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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?
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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/liver
diseases.html
http://www.mva.org/composite-398.htm
Liver dysfunctions
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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 bloodbrain barrier
Ammonium, NH3
http://healthguide.howstuffworks.com/cirrhosis-indepth.htm
http://en.wikipedia.org/wiki/File:Ammonia-3D-balls-A.png
Hepatitis C
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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
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 (posttransplantation 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
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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:
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Also discouraged by:
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Steroid addiction
Diabetes mellitus
Loss of nerve endings
Progressive fibrosis despite sustained virologic response (SVR)
Renal failure
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