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, 3 (11), 1482-1495
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A Prospective Trial of Withdrawal and Reinstitution of Ursodeoxycholic Acid in Pediatric Primary Sclerosing Cholangitis

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A Prospective Trial of Withdrawal and Reinstitution of Ursodeoxycholic Acid in Pediatric Primary Sclerosing Cholangitis

Dennis D Black et al. Hepatol Commun.

Abstract

Ursodeoxycholic acid (UDCA) is commonly used to treat several liver disorders in adults and children, including primary sclerosing cholangitis (PSC) for which it is not U.S. Food and Drug Administration approved. UDCA treatment has an uncertain impact on disease outcomes and has been reported in high doses to be associated with worse outcome in adults with PSC. In this context, controlled withdrawal and reintroduction of UDCA in children with PSC were studied. Prior to study initiation, participants were required to have alanine aminotransferase (ALT) and gamma-glutamyl transpeptidase (GGT) <2 times the upper limit of normal on stable UDCA dosing. The study included four phases: I (stable dosing), II (50% UDCA reduction), III (UDCA discontinuation), IV (UDCA reintroduction), with a primary endpoint of change in ALT and GGT between phases I and III. We enrolled 27 participants (22 completed) between March 2011 and June 2016. Changes in mean ALT and GGT between phases I and III were ALT, +29.5 IU/L (P = 0.105) and GGT, +60.4 IU/L (P = 0.003). In 7 participants, ALT and GGT ≤29 IU/L did not rise above 29 IU/L (null response group). Eight participants had increases of ALT or GGT >100 IU/L (flare group). None developed elevated bilirubin. All flares responded to UDCA reinstitution. Serum GGT, interleukin-8, and tumor necrosis factor α levels were higher in the flare group at baseline. Liver biochemistries increased in children with PSC during controlled UDCA withdrawal; one third increased above 100 IU/L and one third remained normal during UDCA withdrawal. Conclusion: The impact of prolonged UDCA use in childhood PSC and the significance of a biochemical flare are unclear. Further studies of the natural history and treatment of pediatric PSC and UDCA use are needed.

Figures

Figure 1
Figure 1
Serum ALT and GGT levels in study participant response groups. (A,B) Null group; (C,D) flare group; (E,F) indeterminant group. The y axis shows serum levels, and the x axis shows study week and phase. Colored lines depict individual participants. In the flare group (C,D), visits 8S and 12S are off‐study visits and red arrows indicate time of early reinstitution of UDCA due to SDF in 2 participants.
Figure 2
Figure 2
Serum ALT and GGT levels for study endpoints. (A) Results of the analysis of change in serum ALT and GGT levels from study baseline to end of phase III for total participants and response groups. (B) Change in serum ALT and GGT levels from baseline to maximum values in phases II and III. (C) Change in serum ALT and GGT levels from the end of phase III to the end of phase IV. (D) Change in serum ALT and GGT levels from the maximum value in phases II and III to the minimum value in phase IV. Data in all panels represent mean + SD. P values shown at the top of bars for test of within‐group change between the two time points were calculated using paired t test.
Figure 3
Figure 3
Baseline plasma levels from 4 null, 8 flare, and 7 indeterminant participants. (A) IL‐8 and (B) TNF‐α treatment response groups. Null, circle; flare, square; indeterminant, triangle. Each symbol represents an individual participant. Horizontal lines depict mean and SD for each group.
Figure 4
Figure 4
Plasma UDCA levels in 13 study participants at baseline (circle) and at 16 (square) and 24 (triangle) weeks. Each line represents an individual participant.

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