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ARTICLE IN PRESS Digestive and Liver Disease xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Short Report
The overlap syndrome between primary biliary cirrhosis and primary sclerosing cholangitis Annarosa Floreani a,∗ , Raffaella Motta b , Nora Cazzagon a , Irene Franceschet a , Massimo Roncalli c , Teresa Del Ross b , Floriano Rosina d , Ana Lleo f , Claudia Mescoli b , Guido Colloredo e , Pietro Invernizzi f a
Department of Surgery, Oncology and Gastroenterology, University of Padova, Italy Department of Medicine, University of Padova, Italy c Pathology Unit, Humanitas Research Hospital & University of Milan Medical School, Italy d Gastroenterologia & Epatologia, Presidio Sanitario Gradenigo, Torino, Italy e Liver Unit, Seriate Hospital, Bergamo, Italy f Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, MI, Italy b
a r t i c l e
i n f o
Article history: Received 28 October 2014 Accepted 4 February 2015 Available online xxx Keywords: Overlap syndrome Primary biliary cirrhosis Primary sclerosing cholangitis
a b s t r a c t Background: The overlap syndrome between primary biliary cirrhosis and primary sclerosing cholangitis is an extremely rare condition that has been reported in only six published cases so far. Methods: Here we report two cases showing the clinical manifestations of both primary biliary cirrhosis and primary sclerosing cholangitis. Results: In one case the overlap condition was associated with psoriatric arthritis, and the patient successfully underwent dual treatment with ursodeoxycholic acid and the anti-tumour necrosis factor-alpha agent adalimumab. In the second case, the predominant condition was, initially, an antimitochondrial antibody-negative primary biliary cirrhosis with progressive course towards end-stage liver disease; the patient then developed either antimitochondrial antibody positivity or changes in the biliary tree compatible with primary sclerosing cholangitis. Conclusions: These two cases add information on a controversial issue in the literature, and indicate the importance of recognizing a possible overlap syndrome to optimize treatment. © 2015 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.
1. Introduction Some patients presenting with an autoimmune liver disease have a phenotype with evidence of two overlapping conditions [1]. In the majority of the cases, the so-called overlap syndromes are between autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) or AIH and primary sclerosing cholangitis (PSC) [2]. Overlap between PBC and PSC has been described in only 6 cases so far [3–7; Supplementary Table S1]. The first reported case was described in a 52-year-old man with AMA positivity, whose cholestatic history started at the age of 44 years. An oral cholecystography was performed when the patient was 51 years old, revealing multiple strictures and dilatations of the intrahepatic
∗ Corresponding author at: Department of Surgery, Oncology and Gastroenterology, Via Giustiniani, 2, 35128 Padova, Italy. Tel.: +39 049 8212894; fax: +39 049 8760820. E-mail address: annarosa.fl[email protected] (A. Floreani).
biliary tree. A liver biopsy showed findings that were non-specific for either PBC or PSC, and the authors thus hypothesized a coexisting PBC and PSC, without excluding biliary carcinoma or drug-induced cholestasis. The second reported case [4] was described in a 40-yearold female with past cholecystectomy and with recurrent bouts of ascending cholangitis. The patient underwent two liver biopsies, of which the first showed results consistent with PBC, and the second revealed the classical onion-skinning fibrosis around medium-sized ducts. Intrahepatic and extrahepatic PSC was well documented by endoscopic retrograde cholangiopancreatography. Kingham and Abbasi [5] reported two cases of overlapping PBC/PSC from a cohort of 261 consecutive patients with autoimmune liver disease followed prospectively over a 20-year period. Jevaagan [6] reported a case of PBC/PSC overlap syndrome in a 64-year-old woman who was diagnosed as having AMA-negative PBC and then had a cholangiography consistent with PSC. The
http://dx.doi.org/10.1016/j.dld.2015.02.002 1590-8658/© 2015 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.
Please cite this article in press as: Floreani A, et al. The overlap syndrome between primary biliary cirrhosis and primary sclerosing cholangitis. Dig Liver Dis (2015), http://dx.doi.org/10.1016/j.dld.2015.02.002
G Model YDLD-2826; No. of Pages 4
ARTICLE IN PRESS
2
A. Floreani et al. / Digestive and Liver Disease xxx (2015) xxx–xxx
Fig. 1. Consecutive sections of core needle biopsy stained by (a) Haematoxylin &Eosin and (b) Cytokeratin 7 showing two expanded portal tracts with porto-septal fibrosis and bile duct loss. Native bile ducts are absent or very lacking as shown by Cytokeratin 7 immunostaining; notice the ductular metaplasia of periportal hepatocytes and ductular reaction (c, a higher magnification from b, arrow); interface hepatitis can also be seen (d, a higher magnification from a, arrow). a, b: ×4, c: ×20, d: ×40.
more recent report in the literature describes a patient with PBC, with normal cholangiography, showing “onion-skin” type periductal fibrosis at liver histology [7]. None of the cases reported in the literature was associated with inflammatory bowel disease (IBD). Moreover, the diagnosis of overlapping was controversial in some cases, mainly due to the insufficient definition of the biliary tree with the new generation imaging techniques, the poor description of extrahepatic manifestations, and the incomplete information on the autoimmune serologic profile. Here we report two cases showing the clinical manifestations of both PBC and PSC.
2. Case 1 A 51-year-old woman presented in April 2012 with persistent abnormal cholestasis enzymes since 2009. Clinical history included a laparoscopic cholecystectomy in 1987 for symptomatic gallstones. In September 2010, a magnetic resonance imaging (MRI) of the upper abdomen revealed a slightly irregular profile of the right hepatic ducts proximal to the insertion with the common bile duct; no intrahepatic bile stones were observed. The patient was started on ursodeoxycholic acid (UDCA) at a dose of 10 mg/kg/day. In September 2011, she also developed a mild psoriasis with 4th right finger dactylitis and arthritis of the 4th right metacarpo-phalangeal joint. Treatment with tapered steroids and oral methotrexate gave poor results. In April 2012, her biochemical tests showed: alkaline phosphatase 201 IU/ml (ULN, 141), gamma-glutamyltransferase (GGT) 229 IU/ml (ULN, 45), AMA positivity (1:160 titre), and an immunoblotting positivity for M2, 3E, and anti-pg210, as well as antinuclear antibody positivity (1:40 titre with speckled pattern), negative ANCA antibodies, normal IgG4 serum levels, total serum cholesterol 240 mg/dL, increased serum IgM (7.31 mg/dL), normal aminotransferases, and negative serum markers for hepatitis B and C. On physical examination, dactylitis of the 4th right finger, as well as swelling, redness, and pain of the distal interphalangeal (DIP) joint of the 2nd right finger were observed. The patient’s body mass index (BMI) was 24.9. In May 2012, a liver biopsy showed marked fibrosis in the portal tracts extending to the parenchyma, interface hepatitis, and a vanishing bile duct picture with the remaining ducts showing regressive alterations of cholangiocytes together with biliary metaplasia (Fig. 1). As histology was compatible with stage III PBC, UDCA
Fig. 2. Magnetic resonance cholangiopancreatography, maximum intensity projection rendering image, showing an ectopic drainage of the common bile duct in the distal part of descending duodenum; marked stenosis of the right antero-inferior segmental duct and the left hepatic duct with upstream dilatation, and multiple segmental irregularity, narrowing and dilatation of intrahepatic bile ducts.
dosage was increased to 15 mg/kg/day; a partial reduction in GGT and alkaline phosphatase followed. In July 2012, the patient underwent an upper abdomen MRI that revealed a marked reduction of the right segmental duct extended for 2.5 cm, with upstream dilatation, and a marked stenosis of the biliary tree in the 5th and 6th hepatic segment with the characteristics of PSC. Colonoscopy was negative for IBD. In October 2012, the patient developed a distal interphalangeal arthritis in the 4th right finger with severe onychodystrophy. After a collegial discussion of the case, treatment with human anti-tumour necrosis factor-alpha (TNF␣) adalimubab (40 mg every other week) was started. The patient reported marked relief in pain and stiffness. After 3 months, the rheumatologic assessment with 4 questionnaires (the Health Assessment Questionnaire, the Disease Activity score, the Clinical Disease Activity Index, and the Simplified Disease Activity Index) indicated disease remission. Liver function tests improved together with a normalization of alkaline phosphatase levels and a decrease in GGT (to 124 IU/L) and IgM (to 5.35 mg/L). In December 2014, a new MRI confirmed the previous changes of the biliary tree (Fig. 2). 3. Case 2 A 60-year-old woman presented in January 2013 for a reevaluation of hepatic cholangitis (possible overlap PBC/PSC). Her relevant medical history included: excision of malignant melanoma in her right arm in 1978, left ovariectomy in 1994, and excision of a frontal meningioma in 2003. In 2000 the patient was diagnosed with arterial hypertension, and in 2010 with type-1 diabetes and subclinical hypothyroidism. Her BMI was 24. Since 1989 the patient was aware of her abnormal cholestasis enzymes; in 1996, she underwent a laparoscopic cholecystectomy for symptomatic gallstones. In 2001, a liver biopsy showed oedematous portal tracts with granulomatous destructive infiltrate compatible with PBC (Fig. 3). The immunologic profile revealed ANA positivity (1:80) and AMA negativity. Since October 2010, the
Please cite this article in press as: Floreani A, et al. The overlap syndrome between primary biliary cirrhosis and primary sclerosing cholangitis. Dig Liver Dis (2015), http://dx.doi.org/10.1016/j.dld.2015.02.002
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Fig. 3. Oedematous portal tract with an injured bile duct (Haematoxylin & Eosin, arrow, ×40) and nearby moderate ductular reaction (Cytokeratin 7, inset, ×4); Oedematous portal tract with a granulomatous destructive inflammatory infiltrate targeting a bile duct (asterisk) Haematoxylin & Eosin ×40.
patient reported pruritus that did not resolve with standard therapy. At that time, a liver ultrasound showed hepatomegaly with a patchy structure without bile duct dilatations or indirect signs of portal hypertension. In October 2011, the patient was evaluated for liver transplant. Serum biochemistry showed: total serum bilirubin 4 mg/dL (conjugated bilirubin 3.5 mg/dL), AST/ALT 77/85 IU/L, GGT 534 IU/L, alkaline phosphatase 621 IU/L (ULN 141 IU/L), albumin 4 g/dL, and INR 0.88; IgG 1248 mg/dL, IgM 121 mg/dL, and IgA 159 mg/dL; finally, serum markers for hepatitis B and C, ANA, ANCA, ASMA, AMA, and LKM were negative. In November 2012, an abdominal MRI revealed bile duct changes with multifocal strictures and segmental dilatation in the left liver and no dilations in the primary biliary ducts (Fig. 4). Upper endoscopy showed no evidence of oesophageal or gastric varices, and colonoscopy was negative for IBD. In January 2013, the patient was asymptomatic for cholestasis. Her biochemical tests showed: total serum bilirubin 2.2 mg/dL,
Fig. 4. Magnetic resonance image showing a focal stenosis of the left hepatic duct towards the hilum with mild upstream dilatation, and minor segmental irregularity of the intrahepatic bile ducts with pruning of more distal branches; a low-grade short stenosis of the common bile duct is also present. An aberrant right posterior duct draining into the common hepatic duct is shown.
alkaline phosphatase 449 IU/L, GGT 475 IU/L, AST/ALT 52/71 IU/L, and INR 0.86. Autoimmunity testing (ELISA assay) revealed: AMA and anti-GP210 positivity, weak anti-SP100 positivity, while antiLKM, anti-SLA, and anti-actin were negative. In March 2013, the total serum bilirubin was slightly increased (2.7 mg/dL) and MELD score was 10. 4. Discussion The overlap syndrome between PBC and PSC is a very rare condition because the two disorders are clearly distinguished by two specific findings: AMA positivity for PBC, and typical cholangiographic changes for PSC [8]. The two cases here reported have been rigorously diagnosed by means of immunological biochemistry, liver biopsy, and MRI cholangiography. Biopsy samples, as well as MRI imaging results, were re-examined by a dedicated pathologist in a blinded fashion. In case #1, the MRIs performed in 2010, 2012, and 2014, allowed ruling out the hypotheses of secondary sclerosing cholangitis (particularly ischaemic and post-surgery cholangitis) [9]. However, the most recent MRI clearly showed the typical changes compatible with PSC involving the intrahepatic biliary tree. Although the patient was asymptomatic for liver disease, we can argue that the two conditions were coincidental, for the long-term history of altered liver function tests. However, the presented case shows several noteworthy points. Firstly, the predominant phenotype was PBC: female gender, middle age, AMA-positive, and compatible liver histology. Similarly to the other cases reported in the literature, we could not find any association with IBD (Supplementary Table S1). However, the real novelty of the present case is the treatment with adalimubab, given for a complex case of autoimmunity. As far as we know, this is the first case of overlap syndrome involving PBC treated with an anti-TNF␣ agent. A single case of PBC associated with rheumatoid arthritis showed an amelioration of liver enzymes and controlled arthritis with TNF␣ blockade (etanercept) plus methylprednisolone, while another anti-TNF␣ treatment (infliximab) was unsuccessful [10]. In case #2, AMA-negative PBC was the predominant phenotype. Twelve years later AMA positivity appeared together with autoantibodies highly specific for PBC, i.e., anti-GP210, and anti-SP100. Thus, we can presume that this was a consecutive form of overlapping, with an onset as PBC and later development of PSC. In conclusion, a review of the literature and the two reported cases contribute to better define the still controversial issue of PBC/PSC overlap, and indicate the importance of correctly recognizing this syndrome for treatment optimization.
Please cite this article in press as: Floreani A, et al. The overlap syndrome between primary biliary cirrhosis and primary sclerosing cholangitis. Dig Liver Dis (2015), http://dx.doi.org/10.1016/j.dld.2015.02.002
G Model YDLD-2826; No. of Pages 4
ARTICLE IN PRESS
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A. Floreani et al. / Digestive and Liver Disease xxx (2015) xxx–xxx
Conflict of interest None declared. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.dld.2015.02.002. References [1] Trivedi PJ, Hirschfield GM. Review article: overlap syndromes and autoimmune liver disease. Alimentary Pharmacology and Therapeutics 2012;36:517–33. [2] Boberg KM, Chapman RW, Hirschfield GM, et al. Overlap syndromes: the international autoimmune hepatitis group (IAIHG) position statement on a controversial issue. Journal of Hepatology 2011;54:374–85. [3] Rubel LR, Seef LB, Patel V. Primary biliary cirrhosis-primary sclerosing cholangitis overlap syndrome. Archives of Pathology and Laboratory Medicine 1984;108:35–6.
[4] Burak KW, Urbanski SJ, Swain MG. A case of coexisting primary biliary cirrhosis and primary sclerosing cholangitis. A new overlap of autoimmune liver diseases. Digestive Diseases and Sciences 2001;46: 2043–7. [5] Kingham JGC, Abbasi A. Co-existence of primary biliary cirrhosis and primary sclerosing cholangitis: a rare overlap syndrome put in perspective. European Journal of Gastroenterology and Hepatology 2005;17:1077–80. [6] Jeevagan A. Overlap of primary biliary cirrhosis and primary sclerosing cholangitis–a rare coincidence or a new syndrome. International Journal of General Medicine 2010;3:143–6. [7] Oliveira EM, Oliveira PM, Becker V, et al. Overlapping of primary biliary cirrhosis and small duct primary sclerosing cholangitis: first case report. Journal of Clinical Medicine Research 2012;4:429–33. [8] Czaja AJ. The overlap syndromes of autoimmune hepatitis. Digestive Diseases and Sciences 2013;58:326–43. [9] Azizi L, Raynal M, Cazejust J, et al. MR imaging of sclerosing cholangitis. Clinics and Research in Hepatology and Gastroenterology 2012;36: 130–8. [10] Spadaro A, Scrivo R, Riccieri V, et al. Effect of tumor necrosis factor alpha antagonists in a patient with rheumatoid arthritis and primary biliary cirrhosis. Joint Bone Spine 2008;75:87–9.
Please cite this article in press as: Floreani A, et al. The overlap syndrome between primary biliary cirrhosis and primary sclerosing cholangitis. Dig Liver Dis (2015), http://dx.doi.org/10.1016/j.dld.2015.02.002
ARTICLE IN PRESS Digestive and Liver Disease xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Short Report
The overlap syndrome between primary biliary cirrhosis and primary sclerosing cholangitis Annarosa Floreani a,∗ , Raffaella Motta b , Nora Cazzagon a , Irene Franceschet a , Massimo Roncalli c , Teresa Del Ross b , Floriano Rosina d , Ana Lleo f , Claudia Mescoli b , Guido Colloredo e , Pietro Invernizzi f a
Department of Surgery, Oncology and Gastroenterology, University of Padova, Italy Department of Medicine, University of Padova, Italy c Pathology Unit, Humanitas Research Hospital & University of Milan Medical School, Italy d Gastroenterologia & Epatologia, Presidio Sanitario Gradenigo, Torino, Italy e Liver Unit, Seriate Hospital, Bergamo, Italy f Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, MI, Italy b
a r t i c l e
i n f o
Article history: Received 28 October 2014 Accepted 4 February 2015 Available online xxx Keywords: Overlap syndrome Primary biliary cirrhosis Primary sclerosing cholangitis
a b s t r a c t Background: The overlap syndrome between primary biliary cirrhosis and primary sclerosing cholangitis is an extremely rare condition that has been reported in only six published cases so far. Methods: Here we report two cases showing the clinical manifestations of both primary biliary cirrhosis and primary sclerosing cholangitis. Results: In one case the overlap condition was associated with psoriatric arthritis, and the patient successfully underwent dual treatment with ursodeoxycholic acid and the anti-tumour necrosis factor-alpha agent adalimumab. In the second case, the predominant condition was, initially, an antimitochondrial antibody-negative primary biliary cirrhosis with progressive course towards end-stage liver disease; the patient then developed either antimitochondrial antibody positivity or changes in the biliary tree compatible with primary sclerosing cholangitis. Conclusions: These two cases add information on a controversial issue in the literature, and indicate the importance of recognizing a possible overlap syndrome to optimize treatment. © 2015 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.
1. Introduction Some patients presenting with an autoimmune liver disease have a phenotype with evidence of two overlapping conditions [1]. In the majority of the cases, the so-called overlap syndromes are between autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) or AIH and primary sclerosing cholangitis (PSC) [2]. Overlap between PBC and PSC has been described in only 6 cases so far [3–7; Supplementary Table S1]. The first reported case was described in a 52-year-old man with AMA positivity, whose cholestatic history started at the age of 44 years. An oral cholecystography was performed when the patient was 51 years old, revealing multiple strictures and dilatations of the intrahepatic
∗ Corresponding author at: Department of Surgery, Oncology and Gastroenterology, Via Giustiniani, 2, 35128 Padova, Italy. Tel.: +39 049 8212894; fax: +39 049 8760820. E-mail address: annarosa.fl[email protected] (A. Floreani).
biliary tree. A liver biopsy showed findings that were non-specific for either PBC or PSC, and the authors thus hypothesized a coexisting PBC and PSC, without excluding biliary carcinoma or drug-induced cholestasis. The second reported case [4] was described in a 40-yearold female with past cholecystectomy and with recurrent bouts of ascending cholangitis. The patient underwent two liver biopsies, of which the first showed results consistent with PBC, and the second revealed the classical onion-skinning fibrosis around medium-sized ducts. Intrahepatic and extrahepatic PSC was well documented by endoscopic retrograde cholangiopancreatography. Kingham and Abbasi [5] reported two cases of overlapping PBC/PSC from a cohort of 261 consecutive patients with autoimmune liver disease followed prospectively over a 20-year period. Jevaagan [6] reported a case of PBC/PSC overlap syndrome in a 64-year-old woman who was diagnosed as having AMA-negative PBC and then had a cholangiography consistent with PSC. The
http://dx.doi.org/10.1016/j.dld.2015.02.002 1590-8658/© 2015 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.
Please cite this article in press as: Floreani A, et al. The overlap syndrome between primary biliary cirrhosis and primary sclerosing cholangitis. Dig Liver Dis (2015), http://dx.doi.org/10.1016/j.dld.2015.02.002
G Model YDLD-2826; No. of Pages 4
ARTICLE IN PRESS
2
A. Floreani et al. / Digestive and Liver Disease xxx (2015) xxx–xxx
Fig. 1. Consecutive sections of core needle biopsy stained by (a) Haematoxylin &Eosin and (b) Cytokeratin 7 showing two expanded portal tracts with porto-septal fibrosis and bile duct loss. Native bile ducts are absent or very lacking as shown by Cytokeratin 7 immunostaining; notice the ductular metaplasia of periportal hepatocytes and ductular reaction (c, a higher magnification from b, arrow); interface hepatitis can also be seen (d, a higher magnification from a, arrow). a, b: ×4, c: ×20, d: ×40.
more recent report in the literature describes a patient with PBC, with normal cholangiography, showing “onion-skin” type periductal fibrosis at liver histology [7]. None of the cases reported in the literature was associated with inflammatory bowel disease (IBD). Moreover, the diagnosis of overlapping was controversial in some cases, mainly due to the insufficient definition of the biliary tree with the new generation imaging techniques, the poor description of extrahepatic manifestations, and the incomplete information on the autoimmune serologic profile. Here we report two cases showing the clinical manifestations of both PBC and PSC.
2. Case 1 A 51-year-old woman presented in April 2012 with persistent abnormal cholestasis enzymes since 2009. Clinical history included a laparoscopic cholecystectomy in 1987 for symptomatic gallstones. In September 2010, a magnetic resonance imaging (MRI) of the upper abdomen revealed a slightly irregular profile of the right hepatic ducts proximal to the insertion with the common bile duct; no intrahepatic bile stones were observed. The patient was started on ursodeoxycholic acid (UDCA) at a dose of 10 mg/kg/day. In September 2011, she also developed a mild psoriasis with 4th right finger dactylitis and arthritis of the 4th right metacarpo-phalangeal joint. Treatment with tapered steroids and oral methotrexate gave poor results. In April 2012, her biochemical tests showed: alkaline phosphatase 201 IU/ml (ULN, 141), gamma-glutamyltransferase (GGT) 229 IU/ml (ULN, 45), AMA positivity (1:160 titre), and an immunoblotting positivity for M2, 3E, and anti-pg210, as well as antinuclear antibody positivity (1:40 titre with speckled pattern), negative ANCA antibodies, normal IgG4 serum levels, total serum cholesterol 240 mg/dL, increased serum IgM (7.31 mg/dL), normal aminotransferases, and negative serum markers for hepatitis B and C. On physical examination, dactylitis of the 4th right finger, as well as swelling, redness, and pain of the distal interphalangeal (DIP) joint of the 2nd right finger were observed. The patient’s body mass index (BMI) was 24.9. In May 2012, a liver biopsy showed marked fibrosis in the portal tracts extending to the parenchyma, interface hepatitis, and a vanishing bile duct picture with the remaining ducts showing regressive alterations of cholangiocytes together with biliary metaplasia (Fig. 1). As histology was compatible with stage III PBC, UDCA
Fig. 2. Magnetic resonance cholangiopancreatography, maximum intensity projection rendering image, showing an ectopic drainage of the common bile duct in the distal part of descending duodenum; marked stenosis of the right antero-inferior segmental duct and the left hepatic duct with upstream dilatation, and multiple segmental irregularity, narrowing and dilatation of intrahepatic bile ducts.
dosage was increased to 15 mg/kg/day; a partial reduction in GGT and alkaline phosphatase followed. In July 2012, the patient underwent an upper abdomen MRI that revealed a marked reduction of the right segmental duct extended for 2.5 cm, with upstream dilatation, and a marked stenosis of the biliary tree in the 5th and 6th hepatic segment with the characteristics of PSC. Colonoscopy was negative for IBD. In October 2012, the patient developed a distal interphalangeal arthritis in the 4th right finger with severe onychodystrophy. After a collegial discussion of the case, treatment with human anti-tumour necrosis factor-alpha (TNF␣) adalimubab (40 mg every other week) was started. The patient reported marked relief in pain and stiffness. After 3 months, the rheumatologic assessment with 4 questionnaires (the Health Assessment Questionnaire, the Disease Activity score, the Clinical Disease Activity Index, and the Simplified Disease Activity Index) indicated disease remission. Liver function tests improved together with a normalization of alkaline phosphatase levels and a decrease in GGT (to 124 IU/L) and IgM (to 5.35 mg/L). In December 2014, a new MRI confirmed the previous changes of the biliary tree (Fig. 2). 3. Case 2 A 60-year-old woman presented in January 2013 for a reevaluation of hepatic cholangitis (possible overlap PBC/PSC). Her relevant medical history included: excision of malignant melanoma in her right arm in 1978, left ovariectomy in 1994, and excision of a frontal meningioma in 2003. In 2000 the patient was diagnosed with arterial hypertension, and in 2010 with type-1 diabetes and subclinical hypothyroidism. Her BMI was 24. Since 1989 the patient was aware of her abnormal cholestasis enzymes; in 1996, she underwent a laparoscopic cholecystectomy for symptomatic gallstones. In 2001, a liver biopsy showed oedematous portal tracts with granulomatous destructive infiltrate compatible with PBC (Fig. 3). The immunologic profile revealed ANA positivity (1:80) and AMA negativity. Since October 2010, the
Please cite this article in press as: Floreani A, et al. The overlap syndrome between primary biliary cirrhosis and primary sclerosing cholangitis. Dig Liver Dis (2015), http://dx.doi.org/10.1016/j.dld.2015.02.002
G Model YDLD-2826; No. of Pages 4
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3
Fig. 3. Oedematous portal tract with an injured bile duct (Haematoxylin & Eosin, arrow, ×40) and nearby moderate ductular reaction (Cytokeratin 7, inset, ×4); Oedematous portal tract with a granulomatous destructive inflammatory infiltrate targeting a bile duct (asterisk) Haematoxylin & Eosin ×40.
patient reported pruritus that did not resolve with standard therapy. At that time, a liver ultrasound showed hepatomegaly with a patchy structure without bile duct dilatations or indirect signs of portal hypertension. In October 2011, the patient was evaluated for liver transplant. Serum biochemistry showed: total serum bilirubin 4 mg/dL (conjugated bilirubin 3.5 mg/dL), AST/ALT 77/85 IU/L, GGT 534 IU/L, alkaline phosphatase 621 IU/L (ULN 141 IU/L), albumin 4 g/dL, and INR 0.88; IgG 1248 mg/dL, IgM 121 mg/dL, and IgA 159 mg/dL; finally, serum markers for hepatitis B and C, ANA, ANCA, ASMA, AMA, and LKM were negative. In November 2012, an abdominal MRI revealed bile duct changes with multifocal strictures and segmental dilatation in the left liver and no dilations in the primary biliary ducts (Fig. 4). Upper endoscopy showed no evidence of oesophageal or gastric varices, and colonoscopy was negative for IBD. In January 2013, the patient was asymptomatic for cholestasis. Her biochemical tests showed: total serum bilirubin 2.2 mg/dL,
Fig. 4. Magnetic resonance image showing a focal stenosis of the left hepatic duct towards the hilum with mild upstream dilatation, and minor segmental irregularity of the intrahepatic bile ducts with pruning of more distal branches; a low-grade short stenosis of the common bile duct is also present. An aberrant right posterior duct draining into the common hepatic duct is shown.
alkaline phosphatase 449 IU/L, GGT 475 IU/L, AST/ALT 52/71 IU/L, and INR 0.86. Autoimmunity testing (ELISA assay) revealed: AMA and anti-GP210 positivity, weak anti-SP100 positivity, while antiLKM, anti-SLA, and anti-actin were negative. In March 2013, the total serum bilirubin was slightly increased (2.7 mg/dL) and MELD score was 10. 4. Discussion The overlap syndrome between PBC and PSC is a very rare condition because the two disorders are clearly distinguished by two specific findings: AMA positivity for PBC, and typical cholangiographic changes for PSC [8]. The two cases here reported have been rigorously diagnosed by means of immunological biochemistry, liver biopsy, and MRI cholangiography. Biopsy samples, as well as MRI imaging results, were re-examined by a dedicated pathologist in a blinded fashion. In case #1, the MRIs performed in 2010, 2012, and 2014, allowed ruling out the hypotheses of secondary sclerosing cholangitis (particularly ischaemic and post-surgery cholangitis) [9]. However, the most recent MRI clearly showed the typical changes compatible with PSC involving the intrahepatic biliary tree. Although the patient was asymptomatic for liver disease, we can argue that the two conditions were coincidental, for the long-term history of altered liver function tests. However, the presented case shows several noteworthy points. Firstly, the predominant phenotype was PBC: female gender, middle age, AMA-positive, and compatible liver histology. Similarly to the other cases reported in the literature, we could not find any association with IBD (Supplementary Table S1). However, the real novelty of the present case is the treatment with adalimubab, given for a complex case of autoimmunity. As far as we know, this is the first case of overlap syndrome involving PBC treated with an anti-TNF␣ agent. A single case of PBC associated with rheumatoid arthritis showed an amelioration of liver enzymes and controlled arthritis with TNF␣ blockade (etanercept) plus methylprednisolone, while another anti-TNF␣ treatment (infliximab) was unsuccessful [10]. In case #2, AMA-negative PBC was the predominant phenotype. Twelve years later AMA positivity appeared together with autoantibodies highly specific for PBC, i.e., anti-GP210, and anti-SP100. Thus, we can presume that this was a consecutive form of overlapping, with an onset as PBC and later development of PSC. In conclusion, a review of the literature and the two reported cases contribute to better define the still controversial issue of PBC/PSC overlap, and indicate the importance of correctly recognizing this syndrome for treatment optimization.
Please cite this article in press as: Floreani A, et al. The overlap syndrome between primary biliary cirrhosis and primary sclerosing cholangitis. Dig Liver Dis (2015), http://dx.doi.org/10.1016/j.dld.2015.02.002
G Model YDLD-2826; No. of Pages 4
ARTICLE IN PRESS
4
A. Floreani et al. / Digestive and Liver Disease xxx (2015) xxx–xxx
Conflict of interest None declared. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.dld.2015.02.002. References [1] Trivedi PJ, Hirschfield GM. Review article: overlap syndromes and autoimmune liver disease. Alimentary Pharmacology and Therapeutics 2012;36:517–33. [2] Boberg KM, Chapman RW, Hirschfield GM, et al. Overlap syndromes: the international autoimmune hepatitis group (IAIHG) position statement on a controversial issue. Journal of Hepatology 2011;54:374–85. [3] Rubel LR, Seef LB, Patel V. Primary biliary cirrhosis-primary sclerosing cholangitis overlap syndrome. Archives of Pathology and Laboratory Medicine 1984;108:35–6.
[4] Burak KW, Urbanski SJ, Swain MG. A case of coexisting primary biliary cirrhosis and primary sclerosing cholangitis. A new overlap of autoimmune liver diseases. Digestive Diseases and Sciences 2001;46: 2043–7. [5] Kingham JGC, Abbasi A. Co-existence of primary biliary cirrhosis and primary sclerosing cholangitis: a rare overlap syndrome put in perspective. European Journal of Gastroenterology and Hepatology 2005;17:1077–80. [6] Jeevagan A. Overlap of primary biliary cirrhosis and primary sclerosing cholangitis–a rare coincidence or a new syndrome. International Journal of General Medicine 2010;3:143–6. [7] Oliveira EM, Oliveira PM, Becker V, et al. Overlapping of primary biliary cirrhosis and small duct primary sclerosing cholangitis: first case report. Journal of Clinical Medicine Research 2012;4:429–33. [8] Czaja AJ. The overlap syndromes of autoimmune hepatitis. Digestive Diseases and Sciences 2013;58:326–43. [9] Azizi L, Raynal M, Cazejust J, et al. MR imaging of sclerosing cholangitis. Clinics and Research in Hepatology and Gastroenterology 2012;36: 130–8. [10] Spadaro A, Scrivo R, Riccieri V, et al. Effect of tumor necrosis factor alpha antagonists in a patient with rheumatoid arthritis and primary biliary cirrhosis. Joint Bone Spine 2008;75:87–9.
Please cite this article in press as: Floreani A, et al. The overlap syndrome between primary biliary cirrhosis and primary sclerosing cholangitis. Dig Liver Dis (2015), http://dx.doi.org/10.1016/j.dld.2015.02.002
