A fatty liver epidemic! What are we doing about it?
With the expanding obesity epidemic, fatty liver has become the most common liver disease in children and adults in the US. Studies suggest that a tenth of US children and a third of US adults have fatty liver. The disease has a wide spectrum: some patients may only simple fatty infiltration of the liver and are diagnosed as having simple steatosis or simple fatty liver, while other patients have in addition to fatty infiltration, inflammation, ballooning of the liver cells and fibrosis. These patients are diagnosed with steatohepatitis [if the patient does not drink more than 2 drinks daily its labeled non-alcoholic (NA) and thus the abbreviation NASH]. NASH, but not simple fatty liver, can progress to cirrhosis and liver failure. Liver biopsy remains the gold standard for diagnosing and classifying different forms of fatty liver.
Our group has been working to improve the diagnosis of fatty liver disease. Our studies demonstrated that pathologists had good agreement on detecting fatty infiltration and fibrosis on liver biopsy but little agreement on detecting other essential features of NASH, particularly inflammation and ballooning. This led to poor agreement of two pathologists practicing at the same institution when reading one liver biopsy for fatty liver. While one pathologist may report the diagnosis as simple fatty liver, another pathologist may diagnose NASH. Our group introduced an educational intervention to pathologists that improved the intraobserver consistency/agreement on diagnosing NASH and its features but did not result in improvement of inter-pathologists agreements. We therefore sought automation of the reading of the biopsy as a way to aid pathologist in accurately diagnosing NASH. Our efforts thus far have yielded exceptional ability of the software program we designed to detect and classify fatty infiltration and also locate the anatomical landmarks in the liver. Our efforts are ongoing to improve the programs ability to automatically detect the other cardinal features of NASH.
Elucidating the genetic factors that determines the form and severity of fatty liver disease has also been a major area of interest to our group. We have studied the different patterns of gene expression in the liver that separate patients with fatty liver from controls with normal liver. We described how these sets of fatty liver associated genes interact in networks. This approach allowed highlighting the key genes in each up- or down-regulated gene sets associated with fatty liver. We have also studied how candidate genes variants may influence the severity of fatty liver. Two significant findings of our research were that variants of both PPARG and PNPLA3 were associated with NASH.
We hope that our collaborative efforts will continue to produce significant exiting findings and translate into better patient care.
Samer Gawrieh, MD
Associate Professor of Medicine
Medical Director of Liver Transplantation
Division of Gastroenterology and Hepatology
Medical College of Wisconsin
Role of a Clinical Research Coordinator
Karen Woodlin (p176) defines a Clinical Research Coordinator as “the person at an investigational site who manages the daily operations of a clinical investigation and who is responsible to the investigator.” Interpretation of this is variable from department to department; even from investigator to investigator.
In order to understand the role of a CRC, it is essential to first understand what is meant by a “clinical investigation” or clinical research. A clinical investigation or clinical research, for the purposes of this article, involves the utilization of observation or of investigational product over a pre-defined period of time, which is attempting to meet an outcome or goal, in a research subject with a specific medical diagnosis. An investigational product is most often a drug or device not currently approved by the FDA for general patient use, or that is approved by the FDA for one indication and additional approved indications are being requested.
Personal observation and experience indicate that, when hired, many CRC’s at the Medical College of Wisconsin have minimal or no experience in clinical research. The most common reason given as to why an individual is interested in a CRC position without previous experience is “I was looking for something different” and “the CRC or Study Nurse position interested me.”
A CRC, coming from a multitude of backgrounds, dictates that their background plus the training they receive after beginning the position, ultimately determines what their role will eventually become. The department and investigator need to define exactly what the CRC‘s duties will be. This is essential for research team success with both new and experienced CRC’s. The interpretation of the investigator regarding the complexity or nature of the clinical investigation will impact whether the CRC should be a licensed individual (typically, a nurse), or other individual, in order to adequately fulfill the CRC responsibilities.
Successful completion of a clinical investigation requires subject safety vigilance, the production of high quality research data, protocol compliance and adherence to all regulatory standards governing a particular trial. In order to successfully accomplish these tasks, all CRC’s regardless of background, need to be provided basic and ongoing training opportunities.
A CRC’s roles or tasks include administrative, regulatory, medical, interpersonal communication and financial components. These roles incorporate, but are not limited to: 1) trial feasibility assessments-inclusive of facility feasibility, trial population availability and financial feasibility; 2) IRB and Grants and Contracts submissions; 3) Regulatory documentation preparation, submission and maintenance; 4) Investigational Product accountability; 5) Subject recruitment, enrollment, follow-up and retention practices; 6) Data collection and monitoring; 7) Adherence to Good Clinical Practices; 8) Process of Informed Consent; 9) Adverse event and ongoing safety monitoring; 10) How to communicate with the sponsor, IRB and other regulatory agencies; inclusive of audits; 11) Managing the financial side of clinical research; 12) Being aware of who and where your resources are, and understanding why this is vital; 13) Recognizing and understanding what and where your boundaries are.
The reality of CRC roles and knowledge requirements are directly proportional to the expectations of the department or individual investigator. Roles and responsibilities may be divided among research team members in larger research operations or, in other cases, a single CRC may have all responsibilities of a single clinical investigation. Roles can vary, but what cannot vary is adherence to institutional and research industry regulations which require all study team members must be provided with all necessary training, and that the CRC has all experience necessary to fulfill trial obligations. Part of this experience should include knowledge, or current training, in the disease area of the clinical investigation.
Recognizing that the vast responsibilities and accountabilities of the CRC often seem endless, what every team member needs to consider is that, ultimately, the assurance of proper conduct of clinical investigations falls back to the investigator. The CRC must recognize this and realize their boundaries. As a professional, the CRC should hold themselves accountable to seek the knowledge and training required to properly conduct clinical trials. This is effectively accomplished by early and continuous nurturing of good communication lines between the investigators and the research team.
Recognizing most of the above information falls in agreed to be the responsible for but do not find great pleasure with category; why would anyone want to be a CRC? This answer should be found in the same category as why most research subjects participate in clinical research. The writer believes most CRC’s would like to have an opportunity to provide improved treatment to future generations of patients, which is more effective and efficient than what is currently available. Medical advancement is in a constant state of evolution through all levels of research, CRC’s are afforded an opportunity to be a significant contributor to this process.
The advancement of the science is significant, but is not the only vital role the CRC plays. CRC’s are in a unique position within their participation of clinical research. The CRC is the liaison between the participant and the sponsor and, in most situations, between the subject and the investigator. The CRC is the fortunate individual who spends the largest proportion of the time related to study activities with the subject. The CRC is fortunate because not only have they been given an opportunity to teach about the value of clinical research, but also highlight what is happening to the subject because of the disease process or condition which initially brought them to the clinical investigation. The value of this teaching opportunity is the ability to empower the subject with knowledge. In other words, the subjects helping future generations and also are better able to care for themselves with this new found knowledge and understanding of their disease. Always remember – knowledge is powerful in many different ways.
Concluding thoughts? We are all fortunate to work at an Institution which includes research as a large component of its mission. What we as CRC’s do with this opportunity should be beyond what our personal mission is (or was) when we accepted the position. Most of us – writer included – were only aware of what duties were outlined in the job description; we could not possibly have envisioned what a wonderful opportunity the CRC position would become.
Article written by Susan K. Mauermann, RN, CCRC
Manager, Clinical Research
Division of Cardiovascular Medicine