Overlap Syndromes of Primary Sclerosing Cholangitis


Diagnostic templates

PSC and AIH

PSC and PBC

Clinical criteria

Histological or cholangiographic PSC [15]:

 Portal tract edema and fibrosis

 Bile duct loss or periductal fibrosis

 Focal biliary strictures and dilations

Characteristic features of AIH [15, 17]:

 Markedly increased serum AST level

 Hypergammaglobulinemia

 Increased serum IgG level

 Autoantibodies (ANA, SMA, or LKM1)

 Interface hepatitis, plasma cells

Normal cholangiography in 27 % [29]

Histological or cholangiographic PSC [36]:

 Small duct PSC possible

Characteristic features of PBC [15]:

 AMA

 Destructive cholangitis

Nonstandard features of PBC [33, 35, 37]:

 No AMA

 AMA develop later

 AMA detected by immunoblotting

 Antibodies to gp210 and sp100

Diagnostic standard, clinical judgment [15]

Diagnostic scoring systems

Not validated for AIH or overlaps [48, 60]

Poor sensitivity (50–62 %) [66, 67]

Use discouraged by IAIHG [47]

ALP/AST ratio ≥1.5 useful index [48]

Not validated for PBC [68]

Key cholestatic indices

Serum ALP ≥ 4-fold ULN in AIH [71]

Serum GGT ≥ 4-fold ULN in AIH [72]

Serum ALP/AST ratio ≥1.5-fold ULN [48]

None applicable [15]

Key histological findings

Histological clues of AIH in PSC [74]:

 Dense lymphoplasmacytic infiltration

 Moderate interface hepatitis

 Hepatocyte rosettes

Histological clues of PSC in AIH [74]:

 Portal edema, fibrosis, ductopenia

 Periductal fibrosis

Histological clues of PBC in PSC [35]:

 Destructive cholangitis

 Portal granulomatous changes

Histological clues of PSC in PBC [36]:

 Periductal fibrosis


Numbers in brackets are references

AIH autoimmune hepatitis, ALP alkaline phosphatase, AMA antimitochondrial antibodies, ANA antinuclear antibodies, AST aspartate aminotransferase, GGT gamma glutamyl transferase, IAIHG International Autoimmune Hepatitis Group, IgG immunoglobulin G, LKM1 antibodies to liver kidney microsome type 1, PBC primary biliary cholangitis, PSC primary sclerosing cholangitis, SMA smooth muscle antibodies, ULN upper limit of normal range



Patients with the overlap syndromes typically score less than patients with classical AIH. Scores are based on laboratory and histological findings at presentation which may change during the course of the disease, and scores in retrospective studies of the overlap syndromes have varied widely [48]. Cutoff values for the diagnosis of an autoimmune component have not been established, and the scores have not correlated with outcomes. The ratio of the serum alkaline phosphatase (ALP) level to the serum aspartate aminotransferase (AST) level may be the single most valuable component of the scoring system for assessing an overlap syndrome. The ALP/AST ratio can suggest an unusual cholestatic feature in patients with AIH, especially if it exceeds 1.5 [20, 24]. Furthermore, an increased ratio has also been associated with reduced survival [48]. A similar diagnostic scoring system for PBC has been promulgated for assessing the strength of the PBC component in the overlap syndromes, but it has not been validated or widely used [68].



Diagnostic Requisites


Clinical judgment is the principal basis for diagnosing the overlap syndromes of PSC (Table 4.1). The diagnosis of an overlap syndrome between PSC and AIH requires histological and/or cholangiographic features typical of PSC and prominent features of AIH as reflected in characteristic laboratory tests of inflammatory activity, serological tests of immune reactivity (ANA, SMA, and/or antibodies to liver kidney microsome type 1 [anti-LKM1]), hypergammaglobulinemia (especially, increased serum immunoglobulin G [IgG] level), and dense lymphoplasmacytic infiltration of liver tissue with interface hepatitis. Twenty-seven percent of patients with histological overlap between AIH and PSC have small duct PSC, and normal cholangiography does not exclude this overlap syndrome [29].

The diagnosis of the overlap syndrome between PSC and PBC requires histological and/or cholangiographic features typical of PSC, AMA, and characteristic biliary changes of PBC (destructive or granulomatous cholangitis) [15, 17, 33, 34, 37] (Table 4.1). The serum immunoglobulin M (IgM) concentration is increased in 45 % of patients with PSC [57], but AMA are rarely detected (0–8 %) [55, 57, 69]. Antimitochondrial antibodies in patients with histological and/or cholangiographic features of PSC justify histological review and consideration of an overlap syndrome with PBC.

Patients with the overlap syndrome of PSC and PBC may have absent AMA at presentation but compelling histological features of PBC [33, 35] (Table 4.1). These patients may be seronegative for AMA by the indirect immunofluorescence assay (IIF) and seropositive for AMA by the immunoblotting assay [33]. They may also develop AMA later in the course of their disease and express reactivities to gp210 and sp100 [37]. Characteristic cholangiographic changes of PSC may be absent but not invalidate the diagnosis [36, 70]. Histological findings of concentric periductal fibrous (fibrous obliterative cholangitis) may indicate small duct PSC and an overlap syndrome with PBC that is characterized by AMA and antibodies to gp210 and sp100 [36]. The diagnosis of the overlap syndromes by clinical judgment is characterized by the absence of rigid clinical phenotypes.


Key Cholestatic Indices


The serum ALP level can be the sole indication of an overlap syndrome in adults with otherwise classical AIH. The serum ALP level is abnormally increased in 81 % of patients with severe AIH, but it is more than twofold the upper limit of the normal range (ULN) in only 33 % and more than fourfold ULN in only 10 % [71]. A serum ALP level more than twofold ULN in a patient with classical AIH should generate suspicion about the possibility of an overlap syndrome, and the diagnosis should be pursued if the serum ALP level exceeds fourfold ULN.

The serum gamma glutamyl transferase (GGT) level can also be useful in suggesting an unusual cholestatic component in a patient with otherwise classical AIH. Serum GGT levels are commonly increased in adults with AIH, and the mean serum level has ranged from 1.1- to 3.4-fold ULN [72, 73]. Men have significantly higher serum levels of GGT than women [72], and an upper limit of abnormality still compatible with the diagnosis of classical AIH has not been defined. Nevertheless, a serum GGT level exceeding fourfold ULN should suggest the possibility of an overlapping cholestatic process and justify pursuit of this diagnosis.


Histological Examination


Liver tissue examination has been the strongest independent predictor of the overlap syndromes [66, 67, 74] (Table 4.1). Whereas liver tissue examination is seldom necessary in the diagnosis of classical PSC [75, 76], it can direct the diagnosis of an overlap syndrome between PSC and AIH or PBC [20, 28, 33, 35, 66, 67, 74]. Dense lymphoplasmacytic infiltration of the portal tract, moderate-severe interface hepatitis, rosetting of hepatocytes, and lobular hepatitis are atypical of classical PSC, but they are hallmarks of AIH [63, 74, 77]. Similarly, destructive cholangitis (florid duct lesions) compels the consideration of PBC in patients with otherwise classical features of PSC, even in the absence of AMA [35, 76, 78, 79]. Fibrous obliterative cholangitis is the hallmark of PSC, and its presence supports this diagnosis, even in the absence of characteristic cholangiographic abnormalities [36, 70].



Salient Clinical Features of the Overlap Syndrome of PSC and AIH


One hundred thirteen patients with the overlap syndrome of PSC and AIH or PBC have been reported in ten clinical studies, and the publications vary widely in the amount of detail provided [12, 20, 2226, 28, 30, 48] (Table 4.2). Patients with the overlap syndrome of PSC and AIH are mainly young men with active liver inflammation. Serum AST and alanine aminotransferase (ALT) levels are markedly abnormal, and hypergammaglobulinemia and elevated serum IgG levels attest to the severity of the inflammatory and immunological activity [20, 22, 23, 26, 28, 30, 48] (Table 4.2). Autoantibodies (ANA, SMA, and/or pANCA) are commonly present, and an atypical cholestatic component is commonly suggested by an abnormally increased serum ALP and/or GGT level. Chronic ulcerative colitis is present in 24–89 % [20, 23, 24, 26, 28, 30], and histological examination typically discloses features of AIH (interface hepatitis, lymphoplasmacytic infiltration, or rosetting of hepatocytes) [20, 22, 23] and bile duct changes associated with PSC [20, 22]. This characteristic clinical phenotype is similar between patients discovered in large cohorts of individuals originally diagnosed as having AIH (AIH-predominant overlap syndrome) or in large cohorts of individuals originally diagnosed as having PSC (PSC-predominant overlap syndrome) (Table 4.2).


Table 4.2
Clinical features of overlap syndrome of PSC and autoimmune hepatitis




























































Clinical features

AIH predominant

PSC predominant

Age (years)

Median, 20–34 (range,14–74) [20, 28, 48]

Median, 21–22 (range, 7–54) [23, 26]

Male gender

55–81 % [12, 20, 28, 48]

45 % (children) [24]

43–67 % [22, 23, 26]

AST

1.6–35-fold ULN [12, 48]

>5-fold ULN [20]

Lower than in children with normal cholangiography [24]

≥10-fold ULN (median, 18-fold ULN) [23]

Same as in PSC [22]

Higher than PSC [26]

ALP

>4-fold ULN, 80 % [20]

1.2–9.6-fold ULN [12, 48]

1.2–6-fold ULN (median, 1.8-fold ULN) [23]

Similar to PSC [26]

γ-Globulin

>1.5 ULN, 100 % [20]

>ULN, 24 % [28]

>ULN, 100 % [23]

IgG

>ULN, 100 % [20]

Similar to AIH [48]

>ULN, 61–100 % [23]

Higher than in PSC [22, 26]

GGT

>ULN, 100 % [28]

Similar to AIH [48]

Similar to PSC [26]

ANA and/or SMA

50–100 % [12, 20, 28, 30, 48]

73–100 % [22, 23, 26]

pANCA

74–81 % [24, 28]

60 % [23]

CUC

24–44 % [20, 24, 28, 30, 48]

28–89 % [23, 26]

Interface hepatitis

100 % [12, 20]

46–100 % [22, 23]

Lymphoplasmacytic infiltrate, 75 % [22]

Rosetting, 25 % [22]

Bile duct changes

60 % [20]

75 % [22]


Composite of findings reported in ten clinical studies involving 113 patients

Numbers in brackets are references

AIH autoimmune hepatitis, ALP alkaline phosphatase, ALT alanine aminotransferase, ANA antinuclear antibodies, AST aspartate aminotransferase, CUC chronic ulcerative colitis, GGT gamma glutamyl transferase, IgG immunoglobulin G, pANCA perinuclear anti-neutrophil cytoplasmic antibodies, PSC primary sclerosing cholangitis, SMA smooth muscle antibodies, ULN upper limit of the normal range

The typical clinical phenotype in children with the overlap syndrome of AIH and PSC is different than that in adults [80, 81]. A distinction has been made between the classical PSC common in adults, which may have multiple etiologies and few or no autoantibodies, and “autoimmune sclerosing cholangitis” (ASC) in children. Children with ASC have typical features of AIH and cholangiographic changes of PSC in association with autoantibodies that suggest an immune-mediated process [24, 82]. There is little gender difference in children with the overlap syndrome of AIH and ASC (45 % male versus 55 % female); the serum AST level is lower than in children with classical AIH; and cholestatic features frequently are absent or mild [24]. The serum ALP level is normal in 59 % of these children, and the GGT level is normal in 30 %. An increased serum ALP/AST ratio (3.96 in ASC versus 1.1 in AIH) is the most compelling clinical finding that suggests the presence of ASC [24]. Small duct PSC has been described in a 7-year-old girl with anti-LKM1, and this overlap should be considered in children with normal cholangiography and periductal fibrosis on histological examination [70].

Jaundice is present in as many as 69 % of adults at presentation, but at least 18 % are asymptomatic [48]. The presence of ulcerative colitis in a patient with AIH justifies the performance of endoscopic resonance cholangiography (ERC) or magnetic resonance cholangiography (MRC) regardless of other clinical features. Chronic ulcerative colitis is present in 16 % of adults with AIH, and 42 % of those undergoing cholangiography have PSC [49]. MRC has been preferred in the evaluation of patients with PSC because of its comparability to ERC, lower cost, and relative safety (mainly by avoiding the complication of pancreatitis) [810]. The major caveat in ERC and MRC is the misinterpretation of bile duct distortions by fibrosis as indicative of PSC. Hepatic fibrosis has been a strong independent factor associated with bile duct distortions in AIH [83], and it may account for the high (10 %) frequency of presumed PSC in patients with otherwise classical AIH [84]. Routine cholangiography in adults with AIH and no evidence of inflammatory bowel disease has not been recommended [83].


Salient Clinical Features of the Overlap Syndrome of PSC and PBC


Eight patients with the overlap syndrome of PSC and PBC have been reported in six clinical studies [3237]. The publications vary widely in the amount of detail provided, but the composite findings allow a clinical phenotype to emerge (Table 4.3). The median age has been 52 years (range, 40–72 years), and all but one have been women. Markedly abnormal elevations of the serum ALP and GGT levels are commonly present [32, 33, 35], and serum levels of IgG and IgM have been abnormally increased when measured [32]. ANA have been detected in 62 % (median titer, 1:40; range, 0–1:1280); SMA have been uniformly absent in those patients who were tested; and AMA have been detected by IIF or immunoblotting in 88 % at presentation or during the course of the disease [3234].


Table 4.3
Clinical features of overlap syndrome of PSC and PBC




















































Clinical features

Findings (N = 8)

Age (years)

Median, 52 (range, 40–72) [3237]

Gender

Women, 7 (88 %) [3236]

Past history gallstones, biliary surgery

4 (50 %) [33, 34, 37]

Biliary pain as presenting symptom

3 (38 %) [33, 34]

Aspartate aminotransferase (AST)

0–4-fold ULN [32, 33, 37]

Alkaline phosphatase (ALP)

2–20-fold ULN [32, 33, 35]

Gamma glutamyl transferase (GGT)

Fivefold ULN [33]

Antinuclear antibodies (ANA)

5 (62 %) (including patient negative at entry and 1:80 later) [34]

Median titer, 1:40 (range, 0–1:1280 [3237]

Smooth muscle antibodies (SMA)

0 % [3335, 37]

Antimitochondrial antibodies (AMA)

7 (88 %) (titer range, 0–1:1280) [3237]

Negative at presentation, 3 (38 %) [33, 35]

Positive later or by immunoblotting, 2 (25 %) [33, 37]

Antibodies to gp210 and sp100 [36, 37]

Chronic ulcerative colitis (CUC)

None [33]

pANCA

Negative [35]

Endoscopic or magnetic resonance cholangiography

Diagnostic, 88 % [3235, 37]

Normal, 12 % [36]

Histological features

(7 of 8 patients biopsied)

Destructive (granulomatous) cholangitis, 4 (57 %) [33, 35, 37]

Fibrous obliterative cholangitis, 1 (14 %) [36]

Nondestructive cholangitis, 1 (14 %) [34]

Ductopenia, portal fibrosis, ductular proliferation, 1 (14 %) [32]


Composite of findings reported in six clinical studies involving eight patients

Numbers in brackets are references

pANCA perinuclear anti-neutrophil cytoplasmic antibodies

Patients with the overlap syndrome of PSC and PBC commonly have had a past history of gallstones or biliary surgery (50 % occurrence) [33, 34, 37], and biliary pain has been a presenting symptom in 38 % [33, 34]. Chronic ulcerative colitis has been absent in all patients, and atypical pANCA have not been detected in the one patient in whom it was sought [35]. Histological findings have been commonly those of PBC with destructive (granulomatous) cholangitis in four of the seven patients who underwent liver tissue examination (57 %) [33, 35, 37]. Nondestructive cholangitis has been present in one patient (14 %) [34]; one patient (14 %) has had portal fibrosis, ductopenia, nondestructive cholangitis, and mild ductular proliferation [32]; and one patient (14 %) has had fibrous obliterative cholangitis [36]. Cholangiography has been diagnostic of PSC in 88 %. The one patient with normal MRC has had compelling histological features of PSC (fibrous obliterative cholangitis) and small duct PSC [36].

PSC and PBC have been recognized together in one patient [36]; PSC has preceded the diagnosis of PBC in two patients [33, 37], and PBC has preceded the diagnosis of PSC in five patients [32, 34, 35, 37]. The diagnosis should be considered in patients with PSC who have or develop AMA and histological features of PBC, and it should be considered in patients with classical PBC who have or develop biliary pain, fever, or worsening cholestatic features [32, 34, 35, 37].


Frequency


The frequency of the overlap syndrome of PSC and AIH ranges from 0 to 54 %. This variability probably reflects the size and age of the cohort under study, the predominant disease within that cohort, and the diagnostic criteria that are applied. Studies based mainly on the presence of cholestatic features (laboratory or radiographic findings) in patients with AIH have a frequency of PSC that ranges from 0 to 10 % [12, 30, 84, 85]. Studies based mainly on the presence of autoimmune features in patients with PSC determined by the diagnostic scoring systems of the IAIHG have a frequency of AIH that ranges from 4 to 54 % [12, 22, 23, 26, 28, 48].

The high frequency of the overlap syndrome in some studies of PSC attests mainly to the occurrence of inflammatory features shared by AIH in 35–54 % of patients with severe PSC. The nondiscriminative nature of the diagnostic scoring system of the IAIHG between AIH and PSC also contributes to this variability [12, 18, 86]. The 27 individual clinical manifestations that are graded in the scoring system of the IAIHG include nondiscriminative findings such as gender, the absence of drug and alcohol exposure, negative studies for viral infection, the absence of AMA, and concurrent immune diseases including chronic ulcerative colitis [60]. Many patients with classical PSC may have a score close to that required for probable AIH based simply on these findings. Studies assessing cholangiographic changes of PSC in children with AIH estimate the frequency of overlapping features as 49 % [24], and studies in adults suggest that the frequency of the overlap syndrome is best estimated at 4–17 % [22, 23, 28, 37, 48].

The overlap syndrome of PSC and PBC has been reported in only eight patients [3237], and one of these patients had overlapping features of AIH, PBC, and PSC [34]. The frequency of this rare overlap syndrome between PSC and PBC has been estimated as 0.7 % (two patients) of 261 patients with autoimmune liver disease [34].


Autoimmune Cholangitis


Patients with AIH may have a cholestatic syndrome in the absence of classical clinical features of PSC or PBC [15, 17]. They lack AMA, have normal cholangiograms, and manifest bile duct injury or loss on histological examination. These patients have been classified as having autoimmune cholangitis [39, 43, 8790], but they probably constitute a heterogeneous population that includes patients with AMA-negative PBC [38, 44, 91] and small duct PSC [41, 42]. The status of these patients as an overlap syndrome is unsettled since the features of AIH that accompany the cholestatic laboratory and histological changes are not disease specific, and autoimmune cholangitis may simply be a variant of PBC or PSC.

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Oct 9, 2017 | Posted by in GASTROENTEROLOGY | Comments Off on Overlap Syndromes of Primary Sclerosing Cholangitis
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