81 year old, female 81 year old, female diagnosis of primary biliary cirrhosis (PBC) in 2000, at the age of 67, based on: diagnosis of primary biliary cirrhosis (PBC) in 2000, at the age of 67, based on: increased levels of serum biliary enzymes [alkaline phosphatase (ALP), γ- glutamyl-transferase (γ-GT)] and aminotransferases [aspartate aminotransferase (AST or SGOT), alanine aminotransferase (ALT or SGPT)] positive immunological tests for antimitochondrial antibodies M2 (AMAM2) an perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) liver biopsy consistent with histological lesions compatible with “PBC stage 3, along with evidence indicative of concurrent autoimmune hepatitis (AIH) in the context of an overlapping syndrome”

the patient was also diagnosed with Hashimoto thyroiditis the patient was also diagnosed with Hashimoto thyroiditis treatment with Ursodeoxycholic Acid (UDCA) ( 1000mg b.i.d) treatment with Ursodeoxycholic Acid (UDCA) ( 1000mg b.i.d)

PRIMARY BILIARY CIRRHOSIS auto-immune mediated, chronic cholestatic liver disease auto-immune mediated, chronic cholestatic liver disease predominantly affects middle-aged women predominantly affects middle-aged women initial symptom is most often pruritus initial symptom is most often pruritus increased levels of serum biliary enzymes increased levels of serum biliary enzymes detection of AMAs with a specificity of 98% for the disease when using the most sensitive detection techniques detection of AMAs with a specificity of 98% for the disease when using the most sensitive detection techniques elevated serum IgM concentration 1 elevated serum IgM concentration 1 common the co-existance of other the autoimmune diseases common the co-existance of other the autoimmune diseases

URSODEOXYCHOLIC ACID (UDCA) UDCA is 3α,7β-dihydroxy-5β-cholan-24-oic acid. It’s a hydrophilic, non-cytototoxic/hepatotoxic bile acid - a natural bile acid in many mammals, though in very small quantities in humans.

URSODEOXYCHOLIC ACID (UDCA) first-line treatment for PBC first-line treatment for PBC not a completely curative treatment not a completely curative treatment it is the only drug approved by UFDA for the treatment of PBC 3,10 it is the only drug approved by UFDA for the treatment of PBC 3,10 delays the progression delays the progression no significant benefit at the advanced stage no significant benefit at the advanced stage improves the serum biochemical values of PBC patients improves the serum biochemical values of PBC patients prolongs the period to death or liver transplantation prolongs the period to death or liver transplantation

URSODEOXYCHOLIC ACID (UDCA) inhibition of liver cell apoptosis inhibition of liver cell apoptosis protection of cholangiocytes against cytotoxicity of hydrophobic bile acids protection of cholangiocytes against cytotoxicity of hydrophobic bile acids stimulation of impaired biliary secretion 3,5 stimulation of impaired biliary secretion 3,5

recommended dose 13-15mg/kg/day [based on the clinical guidelines for PBC by the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (ASSD)] 2,7 recommended dose 13-15mg/kg/day [based on the clinical guidelines for PBC by the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (ASSD)] 2,7 URSODEOXYCHOLIC ACID (UDCA)

IN 2002… the patient developed dermatologic lesions on both legs, which would regress each time she would discontinue the drug the patient developed dermatologic lesions on both legs, which would regress each time she would discontinue the drug the lesions, as described by the patient, were red and painful with accompanied pruritus and after the regression would leave a red-bluish colored cavity the lesions, as described by the patient, were red and painful with accompanied pruritus and after the regression would leave a red-bluish colored cavity

SKIN LESIONS

SKIN DURING REGRESSION

IN 2003… during the investigation of these lesions, a skin biopsy was performed, though it was not diagnostic for any systematic skin disease.

BIOPSY OF SKIN ERUPTION FROM THE RIGHT SHIN “The histological findings could not be considered sufficient to establish the diagnosis of panniculitis, although they could be attributed to a recent inflammation. An alteration of the histological picture by a medication cannot be excluded.”

BIOPSY OF SKIN ERUPTION FROM THE RIGHT SHIN

IN …based on the patient’s history, when each discontinuation of UDCA would lead to regression of the skin lesions, there was another effort for further investigation. …based on the patient’s history, when each discontinuation of UDCA would lead to regression of the skin lesions, there was another effort for further investigation. The patient was admitted ti Laiko General Hospital of Athens. She had discontinued UDCA 3 months prior to admission, since it was concidered to be the cause of her skin lesions, with their subsequent regression and parallel elevation of cholestatic liver enzymes and pruritus. The patient was admitted ti Laiko General Hospital of Athens. She had discontinued UDCA 3 months prior to admission, since it was concidered to be the cause of her skin lesions, with their subsequent regression and parallel elevation of cholestatic liver enzymes and pruritus.

Further work-up revealed no other systematic disease responsible for the skin lesions. Further work-up revealed no other systematic disease responsible for the skin lesions. The patient’s lesion was diagnosed as erythema nodosum and the final skin lesion, as well as the primary erythema nodosum, are postulated to be due to the use of the UDCA. The patient’s lesion was diagnosed as erythema nodosum and the final skin lesion, as well as the primary erythema nodosum, are postulated to be due to the use of the UDCA.

UDCA’S POSSIBLE DRUG RELATED SIDE EFFECTS 7 hypertension hypertension creatinine elevation creatinine elevation thrombocytopenia thrombocytopenia leukopenia leukopenia nausea vomiting nausea vomiting diarrhea diarrhea fever fever rash rash other other

fever fever hepatitis hepatitis cholangitis cholangitis vanishing bile duct syndrome vanishing bile duct syndrome liver cell failure liver cell failure severe watery diarrhea severe watery diarrhea pneumonia pneumonia interstitial lung disease interstitial lung disease convulsions convulsions mutagenic effects mutagenic effects pruritus pruritus ascites ascites death death dysuria dysuria immune-suppression immune-suppression weight gain weight gain withdrawal syndrome upon sudden discontinuation withdrawal syndrome upon sudden discontinuation UDCA’S TOXICITY SIDE EFFECTS 9

UDCA is the first line treatment of PBC UDCA is the first line treatment of PBC Erythema nodosum is not a known side effect of UDCA. Erythema nodosum is not a known side effect of UDCA.

References: 1.Working Subgroup (English version) for Clinical Practice Guidelines for Primary Biliary Cirrhosis, Guidelines for the management of primary biliary cirrhosis. Hepatology Research, 44, pp.71–90. 2.European Association for the Study of the Liver, EASL Clinical Practice Guidelines: management of cholestatic liver diseases. Journal of hepatology, 51(2), pp.237– Amaral, J.D. et al., Bile acids: regulation of apoptosis by ursodeoxycholic acid. Journal of lipid research, 50(9), pp.1721– Beuers, U., Boyer, J.L. & Paumgartner, G., Ursodeoxycholic acid in cholestasis: potential mechanisms of action and therapeutic applications. Hepatology, 28(6), pp.1449– Lazaridis, K.N., Gores, G.J. & Lindor, K.D., Ursodeoxycholic acid 'mechanisms of action and clinical use in hepatobiliary disorders'. Journal of hepatology, 35(1), pp.134– Paumgartner, G. & Beuers, U., Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Hepatology, 36(3), pp.525– Angulo, P. et al., Comparison of three doses of ursodeoxycholic acid in the treatment of primary biliary cirrhosis: a randomized trial. Journal of hepatology, 30(5), pp.830– Poupon, R. et al., Is ursodeoxycholic acid an effective treatment for primary biliary cirrhosis? The Lancet, 1(8537), pp.834– Kotb, M.A., Molecular Mechanisms of Ursodeoxycholic Acid Toxicity. International Journal of Molecular Sciences, 13(12), pp.8882– Zhang, L.-N. et al., Early biochemical response to ursodeoxycholic acid and long-term prognosis of primary biliary cirrhosis: Results of a 14-year cohort study. Hepatology, 58(1), pp.264–272.

Thank You...