Cystic Fibrosis: Diagnosis, Imaging, and Treatment Advances

Introduction: Cystic Fibrosis in the Modern Era

Cystic fibrosis (CF) is a disease that steals childhood, adolescence, and adulthood in an assault on the lungs and other vital organs, causing every aspect of a patient's life to revolve around diagnosis, care, and treatment. In the United Kingdom, CF has been identified by the Cystic Fibrosis Trust as the nation's most common inherited life-threatening disease (Cystic Fibrosis Trust, 2008). According to the Trust, more than 8,000 people in the UK suffer from the disease, and more than 2,000,000 people carry the defective CF gene — that is 1 in 25 people. It is an unrelenting condition that usually claims the life of its victim anywhere between birth and early adulthood, with few patients living beyond their early thirties.

Millions of dollars are donated to the Cystic Fibrosis Trust each year to fund research for new and innovative life-extending treatments and, ultimately, a cure. The work of the Trust and others who devote their lives to research are now working in an era of incredible technological advancement and information exchange, which holds great promise for eliminating CF in the future. This paper examines the history and pathology of the disease, methods of diagnosis, and advances in treatment and life expectancy as science explores the vast complexities of human genetics in unraveling the mysteries of cystic fibrosis.

The study begins with a literature review introducing the significant sources that form the bulk of this paper. The literature review is followed by five chapters: Chapter One covers the anatomy and physiology of the disease; Chapter Two covers imaging modalities; Chapter Three examines the unique role of MRI, as well as its drawbacks; Chapter Four addresses the drawbacks of other imaging modalities and the future of imaging technology in CF diagnosis and treatment; and Chapter Five presents a summary and conclusion.

Research of the past two decades has been especially prolific in the production of books and peer-reviewed journal articles addressing the diagnosis, treatment, and research advances in CF. Using keywords such as cystic fibrosis, cystic fibrosis pathology, CF radiology, CF lungs, CF pancreas, and CF digestive yielded thousands of books, journal articles, magazine articles, and newspaper articles. For the purposes of this study, non-peer-reviewed magazine or newspaper articles were eliminated, as were most sources older than ten years, with the exception of a few books and journal articles that help demonstrate the historical progression of diagnosis, treatment, and research in CF.

Of the remaining works, the field was narrowed to those contributing the most significant understanding of the research progress in improving the quality of life for individuals afflicted with the disease.

Literature Review

A.R. Colón and P.A. Colón's (1999) Nurturing Children: A History of Pediatrics discusses the early advancements in diagnosing CF through radiology. While radiology advanced diagnostics, it helped key researchers of the era understand and draw conclusions about CF.

"Identification and Assessment of Ongoing Stressors in Adolescents With a Chronic Illness: An Application of the Behavior-Analytic Model" by M. Digirolamo and Alexandra L. Quittner highlights the relationship between stress and chronic diseases (pp. 53–). The study involved 45 adolescents aged 12–17 with CF, and the findings have informed this paper.

Chris Bennett and Daniel Peckham's (2002) The Genetics of Cystic Fibrosis, available from Leeds Teaching Hospitals, provides input on the genetics of CF, contributing diagrams and statistical information to this paper.

Talissa A. Altes, Monika Eichinger, and Michael Puderbach's (2007) article "Magnetic Resonance Imaging of the Lung in Cystic Fibrosis" explores the advances MRI has brought to the body of knowledge on CF by imaging the changing condition as it impacts vital organs at different stages of the disease (pp. 321–327).

ZA Aziz, JC Davies, EW Alton, AU Wells, DM Geddes, and DM Hansel's "Computed Tomography and Cystic Fibrosis: Promises and Problems" (pp. 181–186) discusses CT's contribution to the progress of CF understanding through modern technology. The CT scan has contributed substantially to understanding CF and other diseases, and these authors examine the technology in terms of how it has advanced that understanding.

The availability of modern technologies does not justify careless use of those technologies. For people suffering from chronic illness like CF, risks are associated with being subjected to modern imaging, and physicians must therefore exercise cautious judgment. "Cystic Fibrosis: When Should High-Resolution Computed Tomography of the Chest Be Obtained?" by F. Santamaria, G. Grillo, G. Guidi, A. Rotondo, V. Raia, G. de Ritis, P. Sarnelli, M. Caterino, and L. Greco (pp. 908–913) addresses this question directly.

Cystic Fibrosis in Children and Adults: The Leeds Method of Management by S.P. Conway, J.M. Littlewood, K.G. Brownlee, and D.G. Peckham (2003), all members of the Leeds Regional CF Units at St. James's and Seacroft University Hospitals, provides an informative and useful account of the CF patient experience at these hospitals. The book recognizes the many staff positions and ancillary specialists who play vital roles in helping patients achieve and maintain quality of life in the face of this daunting illness.

Teresa Berrocal, Manuel Parron Pajares, and Amelia Fernandez Zubillaga (2004, pp. 305–309) discuss "Pancreatic Cystosis in Children and Young Adults with Cystic Fibrosis: Sonographic, CT, and MRI Findings," supporting the previously mentioned bodies of research. Clearly, modern technology and the ability of professionals to interpret these technologies has generated vast amounts of work analyzed from the peer-reviewed perspective, furthering other researchers and physicians in their own progress.

John C. Avise (2004) addresses the Hope, Hype, and Reality of Genetic Engineering as it relates to CF. Many people rely on expectations that genetic engineering has advanced to a point where it will be possible to save the lives of CF patients approaching critical stages of the disease. While that is a goal of genetic researchers and the hope of patients, families, and the medical community, the question of whether it is achievable in the near or distant future is discussed in his book.

Chapter One: Anatomy, Physiology, and Diagnosis of Cystic Fibrosis

Much has been investigated regarding existing technologies — CT, MRI, and radiological services — in advancing CF diagnosis and treatment. To what extent "New Tools, New Dilemmas: Genetic Frontiers" continue to present challenges is discussed by Kathleen Nolan and Sara Swenson (1988), providing a historical baseline for evaluating progress made over two decades. The official websites of the Cystic Fibrosis Foundation, the National Institutes of Health, and the Cystic Fibrosis Trust will each serve as sources of information throughout this paper. There is a wealth of available information, data, and studies on CF, and what it all means for patients who suffer from this debilitating and life-threatening disease will become clear as this paper proceeds.

Every child born in the UK has, since 2007, been tested for CF — the most common inherited life-threatening disease prevalent among Caucasians, where 1 in 25 people carry the faulty gene that causes it (Cystic Fibrosis Trust, 2008). While the Cystic Fibrosis Trust cites the average life expectancy of a person with CF as 31, information on the Trust's site also indicates that children born with the disease today may expect to live even longer, presumably because of advances in diagnosis and treatment. It is toward the goal of increasing the quality and length of life that the Trust works, since a cure appears to be a long way off.

Discovery of the genetic basis of CF has led to the current ability to diagnose the condition prior to birth through a process called amniocentesis (Conway, Littlewood, Brownlee, and Peckham, 2003, p. 10). Amniotic fluid is aspirated from the fluid surrounding the baby, but the procedure is invasive and carries with it the risk of miscarriage. Chorionic biopsy is an embryonic testing method that poses a "small but definite risk to the baby" and should only be performed when termination of the pregnancy is under consideration following a CF-positive diagnosis (p. 10). After birth, CF can be identified by the fairly simple Guthrie test, which involves pricking the infant's heel and which also reveals other diagnostic information (Cystic Fibrosis Trust, 2008). Modern technology now also allows the disease to be detected even before conception for couples with a family history of CF (Conway et al., 2003, p. 10).

In the 1930s, Dr. Dorothy Andersen, a pathologist at Columbia University, noted pathological similarities in the cases of certain children who were days to several years old (Clark, 1997, p. 27). In 1938, Andersen published a paper identifying the disease that would come to be known as cystic fibrosis, opening the doors for research that would, by the 21st century, identify the genetic mutation responsible for the disease and generate a vast body of research around its diagnostics and physiology (p. 27).

CF is an autosomal recessive disease identified by its genetic footprint: a defective cystic fibrosis transmembrane conductance regulator (CFTR) (Berrocal et al., 2004, p. 1305). This genetic defect results in the body's inability to transport chloride across the membrane of epithelial cells where CFTR is expressed (p. 1305). The result is abnormally thick secretions that impact every vital organ: the pancreas, liver, lungs, paranasal sinuses, and even the reproductive organs (p. 1305). It is the resultant organ dysfunction and inability to manage these thick secretions that eventually brings about death, usually through respiratory failure (p. 1305). If an individual suffering from CF did not die from breathing disorders, the impact on other vital organs would eventually bring about death in any case (p. 1305). The average life expectancy of individuals with CF has risen from about five years old in the 1960s to an average of 31 years today (Cystic Fibrosis Trust, 2008).

CF is an inherited disease most commonly passed on when both parents — usually of Caucasian European ancestry, as it is seldom found in Asians or people of Black African descent (Berrocal et al., 2004, p. 1305) — each carry a copy of the mutated CFTR (Lewis, 1993, p. 22). The child to whom it is passed on receives one copy of the mutated gene, which can cause the illness, and one copy of a normal gene, which can prevent it (p. 22). A child of carrier parents has a 1 in 4 chance of being entirely free of the disease and a 1 in 2 chance of being a carrier like the parents (p. 22).

While CF is a very physical and painful disease, it has a psychosocial dimension as well. Social researcher and physician Dr. John S. Rolland (1994) states that for families into which a child with CF is born, the experience requires the family to define itself in a new way consistent with the chronic disability, which will likely one day result in their loved one's death (p. 19). Rolland argues that the family needs a way of describing systemic illness that recasts the biological disease in psychosocial terms, allowing movement and discourse between the family's world and the world around them (p. 19).

Even though there is a recognized social aspect to CF — as acknowledged by the Leeds Method of Management (Conway et al., 2003) — Simon J. Williams, Lynda Birke, and Gillian A. Bendelow (2003) conclude that a disjoint remains between biologists and sociologists, causing biologists to largely ignore the social aspect of disease and concentrate solely on its "proximal" causes (p. 16). Ultimately, it is unraveling the biological, molecular, and genetic mysteries of the disease that will one day yield a cure.

To begin understanding the physiology of CF, consider that the body has a vast network of ducts lined with epithelial cells, serving as internal "tunnels" between the body's organs for the delivery of substances — including nutritional substances that sustain the body's ability to convert food to energy (Clark, 1997, p. 28). The pancreas and liver, for example, produce and send digestive enzymes along epithelial duct routes to the intestines, without which the body could not digest food (p. 28). Epithelial ducts also line the lungs and reproductive organs (p. 28).

The cells lining the epithelial ducts, like most human cells, have a nucleus containing 46 chromosomes (Bennett and Peckham, 2002). The chromosomes are long coils of double-stranded DNA. Forty-four chromosomes are matched into twenty-two pairs (autosomes), numbered 1 to 22. The last pair makes up the sex chromosomes, X or Y. Females receive two X chromosomes, while males receive an X from their mother and a Y from their father. The chromosomes contain approximately 35,000 genes made up of segments of DNA, which dictate the body's production of protein. It is in this production of protein — or the lack thereof — that cystic fibrosis resides.

As Bennett and Peckham (2002) explain: "In 1985 the gene was localised to 7q21-34 on the long arm of chromosome 7 (Wainwright et al., 1985) and this was soon followed by identification of the gene sequence (Rommens et al., 1989; Riordan et al., 1989; Kerem et al., 1989). The gene encodes a 1480 amino acid protein, which has been named the cystic fibrosis transmembrane conductance regulator, or CFTR."

According to Bennett and Peckham (2002), CFTR is a protein found in various cell types, including lung epithelium, submucosal glands, the pancreas, liver, sweat ducts, and the reproductive tract. It comprises two membrane-spanning domains and two nucleotide-binding domains separated by a regulatory R-domain. The two membrane-spanning domains form a low-conductance chloride channel pore. This channel is regulated by the binding and hydrolysis of ATP at the nucleotide-binding domains following initial phosphorylation of the R-domain. CFTR also regulates ion transport, exerting inhibitory effects on apical sodium permeability across epithelial surfaces and activating non-CFTR chloride channels. Because CFTR is transported throughout each of the body's vital organs and interactive systems, it is logical that CF is a multi-systemic disease.

Mucus serves an important function in the body, and when the epithelial ducts are blocked, mucus can no longer perform its bodily function and becomes clogged in the ducts (Clark, 1997, p. 28). It no longer lubricates the gut, and the very process of food intake can become painful (p. 28). Epithelial cells are no longer adequately protected, and food textures, seeds, or even bones can become a painful or even life-threatening event (p. 28).