Predicting Outcomes of HCV Recurrence in Liver Transplants; Bilirubin as a Marker for Preservation Injury Joseph Park Advisor: Richard Gilroy, M.D. Kansas University Medical Center

What is the liver? 3 lb – largest organ in the body Upper left quadrant of abdomen Four lobes, blood perfusion Remarkable regeneratory capacity—only organ that can completely reheal itself Vital for human survival More than 100 functions Detoxification of blood, protein synthesis, digestive biochemistry, metabolic regulation… Hepatocytes are the basic functional cells of the liver Hepato- Gk. for “Liver” Histological analysis and biopsy diseases.html

Liver dysfunctions Cirrhosis is scarring of the liver Replacement of dead hepatocytes— fibrous connective tissue, regenerative nodules Common consequence of alcoholism, hepatitis B and C, or fatty liver disease Cirrhosis is irreversible and can only be prevented from progressing and causing other complications One concerning consequence is hepatic encephalopathy Confusion, coma or altered mental function due to liver failure Toxic substances remain in the bloodstream and can cross the blood- brain barrier Ammonium, NH 3 depth.htm

Hepatitis C Hepato- + -itis Inflammation of the liver Infection by blood-bourne virus RNA virus, similar to HIV No vaccination available Symptoms of jaundice, acute fatigue, and more chronically facile bruising and bleeding Liver biopsy shows hepatocellular inflammation, and more chronically, fibrosis and cirrhosis Treatment with peginterferon and ribovirin—but not cure End-stage liver disease: liver transplantation is the only option _EM_picture_2.png Senecal, Morelli (2007). JAAPA 20(10), October 2007:21

World Health Organization. Hepatitis C - Global Surveillance Update. Weekly Epidemiological Record 75:17-28, 2000.

Dilemma After liver transplantation, recurrence of HCV is widely reported and endemic HCV RNA+ in bloodstream is not fully eliminated pre-transplant Transplants require that the patient undergoes a regimen of immunosuppressive drugs post-transplant Susceptibility to greater cirrhosis due to immunosuppression; disabled immune system cannot clear HCV Aggressive return of HCV post-transplant; factor of 1 log in comparison to pre-transplant Peginterferon and ribavirin can be used to maintain SVR (sustained virologic response)—but side effects Question of balance: Antiviral drugs versus immunosuppression Ultimate end is to slow rate or halt progression of cirrhosis and fibrosis

Terrault, Norah. (n.d.) HCV Infection in Solid Organ Transplant Recipients. U California, San Francisco.

Predicting the severity of cirrhosis due to post-transplant HCV Utility: know level of drug regimen before the onset of cirrhosis— predictive function Also, quality control: did we use the right level of antiviral therapy? Hence – retroactive study of patients at Kansas University Medical Center Some predictive variables: donor age, cold ischemic time, warm ischemic time, donor sex, certain chemicals in the blood… Bilirubin: conjugated as a product of blood cell decomposition. Molecular marker for hepatocellular function. Abnormal levels of bilirubin suggest dysfunction, most likely preservation injury (fibrosis) Research question: is there a way to predict the onset of cirrhosis (post- transplantation recurrent HCV) with bilirubin? Literature suggests abnormal levels of bilirubin => early cirrhosis Is there a correlation between bilirubin concentrations and progression of cirrhosis?

Research Study Patients at Kansas University Medical Center Liver transplantation cases in time range January 2000 – June 2010 at KUMC Data was collected from electronic and physical patient records – Demographic Data: Patient age, sex, height, weight, status, donor age and donor sex. – Laboratory Data: Hepatitis C Genotype, Hepatitis C Quantitative PCR (at 12 weeks after start of AVT, end of AVT and 3 months after AVT course), AST, ALT, Alkaline Phosphatase, GGTP, and Total Bilirubin (at time of first post-transplant biopsy)

Methods 224 patients identified on initial database query Level of Total Bilirubin (as measured in the bloodstream) was recorded for times after liver transplantation: 1, 2, 3, 4, 5, 6, 7, 10, 14, 21 days Liver biopsy reports, indications of fibrosis and cirrhosis as measured quantitatively according to Child-Pugh system (stage 1-4, grade 1-6) Decay constant of Total Bilirubin vs. severity of onset of fibrosis Also noted ALT, AST, GGTP (also found in the bloodstream), markers of abnormal liver function Elevated levels of these compounds has been shown to lead to early cirrhosis (<6 months post-transplant)

Results Multivariate analysis yet to be conducted Control patients yet to be added to dataset It seems that there are many other variables that influence the severity of the HCV recurrence HCV Genotype and AVT drug type (Parallel research study by Cowan, Gilroy et. al, 2009) Complex interactions—requires greater statistical analysis

Discussion AVT and immunosuppression levels must be individualised Peginterferon and ribovirin are the only two drugs known to eradicate recurrent HCV Treatment factors: How long? How much? How to taper? Variable factors: Age, weight, sex, extent of cirrhosis, race Significant risks of overcompensation: – Steroid addiction – Diabetes mellitus – Loss of nerve endings – Progressive fibrosis despite sustained virologic response (SVR) – Renal failure Also discouraged by: – Expensive costs of drugs Being able to predict the severity of HCV recurrence is extremely powerful clinically If we can show that there are clear predictors of HCV recurrence post-liver transplant… More accurate prescription of AVT and immunosuppression Decrease risk of unintended side-effects More cost-effective

Acknowledgements Princeton University – PEI/Grand Health Challenges Dr. Richard Gilroy, Director of Liver Transplants Dr. Tamer Malik, Liver Transplant Surgeon Kansas University Medical Center, KS