- Email: [email protected]
Primary biliary cirrhosis: When and why does the disease develop?
Digestive and Liver Disease 38 (2006) 272–275
Brief Clinical Observation
Primary biliary cirrhosis: When and why does the disease develop? A. Floreani a,∗ , P.A. Ostuni b , F. Ferrara a , M. Guido c a
Department of Surgical and Gastroenterological Sciences, University of Padova, Padua, Italy b Department of Medical and Surgical Sciences, University of Padova, Padua, Italy c Department of Pathology, University of Padova, Padua, Italy
Abstract Primary biliary cirrhosis is a chronic cholestatic liver disease with an autoimmune pathogenesis, that generally develops in adult life, often in perimenopausal age. The clinical features are heterogeneous, ranging from an asymptomatic presentation to end-stage liver disease. Primary biliary cirrhosis is unknown in children and its natural history has yet to be elucidated. Following a Canadian report of primary biliary cirrhosis in two girls (16 and 15 years old), we describe a clinical case developing at 17 years of age. A temporal association between Borrelia Burgdorferi infection and diagnosis of primary biliary cirrhosis was observed. © 2006 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: AMA; Primary biliary cirrhosis
1. Introduction Primary biliary cirrhosis (PBC) is a chronic liver disease characterised by cholestasis, antimitochondrial antibody (AMA) positivity and lymphocyte-predominant portal inflammation with a variable degree of fibrosis that usually affects middle-aged women [1]. Incidental cases of PBC have hitherto been diagnosed in post-menopausal age. Table 1 summarises the mean/median age of presentation in several series of PBC. The youngest age of onset is 19 years in a French series [7]. The incidence and prevalence of PBC have increased in recent years, probably because most of the patients are diagnosed in the early, asymptomatic phase of the disease [10]. A recent study conducted in a large cohort of PBC patients followed up for up to 28 years indicates that even in the more recently diagnosed cases, this disease carries a significant morbidity and mortality [11]. PBC is unknown in children, so the earliest age at which AMA may be detected is not known. Dahlan et al. [12] recently reported two cases of PBC diagnosed at 16 and 15 years old, respectively. Both patients had earlyonset cholelithiasis and biopsy-proven stage II PBC. The ∗ Correspondence to: Division of Gastroenterologia, Via Giustiniani, 2, 35128 Padua, Italy. Tel.: +39 049 8212894; fax: +39 049 8760820. E-mail address: [email protected] (A. Floreani).
first developed progressive cholestasis and underwent liver transplantation. The second had an excellent response after ursodeoxycholic acid (UDCA) therapy. We describe a clinical case of well-documented PBC newly diagnosed in a 17-year-old girl. This is the third youngest case of PBC described in the world, and offers us an opportunity to discuss the infectious event that may have triggered the immunological damage.
2. Case report A.S., a 17-year-old girl, was admitted in April 2002 to the Rheumatology Department with arthralgia and stiffness of the fingers. She denied any alcohol intake, drug abuse or blood transfusions. She had no family history of either autoimmune or liver diseases in first-degree relatives. She appeared well, but reported pre-menstrual itching during the last 12 months and the onset of Raynaud’s phenomenon during the last 6 months. She reported having had pharyngitis and erythematous rash with a temperature of 38 ◦ C 6 months earlier, treated with antibiotics. Her physical examination was normal except for mild arthritis of several dip joints of both hands, and some hyperchromic papules in the periumbilical area. Laboratory data
1590-8658/$30 © 2006 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2006.03.001
A. Floreani et al. / Digestive and Liver Disease 38 (2006) 272–275
273
Table 1 Age at presentation of PBC patients Author
Year
Symptoms
N
Mean/median age
Range (years)
Country
Long et al. [2] Christensen et al. [3] Sasaki et al. [4] Sasaki et al. [4] Mitchison et al. [5] Balasubramaniam et al. [6] Brenard et al. [7] Brenard et al. [7] Uddenfeldt and Danielsson [8] Howel et al. [9]
1977 1980 1985 1985 1986 1990 1990 1990 2000 2000
Asymptomatic Symptomatic Asymptomatic Symptomatic Asymptomatica Asymptomatic Symptomaticb Asymptomaticb Asymptomatic and symptomatic Asymptomatic and symptomatic
20 236 120 160 29 73
47 55 51.8 48
23–62 24–78 28–78 22–76 27–74 35–75 19–83 29–90 31–78 34–82
England Europe, USA Japan Japan England USA France France Sweden England
a b
86 100
54 49.3 51.5 56 62.5
Normal alkaline phosphatase. Total number of symptomatic and asymptomatic patients = 206.
were remarkable in the following respects: ANA positivity 1:320 (speckled patter) and AMA positivity 1:160 (with confirmed M2 reactivity [74 kDa band] on immunoblotting). Liver biochemical tests (serum transaminases, alkaline phosphatase, GGT, prothrombin time, IgG, IgA, IgM) were within the normal range. Anti-ENA, ANCA and rheumatoid factor were negative, and total complement, C3 and C4 were within the normal range. Common causes of itching (thyroid disease, allergic disease, parasitic disease, lymphoma) were ruled out. HLA typing was negative for B 27. Serum IgM antibodies against Borrelia Burgdorferi were found by ELISA. IgM positivity was confirmed by recognition of reactivity in two of the three proteins (24 and 41 kDa) on Western blotting. Cultures of blood and urine were negative. Liver ultrasound revealed a normal liver size and echogenicity, and no dilation of the biliary tree. She was treated with a brief course of steroids (prednisone 25 mg/day
for 3 weeks), which prompted the total disappearance of the arthralgia and skin lesions. She was subsequently referred to the Gastroenterology Department for pre-menstrual itching and AMA positivity. Six months later, liver biochemical tests were still within the normal range. A liver biopsy was taken, which revealed a mild lymphomonocytic inflammation in some portal tracts associated with minimal duct damage, consisting in swollen bile duct cells and occasional lymphocytes within the duct. A pseudoglandular arrangement of hepatocytes was noted in the lobular parenchyma. This picture was consistent with stage I PBC (Fig. 1). The patient was started on UDCA 15 mg/(kg day) and now has a 2-year follow-up since the liver biopsy. Her liver function tests remain normal, but she is still both AMA+ve (at a titre of 1:160) and ANA+ve (at a titre of 1:160), and has an IgM above the normal range. She occasionally complains of pre-menstrual pruritus.
Fig. 1. A portal tract showing minimal duct damage consisting in swollen bile duct cells and occasional lymphocytes within the duct. A mild lymphomonocytic inflammation is also present.
274
A. Floreani et al. / Digestive and Liver Disease 38 (2006) 272–275
3. Discussion We present a case of PBC developing at the age of 17 years. This is the third youngest case described in the world, following the report on two Canadian cases (16 and 15 years of age) [12]. Lyme disease may explain the early onset of PBC in our case, while there was no apparent reason for its early presentation in the Canadian cases, except for a strong genetic predisposition in one of the two cases [12]. Our patient had complained of itching 1 year before the histological examination and had developed Raynaud’s phenomenon 6 months before her arthralgia, which was interpreted as being due to Lyme disease because she was positive for anti-B. Burgdorferi IgM antibodies. Recognition of two of the three proteins by immunoblotting (24 and 41 kDa, respectively) fulfils the recommended criteria for the serodiagnosis of Lyme disease [13]. In recent years, much more insight on the mechanisms contributing to the breakdown of immune tolerance to self antigen pyruvate dehydrogenase complex, and to the disruption of the biliary epithelial cells, has focused on the several infectious agents potentially capable of triggering the disease. Several putative infectious agents have been suggested to play a pathogenic role in PBC, including bacteria, viruses and xenobiotics [14]. Molecular mimicry between host antigens and unrelated exogenous proteins is one of the hypotheses suggested to explain how autoantibodies and unrelated exogenous proteins arise, break tolerance and lead to autoimmune disease. Evidence in support of molecular mimicry in the aetiopathogenesis of PBC comes from several models, including Escherichia coli [15,16], Psudomonas aeruginosa [17], Mycobacterium gordonae [18,19], Novosfingobium aromaticivorans [20] and Chlamydia pneumoniae [21]. To our knowledge, there is no reported evidence of molecular mimicry from B. Burgdorferi and PBC, although this relationship has been identified in autoimmune heart disease [22]. We have no anamnestic report of any tick-borne infection in our girl, but she did have pharyngitis and erythematous rash with a temperature of 38 ◦ C 6 months earlier, which was treated with antibiotics. The clinical picture suggests Lyme disease, but no skin biopsy has been performed. In our patient, Borrelia was determined in the serum 4 months after the onset of itching, but it is worth noting that the symptoms disappeared after she developed anti-Borrelia IgG antibodies. The decision to make a liver biopsy has been made despite the normality of liver function tests because the young woman was symptomatic for itching (during pre-menstrual phase) associated with AMA positivity. In fact, the finding of an AMA titre greater or equal to 1:40 is strongly suggestive of PBC even in the absence of symptoms and the presence of a normal alkaline phosphatase [23]. For the time being, the earliest age at which AMA might be detected is not known. In a multicentre survey (involving 10 Italian centres) conducted by the Italian Association for Liver Disease, an overall 42 paediatric cases of autoimmune hepatitis were collected over 18 years and no AMA+ve cases
were detected [24]. In an overall 25,000 assays of non-organspecific autoantibodies over the last 5 years at our university hospital laboratory, only one case of AMA positivity has been detected in paediatric age (in a 9-year-old), but the girl suffered from anti-phospholipid antibody syndrome, with no evidence of cholestasis [25]. In conclusion, the practical message emerging from this case report is that PBC can occur in young people, but we still do not know how early the disease can occur and the pathogenic mechanisms that trigger the immunological damage. An unexplained itching should be investigated with AMA testing even in young girls. Our own and the Canadian cases would suggest that, if AMA screening were extended to paediatric family members of index cases, then further cases of PBC in very young people would be discovered. Conflict of interest There is no conflict of interest, financially or personally, with other people or organisations that could inappropriately influence or work, all authors agree with the final version of the manuscript. References [1] Kaplan M. Primary biliary cirrhosis: past, present, and future. Gastroenterology 2002;123:1392–4. [2] Long RG, Scheuer PJ, Sherlock S. Presentation and course of asymptomatic primary biliary cirrhosis. Gastroenterology 1977;72:1204–7. [3] Christensen E, Crowe J, Doniach D, Popper H, Ranek L, Rodes J, et al. Clinical pattern and course of disease in primary biliary cirrhosis based on an analysis of 236 patients. Gastroenterology 1980;78:236–46. [4] Sasaki H, Inoue K, Higuchi K, Yasuyama T, Koyata H, Kuroki T, et al. Primary biliary cirrhosis in Japan: national survey by the subcommittee on autoimmune hepatitis. Gastroenterol Jpn 1983;20:476–85. [5] Mitchison HC, Bassendine MF, Hendrick A, Bennett M, Bird G, Watson AJ, et al. Positive antimitochondrial antibody but normal alkaline phosphatase: is this primary biliary cirrhosis? Hepatology 1986;6:1279–84. [6] Balasubramaniam K, Grambsch PM, Wiesner RH, Lindor KD, Dickson R. Diminished survival in asymptomatic primary biliary cirrhosis. Gastroenterology 1990;98:1567–71. [7] Brenard R, Degos F, Degott C, Lassoued K, Benhamou JP. La cirrhose biliaire primitive: modes actuels de presentation. Gastroenterol Clin Biol 1990;14:307–12. [8] Uddenfeldt P, Danielsson A. Primary biliary cirrhosis: survival of a cohort followed for 10 years. J Int Med 2000;248:292–8. [9] Howel D, Fischbacher CM, Bhopal RS, Gray J, Metcalf JV, James OFW. An exploratory population-based case-control study of primary biliary cirrhosis. Hepatology 2000;31:1055–60. [10] Prince MI, James OFW. The epidemiology of primary biliary cirrhosis. Clin Liver Dis 2003;7:795–819. [11] Prince M, Chetwynd A, Newman W, Metcalf J, James OFW. Asymptomatic primary biliary cirrhosis: clinical features, prognosis, and symptom progression in a large population based cohort. Gut 2004;53:865–70. [12] Dahlan Y, Smith L, Simmonds D, Douglas L, Jewell LD, Wanless I, et al. Pediatric-onset primary biliary cirrhosis. Gastroenterology 2003;125:1476–9. [13] Engstrom SM, Shoop E, Johnson RC. Immunoblot interpretation criteria for serodiagnosis of early Lyme disease. J Clin Microbiol 1995;33:419–27.
A. Floreani et al. / Digestive and Liver Disease 38 (2006) 272–275 [14] Kita H, He XS, Gershwin ME. Autoimmunity and environmental factors in the pathogenesis of primary biliary cirrhosis. Ann Med 2004;36:72–80. [15] Mayo I, Arizti P, Pares A, Oliva J, Deforno RA, de Sagarra MR, et al. Antibodies against the COOH-terminal region of E. coli ClpP protease in patients with primary biliary cirrhosis. J Hepatol 2000;33:528–36. [16] Bogdanos D-P, Baum H, Grasso A, Okamoto M, Butler P, Ma Y, et al. Microbial mimics are major targets of crossreactivity with human pyruvate dehydrogenase in primary biliary cirrhosis. J Hepatol 2004;40:31–9. [17] Kita H, Matsumura S, He XS, Ansari AA, Lian ZX, Van de Waters J, et al. Analysis of TCR antagonism and molecular mimicry of an HLA-A0201-restricted CTL epitope in primary biliary cirrhosis. Hepatology 2002;36:918–26. [18] Vilagut L, Pares A, Vinas O, Vila J, Jimenez de Anta MT, Rodes J. Antibodies to mycobacterial 65-kD heat shock protein cross-react with the main mitochondrial antigens with primary biliary cirrhosis. Eur J Clin Invest 1997;27:667–72. [19] Bogdanos DP, Pares A, Baum H, Caballeria L, Rigonopoulou EI, Ma Y, et al. Disease-specific cross-reactivity between mimicking peptides of heat shock protein of Mycobacterium gordonae and dominant epi-
[20]
[21]
[22]
[23]
[24] [25]
275
tope of E2 subunit of pyruvate dehydrogenase is common in Spanish but not British patients with primary biliary cirrshosis. J Autoimmun 2004;22:353–62. Selmi C, Balkwill DL, Invernizzi P, Ansari AA, Coppel RL, Podda M, et al. Patients with primary biliary cirrhosis react against a ubiquitous xenobiotic-metabolizing bacterium. Hepatology 2003;38:1250–7. Abdulkarim AS, Petrovic LM, Kim WR, Angulo P, Lloyd RV, Lindor KD. Primary biliary cirrhosis: an infectious disease caused by Chlamydia pneumoniae? J Hepatol 2004;40:380–4. Trollmo C, Meyer AL, Steere AC, Hafler DA, Huber BT. Molecular mimicry in Lyme arthritis demonstrated at the single cell level: LFA1 alpha L is a partial agonist for outer surface protein A-reactive T cells. J Immunol 2001;166:5286–91. Mitchison HC, Bassendine MF, Hendrick A, Bennett MK, Bird G, Watson AJ, et al. Positive antimitochondrial antibody but normal alcaline phosphatase: is this primary biliary cirrhosis? Hepatology 1986;6:1279–84. Balli F, Di Biase AR, Viola L. Autoimmune hepatitis: paediatric aspects. Pediatr Med Chir 1996;18:123–9. Floreani A. Preventative therapy in primary biliary cirrhosis. Clin Liver Dis 2003;7:911–21.
Brief Clinical Observation
Primary biliary cirrhosis: When and why does the disease develop? A. Floreani a,∗ , P.A. Ostuni b , F. Ferrara a , M. Guido c a
Department of Surgical and Gastroenterological Sciences, University of Padova, Padua, Italy b Department of Medical and Surgical Sciences, University of Padova, Padua, Italy c Department of Pathology, University of Padova, Padua, Italy
Abstract Primary biliary cirrhosis is a chronic cholestatic liver disease with an autoimmune pathogenesis, that generally develops in adult life, often in perimenopausal age. The clinical features are heterogeneous, ranging from an asymptomatic presentation to end-stage liver disease. Primary biliary cirrhosis is unknown in children and its natural history has yet to be elucidated. Following a Canadian report of primary biliary cirrhosis in two girls (16 and 15 years old), we describe a clinical case developing at 17 years of age. A temporal association between Borrelia Burgdorferi infection and diagnosis of primary biliary cirrhosis was observed. © 2006 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: AMA; Primary biliary cirrhosis
1. Introduction Primary biliary cirrhosis (PBC) is a chronic liver disease characterised by cholestasis, antimitochondrial antibody (AMA) positivity and lymphocyte-predominant portal inflammation with a variable degree of fibrosis that usually affects middle-aged women [1]. Incidental cases of PBC have hitherto been diagnosed in post-menopausal age. Table 1 summarises the mean/median age of presentation in several series of PBC. The youngest age of onset is 19 years in a French series [7]. The incidence and prevalence of PBC have increased in recent years, probably because most of the patients are diagnosed in the early, asymptomatic phase of the disease [10]. A recent study conducted in a large cohort of PBC patients followed up for up to 28 years indicates that even in the more recently diagnosed cases, this disease carries a significant morbidity and mortality [11]. PBC is unknown in children, so the earliest age at which AMA may be detected is not known. Dahlan et al. [12] recently reported two cases of PBC diagnosed at 16 and 15 years old, respectively. Both patients had earlyonset cholelithiasis and biopsy-proven stage II PBC. The ∗ Correspondence to: Division of Gastroenterologia, Via Giustiniani, 2, 35128 Padua, Italy. Tel.: +39 049 8212894; fax: +39 049 8760820. E-mail address: [email protected] (A. Floreani).
first developed progressive cholestasis and underwent liver transplantation. The second had an excellent response after ursodeoxycholic acid (UDCA) therapy. We describe a clinical case of well-documented PBC newly diagnosed in a 17-year-old girl. This is the third youngest case of PBC described in the world, and offers us an opportunity to discuss the infectious event that may have triggered the immunological damage.
2. Case report A.S., a 17-year-old girl, was admitted in April 2002 to the Rheumatology Department with arthralgia and stiffness of the fingers. She denied any alcohol intake, drug abuse or blood transfusions. She had no family history of either autoimmune or liver diseases in first-degree relatives. She appeared well, but reported pre-menstrual itching during the last 12 months and the onset of Raynaud’s phenomenon during the last 6 months. She reported having had pharyngitis and erythematous rash with a temperature of 38 ◦ C 6 months earlier, treated with antibiotics. Her physical examination was normal except for mild arthritis of several dip joints of both hands, and some hyperchromic papules in the periumbilical area. Laboratory data
1590-8658/$30 © 2006 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2006.03.001
A. Floreani et al. / Digestive and Liver Disease 38 (2006) 272–275
273
Table 1 Age at presentation of PBC patients Author
Year
Symptoms
N
Mean/median age
Range (years)
Country
Long et al. [2] Christensen et al. [3] Sasaki et al. [4] Sasaki et al. [4] Mitchison et al. [5] Balasubramaniam et al. [6] Brenard et al. [7] Brenard et al. [7] Uddenfeldt and Danielsson [8] Howel et al. [9]
1977 1980 1985 1985 1986 1990 1990 1990 2000 2000
Asymptomatic Symptomatic Asymptomatic Symptomatic Asymptomatica Asymptomatic Symptomaticb Asymptomaticb Asymptomatic and symptomatic Asymptomatic and symptomatic
20 236 120 160 29 73
47 55 51.8 48
23–62 24–78 28–78 22–76 27–74 35–75 19–83 29–90 31–78 34–82
England Europe, USA Japan Japan England USA France France Sweden England
a b
86 100
54 49.3 51.5 56 62.5
Normal alkaline phosphatase. Total number of symptomatic and asymptomatic patients = 206.
were remarkable in the following respects: ANA positivity 1:320 (speckled patter) and AMA positivity 1:160 (with confirmed M2 reactivity [74 kDa band] on immunoblotting). Liver biochemical tests (serum transaminases, alkaline phosphatase, GGT, prothrombin time, IgG, IgA, IgM) were within the normal range. Anti-ENA, ANCA and rheumatoid factor were negative, and total complement, C3 and C4 were within the normal range. Common causes of itching (thyroid disease, allergic disease, parasitic disease, lymphoma) were ruled out. HLA typing was negative for B 27. Serum IgM antibodies against Borrelia Burgdorferi were found by ELISA. IgM positivity was confirmed by recognition of reactivity in two of the three proteins (24 and 41 kDa) on Western blotting. Cultures of blood and urine were negative. Liver ultrasound revealed a normal liver size and echogenicity, and no dilation of the biliary tree. She was treated with a brief course of steroids (prednisone 25 mg/day
for 3 weeks), which prompted the total disappearance of the arthralgia and skin lesions. She was subsequently referred to the Gastroenterology Department for pre-menstrual itching and AMA positivity. Six months later, liver biochemical tests were still within the normal range. A liver biopsy was taken, which revealed a mild lymphomonocytic inflammation in some portal tracts associated with minimal duct damage, consisting in swollen bile duct cells and occasional lymphocytes within the duct. A pseudoglandular arrangement of hepatocytes was noted in the lobular parenchyma. This picture was consistent with stage I PBC (Fig. 1). The patient was started on UDCA 15 mg/(kg day) and now has a 2-year follow-up since the liver biopsy. Her liver function tests remain normal, but she is still both AMA+ve (at a titre of 1:160) and ANA+ve (at a titre of 1:160), and has an IgM above the normal range. She occasionally complains of pre-menstrual pruritus.
Fig. 1. A portal tract showing minimal duct damage consisting in swollen bile duct cells and occasional lymphocytes within the duct. A mild lymphomonocytic inflammation is also present.
274
A. Floreani et al. / Digestive and Liver Disease 38 (2006) 272–275
3. Discussion We present a case of PBC developing at the age of 17 years. This is the third youngest case described in the world, following the report on two Canadian cases (16 and 15 years of age) [12]. Lyme disease may explain the early onset of PBC in our case, while there was no apparent reason for its early presentation in the Canadian cases, except for a strong genetic predisposition in one of the two cases [12]. Our patient had complained of itching 1 year before the histological examination and had developed Raynaud’s phenomenon 6 months before her arthralgia, which was interpreted as being due to Lyme disease because she was positive for anti-B. Burgdorferi IgM antibodies. Recognition of two of the three proteins by immunoblotting (24 and 41 kDa, respectively) fulfils the recommended criteria for the serodiagnosis of Lyme disease [13]. In recent years, much more insight on the mechanisms contributing to the breakdown of immune tolerance to self antigen pyruvate dehydrogenase complex, and to the disruption of the biliary epithelial cells, has focused on the several infectious agents potentially capable of triggering the disease. Several putative infectious agents have been suggested to play a pathogenic role in PBC, including bacteria, viruses and xenobiotics [14]. Molecular mimicry between host antigens and unrelated exogenous proteins is one of the hypotheses suggested to explain how autoantibodies and unrelated exogenous proteins arise, break tolerance and lead to autoimmune disease. Evidence in support of molecular mimicry in the aetiopathogenesis of PBC comes from several models, including Escherichia coli [15,16], Psudomonas aeruginosa [17], Mycobacterium gordonae [18,19], Novosfingobium aromaticivorans [20] and Chlamydia pneumoniae [21]. To our knowledge, there is no reported evidence of molecular mimicry from B. Burgdorferi and PBC, although this relationship has been identified in autoimmune heart disease [22]. We have no anamnestic report of any tick-borne infection in our girl, but she did have pharyngitis and erythematous rash with a temperature of 38 ◦ C 6 months earlier, which was treated with antibiotics. The clinical picture suggests Lyme disease, but no skin biopsy has been performed. In our patient, Borrelia was determined in the serum 4 months after the onset of itching, but it is worth noting that the symptoms disappeared after she developed anti-Borrelia IgG antibodies. The decision to make a liver biopsy has been made despite the normality of liver function tests because the young woman was symptomatic for itching (during pre-menstrual phase) associated with AMA positivity. In fact, the finding of an AMA titre greater or equal to 1:40 is strongly suggestive of PBC even in the absence of symptoms and the presence of a normal alkaline phosphatase [23]. For the time being, the earliest age at which AMA might be detected is not known. In a multicentre survey (involving 10 Italian centres) conducted by the Italian Association for Liver Disease, an overall 42 paediatric cases of autoimmune hepatitis were collected over 18 years and no AMA+ve cases
were detected [24]. In an overall 25,000 assays of non-organspecific autoantibodies over the last 5 years at our university hospital laboratory, only one case of AMA positivity has been detected in paediatric age (in a 9-year-old), but the girl suffered from anti-phospholipid antibody syndrome, with no evidence of cholestasis [25]. In conclusion, the practical message emerging from this case report is that PBC can occur in young people, but we still do not know how early the disease can occur and the pathogenic mechanisms that trigger the immunological damage. An unexplained itching should be investigated with AMA testing even in young girls. Our own and the Canadian cases would suggest that, if AMA screening were extended to paediatric family members of index cases, then further cases of PBC in very young people would be discovered. Conflict of interest There is no conflict of interest, financially or personally, with other people or organisations that could inappropriately influence or work, all authors agree with the final version of the manuscript. References [1] Kaplan M. Primary biliary cirrhosis: past, present, and future. Gastroenterology 2002;123:1392–4. [2] Long RG, Scheuer PJ, Sherlock S. Presentation and course of asymptomatic primary biliary cirrhosis. Gastroenterology 1977;72:1204–7. [3] Christensen E, Crowe J, Doniach D, Popper H, Ranek L, Rodes J, et al. Clinical pattern and course of disease in primary biliary cirrhosis based on an analysis of 236 patients. Gastroenterology 1980;78:236–46. [4] Sasaki H, Inoue K, Higuchi K, Yasuyama T, Koyata H, Kuroki T, et al. Primary biliary cirrhosis in Japan: national survey by the subcommittee on autoimmune hepatitis. Gastroenterol Jpn 1983;20:476–85. [5] Mitchison HC, Bassendine MF, Hendrick A, Bennett M, Bird G, Watson AJ, et al. Positive antimitochondrial antibody but normal alkaline phosphatase: is this primary biliary cirrhosis? Hepatology 1986;6:1279–84. [6] Balasubramaniam K, Grambsch PM, Wiesner RH, Lindor KD, Dickson R. Diminished survival in asymptomatic primary biliary cirrhosis. Gastroenterology 1990;98:1567–71. [7] Brenard R, Degos F, Degott C, Lassoued K, Benhamou JP. La cirrhose biliaire primitive: modes actuels de presentation. Gastroenterol Clin Biol 1990;14:307–12. [8] Uddenfeldt P, Danielsson A. Primary biliary cirrhosis: survival of a cohort followed for 10 years. J Int Med 2000;248:292–8. [9] Howel D, Fischbacher CM, Bhopal RS, Gray J, Metcalf JV, James OFW. An exploratory population-based case-control study of primary biliary cirrhosis. Hepatology 2000;31:1055–60. [10] Prince MI, James OFW. The epidemiology of primary biliary cirrhosis. Clin Liver Dis 2003;7:795–819. [11] Prince M, Chetwynd A, Newman W, Metcalf J, James OFW. Asymptomatic primary biliary cirrhosis: clinical features, prognosis, and symptom progression in a large population based cohort. Gut 2004;53:865–70. [12] Dahlan Y, Smith L, Simmonds D, Douglas L, Jewell LD, Wanless I, et al. Pediatric-onset primary biliary cirrhosis. Gastroenterology 2003;125:1476–9. [13] Engstrom SM, Shoop E, Johnson RC. Immunoblot interpretation criteria for serodiagnosis of early Lyme disease. J Clin Microbiol 1995;33:419–27.
A. Floreani et al. / Digestive and Liver Disease 38 (2006) 272–275 [14] Kita H, He XS, Gershwin ME. Autoimmunity and environmental factors in the pathogenesis of primary biliary cirrhosis. Ann Med 2004;36:72–80. [15] Mayo I, Arizti P, Pares A, Oliva J, Deforno RA, de Sagarra MR, et al. Antibodies against the COOH-terminal region of E. coli ClpP protease in patients with primary biliary cirrhosis. J Hepatol 2000;33:528–36. [16] Bogdanos D-P, Baum H, Grasso A, Okamoto M, Butler P, Ma Y, et al. Microbial mimics are major targets of crossreactivity with human pyruvate dehydrogenase in primary biliary cirrhosis. J Hepatol 2004;40:31–9. [17] Kita H, Matsumura S, He XS, Ansari AA, Lian ZX, Van de Waters J, et al. Analysis of TCR antagonism and molecular mimicry of an HLA-A0201-restricted CTL epitope in primary biliary cirrhosis. Hepatology 2002;36:918–26. [18] Vilagut L, Pares A, Vinas O, Vila J, Jimenez de Anta MT, Rodes J. Antibodies to mycobacterial 65-kD heat shock protein cross-react with the main mitochondrial antigens with primary biliary cirrhosis. Eur J Clin Invest 1997;27:667–72. [19] Bogdanos DP, Pares A, Baum H, Caballeria L, Rigonopoulou EI, Ma Y, et al. Disease-specific cross-reactivity between mimicking peptides of heat shock protein of Mycobacterium gordonae and dominant epi-
[20]
[21]
[22]
[23]
[24] [25]
275
tope of E2 subunit of pyruvate dehydrogenase is common in Spanish but not British patients with primary biliary cirrshosis. J Autoimmun 2004;22:353–62. Selmi C, Balkwill DL, Invernizzi P, Ansari AA, Coppel RL, Podda M, et al. Patients with primary biliary cirrhosis react against a ubiquitous xenobiotic-metabolizing bacterium. Hepatology 2003;38:1250–7. Abdulkarim AS, Petrovic LM, Kim WR, Angulo P, Lloyd RV, Lindor KD. Primary biliary cirrhosis: an infectious disease caused by Chlamydia pneumoniae? J Hepatol 2004;40:380–4. Trollmo C, Meyer AL, Steere AC, Hafler DA, Huber BT. Molecular mimicry in Lyme arthritis demonstrated at the single cell level: LFA1 alpha L is a partial agonist for outer surface protein A-reactive T cells. J Immunol 2001;166:5286–91. Mitchison HC, Bassendine MF, Hendrick A, Bennett MK, Bird G, Watson AJ, et al. Positive antimitochondrial antibody but normal alcaline phosphatase: is this primary biliary cirrhosis? Hepatology 1986;6:1279–84. Balli F, Di Biase AR, Viola L. Autoimmune hepatitis: paediatric aspects. Pediatr Med Chir 1996;18:123–9. Floreani A. Preventative therapy in primary biliary cirrhosis. Clin Liver Dis 2003;7:911–21.