G&H What is the current understanding of the relationship between portal hypertension and metabolic dysfunction-associated steatohepatitis?
JA Regardless of the etiology of chronic liver disease, portal hypertension arises mainly in patients who progress to cirrhosis. In most cases of patients with metabolic dysfunction-associated steatotic liver disease (MASLD), including metabolic dysfunction-associated steatohepatitis (MASH), effective therapy is not currently available specifically in cirrhosis to suppress the activity of the disease. When these patients progress in the natural history of cirrhosis, they eventually develop portal hypertension. It is very unusual that portal hypertension occurs without cirrhosis. If that is the case, clinicians look for alternative causes of portal hypertension.
Portal hypertension develops in patients with MASLD that progresses to cirrhosis in part because of mechanical obstruction of the portal circulation. Portal hypertension is clearly associated with the degree of fibrosis, which creates a mechanical obstruction at the level of the portal venules. This increases hepatic resistance to portal blood flow, which induces back-pressure on the portal circulation. As portal hypertension evolves, after this initial increase in portal pressure, there are other mechanisms, as with any other course of cirrhosis, that alter the splanchnic circulation and systemic circulation. This increases not only hepatic resistance, but also portal blood inflow that contributes to portal hypertension, despite the development of portal systemic collaterals that could, in theory, decompress the system. Because of this persistent increase in portal blood flow, portal hypertension is maintained. There is not only a mechanical problem of the portal circulation, but also a functional component in the liver microvasculature. Years ago, endothelial dysfunction in the sinusoidal cells at the level of the hepatic microcirculation was described in any cause of cirrhosis. It could be that because patients with MASLD or MASH have an increased overall systemic endothelial dysfunction because of cardiovascular risk factors, this microvascular dysfunction at the liver microcirculation might be more prominent in these patients. This has been demonstrated in animal models.
In summary, in patients with progression of cirrhosis, portal hypertension is a consequence initially of both a mechanical obstruction at the level of the liver microcirculation related to fibrosis and regenerative nodules. There is also an active liver vascular component, and then once portal hypertension is established, a systemic component resulting in an increase in portal blood flow contributes to portal hypertension as well. This is common to patients with cirrhosis of any etiology. The more MASH patients progress to advanced fibrosis, the more these patients behave like patients with other causes of cirrhosis.
G&H What are the most common clinical manifestations and imaging findings of portal hypertension in patients with MASH?
JA Portal hypertension can be completely silent for a long period of time. If the portal pressure gradient is between 5 and 10 mm Hg, there are not many manifestations of disease. When the portal pressure gradient threshold of 10 mm Hg is exceeded, patients start to be at risk of developing complications such as ascites, hepatic encephalopathy, and variceal bleeding. It was thought that hepatic encephalopathy was more common as the first complication of cirrhosis specifically in MASH patients, but subsequent series have not provided confirmation. It now looks like the most common first complication is ascites, as with any other cause of cirrhosis. During this silent phase, the only way of detecting portal hypertension could be with imaging findings, such as an ultrasound finding of an enlarged portal vein, enlarged spleen, or collaterals. All these suggest from an imaging perspective that the patient is already at the stage of portal hypertension.
G&H Which noninvasive methods should be used to detect clinically significant portal hypertension in MASH patients?
JA Clinically significant portal hypertension has been traditionally defined as a portal pressure gradient of more than 10 mm Hg because that is the threshold for having an increased risk of developing complications. Because the degree of fibrosis is the main determinant of the development of portal hypertension, any noninvasive marker that is tied to the degree of fibrosis in MASH could predict the presence of clinically significant portal hypertension. The most common markers include elastography techniques, either vibration-controlled transient elastography (VCTE) or magnetic resonance elastography, as well as blood tests (eg, the Enhanced Liver Fibrosis test has a strong association with the presence of clinically significant portal hypertension). Another noninvasive marker is a larger spleen, which leads to thrombocytopenia. Platelet count, which is very easy to measure, has been combined with elastography methods in scores, for example, the ANTICIPATE-NASH model or the NICER score, which incorporates spleen stiffness for the prediction of clinically significant portal hypertension. The Baveno VII criteria simplify these models, suggesting the presence of clinically significant portal hypertension with VCTE of more than 25 kilopascals (kPa), VCTE between 20 to 25 kPa and a platelet count less than 150,000/µL, or VCTE between 15 to 20 kPa and platelet count less than 110,000/µL.
However, these criteria do not work very well in patients with MASH, especially those with significant obesity, and have a very low positive predictive value. One of the reasons the ANTICIPATE-NASH model was developed was to introduce a correction for obesity within these noninvasive predictors. The model produces a number from 0 to 1 that represents the probability of finding clinically significant portal hypertension. For simplification, the recent Baveno VIII meeting suggested that VCTE of more than 25 kPa in any patients or an ANTICIPATE-NASH score of more than 0.75 in patients with MASH and obesity has a very high positive predictive value to diagnose clinically significant portal hypertension.
G&H How can these noninvasive markers help determine when to initiate beta blocker therapy or endoscopic surveillance in this setting?
JA This is an important question because the field has evolved to use beta blockers for the prevention of decompensation. After the PREDESCI trial, which was published in 2019, recommendations have suggested that beta blockers be initiated in patients with suspected clinically significant portal hypertension. Currently, the criteria to initiate beta blockers are VCTE or FibroScan of more than 25 kPa or, in patients with MASH and obesity, an ANTICIPATE-NASH score of more than 0.75. If patients are already taking beta blockers and are compensated, there is no reason to perform an endoscopy unless there is another indication. If an endoscopy is performed and varices are found, the patient should continue to be treated with beta blockers, and nothing else needs to be done. In patients who have contraindications or who do not tolerate beta blockers, the question is whether an endoscopy is needed to assess for varices, and the answer is yes. The old Baveno VI criteria can be applied in this scenario such that VCTE of more than 20 kPa or a platelet count of less than 150,000/µL triggers an endoscopy to assess for potential varices. If large varices are found, variceal ligation is indicated.
G&H How should clinically significant portal hypertension be managed in MASH patients?
JA For now, the only effective treatment to decrease portal pressure and, in that way, prevent decompensation in MASH patients involves beta blockers. Currently, carvedilol is mainly used because it is best tolerated and is the most effective in decreasing portal pressure. A meta-
analysis showed clearly that carvedilol can decrease the risk of decompensation and perhaps improve mortality.
Additionally, there is no question that it is beneficial to try to control the primary liver disease causing cirrhosis. Patients should abstain from alcohol, and the metabolic milieu contributing to MASH and disease progression should be controlled as best as possible. At this point, there are very little data on the effect of MASH-specific medications in patients who already have cirrhosis and whether these agents can prevent progression to decompensation or to clinically significant portal hypertension.
G&H Could you discuss any research on emerging MASH therapies such as resmetirom or semaglutide in this setting?
JA Trials are currently ongoing. Recent data show that medications such as resmetirom (Rezdiffra, Madrigal) and fibroblast growth factor 21 agents might improve markers of clinically significant portal hypertension in patients with MASH. However, confirmation of clinical benefit is needed in phase 3 trials. There are no contraindications to using semaglutide (Wegovy, Novo Nordisk) in patients with compensated cirrhosis, but clinicians should be aware that, as with any patient, efforts have to be made in preventing sarcopenia with semaglutide. Phase 3 trials with a glucagon-like peptide-1 receptor agonist, as well as dual and triple agonist, are also needed. Resmetirom and semaglutide have been approved in patients with MASH without cirrhosis based on regulatory endpoints for accelerated approval for improving fibrosis without worsening of MASH, which is highly predictive for a reduction in cirrhosis progression. If a medication can prevent the progression of cirrhosis, it will also be able to prevent the progression of clinically significant portal hypertension.
G&H What further research is needed?
JA As mentioned, the only treatment at this point for portal hypertension in any patient, with or without MASH, is the use of beta blockers. Beta blockers are thought to be equally effective in patients with MASH, but there are not much data and some have been contradictory. Therefore, further research is needed to understand whether there is any differential effect in patients with MASH. Additionally, there is a need to understand better whether there is some specificity of the mechanisms leading to portal hypertension in MASH compared with other etiologies. Most of the initial studies on pathophysiology, especially studies using portal pressure measurements in patients with cirrhosis, were performed in Europe when the prevalence of MASH was very low; therefore, these studies mainly included patients with alcohol-associated liver disease and hepatitis C. Also, with the progressive use of noninvasive tests, it is becoming increasingly difficult to obtain information with portal pressure measurements. I do not think there is much difference in the portal hypertension mechanisms between patients with MASH and other etiologies. Where there is a difference is in the degree of comorbidities when portal hypertension occurs in the context of a patient who has diabetes or high blood pressure; the systemic part of the circulatory dysfunction observed in cirrhosis might be substantially different from a patient with, for example, alcohol-associated liver disease who does not have any of these risk factors. Further research is needed. Finally, there needs to be an evolution in how to assess benefit in treatments for MASH cirrhosis with and without portal hypertension by refining trial design with outcomes that potentially occur earlier. It is difficult to achieve the hard clinical outcomes currently being used. These earlier outcomes could include noninvasive tests that predict clinically significant portal hypertension.
Disclosures
Professor Abraldes has received consulting fees from Madrigal, Boehringer Ingelheim, 89bio, Novo Nordisk, AstraZeneca, Boston Pharmaceuticals, Agomab, Biossil, Stately Bio, Bausch Health, Roche, HepQuant, and AbbVie; holds stock options in Biossil; has received speaker fees from Terumo and Ferring; and has received institutional grant support from Gilead.
Suggested Reading
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