Posttransplant considerations in autoimmune liver disease: Recurrence of disease and de novo

CONSIDERATIONS FOR TRANSPLANT IN AUTOIMMUNE LIVER DISEASE

Autoimmune liver diseases (ALDs), including autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and primary biliary cholangitis (PBC), are an indication for liver transplantation (LT) in 3%–5% of transplants in the United States. ¹ , ² Not all patients with ALD go on to need LT, but indications for LT can include acute liver failure, decompensated cirrhosis, a Model for End‐Stage Liver Disease/Pediatric End‐Stage Liver Disease score ≥ 15, malignancy, or refractory pruritus (PBC). Transplantation for ALD presents unique considerations given the possibility of recurrent disease and increased incidence of rejection. ³ , ⁴

Despite the potential for recurrent disease, outcomes after LT for ALD are similar to other indications. In adult LT recipients, long‐term survival for AIH was similar to alcoholic cirrhosis, although worse than PBC and PSC, possibly related to immunosuppression and serious infections. ⁵ Patients with AIH post‐LT were also at an increased risk for graft loss compared with PBC, PSC, and alcoholism, with a graft survival rate of 73.2% at 5 years and 50.9% at 15 years. ⁵ According to a United Network for Organ Sharing database analysis, patient survival for children transplanted for both AIH and PSC was >90% at 5 years. ⁶

RECURRENT DISEASE AFTER TRANSPLANT

Biochemical, imaging, histological features, and treatment of recurrent ALD are summarized in Table 1. Patients with recurrent AIH, similar to pretransplant patients, may be diagnosed based on the following criteria: elevated serum aminotransferases, elevated immunoglobulin G (IgG) levels, and circulating autoantibodies, including antinuclear (ANA), anti‐smooth muscle antibody (SMA), and anti–liver, kidney, muscle antibody (anti‐LKM). Biopsy shows lymphoplasmacytic portal cell infiltrates, interface hepatitis, ductal injury/reaction, and/or pseudorosettes of hepatocytes. Liver biopsy abnormalities may be present before laboratory findings. ⁷ It is important to exclude other causes of hepatitis or graft failure, specifically acute cellular rejection, which often has findings of endothelialitis or biliary injury.

TABLE 1.

Features of recurrent AIH, de novo AIH, recurrent PSC, and recurrent PBC

	Recurrent AIH	De Novo AIH	Recurrent PSC	Recurrent PBC
Definition	AIH prior to LT	No history of AIH	PSC prior to LT	PBC prior to LT
Laboratory findings	Elevated AST, ALT, IgG	Elevated AST, ALT, IgG	Elevated GGT, AST, ALT, bilirubin, serum bile acids	Elevated GGT, AST, ALT, bilirubin
Antibody markers	Positive ANA, SMA, and/or anti‐LKM	Positive ANA, SMA, and/or anti‐LKM	None	AMA, AMA‐M2
Imaging findings	None	None	Bile duct abnormalities, including beading and/or strictures	None
Histology	Lymphoplasmacytic portal cell infiltrates, interface hepatitis, ductal injury/reaction, and/or pseudorosettes of hepatocytes	Lymphoplasmacytic portal cell infiltrates, interface hepatitis	Cholestasis, portal fibrosis, ductular reaction, periductal edema and chronic inflammation; ductopenia; ± onion skinning fibrosis	Epithelioid granulomas, mononuclear inflammatory infiltrates, lymphoid aggregates, and bile duct damage
Treatment	Steroids, AZA or MMF, and CI	Steroids, AZA, CI	No proven treatment	No proven treatment
Rescue treatment	Cyclosporine, sirolimus	MMF, cyclosporine, sirolimus	Ursodiol, oral vancomycin, biliary dilation	Ursodiol

Abbreviations: AIH, autoimmune hepatitis; ALT, alanine aminotransferase; AMA, anti‐mitochondrial antibody; AMA‐M2, antimitochondrial M2 antibody; ANA, anti‐nuclear antibody; anti‐LKM, anti‐liver kidney microsomal antibody; AST, aspartate aminotransferase; AZA, azathioprine; CI, calcineurin inhibitor; GGT, gamma‐glutamyl transferase; IgG, immunoglobulin G; LT, liver transplant; MMF, mycophenolate mofetil; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis; SMA, smooth muscle antibody.

Recurrence of AIH after LT is approximately 8%–12% within the first year and 36%–68% after 5 years in both adult and pediatric patients. ⁷ Risk factors include longer time from transplant, discontinuation of steroids, type I AIH, recipient's positivity for HLA‐DRB1*03 or DRB1*04, tacrolimus‐based immunosuppression, and moderate‐to‐severe inflammation in the native liver. ⁸ , ⁹ The type of graft, living‐related, living‐unrelated, and deceased donors, did not affect the frequency of recurrence. ¹⁰ ANA and SMA levels pretransplant do not appear to influence AIH recurrence. ¹¹ AIH presenting as acute liver failure may actually decrease the risk for recurrent AIH posttransplant. ¹² The amount and type of immunosuppression for AIH post‐LT remains controversial. Puustinen et al. ¹³ conducted a single‐center retrospective study and found that dual immunosuppression with calcineurin inhibitor (CI) and steroids has a higher rate of AIH recurrence post‐LT compared with patients on triple immunosuppression. Another study demonstrated that the proportion of patients on triple immunosuppression post‐LT was similar between patients who developed and did not develop recurrent AIH. ¹⁴ At this time, the American Association for the Study of Liver Diseases (AASLD) does not recommend alternate immunosuppression post‐LT in AIH. ⁷

Recurrence of PSC occurs in 20%–25% of adult patients after LT. ¹⁵ Recurrent PSC can be difficult to distinguish from other posttransplant complications, including anastomotic strictures, chronic rejection, acute cellular rejection, and hepatic artery complications. Characteristic features of recurrent PSC on histology are shown in Figure 1. Graziadei et al. ¹⁶ defined recurrent PSC based on criteria listed in Table 2. To make the diagnosis of recurrent PSC, the patient must have PSC before LT and imaging characteristics, such as intrahepatic and/or extrahepatic biliary strictures, beading, and irregularity more than 90 days post‐LT, or histological changes, including fibrous cholangitis and/or fibro‐obliterative lesions with or without ductopenia, biliary fibrosis, or biliary cirrhosis. Hepatic artery thrombosis/stenosis, anastomotic strictures, nonanastomotic strictures before posttransplantation day 90, ductopenic rejection, and ABO incompatibility must be excluded. In a retrospective, multicenter pediatric cohort, rate of recurrent PSC was 27% within 5 years of transplant, and risk factors for recurrent PSC included younger age at time of LT, shorter time from diagnosis of PSC to LT, and concomitant inflammatory bowel disease (IBD) diagnosis. ¹⁷ Active IBD and an intact colon have also been shown to be risk factors for recurrent PSC in adult patients. ¹⁵ , ¹⁸ Other risk factors for recurrent disease that have been described in adults include higher Model for End‐Stage Liver Disease score at transplant, presence of cholangiocarcinoma, and more frequent episodes of acute cellular rejection. ¹⁵ , ¹⁹ , ²⁰

FIGURE 1.

Posttransplant recurrent PSC. (A) Branching portal tract with mild chronic inflammatory infiltrate. Two interlobular bile ducts (between arrowheads) show periductal edema and inflammation. (B) Prominent periductal edema and periductal fibrosis (between arrowheads). (C) The periductal inflammatory infiltrate here is moderate and primarily lymphoplasmacytic between arrowheads). (D) The periductal fibrosis, onion skinning type, is better observed with the Masson trichrome special stain highlighting the concentric wisps of mature collagen in blue (between arrowheads).

TABLE 2.

Diagnostic criteria for recurrent PSC ¹⁶

1. Diagnosis	Diagnosis of PSC prior to LT
AND
2a. Imaging	Intrahepatic and/or extrahepatic biliary strictures, beading, and irregularity >90 days post‐LT
OR
2b. Histology	Fibrous cholangitis and/or fibro‐obliterative lesions with or without ductopenia, biliary fibrosis or biliary cirrhosis
3. Exclusion criteria	Hepatic artery thrombosis/stenosis	Established ductopenic rejection
	Anastomotic strictures alone	Nonanastomotic strictures before posttransplantation day 90
	ABO incompatibility

Abbreviations: LT, liver transplant; PSC, primary sclerosing cholangitis. Adapted from Ref. [16] Hepatology. 1999 Apr;29(4):1050–6. doi: 10.1002/hep.510290427. PMID: 10094945.

Recurrence of PBC in adults is 20%–30% at 5 years and up to 50% at 10 years posttransplant. ²¹ Despite this recurrence rate, graft failure is rare. ²² A symptom of recurrence can include pruritus, but fatigue can persist post‐LT and is not an indication of recurrent disease. ²³ Recurrent PBC cannot be defined solely by persistence of anti‐mitochondrial antibodies (AMAs) but must also be accompanied by histological features and exclusion of other causes of abnormal liver tests. ²⁴ Recurrent disease has been reported to be common in patients on tacrolimus‐based immunosuppression compared with those on cyclosporin, although these data are conflicting. ¹⁹ , ²¹ , ²⁵

TREATMENT STRATEGIES FOR RECURRENT DISEASE

Per the most recent AASLD guidelines, recurrent AIH is best treated with reintroduction of steroids and addition of azathioprine (AZA) or mycophenolate mofetil (MMF) while continuing a CI. Goal CI troughs have not been studied, but it could be reasonable to increase trough goal, if able. If serum transaminases do not normalize, consider replacing AZA with MMF or vice versa, switching CI, or replacing CIs with sirolimus (Figure 2). ⁷ One randomized controlled trial replaced steroids with MMF and found no difference between graft or patient survival and found no difference between recurrence of AIH. ²⁶ Two retrospective studies found no difference in the recurrence of AIH in patients on and off corticosteroids. ²⁷ , ²⁸ The AASLD guidelines made a conditional recommendation that gradual withdrawal of steroids after transplant be considered, because the risks associated with steroids outweigh the potential benefits. ⁷ Budesonide has been used in combination with AZA as a first‐line treatment for mild‐to‐moderate AIH, but it has not been studied in the posttransplant population. Rituximab and plasmapheresis have been successfully used in recurrent AIH post‐LT ²⁹ but are currently not standard of care.

FIGURE 2.

Treatment strategies for recurrent AIH post‐LT.

There are no guidelines for the treatment of recurrent PSC after transplantation. Ursodeoxycholic acid is used commonly for pruritus and biochemical abnormalities but has not been shown to improve long‐term graft or patient survival in recurrent PSC. ³⁰ Similar to pre‐LT PSC, immunosuppressive agents do not seem to be protective against progressive disease. Vancomycin has been studied in the treatment of pediatric PSC, but this has not been studied in disease recurrence post‐LT. ³¹

Ursodeoxycholic acid has been shown to improve liver biochemistries post‐LT in those with recurrent PBC, but no data have shown its long‐term efficacy. ²⁵ Previous studies have shown an increased recurrence rate in those on tacrolimus‐based immunosuppressant regimens compared with cyclosporine; however, data are mixed, and tacrolimus‐based regimens are still used in patients with PBC post‐LT. ²² Obeticholic acid is approved for treatment of PBC, but this has not been studied in LT recipients.

DE NOVO AIH

De novo AIH is defined as the onset of AIH after LT in a patient transplanted for a reason other than AIH. In North America, this occurs in 1%–7% of pediatric transplant recipients and 1%–3% of adult transplant recipients. ⁷ It is hypothesized that de novo AIH is an atypical form of rejection in genetically predisposed individuals for autoimmune diseases. ³² Recipients of female and older grafts, as well as recipients using tacrolimus or MMF, had a higher risk for de novo AIH compared with those maintained on cyclosporine at one center. ³³ GSTT1 (glutathione S‐transferase theta 1) is an enzyme expressed in the liver that is involved in the metabolism of xenobiotics. ³⁴ , ³⁵ , ³⁶ A GSTT1 mismatch between recipient and donor may lead to the development of de novo AIH. ³⁴ , ³⁵ , ³⁶ Episodes of acute rejection and antiviral treatment for hepatitis C infection after LT are other possible risk factors. ³⁷ , ³⁸ , ³⁹

De novo AIH presents like typical AIH, with increased transaminases, elevated IgG, and positive autoantibodies. On histology, interface hepatitis and lymphoplasmacytic infiltrates may be seen. Treatment is the same as recurrent AIH: steroids, AZA, and CI. If transaminases do not normalize, consider switching to MMF, another CI, and/or sirolimus. Sirolimus has been used successfully at several centers. ⁴⁰ , ⁴¹

In conclusion, ALD presents unique considerations post‐LT given the risk for recurrent disease. Treatment of recurrent disease is similar to pre‐LT treatment, but LT‐specific complications such as rejection and vascular abnormalities must be ruled out before a diagnosis of recurrent disease can be made.

CONFLICT OF INTEREST

A.W. received grants from Albireo.

Gumm A, Perez‐Atayde A, Wehrman A. Posttransplant considerations in autoimmune liver disease: Recurrence of disease and de novo . Clinical Liver Disease. 2022;20:130–135. 10.1002/cld.1239