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Journal of Digestive Diseases 2016; 17; 128–131
doi: 10.1111/1751-2980.12303
Case report
Primary biliary cholangitis associated with warm autoimmune hemolytic anemia Emmanuel I. GONZALEZ-MORENO,* Sylvia A. MARTINEZ-CABRIALES,† Miguel A. CRUZ-MORENO,‡ Omar D. BORJAS-ALMAGUER,‡ Carlos A. CORTEZ-HERNANDEZ,* Francisco J. BOSQUES-PADILLA,* Aldo A. GARZA,* Jose A. GONZALEZ-GONZALEZ,* Diego GARCIA-COMPEAN,* Jorge OCAMPO-CANDIANI† & Hector J. MALDONADO-GARZA* *Gastroenterology Division, † Dermatology Division, and ‡ Internal Medicine Department, Hospital Universitario ‘Dr. José Eleuterio González’, Universidad Autónoma de Nuevo León, Monterrey, Mexico
There are many autoimmune diseases associated with primary biliary cholangitis (PBC), known as primary biliary cirrhosis; however, the association between PBC and warm autoimmune hemolytic anemia (wAIHA) has rarely been reported. It is documented that hemolysis is present in over 50% of the patients with chronic liver disease, regardless of the etiologies. Due to the clear and frequent relationship between PBC and many autoimmune diseases, it is reasonable to suppose that wAIHA may be another autoimmune disorder seen in association with PBC. Here we reported a 53-year-old female patient diagnosed with wAIHA associated with PBC. KEY WORDS: autoimmune hemolytic anemia, autoimmunity, cholestasis, primary biliary cirrhosis, ursodeoxycholic acid.
INTRODUCTION Primary biliary cholangitis (PBC), known as primary biliary cirrhosis, is an autoimmune liver disease characterized by progressive destruction of intrahepatic bile ducts, resulting in chronic cholestasis, portal inflammation and fibrosis that can further lead to cirrhosis.1 Many autoimmune disorders may coexist with PBC. Among them, both Sjögren’s syndrome and autoimmune thyroid diseases are the most frequently reported. Other PBC-associated disorders include calcinosis, Raynaud’s phenomenon, esophageal Correspondence to: Emmanuel I. GONZÁLEZ-MORENO, Gastroenterology Division, Hospital Universitario ‘Dr. José Eleuterio Gonzalez,’ Universidad Autónoma de Nuevo León, Madero y Gonzalitos S/N, Monterrey, Nuevo León, 64460 Mexico. Email: [email protected] Conflict of interest: None.
© 2016 Chinese Medical Association Shanghai Branch, Chinese
Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd
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dysmotility, sclerodactyly, telangiectasia syndrome, scleroderma, systemic lupus erythematosus, autoimmune hepatitis, rheumatoid arthritis, Raynaud’s disease, glomerulonephritis, celiac disease, ulcerative colitis, pulmonary fibrosis and gallstone disease.2 The association between PBC and warm autoimmune hemolytic anemia (wAIHA) is quite rare. To our knowledge, only 20 case reports have been described in the literature.3–18 Here we reported a case of PBC-associated wAIHA. CASE REPORT A 53-year-old woman was admitted to our hospital in August 2014 complaining of a 3-month exertional dyspnea, progressive fatigue, anorexia, palpitations, jaundice and pruritus. Jaundice and mild splenomegaly were noted on her physical examination. The patient also presented with yellow-brown atrophic plaques on both shins for more than 15 years. Her body weight was 70 kg. Laboratory data
Journal of Digestive Diseases 2016; 17; 128–131
Figure 1. Patient’s clinical course. PSL, prednisolone; UDCA, ursodeoxycholic acid; Hemoglobin, g/L (circle); alkaline phosphatase, U/L (square); total bilirubin, μmol/L (rhombus).
revealed that the level of hemoglobin (Hb) was 54.3 g/L (normal range 122–181 g/L), but her platelet (PLT) and white blood cell (WBC) count were within normal ranges (Fig. 1). Reticulocyte (RET) was 49% (normal range 1.0–2.0%) and haptoglobin < 41 mg/dL (normal range 41–165 mg/dL). Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were both with the normal ranges, serum total bilirubin (TB) 94.05 μmol/L (normal range 3.42–17.10 μmol/L), direct bilirubin (DB) 37.62 μmol/L (normal range 0–3.42 μmol/L), indirect bilirubin (IB) 56.43 μmol/L (normal range 3.42–13.68 μmol/L), alkaline phosphatase (ALP) 515 U/L (normal range 38–126 U/L), lactic dehydrogenase (LDH) 385 U/L (normal range 91–180 U/L), γ-glutamyl transpeptidase (GT) 335 U/L (normal range 0–50 U/L). And the albumin level was within normal range. Direct Coombs test was positive for anti-immunoglobulin G (IgG). Antinuclear antibody (ANA) was positive at a titer of 1:640. Hepatitis B
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surface antigen (HBsAg) and the antibody to hepatitis C virus were both negative. Peripheral blood smear only showed spherocytes. Upper abdominal ultrasonography demonstrated increased echogenicity in the parenchyma of the liver, mild splenomegaly, normal gallbladder in the absence of biliary duct dilatation. Gathering previous information, the patient was diagnosed as wAIHA and was given prednisolone 60 mg/day with subsequent improvement in the following days. A skin biopsy of both plaques was performed, showing an atrophic epidermis, multiple palisaded granulomas in the entire dermis with horizontal tiers of degenerated collagen and perivascular infiltration of lymphocytes and plasma cells. Clinical and histological diagnoses were necrobiosis lipoidica. After 5 days of treatment, the patient was discharged; at that time she had an Hb level of 76.0 g/L. She was readmitted to hospital in October 2014 due to worsening symptomatology. She discontinued the therapy herself after one week of discharge. Physical examination revealed overt jaundice and splenomegaly. Laboratory test showed levels of Hb of 44.8 g/L, RET 60.8%, TB 384.75 μmol/L, DB 229.14 μmol/L, IB 155.61 μmol/L, ALP 450 U/L, AST 69 U/L (normal range 10–42 U/L), ALT 68 U/L (normal range 10–42 U/L), albumin 30 g/L (normal range 32–55 g/L), LDH 606 U/L, γ-GT 210 U/L. Prednisolone 60 mg/day was restarted with subsequent improvement in the levels of Hb and LDH, and symptomatology; however, we observed a progressive worsening of TB and ALP levels to 595.08 μmol/L, and 509 U/L, respectively. We then considered PBC as a possible explanation for her disease. Anti-mitochondrial antibody (AMA) was positive (titer 1:5 120). Liver biopsy was performed and the specimen contained 13 portal areas showing mild portal fibrosis and portal infiltration of chronic inflammatory cells with early duct destruction and lymphocytic infiltration (Fig. 2). A diagnosis of PBC was confirmed and ursodeoxycholic acid (UDCA)
Figure 2. Liver biopsy showing (a) cholangitis with chronic lymphocytic infiltration (black arrow); (b) portal triad without bile duct (arrow head); (c) immunohistochemistry (cytokeratin 7 stain) showing an absence of ducts.
© 2016 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd
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500 mg orally twice daily was added. Over the next week the levels of ALP, TB and γ-GT were gradually decreased and the patient was discharged with tapered prednisolone dose. At 3-month follow-up, her Hb level had risen to 126 g/L with a normal liver function.
DISCUSSION The diagnosis of PBC can be made if two of three objective criteria are met: (i) serum AMA at titers 1:40 or higher; (ii) unexplained increase in ALP level of ≥ 1.5-fold the upper limit of normal (ULN) for ≥ 24 weeks and (iii) a characteristic finding on liver biopsy that indicates PBC, especially non-suppurative cholangitis and interlobular bile duct injury.19,20 Other characteristic features include PBC-specific ANA (Sp100 and gp210), elevated serum immunoglobulin (Ig) M, hypercholesterolemia or xanthomas, Sicca syndrome, pruritus and fatigue.21 Our patient showed positive serum AMA, elevated ALP (documented for at least 12 weeks) and a compatible histology. She also referred to pruritus and fatigue. It has been suggested that PBC develops when an individual with a susceptible genetic makeup encounters a superimposed environmental trigger that, in combination with other factors, leads to the dysregulation of the immune system and an attack on target tissues within the liver.2 The high concordance rate between monozygotic twins (63%) versus null concordance in dizygotic sets (0%)22 demonstrates an important genetic component in disease susceptibility. First-degree relatives of approximately 1–6% of the patients with PBC are also affected with PBC.23 The risk of developing PBC is nearly 100-fold higher in the general population if a first-degree relative has the same disorder.24 The findings of a genome-wide association study in a North American cohort indicated there was a significant association between PBC and polymorphisms of HLA-DQB1, interleukin 12A (IL12A), IL12RB2, and STAT4,25 and these associations have been confirmed in an Italian cohort.26 Most autoimmune disorders are more frequent in women, and this is particularly the case in PBC, where women outnumber men with ratios reported to be as high as 10:1.27 Serological results in large groups of unselected serum samples showed that the prevalence of AMA positivity in the general population can be as high as 0.5%;28 however, with a lower sex ratio than in PBC, suggesting that the progression from loss of
Journal of Digestive Diseases 2016; 17; 128–131 tolerance to the auto antigen to clinical disease is predominant in women.29 A decrease in the erythrocyte survival time has been well documented in association with all types of chronic liver disease, including PBC.30 Hemolysis can be detected in over 50% of all patients with chronic liver disease, regardless of the etiologies, although the mechanism involved could be either intracorpuscular or extracorpuscular.14 Due to a clear and common association between PBC and other autoimmune diseases,30,31 it is reasonable to consider that wAIHA may be another autoimmune condition seen in association with PBC. AIHA is a rare autoimmune disorder affecting approximately 3 in 100 000 annually, in which auto antibodies directed against erythrocytes antigens lead to their increased destruction.32 The classification of AIHA pathophysiologically divides AIHA into warm, mixed or cold-reactive subtypes. This classification is based on the optimal red blood cells (RBC)autoantibody reactivity temperatures.33 AIHA is idiopathic (50%) or secondary to lymphoproliferative disorders (20%), autoimmune diseases (20%), infections and tumors.34 To our knowledge, there have been no diagnostic criteria for wAIHA, but it is suspected with the following laboratory findings: normocytic or macrocytic anemia, increased reticulocyte level, low serum haptoglobin levels, increased serum LDH and IB levels and a positive direct Coombs test against immunoglobulin and/or its complement. When erythrocytes are covered with IgG or IgG plus C3d, the antibody is usually a warm antibody (wAIHA). When RBC are coated with C3d only, the antibody is usually but not always a cold antibody (cAIHA). For definite diagnosis of cAIHA, the cold agglutinin titer must be significantly elevated.35 The recommended treatment for PBC-related AIHA includes prednisone (1 mg/kg per day) to manage the hemolysis at the acute setting,35 and UDCA (13–15 mg/kg per day),15,19,20 although a successful outcome has been reported with only UDCA therapy in a patient having PBC associated with mild AIHA.7 Although the association between PBC and wAIHA has been rarely described, it is important to consider that in a patient with PBC and anemia, mainly because of a previous recognition of the augmented hemolysis in cirrhosis and a common coexistence of PBC with many autoimmune diseases.
© 2016 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School
of Medicine and John Wiley & Sons Australia, Ltd
Journal of Digestive Diseases 2016; 17; 128–131 REFERENCES 1 Selmi C, Bowlus CL, Gershwin ME, Coppel RL. Primary biliary cirrhosis. Lancet 2011; 377: 1600–9. 2 Bhandari BM, Bayat H, Rothstein KD. Primary biliary cirrhosis. Gastroenterol Clin North Am 2011; 40: 373–86, viii. 3 Azad A, Berera V, Jayarajan J, Lim K. Evans syndrome and primary biliary cirrhosis. Int J Lab Hematol 2007; 29: 145–8. 4 Kaibori M, Uchida Y, Ishizaki M et al. Living donor liver transplantion for primary biliary cirrhosis with autoimmune hemolytic anemia: a case report. Dig Dis Sci 2007; 52: 3237–9. 5 Retana AK, Kaplan MM, Erban JK. Autoimmune hemolytic anemia in patients with liver transplants for primary biliary cirrhosis: three case reports and a review of the literature. Am J Gastroenterol 2007; 102: 197–200. 6 Cantalapiedra A, Peñarrubia MJ, Gutiérrez O et al. Primary biliary cirrhosis, ‘sicca’ sindrome and autoimmune hemolytic anemia. Rev Esp Enferm Dig 2005; 97: 678–9 (in Spanish). 7 Fuller SJ, Kumar P, Weltman M, Wiley JS. Autoimmune hemolysis associated with primary biliary cirrhosis responding to ursodeoxycholic acid as sole treatment. Am J Hematol 2003; 72: 31–3. 8 Nakasone H, Sakugawa H, Fukuchi J et al. A patient with primary biliary cirrhosis associated with autoimmune hemolytic anemia. J Gastroenterol 2000; 35: 245–9. 9 Brackstone M, Ghent CN. Primary biliary cirrhosis and hemolytic anemia confusing serum bilirubin levels. Can J Gastroenterol 2000; 14: 445–7. 10 Chen CY, Lu CL, Chiu CF, Chang FY, Lee SD. Primary biliary cirrhosis associated with mixed type autoimmune hemolytic anemia and sicca syndrome: a case report and review of literature. Am J Gastroenterol 1997; 92: 1547–9. 11 Yoshida EM, Nantel SH, Owen DA et al. Case report: A patient with primary biliary cirrhosis and autoimmune hemolytic anemia. J Gastroenterol Hepatol 1996; 11: 439–42. 12 Shichiri M, Koyama W, Tozuka S, Sakamoto S, Kanayama M. Primary biliary cirrhosis. A patient with adverse reactions to tiopronin and autoimmune hemolytic anemia with reticulocytopenia. Arch Intern Med 1984; 144: 89–91. 13 Orlin JB, Berkman EM, Matloff DS, Kaplan MM. Primary biliary cirrhosis and cold autoimmune hemolytic anemia: effect of partial plasma exchange. Gastroenterology 1980; 78: 576–8. 14 Hume R, Williamson JM, Whitelaw JW. Red cell survival in biliary cirrhosis. J Clin Pathol 1970; 23: 397–401. 15 Tian Y, Wang C, Liu JX, Wang HH. Primary biliary cirrhosisrelated autoimmune hemolytic anemia: three case reports and review of the literature. Case Rep Gastroenterol 2009; 3: 240–7. 16 Gentile M, Verta M, Vigna E et al. Autoimmune hemolityc anemia concomitant with sequential autoimmune hepatitisprimary biliary cirrhosis overlap syndrome and Hashimoto’s thyroiditis: a new entity of autoimmune polyendocrine syndrome. J Endocrinol Invest 2009; 32: 287–8. 17 Efe C, Wahlin S, Ozaslan E et al. Autoimmune hepatitis/primary biliary cirrhosis overlap syndrome and associated extrahepatic autoimmune diseases. Eur J Gastroenterol Hepatol 2012; 24: 531–4.
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18 Korkmaz H, Bugdaci MS, Temel T, Dagli M, Karabagli P. Autoimmune hepatitis-primary biliary cirrhosis overlap syndrome concomitant with immune hemolytic anemia and immune thrombocytopenic purpura (Evans syndrome). Clin Res Hepatol Gastroenterol 2013; 37: e45–50. 19 European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 2009; 51: 237–67. 20 Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ; American Association for Study of Liver Diseases. Primary biliary cirrhosis. Hepatology 2009; 50: 291–308. 21 Bowlus CL, Gershwin ME. The diagnosis of primary biliary cirrhosis. Autoimmun Rev 2014; 13: 441–4. 22 Selmi C, Mayo MJ, Bach N et al. Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment. Gastroenterology 2004; 127: 485–92. 23 Gross RG, Odin JA. Recent advances in the epidemiology of primary biliary cirrhosis. Clin Liver Dis 2008; 12: 289–303. 24 Prince MI, James OF. The epidemiology of primary biliary cirrhosis. Clin Liver Dis 2003; 7: 795–819. 25 Hirschfield GM, Liu X, Xu C et al. Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. N Engl J Med 2009; 360: 2544–55. 26 Liu X, Invernizzi P, Lu Y et al. Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis. Nat Genet 2010; 42: 658–60. 27 Jones DE. Pathogenesis of primary biliary cirrhosis. Postgrad Med J 2008; 84: 23–33. 28 Mattalia A, Quaranta S, Leung PS et al. Characterization of antimitochondrial antibodies in health adults. Hepatology 1998; 27: 656–61. 29 Lleo A, Battezzati PM, Selmi C, Gershwin ME, Podda M. Is autoimmunity a matter of sex? Autoimmun Rev 2008; 7: 626–30. 30 Culp KS, Fleming CR, Duffy J, Baldus WP, Dickson ER. Autoimmune associations in primary biliary cirrhosis. Mayo Clin Proc 1982; 57: 365–70. 31 Zukowski TH, Jorgensen RA, Dickson ER, Lindor KD. Autoimmune conditions associated with primary biliary cirrhosis: response to ursodeoxycholic acid therapy. Am J Gastroenterol 1998; 93: 958–61. 32 Michel M. Classification and therapeutic approaches in autoimmune hemolytic anemia: an update. Expert Rev Hematol 2011; 4: 607–18. 33 Bass GF, Tuscano ET, Tuscano JM. Diagnosis and classification of autoimmune hemolytic anemia. Autoimmun Rev 2014; 13: 560–4. 34 Valent P, Lechner K. Diagnosis and treatment of autoimmune haemolytic anaemias in adults: a clinical review. Wien Klin Wochenschr 2008; 120: 136–51. 35 Lechner K, Jäger U. How I treat autoimmune hemolytic anemias in adults. Blood 2010; 116: 1831–8.
© 2016 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd
Journal of Digestive Diseases 2016; 17; 128–131
doi: 10.1111/1751-2980.12303
Case report
Primary biliary cholangitis associated with warm autoimmune hemolytic anemia Emmanuel I. GONZALEZ-MORENO,* Sylvia A. MARTINEZ-CABRIALES,† Miguel A. CRUZ-MORENO,‡ Omar D. BORJAS-ALMAGUER,‡ Carlos A. CORTEZ-HERNANDEZ,* Francisco J. BOSQUES-PADILLA,* Aldo A. GARZA,* Jose A. GONZALEZ-GONZALEZ,* Diego GARCIA-COMPEAN,* Jorge OCAMPO-CANDIANI† & Hector J. MALDONADO-GARZA* *Gastroenterology Division, † Dermatology Division, and ‡ Internal Medicine Department, Hospital Universitario ‘Dr. José Eleuterio González’, Universidad Autónoma de Nuevo León, Monterrey, Mexico
There are many autoimmune diseases associated with primary biliary cholangitis (PBC), known as primary biliary cirrhosis; however, the association between PBC and warm autoimmune hemolytic anemia (wAIHA) has rarely been reported. It is documented that hemolysis is present in over 50% of the patients with chronic liver disease, regardless of the etiologies. Due to the clear and frequent relationship between PBC and many autoimmune diseases, it is reasonable to suppose that wAIHA may be another autoimmune disorder seen in association with PBC. Here we reported a 53-year-old female patient diagnosed with wAIHA associated with PBC. KEY WORDS: autoimmune hemolytic anemia, autoimmunity, cholestasis, primary biliary cirrhosis, ursodeoxycholic acid.
INTRODUCTION Primary biliary cholangitis (PBC), known as primary biliary cirrhosis, is an autoimmune liver disease characterized by progressive destruction of intrahepatic bile ducts, resulting in chronic cholestasis, portal inflammation and fibrosis that can further lead to cirrhosis.1 Many autoimmune disorders may coexist with PBC. Among them, both Sjögren’s syndrome and autoimmune thyroid diseases are the most frequently reported. Other PBC-associated disorders include calcinosis, Raynaud’s phenomenon, esophageal Correspondence to: Emmanuel I. GONZÁLEZ-MORENO, Gastroenterology Division, Hospital Universitario ‘Dr. José Eleuterio Gonzalez,’ Universidad Autónoma de Nuevo León, Madero y Gonzalitos S/N, Monterrey, Nuevo León, 64460 Mexico. Email: [email protected] Conflict of interest: None.
© 2016 Chinese Medical Association Shanghai Branch, Chinese
Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd
128
dysmotility, sclerodactyly, telangiectasia syndrome, scleroderma, systemic lupus erythematosus, autoimmune hepatitis, rheumatoid arthritis, Raynaud’s disease, glomerulonephritis, celiac disease, ulcerative colitis, pulmonary fibrosis and gallstone disease.2 The association between PBC and warm autoimmune hemolytic anemia (wAIHA) is quite rare. To our knowledge, only 20 case reports have been described in the literature.3–18 Here we reported a case of PBC-associated wAIHA. CASE REPORT A 53-year-old woman was admitted to our hospital in August 2014 complaining of a 3-month exertional dyspnea, progressive fatigue, anorexia, palpitations, jaundice and pruritus. Jaundice and mild splenomegaly were noted on her physical examination. The patient also presented with yellow-brown atrophic plaques on both shins for more than 15 years. Her body weight was 70 kg. Laboratory data
Journal of Digestive Diseases 2016; 17; 128–131
Figure 1. Patient’s clinical course. PSL, prednisolone; UDCA, ursodeoxycholic acid; Hemoglobin, g/L (circle); alkaline phosphatase, U/L (square); total bilirubin, μmol/L (rhombus).
revealed that the level of hemoglobin (Hb) was 54.3 g/L (normal range 122–181 g/L), but her platelet (PLT) and white blood cell (WBC) count were within normal ranges (Fig. 1). Reticulocyte (RET) was 49% (normal range 1.0–2.0%) and haptoglobin < 41 mg/dL (normal range 41–165 mg/dL). Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were both with the normal ranges, serum total bilirubin (TB) 94.05 μmol/L (normal range 3.42–17.10 μmol/L), direct bilirubin (DB) 37.62 μmol/L (normal range 0–3.42 μmol/L), indirect bilirubin (IB) 56.43 μmol/L (normal range 3.42–13.68 μmol/L), alkaline phosphatase (ALP) 515 U/L (normal range 38–126 U/L), lactic dehydrogenase (LDH) 385 U/L (normal range 91–180 U/L), γ-glutamyl transpeptidase (GT) 335 U/L (normal range 0–50 U/L). And the albumin level was within normal range. Direct Coombs test was positive for anti-immunoglobulin G (IgG). Antinuclear antibody (ANA) was positive at a titer of 1:640. Hepatitis B
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surface antigen (HBsAg) and the antibody to hepatitis C virus were both negative. Peripheral blood smear only showed spherocytes. Upper abdominal ultrasonography demonstrated increased echogenicity in the parenchyma of the liver, mild splenomegaly, normal gallbladder in the absence of biliary duct dilatation. Gathering previous information, the patient was diagnosed as wAIHA and was given prednisolone 60 mg/day with subsequent improvement in the following days. A skin biopsy of both plaques was performed, showing an atrophic epidermis, multiple palisaded granulomas in the entire dermis with horizontal tiers of degenerated collagen and perivascular infiltration of lymphocytes and plasma cells. Clinical and histological diagnoses were necrobiosis lipoidica. After 5 days of treatment, the patient was discharged; at that time she had an Hb level of 76.0 g/L. She was readmitted to hospital in October 2014 due to worsening symptomatology. She discontinued the therapy herself after one week of discharge. Physical examination revealed overt jaundice and splenomegaly. Laboratory test showed levels of Hb of 44.8 g/L, RET 60.8%, TB 384.75 μmol/L, DB 229.14 μmol/L, IB 155.61 μmol/L, ALP 450 U/L, AST 69 U/L (normal range 10–42 U/L), ALT 68 U/L (normal range 10–42 U/L), albumin 30 g/L (normal range 32–55 g/L), LDH 606 U/L, γ-GT 210 U/L. Prednisolone 60 mg/day was restarted with subsequent improvement in the levels of Hb and LDH, and symptomatology; however, we observed a progressive worsening of TB and ALP levels to 595.08 μmol/L, and 509 U/L, respectively. We then considered PBC as a possible explanation for her disease. Anti-mitochondrial antibody (AMA) was positive (titer 1:5 120). Liver biopsy was performed and the specimen contained 13 portal areas showing mild portal fibrosis and portal infiltration of chronic inflammatory cells with early duct destruction and lymphocytic infiltration (Fig. 2). A diagnosis of PBC was confirmed and ursodeoxycholic acid (UDCA)
Figure 2. Liver biopsy showing (a) cholangitis with chronic lymphocytic infiltration (black arrow); (b) portal triad without bile duct (arrow head); (c) immunohistochemistry (cytokeratin 7 stain) showing an absence of ducts.
© 2016 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd
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500 mg orally twice daily was added. Over the next week the levels of ALP, TB and γ-GT were gradually decreased and the patient was discharged with tapered prednisolone dose. At 3-month follow-up, her Hb level had risen to 126 g/L with a normal liver function.
DISCUSSION The diagnosis of PBC can be made if two of three objective criteria are met: (i) serum AMA at titers 1:40 or higher; (ii) unexplained increase in ALP level of ≥ 1.5-fold the upper limit of normal (ULN) for ≥ 24 weeks and (iii) a characteristic finding on liver biopsy that indicates PBC, especially non-suppurative cholangitis and interlobular bile duct injury.19,20 Other characteristic features include PBC-specific ANA (Sp100 and gp210), elevated serum immunoglobulin (Ig) M, hypercholesterolemia or xanthomas, Sicca syndrome, pruritus and fatigue.21 Our patient showed positive serum AMA, elevated ALP (documented for at least 12 weeks) and a compatible histology. She also referred to pruritus and fatigue. It has been suggested that PBC develops when an individual with a susceptible genetic makeup encounters a superimposed environmental trigger that, in combination with other factors, leads to the dysregulation of the immune system and an attack on target tissues within the liver.2 The high concordance rate between monozygotic twins (63%) versus null concordance in dizygotic sets (0%)22 demonstrates an important genetic component in disease susceptibility. First-degree relatives of approximately 1–6% of the patients with PBC are also affected with PBC.23 The risk of developing PBC is nearly 100-fold higher in the general population if a first-degree relative has the same disorder.24 The findings of a genome-wide association study in a North American cohort indicated there was a significant association between PBC and polymorphisms of HLA-DQB1, interleukin 12A (IL12A), IL12RB2, and STAT4,25 and these associations have been confirmed in an Italian cohort.26 Most autoimmune disorders are more frequent in women, and this is particularly the case in PBC, where women outnumber men with ratios reported to be as high as 10:1.27 Serological results in large groups of unselected serum samples showed that the prevalence of AMA positivity in the general population can be as high as 0.5%;28 however, with a lower sex ratio than in PBC, suggesting that the progression from loss of
Journal of Digestive Diseases 2016; 17; 128–131 tolerance to the auto antigen to clinical disease is predominant in women.29 A decrease in the erythrocyte survival time has been well documented in association with all types of chronic liver disease, including PBC.30 Hemolysis can be detected in over 50% of all patients with chronic liver disease, regardless of the etiologies, although the mechanism involved could be either intracorpuscular or extracorpuscular.14 Due to a clear and common association between PBC and other autoimmune diseases,30,31 it is reasonable to consider that wAIHA may be another autoimmune condition seen in association with PBC. AIHA is a rare autoimmune disorder affecting approximately 3 in 100 000 annually, in which auto antibodies directed against erythrocytes antigens lead to their increased destruction.32 The classification of AIHA pathophysiologically divides AIHA into warm, mixed or cold-reactive subtypes. This classification is based on the optimal red blood cells (RBC)autoantibody reactivity temperatures.33 AIHA is idiopathic (50%) or secondary to lymphoproliferative disorders (20%), autoimmune diseases (20%), infections and tumors.34 To our knowledge, there have been no diagnostic criteria for wAIHA, but it is suspected with the following laboratory findings: normocytic or macrocytic anemia, increased reticulocyte level, low serum haptoglobin levels, increased serum LDH and IB levels and a positive direct Coombs test against immunoglobulin and/or its complement. When erythrocytes are covered with IgG or IgG plus C3d, the antibody is usually a warm antibody (wAIHA). When RBC are coated with C3d only, the antibody is usually but not always a cold antibody (cAIHA). For definite diagnosis of cAIHA, the cold agglutinin titer must be significantly elevated.35 The recommended treatment for PBC-related AIHA includes prednisone (1 mg/kg per day) to manage the hemolysis at the acute setting,35 and UDCA (13–15 mg/kg per day),15,19,20 although a successful outcome has been reported with only UDCA therapy in a patient having PBC associated with mild AIHA.7 Although the association between PBC and wAIHA has been rarely described, it is important to consider that in a patient with PBC and anemia, mainly because of a previous recognition of the augmented hemolysis in cirrhosis and a common coexistence of PBC with many autoimmune diseases.
© 2016 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School
of Medicine and John Wiley & Sons Australia, Ltd
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