Dig Dis Sci (2014) 59:2831–2835 DOI 10.1007/s10620-014-3216-1
CASE REPORT
Co-occurrence of Idiopathic Granulomatous Hepatitis and Primary Biliary Cirrhosis Sonali Paul • Golrokh Javid Sepehr Barbara Weinstein • Jatin Roper
•
Received: 22 October 2013 / Accepted: 12 May 2014 / Published online: 10 August 2014 Ó Springer Science+Business Media New York 2014
Abstract Background PBC is an autoimmune disease affecting the bile ducts. Granulomas can be found in portal triads in 45 % of patients with PBC. Idiopathic granulomatous hepatitis is a rare disease of unknown cause which is characterized by recurrent fevers, sweats, elevated levels of liver enzyme tests, particularly the serum alkaline phosphatase, and granulomas in the portal and lobular regions of the liver. Previous literature suggests that a diagnosis of idiopathic granulomatous hepatitis can be made only if PBC has been excluded. Study We reviewed instances in which PBC and idiopathic granulomatous hepatitis occurred in the same patient. Results We report three patients in whom both diseases occurred: 1) A patient with PBC who was diagnosed 15 years later with idiopathic granulomatous hepatitis; 2) A patient with idiopathic granulomatous hepatitis who developed PBC 12 years later; and 3) A patient who had
S. Paul (&) J. Roper (&) Division of Gastroenterology and Hepatology, Tufts Medical Center, 800 Washington Street, Box #233, Boston, MA 02111, USA e-mail: [email protected] J. Roper e-mail: [email protected] G. J. Sepehr Division of Pathology, Brigham and Women’s Hospital, Tufts Medical Center, 75 Francis Street, Boston, MA 02115, USA e-mail: [email protected] B. Weinstein Division of Pathology, Tufts Medical Center, 800 Washington Street, Box #115, Boston, MA 02111, USA e-mail: [email protected]
features of both idiopathic granulomatous hepatitis and PBC at the time of initial diagnosis. Conclusions Our experience with these patients suggests that idiopathic granulomatous hepatitis and PBC can occur in the same individual. Knowing this association is important, as clinical deterioration in a patient with either disease could suggest the presence of the other and should be treated accordingly. Keywords Primary biliary cirrhosis Idiopathic granulomatous hepatitis Liver granuloma Alkaline phosphatase
Introduction Primary biliary cirrhosis (PBC) is a cholestatic liver disease characterized by pruritus, elevated serum alkaline phosphatase levels, positive anti-mitochondrial antibody, and progressive bile duct destruction. PBC is considered to be a model autoimmune disease in which mitochondrial antigens found in the apical region of bile duct epithelial cells are recognized as ‘‘foreign’’ and targeted by activated T lymphocytes. Granulomas are found exclusively in the portal triads in up to 45 % of patients with PBC [1]. Hepatic granulomas are not exclusive to PBC and can be seen in other autoimmune diseases, drug-induced liver injury, and several infections. Idiopathic granulomatous hepatitis is a rare condition of unknown etiology characterized by recurrent fevers, hepatomegaly, and elevated liver function tests (LFTs), particularly the serum alkaline phosphatase. Unlike PBC, granulomas are seen in both the portal and lobular regions of the liver in idiopathic granulomatous hepatitis [2]. A relationship between PBC and idiopathic granulomatous hepatitis has not been reported.
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Fig. 1 Idiopathic granulomatous hepatitis in a patient with PBC. a Chronic nonsuppurative cholangitis with peri-ductal granuloma (trichrome stain, 940). b Lobular granuloma with giant cells
(trichrome stain, 940). c Portal tract showing minimal fibrosis with preserved ducts (trichrome stain, 940). d Trichrome stain, low-power image (94)
Previous literature suggests that a diagnosis of idiopathic granulomatous hepatitis can only be made once PBC has been excluded [3–7]. We describe three cases in which clinical and histological evidence suggest the diagnosis of both PBC and idiopathic granulomatous hepatitis in the same patient. None of these cases have been previously published.
abnormal, with AST 58 IU/L, ALT 83 IU/L, alkaline phosphatase 313 IU/L, and total bilirubin 1.3 mg/dL. Liver biopsy showed numerous granulomas with giant cells throughout the liver lobule with large central areas of necrosis and intense inflammation (Fig. 1b). Acid fast and GMS stains were negative for mycobacteria and fungi. An extensive infectious workup was negative for viruses (including hepatitis A, B, and C, CMV, and EBV) and parasites (including toxoplasmosis and schistosomiasis). A diagnosis of idiopathic granulomatous hepatitis was made. The methotrexate dose was increased to 22.5 mg/week. Her symptoms resolved, LFTs normalized, and a repeat liver biopsy was essentially normal (Fig. 1c). She was last seen in follow-up in 2006 and was asymptomatic, without fevers, pruritus, or fatigue. She remains on methotrexate 15 mg daily and her LFTs remain normal.
Case 1 A 42-year-old woman with a history of vitiligo but otherwise asymptomatic presented with an elevated alkaline phosphatase, 343 IU (normal \130), abnormal AST and ALT of 54 and 63 IU/L, respectively, but normal total bilirubin and albumin. She had a normal WBC of 4.7 9 103/mm3 with 20 % peripheral eosinophilia on the differential. Further studies revealed a positive anti-mitochondrial antibody (1:640). A liver biopsy in 1989 demonstrated florid bile duct lesions with minimal fibrosis, consistent with Stage II PBC (Fig. 1a). She was treated with methotrexate 15 mg weekly (ursodiol was unavailable at the time). Six months later, her alkaline phosphatase normalized to 75 IU, as did her AST and ALT. She continued methotrexate with three normal liver biopsies in the next 10 years. In 2004, 15 years after her PBC diagnosis, the patient presented with 1 week of fevers, chills, and night sweats. She had no pruritus. Her LFTs were again
123
Case 2 A 42-year-old female with a history of hypothyroidism was referred for an elevated alkaline phosphatase level of 149 IU/L. She had chronic fatigue but no fevers or pruritus. Her other LFTs and albumin were normal. A GGT level was not assessed during her initial workup. An anti-mitochondrial antibody was negative. A liver biopsy in 1996 showed granulomatous inflammation of the portal tracts. An infectious workup was negative, and there was no
Dig Dis Sci (2014) 59:2831–2835
2833
Fig. 2 PBC in a patient with idiopathic granulomatous hepatitis. a Chronic nonsuppurative cholangitis with peri-ductal granuloma (H&E stain, 940). b Lobular granuloma with giant cells (H&E stain, 940). c H&E stain, low-power image (94)
evidence of sarcoidosis. The biopsy was thought to be consistent with idiopathic granulomatous hepatitis. She was treated with oral methotrexate. Her alkaline phosphatase normalized, and liver biopsies 2 and 7 years later showed only minor, nonspecific changes. In 2008, 12 years after her initial diagnosis, the patient’s alkaline phosphatase level increased to 284 IU/L, AST 45 IU/L, ALT 37 IU/L and total bilirubin 0.3 mg/dL. She also had a strongly positive anti-mitochondrial antibody (113.2 units by ELISA; normal \20). Liver biopsy showed bile duct inflammation and occasional bridging fibrosis, consistent with a diagnosis of Stage II–III PBC, and occasional lobular granulomas (Fig. 2a, b). Ursodiol therapy was initiated (13–15 mg/kg body weight). At last follow-up in 2014, she continues to be asymptomatic, with normalization of her LFTs, on a regimen of methotrexate and ursodiol. Case 3 A 45 year-old woman with a history of Hashimoto’s thyroiditis on levothyroxine presented with shoulder pain and was incidentally found to have elevated LFTs: AST 80 IU/ L, ALT 60 IU/L, alkaline phosphatase 115 IU/L, and a positive anti-mitochondrial antibody (titer 1:80). She had no fatigue, fevers, or pruritus. A liver biopsy in 1971 revealed a mixed inflammatory infiltrate in the portal tracts with lymphocytes, plasma cells, and several large noncaseating granulomas without giant cells (Fig. 3a, b). Purified protein derivative (PPD), histoplasmin, and coccidiomycosis skin tests were negative. A chest radiograph was normal. The liver biopsy findings were most consistent with granulomatous hepatitis. The patient was treated with
prednisone 10 mg daily for 6 years. Her LFTs returned to normal. Repeat liver biopsy in 1977 demonstrated less inflammation in the portal triads but persistent granulomas. In 1981, 10 years after her initial presentation, her serum alkaline phosphatase level increased to 1,195 IU/L. A repeat liver biopsy then showed increased peri-portal granulomatous inflammation, decreased number of bile ducts, and portal fibrosis (Fig. 3c). Given her elevated alkaline phosphatase and persistent granulomas despite prednisone therapy, the biopsy findings were considered to be most consistent with PBC. She was treated with colchicine 0.6 mg twice daily as part of a clinical trial (ursodiol was unavailable at that time). Two years later, the patient presented with fatigue and extreme weakness. Her symptoms completely resolved with prednisone, 7.5 mg daily. A repeat liver biopsy 1 year later showed bridging fibrosis and increased peri-portal inflammation. The patient eventually died of mycoplasma avium complex (MAC) pneumonia and sepsis.
Discussion Granulomas are collections of multinucleated giant cells with a surrounding rim of lymphocytes and fibroblasts. They represent a delayed-type hypersensitivity reaction to antigenic stimulation. Hepatic granulomas have been reported in 1–15 % of randomly selected liver biopsies in patients with PBC, sarcoidosis, and tuberculosis, and these diseases account for [75 % of cases of hepatic granuloma [6, 8–14]. Once seen on biopsy, an extensive search for other autoimmune and infectious causes should be
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Fig. 3 Overlap of idiopathic granulomatous hepatitis and PBC. a Chronic nonsuppurative cholangitis with peri-ductal granuloma (trichrome stain, 940). b Lobular granuloma (trichrome stain, 920).
c Chronic nonsuppurative cholangitis with peri-ductal granuloma (trichrome stain, 920). d Trichrome stain, low-power image (94)
performed [3, 14–16]. In a report of 442 patients with hepatic granulomas, a definitive diagnosis could not be established in 36 % of cases [16]. Older studies cite an idiopathic etiology in 10 % of cases [14, 16]. Granulomas in PBC are typically located in the periportal region of the liver and not in the parenchyma, as they are in idiopathic granulomatous hepatitis [2]. A case series in 1973 found that approximately 50 % of patients with idiopathic liver granulomas were diagnosed with idiopathic granulomatous hepatitis [17]. The report also demonstrated that prednisone is an effective treatment [17]. In a series of seven patients with idiopathic granulomatous hepatitis at our hospital who were refractory to prednisone or who developed severe side effects from steroid use, low-dose methotrexate (0.25 mg/kg weekly) successfully resolved fever, fatigue, and weight loss and improved liver histology [18]. Cyclophosphamide and infliximab have also been used successfully in resistant cases [19, 20]. Our first patient met the criteria for PBC at the time of her presentation [2]. She subsequently had fevers, elevation in alkaline phosphatase levels, and granulomas in the liver lobule 15 years later. An extensive workup for infectious etiologies was negative. The diagnosis most consistent with these findings was idiopathic granulomatous hepatitis. She had a rapid response to treatment with methotrexate. Our second patient had idiopathic granulomatous hepatitis at the time of her initial presentation with a complete response to treatment with methotrexate. Twelve years later, her serum alkaline phosphatase levels increased while
on the same dose of methotrexate and a repeat liver biopsy showed classical histological features of PBC; she responded well to the addition of ursodiol. In our third patient, idiopathic granulomatous hepatitis and PBC occurred together over a 10-year period. Her symptoms of fatigue and weakness responded to low-dose prednisone, but her disease progressed despite treatment. MAC infection is unlikely to have caused her granulomatous disease, as the infection developed almost 16 years after initial granuloma formation. It is important to note that Cases 1 and 3 had concurrent PBC and idiopathic granulomatous hepatitis and were treated with methotrexate but not ursodiol, as it was unavailable at the time. Ursodiol may influence the natural course of PBC patients who are treated with methotrexate alone at presentation [21]. The treatment of PBC with methotrexate without ursodiol has been reported previously in a report of two cases [22]. Cases 1 and 3 in our series add to this literature. Methotrexate, alone or in combination with ursodiol, has been used in patients with intense inflammation and granulomas in the portal triads to achieve disease remission [23]. Our experience suggests that idiopathic granulomatous hepatitis and PBC can occur in the same individual, either concurrently or at separate time points. PBC can also cooccur with other immune-mediated liver diseases such as autoimmune hepatitis [24]. Further studies should explore the possibility that similar immune mechanisms are involved in the pathogenesis of PBC, idiopathic
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granulomatous hepatitis, and autoimmune hepatitis. Our findings suggest that physicians should be aware of a possible link between PBC and idiopathic granulomatous, as clinical deterioration in a patient with either disease could suggest the presence of the other and should be treated accordingly. First line therapy for PBC is ursodiol (13–15 mg/kg body weight/day) while prednisone or methotrexate is used in idiopathic granulomatous hepatitis.
Conclusion Patients with PBC and granulomas in the lobular region of the liver may have co-existing idiopathic granulomatous hepatitis. This novel association has important clinical implications in the management of these patients. Acknowledgments J. Roper is supported by the Fellowship to Faculty Transition Award (American Gastroenterological Association Foundation) and S. Paul by the Bristol-Myers Squibb Virology Fellows Research Training Program. The authors wish to thank Dr. Marshall M. Kaplan, a dedicated physician, educator, and mentor who influenced the lives of countless patients and trainees at New England Medical Center (now Tufts Medical Center). He followed the patients in this case series through their clinical course and contributed substantially to this manuscript. He is and will continue to be dearly missed. Conflict of interest
None.
References 1. Kaplan MM, Gershwin ME. Primary biliary cirrhosis. N Engl J Med. 2005;353:1261–1273. 2. Hughes M, Fox H. A histological analysis of granulomatous hepatitis. J Clin Pathol. 1972;25:817–820. 3. Anderson CS, Nicholls J, Rowland R, LaBrooy JT. Hepatic granulomas: a 15-year experience in the Royal Adelaide Hospital. Med J Aust. 1988;148:71–74. 4. Geramizadeh B, Jahangiri R, Moradi E. Causes of hepatic granuloma: a 12-year single center experience from southern Iran. Arch Iran Med. 2011;14:288–289. 5. Lagana SM, Moreira RK, Lefkowitch JH. Hepatic granulomas: pathogenesis and differential diagnosis. Clin Liver Dis. 2010;14: 605–617. 6. McCluggage WG, Sloan JM. Hepatic granulomas in Northern Ireland: a thirteen year review. Histopathology. 1994;25:219–228. 7. Turhan N, Kurt M, Ozderin YO, Kurt OK. Hepatic granulomas: a clinicopathologic analysis of 86 cases. Pathol Res Pract. 2011; 207:359–365.
2835 8. Wagoner GP, Anton AT, Gall EA, Schiff L. Needle biopsy of the liver. VIII. Experiences with hepatic granulomas. Gastroenterology. 1953;25:487–494. 9. Guckian JC, Perry JE. Granulomatous hepatitis. An analysis of 63 cases and review of the literature. Ann Intern Med. 1966;65: 1081–1100. 10. Sartin JS, Walker RC. Granulomatous hepatitis: a retrospective review of 88 cases at the Mayo Clinic. Mayo Clin Proc. 1991; 66:914–918. 11. Cunnigham D, Mills PR, Quigley EM, et al. Hepatic granulomas: experience over a 10-year period in the West of Scotland. Q J Med. 1982;51:162–170. 12. Satti MB, Al-Freihi H, Ibrahim EM, et al. Hepatic granuloma in Saudi Arabia: a clinicopathological study of 59 cases. Am J Gastroenterol. 1990;85:669–674. 13. Mir-Madjlessi SH, Farmer RG, Hawk WA. Granulomatous hepatitis. A review of 50 cases. Am J Gastroenterol. 1973;60: 122–134. 14. Neville E, Piyasena KHG, James DG. Granulomas of the liver. Postgrad Med J. 1975;51:361–365. 15. Gaya DR, Thorburn D, Oien KA, Morris AJ, Stanley AJ. Hepatic granulomas: a 10 year single centre experience. J Clin Pathol. 2003;56:850–853. 16. Drebber U, Kasper H-U, Ratering J, Wedemeyer I, et al. Hepatic granulomas: histological and molecular pathological approach to differential diagnosis—a study of 442 cases. Liver Int. 2008;28: 828–834. 17. Simon HB, Wolff SM. Granulomatous hepatitis and prolonged fever of unknown origin: a study of 13 patients. Medicine (Baltim). 1973;52:1–21. 18. Knox TA, Kaplan MM, Gelfand JA, Wolff SM. Methotrexate treatment of idiopathic granulomatous hepatitis. Ann Intern Med. 1995;15:592–595. 19. Kapoor SR, Snowden N. The use of infliximab in a patient with idiopathic granulomatous hepatitis. BMJ Case Rep. 2009. doi:10. 1136/bcr.06.2008.0319. 20. Longstreth GF, Bender RA. Cyclophosphamide therapy of idiopathic hepatic granulomatosis. Dig Dis Sci. 1989;34:1615–1616. 21. Leung JL, Bonis PA, Kaplan MM. Colchicine or methotrexate, with ursodiol, are effective after 20 years in a subset of patients with primary biliary cirrhosis. Clin Gastroenterol Hepatol. 2011;9:776–780. 22. Kaplan MM, Knox TA, Arora SA. Primary biliary cirrhosis treated with low-dose oral pulse methotrexate. Ann Intern Med. 1988;109:429–431. 23. Kaplan MM. The use of methotrexate, colchicine, and other immunomodulatory drugs in the treatment of primary biliary cirrhosis. Semin Liver Dis. 1997;17:129–136. 24. Joshi S, Cauch-Dudek K, Wanless IR, et al. Primary biliary cirrhosis with additional features of autoimmune hepatitis: response to therapy with ursodeoxycholic acid. Hepatology. 2002;35: 409–413.
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CASE REPORT
Co-occurrence of Idiopathic Granulomatous Hepatitis and Primary Biliary Cirrhosis Sonali Paul • Golrokh Javid Sepehr Barbara Weinstein • Jatin Roper
•
Received: 22 October 2013 / Accepted: 12 May 2014 / Published online: 10 August 2014 Ó Springer Science+Business Media New York 2014
Abstract Background PBC is an autoimmune disease affecting the bile ducts. Granulomas can be found in portal triads in 45 % of patients with PBC. Idiopathic granulomatous hepatitis is a rare disease of unknown cause which is characterized by recurrent fevers, sweats, elevated levels of liver enzyme tests, particularly the serum alkaline phosphatase, and granulomas in the portal and lobular regions of the liver. Previous literature suggests that a diagnosis of idiopathic granulomatous hepatitis can be made only if PBC has been excluded. Study We reviewed instances in which PBC and idiopathic granulomatous hepatitis occurred in the same patient. Results We report three patients in whom both diseases occurred: 1) A patient with PBC who was diagnosed 15 years later with idiopathic granulomatous hepatitis; 2) A patient with idiopathic granulomatous hepatitis who developed PBC 12 years later; and 3) A patient who had
S. Paul (&) J. Roper (&) Division of Gastroenterology and Hepatology, Tufts Medical Center, 800 Washington Street, Box #233, Boston, MA 02111, USA e-mail: [email protected] J. Roper e-mail: [email protected] G. J. Sepehr Division of Pathology, Brigham and Women’s Hospital, Tufts Medical Center, 75 Francis Street, Boston, MA 02115, USA e-mail: [email protected] B. Weinstein Division of Pathology, Tufts Medical Center, 800 Washington Street, Box #115, Boston, MA 02111, USA e-mail: [email protected]
features of both idiopathic granulomatous hepatitis and PBC at the time of initial diagnosis. Conclusions Our experience with these patients suggests that idiopathic granulomatous hepatitis and PBC can occur in the same individual. Knowing this association is important, as clinical deterioration in a patient with either disease could suggest the presence of the other and should be treated accordingly. Keywords Primary biliary cirrhosis Idiopathic granulomatous hepatitis Liver granuloma Alkaline phosphatase
Introduction Primary biliary cirrhosis (PBC) is a cholestatic liver disease characterized by pruritus, elevated serum alkaline phosphatase levels, positive anti-mitochondrial antibody, and progressive bile duct destruction. PBC is considered to be a model autoimmune disease in which mitochondrial antigens found in the apical region of bile duct epithelial cells are recognized as ‘‘foreign’’ and targeted by activated T lymphocytes. Granulomas are found exclusively in the portal triads in up to 45 % of patients with PBC [1]. Hepatic granulomas are not exclusive to PBC and can be seen in other autoimmune diseases, drug-induced liver injury, and several infections. Idiopathic granulomatous hepatitis is a rare condition of unknown etiology characterized by recurrent fevers, hepatomegaly, and elevated liver function tests (LFTs), particularly the serum alkaline phosphatase. Unlike PBC, granulomas are seen in both the portal and lobular regions of the liver in idiopathic granulomatous hepatitis [2]. A relationship between PBC and idiopathic granulomatous hepatitis has not been reported.
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Fig. 1 Idiopathic granulomatous hepatitis in a patient with PBC. a Chronic nonsuppurative cholangitis with peri-ductal granuloma (trichrome stain, 940). b Lobular granuloma with giant cells
(trichrome stain, 940). c Portal tract showing minimal fibrosis with preserved ducts (trichrome stain, 940). d Trichrome stain, low-power image (94)
Previous literature suggests that a diagnosis of idiopathic granulomatous hepatitis can only be made once PBC has been excluded [3–7]. We describe three cases in which clinical and histological evidence suggest the diagnosis of both PBC and idiopathic granulomatous hepatitis in the same patient. None of these cases have been previously published.
abnormal, with AST 58 IU/L, ALT 83 IU/L, alkaline phosphatase 313 IU/L, and total bilirubin 1.3 mg/dL. Liver biopsy showed numerous granulomas with giant cells throughout the liver lobule with large central areas of necrosis and intense inflammation (Fig. 1b). Acid fast and GMS stains were negative for mycobacteria and fungi. An extensive infectious workup was negative for viruses (including hepatitis A, B, and C, CMV, and EBV) and parasites (including toxoplasmosis and schistosomiasis). A diagnosis of idiopathic granulomatous hepatitis was made. The methotrexate dose was increased to 22.5 mg/week. Her symptoms resolved, LFTs normalized, and a repeat liver biopsy was essentially normal (Fig. 1c). She was last seen in follow-up in 2006 and was asymptomatic, without fevers, pruritus, or fatigue. She remains on methotrexate 15 mg daily and her LFTs remain normal.
Case 1 A 42-year-old woman with a history of vitiligo but otherwise asymptomatic presented with an elevated alkaline phosphatase, 343 IU (normal \130), abnormal AST and ALT of 54 and 63 IU/L, respectively, but normal total bilirubin and albumin. She had a normal WBC of 4.7 9 103/mm3 with 20 % peripheral eosinophilia on the differential. Further studies revealed a positive anti-mitochondrial antibody (1:640). A liver biopsy in 1989 demonstrated florid bile duct lesions with minimal fibrosis, consistent with Stage II PBC (Fig. 1a). She was treated with methotrexate 15 mg weekly (ursodiol was unavailable at the time). Six months later, her alkaline phosphatase normalized to 75 IU, as did her AST and ALT. She continued methotrexate with three normal liver biopsies in the next 10 years. In 2004, 15 years after her PBC diagnosis, the patient presented with 1 week of fevers, chills, and night sweats. She had no pruritus. Her LFTs were again
123
Case 2 A 42-year-old female with a history of hypothyroidism was referred for an elevated alkaline phosphatase level of 149 IU/L. She had chronic fatigue but no fevers or pruritus. Her other LFTs and albumin were normal. A GGT level was not assessed during her initial workup. An anti-mitochondrial antibody was negative. A liver biopsy in 1996 showed granulomatous inflammation of the portal tracts. An infectious workup was negative, and there was no
Dig Dis Sci (2014) 59:2831–2835
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Fig. 2 PBC in a patient with idiopathic granulomatous hepatitis. a Chronic nonsuppurative cholangitis with peri-ductal granuloma (H&E stain, 940). b Lobular granuloma with giant cells (H&E stain, 940). c H&E stain, low-power image (94)
evidence of sarcoidosis. The biopsy was thought to be consistent with idiopathic granulomatous hepatitis. She was treated with oral methotrexate. Her alkaline phosphatase normalized, and liver biopsies 2 and 7 years later showed only minor, nonspecific changes. In 2008, 12 years after her initial diagnosis, the patient’s alkaline phosphatase level increased to 284 IU/L, AST 45 IU/L, ALT 37 IU/L and total bilirubin 0.3 mg/dL. She also had a strongly positive anti-mitochondrial antibody (113.2 units by ELISA; normal \20). Liver biopsy showed bile duct inflammation and occasional bridging fibrosis, consistent with a diagnosis of Stage II–III PBC, and occasional lobular granulomas (Fig. 2a, b). Ursodiol therapy was initiated (13–15 mg/kg body weight). At last follow-up in 2014, she continues to be asymptomatic, with normalization of her LFTs, on a regimen of methotrexate and ursodiol. Case 3 A 45 year-old woman with a history of Hashimoto’s thyroiditis on levothyroxine presented with shoulder pain and was incidentally found to have elevated LFTs: AST 80 IU/ L, ALT 60 IU/L, alkaline phosphatase 115 IU/L, and a positive anti-mitochondrial antibody (titer 1:80). She had no fatigue, fevers, or pruritus. A liver biopsy in 1971 revealed a mixed inflammatory infiltrate in the portal tracts with lymphocytes, plasma cells, and several large noncaseating granulomas without giant cells (Fig. 3a, b). Purified protein derivative (PPD), histoplasmin, and coccidiomycosis skin tests were negative. A chest radiograph was normal. The liver biopsy findings were most consistent with granulomatous hepatitis. The patient was treated with
prednisone 10 mg daily for 6 years. Her LFTs returned to normal. Repeat liver biopsy in 1977 demonstrated less inflammation in the portal triads but persistent granulomas. In 1981, 10 years after her initial presentation, her serum alkaline phosphatase level increased to 1,195 IU/L. A repeat liver biopsy then showed increased peri-portal granulomatous inflammation, decreased number of bile ducts, and portal fibrosis (Fig. 3c). Given her elevated alkaline phosphatase and persistent granulomas despite prednisone therapy, the biopsy findings were considered to be most consistent with PBC. She was treated with colchicine 0.6 mg twice daily as part of a clinical trial (ursodiol was unavailable at that time). Two years later, the patient presented with fatigue and extreme weakness. Her symptoms completely resolved with prednisone, 7.5 mg daily. A repeat liver biopsy 1 year later showed bridging fibrosis and increased peri-portal inflammation. The patient eventually died of mycoplasma avium complex (MAC) pneumonia and sepsis.
Discussion Granulomas are collections of multinucleated giant cells with a surrounding rim of lymphocytes and fibroblasts. They represent a delayed-type hypersensitivity reaction to antigenic stimulation. Hepatic granulomas have been reported in 1–15 % of randomly selected liver biopsies in patients with PBC, sarcoidosis, and tuberculosis, and these diseases account for [75 % of cases of hepatic granuloma [6, 8–14]. Once seen on biopsy, an extensive search for other autoimmune and infectious causes should be
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Fig. 3 Overlap of idiopathic granulomatous hepatitis and PBC. a Chronic nonsuppurative cholangitis with peri-ductal granuloma (trichrome stain, 940). b Lobular granuloma (trichrome stain, 920).
c Chronic nonsuppurative cholangitis with peri-ductal granuloma (trichrome stain, 920). d Trichrome stain, low-power image (94)
performed [3, 14–16]. In a report of 442 patients with hepatic granulomas, a definitive diagnosis could not be established in 36 % of cases [16]. Older studies cite an idiopathic etiology in 10 % of cases [14, 16]. Granulomas in PBC are typically located in the periportal region of the liver and not in the parenchyma, as they are in idiopathic granulomatous hepatitis [2]. A case series in 1973 found that approximately 50 % of patients with idiopathic liver granulomas were diagnosed with idiopathic granulomatous hepatitis [17]. The report also demonstrated that prednisone is an effective treatment [17]. In a series of seven patients with idiopathic granulomatous hepatitis at our hospital who were refractory to prednisone or who developed severe side effects from steroid use, low-dose methotrexate (0.25 mg/kg weekly) successfully resolved fever, fatigue, and weight loss and improved liver histology [18]. Cyclophosphamide and infliximab have also been used successfully in resistant cases [19, 20]. Our first patient met the criteria for PBC at the time of her presentation [2]. She subsequently had fevers, elevation in alkaline phosphatase levels, and granulomas in the liver lobule 15 years later. An extensive workup for infectious etiologies was negative. The diagnosis most consistent with these findings was idiopathic granulomatous hepatitis. She had a rapid response to treatment with methotrexate. Our second patient had idiopathic granulomatous hepatitis at the time of her initial presentation with a complete response to treatment with methotrexate. Twelve years later, her serum alkaline phosphatase levels increased while
on the same dose of methotrexate and a repeat liver biopsy showed classical histological features of PBC; she responded well to the addition of ursodiol. In our third patient, idiopathic granulomatous hepatitis and PBC occurred together over a 10-year period. Her symptoms of fatigue and weakness responded to low-dose prednisone, but her disease progressed despite treatment. MAC infection is unlikely to have caused her granulomatous disease, as the infection developed almost 16 years after initial granuloma formation. It is important to note that Cases 1 and 3 had concurrent PBC and idiopathic granulomatous hepatitis and were treated with methotrexate but not ursodiol, as it was unavailable at the time. Ursodiol may influence the natural course of PBC patients who are treated with methotrexate alone at presentation [21]. The treatment of PBC with methotrexate without ursodiol has been reported previously in a report of two cases [22]. Cases 1 and 3 in our series add to this literature. Methotrexate, alone or in combination with ursodiol, has been used in patients with intense inflammation and granulomas in the portal triads to achieve disease remission [23]. Our experience suggests that idiopathic granulomatous hepatitis and PBC can occur in the same individual, either concurrently or at separate time points. PBC can also cooccur with other immune-mediated liver diseases such as autoimmune hepatitis [24]. Further studies should explore the possibility that similar immune mechanisms are involved in the pathogenesis of PBC, idiopathic
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granulomatous hepatitis, and autoimmune hepatitis. Our findings suggest that physicians should be aware of a possible link between PBC and idiopathic granulomatous, as clinical deterioration in a patient with either disease could suggest the presence of the other and should be treated accordingly. First line therapy for PBC is ursodiol (13–15 mg/kg body weight/day) while prednisone or methotrexate is used in idiopathic granulomatous hepatitis.
Conclusion Patients with PBC and granulomas in the lobular region of the liver may have co-existing idiopathic granulomatous hepatitis. This novel association has important clinical implications in the management of these patients. Acknowledgments J. Roper is supported by the Fellowship to Faculty Transition Award (American Gastroenterological Association Foundation) and S. Paul by the Bristol-Myers Squibb Virology Fellows Research Training Program. The authors wish to thank Dr. Marshall M. Kaplan, a dedicated physician, educator, and mentor who influenced the lives of countless patients and trainees at New England Medical Center (now Tufts Medical Center). He followed the patients in this case series through their clinical course and contributed substantially to this manuscript. He is and will continue to be dearly missed. Conflict of interest
None.
References 1. Kaplan MM, Gershwin ME. Primary biliary cirrhosis. N Engl J Med. 2005;353:1261–1273. 2. Hughes M, Fox H. A histological analysis of granulomatous hepatitis. J Clin Pathol. 1972;25:817–820. 3. Anderson CS, Nicholls J, Rowland R, LaBrooy JT. Hepatic granulomas: a 15-year experience in the Royal Adelaide Hospital. Med J Aust. 1988;148:71–74. 4. Geramizadeh B, Jahangiri R, Moradi E. Causes of hepatic granuloma: a 12-year single center experience from southern Iran. Arch Iran Med. 2011;14:288–289. 5. Lagana SM, Moreira RK, Lefkowitch JH. Hepatic granulomas: pathogenesis and differential diagnosis. Clin Liver Dis. 2010;14: 605–617. 6. McCluggage WG, Sloan JM. Hepatic granulomas in Northern Ireland: a thirteen year review. Histopathology. 1994;25:219–228. 7. Turhan N, Kurt M, Ozderin YO, Kurt OK. Hepatic granulomas: a clinicopathologic analysis of 86 cases. Pathol Res Pract. 2011; 207:359–365.
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