Clin J Gastroenterol (2012) 5:183–188 DOI 10.1007/s12328-012-0294-5
CASE REPORT
Overlap syndrome of autoimmune hepatitis and primary sclerosing cholangitis complicated with hepatocellular carcinoma Kazuto Fukuda • Sachiyo Kogita • Yusuke Tsuchimoto • Yoshiyuki Sawai Takumi Igura • Hideko Ohama • Yuki Makino • Yasushi Matsumoto • Masanori Nakahara • Shin-ichirou Zushi • Yasuharu Imai
•
Received: 18 January 2012 / Accepted: 29 February 2012 / Published online: 7 April 2012 Ó Springer 2012
Abstract Development of hepatocellular carcinoma (HCC) in patients with autoimmune liver disease is less common than in those with other types of chronic liver disease. Here we report a rare case of overlap syndrome consisting of autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC) that was subsequently complicated with HCC. A 72-year-old man was initially diagnosed as being in the cirrhotic stage of AIH on the basis of blood chemistry tests and histological examinations. Computed tomography and magnetic resonance cholangiography 20 months later showed diffuse stricturing of the intrahepatic bile duct with dilatation of the areas between the strictures, compatible with the findings of PSC, which resulted in a diagnosis of AIH/PSC overlap syndrome. The level of serum protein induced by vitamin K absence or antagonist II increased 22 months later, and HCC was diagnosed by radiological examinations. Four cycles of transarterial infusion therapy with cisplatin were performed, but the patient died one year later. Sequential overlap of PSC may have played a part in accelerating AIH disease progression, leading to the development of HCC in this patient. Therefore, HCC surveillance may be important in advanced stages of autoimmune disease, especially in the cirrhotic stage.
K. Fukuda (&) S. Kogita Y. Tsuchimoto Y. Sawai T. Igura H. Ohama Y. Makino Y. Matsumoto M. Nakahara S. Zushi Y. Imai Department of Gastroenterology, Ikeda Municipal Hospital, 3-1-18 Jonan, Ikeda, Osaka 563-8510, Japan e-mail: [email protected]
Keywords Autoimmune hepatitis Primary sclerosing cholangitis Overlap syndrome Hepatocellular carcinoma
Introduction Both autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC) are considered to be autoimmune diseases of the liver. AIH is an idiopathic chronic hepatitis affecting predominantly middle-aged women, and is characterized by liver necroinflammation and the presence of autoantibodies and elevated serum immunoglobulin (Ig) levels [1]. On the other hand, PSC is a chronic disease of the intra- and/or extrahepatic bile ducts characterized by a concentric obliterative fibrosis that leads to bile duct strictures and occurs more frequently in men than in women [2]. These two diseases are typically well categorized by clinical, blood biochemical, and histological features. However, the overlap syndrome, in which patients present with features of both AIH and PSC, has been recently documented, although there is currently no clear definition for this entity [3–5]. The development of hepatocellular carcinoma (HCC) in patients with autoimmune liver disease is considered to be less common than in other chronic liver diseases such as viral hepatitis and alcoholic liver disease. AIH patients have not been identified as a high-risk group, which would mandate surveillance for HCC according to the guidelines of the American Association for the Study of Liver Disease [6]; however, several reports have suggested the potential risk of HCC occurring in these patients, especially in those in the cirrhotic stage [7, 8]. Here we report a case of AIH/PSC overlap syndrome with subsequent development of HCC, which is of interest from the perspective of the mechanism of carcinogenesis in autoimmune liver disease.
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184
Case report A 72-year-old man was admitted to a local hospital for severe abdominal distension in March 2005. He did not drink alcohol and family history of liver disease was not observed. He had suffered from acute hepatitis of unknown etiology in 1997, but did not undergo a follow-up since that time. A diagnosis of hepatic cirrhosis was made on the basis of laboratory tests and computed tomography (CT). He was administered diuretics and human serum albumin products to decrease the ascites. After being discharged from hospital, the patient visited our department for further examination. Table 1 shows the laboratory data from his first visit. A liver function test revealed the following: serum albumin 1.6 g/dL, bilirubin 2.5 mg/dL, aspartate aminotransferase 66 IU/L, alanine aminotransferase 33 IU/L, prothrombin time 59 %, and platelet count 7.4 9 104/lL; these findings were compatible with a diagnosis of cirrhosis. Tests for hepatitis B virus (HBV) surface antigen and hepatitis C antibodies were negative. HBV-core antibody was detected, but HBV DNA was undetectable in the serum. The level of serum IgG was markedly elevated, and anti-nuclear antibodies were detected. The human leukocyte antigen genotype was DRB1*0405/0901. A percutaneous needle biopsy of the liver showed lymphocytic interface hepatitis and rosette formation, but emperipolesis was not recognized. It also showed bridging fibrosis and pseudo-lobular formation, thereby confirming the diagnosis of cirrhosis. There were no pathological changes of bile ducts, such as loss of bile ducts, ductular proliferation, or periductal fibrosis (Fig. 1). The pretreatment score according to the International Autoimmune Hepatitis Group simplified criteria [9] in this patient was 6 points, corresponding to a probable diagnosis of AIH, and treatment with prednisolone (PSL) (15 mg daily) and ursodeoxycholic acid (UDCA) (600 mg daily) was initiated. Concomitant autoimmune disease was not observed. Endoscopic study of the upper gastrointestinal tract revealed the presence of esophageal varices, and endoscopic variceal ligation therapy was performed. The patient’s liver function gradually improved with PSL and UDCA treatment, and he was in good health until January 2008, when dilatation of the intrahepatic bile duct (IHBD) was detected on routine ultrasonography (US) and CT (Fig. 2). Magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiography (ERC) showed diffuse stricturing of the IHBD with dilatation of the areas between strictures, compatible with the finding of PSC (Fig. 3). Irregularity of the pancreatic duct or diffuse swelling of the pancreas was not detected. Serum levels of IgG4 and anti-nuclear cytoplasmic antibodies were within normal limits. A colonoscopy did not show evidence of
123
Clin J Gastroenterol (2012) 5:183–188 Table 1 Laboratory data of first medical examination WBC
3500/lL
RBC
292 9 104/lL
PT
59.2 %
Hb Ht
10.0 g/dL
IgG
5295 mg/dL
29.2 %
IgM
436 mg/dL
Plt
7.4 9 104/lL
ANA
940
SMA
\920
T. protein
7.9 g/dL
AMA-M2
6 U/mL
Alb
1.6 g/dL
T. bilirubin
2.5 mg/dL
AFP
4.1 ng/mL
D. bilirubin
1.5 mg/dL
PIVKA-II
6 mAU/mL
AST
66 IU/L
CEA
3.8 ng/mL
ALT
33 IU/L
ALP
305 IU/L
HBsAg
(-)
cGTP
19 IU/L
HCVAb
(-)
LDH FPG
196 IU/L 110 mg/dL
HBcAb HBVDNA
(?) \2.6 log copy/mL
BUN
23 mg/dL
Cre
0.96 mg/dL
HLA genotype
DRB1*0405/0901
CRP
0.2 mg/dL
ANA anti-nuclear antibody, SMA anti-smooth muscle antibody, AMA anti-mitochondrial antibody, HLA human leukocyte antigen
ulcerative colitis. The second liver biopsy was performed, which showed significant alleviation of interface hepatitis, but pathological changes of bile ducts were not observed again (Fig. 4). Specific causes of sclerosing cholangitis, such as infection, bile duct stones, or neoplasm, were not identified, and the diagnosis of PSC was made. Since no deterioration of symptoms or laboratory data was observed, the same medications were continued. In December 2009, his serum level of protein induced by vitamin K absence or antagonist II (PIVKA-II) increased to 460 mAU/mL. A dynamic CT scan showed a hypervascular tumor, 25 mm in diameter, in the S8 segment of the liver. CT during hepatic arteriography and CT during arterial portography were performed and the tumor was diagnosed as HCC (Fig. 5). Transarterial infusion therapy (TAI) with cisplatin was performed because of the impaired liver function and the presence of IHBD dilatation. After two cycles of TAI, PIVKA-II levels temporally decreased, but started increasing again from April 2010. CT revealed diffuse progression of tumors in the liver. Another two cycles of TAI were performed, but the patient died in December 2010. An autopsy was not performed.
Discussion Overlap syndrome of autoimmune disease is defined as the concurrent presence of the main characteristics of two
Clin J Gastroenterol (2012) 5:183–188
185
Fig. 1 Percutaneous biopsy samples of liver tissue at May 2005. a H&E staining showed lymphocytic interface hepatitis and rosette formation. b Azan staining showed bridging fibrosis and pseudo-lobular formation
autoimmune conditions at the same time or during the course of the illness. AIH/PSC overlap syndrome is considered to be relatively common in children. In a large pediatric series, half the children with a definitive diagnosis of AIH demonstrated cholangiographic features of PSC at presentation [10]. On the other hand, the prevalence of PSC in adults with AIH is found to a lesser extent. Abdalian et al. [11] reported that magnetic resonance cholangiography (MRC) findings consistent with sclerosing cholangitis (SC) were observed in 10 % of adult AIH patients, suggesting that routine radiological evaluation of the biliary tree should be performed. In contrast, Lewin et al. [12] reported a much lower SC prevalence of 1.7 %. This discrepancy may be due to the differences in diagnostic criteria of SC, stage of disease, and length of follow-up period between the two studies. It has been suggested that AIH and PSC may be sequential in their occurrence, whereby patients have features of AIH and then after a number of years develop features of PSC [13]. Buuren et al. [14] reported on nine (8 %) of 113 PSC patients diagnosed as having overlap syndrome. In their report, four patients initially presented with features of AIH and in five cases PSC was diagnosed first. Compared with Caucasians, the overlap of AIH and PSC in adults is considered to be extremely rare in Japan. This is
probably due to the low prevalence of PSC in Japan. The incidence of PSC in inflammatory bowel disease is also much lower than that reported in Western countries [15]. To the best of our knowledge, there has only been one case report of the overlap of AIH and PSC [16]. In that case, the features of PSC were recognized by ERC one year after the diagnosis of AIH. The levels of biliary enzymes were moderately increased, but histological examination did not show pathological changes of bile ducts. In our case, it was unclear when the features of PSC had appeared. When the diagnosis of AIH was made in 2005, the disease had already progressed to the cirrhotic stage. CT and US did not show features of PSC at that time, but the presence of occult PSC could not be excluded because of a lack of an MRC or ERC study. However, it could be inferred that features of PSC had progressed over a relatively short period, since CT and MRC 3 years after the first visit revealed features typical of PSC. Pathological bile duct changes were not observed in liver biopsy, as in the case report by Takiguchi et al. Recently however, it has been recognized that histological findings of the liver are not required to make a diagnosis of SC if the radiological findings show typical bile duct changes [2]. The levels of serum biliary enzymes fluctuated near the upper limits of normal range throughout the
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Fig. 2 Portal phase of dynamic CT of the liver in May 2005 (a, b), and in January 2008 (c, d). Development of dilatation of intrahepatic bile ducts in January 2008
Fig. 3 a MRC and b ERC showed diffuse stricturing of intrahepatic bile ducts with dilatation of the areas between strictures
course. Early administration of PSL and UDCA might suppress the elevation, although it could not prevent the progression of bile duct changes. Although the occurrence of HCC in autoimmune liver disease has been considered to be relatively rare, the true
123
incidence remains unknown due to a paucity of data addressing this issue. Montano-Lazo et al. reported that male gender, features of portal hypertension, treatment failure, and immunosuppressive treatment may be important predisposing factors for HCC. They also showed that
Clin J Gastroenterol (2012) 5:183–188
187
Fig. 4 Percutaneous biopsy samples of liver tissue in March 2008. H&E staining showed significant alleviation of interface hepatitis. Bile duct damage was not observed
Fig. 5 a CT during hepatic arteriography showed hypervascular tumor in the S8 segment of the liver. b CT during arterial portography showed a defect in the portal vein supply of the tumor
the presence of cirrhosis in AIH is significantly associated with an increased risk of HCC, which subsequently occurs at a rate of 1.1 % per year [17]. Wong et al. [8] reported in their large cohort study that the overall estimated HCC risk in AIH patients was \0.2 %; however, the prevalence among patients with cirrhosis rose to 1.9 %, comparable to the HCC risk in cirrhosis caused by viral hepatitis. PSC is associated with an increased risk of hepatobiliary carcinoma. Cholangiocarcinoma is the most common malignancy complicating PSC, with a life-time prevalence of approximately 8–30 % [18, 19]. A third of patients who developed cholangiocarcinoma were diagnosed within a year of their PSC diagnosis, suggesting that cholangiocarcinoma is not necessarily a late complication of end-stage PSC. On the other hand, HCC usually complicates advanced-stage PSC. The risk of HCC for PSC patients with cirrhosis has been estimated to be up to 2 % per year [20]. Leidenius et al. [21] reported that varices were more common in PSC patients developing HCC than in PSC patients with other hepatobiliary carcinomas. These reports
suggested that cirrhosis is the sine qua non for HCC development in autoimmune liver disease. However, Maeda et al. [22] recently reported a case of HCC associated with noncirrhotic AIH, suggesting a possible mechanism other than cirrhosis for hepatocarcinogenesis. In the present case, the liver was already in the cirrhotic stage of AIH at the time of the patient’s first visit to our department. Therefore, HCC occurrence may be caused mainly by cirrhosis of AIH. However, the possibility remains that overlap of PSC may have accelerated disease progression, leading to the development of HCC. We could not completely exclude the possibility that ‘occult’ HBV infection may have played a part in HCC development, since the HBV-core antibody was detected in the serum. But we think that progression of liver disease was mainly due to the autoimmune process, considering that HBV DNA was not detected in the serum when hepatitis was prominent. In conclusion, we reported a case of AIH/PSC overlap syndrome complicated with HCC, which leads us to
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believe that HCC surveillance of HCC may be important in advanced stages of autoimmune disease, especially in the cirrhotic stage. Conflict of interest of interest.
The authors declare that they have no conflict
References 1. Czala AL, Manns MP. Advances in the diagnosis, pathogenesis, and management of autoimmune hepatitis. Gastroenterology. 2010;139:58–72. 2. Chapman R, Fevery J, Kalloo A, Nagorney DM, Boberg KM, Shneider B, et al. Diagnosis and management of primary sclerosing cholangitis. Hepatology. 2010;51:660–78. 3. Kaya M, Angulo P, Lindor KD. Overlap of autoimmune hepatitis and primary sclerosing cholangitis: an evaluation of a modified scoring system. J Hepatol. 2000;33:537–42. 4. Floreani A, Rizzotto ER, Ferrara F, Carderi I, Caroli D, Blasone L, et al. Clinical course and outcome of autoimmune hepatitis/ primary sclerosing cholangitis overlap syndrome. Am J Gastroenterol. 2005;100:1516–22. 5. Lu¨th S, Kanzler S, Frenzel C, Kasper HU, Dienes HP, Schramm C, et al. Characteristics and long-term prognosis of the autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome. J Clin Gastroenterol. 2009;43:75–80. 6. Bruix J, Sherman M. AASLD practice guideline. Management of hepatocellular carcinoma: an update. Hepatology. 2011;3:1020–2. 7. Yeoman AD, Al-Chalabi T, Karani JB, Quaglia A, Devlin J, Mieli-Vergani G, et al. Evaluation of risk factors in the development of hepatocellular carcinoma in autoimmune hepatitis: implications for follow-up and screening. Hepatology. 2008;48: 863–70. 8. Wong RJ, Gish R, Frederick T, Bzoweji N, Frenette C. Development of hepatocellular carcinoma in autoimmune hepatitis patients: a case series. Dig Dis Sci. 2011;56:578–85. 9. Hennes EM, Zeniya M, Czaja AJ, Pares A, Dalekos GN, Krawitt EJ, et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology. 2008;48:169–76. 10. Gregorio GV, Portmann B, Karani J, Harrison P, Donaldson PT, Vergani D, et al. Autoimmune hepatitis/sclerosing overlap
123
11.
12.
13.
14.
15. 16.
17.
18.
19.
20.
21.
22.
syndrome in childhood: a 16-year prospective study. Hepatology. 2001;33:544–53. Abdalian R, Dhar P, Jhaveri K, Haider M, Guindi M, Heathcote EJ. Prevalence of sclerosing cholangitis in adults with autoimmune hepatitis: evaluating the role of routine magnetic resonance imaging. Hepatology. 2008;47:949–57. Lewin M, Vilgrain V, Ozenne V, Lemoine M, Wendum D, Paradis V, et al. Prevalence of sclerosing cholangitis in adults with autoimmune hepatitis: a prospective magnetic resonance imaging and histological study. Hepatology. 2009;50:528–37. Abdo AA, Bain VG, Kichian K, Lee SS. Evolution of autoimmune hepatitis to primary sclerosing cholangitis: a sequential syndrome. Hepatology. 2002;36:1393–9. Buuren HR, Hoogstraten HJF, Terkivatan T, Schalm SW, Vleggaar FP. High prevalence of autoimmune hepatitis among patients with primary sclerosing cholangitis. J Hepatol. 2000;33: 543–8. Takikawa H, Manabe T. Primary sclerosing cholangitis in Japananalysis of 192 cases. J Gastroenterol. 1997;32:919–35. Takiguchi J, Ohira H, Rai T, Shishido S, Tojo J, Sato Y, et al. Autoimmune hepatitis overlapping with primary sclerosing cholangitis. Intern Med. 2002;41:696–700. Montano-Loza AJ, Carpenter HA, Czaja AJ. Predictive factors for hepatocellular carcinoma in type 1 autoimmune hepatitis. Am J Gastroenterol. 2008;103:1944–51. Burak K, Angulo P, Pasha TM, Egan K, Petz J, Lindor KD. Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis. Am J Gastroenterol. 2004;99:523–6. Prytz H, Keiding S, Bjornsson E. Dynamic FDG-PET is useful for detection of cholangiocarcinoma in patients with PSC listed for liver transplantation. Hepatology. 2006;44:1572–80. Harnois DM, Gores JG, Ludwig J, Steers JL, LaRusso NE, Wiesner RH. Are patients with cirrhotic stage primary sclerosing cholangitis at risk for the development of hepatocellular cancer? J Hepatol. 1997;27:512–6. Leidenius M, Hockersted K, Broome U, Ericzon BG, Friman S, Olauson M, et al. Hepatobiliary carcinoma in primary sclerosing cholangitis: a case control study. J Hepatol. 2001;34:792–8. Maeda C, Tamano M, Murohisa T, Yamagishi T, Hashimoto T, Kojima K, et al. Hepatocellular carcinoma associated with noncirrhotic autoimmune hepatitis. Clin J Gastroenterol. 2010;3: 111–5.
CASE REPORT
Overlap syndrome of autoimmune hepatitis and primary sclerosing cholangitis complicated with hepatocellular carcinoma Kazuto Fukuda • Sachiyo Kogita • Yusuke Tsuchimoto • Yoshiyuki Sawai Takumi Igura • Hideko Ohama • Yuki Makino • Yasushi Matsumoto • Masanori Nakahara • Shin-ichirou Zushi • Yasuharu Imai
•
Received: 18 January 2012 / Accepted: 29 February 2012 / Published online: 7 April 2012 Ó Springer 2012
Abstract Development of hepatocellular carcinoma (HCC) in patients with autoimmune liver disease is less common than in those with other types of chronic liver disease. Here we report a rare case of overlap syndrome consisting of autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC) that was subsequently complicated with HCC. A 72-year-old man was initially diagnosed as being in the cirrhotic stage of AIH on the basis of blood chemistry tests and histological examinations. Computed tomography and magnetic resonance cholangiography 20 months later showed diffuse stricturing of the intrahepatic bile duct with dilatation of the areas between the strictures, compatible with the findings of PSC, which resulted in a diagnosis of AIH/PSC overlap syndrome. The level of serum protein induced by vitamin K absence or antagonist II increased 22 months later, and HCC was diagnosed by radiological examinations. Four cycles of transarterial infusion therapy with cisplatin were performed, but the patient died one year later. Sequential overlap of PSC may have played a part in accelerating AIH disease progression, leading to the development of HCC in this patient. Therefore, HCC surveillance may be important in advanced stages of autoimmune disease, especially in the cirrhotic stage.
K. Fukuda (&) S. Kogita Y. Tsuchimoto Y. Sawai T. Igura H. Ohama Y. Makino Y. Matsumoto M. Nakahara S. Zushi Y. Imai Department of Gastroenterology, Ikeda Municipal Hospital, 3-1-18 Jonan, Ikeda, Osaka 563-8510, Japan e-mail: [email protected]
Keywords Autoimmune hepatitis Primary sclerosing cholangitis Overlap syndrome Hepatocellular carcinoma
Introduction Both autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC) are considered to be autoimmune diseases of the liver. AIH is an idiopathic chronic hepatitis affecting predominantly middle-aged women, and is characterized by liver necroinflammation and the presence of autoantibodies and elevated serum immunoglobulin (Ig) levels [1]. On the other hand, PSC is a chronic disease of the intra- and/or extrahepatic bile ducts characterized by a concentric obliterative fibrosis that leads to bile duct strictures and occurs more frequently in men than in women [2]. These two diseases are typically well categorized by clinical, blood biochemical, and histological features. However, the overlap syndrome, in which patients present with features of both AIH and PSC, has been recently documented, although there is currently no clear definition for this entity [3–5]. The development of hepatocellular carcinoma (HCC) in patients with autoimmune liver disease is considered to be less common than in other chronic liver diseases such as viral hepatitis and alcoholic liver disease. AIH patients have not been identified as a high-risk group, which would mandate surveillance for HCC according to the guidelines of the American Association for the Study of Liver Disease [6]; however, several reports have suggested the potential risk of HCC occurring in these patients, especially in those in the cirrhotic stage [7, 8]. Here we report a case of AIH/PSC overlap syndrome with subsequent development of HCC, which is of interest from the perspective of the mechanism of carcinogenesis in autoimmune liver disease.
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Case report A 72-year-old man was admitted to a local hospital for severe abdominal distension in March 2005. He did not drink alcohol and family history of liver disease was not observed. He had suffered from acute hepatitis of unknown etiology in 1997, but did not undergo a follow-up since that time. A diagnosis of hepatic cirrhosis was made on the basis of laboratory tests and computed tomography (CT). He was administered diuretics and human serum albumin products to decrease the ascites. After being discharged from hospital, the patient visited our department for further examination. Table 1 shows the laboratory data from his first visit. A liver function test revealed the following: serum albumin 1.6 g/dL, bilirubin 2.5 mg/dL, aspartate aminotransferase 66 IU/L, alanine aminotransferase 33 IU/L, prothrombin time 59 %, and platelet count 7.4 9 104/lL; these findings were compatible with a diagnosis of cirrhosis. Tests for hepatitis B virus (HBV) surface antigen and hepatitis C antibodies were negative. HBV-core antibody was detected, but HBV DNA was undetectable in the serum. The level of serum IgG was markedly elevated, and anti-nuclear antibodies were detected. The human leukocyte antigen genotype was DRB1*0405/0901. A percutaneous needle biopsy of the liver showed lymphocytic interface hepatitis and rosette formation, but emperipolesis was not recognized. It also showed bridging fibrosis and pseudo-lobular formation, thereby confirming the diagnosis of cirrhosis. There were no pathological changes of bile ducts, such as loss of bile ducts, ductular proliferation, or periductal fibrosis (Fig. 1). The pretreatment score according to the International Autoimmune Hepatitis Group simplified criteria [9] in this patient was 6 points, corresponding to a probable diagnosis of AIH, and treatment with prednisolone (PSL) (15 mg daily) and ursodeoxycholic acid (UDCA) (600 mg daily) was initiated. Concomitant autoimmune disease was not observed. Endoscopic study of the upper gastrointestinal tract revealed the presence of esophageal varices, and endoscopic variceal ligation therapy was performed. The patient’s liver function gradually improved with PSL and UDCA treatment, and he was in good health until January 2008, when dilatation of the intrahepatic bile duct (IHBD) was detected on routine ultrasonography (US) and CT (Fig. 2). Magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiography (ERC) showed diffuse stricturing of the IHBD with dilatation of the areas between strictures, compatible with the finding of PSC (Fig. 3). Irregularity of the pancreatic duct or diffuse swelling of the pancreas was not detected. Serum levels of IgG4 and anti-nuclear cytoplasmic antibodies were within normal limits. A colonoscopy did not show evidence of
123
Clin J Gastroenterol (2012) 5:183–188 Table 1 Laboratory data of first medical examination WBC
3500/lL
RBC
292 9 104/lL
PT
59.2 %
Hb Ht
10.0 g/dL
IgG
5295 mg/dL
29.2 %
IgM
436 mg/dL
Plt
7.4 9 104/lL
ANA
940
SMA
\920
T. protein
7.9 g/dL
AMA-M2
6 U/mL
Alb
1.6 g/dL
T. bilirubin
2.5 mg/dL
AFP
4.1 ng/mL
D. bilirubin
1.5 mg/dL
PIVKA-II
6 mAU/mL
AST
66 IU/L
CEA
3.8 ng/mL
ALT
33 IU/L
ALP
305 IU/L
HBsAg
(-)
cGTP
19 IU/L
HCVAb
(-)
LDH FPG
196 IU/L 110 mg/dL
HBcAb HBVDNA
(?) \2.6 log copy/mL
BUN
23 mg/dL
Cre
0.96 mg/dL
HLA genotype
DRB1*0405/0901
CRP
0.2 mg/dL
ANA anti-nuclear antibody, SMA anti-smooth muscle antibody, AMA anti-mitochondrial antibody, HLA human leukocyte antigen
ulcerative colitis. The second liver biopsy was performed, which showed significant alleviation of interface hepatitis, but pathological changes of bile ducts were not observed again (Fig. 4). Specific causes of sclerosing cholangitis, such as infection, bile duct stones, or neoplasm, were not identified, and the diagnosis of PSC was made. Since no deterioration of symptoms or laboratory data was observed, the same medications were continued. In December 2009, his serum level of protein induced by vitamin K absence or antagonist II (PIVKA-II) increased to 460 mAU/mL. A dynamic CT scan showed a hypervascular tumor, 25 mm in diameter, in the S8 segment of the liver. CT during hepatic arteriography and CT during arterial portography were performed and the tumor was diagnosed as HCC (Fig. 5). Transarterial infusion therapy (TAI) with cisplatin was performed because of the impaired liver function and the presence of IHBD dilatation. After two cycles of TAI, PIVKA-II levels temporally decreased, but started increasing again from April 2010. CT revealed diffuse progression of tumors in the liver. Another two cycles of TAI were performed, but the patient died in December 2010. An autopsy was not performed.
Discussion Overlap syndrome of autoimmune disease is defined as the concurrent presence of the main characteristics of two
Clin J Gastroenterol (2012) 5:183–188
185
Fig. 1 Percutaneous biopsy samples of liver tissue at May 2005. a H&E staining showed lymphocytic interface hepatitis and rosette formation. b Azan staining showed bridging fibrosis and pseudo-lobular formation
autoimmune conditions at the same time or during the course of the illness. AIH/PSC overlap syndrome is considered to be relatively common in children. In a large pediatric series, half the children with a definitive diagnosis of AIH demonstrated cholangiographic features of PSC at presentation [10]. On the other hand, the prevalence of PSC in adults with AIH is found to a lesser extent. Abdalian et al. [11] reported that magnetic resonance cholangiography (MRC) findings consistent with sclerosing cholangitis (SC) were observed in 10 % of adult AIH patients, suggesting that routine radiological evaluation of the biliary tree should be performed. In contrast, Lewin et al. [12] reported a much lower SC prevalence of 1.7 %. This discrepancy may be due to the differences in diagnostic criteria of SC, stage of disease, and length of follow-up period between the two studies. It has been suggested that AIH and PSC may be sequential in their occurrence, whereby patients have features of AIH and then after a number of years develop features of PSC [13]. Buuren et al. [14] reported on nine (8 %) of 113 PSC patients diagnosed as having overlap syndrome. In their report, four patients initially presented with features of AIH and in five cases PSC was diagnosed first. Compared with Caucasians, the overlap of AIH and PSC in adults is considered to be extremely rare in Japan. This is
probably due to the low prevalence of PSC in Japan. The incidence of PSC in inflammatory bowel disease is also much lower than that reported in Western countries [15]. To the best of our knowledge, there has only been one case report of the overlap of AIH and PSC [16]. In that case, the features of PSC were recognized by ERC one year after the diagnosis of AIH. The levels of biliary enzymes were moderately increased, but histological examination did not show pathological changes of bile ducts. In our case, it was unclear when the features of PSC had appeared. When the diagnosis of AIH was made in 2005, the disease had already progressed to the cirrhotic stage. CT and US did not show features of PSC at that time, but the presence of occult PSC could not be excluded because of a lack of an MRC or ERC study. However, it could be inferred that features of PSC had progressed over a relatively short period, since CT and MRC 3 years after the first visit revealed features typical of PSC. Pathological bile duct changes were not observed in liver biopsy, as in the case report by Takiguchi et al. Recently however, it has been recognized that histological findings of the liver are not required to make a diagnosis of SC if the radiological findings show typical bile duct changes [2]. The levels of serum biliary enzymes fluctuated near the upper limits of normal range throughout the
123
186
Clin J Gastroenterol (2012) 5:183–188
Fig. 2 Portal phase of dynamic CT of the liver in May 2005 (a, b), and in January 2008 (c, d). Development of dilatation of intrahepatic bile ducts in January 2008
Fig. 3 a MRC and b ERC showed diffuse stricturing of intrahepatic bile ducts with dilatation of the areas between strictures
course. Early administration of PSL and UDCA might suppress the elevation, although it could not prevent the progression of bile duct changes. Although the occurrence of HCC in autoimmune liver disease has been considered to be relatively rare, the true
123
incidence remains unknown due to a paucity of data addressing this issue. Montano-Lazo et al. reported that male gender, features of portal hypertension, treatment failure, and immunosuppressive treatment may be important predisposing factors for HCC. They also showed that
Clin J Gastroenterol (2012) 5:183–188
187
Fig. 4 Percutaneous biopsy samples of liver tissue in March 2008. H&E staining showed significant alleviation of interface hepatitis. Bile duct damage was not observed
Fig. 5 a CT during hepatic arteriography showed hypervascular tumor in the S8 segment of the liver. b CT during arterial portography showed a defect in the portal vein supply of the tumor
the presence of cirrhosis in AIH is significantly associated with an increased risk of HCC, which subsequently occurs at a rate of 1.1 % per year [17]. Wong et al. [8] reported in their large cohort study that the overall estimated HCC risk in AIH patients was \0.2 %; however, the prevalence among patients with cirrhosis rose to 1.9 %, comparable to the HCC risk in cirrhosis caused by viral hepatitis. PSC is associated with an increased risk of hepatobiliary carcinoma. Cholangiocarcinoma is the most common malignancy complicating PSC, with a life-time prevalence of approximately 8–30 % [18, 19]. A third of patients who developed cholangiocarcinoma were diagnosed within a year of their PSC diagnosis, suggesting that cholangiocarcinoma is not necessarily a late complication of end-stage PSC. On the other hand, HCC usually complicates advanced-stage PSC. The risk of HCC for PSC patients with cirrhosis has been estimated to be up to 2 % per year [20]. Leidenius et al. [21] reported that varices were more common in PSC patients developing HCC than in PSC patients with other hepatobiliary carcinomas. These reports
suggested that cirrhosis is the sine qua non for HCC development in autoimmune liver disease. However, Maeda et al. [22] recently reported a case of HCC associated with noncirrhotic AIH, suggesting a possible mechanism other than cirrhosis for hepatocarcinogenesis. In the present case, the liver was already in the cirrhotic stage of AIH at the time of the patient’s first visit to our department. Therefore, HCC occurrence may be caused mainly by cirrhosis of AIH. However, the possibility remains that overlap of PSC may have accelerated disease progression, leading to the development of HCC. We could not completely exclude the possibility that ‘occult’ HBV infection may have played a part in HCC development, since the HBV-core antibody was detected in the serum. But we think that progression of liver disease was mainly due to the autoimmune process, considering that HBV DNA was not detected in the serum when hepatitis was prominent. In conclusion, we reported a case of AIH/PSC overlap syndrome complicated with HCC, which leads us to
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believe that HCC surveillance of HCC may be important in advanced stages of autoimmune disease, especially in the cirrhotic stage. Conflict of interest of interest.
The authors declare that they have no conflict
References 1. Czala AL, Manns MP. Advances in the diagnosis, pathogenesis, and management of autoimmune hepatitis. Gastroenterology. 2010;139:58–72. 2. Chapman R, Fevery J, Kalloo A, Nagorney DM, Boberg KM, Shneider B, et al. Diagnosis and management of primary sclerosing cholangitis. Hepatology. 2010;51:660–78. 3. Kaya M, Angulo P, Lindor KD. Overlap of autoimmune hepatitis and primary sclerosing cholangitis: an evaluation of a modified scoring system. J Hepatol. 2000;33:537–42. 4. Floreani A, Rizzotto ER, Ferrara F, Carderi I, Caroli D, Blasone L, et al. Clinical course and outcome of autoimmune hepatitis/ primary sclerosing cholangitis overlap syndrome. Am J Gastroenterol. 2005;100:1516–22. 5. Lu¨th S, Kanzler S, Frenzel C, Kasper HU, Dienes HP, Schramm C, et al. Characteristics and long-term prognosis of the autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome. J Clin Gastroenterol. 2009;43:75–80. 6. Bruix J, Sherman M. AASLD practice guideline. Management of hepatocellular carcinoma: an update. Hepatology. 2011;3:1020–2. 7. Yeoman AD, Al-Chalabi T, Karani JB, Quaglia A, Devlin J, Mieli-Vergani G, et al. Evaluation of risk factors in the development of hepatocellular carcinoma in autoimmune hepatitis: implications for follow-up and screening. Hepatology. 2008;48: 863–70. 8. Wong RJ, Gish R, Frederick T, Bzoweji N, Frenette C. Development of hepatocellular carcinoma in autoimmune hepatitis patients: a case series. Dig Dis Sci. 2011;56:578–85. 9. Hennes EM, Zeniya M, Czaja AJ, Pares A, Dalekos GN, Krawitt EJ, et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology. 2008;48:169–76. 10. Gregorio GV, Portmann B, Karani J, Harrison P, Donaldson PT, Vergani D, et al. Autoimmune hepatitis/sclerosing overlap
123
11.
12.
13.
14.
15. 16.
17.
18.
19.
20.
21.
22.
syndrome in childhood: a 16-year prospective study. Hepatology. 2001;33:544–53. Abdalian R, Dhar P, Jhaveri K, Haider M, Guindi M, Heathcote EJ. Prevalence of sclerosing cholangitis in adults with autoimmune hepatitis: evaluating the role of routine magnetic resonance imaging. Hepatology. 2008;47:949–57. Lewin M, Vilgrain V, Ozenne V, Lemoine M, Wendum D, Paradis V, et al. Prevalence of sclerosing cholangitis in adults with autoimmune hepatitis: a prospective magnetic resonance imaging and histological study. Hepatology. 2009;50:528–37. Abdo AA, Bain VG, Kichian K, Lee SS. Evolution of autoimmune hepatitis to primary sclerosing cholangitis: a sequential syndrome. Hepatology. 2002;36:1393–9. Buuren HR, Hoogstraten HJF, Terkivatan T, Schalm SW, Vleggaar FP. High prevalence of autoimmune hepatitis among patients with primary sclerosing cholangitis. J Hepatol. 2000;33: 543–8. Takikawa H, Manabe T. Primary sclerosing cholangitis in Japananalysis of 192 cases. J Gastroenterol. 1997;32:919–35. Takiguchi J, Ohira H, Rai T, Shishido S, Tojo J, Sato Y, et al. Autoimmune hepatitis overlapping with primary sclerosing cholangitis. Intern Med. 2002;41:696–700. Montano-Loza AJ, Carpenter HA, Czaja AJ. Predictive factors for hepatocellular carcinoma in type 1 autoimmune hepatitis. Am J Gastroenterol. 2008;103:1944–51. Burak K, Angulo P, Pasha TM, Egan K, Petz J, Lindor KD. Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis. Am J Gastroenterol. 2004;99:523–6. Prytz H, Keiding S, Bjornsson E. Dynamic FDG-PET is useful for detection of cholangiocarcinoma in patients with PSC listed for liver transplantation. Hepatology. 2006;44:1572–80. Harnois DM, Gores JG, Ludwig J, Steers JL, LaRusso NE, Wiesner RH. Are patients with cirrhotic stage primary sclerosing cholangitis at risk for the development of hepatocellular cancer? J Hepatol. 1997;27:512–6. Leidenius M, Hockersted K, Broome U, Ericzon BG, Friman S, Olauson M, et al. Hepatobiliary carcinoma in primary sclerosing cholangitis: a case control study. J Hepatol. 2001;34:792–8. Maeda C, Tamano M, Murohisa T, Yamagishi T, Hashimoto T, Kojima K, et al. Hepatocellular carcinoma associated with noncirrhotic autoimmune hepatitis. Clin J Gastroenterol. 2010;3: 111–5.
