Correspondence *Department of Internal Medicine III, Aachen University (RWTH), Pauwelsstrasse 30, D-52074 Aachen, Germany

Email ageier@ukaachen.de

The case

A 24-year-old white man was diagnosed as having Crohn's disease by clinical, endoscopic and histological assessments and was successfully treated with short-course prednisolone (60 mg for 2 weeks, reduced to 0 mg over 2 months). He relapsed 2 years later and was again treated with short-course prednisolone at the same dose as 2 years earlier, which was effective in inducing long-term remission.

After another 2 years, while the Crohn's disease was still in remission, the patient presented with cholestasis and hyperbilirubinemia, but with normal alanine aminotransferase (ALT) levels (25 U/l). The results of serological tests for infectious causes of hepatopathy were negative, and -globulin levels were within the normal range (10 g/l, normal range 7–16 g/l). The patient underwent ultrasonography and endoscopic retrograde cholangiopancreatography (ERCP), which revealed diffuse irregularities of the biliary tree, and a diagnosis of primary sclerosing cholangitis (PSC) was made. Treatment with 750 mg ursodeoxycholic acid (UDCA) daily was started and prescribed for an unlimited time.

When the patient was aged 33 years, he was readmitted to hospital because of markedly elevated liver enzymes that had been detected in the routine follow-up laboratory assessments. In addition, he suffered from fatigue. The following laboratory findings were reported: ALT 1,276 U/l, bilirubin 47.0 mol/l (2.75 mg/dl), normal serum alkaline phosphatase levels (53 U/l, normal range 35–104 U/l) and slightly elevated -glutamyltransferase levels (51 U/l, normal range 6–42 U/l). Furthermore, the titer for antinuclear antibodies (ANA) was notably raised at 1:1,280, tests for hepatotropic viruses were negative, and perinuclear antineutrophil cytoplasmic antibodies (ANCA) titers were not notably raised (1:20, negative when below 1:20). No new medications had been started and the patient denied any alcohol consumption.

A liver biopsy was carried out and revealed histological features of interface hepatitis with no changes typical of PSC. A magnetic resonance cholangiopancreatography was carried out to determine the activity of the PSC diagnosed previously and revealed no substantial changes in the biliary tree. Magnetic resonance cholangiopancreatography was chosen over ERCP because of the lower risk of complications and because the patient had no laboratory signs of cholestasis. The autoimmune hepatitis (AIH) score on the International AIH Group scoring system was 21 (definite AIH), and, therefore, a diagnosis of AIH was made. Steroid treatment (60 mg prednisolone daily) was started and, following normalization of liver enzymes, tapered carefully to 5 mg over 6 months and stopped after 2 years, while treatment with UDCA was continued at 750 mg daily.

Two years after the previous admission, the patient's liver enzyme levels had normalized but ERCP, which was conducted routinely as part of PSC follow-up, revealed irregular bile ducts within and outside the liver. A temporary bile duct stent was implanted because of a significant stenosis of the distal common bile duct. At that time the results of a liver biopsy revealed characteristics of a well-established sclerosing cholangitis with micronodular cirrhotic remodeling of the liver parenchyma. In addition, a faint inflammatory infiltrate was also identified and was interpreted as residual AIH activity. The patient's AIH score was 12 (indicating probable AIH). Prednisolone (10 mg daily) was added to the continuing UDCA treatment (750 mg daily).

One year later the patient's ALT levels again were elevated (457 U/l), whereas serum alkaline phosphatase and bilirubin levels were within normal ranges and -glutamyltransferase was only slightly elevated. In contrast to the immunological findings of 3 years earlier, ANA titers were low and the total serum IgG level was normal. Cholangiography showed little change from 1 year earlier. The daily UDCA dose of 750 mg was increased to 1,000 mg and prednisolone was continued at 10 mg daily.

After 1 year on this regimen, the patient's serum ALT levels were only slightly elevated (102 U/l) and the levels of serum markers of cholestasis were all within normal ranges. Moreover, he tested negative for ANA, antibodies to soluble liver antigen and to mitochondria, although findings were positive for ANCA (titer 1:160) and antibodies to smooth muscle actin (titer 1:40). Prednisolone medication was stopped.

The following year, an increase in the patient's ALT level (279 U/l) was recognized through routine testing, along with marked blood eosinophilia (24%, 1.4 g/l) and slightly increased concentrations of angiotensin-converting enzyme. The patient's ANCA titer was strongly positive (1:340). A CT scan of the thorax and abdomen revealed bihilar lymphadenopathy as well as lymph node conglomerates in the liver hilum and the celiac truncus, which are indicative of sarcoidosis. CT-guided lymph node biopsy confirmed this diagnosis, while a liver biopsy revealed reactive hepatitis with accompanying massive hypereosinophilia but no granulomas (Figure 1A). Once more, the patient was given prednisolone (60 mg daily) and his aminotransferase levels and lymphadenopathy responded well to the treatment. Liver enzyme levels were tested routinely, showing an improvement after 2 weeks and a return to within normal ranges after 4 months. A CT scan, carried out 6 months after diagnosis as part of follow-up, revealed lymph nodes that were regressing to normal. Systemic prednisolone was carefully tapered to 5 mg over 12 months. As no extrahepatic manifestations were detected and because of the patient's desire for local treatment, maintenance therapy with budesonide (9 mg daily) was started and continued for 4 years.

Figure 1 Histological and cholangiographic features.

(A) Histological image from the liver biopsy of the case patient taken at the time of his diagnosis with sarcoidosis. Reactive hepatitis is evident; note the marked eosinophilic infiltrate (arrow heads). Hematoxylin and eosin staining, normal magnification 40. (B) Histological image from the liver biopsy of the case patient taken at the time that a diagnosis of autoimmune hepatitis (AIH) was confirmed. Lymphocytic interface hepatitis (a typical feature of AIH) can be seen. Hematoxylin and eosin staining, normal magnification 40. (C) Endoscopic retrograde cholangiopancreatogram of the case patient taken 8 months after a diagnosis of AIH was confirmed. Irregularities and significant strictures (arrow heads) of extrahepatic bile ducts with prestenotic dilatation can be seen, suggesting the need for intervention.

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After 4 years, another rise in serum ALT to 297 U/l was recognized. Laboratory screening and liver biopsy (Figure 1B) confirmed AIH (International AIH Group score of 16, indicating definite AIH) and ruled out residual sarcoidosis. Furthermore, human leukocyte antigen (HLA) typing revealed an HLA B8 DR4 phenotype, which is highly associated with AIH and autoimmune cholangitis. Again, systemic steroid treatment was increased (60 mg prednisolone daily) and laboratory tests indicated a good response. After normalization of liver enzymes, azathioprine (AZA) treatment (2mg/kg =150 mg daily) was initiated and prednisolone was tapered to 7.5 mg over 12 months. Despite histological signs of liver cirrhosis, the synthetic capacity of the patient's liver was unaffected, as expressed by a normal international normalized ratio, albumin concentration and pseudocholinesterase activity level. The course of the autoimmune overlap syndrome was, therefore, deemed generally benign. Nevertheless, a routine ERCP conducted 8 months later again revealed significant strictures of the common bile duct that required dilatation and stent implantation (Figure 1C). The patient currently receives AZA (150 mg daily), budesonide (9 mg daily) and UDCA (1,750 mg daily) and is closely monitored for hepatitis activity or signs of cholestasis.

Discussion of diagnosis

The present case represents hepatic overlap syndrome with an uncommon course and constantly changing phenotype associated with additional autoimmune disorders (Crohn's disease and sarcoidosis). Overlapping AIH and PSC are mostly diagnosed simultaneously,¹ and occur together in about 6–8% of all infants, adolescents and young adults with AIH or PSC.^{2, 3} Nevertheless, sequential manifestations of PSC following AIH have been observed.⁴ As overlap syndromes usually involve the simultaneous manifestation of two autoimmune disorders, a sequential manifestation can easily distract from the fact that there is an underlying overlap. Sequential manifestation can, therefore, delay diagnosis and treatment initiation, particularly when other (autoimmune) disorders also have to be considered as probable causes for hepatopathies (e.g. sarcoidosis, as in the present case). So far, only two cases of AIH developing on a background of established PSC have been reported, but neither showed an alternating disease course.^{5, 6}

In the present case, a final diagnosis of AIH–PSC overlap was not reached until a decade after the first manifestations of liver disease. The short course of prednisolone that brought about initial remission of Crohn's disease in the case is unlikely to have masked a pre-existing AIH; however, later long-term steroid treatment of AIH might in turn have masked chronic activity of Crohn's disease.

The clinical presentation, prognosis and underlying mechanism of this AIH–PSC syndrome remain elusive. Gregorio and colleagues⁷ followed up 55 infant AIH patients for 16 years and identified an autoimmune hepatitis/sclerosing cholangitis overlap in 27 (49.1%). They noted a strong association with IBD in affected patients, indicating an increased susceptibility to autoimmune disorders or a probable pathogenetic link.

Whether AIH–PSC overlap represents the coexistence of two distinct autoimmune liver diseases or a single autoimmune syndrome remains unclear. PSC and AIH present differently, but certain genetic risk factors and biochemical and immunological features are similar: for example, autoantibody expression (antibodies to smooth muscle antigen are found in up to 16% of PSC patients [40% in AIH patients] and anti-ANA in up to 32% [80% in AIH patients]) and elevated serum IgG.⁸ Up to 81% of AIH patients have elevated alkaline phosphatase levels (typically elevated in PSC patients owing to cholestasis). Genetic and immunological risk factors also overlap in the two disorders. For example, HLA B8 DR3 and B8 DR4 phenotypes are frequently found in both groups;^{9, 10} the case patient had an HLA B8 DR4 phenotype. Thirdly, the clinical course and outcome of patients with an AIH–PSC overlap syndrome differ substantially from patients with PSC alone. A small prospective study showed markedly reduced survival in a group of PSC patients compared with an AIH–PSC overlap group.¹¹

The present case suggests that considering the coexistence or de novo development of AIH in PSC patients is important. Whenever clinical evidence of AIH is noted (e.g. elevated or increasing aminotransferase levels), autoantibody status should be assessed and a liver biopsy should be carefully considered. Furthermore, since the course of PSC is fatal and liver transplantation is the only available cure, liver biopsy should be performed before enrolment on the transplantation register in order to stage the disease.

Differential diagnosis

Autoimmunological disorders of the liver and the biliary tract have to be considered after infectious, toxic or genetic causes of hepatopathy have been ruled out. Laboratory tests and clinical features are crucial to distinguish the most common autoimmune diseases (e.g. PSC, primary biliary cirrhosis, AIH, autoimmune cholangitis) and overlap syndromes. Table 1 and Figure 2 illustrate the results of clinical and laboratory assessments that were undertaken during the present case.

Figure 2 Graph showing the course of serum liver tests.

The results of liver function tests in the case patient are correlated with different clinical manifestations over time, demonstrating the complexity of disease presentation as well as the difficulty involved in reaching a final diagnosis (data points shown at 2 years before current admission were obtained from an external center). Abbreviations: AIH, autoimmune hepatitis; ALT, alanine aminotransferase; -GT, -glutamyltransferase; PSC, primary sclerosing cholangitis.

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Table 1 An overview of the histological and cholangiographic findings (endoscopic retrograde cholangiopancreatography or magnetic resonance cholangiopancreatography) in the case patient. The alternating course of the different disease components is clearly demonstrated.

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Important differential diagnostic clues between different forms of hepatic autoimmune diseases are itemized in Figure 3. Although transient elevations of aminotransferase levels are commonly seen in PSC patients, they can be ruled out in the case patient. Elevations in his aminotransferase levels were rapid, drastic and occurred in conjunction with a substantial increase in ANA titers, histological evidence of interface hepatitis and a good response to steroid treatment, and without the concurrent introduction of new medication.

Figure 3 Diagnostic pathways in autoimmune liver disease.

Characteristic features of the most common differential diagnoses within the spectrum of autoimmune liver diseases, all of which can present as overlap syndromes, are shown in boxes at the bottom of the figure. ASC, in contrast to other overlap syndromes, can often be observed in infant patients and is characterized by the presence of cholangiographic signs of cholangitis in the background of AIH. UDCA treatment should be considered. Specific attention should be paid to associated autoimmune disorders listed in the lower left box. ^aSarcoidosis can resemble other autoimmune liver disease and should be considered and ruled out in uncharacteristic presentations. Abbreviations: AIC, autoimmune cholangitis; AIH, autoimmune hepatitis; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AMA, antimitochondrial antibody; AMA-M2, antimitochondrial antibody M2; ANA, antinuclear antibody; ASC, autoimmune sclerosing cholangitis; ASMA, anti-smooth muscle antibody; AST, aspartate aminotransferase; ERCP, endoscopic retrograde cholangiopancreatography; -GT, -glutamyltransferase; HLA, human leukocyte antigen; LKM, liver–kidney microsome; pANCA, perinuclear antineutrophil cytoplasmic antibody; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; SLA, soluble liver antigen; UDCA, ursodeoxycholic acid.

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Treatment and management

As in the presented case, overlap syndromes seem to respond well to combined immunosuppression and UDCA therapy. Relapsing courses of AIH require long term immunosuppression. As in the present case, this can be done with AZA, as long-term steroid treatment should be avoided due to considerable adverse effects. In the present case we chose a combination of a steroid with a high first-pass effect (budesonide) and, therefore, very limited adverse effects, AZA and UDCA. UDCA has proven efficient in reducing both symptoms such as pruritus and progression of the disease, and should be given at a daily dose of 20–25 mg/kg. Major strictures of the biliary tree should be subjected to endoscopic intervention. In the present case the patient received a bile duct stent implant.

Conclusions

The present case shows an unusual accumulation of autoimmune disorders with relapsing–remitting PSC and AIH that was ultimately diagnosed as an AIH–PSC overlap. This case might help strengthen the concept of an underlying autoimmune syndrome as a cause of hepatocholangiopathic overlap syndromes. Moreover, it clearly demonstrates the need for close follow-up of patients with autoimmune disorders of the gastrointestinal tract and the liver, especially as these tend to develop into other autoimmune conditions that require adjustment of therapy over time.

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Subject areas under which this article appears: Liver | Hepatitis