Role of endoscopic ultrasound-guided portal pressure gradient measurement in assessing liver function before liver-directed therapies

Abstract

Liver-directed therapies such as resection, ablation, and embolization offer potentially curative options for patients with primary and metastatic liver tumors as part of multidisciplinary oncology care. However, these treatments pose significant hepatic decompensation risks, particularly with underlying liver disease and chemotherapy-associated steatohepatitis. Accurate assessment of liver function and portal hypertension (PH) is critical for candidate selection. While Child-Pugh score and model for end-stage liver disease are commonly used, they have substantial limitations. Hepatic venous pressure gradient (HVPG) measurement remains the gold standard for assessing PH but is invasive and not widely available. Endoscopic ultrasound (EUS) guided portal pressure gradient (PPG) measurement has emerged as a promising minimally invasive alternative. EUS-PPG demonstrates excellent technical success rates, safety profile, and correlation with HVPG in early studies. By providing direct portal pressure measurement, EUS-PPG offers several advantages over existing methods for prognostication and risk stratification prior to liver-directed therapies, particularly in detecting presinusoidal hypertension. Furthermore, it has potential applications in assessing response to neoadjuvant treatments and guiding adjuvant therapies. However, research is needed to validate its predictive performance and cost-effectiveness in larger prospective cohorts and to establish its accuracy compared to non-invasive assessment of liver function.

Key Words: Liver function; Portal hypertension; Hepatic venous pressure gradient; Endoscopic ultrasound; Portal pressure gradient; Liver resection; Endo-hepatology

Core Tip: Assessment of portal hypertension, hepatic steatosis and fibrosis provides valuable prognostic information prior to liver-directed therapies. Endoscopic ultrasound-guided portal pressure gradient is an exciting emerging technique that warrants further investigation as a potentially safer and more accessible alternative to trans-jugular hepatic venous pressure gradient measurement.

INTRODUCTION

Primary and secondary liver malignancies are common and lethal. Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide, with roughly 800000 new cases annually[1], and colorectal liver metastases develop in over 50% of the one million yearly colorectal cancer cases[2]. Liver-directed therapies, including surgical resection, tumor ablation, and transarterial embolization, are cornerstone treatments for liver tumors in both curative and palliative settings[3]. Curative-intent hepatectomy offers the best long-term outcomes for eligible patients, while ablation and intra-arterial therapies benefit those who are not surgical candidates[4].

A major challenge with these therapies is the risk of precipitating liver failure or decompensation in patients with compromised hepatic reserve. Underlying chronic liver disease is present in most HCC patients and a substantial fraction of those with metastases[4,5]. Post-hepatectomy liver failure remains a leading cause of postoperative mortality, occurring in up to 20% of patients after major liver resection[6,7]. Risk factors include cirrhosis, significant fibrosis, steatosis (often from chemotherapy-associated liver injury), and portal hypertension (PH). Notably, even with improvements in surgical technique and perioperative care, patients with subtle liver dysfunction can decompensate after intervention[7]. Careful assessment of liver function and PH is therefore critical in selecting appropriate patients for these liver-directed therapies and might guide the choice of interventions for liver directed therapy, systemic therapy and even possibly therapies aimed for liver rehab. There is growing recognition that optimizing and assessing the liver prior to therapy, including managing steatosis and fibrosis, may improve outcomes[8,9].

Accurate preoperative assessment of both liver function and PH is therefore critical. Traditional clinical scoring systems and lab tests provide some prognostic information, but they may not fully capture the risk, especially in borderline cases. Likewise, the presence of PH greatly increases the risk of post-treatment complications such as ascites, variceal bleeding, and liver failure. In this context, new tools like endoscopic ultrasound-guided portal pressure gradient (EUS-PPG) measurement have emerged to address the shortcomings of existing approaches. In the following sections, we provide a comparative overview of current methods for assessing liver function and PH, and then focus on the EUS-PPG technique, describing its methodology, advantages (including scenarios like Budd-Chiari syndrome where it may be uniquely beneficial), clinical applications, and limitations. We then discuss the implications of integrating EUS-PPG into practice and future directions for research in this evolving field[10].

CURRENT METHODS FOR ASSESSING LIVER FUNCTION

Assessment of hepatic functional reserve is paramount before liver-directed therapies. The Child-Turcotte-Pugh (Child-Pugh) score and the model for end-stage liver disease (MELD) score are the most commonly used tools in clinical practice to stratify surgical risk[11,12]. Child-Pugh class A patients, for example, are generally considered for resection, whereas class B/C carry high risk. However, these scores have important limitations. The Child-Pugh score includes subjective variables (encephalopathy and ascites grading) which can vary between observers. MELD, while entirely lab-based, was designed to predict survival in cirrhosis and transplant settings, and may not directly predict post-resection liver failure in all cases. Both scores also give a broad estimate of liver function and do not directly measure the dynamic functional reserve or portal pressure.

Several alternative or supplemental liver function tests exist. The indocyanine green (ICG) retention test measures plasma clearance of a dye by the liver. It provides a quantitative assessment and has been used to guide resection decisions[12]. An elevated ICG retention (> 20% at 15 minutes) suggests poorer functional reserve. While useful, the ICG test requires intravenous dye injection and specialized equipment, and some studies have found it inferior to other metrics in predictive value[13]. The albumin-bilirubin (ALBI) grade is a newer score that, unlike Child-Pugh, relies only on albumin and bilirubin levels to stratify liver dysfunction severity. ALBI has shown prognostic value in HCC patients[14] and avoids subjective measures; however, it still needs further validation specifically in perioperative risk assessment[15]. Other investigational assessments include the liver maximum function capacity test and 99mTc-galactosyl human serum albumin scintigraphy (GSA scan), which can provide quantitative liver function measures, but these are not widely available and can be costly or invasive[15,16].

In practice, a combination of methods is often employed. Patients are evaluated clinically for signs of PH (e.g., low platelets, splenomegaly, varices) and liver dysfunction, scored with Child-Pugh/MELD, and often undergo liver volumetry by imaging to ensure an adequate future liver remnant. Dynamic tests like ICG are used in some centers. Despite these tools, accurately predicting who will develop liver failure after resection remains difficult. This drives the need for more direct and precise assessments of liver health.

Current methods for assessing PH

PH is a key predictor of complications after liver resection and other interventions. Clinically significant PH (CSPH) is typically defined as a hepatic venous pressure gradient (HVPG) ≥ 10 mmHg, which is associated with markedly higher risks of ascites, variceal hemorrhage, and hepatic decompensation[17]. The presence of CSPH in cirrhotic patients is often a contraindication to major hepatectomy because of the high likelihood of postoperative liver failure. Therefore, evaluating portal pressure is integral to preoperative workup.

The gold standard for measuring portal pressure Is the HVPG. HVPG is an indirect measure obtained via a transjugular catheter: A wedged hepatic vein pressure (reflecting portal vein pressure) minus the free hepatic vein pressure[18]. An HVPG ≥ 16 mmHg has been shown to strongly predict post-hepatectomy liver failure and death in cirrhosis[18]. However, HVPG measurement requires an experienced interventional radiologist, fluoroscopy, and jugular vein access. It is an invasive procedure with potential complications (neck hematoma, carotid puncture, arrhythmias), and its availability is limited outside specialized centers[18]. In addition, HVPG may not be reliable or feasible in certain scenarios, for example, in Budd-Chiari syndrome (hepatic vein thrombosis) where the hepatic veins are occluded, one cannot obtain a valid wedged hepatic pressure.

Given these limitations, non-invasive surrogates of PH have been developed. Imaging-based methods include ultrasound elastography to measure liver stiffness and spleen stiffness, which correlate with portal pressure. Techniques such as transient elastography (FibroScan) or magnetic resonance elastography can identify patients with high portal pressure risk (for instance, liver stiffness > 20-25 kPa suggests CSPH in cirrhosis). Spleen stiffness measurement has shown promise in detecting varices and CSPH as well[19]. While valuable as screening tools, these modalities have their own limitations, overlap in values between patients with and without CSPH, and less validation in surgical candidates specifically[18]. Additionally, non-invasive tests cannot directly measure pressure and may be confounded by acute changes or other factors (for example, inflammation can raise stiffness readings).

Another indirect marker is platelet count and spleen size (as incorporated in some scores like the Lok index), since PH often causes hypersplenism and thrombocytopenia. However, these are crude indicators. The presence of varices on endoscopy is a definitive sign of PH, but by then PH is well advanced, and absence of varices does not rule out moderate PH.

In summary, HVPG remains the reference standard for assessing PH severity, but its invasiveness and technical requirements make it underutilized. Non-invasive tests can provide supportive information but are not yet replacements for direct portal pressure measurement in precision risk assessment. This gap has paved the way for an innovative approach: EUS-guided PPG measurement, which aims to directly measure portal pressure in a minimally invasive fashion.

EUS-GUIDED PPG MEASUREMENT: TECHNIQUE AND ADVANTAGES

EUS-guided PPG measurement is an emerging technique that allows direct assessment of PH from within the gastrointestinal tract[20]. In an EUS-PPG procedure, a therapeutic echoendoscope is used to access the liver vasculature via the stomach or duodenum. Under real-time ultrasound guidance, a fine needle (typically 25-gauge) is advanced through the stomach/duodenal wall into the left or right portal vein branch. The needle is connected to a pressure transducer, and the portal pressure is recorded. The needle is then partially withdrawn and repositioned into a hepatic vein (or the inferior vena cava/hepatic outflow) via the same transhepatic tract to measure hepatic venous pressure[21]. The difference between portal and hepatic venous pressures yields the portal pressure gradient. The procedure is often performed under general anesthesia or deep sedation for patient comfort and to minimize motion.

Several early studies have demonstrated the feasibility and accuracy of EUS-PPG. In initial pilot studies in humans, EUS-PPG readings showed strong correlation with HVPG measurements, suggesting that the technique is an effective surrogate for the gold standard[20,21]. Technical success rates for EUS-PPG are consistently high. For example, Hajifathalian et al[22] reported a 96% technical success in simultaneous EUS-PPG and liver biopsy performed in 24 patients[22]. Similarly, Choi et al[23] achieved a 100% success rate in a series of 64 patients undergoing EUS-PPG, with no serious complications observed[23]. Across multiple studies, EUS-PPG appears safe, the most commonly reported issues have been minor, such as transient pain with essentially no significant adverse events attributable to EUS-PPG[24]. This safety profile is very favorable when compared to the invasive HVPG procedure (which, while generally safe, can cause bleeding or rarely more serious complications in a small percentage of cases[19]).

EUS-PPG offers several clinical advantages over traditional methods of assessing portal pressure. First, it provides a direct measurement of portal venous pressure, rather than the indirect wedged hepatic pressure of HVPG[25]. This can be particularly important in situations of presinusoidal hypertension. For instance portal pressure may be elevated due to presinusoidal pathology while HVPG (which reflects sinusoidal/post-sinusoidal pressure) remains normal. EUS-PPG would directly capture the elevated portal pressure in such cases, potentially detecting CSPH earlier[24]. Another scenario is portal vein thrombosis: HVPG might not detect the resultant PH (or be contraindicated), whereas EUS could in theory sample pressure in the thrombus-affected portal branches to gauge severity.

Perhaps one of the most powerful advantages of the EUS-based approach is the ability to combine diagnostic and therapeutic maneuvers in one session, the concept of“"endo-hepatolog”". During the same endoscopic procedure, in addition to measuring the portal pressure, clinicians can perform EUS-guided liver biopsy (obtaining histology from the left and/or right lobe) and evaluate for varices. This one-stop approach can provide a comprehensive assessment of liver status: Hemodynamic (portal pressure), histologic (fibrosis/inflammation grade), and endoscopic (variceal status) in a single visit. Such efficiency is especially valuable in patients being evaluated for surgery, as it can expedite decision-making without multiple separate tests[26].

Clinical applications of EUS-PPG

EUS-PPG is being explored in a variety of clinical contexts. One important application is preoperative risk stratification before liver resection or other invasive liver-directed therapy. By identifying patients with subclinical PH, EUS-PPG may inform the decision to proceed with surgery or perhaps pursue alternative therapies. For example, a patient with borderline lab tests but an EUS-PPG demonstrating CSPH (≥ 10 mmHg gradient) might be at high risk for post-hepatectomy liver failure and could be redirected to non-surgical therapies or a smaller resection. On the other hand, a patient with well-compensated cirrhosis but low portal pressures might safely undergo a more extensive resection than otherwise thought.

Another use case is evaluation of liver disease severity and fibrosis in patients undergoing locoregional therapies or transplant workups. EUS-PPG has shown correlation with underlying disease markers: Choi et al[23] demonstrated that an EUS-measured gradient ≥ 5 mmHg was significantly associated with advanced fibrosis (stage F3-4 on biopsy) and other indicators of PH (e.g., varices, thrombocytopenia)[23]. This suggests EUS-PPG could complement liver biopsy in gauging disease stage, for instance, an intermediate fibrosis (F2) but with high portal pressure might prompt closer monitoring or treatment.

For patients undergoing neoadjuvant chemotherapy or locoregional therapy prior to surgery, EUS-PPG might be employed to assess if these treatments have impacted liver health. Certain chemotherapeutic agents (like oxaliplatin) can cause sinusoidal injury and raise portal pressures, even without overt cirrhosis. If a patient with colorectal metastases undergoes months of chemotherapy and then is being considered for resection, an EUS-PPG could reveal subclinical PH that would elevate surgical risk. This information could guide a decision to delay surgery, modify the surgical plan (e.g. perform a portal decompression or smaller resection), or pursue liver transplantation if appropriate. Similarly, after HCC locoregional therapies (Transarterial chemoembolization, Y-90 radioembolization), measuring portal pressures may inform whether the patient can tolerate subsequent therapy.

In the postoperative or post-treatment setting, EUS-PPG could help identify early PH or guide adjunct therapies. For instance, after a liver resection, if an EUS-PPG a few weeks post-op shows a significantly elevated gradient, that patient might benefit from closer monitoring, prophylactic non-selective beta-blockers, or consideration of a portosystemic shunt to prevent late complications. In a transplant scenario (although our focus is pre-surgical, some have speculated about post-transplant monitoring), unexplained liver dysfunction could be evaluated with EUS-PPG to check for graft fibrosis or outflow issues without an invasive biopsy initially.

LIMITATIONS OF EUS-PPG AND ONGOING CHALLENGES

Despite its promise, EUS-PPG is not without limitations. The technique requires specialized skills in interventional endoscopy and EUS, as well as specific equipment (a needle catheter system with a high-fidelity pressure sensor). The procedure time adds on to a standard endoscopy/EUS; in one report the average time for EUS-PPG was around 38 minutes (versus about 37 minutes for HVPG)[25]. This is efficient, but widespread adoption will depend on training more endoscopists in the technique. There is a learning curve to safely puncture the portal vasculature and obtain reliable readings. Guidance documents and standardization of the technique (needle selection, zeroing of pressure transducers, patient position, etc.) are still evolving.

Another consideration is patient selection. While minimally invasive, EUS-PPG still involves an invasive needle puncture into the portal venous system. Patients with significant coagulopathy or very large varices at the puncture site might be at higher risk for bleeding. So far, reported complication rates are extremely low[24], but prudence dictates careful patient screening (e.g., correction of international normalization ratio, platelets) similar to any invasive procedure. Moreover, if a patient already has obvious clinical PH (like large varices), the incremental value of measuring an exact gradient might be limited, one could argue the management would be the same without exact HVPG. Thus, EUS-PPG will likely be most useful in cases where the presence or degree of PH is uncertain.

"The accuracy and reproducibility of EUS-PPG..." need further validation. Most studies are single-center and involve experienced operators. We need multicenter data to ensure the readings are consistent across centers and endoscopists. Inter-observer variability in identifying the appropriate vessels and obtaining a stable tracing is an area to study. In HVPG measurement, small differences in technique can cause variability (e.g., over-wedging). For EUS-PPG, factors like respiratory variation and patient position might influence measurements and should be standardized. Also, defining the threshold values for risk stratification is important, for instance, is the classical ≥ 10 mmHg (CSPH) threshold equally applicable for EUS-PPG measurements in surgical candidates, or do we need different cut-offs? As more data accrue, these questions can be answered.

Finally, there are logistical and cost considerations. Setting up EUS-PPG in a practice requires coordination between hepatology, oncology, surgery, and endoscopy teams. The cost of an EUS-PPG procedure vs the standard of care must be justified by improved outcomes. Encouragingly, a recent cost-analysis by Wang and Ryou[27] suggests that combining EUS-PPG with liver biopsy in a single session may have favorable cost-utility compared to the traditional approach of separate transjugular biopsy with HVPG[27]. By potentially obviating the need for two separate procedures (endoscopy and interventional radiology), and by preventing complications through better patient selection, the EUS approach could prove cost-effective. However, these economic models need real-world outcome data for confirmation.

The advent of EUS-guided portal pressure measurement represents a significant development in the preoperative evaluation of liver tumor patients. Despite advances in risk stratification, hepatic decompensation after liver-directed therapy remains a serious problem, underscoring the need for improved assessment strategies[10]. Traditional metrics (clinical scores, imaging, standard labs) provide indirect and sometimes inconsistent insight into how a given patient will tolerate liver therapy. By directly quantifying portal pressure, a key driver of decompensation risk, EUS-PPG has the potential to refine our decision-making. The implications of this are far-reaching: More precise patient selection, tailored extent of surgery, and possibly improved outcomes through avoiding procedures in those at highest risk. Early clinical experiences have been encouraging in this regard. Another important point is that EUS-PPG provides complementary information to liver biopsy and noninvasive tests. In an era of precision medicine, having a comprehensive profile of the patient's liver, combining functional reserve, structural integrity (fibrosis), and hemodynamic status, is ideal. For instance, two patients might both be Child-Pugh A and have similar lab profiles, but one could have subclinical PH and the other not, which might not be discovered without measuring directly. Only the patient with PH might be at risk of complications, and EUS-PPG helps unmask that. Conversely, if EUS-PPG confirms low portal pressure, one might proceed more confidently with aggressive therapy. This tailoring exemplifies a move toward precision hepatology in surgical oncology.

The clinical impact of integrating EUS-PPG could be significant. If prospective trials demonstrate that using EUS-PPG to guide decisions leads to fewer liver failures or better survival, it could change guidelines. For example, current guidelines often use surrogates like platelet count or presence of varices to infer PH in surgical candidates; a future guideline might recommend EUS-PPG for direct measurement in patients with cirrhosis being considered for resection, similar to how HVPG is used in some transplant evaluations. Moreover, EUS-PPG might allow more patients to safely undergo needed cancer therapy by identifying those who can tolerate it. Patients who otherwise might be denied surgery due to fear of cirrhosis could be cleared if their PPG is low, potentially offering curative treatment to more individuals.

Another potential application of EUS-PPG is in assessing any worsening in liver function related to neoadjuvant therapies prior to liver directed therapy including surgical resection. For example, in patients with advanced HCC undergoing locoregional therapies like transarterial chemoembolization, EUS-PPG could provide a direct measure of treatment impact on portal pressures. This information could guide decisions about timing and safety of subsequent surgical resection. Similarly, in the post-resection setting, EUS-PPG may help identify patients who would benefit from adjuvant therapies or closer surveillance based on their portal pressure dynamics.

It is also worth discussing the scenario of hepatic steatosis and newer therapies in the context of preoperative optimization, as this intersects with liver function assessment. Hepatic steatosis (fatty liver), especially when exacerbated by chemotherapy (so-called chemoembolization or chemotherapy-associated steatohepatitis), has been shown to worsen surgical outcomes[7]. The original question arises: Can we improve liver health (e.g., reduce steatosis or fibrosis) in the interval before surgery to reduce risk? Traditionally, this has been attempted with lifestyle changes (diet, exercise), but with limited time (a few weeks) and often suboptimal results[8]. Recently, new pharmacologic agents for non-alcoholic steatohepatitis (such as resmetirom, a thyroid hormone receptor-β agonist) have become available and shown efficacy in reducing liver fat and fibrosis markers[9]. While speculative, one could envision using such a drug in the preoperative period to "rehabilitate" the liver. Our review's scope is primarily portal pressure assessment, but we acknowledge that improving the underlying parenchymal health is another important facet of optimizing patients. Future studies should explore if short-term interventions (medical or otherwise) to reduce steatosis or portal pressure (e.g., beta-blockers, vitamin E, or MASH drugs) can translate to fewer complications when surgery is performed. Combining such therapies with monitoring tools like EUS-PPG (to see if the portal pressure improves with intervention) would be an exciting area of research.

Finally, it must be emphasized that further research is essential before EUS-PPG can be widely adopted in routine practice. The current evidence consists of small studies and case series. We need larger, ideally multi-center prospective studies that examine how EUS-PPG-guided decision making compares to standard care. Endpoints should include rates of post-operative liver failure, complication rates, and perhaps cost-benefit analyses.

In summary, EUS-guided PPG measurement exemplifies the innovative convergence of endoscopy and hepatology. It holds the promise of providing more precise risk assessment for patients undergoing liver-directed therapies, thus enabling better-informed clinical decisions. As part of a broader trend of endo-hepatology, it complements existing methods by filling a crucial gap, directly measuring what was previously inferred. The coming years will determine how this technique is integrated into practice, but its potential to improve patient outcomes makes it a highly significant development in the field of liver surgery and interventional gastroenterology.

However, as an emerging technique, EUS-PPG needs further rigorous evaluation before widespread clinical implementation. The clinical utility of EUS-PPG should be validated in larger prospective cohorts, with hard endpoints assessing its incremental impact beyond established functional and morphologic factors for improving outcomes of liver-directed therapies. Studies focusing on patients undergoing neoadjuvant, or adjuvant treatments would be particularly informative. In addition, Resmetiron has not been studied in cancer patients, or the preoperative stage and studies will need to be done to see if it will be helpful.

Careful assessment of liver function and PH is fundamental to the safe and effective use of liver-directed therapies for cancer. Traditional scoring systems (Child-Pugh, MELD) and tests (ICG clearance, elastography) provide valuable information but may fail to fully predict the risk of post-treatment liver failure in all patients. EUS-guided PPG measurement is an exciting new tool that offers a more direct and possibly more accurate evaluation of PH, especially in scenarios where standard measures are unavailable or inadequate. By integrating EUS-PPG into the preoperative workup, especially in patients receiving potential hepatotoxic systemic therapy, clinicians can gain a more nuanced understanding of a patient's liver reserve and tailor management accordingly, for example, avoiding major resection in a patient found to have significant PH despite otherwise mild liver disease.

Looking ahead, the clinical relevance of EUS-PPG will be determined by ongoing research. If studies confirm that EUS-PPG guided decision-making improves outcomes (such as reducing liver failure or guiding successful downstaging of portal pressure), it could become a standard component of pre-surgical evaluation. In addition, adjunctive strategies like pharmacologic optimization of liver health (e.g., treating steatosis or hepatitis in the window before surgery) may work synergistically to improve patient outcomes.

CONCLUSION

In conclusion, EUS-guided PPG measurement represents a pivotal development in assessing liver fitness for intervention. It addresses an unmet need for safer, more accurate portal pressure evaluation and has multiple potential applications in liver oncology and hepatology. With further validation, EUS-PPG has the potential to usher in a more precision-based approach to liver-directed therapies, improving patient selection, reducing complications, and ultimately enhancing the care of patients with primary and metastatic liver cancer.