Alloimmune versus autoimmune hepatitis following liver transplantation

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INTRODUCTION

Plasma cell–rich acute rejection (PCAR), previously known as plasma cell hepatitis or de novo autoimmune hepatitis (DAIH), is a form of late graft dysfunction (>6 months) that occurs in 3% to 5% of liver transplant recipients (LTRs) without a prior history of autoimmune liver disease. ¹ The Banff Working Group has created minimal diagnostic criteria that requires criteria 1 and 3: (1) portal and/or perivenular plasma cell–rich (>30%) infiltrates (Figure 1), (2) lymphocytic cholangitis, and (3) original disease other than autoimmune hepatitis (AIH) ¹ (Table 1). Other nonessential features of PCAR include antibodies to glutathione S‐transferase theta 1 (GSTT1) and appearance of donor‐specific human leukocyte antigen antibodies (DSAs). ¹ It is important to note that PCAR can be seen in LTRs after receiving gamma‐interferon and direct‐acting antiviral therapy for hepatitis C. ² , ³ There has been significant debate surrounding whether PCAR is a de novo autoimmune process or more consistent with the alloimmune rejection process because of its similarities with both processes.

FIGURE 1.

Histopathology of PCAR. (A) Extensive portal and lobular inflammation with bridging necrosis. (B) High‐power view showing sheet pattern of plasma cell infiltration in the portal area.

TABLE 1.

Diagnostic criteria for plasma cell hepatitis

Clinical findings	✓Indication for transplant other than AIH ✓Evidence of graft dysfunction ✓Exclusion of other known causes of graft dysfunction (i.e. rejection, drug related)
Serology	Anti‐GSTT1 antibodies DSAs Hypergammaglobulinemia Autoantibodies ◦ ANAs ◦ SMAs ◦ Antibodies to LKM type 1
Histology	✓Interface hepatitis ✓Portal lymphocytic infiltrates with plasma cell‐rich infiltrates (>30%) ✓Lymphocytic cholangitis

Note: Checkmark (✓) signifies required criteria.

The pathogenesis of PCAR is not currently known. Some believe that an initial episode of rejection may introduce neoantigens that then result in an alloimmune response against the graft causing potential self‐sensitization because of molecular mimicry. There has also been evidence that potential mismatching of GSTT1 may lead to immune sensitization, rejection, and the clinical picture of PCAR (Figure 2). ⁴ PCAR also shares similarities with antibody‐mediated rejection (AMR) with its association with DSA and C4d deposition, supporting a component of AMR in the pathogenesis. Ultimately, it is thought to be a mixed T cell–mediated rejection/AMR with a component of autoimmunity.

FIGURE 2.

Hypothesized pathogenesis of PCAR. Theories about the pathogenesis of PCAR include neoantigens that result in an alloimmune response against the graft, causing potential self‐sensitization due to molecular mimicry, as well as potentially mismatching of GSST1 and subsequent production of antibodies. Reprint with permission Clin Liver Dis 2021; 25:53‐72

PCAR versus AIH

It is challenging to distinguish between PCAR and true AIH because they are both immune mediated and have very similar characteristics. Hence PCAR was previously referred to as DAIH or vice versa. Their similarities include histological findings of interface hepatitis, presence of autoantibodies, and hypergammaglobulinemia (Table 2). ⁵ It is important to note, though, that although autoantibodies and hypergammaglobulinemia are required for a diagnosis of AIH, they are no longer required for a diagnosis of PCAR per the new Banff Working Group. ¹

TABLE 2.

Plasma cell–rich acute rejection versus AIH

	Plasma cell–rich acute rejection	Recurrent AIH
Clinical presentation	2‐5 years posttransplant a	>5 years posttransplant a
Serology	Autoantibodies (ANA, SMA, anti‐LKM type 1, anti‐GSTT1, a DSA a ) may/may not be present	High titers of autoantibodies (ANA, SMA, anti‐LKM type 1)
	Elevated IgG	Elevated IgG
Histology	Interface hepatitis	Interface hepatitis
	Plasma cell population at least 30% of total cell population a	+/− Plasma cell infiltration a
	Bridging necrosis	Confluent or bridging necrosis
	Immunohistochemical staining for C4d to evaluate for AMR a
Management	Steroid bolus +/−	Steroid bolus +/−
	Azathioprine	Azathioprine
	MMF (substitute for azathioprine)	MMF (substitute for azathioprine)
	Sirolimus (if both azathioprine and MMF are ineffective) a
	Anti‐thymocyte globulin and/or Treatment of AMR if present
Outcomes
Treatment response	Rapid resolution of plasma cell infiltrates unless refractory a	Less responsive a
Progressive fibrosis	~60%	~60%
Retransplantation	23% a	50% a

^a Distinguishes differences between plasma cell hepatitis and AIH.

Fiel et al. ⁶ presented a persuasive argument that PCAR is a form of rejection due to the fact that risk factors for PCAR include suboptimal immunosuppression and prior incidences of acute rejection, as well as the noted improved outcomes when PCAR is treated with augmented immunosuppression. They also revealed clinical distinctions that PCAR and AIH are distinct disease processes. The time course of the disease may be different because AIH generally occurs after 5 years, while PCAR generally presents sooner posttransplant. PCAR is more predominant in male individuals and also has a rapid response with a significant decrease in plasma cell infiltrates after an increase in immunosuppression that is less successful in AIH. ⁶ There is also evidence of histopathological differences in which PCAR is associated with more severe lymphocytic cholangitis, plasma cell–rich central perivenulitis, and increased immunoglobulin G4⁺ (IgG4⁺) plasma cell representation ¹ (Table 2). Due to these various differences, PCAR is a distinct entity from AIH and is a type of rejection that is likely primarily driven by an antigen unique to the allograft liver (i.e., alloimmune), while recurrent AIH has a target antigen that is shared by both the donor and the recipient (i.e., autoimmune). Proposed clinically significant targets for PCAR include targets in the glutathione family, such as theta, alpha, mu, and pi for anti–liver kidney microsome (LKM) antibodies. Potential autoantigen targets in recurrent AIH include cytochrome P450 family 2 subfamily D member 6, asialoglycoprotein receptor, and ribonucleoproteins.

There are several reasons why PCAR can be a relatively challenging diagnosis. First, there are no precise findings that distinguish PCAR because it is more of a combination of diagnostic criteria of T cell–mediated rejection/AMR/AIH, making it difficult to identify. ¹ There is also variability among the etiologies for liver transplant, such as primary biliary cholangitis, primary sclerosing cholangitis, and hepatitis C virus (HCV), which each have an independent association with autoimmunity regardless of transplant status. It is most likely that these disease processes are on a spectrum because the initial alloimmune response in PCAR may lead to a de novo autoimmune response. We currently do not have the ability to distinguish between an alloimmune or autoimmune response, and the crosstalk between these two requires further study and elucidation.

MANAGEMENT

The distinction of alloimmune or autoimmune injury may not be so clinically relevant because the management of PCAR and AIH are very similar. The standard of care in AIH is treatment with corticosteroids in addition to azathioprine. ⁵ The treatment of PCAR also consists of prednisone and azathioprine, as well as optimization of the current immunosuppression. Mycophenolate mofetil (MMF) can also be used in place of azathioprine. Alternatively, mammalian target of rapamycin inhibitors such as everolimus (in combination with cyclosporine) and rapamycin have been seen to be effective in some cases. ⁷ One may also consider intravenous immunoglobulin, rituximab, or bortezomib in steroid‐resistant cases because of its similar pathogenesis to AMR. Although they may be effective in renal transplant recipients, their efficacy in LTRs has not been shown. ¹ , ⁸ In terms of outcomes, comparing PCAR with recurrent AIH, there are similar rates of progressive fibrosis and cirrhosis with slightly lower rates of retransplantation in PCAR (23%) ⁹ compared with recurrent AIH (Table 2). ¹⁰

In conclusion, it is unclear whether PCAR is primarily driven by an autoimmune or alloimmune process, because it seems to have distinct characteristics that distinguish it from AIH, but the treatment is similar. Therefore, more research into the pathogenesis of PCAR is required, as well as creating a more detailed set of diagnostic and management criteria to improve outcomes.

CONFLICT OF INTEREST

J.L. advises and received grants from Eurofins, Viracor, Transplant Genomics Inc., and Novartis.

Harrington CR, Levitsky J. Alloimmune versus autoimmune hepatitis following liver transplantation. Clin. Liver Dis. 2022;20:21–24. 10.1002/cld.1234