The 21st century hepatologist and a systems biology based approach to liver diseases

Abstract

It is striking how often it is that a 30- to 50-year-old patient will walk into my office with a seemingly mild yet enigmatic problem such as an abnormal aminotransferase level or epigastric pain that persists despite thorough investigation and treatment from their internist. These patients invariably have complicated family histories of multiple cancers or chronic diseases such as diabetes, rheumatoid arthritis, Alzheimer’s disease, and others. Recently, I began linking some of these clinical findings to potentially dysfunctional genetic pathways to effect a diagnosis, treatment, and management plan, and possibly avert disease escalation. Take one recent example of a patient who presented with abnormal aminotransferases and gastric fundic gland polyps (not on proton pump inhibitors). I noted her family history of hepatocellular carcinoma (HCC) and gastric cancer spanning three generations. Familial adenomatous polyposis coli/Gardner’s syndrome with dysfunctional wnt signaling, epigenetic loss of E-cadherin, and silencing of transforming growth factor β signaling are some of the possibilities.1–3 With the right information at hand, this patient’s management plan could include: a screening strategy for HCC and gastric cancer; identifying mutations in affected family members; examining affected gastric tissue for loss of E-cadherin; instituting simple preventive/disease modifying measures such as vitamin D, calcium, and aspirin that switch off pro-oncogenic activated wnt signaling.4,5 Clearly, many patients will need to be studied carefully with genetic networks and a systems biology approach to identify key modifying factors that will effectively work on an individual basis.6 I have most definitely embarked on a steep learning curve as I continue to manage my patients. Possibly, as in hereditary non-polyposis colorectal carcinoma (HNPCC) studies, this patient and her family will eventually fall into a specific genetic group, and we will be able to look to future prevention of other cancers, such as the uterine cancers by earlier hysterectomies in HNPCC patients.7