving patient outcome as defining the primary functional disturbance that results in their complex symptom profile.

A recent published review of functional somatic syndromes stated:

The future classification of functional somatic syndromes should reflect the need for a balance between organic and psychological approaches. At present, patients with functional somatic syndromes are often dissatisfied with the care they receive, so training of medical students and doctors is mandatory to improve their skills regarding these conditions.12

This need for improved understanding and approach to complex medical problems that fall between the cracks of a discrete “disease” and a transient, self-limiting set of symptoms represents the domain of a systems biology approach to functional somatic syndromes. As I look back at my 15-year friendship with Michael, I recognize that he knew instinctively that the concept of a “disease” was somewhat arbitrary, whereas identifying and treating the origin of the specific functional disturbances underlying the patient’s presenting signs and symptoms represented the key to a successful outcome.