Overlap syndromes

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Abbreviations

AASLD

American Association for the Study of Liver Diseases

AIH

autoimmune hepatitis

ALT

alanine aminotransferase

AMA

anti‐mitochondrial antibody

ANA

anti‐nuclear antibody

AP

alkaline phosphatase

AST

aspartate aminotransferase

CUC

chronic ulcerative colitis

EASL

European Association for the Study of the Liver

ERC; endoscopic retrograde cholangiography; GGT

gamma‐glutamyltransferase

IgG

immunoglobulin G

MRC

or magnetic resonance cholangiography

PBC

primary biliary cirrhosis

PSC

primary sclerosing cholangitis

SMA

smooth muscle antibody

UDCA

ursodeoxycholic acid

ULN

upper limit of normal

Patients with autoimmune hepatitis (AIH) may have features of primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC).1, 2 Similarly, patients with classic features of PBC or PSC may have features of AIH. The diagnostic boundaries between these diseases are porous, and clinical, laboratory, and histological features can be shared (Fig. 1). AIH has the least disease‐specific clinical findings, and it is the most common component of the overlap syndromes. In contrast, PBC and PSC have the most disease‐specific clinical features, and they rarely constitute an overlap syndrome. The overlap syndromes occur in 3% to 17% of patients with autoimmune liver disease, and the frequencies of each overlap combination (outside PBC and PSC) are similar, regardless of the predominant disease component.1, 2

Figure 1.

Porous diagnostic boundaries and commonly shared features of AIH, PBC, and PSC. ANAs and abnormalities in the serum levels of AP, GGT, and gamma‐globulin are among the laboratory changes that are commonly shared between the diseases. Similarly, interface hepatitis, plasma cell infiltration, and cholangitis are frequently shared histological changes. PBC and PSC have highly disease‐specific features that rarely overlap.

Pathogenic Hypotheses

The overlap syndromes may simply be variants or atypical forms of classic diseases. The features of AIH are not disease‐specific, and their occurrence in patients with PBC or PSC may simply denote an inflammatory form of the classic disease.1, 2 The overlap syndromes could be transition stages in the evolution of classic diseases. The observed transitions between the diseases may exemplify these diverse evolutionary pathways.1, 2, 3 The overlap syndromes could represent concurrent diseases in the same individual. This hypothesis is possible but unlikely because two diseases with highly specific features, PBC and PSC, rarely coexist.1, 2, 3 Lastly, the overlap syndromes could be separate pathological entities with their own distinctive pathogenic mechanisms and clinical outcomes.1, 2

Diagnosis

The predominant disease component determines the nature and behavior of the overlap syndrome.4 An overlap syndrome should be suspected in all patients with predominant manifestations of AIH, PBC, or PSC who have atypical findings (Fig. 2). Patients with laboratory, serological, and histological features that denote inflammatory or cholestatic changes outside the classic phenotype, individuals refractory to conventional treatment regimens, and patients with concurrent inflammatory bowel disease are prime candidates for an overlap syndrome.1, 2

Figure 2.

Diagnostic algorithm for the overlap syndromes. Patients with AIH, PBC, or PSC who have atypical hepatitic or cholestatic laboratory or histologic findings have concurrent inflammatory bowel disease, or do not respond to conventional treatments should undergo ERC or MRC. The cholangiographic findings can then be used in conjunction with the presence or absence of AMAs to distinguish between AIH and PBC (AIH‐PBC), AIH and an indeterminate cholestatic disease (AIH–indeterminate cholestasis), PBC and PSC (PBC‐PSC), and AIH and PSC (AIH‐PSC) in patients with the overlap syndromes. The clinical findings can also be used to distinguish the predominant disease component in each overlap syndrome. The Paris criteria tend to define a syndrome with equivalent AIH and PBC components (AIH = PBC). The other overlap syndromes of AIH and PBC can be either AIH‐predominant (AIH > PBC) or PBC‐predominant (PBC > AIH). Similarly, patients with the overlap syndrome of AIH and PSC (AIH‐PSC) can be either AIH‐predominant (AIH > PSC) or PSC‐predominant (PSC > AIH).

The Paris criteria provide an objective basis for making the diagnosis of the overlap syndrome of AIH and PBC5 (Table 1). The Paris criteria have a sensitivity of 92% and a specificity of 97% with clinical judgment as the gold standard.1, 2 These criteria have been endorsed by the European Association for the Study of the Liver (EASL) with the stipulation that all patients have interface hepatitis on histological examination.4, 6 Patients outside the Paris criteria may have less severe forms of the AIH‐PBC overlap syndrome, and they should not be excluded from the diagnosis.1, 2

Table 1.

Diagnostic Features of the Overlap Syndromes

Overlap Syndrome	Laboratory Features	Histological Findings
AIH‐PBC (Paris criteria modified by EASL)4, 5, 6	AIH features (1 of 2):	Interface hepatitis (required)
	ALT ≥ 5‐fold ULN
	IgG ≥ 2‐fold ULN or SMAs
	PBC features (2 of 3, including histology):	Florid duct lesions
	AP ≥ 2‐fold ULN or GGT ≥ 5‐fold ULN
	AMAs
AIH‐PBC (outside Paris criteria)1, 2, 8	Predominant AST/ALT abnormalities	Interface hepatitis and bile duct injury or loss (lymphocytic, pleomorphic, or destructive cholangitis)
	AP < 2‐fold ULN and GGT < 5‐fold ULN
	Hypergammaglobulinemia (IgG > ULN)
	ANAs or SMAs
	AMAs
AIH‐PSC4, 6, 10	AIH features	Interface hepatitis and portal edema, fibrosis, or ductopenia (obliterative fibrous cholangitis possible but rare)
	AMAs absent
	Focal strictures and dilations by ERC or MRC
AIH–indeterminate cholestasis (possibly AMA‐negative PBC or AIH–small‐duct PSC)1, 2, 8	AIH features	Interface hepatitis and bile duct injury or loss
	AP ≥ 2‐fold ULN or GGT > ULN
	AMAs absent
	Normal ERC or MRC

The diagnosis of the overlap syndrome of AIH and PSC requires features of AIH, an absence of anti‐mitochondrial antibodies (AMAs), and an abnormal cholangiogram with focal bile duct strictures and dilations typical of PSC1, 2 (Table 1). Patients may also have features of AIH and a cholestatic phenotype in the absence of classic features of PSC or PBC1, 2 (Table 1). These patients lack AMAs, and they have a normal cholangiogram. The histological findings of bile duct injury or loss suggest an overlap syndrome, and they may have AMA‐negative PBC or small‐duct PSC.1, 2

The various scoring systems for AIH should not be used to diagnose the overlap syndromes.4 These systems were not designed for this application, and their ability to demonstrate AIH in patients with cholestatic liver disease is poor (sensitivity = 50%‐62%). The liver biopsy examination is the strongest independent predictor of an overlap syndrome, and clinical judgment is the gold standard for the diagnosis.7

Treatment and Outcomes

The treatment of the overlap syndrome of AIH and PBC is influenced by the relative strength of each disease component, and all regimens are empirical.1, 2, 4 The medications used to treat these syndromes are unlicensed for these clinical applications. Corticosteroids in combination with ursodeoxycholic acid (UDCA; 13–15 mg/kg daily) have been recommended for patients who satisfy the Paris criteria4, 6 (Table 2). This regimen has significantly improved laboratory findings, and it has prevented progressive hepatic fibrosis.5 Combination therapy has also been superior to treatment with corticosteroids or UDCA alone in a small subgroup analysis,5 and it has been endorsed by the EASL with a recommendation that is not strongly evidence‐based.4, 6 Treatment with corticosteroids or UDCA alone has been effective in patients whose primary disease of AIH or PBC has heavily outweighed the overlap component8, 9 (Table 2).

Table 2.

Treatment Options for the Overlap Syndromes

Overlap Syndrome	Predominant Component	Treatment Regimen	Outcomes
AIH‐PBC	PBC and AIH equivalent by Paris criteria	Corticosteroids and UDCAa	Improves serum AP, GGT, and ALT5
			Prevents progressive hepatic fibrosis5
			Better than UDCA or corticosteroids alone5
AIH‐PBC	PBC	UDCA	Same laboratory improvements found for classic PBC9
AIH‐PBC	AIH	Corticosteroids alone or with azathioprine	Laboratory and histological improvements as frequently as for classic AIH (improvement, 81% versus 86%; treatment failure, 14% versus 9%)1, 2, 8
AIH‐PSC	AIH or PBC	Corticosteroids and UDCAb	Variable responses (20%‐100%) possibly related to level of cholestasis1, 2
AIH–indeterminate cholestasis (including AMA‐negative PBC and small‐duct PSC)	AIH or cholestatic phenotype	Empirical and unendorsed	Uncertain response1, 2
		Directed by predominant component: corticosteroids, UDCA, or corticosteroids and UDCA	Anecdotal experience1, 2

^aEndorsed by the EASL.4, 6

^bEndorsed by the EASL and the AASLD.4, 6, 10

Combination therapy with corticosteroids and UDCA has been endorsed by the EASL4, 6 and the American Association for the Study of Liver Diseases (AASLD)4, 10 for the overlap syndrome of AIH and PSC with a recommendation that is also not strongly evidence‐based (Table 2). Combination therapy has been effective in 20% to 100% of patients, and the variability of the responses probably reflects differences in diagnostic criteria and dosing schedules.1, 2, 8 Corticosteroids alone have had inconsistent results, mycophenolate mofetil has been ineffective, and calcineurin inhibitors have been rarely used.1, 2, 4 Patients with mixed syndromes of AIH and AMA‐negative PBC or small‐duct PSC lack a recommended strategy, and treatments include corticosteroids, UDCA (13–15 mg/kg daily), or both; this depends on the predominant clinical component and the treatment response1, 2, 8 (Table 2).

Overview

Overlap syndromes are clinical descriptions, and their principal clinical value is that they respond variably to conventional treatment strategies.1, 2, 4, 8 Diagnostic criteria and treatment algorithms have not been codified. Off‐label combination therapy with corticosteroids and UDCA has been recommended for most patients on the basis of weak clinical evidence.6, 10 Treatments can be individualized, and they should be directed at the predominant disease component.1, 2, 4, 8