Overall Bottom Line
- Recurrence of HCV after transplantation is universal.
- Twenty-five percent of patients progress to cirrhosis within 5 years, 50% within 10 years.
- The differential diagnosis of abnormal liver tests post-transplantation is broad and includes viral infection, drug toxicity, rejection and biliary obstruction.
- Anti-viral treatment is difficult for patients to tolerate post-transplantation and thus leads to a frequent need to dose reduce and terminate therapy early.
- Fibrosing cholestatic hepatitis is an infrequent occurrence and carries high morbidity/mortality, typified by hyperbilirubinemia, profound HCV viremia and specific histological features.
Section 1: Background
Definition of disease
- Recurrent HCV infection of the liver allograft occurs in all patients who are HCV-RNA positive at the time of LT. The graft is re-infected as early as the time of re-perfusion and patients may develop histologic and biochemical features of acute HCV in the first few months after transplantation, which is accompanied by a gradual rise in HCV viremia.
Disease classification
- Histologic features of chronic HCV (Figure 52.1) can be demonstrated in >70% HCV recipients after 1 year and in close to 90% 5 years after transplantation. Patients will always be viremic with recurrence being defined as histological evidence of reinfection associated with abnormal liver chemistry tests.
Incidence/prevalence
- In the USA, 45–48% of patients undergoing LT have HCV.
- If the HCV PCR is positive prior to transplantation, it is positive after transplantation.
- Fifty to 70% of patients will have histologic recurrence of HCV within 1 year of transplantation, 90% within 5 years.
Economic impact
- The need to treat recurrent HCV with IFN-based therapy carries appreciable financial burden.
- The complications of graft failure and need for re-transplantation also bear significant economic burden.
Etiology
- Reinfection of the transplanted liver with viral hepatitis.
- The detection of HCV viremia occurs as early as the anhepatic phase of the transplantation surgery.
- Accelerated fibrosis in the transplanted liver leads to graft failure and cirrhosis and the need for re-transplantation.
Pathology/pathogenesis
- Ongoing inflammation of the transplanted liver leads to fibrosis formation. Multiple factors may contribute to this fibrosis:
Factors Associated with Accelerated Fibrosis Progression
High HCV-RNA serum levels pre- and immediately post-LT
HIV co-infection
Older donor age
Concurrent biliary problems post-transplantation
Post-transplantation diabetes mellitus
Severe inflammation/fibrosis at one year
Early histologic recurrence
Infection with CMV and HSV-6
Bolus corticosteroids to treat acute cellular rejection
Plasma cell hepatitis
Concurrent steatohepatitis
Section 2: Prevention
Bottom Line
- Attempting to treat HCV pre-LT is recommended. The International Liver Transplant Society has recommended that patients with MELD scores of 15 or less undergo an attempt at HCV viral eradication prior to transplantation. Studies of early post-transplantation pre-emptive antiviral therapy have shown very poor SVR rates and for this reason the majority of transplantation centers do not pursue this.
- It may also not be practical to treat patients with antiviral therapy early after transplantation as patients may have renal dysfunction and be at great risk for infection as they recuperate from a lengthy pre-transplantation hospitalization. They may be deconditioned, have anemia and are taking a myriad of other medications in the early post-operative period, which is also the peak time for developing rejection.
- Patients with cirrhosis are complex patients to treat with IFN and ribavirin because of their increased risk for infection, liver decompensation, thrombocytopenia and anemia. Most patients require extremely close follow up as well as the use of hematopoietic growth factors, and it is difficult to achieve optimal dosing.
Screening
- Assessment of serum HCV viral loads. There may be no correlation between the degree of viremia and the amount of histologic damage.
Primary prevention
- Pre-LT anti-viral therapy can be effective in carefully selected patients.
Secondary prevention
- Pre-emptive anti-viral therapy post-LT is currently not indicated because of poor sustained viral response rates and appreciable complications.
Section 3: Diagnosis (Algorithm 52.1)
- The diagnosis is based on demonstrating HCV viremia post-LT in a patient with known hepatitis C and typical histologic findings occurring usually in the setting of abnormal liver chemistry tests.
- Patients undergoing transplantation before the early 1990s may have acquired HCV through transfusions or the transplanted graft itself.
- Genotyping gives the clinician helpful information in predicting response to treatment.
- Patients may sometimes receive hepatitis B core antibody positive livers so exclusion of hepatitis B viremia is essential in the appropriate clinical setting.
| Differential diagnosis | Features |
|---|---|
| Drug-induced liver injury | Eosinophilia, suggestive histologic findings, use of known potentially hepatotoxic medications, i.e. sulfonamides |
| Biliary obstruction | Occurs in upwards of 10–20% of all transplantations. Cholestasis may predominate and patients may have symptoms of cholangitis |
| CMV and other viral infections | Patients often have constitutional symptoms, pancytopenia and fever. Typical PCR serologies and histology are seen |
| Acute cellular or chronic ductopenic rejection | Abnormal liver chemistry tests with neither a specific hepatocellular nor cholestatic pattern. Immunosuppressive medication levels may be sub-therapeutic. Liver biopsy is necessary to make the diagnosis |
| Hepatic artery thrombosis/stenosis | High aminotransferases, diagnosed by Doppler US or arteriography |
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