Amit Kakkar, PGY1

1
Ground Glass Changes in Transplanted Livers
Another Toxic Effect of Calcineurin Inhibitors?

• Amit Kakkar, PGY1
• Georgetown University Hospital
• Dept of Medicine
• January 25, 2008

2
Background

• Liver transplantation started in 1950s
• 1st human OLT done in 1963 survival still poor
• 1st anti-rejection meds steroids and
  azathioprine ? graft survival 30
• With introduction calcineurin inhibitors
  (cyclosporine and tacrolimus), 1yr graft survival
  gt90
• Rejection multistep process including
  alloantigen recognition, lymphocyte activation,
  clonal expansion, and inflammation ? meds are
  able to block each step in the pathway

3
(No Transcript)
4
Mechanism of CIN
Fantini et alNature Clinical Practice
Gastroenterology Hepatology (2006) 3, 633-644
5
Cyclosporine vs. Tacrolimus (FK506)

• Landmark Trial occurred in 1994 by the US
  Multicenter FK506 Liver study group with results
  published in N. England Journal ? large,
  multicenter, randomized open label study
• Outcomes 1) Reaffirmed that rejection was an
  important cause of graft loss and
  death 2) Survival between tacrolimus and
  cyclosporine were similar, but less
  significantly less incidence of steroid
  resistant rejection with tacrolimus 3) FK506
  assoc with excess adverse effects including
  neurotoxicity and nephrotoxicity

6
(No Transcript)
7
Dosage/Monitoring

• Therapeutic Trough Range 5-10ng/ml.
• May increase trough goal if OLT 2nd to autoimmune
  hepatitis
• OLT patients likely on extensive drug regimens

Masuda Inuchi. Pharmacology Therapeutics.
8
Mechanisms of Drug Induced Liver Injury
9
The Ground Glass Phenomenon

• Typically, ground glass changes seen with HBV
• EM ?ground glass predominantly glycogen
• Prior studies were not limited to OLT pts, but
  med profile suggested immunosuppressives
• Proposed mechanism altered glycogen metabolism
  2nd polypharmacotherpy
• Adaptive change vs. sign of hepatotoxicity

Wisell et al. Glycogen Am J of Surg Pathology
(2006) vol 30, 9
10
Histology
11
Ground Glass 2nd to CIN?

• My research
• Retrospective chart review of OLT patients _at_GUH
  from 2004-2007, with ground glass changes on
  liver bx
• Record demographics, hepatic panel, time to bx,
  and medication regimen 1 and 3months prior to bx,
  adverse events
• Record CIN levels at 1 and 3months prior to bx
• Exclusion criteria cyanamide tx, HBV
  recurrence, hx glycogen storage disease

12
Results

• Total 8 cases identified
• -1 female, 7 male
• Age 31 -72
• Tx indication 1 PSC, 1 AIH, 3HBV/HCC, 3HCV/HCC
• Bx indication increased LFTs
• Common Medication Tacrolimus, PPI
• Mean AST 151, ALT 224, ALP 241, TP 3.4, Alb 6,
  tbili 1.2, GGTP 413
• Mean days to bx 153
• Fk506 levels 1mo 10.4, 3mo 11.2, lt1wk to bx 10.7
• 3cases with repeat bx 2 cases no longer with
  histologic changes

13
Further Investigation

• Adaptive change vs. sign of hepatotoxicity
• Reanalysis of repeat bx that were negative for
  similar changes
• Medication reconciliation inhibitors? inducers?
  drug levels
• Role of mycophenolate mofetil (MMF) 4 out of
  the cases were concomittantly on MMF
• Analysis of bx by EM

14
Acknowledgements

• Dr. K. Shetty, Dept of Hepatology,
  Gastroenterology
• Staff at the Transplant Institute and
  International Center for Liver Diseases
• Dr. B. Kallakury, Dept of Pathology

15
References

• A comparison of tacrolimus (FK 506) and
  cyclosporine for immunosuppression in liver
  transplantation. The U.S. Multicenter FK506 Liver
  Study Group. N Engl J Med 1994 3311110
• Fantini, Christoph Becker, Ralf Kiesslich and
  Markus F Neurath. Drug Insight novel small
  molecules and drugs for immunosuppression Nature
  Clinical Practice Gastroenterology Hepatology
  (2006) 3, 633-644.
• Hasenbein et al. Long term evaluation of
  cyclosporine and tacrolimus based
  immunosuppression in pediatric liver
  transplantation. Pediatric Transplantation.
  (2006) 10, 938-942.
• Larson, Ann. Drugs and the Liver Patterns of
  Hepatotoxicity. www.uptodate.com.
• Lefkowitch et al. Ground-Glass, Polyglucosan Like
  Hepatocellular Inclusions A New diagnostic
  Entity. Gastroenterology (2006) 131 713-718.
• Masuda and Inui. An uptodate review on
  individualized dosage adjustment of calcineurin
  inhibitors in organ transplant patients.
  Pharmacology and Therapeutics. 112 (2006).
  184-196.
• Wisell et al. Glycogen Psuedoground Glass Change
  in Hepatocytes. Am J of Surg Pathology (2006) vol
  30, 9, 1085-1089.