Introduction

Autoimmune liver diseases (AILDs), such as autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and primary biliary cholangitis (PBC), are classified as rare diseases; however, their incidence is growing. These chronic inflammatory liver diseases are associated with a plethora of physical and mental complaints, even at their early stages,1-3 and may lead to progressive liver fibrosis and eventually liver cirrhosis.4-6 The classic AILDs have all been well-defined in American and European clinical guidelines4-9 in terms of the type of liver injury, the prevalence of autoantibodies, histological findings, and changes in bile duct imaging studies (Table 1). However, these heterogenic diseases tend to share several common features, and thus, each entity may exhibit symptoms, histological patterns, or the presence of antibodies that are typical of other AILDs (Table 2). Additionally, there are genetic risk factors that are common to all AILDs, such as SH2B3,10-13 a non-HLA susceptibility marker that was reported to increase the risk of developing AIH, PSC, PBC, and other autoimmune diseases, for example, type 1 diabetes mellitus.14 As a consequence, in a proportion of patients, 2 different AILDs can be diagnosed, a phenomenon that has been initially called an overlap syndrome. In 2011, the International Autoimmune Hepatitis Group stated that even if a patient presents with the features of 2 diseases, for example, AIH and PSC, the final diagnosis should be made based on the predominant features and called the variant of the leading disease.15

Table 1 Diagnostic criteria for autoimmune liver diseases and their variants

Entity

Diagnostic criteria

References

AIH

The diagnosis of AIH requires:

1 Compatible histologic findings AND

2 Presence of the following features:

- Elevated serum aminotransaminase levels;

- Elevated serum IgG level and / or positive serological marker(s);

- Exclusion of viral, hereditary, metabolic, cholestatic, and drug-induced diseases.

Mack et al7

PBC

The diagnosis of PBC requires 2 of the 3 criteria:

1 Biochemical evidence of cholestasis based on ALP elevation;

2 Presence of AMA or other PBC-specific autoantibodies, including anti-sp100 or anti-gp210, if AMA are negative;

3 Histologic evidence of nonsuppurative destructive cholangitis and destruction of interlobular bile ducts.

Lindor et al8

PSC

The diagnosis of PSC requires:

1 Cholangiographic features of PSC, including intrahepatic and / or extrahepatic strictures alternating with normal or slightly dilated segments (preferably by MRI/MRCP with contrast enhancement);

2 Possible liver biopsy to rule out small-duct PSC, when suspecting PSC in a patient with normal, high-quality MRI/MRCP;

3 Careful exclusion of secondary sclerosing cholangitis.

Bowlus et al9

AIH-PBC

The diagnosis of AIH-PBC requires meeting the following criteria for AIH and PBC:

Two of the 3 criteria for PBC:

1 Serum ALP ≥2-fold the ULN OR serum GGT level ≥5-fold ULN;

2 Presence of AMA;

3 Florid bile duct lesions on liver biopsy.

Criteria for AIH in the setting of PBC (in addition to the presence of interface hepatitis):

1 Serum ALT level ≥5-fold ULN;

2 Serum IgG level ≥2-fold ULN or presence of SMA.

Chazouillères et al41

AIH-PSC

The diagnosis of AIH-PSC requires meeting the following criteria:

1 Typical AIH features;

2 Signs of large-duct PSC on imaging studies or histologic markers of small-duct PSC;

3 Absence of AMA.

Czaja16

Abbreviations: AIH, autoimmune hepatitis; ALP, alkaline phosphatase; AMA, antimitochondrial antibodies; ANA, antinuclear antibodies; GGT, gamma-glutamyl transferase; IgG, immunoglobulin G; MRCP, magnetic resonance cholangiopancreatography; MRI, magnetic resonance imaging; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis; SMA, smooth muscle antibodies, ULN, upper limit of normal

Table 2. Features of autoimmune liver diseases

Characteristics

AIH

PSC

PBC

Sex

Predominantly women

Predominantly men

Predominantly women

Age at the presentation

All age groups

15–35 years

Over 40 years

Liver function tests

Liver injury pattern

Hepatitis or mix

Cholestatic or mix

Cholestatic or mix

Aminotransferases activity

Typically significantly elevated

Might be moderately elevated

Might be moderately elevated

Cholestatic enzymes activity

Might be moderately elevated

Typically elevated

Typically elevated

Immunoglobulins

Typically elevated IgG

Possibly elevated IgG and IgM

Typically elevated IgM

Antibodies (%)

ANA

Approx. 80%54

Up to 50%

More than 30%

(specific ANA antibodies: gp-210, sp-100)

SMA

Approx. 60%54

Might be present

Might be present

Anti–LKM-1

Approx. 3%,54 specific for type 2

No data

No data

Anti–SLA/LP

Approx. 20%55

0%–2%56,57

0%–1%56,57

AMA

Approx. 12%–20%43,58

Rarely or none

Approx. 95%8

pANCA

Approx. 50%59

Approx. 65%59

Approx. 5%59

Abbreviations: anti–LKM-1, antibodies to liver kidney microsome type 1; anti–SLA/LP, antibodies to soluble liver/liver pancreas antigen; pANCA, atypical perinuclear antineutrophil cytoplasmic antibodies; others, see Table 1

A proper diagnosis of an AILD variant is challenging. In contrast to the widely accepted diagnostic criteria for AIH, PBC, and PSC, there is still a lack of well-defined, validated, and internationally agreed upon criteria for these variants. In fact, a large proportion of patients with the features of an overlap syndrome can be easily diagnosed with 2 different AILDs, usually AIH with PSC or PBC, by using current diagnostic criteria for each disease separately. This fact creates a treatment dilemma, as the diagnosis of AIH usually requires starting immunosuppression therapy,4 whereas these drugs are not recommended for classic PSC and PBC. As mentioned above, the leading component of the disease variant should define its first-line therapy.16 Consequently, there is no clear consensus on how to treat these patients, and even expert opinions vary regarding their management.17 These facts highlight the unmet needs for widely accepted guidelines for the diagnosis and treatment of AILD variants. In this review, we briefly present the characteristics of AILDs in adults, with the main focus on their variants in terms of diagnosis and management.

Classic autoimmune liver diseases

Autoimmune hepatitis

AIH is a chronic progressive AILD that is characterized by hypertransaminasemia, an elevated concentration of immunoglobulin G (IgG), and the presence of typical autoantibodies, that is, antinuclear antibodies (ANA) and / or smooth muscle antibodies (SMA) or antibodies to liver kidney microsome type 1 (anti–LKM-1).4,7 Half of the reported cases show positivity for multiple antibodies; however, these antibodies can occur also in other AILDs, as shown in Table 2. In particular, ANA can be found in other liver diseases, such as fatty liver disease, alcoholic liver disease, or viral hepatitis, rheumatologic and other autoimmune disorders, as well as in healthy individuals with lower titers of these antibodies.7,18

A definite diagnosis of AIH is not possible without a liver biopsy,4,7,19 however, histologic features are not pathognomonic, and some of them may also be present in PSC or PBC. The final diagnosis requires exclusion of other possible disorders, such as viral hepatitis, drug-induced liver injury, or Wilson disease. The original revised19 or simplified scoring system20 is usually used to establish a diagnosis, however, the simplified scoring system is more specific and accurate.7 Moreover, proper diagnosis is confirmed by the patient’s response to the immunosuppressive regimen,19 which is crucial for clinicians and for the selected maintenance therapy. Nevertheless, these scoring systems are not dedicated to the diagnosis of AIH with an overlap of PSC or PBC.7

The treatment objective is to acquire a complete remission (ie, biochemical remission, which is understood as normalization of alanine aminotransferase activity and IgG levels, and / or histologic remission), and to prevent the progress of the liver injury to liver cirrhosis. First-line treatment is based on immunosuppression with corticosteroids and azathioprine.4,7 The next lines combine corticosteroids with mycophenolate mofetil, calcineurin inhibitors, or biological agents (eg, anti–tumor necrosis factor or anti-CD20).21 Despite a relatively good treatment response and induction of remission, many patients relapse following the drug reduction or withdrawal, and need a long-term maintenance therapy.4 As in other liver diseases, the patients with end-stage liver disease due to AIH require liver transplantation (LT); however, the recurrence of AIH after LT is observed in around 20% of cases after 5 years and in 31% of cases after 10 years.22-24

Primary sclerosing cholangitis

PSC is characterized by the inflammation and fibrosis of the intra- and extrahepatic bile ducts that lead to the multifocal bile duct strictures.9 This disease is usually diagnosed in young men with a history of inflammatory bowel disease, usually ulcerative colitis (UC).25 Almost half of these patients are asymptomatic at the time of diagnosis;26 however, others may complain of nonspecific symptoms, such as abdominal discomfort or fatigue. In advanced biliary changes, signs of cholestasis (pruritus and jaundice) and recurrent bacterial cholangitis are leading clinical problems. However, the most fatal complication is cholangiocarcinoma, a neoplasm with a disastrous prognosis, which is diagnosed in about 5% to 10% of patients.

The diagnostic criteria comprise elevated cholestatic enzymes, particularly alkaline phosphatase, and characteristic changes (ie, multifocal strictures and segmental dilatations of the biliary tree) in imaging studies, mainly magnetic resonance cholangiography (MRCP).5,27 In contrast to AIH, liver biopsy is not mandatory to establish a diagnosis, if the cholangiogram is typical and secondary causes (eg, choledocholithiasis or IgG4-related cholangitis) are excluded.5

In patients with cholestasis but no changes in biliary imaging studies, small-duct PSC can be diagnosed based on the liver biopsy5,27 showing typical biliary changes, that is, periductal concentric fibrosis (onion-skin lesions), and, in some cases, portal lymphocytic infiltration.5 Moreover, more than half of the patients with PSC have perinuclear antineutrophil cytoplasmic antibodies (pANCA), and up to 50% have ANA and / or ASMA (Table 2).15,27

The management of classic PSC is based on the endoscopic dilatation of high-grade biliary strictures and monitoring of the disease (ie, cholangiocarcinoma surveillance). Unfortunately, to date, an effective pharmacological therapy to prevent the progression of liver injury is lacking.5,27 Ursodeoxycholic acid (UDCA) is beneficial in terms of liver biochemistry;28,29 however, it does not affect prognosis.29 Currently, management without treatment modifying the disease course is frustrating for the patients and may impact their well-being.30 Patients with PSC and chronic liver failure as well recurrent bacterial cholangitis, intractable pruritus, or eventually early-stage cholangiocarcinoma may, in highly specific cases, receive LT as an ultimate form of therapy. As in other AILDs, the patients with PSC are at an increased risk of recurrent PSC after LT, which may occur in up to 25% of cases.31

Primary biliary cholangitis

PBC mainly affects middle-aged women and is characterized by chronic elevation of alkaline phosphatase (ALP), the presence of antimitochondrial antibodies (AMA) in up to 95% of cases, often increased level of IgM, and no changes in biliary imaging studies that can be attributed to other causes. Other antibodies, such as ANA and ASMA, might be present in half of the patients.8 The patients with AMA-negative and ANA-positive results, who have been observed for PBC, should be tested for PBC-specific ANA, namely anti-sp100 and anti-gp210, which are present in one-third of AMA-negative PBC cases.8 In the presence of a cholestatic profile and typical antibodies, liver biopsy is not mandatory to establish the diagnosis.8

The treatment objectives are the prevention of end-stage liver disease and the relief of the symptoms, such as fatigue and itching, which may require a pharmacotherapy or, in rare cases, even plasmapheresis as a rescue therapy.32 UDCA at 13–15 mg/kg/day is a first-line therapy that results in the reduction of ALP activity in up to 90% of patients.6,8 The efficacy of UDCA should be assessed 1 year after commencement of the treatment.6 Inadequate response or intolerance to UDCA is an indication for second-line management, that is, obeticholic acid (OCA). Moreover, fibrates were shown to be an effective offlabel treatment in the patients with an inadequate response to UDCA.33

The efficacy of anti-inflammatory agents, namely budesonide, in PBC is still unresolved. In a recently published report, Hirschfield et al34 presented interesting results from a double-blind randomized placebo-controlled trial evaluating UDCA + budesonide vs UDCA + placebo in selected PBC patients with hepatic inflammation confirmed in a liver biopsy and with persistently increased ALP after at least 6 months of UDCA therapy. The authors stated that recruitment challenges resulted in an underpowered study for the assessment of the impact of budesonide therapy on liver histology, and the histologic end point was not met. However, budesonide significantly reduced ALP activity, and 35% of the budesonide-treated patients reached ALP normalization.34 The patients with PBC and end-stage liver disease might require LT, however, the frequency of recurrent PBC ranges from 17% to 46%.31

Autoimmune liver diseases variants

Autoimmune hepatitis-primary sclerosing cholangitis variants: diagnosis

The first cases of AIH-PSC variants were reported almost 30 years ago.35 The reported incidence of AIH among patients with PSC ranged from 1.4% to 22%.36,37 However, these data were based on the diagnosis of AIH using an AIH-dedicated scoring system rather than on the proper diagnosis of the variant. Nevertheless, neither the simplified nor the revised original scoring system should be used to diagnose the AIH-PSC variants.7,38 However, there is still no widely accepted and prospectively validated scoring system for the diagnosis of this entity. Therefore, the actual incidence of AIH-PSC variants is difficult to assess.

According to the American Association for the Study of Liver Diseases (AASLD) guidelines, the individuals with AIH, in whom biochemical cholestasis, bile duct injury in liver histology, or concomitant UC are present, should be assessed for AIH-PSC variants. In these cases, MRCP is recommended.7 On the other hand, in the patients with PSC and disproportionately elevated aminotransferases, liver biopsy is indicated for the assessment of AIH-PSC variants.27 However, it should be kept in mind that cholestasis can cause secondary hypertransaminasemia, and high IgG levels are commonly seen in cirrhosis that does not have an autoimmune background. Of note, Boberg et al39 reported elevated IgG levels in 61% of patients with PSC that had been confirmed by endoscopic retrograde cholangiography (ERCP).

AIH-PSC variant, known in children as autoimmune sclerosing cholangitis (ASC),40 presents with the clinical, biochemical, and histologic features of AIH and findings in imaging studies typical of large-duct PSC (MRCP or ERCP) or the histologic markers of small-duct PSC,7 as summarized in Table 1. This diagnosis should mainly be considered when the UC is concomitant or when there is no response to the steroid therapy.16 AIH-PSC diagnosis requires liver biopsy.17 The histological features of both entities, that is, AIH and PSC, are shown in Figure 1A, which presents the liver biopsy results of a 28-year-old woman with AIH-PSC variant and spectacular response to corticosteroids. Liver histology should be assessed carefully by an experienced liver pathologist, and a hepatitis activity index (HAI) score might by helpful in making decisions about immunosuppressive treatment.4 However, some features of classic AIH may also occur in PSC (Table 2), but they are not enough to diagnose this variant.7 Portal lymphoplasmacytic hepatitis with more than mild interface activity or more than mild lobular hepatitis with concomitant findings typical of large-duct PSC indicate the presence of the variant and possible benefits of steroid-based therapy.

Figure 1. Histological features of the autoimmune hepatitis-primary sclerosing cholangitis and autoimmune hepatitis-primary biliary cholangitis variants on liver biopsy (hematoxylin-eosin staining, magnification × 100)

Autoimmune hepatitis-primary biliary cholangitis variant: diagnosis

The Parisian criteria are commonly used for the diagnosis of the AIH-PBC variant and are based on the presence of at least 2 of the 3 biochemical, serological, and histologic features of each disease (Table 1).41 To establish the diagnosis of the AIH-PBC variant, liver biopsy is required. The histological features of both entities are shown in Figure 1B, which presents the liver biopsy results of a 47-years-old woman who fulfilled the Parisian criteria for the AIH-PBC variant. Of note, the AIH-PBC criteria may not cover the patients with less advanced cholestasis.7,16,42

In the patients with AIH and a lack of other signs of PBC, AMA positivity is not enough to establish the variant diagnosis.7 O’Brien et al43 reported that 12% of the patients with typical features of AIH were AMA positive but that they did not show the histologic and biochemical features of PBC. Moreover, despite persistence, AMA positivity remained typical of AIH during the follow-up.43

Management of the variants

Therapy for the cholestatic variants of AIH combines the management techniques for classic AIH (basically corticosteroids and azathioprine) with UDCA.4,7,41 In the variants, liver histology is not pathognomonic; however, it may indicate immunosuppression when the HAI score is above 5.4 Due to the relatively low prevalence of the variants, prospective therapeutic studies are lacking,15 and current recommendations are only based on the opinions of respected authorities and descriptive epidemiology.4

Autoimmune hepatitis-primary sclerosing cholangitis variants: management

Patients with AIH-PSC variants are characterized by heterogenous clinical presentation. The disease is difficult to treat,17 and its course shows a lower rate of biochemical remission and a worse prognosis than classic AIH and AIH-PBC variants.44,45 In contrast to classic PSC, in AIH-PSC variants, an immunosuppressive regimen is often recommended,5,27 as the beneficial role of corticosteroids has been confirmed.44-47 Moreover, according to the AASLD guidelines, the patients with the AIH-PSC variant can be treated using a combined therapy of corticosteroids (prednisone 0.5 mg/kg daily tapered to 10–15 mg daily) with UDCA (13–15 mg/kg daily), similarly to the treatment used in children with ASC.7 However, liver fibrosis may progress even during the combined therapy,47 and for the patients with end-stage liver disease, LT is the only viable treatment.

Autoimmune hepatitis-primary biliary cholangitis variant: management

Chazouillères et al41 reported that a combination therapy with prednisolone (30 mg daily tapered over 4 weeks to 10 mg daily) and UDCA (13–15 mg/kg daily) was superior to corticosteroids alone or UDCA alone in the patients with AIH-PBC. A further study with a median follow-up of 7.5 years revealed that in the patients with AIH-PBC, fibrosis progression was less frequent on the combination therapy of corticosteroids and UDCA than on UDCA monotherapy.48 Of importance, the patients who were initially treated with UDCA alone and who did not reach biochemical remission were switched to the combined therapy, and most of them (6/7) reached biochemical remission.48

In 2016, Yang et al49 reported that the patients with AIH-PBC more frequently reached an end point, such as LT, liver decompensation, or liver-related death, than the patients with classic PBC during a 5-year follow-up. In this study, the combined therapy with corticosteroids and UDCA was more beneficial than UDCA monotherapy for AIH-PBC in terms of response after 1 year of follow-up.49 In a multicenter, retrospective study, Ozaslan et al50 analyzed the efficacy of the therapy in 88 patients with AIH-PBC and concluded that severe interface hepatitis in liver histology requires additional immunosuppressive therapy and sometimes also a second-line therapy. A recently published case report described a patient with AIH-PBC not responding to standard therapy and who, when treated with OCA, achieved good results.51

Variants of autoimmune hepatitis and liver transplantation

Because of heterogenic management of the patients with the variants of AIH and relatively low incidence of these entities, studies documenting post-LT outcomes in these populations are limited,52,53 and patients with the variants are usually excluded from the analyses.22 In 2013, Bhanji et al53 published single-center results of LT in 231 patients with AILDs, but only 12 of them had AIH variants. The time from diagnosis to LT was shorter than for pure AIH (35 vs 136 months), PBC (35 vs 92 months), and PSC (35 vs 91 months), all P <⁠0.01, however, there were no discrepancies in rejection episodes.53 The study showed that the patients with the variants of AIH had a higher recurrence rate and shorter time from LT to the recurrence than those with pure AILD.53 In contrast, no differences in the frequency of graft loss and survival between the patients with the variants of AIH and pure AILD were noticed, but only 3 patients with the variants completed a 5-year follow-up in this study.53

Conclusions

A proportion of patients with a single AILD tends to show features of another AILD. In these cases, AIH-PSC or AIH-PBC should be suspected and promptly evaluated in experienced centers. The variants are rather clinical categories than a pathological diagnosis, and the leading component of the disease defines its therapy. However, treating such patients is challenging, even for experienced clinicians. The progression to end-stage liver disease is unfortunately not a rare course despite the use of combined and second-line therapies. Thus, studies based on prospective registers are necessary to elaborate upon the widely accepted guidelines, to provide better care to these patients and to improve their prognosis.