Spleen-To-Liver Stiffness Ratio in MASH

The spleen-to-liver stiffness ratio (SSM/LSM) is an emerging noninvasive biomarker that has shown significant potential in characterizing portal hypertension (PH), particularly in patients with metabolic dysfunction-associated steatohepatitis (MASH). Here is a detailed breakdown of the findings related to SSM/LSM in MASH based on the context provided:

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### **1. Key Observations:**

• **Higher SSM/LSM Ratio in MASH:**

Patients with MASH exhibited a significantly higher spleen-to-liver stiffness ratio (median 1.66) compared to patients with alcohol-related liver disease (ALD) (median 1.28, p = 0.001). This suggests that spleen stiffness increases disproportionately relative to liver stiffness in MASH.

• **Comparison to PSVD:**

MASH values approached those seen in porto-sinusoidal vascular disease (PSVD), which had the highest SSM/LSM ratio (median 3.19). This supports the hypothesis that MASH includes a presinusoidal component of PH, similar to PSVD.

• **Independence from Comorbidities:**

After adjusting for factors like body mass index (BMI), diabetes, hypertension, and statin use, MASH remained an independent predictor of a higher SSM/LSM ratio (β = 0.59, p = 0.046). This indicates that the elevated ratio is specific to the vascular characteristics of MASH and not merely a result of metabolic comorbidities.

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### **2. Clinical and Mechanistic Insights:**

• **Presinusoidal Component in MASH:**

The elevated SSM/LSM ratio in MASH reflects a presinusoidal component of PH that is not captured by traditional hepatic venous pressure gradient (HVPG) measurements. This presinusoidal PH is likely due to periportal vascular injury, ductular reaction, and portal fibrosis, which elevate splenic pressure independently of sinusoidal resistance.

• **Early Detection of Portal Hypertension:**

MASH patients exhibited higher SSM/LSM ratios even at lower HVPG levels, suggesting that the spleen stiffness-to-liver stiffness relationship could serve as an early indicator of portal venous pressure elevation before significant hepatic fibrosis develops. This is crucial for early detection and management of PH in MASH.

• **Spleen Size Correlation:**

Despite having less severe liver disease (lower MELD and HVPG scores), MASH patients had equal or slightly larger spleen diameters compared to ALD patients. When adjusted for HVPG, spleen size per pressure unit was significantly greater in MASH (1.15 cm/mmHg vs. 0.85 cm/mmHg, p < 0.001), further highlighting the presinusoidal vascular changes in MASH.

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### **3. Prognostic Implications:**

• **Risk of Hepatic Decompensation:**

Patients with MASH and higher SSM/LSM ratios demonstrated a numerically higher risk of hepatic decompensation (13–18% at 6–12 months) compared to those with lower ratios. Although not statistically significant (p = 0.67), this suggests potential prognostic value for SSM/LSM in identifying patients at greater risk of complications.

• **Distinct Hemodynamic Patterns:**

The inverse correlation between the SSM/LSM ratio and HVPG (R = −0.35) indicates that as presinusoidal PH increases, the ratio rises despite lower HVPG values. This confirms the distinct hemodynamic patterns in MASH compared to other liver disease etiologies.

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### **4. Comparison Between MASH and ALD:**

• **Different PH Mechanisms:**

ALD patients showed more severe intrahepatic fibrosis (higher LSM values), while MASH patients had greater extrahepatic pressure gradients (higher SSM/LSM ratios). This reinforces the idea that MASH and ALD have different mechanisms of portal hypertension, with MASH being more influenced by presinusoidal vascular changes.

• **Correlation with HVPG:**

While both LSM and SSM correlated significantly with HVPG across all etiologies (R = 0.54 and 0.42, respectively), the correlation was stronger in MASH (R = 0.62 for LSM and 0.55 for SSM). This indicates that these metrics are particularly effective in tracking PH severity in MASH.

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### **5. Potential as a Noninvasive Biomarker:**

The SSM/LSM ratio has the potential to serve as a novel imaging biomarker for identifying MASH patients with early or mixed-type PH. This could reduce reliance on invasive HVPG testing and provide a more comprehensive understanding of portal dynamics in metabolic liver disease.

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### **6. Limitations and Future Directions:**

• **Small MASH Sample Size:**

The study included only 49 MASH patients, which limits the generalizability of the findings. Larger cohorts are needed to validate the results.

• **Lack of Histological Validation:**

The study did not include histological confirmation of presinusoidal fibrosis, which would strengthen the mechanistic insights.

• **Absence of Direct Portal Pressure Measurements:**

While HVPG is the gold standard for measuring portal pressure, it does not adequately capture presinusoidal PH. Future studies could incorporate direct portal pressure measurements to better understand the relationship between SSM/LSM and PH.

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### **7. Conclusion:**

The spleen-to-liver stiffness ratio (SSM/LSM) is a valuable noninvasive marker for detecting presinusoidal components of portal hypertension in MASH. It highlights unique vascular characteristics in MASH, such as early portal venous pressure elevation and splenomegaly, which are not captured by traditional HVPG measurements. This ratio could enhance the diagnosis, risk stratification, and management of portal hypertension in metabolic liver disease, marking a shift toward more precise, etiology-specific assessment of portal dynamics.