Ursodeoxycholic Acid Treatment in Primary Sclerosing Cholangitis

Fig. 11.1

Bile acid physiology and circulation: an avenue for therapeutic applications. Bile acids (BAs) are synthesized by hepatocytes and subsequently secreted into canalicular bile by means of specialized hepatocyte canalicular membrane transporters. Canalicular bile drains into the biliary tree and is modified by the epithelial cells lining it, that is, cholangiocytes. Bile then drains into the proximal small bowel, that is, duodenum, and is metabolized by enteric bacteria. Approximately 95 % of BAs are reabsorbed in the terminal ileum and enter the portal vein to be recycled back to the liver via the enterohepatic circulation. Once in the sinusoids of the liver, BAs can be taken up by hepatocytes and secreted back into bile. A fraction of (unconjugated) BAs in the biliary tree is taken up by cholangiocytes at the apical membrane (i.e., prior to reaching the small intestine) and returned to the liver sinusoids via the cholehepatic shunt. Some endogenous and synthetic BAs as well as BA analogs have considerably distinct pharmacologic properties, including but not limited to the degree to which they are cholehepatically shunted (e.g., nor-UDCA being a potent stimulator of cholehepatic shunting) or their potency for agonizing receptors such as the farnesoid X receptor (e.g., obeticholic acid being a potent FXR agonist). The unique properties of some BAs and BA analogs can be harnessed for therapeutic purposes in hepatobiliary diseases including PSC; indeed, this represents an area of ongoing biomedical research. Key: AE2 anion exchange protein 2, ASBT apical sodium-dependent bile acid transporter, BSEP bile salt export pump, MRP multidrug resistance protein, NTCP Na+ (sodium)-taurocholate cotransporting polypeptide, OATP organic anion-transporting polypeptide, OST organic solute transporter, t-ASBT truncated apical sodium-dependent bile acid transporter, TGR5 G protein-coupled bile acid receptor 1 (Adapted with permission from the Mayo Foundation for Medical Education and Research. All rights reserved)

Based on studies in patients as well as various lines of experimental (e.g., model system) data, the mechanisms through which UDCA is believed to exert therapeutic effects in cholestatic disorders include dilution of hydrophobic (or otherwise “toxic”) BAs, promotion of their excretion, upregulation of the biliary bicarbonate umbrella [18, 19], immunomodulation, and anti-inflammatory actions [2, 12, 15, 20–22. In addition, recent data suggest that UDCA may have anti-senescent properties [23]; while the liver has traditionally been regarded as an organ resistant to aging [24], recent studies have shown cellular senescence (in particular cholangiocyte senescence) to be increased in PSC [5], and this finding has been regarded as a marker and driver of biliary injury [23, 25].

Perhaps somewhat surprisingly, evidence supporting a therapeutic role for UDCA in PSC (or animal models thereof) has been inconsistent, with some studies even suggesting detrimental effects at high doses (discussed further below) [19, 26, 27]. As a result, because of the lack of consistently perceived benefits, in their respective practice guidelines, the American Association for the Study of Liver Diseases (AASLD) [21] and European Association for the Study of the Liver (EASL) [20] advise against and provide no specific recommendation, respectively, regarding the use of UDCA in patients with PSC.

Clinical Trials of UDCA in PSC

The earliest clinical studies of UDCA were published in the late 1980s [21, 28, 29] and, albeit uncontrolled, demonstrated promising symptomatic and objective improvements among patients with PSC [30]. These studies soon led to the first randomized controlled trial (RCT) of UDCA, which demonstrated significant improvements in multiple biochemical end points as well as in liver histology [31]. Since then, seven other RCTs have been conducted, initially with low (10–15 mg per kg body weight per day [mg/kg/d])-, then intermediate (17–23 mg/kg/day)-, and most recently high-dose (28–30 mg/kg/day) UDCA (Table 11.1) [14]. While low-dose UDCA was repeatedly shown to yield biochemical improvements, it has not been convincingly shown to improve outcomes, and thus its routine use in PSC is not recommended [21].

Table 11.1

Characteristics and results of randomized trials comparing UDCA vs. placebo (or no treatment) in patients with PSC

Lead author	Year	n	% male	% IBD	Daily dosage (mg)	Dose	Study duration (years)	Outcomes
								Death/LT, n (%)		Cholangio CA		Histologic progression
								UDCA	Ctrl	UDCA	Ctrl	UDCA	Ctrl
Beuers [31]	1992	14	79 %	79 %	600–800	Low	1	0 %	0 %	NA	NA	0 %	16.7 %
Lo [41]	1992	18	61 %	61 %	200	Low	2	0 %	0 %	NA	NA	NA	NA
Stiehl [42]	1994	20	NA	NA	500–1000	Low	.25	0 %	0 %	NA	NA	NA	NA
De Maria [43]	1996	40	70 %	70 %	750–1,500	Low	2	0 %	0 %	NA	NA	NA	NA
Lindor [44]	1997	102	60 %	60 %	600–800	Low	2	7.8 %	5.9 %	0 %	5.9 %	15.7 %	5.9 %
Mitchell [32]	2001	26	73 %	73 %	20/Kg	Interm.	2	0 %	7.7 %	0 %	0 %	18.2 %	50.0 %
Olsson [33]	2005	198	70 %	70 %	500–1000	Interm.	5	2.1 %	3.0 %	3.1 %	4.0 %	NA	NA
Lindor [19]	2009	149	58 %	557	750–1,500	High	6	6.6 %	4.1 %	2.6 %	2.7 %	NA	NA