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Occurrence of End Stage Liver Disease
Liver Transplantation for Hepatitis C Virus Infection: What have We Learned?
Transplant 2001: The Joint American Transplant Meeting
Day 1 - May 11, 2001
C. Andrew Bonham, MD
Liver Transplantation for Hepatitis C Virus (HCV) Infection
End-stage liver disease resulting from chronic infection with HCV has become the most common indication for liver transplantation. While transplantation eliminates the complications from cirrhosis, reinfection of the graft with HCV is universal. In the majority of patients (75% to 80%), biochemical and histologic evidence of recurrent disease develops, with progressive deterioration of liver function as the graft develops fibrosis, then cirrhosis over a period of 5-20 years. A smaller group of patients (10% to 15%) suffer an aggressive recurrence with rapidly evolving cholestasis, which progresses to liver failure within a year. An even smaller group of patients has detectable HCV viremia, but no evidence of hepatitis. These patients enjoy prolonged survival with normal liver function. The difficulties encountered in caring for these patients has prompted a closer inspection of the factors that impact HCV recurrence following orthotopic liver transplantation.
Outcomes of Liver Transplantation for HCV Infection
Whereas early reports described equivalent outcomes after liver transplantation for HCV-negative and HCV-positive patients,[1,2] more recent studies indicate a bleaker outcome for HCV-positive patients. Improvements in surgical techniques, patient selection, and management of immunosuppression have resulted in improved patient and graft survivals over the last decade. Furthermore, tests for HCV infection have become more sensitive and specific. With these improvements and longer follow-up, it is becoming evident that patients with cirrhosis secondary to HCV infection do not fare as well after transplantation as those with cirrhosis from other causes.
A review of the United Network for Organ Sharing (UNOS) database as reported by Dr. Forman and Dr. Lucey[3] of the University of Pennsylvania, Philadelphia, revealed that 5-year allograft survival was significantly lower in HCV-infected patients compared with all other diagnostic groups except for patients with malignancy. Similar findings were reported by Dr. Jones and colleagues[4] of the Carolinas Medical Center, Charlotte, for the Southeastern Organ Procurement Foundation Liver Committee. HCV infection was associated with a significantly lower patient survival at 10 years. However, while this was statistically significant, they contended that survival rates for HCV-infected patients were still clinically acceptable. These findings were reinforced by a study from UCLA reported by Dr. Ghobrial and colleagues[5] of the University of California at Los Angeles. Follow-up of over 500 patients revealed decreased graft and long-term patient survival associated with recurrence of hepatitis. Of note, recurrence was defined by histology noted on biopsy obtained for clinical indications such as elevated liver enzymes. Thus, a number of patients with recurrent disease but without biochemical abnormalities prompting biopsy may have been excluded from this analysis. Early recurrence was associated with a more aggressive disease course.
The effects of cryoglobulinemia on outcomes after liver transplantation were reported by Dr. Rayhill[6] and colleagues of the University of Iowa, Iowa City. Chronic HCV infection is associated with mixed cryoglobulinemia. This in turn frequently leads to chronic renal disease.[7] Histologic recurrence rates were significantly higher and patient and graft survival were significantly worse in patients with cryoglobulinemia than in those without cryoglobulinemia. Whether renal failure was a contributing factor was not addressed.
Progression of HCV Infection in the Liver Transplant Recipient
Several factors were identified that appear to be associated with the progression of the HCV infection after transplantation. A high viral load at 1 month after transplantation correlated with histologic recurrence and development of fibrosis, according to Dr. Suarez and colleagues[8] of the University of La Coruna Health Institute, Spain.[9] There was also an increased incidence of liver failure and patient death. Similarly, the stage of hepatitis (hepatitis activity index or HAI) and fibrosis on biopsy correlates with viral load at 4 months posttransplantation. The impact of posttransplant diabetes mellitus in patients with HCV infection was described by Dr. Baid and colleagues[10] of Massachusetts General Hospital, Boston. HCV appeared to be an independent risk factor for the development of diabetes as defined by the requirement for glucose-lowering agents posttransplantation. An increased mortality rate was noted in HCV-positive patients in whom diabetes developed. However, this may be at least in part a marker for increased immunosuppression use, which is known to increase the risk of development of diabetes.
HCV Infection vs Rejection?
Distinction between recurrent HCV infection and rejection is frequently a challenge. As treatment of one may exacerbate the other, it is important to determine which process is occurring in the graft. Two groups analyzed gene expression in allograft biopsy specimens to identify molecules that might be associated with either rejection or HCV recurrence. Samples from grafts with histologic evidence of acute rejection displayed increased expression of molecules associated with T-cell activation, such as MHC class 1 and 2, IL-2, and granzyme-B, noted Dr. Sreekumar and colleagues[11] of the Mayo Clinic Foundation, Rochester, Minnesota. These molecules were expressed at levels several-fold higher than in specimens from patients with recurrent HCV infection. A cohort of patients suffering both acute rejection and recurrent HCV infection were examined by Dr. Zekry and colleagues[12] of Sydney University, New South Wales, Australia. IL-10 and IL-4 gene expression were elevated in this group, suggesting that T-helper 2 type responses predominate in this state. Additionally, aggressive cholestatic recurrence of HCV infection was associated with upregulation of IL-10 and IL-4 expression and a high HCV viral load. This area of research is rapidly evolving in attempts to develop a molecular "fingerprint" diagnostic of rejection.
Immunosuppressive
Regimens: A Factor in HCV Infection Recurrence and Progression
As it becomes evident that HCV infection recurrence has a negative impact on graft function and survival and contributes to substantial posttransplant morbidity, more attention has been directed to the effects of immunosuppression on viral recrudescence and disease progression. While the general caveat is that immunosuppression facilitates HCV infection recurrence, the degree to which different immunosuppressive regimens enhance viral replication has not been well studied. Corticosteroids clearly promote disease progression. Viral replication increases, and hepatitis worsens.[13] Antilymphocyte preparations seem to be associated with more aggressive disease, although it is unclear whether this is a direct effect or related to the higher doses of other immunosuppressive drugs frequently given to patients requiring these agents.
There appears to be no advantage to the use of cyclosporine vs tacrolimus (TAC).[14]
Mycophenolate mofetil (MMF) offers some theoretical advantages. As it inhibits purine synthesis, when combined with ribavirin it may limit viral replication. Additionally, the B-cell inhibition produced by MMF may limit the development of cryoglobulinemia.[15] Results of a series of HCV-infected patients randomized to TAC + steroids vs TAC + steroids + MMF after liver transplantation were reported by Dr. Jain and colleagues[16] of the University of Pittsburgh, Pennsylvania. There were no differences with regard to rejection, HCV infection recurrence, graft survival, or patient survival between the 2 groups, suggesting that MMF does not have an adverse effect on the progression of HCV infection after liver transplantation. Similarly, Smallwood and colleagues[17] of Emory University, Atlanta, Georgia, found no adverse effects of MMF on HCV infection recurrence or graft and patient survival. Furthermore, the drug did not have an impact on response to therapy with interferon and ribavirin.
The effects of use of sirolimus in these patients are unclear. As it bears some antiproliferative properties, just as MMF does, sirolimus may have some theoretical advantages. Similarly, there is little experience with the use of IL-2 receptor antagonists. Two reports cite conflicting results. A higher incidence of HCV infection recurrence with the use of daclizumab induction therapy was shown by Dr. Marino and colleagues[18] of Georgetown University, Washington, DC. This recurrence tended to be aggressive, with early development of fibrosis and cholestasis. However, patients continued to receive corticosteroids, and it is unclear what impact rejection (and its treatment) had on the outcomes.
In contrast to the results of this study, Dr. Kato and colleagues[19] of the University of Miami, Florida, demonstrated in a randomized, prospective trial that HCV infection recurrence did not develop in patients receiving daclizumab induction in a corticosteroid-free regimen, whereas 3 patients in the control group had recurrent disease. This finding may be due in part to a higher incidence of rejection requiring higher corticosteroid doses. HCV infection recurrence was defined as histologic evidence of hepatitis seen on biopsy. Biopsies were obtained only when clinically indicated by biochemical abnormalities.
While the best drug combination for immunosuppression in these patients remains to be defined, 1 fact has become clear. Early acute rejection in HCV-infected liver transplant recipients is associated with an increased risk for mortality.[20]
Impact of HCV-Positive Donors
The critical shortage of suitable organ donors has led to the use of less than optimal grafts at a number of centers. Many transplant surgeons will consider using an organ from an HCV-positive donor in a recipient already infected with the virus. The results of this practice have not been well studied.
After transplantation, viral strains from both the donor and recipient can be detected in liver and blood for the first few weeks, based on work by Dr. Vargas and colleagues[21] of the University of Pittsburgh, Pennsylvania.
In a review of the outcomes of liver grafts procured from HCV+ donors, Velidedeoglu and colleagues[22] of the University of Pennsylvania Health System, Philadelphia, found that HCV-positive recipients of HCV-positive grafts had similar patient and graft survival rates compared with HCV-positive recipients of HCV-negative grafts. These findings were confirmed by several single-center experiences. A single-center (UCLA) report[5] showed an association between the use of HCV-positive organs and a shortened time to recurrence as defined by histologic evidence of hepatitis on biopsy. Thus, the use of HCV-positive organs appears to be justified in HCV-infected patients, as overall graft and patient survival are not adversely affected despite earlier recurrence of the virus.
Management of HCV Recurrence After Liver Transplantation
The management of HCV infection is evolving rapidly, with many investigational agents being studied. The suboptimal responses to interferon monotherapy seen in the general population were compounded by immunosuppression in the transplant population, with less than 5% of patients responding to treatment. More recently, combination therapy with interferon and ribavirin has been more encouraging. Dr. Kornberg and colleagues[23] of Friedrich-Schiller-University, Jena, Germany, reported complete responses -- viral clearance, histologic improvement, and biochemical normalization -- in over 50% of patients. Additionally, partial responders had evidence of improved allograft function. While such responses are encouraging, it remains to be seen whether they can be sustained with cessation of therapy. Dr. Nasir and colleagues[24] of Emory University, Atlanta, Georgia, were less optimistic. They noted that a significant number of patients experience disease progression and development of fibrosis, despite combination therapy. Furthermore, both investigators cited the common occurrence of adverse side effects, such as anemia, requiring treatment reduction or withdrawal.
The development and release of pegylated interferons has been anxiously awaited. Conjugation of the polyethylene glycol moiety to the interferon molecule inhibits its degradation. Patients are able to administer the drug at weekly intervals and suffer from fewer side effects. Preliminary results of a multicenter trial employing Pegasys (Peg-interferon) in liver transplant recipients suffering from recurrent HCV infection were shared by Dr. Riely and colleagues[25] of the University of Iowa, Iowa City. After 24 weeks of therapy, 50% of patients had at least a 2-log drop in viral load. This compares favorably to responses seen with interferon and ribavirin. Adverse events were common but minor, and included fatigue and headache. There were no episodes of rejection. Combination therapy utilizing Peg-interferon with ribavirin remains to be tested.
Conclusion
HCV is now the most common reason for liver transplantation. Complications from recurrent disease contribute to decreased long-term patient and graft survival. Strategies to control the disease should focus on preventing rejection, avoiding corticosteroids and antilymphocyte preparations, and instituting therapeutic protocols designed to limit viral replication.
References
Boker K, Dalley G, Bahr M, et al. Long-term outcome of hepatitis C virus infection after liver transplantation. Hepatology. 1997;25:203-210.
Shuhart MC, Bronner MP, Gretch DR, et al. Histological and clinical outcome after liver transplantation for hepatitis C. Hepatology. 1997;26:1646-1652.
Forman LM, Lucey MR. Orthotopic liver transplantation for hepatitis C: Analysis of allograft survival using the UNOS database. In: Concurrent Session 9: Liver Transplantation: Hepatitis C Clinical Outcomes. Program and abstracts of Transplant 2001, The Joint American Transplant Meeting; May 11-16, 2001; Chicago, Illinois. Abstract 82.
Jones JW, Members of the SEOPF Liver Committee Transplant Center, Carolinas Medical Center, Charlotte, NC. Impact of hepatitis C on liver transplant survival over ten years - a report of the SEOPF Liver Committee. In: Concurrent Session 9: Liver Transplantation: Hepatitis C Clinical Outcomes. Program and abstracts of Transplant 2001, The Joint American Transplant Meeting; May 11-16, 2001; Chicago, Illinois. Abstract 83.
Ghobrial RM, Farmer DG, Stedman R, et al. Adverse effects of HCV recurrence in over five hundred liver transplantations. In: Concurrent Session 9: Liver Transplantation: Hepatitis C Clinical Outcomes. Program and abstracts of Transplant 2001, The Joint American Transplant Meeting; May 11-16, 2001; Chicago, Illinois. Abstract 84.
Rayhill SC, Schmidt WN, Bozorgzedeh A, et al. Cryoglobulinemia predicts poor outcome following liver transplantation in patients with hepatitis C. In: Concurrent Session 9: Liver Transplantation: Hepatitis C Clinical Outcomes. Program and abstracts of Transplant 2001, The Joint American Transplant Meeting; May 11-16, 2001; Chicago, Illinois. Abstract 87.
Johnson RJ, Gretch DR, Yamabe H, et al. Membranoproliferative glomerulonephritis associated with hepatitis C virus infection. N Engl J Med. 1993;328:465-470.
Suarez F, Otero A, Gomez-Gutierrez M, et al. HCV viral load at one month after liver transplantation is a prognostic factor for the development of recurrent hepatitis C and liver failure after transplantation. In: Concurrent Session 9: Liver Transplantation: Hepatitis C Clinical Outcomes. Program and abstracts of Transplant 2001, The Joint American Transplant Meeting; May 11-16, 2001; Chicago, Illinois. Abstract 85.
Sreekumar R, Gonzalez-Koch A, Maor-Kendler Y, et al. Early identification of recipients with progressive histologic recurrence of hepatitis C after liver transplantation. Hepatology. 2000;32:1125-1130.
Baid S, Cosimi AB, Farrell ML, et al. Increased mortality risk in hepatitis C-positive liver transplant recipients who develop posttransplant diabetes mellitus. In: Concurrent Session 9: Liver Transplantation: Hepatitis C Clinical Outcomes: Program and abstracts of Transplant 2001, The Joint American Transplant Meeting; May 11-16, 2001; Chicago, Illinois. Abstract 86.
Sreekumar R, Wiesner R, Rosen C. Distinction of acute cellular rejection from recurrence of HCV through intragraft gene expression patterns. In: Concurrent Session 19: Liver Transplantation: Hepatitis C II: Program and abstracts of Transplant 2001, The Joint American Transplant Meeting; May 11-16, 2001; Chicago, Illinois. Abstract 172.
Zekry A, Bishop A, McCaughan GW. Intrahepatic cytokine expression associated with hepatitis C virus (HCV) recurrence post liver transplantation for HCV infection. In: Concurrent Session 19: Liver Transplantation: Hepatitis C II. Program and abstracts of Transplant 2001, The Joint American Transplant Meeting; May 11-16, 2001; Chicago, Illinois. Abstract 174.
Papatheodoridis GV, Barton SG, Andrew D, et al. Longitudinal variation in hepatitis C virus (HCV) viraemia and early course of HCV infection after liver transplantation for HCV cirrhosis: the role of different immunosuppressive regimens. Gut. 1999;45:427-434.
Ghobrial RM, Farmer DG, Baquerizo A, et al. Orthotopic liver transplantation for hepatitis C: outcome, effect of immunosuppression, and causes of retransplantation during an 8-year single-center experience. Ann Surg. 1999;229:824-831.
Roth D, Cirocco R, Zucker K, et al. De novo membranoproliferative glomerulonephritis in hepatitis C virus-infected renal allograft recipients. Transplantation. 1995;59:1676-1682.
Jain AB, Kashyap RS, Fung JJ. Role of mycophenolate mofetil (MMF) in liver transplantation (LTX) for HCV related end stage liver failure (a prospective randomized trial)? In: Concurrent Session 19: Liver Transplantation: Hepatitis C II: Program and abstracts of Transplant 2001, The Joint American Transplant Meeting; May 11-16, 2001; Chicago, Illinois. Abstract 177.
Smallwood GA, de Vera ME, Davis L, Martinez E, Steiber AC, Heffron TG. Is mycophenolate beneficial in the treatment of recurrent hepatitis C following liver transplantation? In: Concurrent Session 19: Liver Transplantation: Hepatitis C II. Program and abstracts of Transplant 2001, The Joint American Transplant Meeting; May 11-16, 2001; Chicago, Illinois. Abstract 176.
Marino G, Rustgi VK, Marroquin CE, et al. Early recurrence of hepatitis C after liver transplantation with daclizumab induction. In: Concurrent Session 9: Liver Transplantation: Hepatitis C Clinical Outcomes. Program and abstracts of Transplant 2001, The Joint American Transplant Meeting; May 11-16, 2001; Chicago, Illinois. Abstract 88.
Kato T, Neff G, Montalbano M, et al. Steroid-free induction with tacrolimus and daclizumab in liver transplant recipients with hepatitis C - a preliminary report of a prospective randomized trial. In: Concurrent Session 19: Liver Transplantation: Hepatitis C II. Program and abstracts of Transplant 2001, The Joint American Transplant Meeting; May 11-16, 2001; Chicago, Illinois. Abstract 173.
Charlton M, Seaberg E. Impact of immunosuppression and acute rejection on recurrence of hepatitis C: results of the National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database. Liver Transplantation and Surgery. 1999;5:S107-S114.
Vargas H, Wang LF, Wilkinson J, Radkowski M, Laskus T, Rakela J. Changes in hepatitis C virus (HCV) population in serum and peripheral blood mononuclear cells in chronically HCV-infected patients receiving liver grafts from HCV-infected donors. In: Concurrent Session 19: Liver Transplantation: Hepatitis C II. Program and abstracts of Transplant 2001, The Joint American Transplant Meeting; May 11-16, 2001; Chicago, Illinois. Abstract 171.
Velidedeoglu E, Desai NM, Campos L, et al. The outcome of livers from HCV+ donors. In: Concurrent Session 9: Liver Transplantation: Hepatitis C Clinical Outcomes. Program and abstracts of Transplant 2001, The Joint American Transplant Meeting; May 11-16, 2001; Chicago, Illinois. Abstract 81.
Kornberg A, Homman M, Tannapfel A, Voigt R, Grube T, Scheele J. Combination of interferon-alpha and ribavarin for recurrent hepatitis C after orthotopic liver transplantation -- impact on histopathology, viremia and graft function. In: Concurrent Session 19: Liver Transplantation: Hepatitis C II. Program and abstracts of Transplant 2001, The Joint American Transplant Meeting; May 11-16, 2001; Chicago, Illinois. Abstract 178.
Nasir A, de Vera ME, Smallwood GA, Stieber AC, Heffron TG. Effect of interferon-A and ribavarin on liver histology in liver transplant patients with recurrent hepatitis C. In: Concurrent Session 19: Liver Transplantation: Hepatitis C II. Program and abstracts of Transplant 2001, The Joint American Transplant Meeting; May 11-16, 2001; Chicago, Illinois. Abstract 179.
Riely C, Ferenci P, Peck-Radosavljevic M, et al. Pegylated (40 kDa) interferon alfa-2A (PegasysŪ) in post-liver transplant recipients with established recurrent hepatitis C: a preliminary report. In: Concurrent Session 9: Liver Transplantation: Hepatitis C Clinical Outcomes. Program and abstracts of Transplant 2001, The Joint American Transplant Meeting; May 11-16, 2001; Chicago, Illinois. Abstract 89.
San Diego Hospital Starts Trial of Liver Dialysis Unit
A San Diego hospital has begun offering advanced liver patients the kind
of life-prolonging dialysis treatment that henceforth has only been
available to kidney patients.
Scripps Green Hospital is the first of several hospitals around the
country that plan to participate in a post-market clinical trial of a
HemoTherapies Unit, designed to clear toxins from the bloodstream. Until
now, the thousands of liver patients awaiting an organ transplant have
not had the equivalent of the life-sustaining therapy of dialysis used
by tens of thousands of patients awaiting kidney transplants.
"Over 600,000 people in California suffer from Hepatitis C alone
and many more suffer from other forms of liver disease or
impairment," said Dr. Lisa Nyberg of Scripps Clinic. "If the
liver disease progresses to end stage disease resulting in mental
confusion or coma, the HemoTherapies treatment may be of benefit. Prior
to this, we've had very few treatment options available to help these
patients."
Nyberg said patients who may be possible candidates for treatment with
Liver Dialysis should be evaluated by their doctor who, in turn, should
contact the treatment center.
THE PHENOMENA OF LEG PIGMENTATION IN CASES OF CHRONIC LIVER DISEASE
Y.A. ELGHAFFAR, M.E.ELWAHAB, S.M. SALEH, A.A.RAOUF,H.M.LIMOUNE. LIVER Institute. Dept of Med. Dep. of biochemistry - Menofeia university
The aim of this work was to study this phenomenon, its relative frequency, its relation to various forms of chronic liver disease its correlation to other features of chronic liver disease, its pathogenesis and the underlying mechanisms of its production. This study included 54 male and female patients with chronic liver disease presenting with pigmentation of skin on the dorsum of their feet. The subjects were divided into 3 groups according to the severity of skin pigmentation. Fifty male and female patients with chronic liver disease without skin pigmentation were also included in this work as a control group. Patients and controls were selected from inpatients and outpatients of the department of medical hepatology of liver institute of Menoufyia University. The study was done in the period from october 1992 to june 1995. The study included : history, clinical examination, urine and stool analysis, rectal biopsy for patients who were negative for bilharzial ova in urine and stool analysis, liver function tests, bleeding and coagulation time, total s. iron, virologic liver profile for HB cAb, HBeAg, HBeAb, HBsAb and anti HCV, ultrasonographic examination of abdomen, direct liver biopsy, and skin biopsy.
Skin pigmentation in our studied patients appeared as bilateral permanent diffuse area of hyperpigmented skin on a big part or the whole of the dorsum of the foot extending in some patients into the shaft of the leg above the ankle joint. In conclusion, it is seen that the phenomenon of pigmentation of the dorsum of the foot has significantly apositive association with : yellow color of the sclera, abdominal distention, bleeding per nose and gums, and disturbed levels of consciousness vascular spiders, and edema of lower limbs decreased size of the liver (shrunken liver), and increased size of spleen (mild splenomegaly), positive schistosomiasis(both in stool &rectal snip), increased level of total s. proteins and decreased level s . albumin, increased level of total s. iron, HCV-Ab, HBcAb. ascites, and increased diameter of the portal vein (portal hypertension) and hemosiderin, hyaline degenerative changes, and melanin of skin biopsy. Thus, we can conclude that the finding of pigmentation of the foot can be considered a confirmatory sign of cirrhosis in the presence of positive histopathology of the liver and a useful suggestive sign of cirrhosis in the absence of histopathlogy.
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Revised: July 26, 2001 .All information is posted without profit or payment for research and is for educational purposes only, in accordance with Title 17 U.S.C. section 107.