primary biliary cirrhosis ( pbc ) is an autoimmune liver disease characterized by the development of autoantibodies ( ama ) directed against mitochondrial components , antibodies against nuclear components , such as anti - sp100 and anti - gp 210 , and by progressive destruction of the intrahepatic bile ducts , resulting in fibrosis , cirrhosis , and finally liver failure ( 1 , 2 ) .
tumor necrosis factor- ( tnf- ) might be related to both the severity and prognosis of patients with pbc ( 3 ) .
crohn 's disease ( cd ) is frequently associated with a number of extraintestinal manifestations .
many hepatobiliary disorders could complicate its course , with some of them , including autoimmune thyroiditis ( 4 ) , harboring immunological mechanisms in their pathogenesis .
the treatment of cd with anti - tnf- agents has dramatically changed the outcome of the disease . on the other hand ,
the treatment of pbc is mainly symptomatic aiming to restore the increased levels of cholestatic liver enzymes , and reduce the severity of clinical symptoms .
we describe herein the case of a male patient with long - standing cd who developed autoimmune hassimoto thyroiditis , pbc , and raynaud 's phenomenon , during the course of long - standing cd of the small bowel . in this patient , the underlying cd , and
a male patient , aged 48 , was admitted in our department in 2009 , complaining mostly of diarrhoea , loss of weight , fatigue , and arthralgias .
the family history revealed that his son , aged 17 , was suffering from cd of the large bowel accompanied by extraintestinal manifestations ( arthritis ) .
his mother was suffering from systemic lupus erythematosus , while his sister from sjogren 's syndrome . from his past history , he mentioned cd of the small bowel accompanied by perineal fistula , diagnosed in 1994 .
two years after the establishment of diagnosis of cd , he underwent total thyroidectomy because of hyperthyroidism were not responding to conservative treatment .
the histology of the surgical specimen revealed that hyperthyroidism developed on the ground of thyroiditis hassimoto .
in the subsequent years , cd was running with exacerbations of mild to moderate severity that promptly responded to oral administration of steroids and mesalamine .
the patient did not receive azathioprine because of serious side - effects . in 2004 , because of a severe flare - up of the disease he was treated with infliximab 5mg / kg bw .
although the biologic agent resulted in favorable clinical and laboratory effects , it was interrupted after 4 sessions , because of the appearance of high fever attributed to the drug itself . at that time ,
an abdominal ct scan revealed liver enlargement and a thickness of many loops of both jejunum and ileum . on admission in our department in 2009 , the laboratory investigation revealed esr 85 mm , hct 35.1% , hb 11.8g / dl , fibrinogen 517 mg / dl ( n.v .
renal function tests , serum amylase , serum albumin , serum electrolytes , and tumor markers were normal .
< 200 ) , hdl 56 mg / dl ( n.v . > 40 ) , ldl 178 mg / dl ( n.v .
hepatitis b and c serum antibodies , p - anca , c - anca , anti - mpo , anti - pr3 , anti - endomysium , anti - gliadine ( g & a ) , and anti - ttg ( g & a ) were negative .
however , anti - tg , anti - nuclear , anti - microsomial , antimitochondrial and anti - m2 serum autoantibodies revealed significantly higher values above the normal limits [ 2700 iu / ml ( n.v . < 200 ) , 1:640 ( n.v .
1:80 ) , 4100 iu / ml ( n.v . < 100 ) , 1:360 ( n.v .
serum igg was 1560 mg / dl , iga 290 mg / dl ( n.v .
serum inflammatory indices , including crp and a1-acid - glycoprotein , were increased [ 36 mg / l ( n.v <3 ) and 1.61 g / l ( n.v .
abdominal mri revealed no abnormal findings from biliary tract , gallbladder , pancreas and liver .
however , mri enterography showed the involvement of cd of multiple ileal loops , liver and spleen enlargement , and a small dilation of portal vein and of veins in the portal of spleen .
the small bowel follow - through confirmed the involvement of many loops of jejunum and ileum .
because of the previous intolerance of infliximab , the patient was treated with adalimumab 160 mg , then 80 mg and finally 40 mg every other week .
anti - m2 antibodies remained positive . in 2011 , ursodeoxucholic acid ( 200mgx2/d ) was added , and was well tolerated . in 2012 ,
the latest ( 2012 ) laboratory investigation revealed no anemia with slightly elevated values of liver cholestatic enzymes .
the titre of antimitochondrial antibodies further reduced to 1:80 . during the 3-year treatment with adalimumab
we plan to continue the treatment with both the biologic agent and the ursodeoxycholic acid for the next few years . 

table 1 shows the values of cholestatic enzymes and serum ama in different time periods before and after the treatment with adalimumab . 
 
liver function tests in different time periods numbers in parentheses are normal values date of starting treatment with a dalimumab
the described case presents some interesting clinical and epidemiological characteristics . the patient was a man with long - standing cd , having many members of his family suffering from a variety of autoimmune disorders .
during the course of cd i ) he developed clinical symptoms of severe hyperthyroidism and as a consequence , he underwent total thyroidectomy the histology of which revealed that hyperthyroidism developed on the ground of hashimoto thyroiditis , ii ) for a long period of time he was suffering from raynaud 's phenomenon , iii ) the laboratory investigation revealed that he was also suffering from pbc . in this patient , the treatment with an anti - tnf- agent ( adalimumab ) resulted not only in a significant improvement of both cd and perineal disease , but also in a significant reduction in the values of cholestatic enzymes and serum titres of ama after a 4-month period . moreover , during the 3-year administration of adalimumab , reynaud 's phenomenon did not appear again .
his clinical situation is now quite satisfactory and we plan to continue the administration of adalimumab at least for the next years .
however , many questions should be addressed concerning the diagnosis and clinical outcome in this patient : i ) how strong is the diagnosis of pbc ? , ii ) are indeed the improvement of the titers of both serum ama and liver enzymes , due to the administration of the biologic agent ? , iii ) might the appearance of thyroid disease with other autoimmune disorders on the ground of cd be considered as an appearance by chance ?
as far as the accuracy of the diagnosis of pbc is concerned , it is widely accepted that this diagnosis could be safely done if at least two of the following three criteria were fulfilled : i.e. serum ama titers > 1:40 , increased serum alkaline phosphatase levels for more than 6 months , and compatible liver histology in the absence of alternative explanation .
however , liver biopsy at the time of diagnosis is currently not indicated except for patients participating in clinical trials and patients requiring accurate staging ( 6 ) .
generally , high serum titers of ama are seen in more than 90% of patients with pbc ( 7 ) , while low - titers are considered to be not specific ( 8) . in our patient ,
the titers of ama and the levels of serum cholestatic enzymes were very high , thus establishing the diagnosis of pbc .
today , the increased availability of serological tests have resulted in the establishment of diagnosis of pbc in a very early and almost asymptomatic clinical stage , as it was happened in the reported patient ( 9 ) .
other immunological serum findings in patients with pbc include the presence of anti - nuclear ( ana ) and anti - smooth muscle antibodies in about 50% of them , a finding that has been linked to a worse prognosis ( 10 ) .
the serum immunoglobulin m levels are also elevated without being correlated to the ama levels . in our patient
, the serum titers of ana were very high , while the levels of serum immunoglobulin m were also above the upper normal limit .
these antibodies have been correlated to elevated iga in patients with pbc suggesting that they might be an indirect sign of an enhanced mucosal immunity ( 11 ) .
it has been long suggested that serum tnf- production is related to the severity and prognosis of pbc ( 12 ) .
moreover , it has been shown that both the levels of serum tnf- and transforming growth factor- could be reduced in patients with pbc as a result of the treatment with ursodeoxycholic acid ( 13 ) .
the patient responded well to the anti - tnf- treatment with etanercept but not with infliximab .
arthritis , and serum levels of cholestatic liver enzymes , improved and this improvement persisted during a 30-month follow - up period ( 14 ) . to the best of our knowledge , our patient is the only case of concurrent pbc , cd and raynaud 's phenomenon described so far , in whom the biologic agent adalimumab was administered .
adalimumab resulted in a great reduction in the serum titers of ama and cholestatic enzymes and a significant clinical improvement .
although the combined results of recent metaanalysis regarding the role of ursodeoxycholic acid in pbc demonstrated no significant favourable effects concerning mortality , pruritus , fatigue , autoimmune conditions , liver histology , and portal pressure , we decided to add this agent in the therapeutic regime because it seems to improve some biochemical variables , like serum bilirubin and jaundice ( 15 ) .
thyroid dysfunction is frequently associated with both pbc and cd sometimes predating the diagnosis of both diseases ( 16 ) .
an imbalance of t cell regulation can initiate or propagate autoimmunity in both inflammatory bowel disease and pbc . in both disorders genetic , environmental and infectious agents
it is concluded that the appearance of pbc during the course of cd , although quite rare , is a reality .
extremely rare is also the combination of cd and pbc with autoimmune thyroiditis and raynaud 's phenomenon .
it is not clear whether these co - morbidities appeared coincidentally or because they share some common immunopathogenetic elements .
 we describe the case of a male patient suffering from long - lasting crohn 's disease of the small bowel who developed thyroiditis hassimoto , raynaud 's phenomenon , and primary biliary cirrhosis , during the course of the underlying bowel disease . 
 it is not clear whether these co - morbidities appeared coincidentally , or because they share some common immunopathogenetic mechanisms . in this patient , 
 crohn 's disease favorably responded to the treatment with an anti - tnf- agent ( adalimumab ) . 
 the serum titers of antimitochondrial antibodyies and cholestatic enzymes considerably reduced during the 3-year treatment with the biologic agent . 
 raynaud 's phenomenon , also , completely disappeared . 
 bearing in mind the possible involvement of tnf- in the pathogenesis of primary biliary cirrhosis , it could be argued that the clinical and laboratory improvement of liver disease , as well as the reduction in serum titers of antimitochondrial antibodies , might be due to the anti - tnf- action of adalimumab . 
 we suggest that it would be worth further investigating the role of biologic agents in the treatment of patients with primary biliary cirrhosis . 
Introduction
Case Report
Discussion