Overall Bottom Line

Autoimmune liver conditions such as AIH, PBC and PSC all recur post-LT but graft loss is uncommon.
Patients with HBV do extremely well post-LT because of the use of hepatitis B immunoglobulin, and now oral medications to prevent HBV recurrence.
NASH is an increasingly common indication for LT and may recur post-transplantation. Many patients with cryptogenic cirrhosis transplanted in the past in reality may have had NASH and it has been shown to recur post-LT.
Hepatitis B core + donor livers potentially may transmit HBV to the recipient so appropriate prophylaxis is necessary.
LT outcomes are excellent in patients with autoimmune liver disease.
Clinically relevant recurrence does not occur with metabolic liver diseases such as hemochromatosis and alpha-1 antitrypsin deficiency.

Section 1: Background

Definition of disease

Most primary liver diseases that necessitate LT have the potential to recur post-transplantation.
Recurrence of HCV is almost universal and progressive disease may lead to graft failure in upwards of 50% of patients within 10 years.
Clinically relevant recurrence does not occur with metabolic liver diseases such as hemochromatosis and alpha-1 antitrypsin deficiency.
Recidivism may lead to liver damage in alcoholics but rarely results in organ failure.
PBC, PSC and AIH, as well as HBV and NASH all may recur post-LT. Transplantation outcomes overall are excellent in these groups of patients, especially those with the autoimmune liver diseases and HBV.

Incidence/prevalence

Recurrence of PBC may ultimately occur in up to 50% of LT recipients but jaundice with a need for re-transplantation is exceedingly rare.
PSC may recur in 20–40% of patients but true recurrence may be underestimated; up to 20% of patients with recurrent disease may develop graft failure necessitating re-transplantation.
AIH may recur in up to 25% of recipients during the first 5 years after transplantation and >50% of patients after 10 years.
Prior to the advent of HBIg, HBV recurrence was universal and led to graft failure in the majority of cases. The use of HBIg and subsequently, oral medications, have almost totally prevented severe HBV recurrence. Breakthroughs of HBV while on HBIg monotherapy occur in up to 20% of cases but are easily treatable with oral combination therapy.
The true incidence of recurrent NASH is unknown but as the number of LTs for NASH increases, it is expected that recurrent NASH will become a problem especially since obesity and the metabolic syndrome commonly occur post-LT.

Economic impact

The true economic impact of recurrent disease after LT above is unknown but in the setting of graft failure would be associated with greater morbidity and mortality and thus, greater economic impact.
Disease recurrence typically necessitates liver biopsy and medical treatment and in PSC, cholangiography.
The prevention of recurrent HBV is extremely costly because of the use of HBIg prophylaxis. Most transplantation centers are now trying to convert HBIg to oral prophylaxis after the immediate post-transplantation period.

Etiology

HBV recurs more frequently in the setting of lamivudine resistance and when patients have high viral loads at transplantation. Patients with fulminant liver failure due to HBV and those with hepatitis delta co-infection have a low risk for re-infection of the new graft.
NASH is associated with the metabolic syndrome, which occurs commonly post-LT due to weight gain, hypercholesterolemia and diabetes mellitus that can stem from immunosuppressive medication use.
All autoimmune liver diseases recur post-transplantation.
Ischemic cholangiopathy resembles recurrent PSC and they may be difficult to differentiate.
De novo AIH (plasma cell hepatitis) may occur after transplantation and appears to be a variant of rejection that can lead to graft loss.

Pathology/pathogenesis

The diagnostic hallmark of PBC recurrence is the presence of granulomatous cholangitis or the florid-duct lesion on liver biopsy; lymphoplasmacytic inflammation may also be present.
Biliary structuring may occur for numerous reasons in the transplanted liver. Large bile duct and anastomotic strictures may be technically related complications and amenable to stenting or surgical revision. Diffuse intrahepatic stricturing that radiologically resembles PSC can occur in liver allografts exposed to prolonged ischemia times, with the use of a donation after cardiac death donor, with ABO incompatibility or in the setting of or a history of hepatic artery thrombosis or stenosis.
In recurrent AIH, the typical histology of prominent plasmacytic infiltration and lobular/necroinflammatory inflammation is present; significantly deranged liver chemistry tests, gamma globulin levels and autoimmune markers may not be present.
HBV core antibody (+) allografts have the potential for transmitting HBV from donor to recipient (see Table “Transmission of HBV from a core + donor”). These donor allografts are routinely used in recipients who do not have HBV; most transplantation centers give recipients prophylaxis with lamivudine or other nucleoside analogues.

Predictive/risk factors

Transmission of HBV from a core + donor

Recipient anti-core	Recipient surface antibody	Risk of HBV transmission
+	+	Low
−	+	Low
+	−	Intermediate
−	−	High (∼ 40%)

Some studies have suggested that PBC recurrence is much more frequent in patients receiving tacrolimus as opposed to cyclosporine as their primary immunosuppression.
Risk factors for recurrence of PSC may include older recipient age, male gender, donor:recipient gender mismatch, the presence of an intact colon or inflammatory bowel disease post-LT, CMV infection and rejection treated with corticosteroids.

Section 2: Prevention

Bottom Line

The use of ursodiol to date has not been shown to prevent PBC recurrence.
Treatment of overweight, diabetes and hypercholesterolemia may slow or prevent the development of recurrent NASH.
Recurrence typically occurs in patients who are no longer receiving corticosteroids or who are being maintained on low levels of immunosuppression.
The use of HBIg has dramatically improved the success of LT in this population to the point that HBV patients do just as well if not better than any group of recipients. Monthly use of HBIg has decreased HBV recurrence rates to less than 20% with graft loss from recurrent HBV now being exceedingly rare. The HBIg infusions typically begin intra-operatively and then often during the first post-operative week. Subsequent frequency of infusions is predicated on the achievement and maintenance of quantitative HBV surface antibody levels, ranging from 100 to 500 IU depending upon the transplantation center.

Screening

For PBC, typically a liver biopsy is performed because of persistent mild–moderate AP elevations. There does not appear to be a correlation between the presence or titer of serum AMA and the development of recurrent disease.
The diagnosis of recurrent PSC is based on the following criteria:
- Confirmed diagnosis of PSC pre-transplantation.
- Cholangiography demonstrating diffuse non-anastomotic biliary strictures >3 months post-transplantation.
- Histology showing fibrous cholangitis and/or fibro-obliterative lesions of the large bile ducts (“onion-skinning”) with or without ductopenia.
In patients with AIH, significantly deranged liver chemistry tests, gamma globulin levels and autoimmune markers may not be present and is why some centers perform protocol liver biopsies in these patients. Recurrence typically occurs in patients who are no longer receiving corticosteroids or who are being maintained on low levels of immunosuppression.
In patients transplanted for HBV or with a hepatitis B core + donor, hepatitis serologies and viral DNA are used to screen for recurrence of disease.

Primary prevention

Prior to the advent of HBIg prophylaxis to prevent recurrence of HBV post-LT, survival rates for patients were extremely poor due to rapid and aggressive recurrence of disease. Recurrence was marked by profound levels of viremia, reappearance of HBSAg(+) and the development of fibrosing cholestatic hepatitis.
The use of HBIg has dramatically improved the success of LT in this population to the point in which HBV patients do just as well if not better than any group of recipients.

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