Nor-ursodeoxycholic acid in hepatobiliary diseases: A narrative review

Abstract

Nor-ursodeoxycholic acid (nor-UDCA) is a side-chain shortened analogue of ursodeoxycholic acid (UDCA). Because of its biochemical modification, it is resistant to amidation. Nor-UDCA undergoes cholehepatic shunt, leading to increased bicarbonate secretion. In addition, it has shown potential antifibrotic activity in the animal model of cholestasis and fibrosis. Nor-UDCA has several advantages over UDCA in its pharmacokinetic and pharmacodynamic properties. However, its safety and efficacy data on cholestatic diseases are largely extrapolated from pre-clinical animal studies. Vitamin E, resmetirom, peroxisome proliferator-activated receptor agonists, and incretin-based therapies dominate the pharmacotherapeutic armamentarium for metabolic dysfunction-associated steatotic liver disease or steatohepatitis. Recently, nor-UDCA has been evaluated in patients with metabolic dysfunction-associated steatotic liver disease with conflicting therapeutic benefits and a controversial trial endpoint. This comprehensive narrative review focuses on its novel mechanism of action, comparison with UDCA, and underscores the limited evidence of its safety and efficacy in various hepatobiliary diseases. This review also discusses future research prospects of nor-UDCA in hepato-biliary diseases, which addresses the research gap in existing literature.

Key Words: Nor-ursodeoxycholic acid; Norucholic acid; Primary sclerosing cholangitis; Cholehepatic shunt; Bicarbonate umbrella; Metabolic dysfunction-associated steatotic liver disease

Core Tip: Nor-ursodeoxycholic acid or norucholic acid is a short-chain shortened derivative of ursodeoxycholic acid. Pre-clinical animal studies have revealed conflicting results. Clinical data on primary cholestatic liver diseases and metabolic dysfunction-associated liver diseases are also limited. This narrative review comprehensively explores the mechanism of action and discusses the pharmacokinetics and pharmacodynamic differences with ursodeoxycholic acid. It also addresses the potential gap in the literature regarding the role of nor-ursodeoxycholic acid in metabolic dysfunction-associated liver diseases and primary sclerosing cholangitis based on primitive data.

INTRODUCTION

24-norursodeoxycholic acid (nor-UDCA), also known as norucholic (NCA) acid, is a side-chain-shortened C23 homologue of ursodeoxycholic acid (UDCA)[1]. Evidence from recent animal data suggests it has an antifibrotic activity and can be beneficial in patients with metabolic dysfunction-associated steatotic liver diseases (MASLD)[1,2]. However, data on its comparative therapeutic benefits in patients with MASLD are scarce. Current therapeutic strategies in MASLD focus on the resolution of inflammation, reduction of steatosis and fibrosis[3]. With the advent of newer drugs, glucagon-like-peptide 1 receptor agonists, i.e. semaglutide, GLP-glucose-dependent inhibitory polypeptide co-agonist (tirzepatide), thyroid β receptor agonists (resmetirom), and peroxisome proliferator receptor agonists (saroglitazar), the positioning of nor-UDCA in the management of patients with MASLD remains a challenge. Because of its limited data, poor quality of evidence and lack of trials in paired-biopsy proven patients with MASLD, it is not approved by major drug safety authorities[3-8]. Hence, limited data and uncertain efficacy discourage practising physicians, gastroenterologists, and hepatologists from prescribing nor-UDCA for the management of MASLD[9]. However, nor-UDCA has been tried in patients with primary cholestatic liver diseases, such as primary sclerosing cholangitis (PSC), with promising results[10]. Given its novel mechanism of action and additional anti-inflammatory and antifibrotic properties in animal studies, the role of nor-UDCA in various hepatobiliary disorders is worth exploring. However, data on nor-UDCA for primary cholestatic diseases should not be extrapolated to manage patients with MASLD.

This comprehensive narrative review focuses on its comparative mechanism of action, current evidence-based safety, and efficacy in different hepatobiliary diseases. It also critically analyses the recent trials on nor-UDCA and discusses future research prospects of nor-UDCA in hepato-biliary diseases, which could address the gap in existing literature.

MECHANISM OF ACTION

Bile acids are steroids which are synthesized from cholesterol[11,12]. Side chain shortening has been shown to alter the physiological properties of bile acids[1,13]. The effects of side-chain length were evaluated in a study by Yoon et al[14]. C23-nor-UDCA was synthesised in radioactive and non-radioactive form. In animal studies, the biliary half-life of nor-UDCA was prolonged compared with other taurine- or glycine-conjugated derivatives. Side-chain-shortened UDCA has shown various unique protective properties for the biliary epithelium and hepatocytes. Because of its peculiar biochemical property, nor-UDCA escapes deamidation and undergoes cholehepatic shunt. Compared with UDCA and other conjugated derivatives, nor-UDCA has a longer biliary half-life due to extensive cholehepatic shunting (Figure 1). Additionally, unlike other bile acid derivatives, it has demonstrated anti-inflammatory, antifibrotic, immunomodulatory and hepatoprotective roles in animal models[12-14].

Figure 1 Effects of nor-ursodeoxycholic acid in the hepatobiliary system. Nor-ursodeoxycholic acid stimulates choleresis and bicarbonate secretion. An unconjugated fraction of nor-ursodeoxycholic acid is secreted into the canalicular biliary system and protonated by hydrogen ions. Hydrogen is generated from carbonic acid, which is synthesised from the hydration of luminal carbon dioxide by carbonic anhydrase. Protonated bile acids are absorbed and generate bicarbonate ions. The bile acid diffuses through cholangiocytes and returns to sinusoids via periductal capillary channels and is secreted into bile. UDCA: Ursodeoxycholic acid; CA: Carbonic anhydrase.

NOR-UDCA IN CHOLESTASIS

Various studies in animal models have demonstrated its effects in intrahepatic [multidrug resistant (mdr^-/-) knock-out mice] and extrahepatic biliary (bile duct ligated mouse model) cholestasis. Nor-UDCA induces choleresis with a linear increase in bicarbonate secretion. An unconjugated fraction of nor-UDCA is secreted into the canalicular biliary system and protonated by hydrogen ions[1,14]. The hydrogen is derived from the carbonic acid that is derived from the hydration of luminal carbon dioxide by carbonic anhydrase (Figure 1). Carbonic anhydrase activity has been demonstrated in the biliary epithelium[14]. Protonated bile acid is absorbed, and it generates bicarbonate ions. Bile acids leak through cholangiocytes and return to sinusoids via periductal capillary channels and are secreted into bile (Figure 1).

Halilbasic et al[15] have demonstrated similar results in mdr-knock-out mice. The hepato-biliary pathophysiology of PSC mimics the mdr2^-/- mice model. Nor-UDCA underwent extensive hydroxylation, sulfation and glucuronidation, which in turn increased the hydrophilicity of biliary secretion[14,15]. The investigators attributed its beneficial effects to a strong stimulation of biliary bicarbonate secretion[15]. It enhanced biliary fluid secretion through a bicarbonate-dependent mechanism, thereby providing a protective shield for cholangiocytes (Figure 1). The novel mechanism and benefits of UDCA-derivative were limited to nor-UDCA. Tauro-nor-UDCA and di-nor-UDCA did not demonstrate a cholangio-protective role in the study. Notably, nor-UDCA improved cholangitis and fibrosis in mdr (-/-) mice[15-17].

ANTI-INFLAMMATORY AND ANTI-FIBROTIC ACTIVITY

Zhu et al[18] investigated the potential immunoregulatory role of nor-UDCA in cluster of differentiation-8+ (CD8+) T cell-mediated liver injury. Hepatic injury was induced by infecting them with non-cytolytic lymphocytic choriomeningitis virus. It causes CD8+ T cell recruitment into the hepatocyte. By suppressing lymphoblastogenesis, nor-UDCA ameliorated CD8+ T cell-mediated liver injury in a mouse model. The antifibrotic activity of nor-UDCA was tested in thioacetamide-treated rats[19]. Thioacetamide induces fibrosis and increased hepatic hydroxyproline content. Following the treatment with nor-UDCA, liver hydroxyproline, serum transforming growth factor-β, and type IV collagen declined (Figure 2). Both UDCA and nor-UDCA were more effective than placebo in reducing type I collagen and procollagen III N-terminal. Nor-UDCA was more effective in reducing serum fibrosis markers[20]. Its antifibrotic activity is attributed to its inhibitory effects on procollagen mRNA expression in periductal myofibroblasts. In contrast, UDCA was shown to increase collagen mRNA expression[20,21]. However, it was conducted in a very small sample size of animals, hence the findings cannot be completely extrapolated. More experimental data are warranted to establish its anti-inflammatory and anti-fibrotic activity in hepatocytes[19]. Unlike UDCA, nor-UDCA does not act on farnesoid-X receptor; however, its anti-inflammatory property is attributed to downregulation of the transforming growth factor-β pathway, modulation of small mother against decapentaplegic/small mother against decapentaplegic 3 phosphorylation, and attenuation of hepatic stellate cell activation[20-22] (Figure 2).

Figure 2 The antifibrotic effects of nor-ursodeoxycholic acid are attributable to its suppressive effects on the transforming growth factor-β-small mothers against decapentaplegic pathway. Suppressing hepatic stellate cell, it inhibits collagen synthesis and attenuates fibrosis. UDCA: Ursodeoxycholic acid; TGF: Transforming growth factor; SMAD: Small mothers against decapentaplegic; SMA: Smooth muscle actin; ECM: Extracellular matrix.

Nor-UDCA inhibits gene expression of the major regulators of lipid synthesis, like steroid regulatory element binding protein and peroxisomal proliferator receptor-gamma, in the steatotic liver model[20]. Ameliorating steatosis, it may improve fibrosis progression[23]. Since most anti-inflammatory and anti-fibrotic properties have been demonstrated in pre-clinical animal models, prospective studies in patients with MASLD using paired liver biopsy can decipher its actual effects on steatohepatitis.

UDCA VS NOR-UDCA

UDCA is the hydrophilic dihydroxy bile acid (3-α,7 β-dihydroxy-5 β-cholan-24-oic acid). UDCA accounts for only 4% of the total bile acid pool in humans[13,19,20]. It is not synthesised in hepatocytes; it is formed via 7-β epimerisation of chenodeoxycholic acid[1,19,20]. In the colon, it gets absorbed and secreted into the bile acid pool. Compared to other bile acids, UDCA is more hydrophilic because of its hydroxyl group[13].

Following oral administration, UDCA constitutes around 20%-70% of bile acid pools depending on the dose. It is associated with notable changes in the concentration of chenodeoxycholic acid and deoxycholic acid[13,19]. Displacement of hepatotoxic endogenous bile acid leads to cell membrane stabilisation of hepatocytes. Apart from that, UDCA exerts anti-inflammatory, immunomodulatory, and choleretic properties[13,19,20]. Other properties of UDCA are summarised in Table 1, with major differences from nor-UDCA.

Table 1 Comparative efficacy of nor-ursodeoxycholic acid and ursodeoxycholic acid in patients with different hepatobiliary diseases.

Properties	UDCA	Nor-UDCA
Chemical name[1]	3-α,7 β-dihydroxy-5 β-cholan-24-oic acid	3-α,7 β-dihydroxy-24-nor-5 β-cholan-23-oic acid
Molecular formula[1]	C24H40O4	C23H3804 (one methylene group less)
Synthesis[1,13]	Secondary bile acid formed by intestinal bacteria from primary bile acids and available synthetically	Synthetic sidechain shortened derivative of UDCA
Hydrophilicity[1,13,14]	Less	More hydrophilic than UDCA
Cytotoxicity[1,16]	Low cytotoxicity in healthy states; but may be toxic in obstructive cholestasis (e.g., bile duct ligated models)	Less cytotoxic; ameliorates injury even in obstructive conditions where UDCA is toxic
Dosage[2,9,44]	Typically, 13-15 mg/kg/day (e.g., for PBC or PSC)	1500 mg/day (approximately equimolar to high dose UDCA)
FXR agonism[1,14]	Negligible effects on FXR activation	No effects on FXR. Most Effects are independent of FXR or TGR5 receptors
Effects on TGF-β[19]	Reduces TGF levels (moderate anti-fibrotic effect)	Significantly reduces TGF-β expression more effectively than UDCA in fibrosis models
Chole-hepatic shunt[1,20]	No. It is conjugated with taurine/glycine and remains in the bile until it reaches the intestine	Yes. Resists conjugation, allowing it to be reabsorbed by bile ducts and return to the liver creating a shunt
Bicarbonate secretion[1,15,20]	Moderate increase in bicarbonate secretion	Significant increase (hypercholeresis); the “bicarbonate umbrella” hypothesis suggests efficient choleresis protects hepatocytes and cholangiocytes
Anti-inflammatory and antifibrotic activity on hepatocyte[18,19]	Moderate; established in PBC but less effective in other fibrosis models	Superior and more potent. Significantly reduces hydroxyproline and collagen in models like Mdr2-/- and TAA-induced fibrosis
Effects on bile duct ligated mice[16]	Detrimental as it increases biliary pressure and may lead to bile infarcts or necrosis	Protective. It reduces liver injury and markers of cholestasis compared to UDCA
Current indications[1]	FDA approved: PBC, gallstone dissolution and intrahepatic cholestasis of pregnancy	Investigational: MASLD and PSC. Approved in India for MASLD by Central Drugs Standard Control Organisation
Adverse events[2,9]	Generally well tolerated; diarrhea, weight gain, hair thinning	Similar safety profile in trials; mild gastrointestinal symptoms reported
Pregnancy safety[43,44]	Safe (category B); widely used for ICP	Unknown
Contraindications[1,44]	Complete biliary obstruction, acute cholecystitis, calcified gallstones	Hypersensitivity (theoretical: Complete obstruction, though animal models suggest it is safer than UDCA)

UDCA: Ursodeoxycholic acid; PSC: Primary sclerosing cholangitis; PBC: Primary biliary cholangitis; FXR: Farnesoid X receptor; TGR: Takeda-G-protein coupled receptor; TGF: Transforming growth factor; TAA: Thioacetamide; FDA: Food and Drug Administration; MASLD: Metabolic dysfunction-associated steatotic liver disease; ICP: Intrahepatic cholestasis of pregnancy.

There is no head-to-head trial comparing UDCA with nor-UDCA in terms of their efficacy and safety. The experimental models have explored the safety of nor-UDCA over UDCA in bile duct-ligated mice[16,24]. UDCA triggered bile infarcts in the ligated lobe of the liver (Figure 3)[24-27]. Higher doses (28-30 mg/kg/day) of UDCA are detrimental in patients with PSC. Despite improvement in liver functions, the UDCA group had a 2.1 times higher risk of death. UDCA gets converted to toxic bile acids, which lead to hepatic injury and liver dysfunction[27].

Figure 3 The key differences between ursodeoxycholic acid and nor-ursodeoxycholic acid lie in the degree of cholehepatic shunt, biocarbonate secretion, choleresis, and farnesoid X receptor agonism. Nor-ursodeoxycholic acid demonstrates higher efficiency in bicarbonate secretion and choleresis in hepatocytes as compared to ursodeoxycholic acid (Table 1). Though nor-ursodeoxycholic acid lacks farnesoid X receptor agonistic property, its direct action on the transforming growth factor-β and small mother against decapentaplegic pathway is responsible for the antifibrotic property. UDCA: Ursodeoxycholic acid; BSEP: Bile salt exporter protein; TGF: Transforming growth factor; SMAD: Small mothers against decapentaplegic; FXR: Farnesoid X receptor; NTCP: Sodium (Na) taurocholate cotransporting polypeptide; SLC10A1: Solute carrier family 10 member A1.

CURRENT THERAPEUTIC LANDSCAPES

Nor-UDCA in MASLD

In a dose finding double blind placebo controlled randomised controlled trial (RCT), 198 patients were randomized into three groups to receive placebo vs 500 mg/day vs 1500 mg/day nor-UDCA in patients with MASLD for 12 weeks[2]. A dose-dependent reduction in alanine aminotransferase (ALT) was observed in patients receiving nor-UDCA [reduction of -27.8%, 95% confidence interval (CI): -34.7 to 14.4; P < 0.0001 in the 1500 mg per day group] (Table 2). Of 112 treatment-emergent adverse events were seen in the 1500 mg group and 99 in the 500 mg group (Table 2). Most reported adverse events were headache, diarrhea, and nasopharyngitis[2].

Table 2 Nor-ursodeoxycholic acid in pre-clinical animal studies and randomised controlled trials on patients with metabolic dysfunction-associated steatotic liver disease and primary sclerosing cholangitis.

Ref.	Study subjects	Patient phenotype	Treatment	Outcome
Buko et al[19]	Thioacetamide-induced liver fibrosis in rat model	Experimental in animal model of liver fibrosis	Fibrotic rats were administered UDCA (80 mg/kg) and nor-UDCA (equimolar 80 mg/kg)	Nor-UDCA decreased liver hydroxyproline content and TGF-β expression. Liver fibrosis regression was more pronounced in UDCA-treated rats
Fickert et al[16]	Bile duct ligated mice	Experimental animal model of cholestasis	0.5% UDCA vs nor-UDCA in Abcb (-/-) mice with bile duct ligated mice	UDCA is toxic to bile duct ligated mice however, nor-UDCA ameliorated liver injury
Marchianò et al[23]	Western diet-fed rat model with hepatic steatosis	Experimental animal study in liver steatosis	UDCA vs nor-UDCA in rat model with steatosis	UDCA and nor-UDCA both protected against steatosis and fibrosis but failed to ameliorate hepatic ballooning and nor-UDCA use was associated development of dyslipidemia
Sombetzki et al[22]	Murine model of schistosomiasis	Experimental animal study with liver fibrosis	UDCA vs nor-UDCA in schistosoma mansoni infected liver	Nor-UDCA affected surface expression of MHC in macrophage and exerts anti-fibrotic property
Traussnigg et al[2]	NAFLD	A double-blind, randomised, placebo-controlled, phase II dose-finding trial	198 patients randomised to 1:1:1 to receive 500 mg/day nor-UDCA vs 1500 mg/day nor-UDCA vs placebo in patients with NAFLD	A dose-dependent reduction in ALT between baseline and end of treatment was observed with nor-UDCA vs placebo, with a significant effect in the 1500 mg group (mean change -27.8%, 95%CI: -34.7 to -14.4; P < 0.0001). Ninety nine and 112 side effects were reported in 63 subjects and 64 subjects, respectively
Panuganti et al[9]	MASLD	Phase III double blind randomised controlled trial	110 received nor-UDCA (1500 mg/day) and 55 received placebo	At 12 weeks: ALT normalization in nor-UDCA group: 89% vs 76% in placebo group (P = 0.022). Fibrosis improvement: 57% in nor-UDCA group vs 40% in placebo (P = 0.035). Major limitations of this study include the absence of established parameters of liver fibrosis and steatosis as a trial endpoint, i.e., paired liver biopsy, and MR-PDFF. The effects on metabolic parameters were not elaborated in the study and they included a small number of patients. Impact of de-novo hyperglycemia and dyslipidemia during the study deserved a special mention and discussion in the trial
Fickert et al[10]	PSC	Randomised control trial	161 patients PSC with or without UDCA randomized for 12 weeks of nor-UDCA with 4 weeks follow-up	Nor-UDCA group showed significant reduction in ALP levels as compared to the placebo: -12.3%, -17.3%, and -26.0% in the 500, 1000, and 1500 mg/day groups (P = 0.029, P = 0.003, and P < 0.0001 respectively)

UDCA: Ursodeoxycholic acid; TGF: Transforming growth factor; MHC: Major histocompatibility complex; NAFLD: Nonalcoholic fatty liver disease; CI: Confidence interval; MASLD: Metabolic dysfunction-associated steatotic liver disease; MR-PDFF: Magnetic resonance proton density fat fraction; PSC: Primary sclerosing cholangitis; ALT: Alanine aminotransferase; ALP: Alkaline phosphatase.

In a recent study from India, 165 patients were randomised in a 2:1 ratio to receive nor-UDCA (n = 110) vs placebo (n = 55) for 24 weeks. The primary endpoint included ALT normalisation at 12 weeks and the proportion of patients with improvement in liver stiffness (Table 2)[9]. At 12 weeks, ALT normalisation was achieved in 89% of the nor-UDCA group, compared to 76% in the placebo arm. ALT levels were significantly lower in the nor-UDCA group [(24.07 U/L; 95%CI: 21.01-27.13) vs (30.59 U/L; 95%CI: 26.31-34.89); P = 0.016][9].

At 12 weeks, the nor-UDCA-treated group showed a greater reduction in liver stiffness measurement LSM value [7.46 kPa; (95%CI: 7.24-7.67), vs 8.02 kPa; (95%CI: 7.73-8.32), P = 0.002]. Dyslipidaemia and diabetes were noted in 13.9% and 2.78% in the nor-UDCA group, respectively. At least one treatment-emergent adverse event was seen in 34 (31%) patients receiving 1500 mg nor-UDCA group, compared to 12 (21.81%) patients in the placebo group.

Abdominal pain and bloating were reported as adverse events in two of 110 patients in the nor-UDCA group (Table 2)[9]. Based on the study, nor-UDCA received authorisation from the Central Drugs Standard Control Organisation for use in non-alcoholic fatty liver disease (currently MASLD) in India. However, the study can be criticised for its several limitations. ALT normalisation, reduction of LSM and non-alcoholic fatty liver disease fibrosis score have not been considered the gold standard therapeutic endpoints in pivotal trials evaluating drugs for MASLD. Most drugs received approval following large data emerging from comparing paired liver biopsies in patients with MASLD[28-31]. The effects of nor-UDCA on other metabolic parameters were not assessed in the trial. Whether its effects are primarily because of hepatic antifibrotic activity or secondary to improvement of overall metabolic derangement remains elusive. Moreover, interpretation of the LSM value in patients with high baseline aspartate aminotransferase and ALT can be erroneous, and reduction of ALT is coupled with a parallel reduction of the LSM value[32-34]. Baseline ALT was 85.2 U/L in the nor-UDCA group[9].

Magnetic resonance proton density fat fraction (MR-PDFF) is an excellent alternative to transient elastography-based fibrosis and steatosis assessment[35-37]. The reduction of liver fat content on MR-PDFF is the standard endpoint in trials involving patients with MASLD/metabolic dysfunction-associated steatohepatitis (MASH)[35,36]. The aforementioned study was conducted based on transient elastography and liver enzymes; hence, the generalisability of the study is questionable[9]. Hence, data based on patients who underwent liver biopsy or MR-PDFF are warranted to establish its role in MASH. Hence, the study can be criticised for using the reduction of non-alcoholic fatty liver disease fibrosis score as a therapeutic endpoint in patients with MASLD[9].

NOR-UDCA IN PSC

PSC is characterised by a repeated cycle of immune-mediated cholangiocyte injury[38]. It is often associated with inflammatory bowel diseases. Current effective medical therapy for PSC is lacking, and patients often resort to liver transplantation[38,39]. UDCA has been used in patients with PSC with variable results. High-dose UDCA is associated with a worse prognosis in patients with PSC[27,38-40]. In a recent RCT (NUC-5), 301 biopsy-confirmed PSC patients with a high alkaline phosphatase (ALP) (> 1.5 X upper limit of normal) were randomised to receive NCA (nor-UDCA) (1500 mg/ day) vs placebo for 192 weeks. At 96 weeks, 15.1% of patients receiving NCA achieved the primary endpoint (normalization of ALP without worsening disease stage on histology) vs 4.2% in the placebo group (P < 0.05). NCA treatment led to improvement by at least one Ludwig stage in 25.2% of patients (vs 10.5% in placebo; P = 0.021). It was presented during the late breaker session at the European Association for the Study of the Liver Congress, 2025.

Fickert et al[16] demonstrated the efficacy of nor-UDCA in the MDR-2 gene knock-out mouse model. Mdr 2 (-/-) mice were fed nor-UDCA for four weeks, and the results were compared to those of the controls. Four weeks of nor-UDCA reduced hepatic inflammation[16].

After initial results of nor-UDCA in animal models, Fickert et al[10] evaluated its role in patients with PSC. In an RCT, 161 patients (placebo = 40; nor-UDCA 500 mg/day: 39; 1000 mg/day: 41; 1500 mg/day: 39) with PSC were randomised to receive 12 weeks of therapy. More than 70% patients were UDCA-experienced (Table 2)[10]. The nor-UDCA group showed a significant reduction in ALP levels as compared to the placebo (-12.3%, -17.3%, and -26.0% in the 500, 1000, and 1500 mg/day groups (P = 0.029, P = 0.003, and P < 0.0001, respectively). Nor-UDCA also reduced ALT, aspartate aminotransferase, and gamma-glutamyl transferase. Serious adverse events occurred in seven, five and three patients in the 500 mg, 1500 mg, and the placebo group, respectively. Dose-dependent reduction of ALP was seen in both genders, irrespective of their prior UDCA therapy (Table 2)[10]. Presence of inflammatory bowel disease, duration of PSC and baseline ALP did not have any impact on the nor-UDCA responsiveness. Poor tolerability of nor-UDCA was seen in only 4.9% of patients. Similar to prior studies, abdominal pain and diarrhea were the most common reported adverse events seen in 12.5% and 10% of patients, respectively (Table 2)[10].

FUTURE RESEARCH PROSPECT

Nor-UDCA has been extensively studied in animal models with cholestasis. Subsequent studies have shown its beneficial impacts on patients with PSC; however, its role has not been studied in other forms of intrahepatic cholestasis, i.e., primary biliary cholangitis (PBC), intrahepatic cholestasis of pregnancy, drug-induced cholestatic liver diseases and overlap syndromes. 30%-40% of patients with PBC don’t respond to UDCA therapy[41,42]. In the landmark POISE trial, obeticholic acid was shown to be effective in patients with UDCA non-responders[43]. However, obeticholic acid worsens pruritus in around half of the patients[43,44]. There are no data on UDCA-non-responding autoimmune hepatitis-PBC, PSC, and autoimmune hepatitis-PSC overlap syndromes[45-47]. Overlap syndromes and refractory autoimmune hepatitis are often difficult to treat and require liver transplantation[47-52]. A large multicenter prospective study may decipher its role in prolonging transplant-free survival in such patients. Nascent data on nor-UDCA yielded conflicting results. Its impact on overall metabolic derangement, steatosis and fibrosis should be evaluated in a large prospective study in biopsy-proven MASLD.

CONCLUSION

Most data on the safety and efficacy of nor-UDCA in cholestatic liver diseases emerge from pre-clinical animal models with cholestasis. Phase II dose-finding study revealed that nor-UDCA can be beneficial in patients with MASLD; however, there is no well-designed, prospective, long-term study on nor-UDCA in patients with biopsy-proven MASH. Long-term comparative data are warranted so that nor-UDCA can claim its suitable position in the management algorithm in MASLD and PSC. Untill then, a nuanced therapeutic approach should be advocated in patients with cholestatic liver diseases and MASH to avoid the ubiquitous and injudicious use of nor-UDCA.

ACKNOWLEDGEMENTS

I express our heartfelt gratitude to all the authors for contributing to this manuscript.