Epidemiology and treatment practices of chronic cholestatic liver disease in India: a physician survey-based study

INTRODUCTION

Chronic cholestatic liver disease (CCLD) comprises a complex spectrum of hereditary and acquired hepatobiliary disorders, resulting in impaired bile secretion or diminished bile formation.^1,2 The disease course is heterogenous most likely involving genetic predisposition and exposure to environmental factors.^2,3 CCLD increases the risk for several complications and rising morbidity and mortality rates associated with the underlying condition and poses a significant healthcare burden. Cholestatic liver disorders manifest from infancy to childhood with clinical signs of fatigue, pruritis, and jaundice. Pruritis is seen in around 80% of CCLD patients, and evidence suggests the signs of metabolic bone disease, fat-soluble vitamin deficiencies, and dyslipidemia in CCLD patients.^4,5 It may also lead to hepatocellular carcinoma or cholangiocarcinoma and eventually death.⁶

CCLD is a primary pathological component of diverse diseases, the most common being primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and biliary atresia (BA).² Globally, the incidence of PBC ranges between 0.33 and 5.8 per 100,000 inhabitants/year and prevalence ranges between 1.91 and 40.2 per 100,000 inhabitants. Further, the incidence rates for PSC range between 0 and 1.3 per 100,000 inhabitants/year and prevalence rates range between 0 and 16.2 per 100,000 inhabitants.⁷ Although robust epidemiologic statistics have been presented across the West, the reported incidence and prevalence of CCLD appear to be lacking from India as well as the must be quantified by leveraging population-based data from the existing registries.

CCLD can be frequently seen among people with excess alcohol abuse leading to alcoholic liver disease (ALD).⁸ In rare instances, CCLD can occur due to the usage of certain drugs, alternative medicines, or some toxic substance, referred to as drug-induced liver injury (DILI).⁹ Data related to DILI in India is quite limited; however, it is one of the important causes of liver failure resulting in significant morbidity and mortality.^10,11 Ursodeoxycholic acid (UDCA) is the primary bile acid used in the treatment of CCLD.⁴ This hydrophilic bile acid works by membrane stabilization, cytoprotection, and immunomodulation of affected liver cells.¹ The American Association for the study of liver diseases (AASLD) and the European association for the study of the liver (EASL) recommend UDCA as the life-long treatment of choice for PBC, with a recommended dose of 13-15 mg/kg/day.^12,13 Treatment with UDCA prevents further progression of PBC, such that duration of survival can be improved by 16-20 years.^4,14

Similarly, UDCA is the most common treatment prescribed for PSC, although long-term results in disease improvement are unclear.⁴ Moreover, poor long-term outcomes and no improvement in survival time were reported with a high dose of UDCA (>28 mg/kg/day) in patients with PSC, and guidelines regarding the use of UDCA in PSC have not been formulated yet.^4,15 In India, there remains lack of data on physicians’ perspectives about the efficacy, tolerance and compliance with UDCA in the treatment of CCLD. Additionally, data in relation to the basis of physicians’ decisions while commencing the treatment with UDCA is also scarce.¹ Therefore, the aim of this physician-survey-based survey was to assess the epidemiology, current treatment strategies, as well as gaps in the management of patients with CCLD in the India.

METHODS

Survey design

This was a cross-sectional, questionnaire-based survey designed to assess the epidemiology, diagnosis, and treatment options for CCLD (ALD) and CCLD (DILI), and the role of UDCA in the management of both across India. A total of 215 physicians involved in the clinical practice of CCLD participated in the survey. Ad board with clinical experts was conducted to develop and validate the questionnaire. Participants were invited to complete the internet-based validated structured survey questionnaire. The survey questionnaire comprised 34 questions, including questions on understanding CCLD prevalence, diagnosis, and current treatment options (Table 1). This survey was performed in accordance with International Conference on Harmonization-Good Clinical Practice (ICH-GCP) and national guidelines. Informed consent was obtained from the participating physicians. Because this survey did not involve direct patient intervention, ethical clearance by an external ethics review board was not obtained. The confidentiality and identity of the participating physicians were preserved throughout the survey and data processing.

Study period

The study period was between May 2022 to September 2022.

Data analysis

Physician responses were gathered and summarized using counts/percentages, as appropriate. The procedure for data quality check was performed along with the query resolution. Data analysis was done post-data lock approval. The rank data were calculated by the weighted linear combination method, in which for each question, the most preferred choice as an answer can be determined. were analyzed using SPSS software version 25.0 (IBM Corp., Armonk, NY, USA) and Microsoft excel (Microsoft Corporation 2019).

RESULTS

Epidemiological patterns and burden of CCLD

A total of 215 physicians responded to the survey. Liver disorders with cholestasis (alanine aminotransferase [ALT]/alkaline phosphatase [ALP] ratio <2 with or without pruritus) were found to be prevalent in 10%-20% of patients by 53.5% physicians, in 21%-30% of patients by 34.9% physicians, in 31%-50% of patients by 8.8% physicians and in >50% of patients by 2.8% physicians (Figure 1). CCLD was found to be more common among males as reported by 52.5% respondents, and 32.6% respondents claimed that the proportion of CCLD was highest among patients aged 41-60 years.

ALD with cholestasis was reported to be prevalent in 10-20%, 21-30%, 31-50% and >50% of patients by 33.5%, 37.2%, 24.2% and 5.1% of physicians, respectively. Additionally, DILI with cholestasis was reported to be prevalent in <5%, 5-10%, 11-20%, and >20% of patients by 13.5%, 34.9%, 29.8%, and 21.9% of physicians, respectively (Figure 1).

Prevalence of A) liver disorders with cholestasis, B) ALD with cholestasis, and C) DILI with cholestasis in the Indian population. *Cholestasis defined as ALT/ALP ratio <2 with or without pruritus. ALD-alcoholic liver disease, ALP-alkaline phosphatase, ALT-alanine transaminase, CCLD-chronic cholestatic liver disease, DILI-drug-induced liver injury, CCLD- chronic cholestatic liver disease.

Comorbidities, complications, diagnosis, and management of CCLD (ALD)

The survey also assessed physicians’ perspectives regarding the symptom burden, comorbidities, diagnosis and treatment of in patients with CCLD (ALD). Typically, patients were found to suffer from CCLD (ALD) symptoms for 1-3 months by 34.9% of physicians. Of the surveyed physicians, >50% stated that <20% of patients who present with CCLD (ALD) discontinue alcohol consumption before consultation, while 29.3%, 18.6%, and 0.9% stated that this proportion was 21-30%, 31-50%, and >50% of patients, respectively (Table 2).

Most physicians (57.2%) reported that multiple comorbidities, including cardiac conditions, diabetes, hypertension, hypertriglyceridemia, or hyperuricemia, are commonly seen in patients with CCLD (ALD). The second most common comorbidity reported was hypertriglyceridemia and hyperuricemia (23.3%), followed by diabetes (14.4%), hypertension (2.3%), and cardiac conditions (1.9%; Table 2). A large number of physicians (75.8%) reported that multiple complications including ascites, gastrointestinal bleeding, hepatic encephalopathy, or hepatorenal syndrome, can be seen among patients with CCLD (ALD) in the Indian population. Ascites (10.7%) was reported to be the second most frequent complication, followed by hepatic encephalopathy (7.4%), and gastrointestinal bleeding (5.1%; Table 2).

Multiple diagnostic techniques, including detailed history taking with clinical features, laboratory investigations, or abdominal ultrasonography, were employed by majority of the participating physicians (83.7%) for diagnosis of CCLD (ALD) investigations included checking for deranged liver function tests (LFTs) including ALT/ALP ratio <2, prothrombin time, and international normalized ratio. Fibroscan was preferred by majority of the physicians (80.9%), while fibrotouch was preferred by approximately half (49.3%) of the physicians (Table 3).

Clinical practices for the management of CCLD (ALD) varied considerably among the surveyed physicians (Table 3). Multiple pharmacological approaches were the most preferred among the majority of the physicians (70.2%), while hepatoprotective agent like UDCA was preferred by 23.7% of physicians. More than half the physicians (68.4%) prescribed corticosteroids to 10%-20% of patients. For patients with alcohol-induced severe hepatitis with cholestasis, 45.1% of physicians prescribed nutritional supplements in >50% of patients, while approximately half the physicians (49.8%) did not prefer to use herbal hepatoprotectives (sylimarin, Capparis spinosa [Himsara], and Cichorium intybus). According to 80% of physicians, herbal hepatoprotective supplements helped in the improvement of LFTs in 10%-20% of patients with CCLD (ALD), while only 1.0% agreed that they show improvement in >50% of patients (Table 3).

Prevalence, complications, diagnosis and management of CCLD (DILI)

Physicians’ perspectives on complications, diagnosis and treatment approaches in relation to DILI-induced CCLD are summarized in Table 4. According to 34.9% of physicians, herbal DILI was observed in 5-10% of patients in their clinical practice, while 15.8% of physicians found it to be observed in <5% of patients.

Association between herbal drug use and CCLD (DILI) was suggested by 31.2% of the physicians in >20% of patients, 29.3% of physicians in 5%-10% of patients, and 28.8% in 11%-20% of patients (Table 4). More than half the physicians (58.6%) reported that patients with CCLD (DILI) experience multiple complications including acute liver failure, acute on chronic liver failure, or drug-induced autoimmune hepatitis.

As per the surveyed physicians, 81.9% used multiple methods for the diagnosis of CCLD (DILI), including detailed history taking with clinical features, laboratory investigations, liver biopsy, or abdominal ultrasonography. Similarly, most participants (71.6%) relied on multiple pharmacological approaches in the management of CCLD (DILI), including N-acetyl cysteine, hepatoprotective like UDCA, corticosteroids, or S-adenosyl methionine (Table 4).

Role of UDCA in the management of CCLD (ALD) and CCLD (DILI)

Table 5 summarizes physicians’ experience with UDCA in management of alcohol-induced and drug-induced CCLD. According to survey, majority of physicians (60.0%) prescribed UDCA for >50% patients with CCLD (ALD), 22.8% physicians prescribed to 31-50% patients; 9.8%, to 21-30% patients, and 6.0%, to 10-20% of patients.

Nearly half they physicians (48.4%) prescribed UDCA for 4-12 weeks in patients with CCLD (ALD), while 12-24 weeks was the most preferred duration for CCLD (DILI; (38.1% physicians). For both the conditions, the recommended UDCA dose was 10-15 mg/kg body weight by most of the survey participants (93.0% for CCLD [ALD] as well as 95.4% for the CCLD [DILI]; Table 5).

There mixed opinion among the participating physicians about improvement in LFTs following treatment with UDCA. Overall, 40.5% and 34.9% of physicians found UDCA to improve LFTs in >50% of patients with CCLD (ALD) and CCLD (DILI), respectively. Only 1.4% and 0.9% physicians opined that UDCA didn’t improve LFTs in patients with CCLD (ALD) and CCLD (DILI), respectively (Table 5). Properties considered by survey physicians when prescribing UDCA for CCLD (ALD) were anti-inflammatory effect alone (6.1% physicians), choleretic effect alone (9.3%), immunomodulatory effect alone (3.3%)/ all 3 effects (81.4%).

Tolerability and efficacy of UDCA in patients with CCLD (ALD) were reported to be good by 87.0% and 69.8% of survey participants, respectively. Likewise, for patients with CCLD (DILI), the tolerability and efficacy of UDCA were found to be good by 85.6% and 69.8%, of physicians, respectively (Figure 2). Majority of the physicians (84.7%) prescribed UDCA for multiple indications (Figure 3).

ALD-alcoholic liver disease, CCLD-chronic cholestatic liver disease, DILI-drug-induced liver injury.

*of any origin. ICP-intrahepatic cholestasis of pregnancy, PBC-primary biliary cholangitis, PSC-primary sclerosing cholangitis, UDCA-ursodeoxycholic acid.

ALD-alcoholic liver disease, ALP-alkaline phosphatase, ALT-alanine transaminase, DILI-drug-induced liver injury, ICP-intrahepatic cholestasis of pregnancy, INR-international normalized ratio; LFT-liver function test, PBC-primary biliary cholangitis, PSC-primary sclerosing cholangitis, PT-prothrombin time, SAMe-S-adenosyl methionine, UDCA-ursodeoxycholic acid, USG- ultrasonography.

ALD-alcoholic liver disease, CCLD-chronic cholestatic liver disease, GI-gastrointestinal.

*LFT deranged (including ALT/ALP ratio < 2), PT and INR values, ALD, alcoholic liver disease, CCLD-chronic cholestatic liver disease, INR-international normalized ratio, LFT-liver function test, ALP-alkaline phosphatase, ALT-alanine transaminase, INR-international normalized ratio, LFT-liver function test.

*LFT deranged (including ALT/ALP ratio < 2), PT and INR values, ALP-alkaline phosphatase, ALT-alanine transaminase, CCLD-chronic cholestatic liver disease, DILI-drug-induced liver injury, INR-international normalized ratio, LFT-liver function test, SAMe-S-adenosyl methionine, UDCA-ursodeoxycholic acid, USG-ultrasonography.

DISCUSSION

This survey was the first to assess the epidemiology, current treatment strategies and gaps in the management of patients with CCLD across diverse Indian clinician groups. Liver cirrhosis has been shown to be a major cause of health burden worldwide.¹⁶ Data from the world health organization suggests that liver cirrhosis has been one of the top ten causes of death in India for years,¹⁷ although data on the prevalence of CCLD, which if left untreated can progress to cirrhosis, remains scarce.⁶ In the current survey, we found that the prevalence of CCLD ranges between 10% and 50% patients in the Indian clinical setting.

Alcohol has been shown to be the most common (34.3% of 4413) etiological factor for liver cirrhosis in India.¹⁸ Alcoholic steatohepatitis is a frequent and serious liver disease caused due to the high alcohol consumption, and cholestasis has been shown to be one of the strong predictors of poor short-term consequences of the disease.¹⁹ Present study results are in line with the existing literature, suggesting ALD with cholestasis to be a common finding in Indian clinical practice. Conversely, DILI is quite rare in India. In our study, DILI with cholestasis was generally seen in <20% of patients with liver disorders.

Most of the survey participants used multiple methods for the diagnosis of CCLD (ALD) in their practice. It has been reported that the diagnosis of ALD can be difficult and may require the results of detailed patient history, clinical features and laboratory investigations including imaging and biopsy in certain cases.²⁰ A similar approach is recommended by the European Association for the Study of the Liver (EASL) clinical practice guidelines on the management of alcohol-related liver disease.²¹ Moreover, transient elastography (Fibroscan) has been shown to yield good results in the diagnosis of various chronic liver diseases.²² Further, it is the most commonly used and verified technique recommended by EASL as well as by the Asian Pacific Association for the Study of the APASL.^23,24 Consistent with these recommendations, the current survey findings indicate that Fibroscan was the most preferred technique in Indian clinical settings.

EASL 2009 clinical practice guidelines on the management of cholestatic liver diseases recommend using multiple drugs for the treatment of PBC, one of the common causes of liver cholestasis.²⁵ Likewise, multiple pharmacological approaches were favored for the management of CCLD (ALD) by our survey physicians. It is noteworthy that, EASL clinical practice guidelines on nutrition in chronic liver disease recommend performing rapid screening to evaluate the nutritional status of a cirrhotic patient and prescribe the supplement accordingly.²⁶ Pertaining to nutritional recommendations, most physicians in our survey prescribed nutritional supplements to CCLD (ALD) patients in their clinical practice. Prevalence of DILI due to use of herbal drugs was low in our survey; however, existing guidelines recommend considering herbal supplements to be strongly associated with liver injury.²⁷ Multiple diagnostic methods were preferred for CCLD (DILI) by our survey participants, which is supported by EASL stating the lack of specific diagnostic markers for suspected DILI require interpretation of several laboratory tests, sometimes including imaging and biopsy results to rule out the final diagnosis.²⁷ Multiple pharmacological approaches were preferred by most of the current survey participants for the management of CCLD (DILI); however, UDCA was often used to treat the condition although its efficacy in CCLD (DILI) is still unproven.²⁷

UDCA was commonly prescribed by the survey physicians for the management of CCLD (ALD), reflecting the evidence obtained from prior literature findings.²⁸ UDCA was previously shown to be efficiently protect of liver function, and combination of S-adenosyl-L-methionine and UDCA treatment in patients with PBC yielded a better outcome with more promising results.^29,30 In the present study, UDCA was frequently prescribed for 4-12 weeks of duration for patients with CCLD (ALD) and for 12-24 weeks for patients with CCLD (DILI). These findings are contrary to the existing literature that suggests UDCA was given daily to patients with PBC for a period of two years.³¹ Further, the British Society of Gastroenterology guidelines recommend treatment with UDCA for a period of 1 year for those with a high level of disease (PBC) progression. It strongly recommended that oral UDCA at a dose of 13-15 mg/kg/ day should be used as the first-line, long term treatment for all patients with PBC, if well-tolerated.³² Similarly, EASL recommends UDCA treatment at a dose of 13-15 mg/kg of body weight for a longer duration.²⁵ In our study, a substantial proportion of physicians prescribed UDCA at a dose of 10-15 mg/kg body weight, which is consistent with the above recommendations.

In the present study, the opinion expressed by participants indicates that UDCA causes LFT improvement in majority of the patients with CLD (ALD) and CLD (DILI). The opinions of clinicians are in agreement with previously published studies.^28,31 A meta-analysis of randomized placebo-controlled clinical trials showed a considerable decrease in various liver enzymes following UDCA treatment, including ALP, aspartate aminotransferase, ALT, gamma-glutamyl transferase, and bilirubin, thereby causing improvement in hepatic function.³³ Further, UDCA treatment depicted excellent long-term survival in patients with PBC after a period of 1 year with a drop in ALP level by >40% of baseline values.³⁴ In fact, clinicians surveyed in this study reported that UDCA treatment exhibited good tolerability and efficacy in both cholestatic conditions, CCLD (ALD) and CCLD (DILI).

The present study has certain limitations and warrant consideration, including the restricted internal validity (generalizability) of the questionnaire. Moreover, modes of data collection by questionnaire may have led to recall bias by the survey participants. Despite having those limitations, to the best of our knowledge, there is yet a lack of studies assessing the burden of CCLD in Indian population. Therefore, we believe the findings of this study provides a novel contribution to the scientific literature. Lastly, the survey respondents included representation of clinician groups treating patients with liver disorders across different parts of the nation.

CONCLUSION

CCLD is a frequently encountered condition in clinical practice in India, and if not treated in time can progress to liver cirrhosis yielding life-threatening consequences. In light of scarce data on CCLD prevalence and management approaches in India, the present survey findings provide useful insights on its prevalence and support the use of UDCA therapy for the management of its symptoms. In particular, the usefulness of UDCA therapy in reducing disease progression was also determined.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: The study was approved by the Institutional Ethics Committee

REFERENCES

1. 1. Lawate P, Rooprai R, Choudhury G, Dutta S. A prospective, multicentre, observational study of patients with chronic cholestatic liver diseases receiving Udiliv® in India: Splendid study. Int J Basic Clin Pharmacol. 2016;5(6):2621-9.
2. 2. Mawardi M, Alalwan A, Fallatah H, Abaalkhail F, Hasosah M, Shagrani M et al. Cholestatic liver disease: Practice guidelines from the Saudi Association for the Study of Liver diseases and Transplantation. Saudi J Gastroenterol. 2021;27(7):S1-26.
3. 3. Tanakaa A, Leung PS, Young HA, Gershwin ME. Toward solving the etiological mystery of primary biliary cholangitis. Hepatol Commun. 2017;1(4):275-87.
4. 4. Hasegawa S, Yoneda M, Kurita Y, Nogami A, Honda Y, Hosono K et al. Cholestatic liver disease: Current treatment strategies and new therapeutic agents. Drugs. 2021;81(10):1181-92.
5. 5. Pedersen MR, Mayo MJ. Managing the symptoms and complications of cholestasis. Clin Liver Dis. 2020;15(3):120-24.
6. 6. Pollock G, Minuk GY. Diagnostic considerations for cholestatic liver disease. J Gastroenterol Hepatol. 2017;32(7):1303-9.
7. 7. Boonstra K, Beuers U, Ponsioen CY. Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review. J Hepatol. 2012;56(5):1181-8.
8. 8. Tung BY, Carithers RL Jr. Cholestasis and alcoholic liver disease. Clin Liver Dis. 1999;3(3):585-601.
9. 9. Wang Q, Huang A, Wang JB, Zou Z. Chronic drug-induced liver injury: Updates and future challenges. Front Pharmacol. 2021;12:627133.
10. 10. Devarbhavi H, Joseph T, Sunil Kumar N, Rathi C, Thomas V, Prasad Singh S et al. The Indian network of drug-induced liver injury: etiology, clinical features, outcome and prognostic markers in 1288 patients. J Clin Experimental Hepatol. 2021;11(3):288-98.
11. 11. Mondal D, Das K, Chowdhury A. Epidemiology of liver diseases in India. Clin Liver Dis (Hoboken). 2022;19(3):114-7.
12. 12. European Association for The Study Of The Liver. EASL Clinical Practice Guidelines: Management of cholestatic liver diseases. J Hepatol. 2009;51(2):237-67.
13. 13. Heathcote EJ. Management of primary biliary cirrhosis. The American Association for the Study of Liver Diseases practice guidelines. Hepatology. 2000;31(4):1005-13.
14. 14. Samant H, Manatsathit W, Dies D, Shokouh-Amiri H, Zibari G, Boktor M et al. Cholestatic liver diseases: An era of emerging therapies. World J Clin Cases 2019;7(13):1571-81.
15. 15. Lindor KD, Kowdley KV, Luketic VA, Harrison ME, McCashland T, Befeler AS et al. High‐dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology. 2009;50(3):808-14.
16. 16. Mokdad AA, Lopez AD, Shahraz S, Lozano R, Mokdad AH, Stanaway J et al. Liver cirrhosis mortality in 187 countries between 1980 and 2010: A systematic analysis. BMC Med. 2014;12:145.
17. 17. World Health Organization. Global health estimates: Leading causes of death. Available at: https://www.who.int/data/gho/data/themes/mortality-and-global-health-estimates/ghe-leading-causes-of-death. Accessed on 2022 Nov 8.
18. 18. Mukherjee PS, Vishnubhatla S, Amarapurkar DN, Das K, Sood A, Chawla YK et al. Etiology and mode of presentation of chronic liver diseases in India: A multi centric study. PLoS One. 2017;12(10):e0187033.
19. 19. Spahr L, Rubbia-Brandt L, Genevay M, Hadengue A, Giostra E. Early liver biopsy, intraparenchymal cholestasis, and prognosis in patients with alcoholic steatohepatitis. BMC Gastroenterology. 2011;11(1):115.
20. 20. Torruellas C, French SW, Medici V. Diagnosis of alcoholic liver disease. World J Gastroenterol. 2014;20(33):11684-99.
21. 21. EASL Clinical Practice Guidelines: Management of alcohol-related liver disease. J Hepatol. 2018;69(1):154-81.
22. 22. Lee J, Kang HJ, Yoon JH, Lee JM. Ultrasound-guided transient elastography and two-dimensional shear wave elastography for assessment of liver fibrosis: emphasis on technical success and reliable measurements. Ultrasonography. 2021;40(2):217-7.
23. 23. EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis-2021 update. J Hepatol. 2021;75(3):659-89.
24. 24. The Asian Pacific Association for the Study of the Liver [APASL] » Guidelines. [cited 2022 Nov 10]. Available at: http://apasl.info/subscription-of-journal/guidelines/. Accessed on 2022 Nov 8.
25. 25. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of cholestatic liver diseases. J Hepatol. 2009;51(2):237-67.
26. 26. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on nutrition in chronic liver disease. J Hepatol. 2019;70(1):172-93.
27. 27. EASL Clinical Practice Guidelines: Drug-induced liver injury. J Hepatol. 2019;70(6):1222-61.
28. 28. Podda M, Ghezzi C, Battezzati PM, Bertolini E, Crosignani A, Petroni ML et al. Effect of different doses of ursodeoxycholic acid in chronic liver disease. Digest Dis Sci. 1989;34(12):S59-65.
29. 29. Kim DJ, Yoon S, Ji SC, Yang J, Kim YK, Lee S et al. Ursodeoxycholic acid improves liver function via phenylalanine/tyrosine pathway and microbiome remodelling in patients with liver dysfunction. Sci Rep. 2018;8(1):11874.
30. 30. Wunsch E, Raszeja-Wyszomirska J, Barbier O, Milkiewicz M, Krawczyk M, Milkiewicz P. Effect of S-adenosyl-L-methionine on liver biochemistry and quality of life in patients with primary biliary cholangitis treated with ursodeoxycholic acid. A prospective, open label pilot study. J Gastrointestin Liver Dis. 2018;27(3):273-9.
31. 31. Poupon RE, Balkau B, Eschwège E, Poupon R. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group. N Engl J Med. 1991;324(22):1548-54.
32. 32. Hirschfield GM, Dyson JK, Alexander GJM, Chapman MH, Collier J, Hübscher S et al. The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines. Gut. 2018;67(9):1568-94.
33. 33. Simental‐Mendía M, Sánchez‐García A, Simental‐Mendía LE. Effect of ursodeoxycholic acid on liver markers: A systematic review and meta‐analysis of randomized placebo‐controlled clinical trials. Br J Clin Pharmacol. 2020;86(8):1476-88.
34. 34. Parés A, Caballería L, Rodés J. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic acid. Gastroenterology. 2006;130(3):715-20.