Portal Hypertension and Non-Selective Beta Blockers: Beyond Varices

| 25 September 2023

Written by Noah James, TMED MSc'24 (Candidate)

On Thursday September 21st, 2023, Dr. Melissa Kelley delivered the Medical Grand Rounds (MGR) lecture. She spoke about the use of non-selective beta-blockers (NSBB) in clinically significant portal hypertension (CSPH) to improve clinical management and patient prognosis. She then met with members of the Translational Medicine Graduate Program (TMED) for an extended discussion.

Dr. Kelley began with an overview of cirrhosis, the pathophysiology underlying CSPH, and the importance of CSPH in chronic liver disease. Cirrhosis is the chronic damage and scarring of the liver often secondary to a chronic inflammatory process. Summarized in Figure 1. Stages of Acute Liver Disease.pdf, cirrhosis is classified as either compensated (can be asymptomatic), or decompensated, the later occurring when liver damage results in clinical complications. Dr. Kelley discussed the importance of early diagnosis and prevention of decompensation through the comparison of median survival times between compensated and decompensated patients (without transplantation), of >12 years and ~2 years, respectively 1. She then elucidated portal hypertension as the main “driver of decompensation” and as a therapeutic target posing the question, “Can we prevent the progression to decompensation? In short, yes.

NSBBs, most notably propranolol and nadolol, were initially used to prevent variceal bleeding after detection through endoscopy. Dr. Kelly described the recent PREDESCI study2, a randomized, double-blind, placebo-controlled, multicenter trial, that looked at using Propranolol or Carvedilol in patients with small or no varices who would have not traditionally received NSBBs. They found patients responding to NSBBs had a significantly reduced number of decompensation events. These results prompted a 2020 meta-analysis which found responders (patients with a physiologic response to the NSBB) on NSBBs had a significantly reduced risk of decompensating events 3. Dr. Kelly highlighted Carvedilol, the now preferred NSBB as it has been found to be more effective at reducing HPVG 4. A common theme across these landmark studies was little to no inclusion of non-alcoholic fatty liver disease (NAFLD) patients. This, despite concern regarding the alarming incidence and prevalence of NAFLD around the globe 5. The underlying pathologic mechanisms and clinical features unique to NAFLD, necessitate a nuanced treatment approach 6. To date, no drug has been approved in North America or Europe for NAFLD 7,8. Despite a lack of data on NSBBs in NAFLD patients, NSBBs are still recommended in the hopes of preventing clinical decompensation with some data emerging 9.

After highlighting the expanded utility of NSBBs in chronic liver disease, Dr. Kelley discussed the challenge of advancing to non-invasive measures for identifying patients eligible for NSBBs. A solution first approved by health Canada in 2009, Transient Elastography (TE), stands as unique example of translational medicine; an ultrasound-based technology first developed to assess cheese maturity in Spain and is now approved as a non-invasive tool to assess fibrosis in chronic liver disease10,11. When combined with platelet count, spleen stiffness and size, TE is considered best practice to assess fibrosis through non-invasive means4. Despite strong consensus on the utility of TE, access in Canada remains a challenge. A study by Aljawad et. al (2015), found that as of January 2015, only 42 TE devices were available in Canada, with 71% located at in academic settings and only eight provinces having devices 12. KHSC if fortunate to have this device. Limited access and variable cost were identified as the primary barriers to routine use. The authors recommended policy action, but as of September 2023, no federal or provincial policies could be found. While TE has been Translated into Canadian practice, significant barriers for routine use persist and warrant our attention before the full benefits of TE can be realized for all eligible patients across Canada.

In the post lecture discussion, TMED graduate students engaged with Dr. Kelly. When asked about the strengths or advantages for patients of an interdisciplinary awareness of contemporary CSPH guidelines, Dr. Kelly highlighted the role of general and internal medicine colleagues. Management of cirrhosis patients is complex requiring interaction between specialists including cardiologists, hepatologists, and respirologists, especially when treating with NSBBs. She went on to note that interdisciplinary awareness will ultimately lead to better patient outcomes. Dr. Kelley also underscored the importance of colleagues and scientific communication when asked how she integrates new research into practice. Finally, when asked about her career, Dr. Kelley had great appreciation for her training as a hepatologist, emphasizing the benefits of both studying and practicing in multiple provinces. Through these experiences she was able to both bring and subsequently gain new perspectives and skills to continue improving patient care.

Thank you, Dr. Kelly, for sharing the contemporary evidence on CSPH and how we can move beyond varices in clinical surveillance and management of liver cirrhosis.

References

1. D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: A systematic review of 118 studies. J Hepatol. 2006;44(1):217-231. doi:10.1016/j.jhep.2005.10.013

2. Villanueva C, Albillos A, Genescà J, et al. β blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial. The Lancet. 2019;393(10181):1597-1608. doi:10.1016/S0140-6736(18)31875-0

3. Turco L, Villanueva C, Mura VL, et al. Lowering Portal Pressure Improves Outcomes of Patients With Cirrhosis, With or Without Ascites: A Meta-Analysis. Clin Gastroenterol Hepatol. 2020;18(2):313-327.e6. doi:10.1016/j.cgh.2019.05.050

4. Franchis R de, Bosch J, Garcia-Tsao G, et al. Baveno VII – Renewing consensus in portal hypertension. J Hepatol. 2022;76(4):959-974. doi:10.1016/j.jhep.2021.12.022

5. Riazi K, Azhari H, Charette JH, et al. The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2022;7(9):851-861. doi:10.1016/S2468-1253(22)00165-0

6. Toshikuni N, Tsutsumi M, Arisawa T. Clinical differences between alcoholic liver disease and nonalcoholic fatty liver disease. World J Gastroenterol. 2014;20(26):8393-8406. doi:10.3748/wjg.v20.i26.8393

7. Prikhodko VA, Bezborodkina NN, Okovityi SV. Pharmacotherapy for Non-Alcoholic Fatty Liver Disease: Emerging Targets and Drug Candidates. Biomedicines. 2022;10(2):274. doi:10.3390/biomedicines10020274

8. Roeb E. Non-alcoholic fatty liver diseases: current challenges and future directions. Ann Transl Med. 2021;9(8):726. doi:10.21037/atm-20-3760

9. Paternostro R, Becker J, Hofer BS, et al. The prognostic value of HVPG-response to non-selective beta-blockers in patients with NASH cirrhosis and varices. Dig Liver Dis. 2022;54(4):500-508. doi:10.1016/j.dld.2021.09.009

10. Benedito J, Carcel J, Clemente G, Mulet A. Cheese Maturity Assessment Using Ultrasonics. J Dairy Sci. 2000;83(2):248-254. doi:10.3168/jds.S0022-0302(00)74871-5

11. Patel K, Wilder J. Fibroscan. Clin Liver Dis. 2014;4(5):97-101. doi:10.1002/cld.407

12. Aljawad M, Sirpal S, Yoshida EM, Chandok N. Transient elastography in Canada: Current state and future directions. Can J Gastroenterol Hepatol. 2015;29(7):373-376.