• 81 year old, female

• 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

• treatment with Ursodeoxycholic Acid (UDCA) ( 1000mg b.i.d)

PRIMARY BILIARY CIRRHOSIS

• auto-immune mediated, chronic cholestatic liver disease

• predominantly affects middle-aged women

• initial symptom is most often pruritus

• increased levels of serum biliary enzymes

• detection of AMAs with a specificity of 98% for the disease when using the most sensitive detection techniques

• elevated serum IgM concentration1

• 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

• not a completely curative treatment

• it is the only drug approved by UFDA for the treatment of PBC3,10

• delays the progression

• no significant benefit at the advanced stage

• improves the serum biochemical values of PBC patients

• prolongs the period to death or liver transplantation

URSODEOXYCHOLIC ACID (UDCA)

• inhibition of liver cell apoptosis

• protection of cholangiocytes against cytotoxicity of hydrophobic bile acids

• stimulation of impaired biliary secretion3,5

• 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

URSODEOXYCHOLIC ACID (UDCA)

IN 2002…

• 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

SKIN LESIONS

SKIN DURING REGRESSION

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.”

IN 2007..

• …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.

• 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.

UDCA’S POSSIBLE DRUG RELATED

SIDE EFFECTS7

• hypertension

• creatinine elevation

• thrombocytopenia

• leukopenia

• nausea vomiting

• diarrhea

• fever

• rash

• other

• fever

• hepatitis

• cholangitis

• vanishing bile duct syndrome

• liver cell failure

• severe watery diarrhea

• pneumonia

• interstitial lung disease

• convulsions

• mutagenic effects

• pruritus

• ascites

• death

• dysuria

• immune-suppression

• weight gain

• withdrawal syndrome upon sudden discontinuation

UDCA’S TOXICITY SIDE EFFECTS9

• UDCA is the first line treatment of PBC

• Erythema nodosum is not a known side effect

of UDCA.

References:1. Working Subgroup (English version) for Clinical Practice Guidelines for Primary Biliary Cirrhosis, 2014. Guidelines for

the management of primary biliary cirrhosis. Hepatology Research, 44, pp.71–90.

2. European Association for the Study of the Liver, 2009. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. Journal of hepatology, 51(2), pp.237–267.

3. Amaral, J.D. et al., 2009. Bile acids: regulation of apoptosis by ursodeoxycholic acid. Journal of lipid research, 50(9), pp.1721–1734.

4. Beuers, U., Boyer, J.L. & Paumgartner, G., 1998. Ursodeoxycholic acid in cholestasis: potential mechanisms of action and therapeutic applications. Hepatology, 28(6), pp.1449–1453.

5. Lazaridis, K.N., Gores, G.J. & Lindor, K.D., 2001. Ursodeoxycholic acid 'mechanisms of action and clinical use in hepatobiliary disorders'. Journal of hepatology, 35(1), pp.134–146.

6. Paumgartner, G. & Beuers, U., 2002. Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Hepatology, 36(3), pp.525–531.

7. Angulo, P. et al., 1999. Comparison of three doses of ursodeoxycholic acid in the treatment of primary biliary cirrhosis: a randomized trial. Journal of hepatology, 30(5), pp.830–835.

8. Poupon, R. et al., 1987. Is ursodeoxycholic acid an effective treatment for primary biliary cirrhosis? The Lancet, 1(8537), pp.834–836.

9. Kotb, M.A., 2012. Molecular Mechanisms of Ursodeoxycholic Acid Toxicity. International Journal of Molecular Sciences, 13(12), pp.8882–8914.

10.Zhang, L.-N. et al., 2013. 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.

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