Combination Therapy of All-Trans Retinoic Acid With Ursodeoxycholic Acid in Patients With Primary Sclerosing Cholangitis

A Human Pilot Study

David N. Assis, Osama Abdelghany, Shi Ying Cai, Andrea A. Gossard, John E. Eaton, Jill C. Keach, Yanhong Deng, Kenneth D R Setchell, Maria Ciarleglio, Keith Lindor, James L. Boyer

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

GOALS:: To perform an exploratory pilot study of all-trans retinoic acid (ATRA) combined with ursodeoxycholic acid (UDCA) in patients with primary sclerosing cholangitis (PSC). BACKGROUND:: PSC is a progressive disorder for which there is no accepted therapy. Studies in human hepatocyte cultures and in animal models of cholestasis indicate that ATRA might have beneficial effects in cholestatic disorders. STUDY:: ATRA (45 mg/m/d, divided and given twice daily) was combined with moderate-dose UDCA in patients with PSC who had incomplete response to UDCA monotherapy. The combination was administered for 12 weeks, followed by a 12-week washout in which patients returned to UDCA monotherapy. We measured alkaline phosphatase (ALP), alanine aminotransferase (ALT), bilirubin, cholesterol, bile acids, and the bile acid intermediate 7α-hydroxy-4-cholesten-3-one (C4) at baseline, week 12, and after washout. RESULTS:: Fifteen patients completed 12 weeks of therapy. The addition of ATRA to UDCA reduced the median serum ALP levels (277±211 to 243±225 U/L, P=0.09) although this, the primary endpoint, did not reach significance. In contrast, median serum ALT (76±55 to 46±32 U/L, P=0.001) and C4 (9.8±19 to 7.9±11 ng/mL, P=0.03) levels significantly decreased. After washout, ALP and C4 levels nonsignificantly increased, whereas ALT levels significantly increased (46±32 to 74±74, P=0.0006), returning to baseline. CONCLUSIONS:: In this human pilot study, the combination of ATRA and UDCA did not achieve the primary endpoint (ALP); however, it significantly reduced ALT and the bile acid intermediate C4. ATRA appears to inhibit bile acid synthesis and reduce markers of inflammation, making it a potential candidate for further study in PSC (NCT 01456468).

Original languageEnglish (US)
JournalJournal of Clinical Gastroenterology
DOIs
StateAccepted/In press - Jul 14 2016

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Ursodeoxycholic Acid
Sclerosing Cholangitis
Tretinoin
Bile Acids and Salts
Alanine Transaminase
Alkaline Phosphatase
Therapeutics
Cholestasis
Serum
Bilirubin
Hepatocytes
Animal Models
Cholesterol
Inflammation

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Combination Therapy of All-Trans Retinoic Acid With Ursodeoxycholic Acid in Patients With Primary Sclerosing Cholangitis : A Human Pilot Study. / Assis, David N.; Abdelghany, Osama; Cai, Shi Ying; Gossard, Andrea A.; Eaton, John E.; Keach, Jill C.; Deng, Yanhong; Setchell, Kenneth D R; Ciarleglio, Maria; Lindor, Keith; Boyer, James L.

In: Journal of Clinical Gastroenterology, 14.07.2016.

Research output: Contribution to journalArticle

Assis, David N. ; Abdelghany, Osama ; Cai, Shi Ying ; Gossard, Andrea A. ; Eaton, John E. ; Keach, Jill C. ; Deng, Yanhong ; Setchell, Kenneth D R ; Ciarleglio, Maria ; Lindor, Keith ; Boyer, James L. / Combination Therapy of All-Trans Retinoic Acid With Ursodeoxycholic Acid in Patients With Primary Sclerosing Cholangitis : A Human Pilot Study. In: Journal of Clinical Gastroenterology. 2016.
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abstract = "GOALS:: To perform an exploratory pilot study of all-trans retinoic acid (ATRA) combined with ursodeoxycholic acid (UDCA) in patients with primary sclerosing cholangitis (PSC). BACKGROUND:: PSC is a progressive disorder for which there is no accepted therapy. Studies in human hepatocyte cultures and in animal models of cholestasis indicate that ATRA might have beneficial effects in cholestatic disorders. STUDY:: ATRA (45 mg/m/d, divided and given twice daily) was combined with moderate-dose UDCA in patients with PSC who had incomplete response to UDCA monotherapy. The combination was administered for 12 weeks, followed by a 12-week washout in which patients returned to UDCA monotherapy. We measured alkaline phosphatase (ALP), alanine aminotransferase (ALT), bilirubin, cholesterol, bile acids, and the bile acid intermediate 7α-hydroxy-4-cholesten-3-one (C4) at baseline, week 12, and after washout. RESULTS:: Fifteen patients completed 12 weeks of therapy. The addition of ATRA to UDCA reduced the median serum ALP levels (277±211 to 243±225 U/L, P=0.09) although this, the primary endpoint, did not reach significance. In contrast, median serum ALT (76±55 to 46±32 U/L, P=0.001) and C4 (9.8±19 to 7.9±11 ng/mL, P=0.03) levels significantly decreased. After washout, ALP and C4 levels nonsignificantly increased, whereas ALT levels significantly increased (46±32 to 74±74, P=0.0006), returning to baseline. CONCLUSIONS:: In this human pilot study, the combination of ATRA and UDCA did not achieve the primary endpoint (ALP); however, it significantly reduced ALT and the bile acid intermediate C4. ATRA appears to inhibit bile acid synthesis and reduce markers of inflammation, making it a potential candidate for further study in PSC (NCT 01456468).",
author = "Assis, {David N.} and Osama Abdelghany and Cai, {Shi Ying} and Gossard, {Andrea A.} and Eaton, {John E.} and Keach, {Jill C.} and Yanhong Deng and Setchell, {Kenneth D R} and Maria Ciarleglio and Keith Lindor and Boyer, {James L.}",
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T1 - Combination Therapy of All-Trans Retinoic Acid With Ursodeoxycholic Acid in Patients With Primary Sclerosing Cholangitis

T2 - A Human Pilot Study

AU - Assis, David N.

AU - Abdelghany, Osama

AU - Cai, Shi Ying

AU - Gossard, Andrea A.

AU - Eaton, John E.

AU - Keach, Jill C.

AU - Deng, Yanhong

AU - Setchell, Kenneth D R

AU - Ciarleglio, Maria

AU - Lindor, Keith

AU - Boyer, James L.

PY - 2016/7/14

Y1 - 2016/7/14

N2 - GOALS:: To perform an exploratory pilot study of all-trans retinoic acid (ATRA) combined with ursodeoxycholic acid (UDCA) in patients with primary sclerosing cholangitis (PSC). BACKGROUND:: PSC is a progressive disorder for which there is no accepted therapy. Studies in human hepatocyte cultures and in animal models of cholestasis indicate that ATRA might have beneficial effects in cholestatic disorders. STUDY:: ATRA (45 mg/m/d, divided and given twice daily) was combined with moderate-dose UDCA in patients with PSC who had incomplete response to UDCA monotherapy. The combination was administered for 12 weeks, followed by a 12-week washout in which patients returned to UDCA monotherapy. We measured alkaline phosphatase (ALP), alanine aminotransferase (ALT), bilirubin, cholesterol, bile acids, and the bile acid intermediate 7α-hydroxy-4-cholesten-3-one (C4) at baseline, week 12, and after washout. RESULTS:: Fifteen patients completed 12 weeks of therapy. The addition of ATRA to UDCA reduced the median serum ALP levels (277±211 to 243±225 U/L, P=0.09) although this, the primary endpoint, did not reach significance. In contrast, median serum ALT (76±55 to 46±32 U/L, P=0.001) and C4 (9.8±19 to 7.9±11 ng/mL, P=0.03) levels significantly decreased. After washout, ALP and C4 levels nonsignificantly increased, whereas ALT levels significantly increased (46±32 to 74±74, P=0.0006), returning to baseline. CONCLUSIONS:: In this human pilot study, the combination of ATRA and UDCA did not achieve the primary endpoint (ALP); however, it significantly reduced ALT and the bile acid intermediate C4. ATRA appears to inhibit bile acid synthesis and reduce markers of inflammation, making it a potential candidate for further study in PSC (NCT 01456468).

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