Joseph Park Advisor: Richard Gilroy, M.D. Kansas University Medical Center

1. 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

2. 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 http://www.nlm.nih.gov/medlineplus/liverdiseases.html http://www.mva.org/composite-398.htm

3. 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, NH3 http://healthguide.howstuffworks.com/cirrhosis-in-depth.htm http://en.wikipedia.org/wiki/File:Ammonia-3D-balls-A.png

4. 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 http://upload.wikimedia.org/wikipedia/commons/3/3b/HCV_EM_picture_2.png Senecal, Morelli (2007). JAAPA 20(10), October 2007:21

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

6. 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

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

8. 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?

9. 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)

10. 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)

11. 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

14. 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

15. 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