Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD), and it is characterized by hepatic steatosis associated with injury to the liver cell and inflammation. The prevalence of NASH has significantly increased in the last decade. There’s an estimate of about 24% of United States adults have NAFLD and about 1.5% to 6.5% have NASH¹. Given this prevalence and health effects, NAFLD/NASH is a significant issue for the public’s health. NAFLD/NASH is closely linked to metabolic complications, diabetes, and dyslipidemia furthermore it appears to be associated with disease comorbidities including pulmonary dysfunction, cardiovascular disease, and kidney failure². With respect to pulmonary function, several epidemiologic studies and longitudinal cohort studies revealed impaired pulmonary function in NAFLD/NASH^3,4. Furthermore, patients with a higher degree of NASH are at an increased risk of decreased lung function⁵.

This impaired pulmonary function in this type of liver disease seems linked to increased metabolic complications and the inflammatory process. In our recent in vivo study, more severe inflammation and mitochondrial dysfunction in pulmonary parenchyma tissues were found in NAFLD model relative to the control⁶. In addition, increased pulmonary inflammation appeared to be highly associated with reduced exercise capacity and pulmonary vascular dysfunction⁷. Therefore, it can be hypothesized that patients with NASH may have lower exercise capacity and pulmonary capacitance compared to similar age-matched healthy adults; however, it has not been investigated extensively. Accordingly, the present study retrospectively investigated exercise capacity (peak oxygen uptake [peak VO₂]), pulmonary capacitance (GX_cap), and dynamic respiratory gas exchange and breathing pattern during exercise in patients with NASH.

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To achieve the purpose of the present preliminary study, a database of patients with NASH, who were clinically diagnosed, and age-matched healthy individuals who underwent cardiopul-monary exercise tests (CPET) in our laboratory was utilized. The exercise modality was a recumbent cycle ergometer (Corival; Lode) and the exercise protocol included 2 minutes of resting phase and an incremental exercise phase. The wattage was increased by 25 W every 2 minutes until volitional fatigue. During CPET, VO₂, breathing patterns and respiratory gas exchange including breathing efficiency (VE/VCO₂) and end-tidal CO₂ (PETCO₂) were measured, and heart rate (HR) was monitored via electro-cardiograph. To determine peak exercise capacity, peak VO₂ was obtained by averaging the last 30 seconds at peak level. In addition, oxygen pulse (O₂ pulse), which represents stroke volume⁸, was calculated using the formula: O₂ pulse=(absolute VO₂×1,000)/HR; and GX_cap was calculated using the formula: GX_cap=O₂ pulse× PETCO₂. This gas exchange-based estimate of GX_cap was pre-viously validated by our laboratory^9,10 and confirmed to be well correlated to invasive measures of mean pulmonary arterial pressure and pulmonary vascular resistance⁹.

All values are illustrated as the mean±standard deviation. To observe the difference between the NASH group and the healthy group, an independent t-test or nonparametric t-test was conducted. Statistical analyses were performed using the IBM SPSS version 28.0 (IBM Corp.). The statistical significance level was set at p<0.05.

The present study was reviewed and approved by the Institutional Review Board of Mayo Clinic (No. 20-007471). This study is a retrospective study and does not require informed consent from the subjects.

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There was no significant difference in age between the NASH group and the healthy group (p>0.05); however, the NASH group demonstrated a higher body mass index (BMI) relative to the healthy group (p<0.05) (Table 1). The NASH group demonstrated reduced peak VO₂ relative to the healthy group (p<0.05; Fig. 1A). With respect to the key gas exchange, the NASH group demonstrated a higher VE/VCO₂ (Table 1) and a lower PETCO₂ (Fig. 1B) compared to the healthy group (p<0.05). In addition, although there was no significant difference in O₂ pulse between groups (p>0.05; Fig. 1C), the NASH group showed lower GX_cap than the healthy group (p<0.05; Fig. 1D).

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In the present study, the NASH group demonstrated higher body weight and BMI compared to the healthy group. They showed reduced peak oxygen uptake, breathing efficiency, and gas exc-hange relative to the healthy group. In addition, they had reduced pulmonary capacitance compared to the Healthy group. Given that there were no significant differences in O₂ pulse and HR at a given VO₂ between groups, reduced pulmonary capacitance in the NASH group was more likely derived from reduced PETCO₂, which is closely pulmonary arterial pressure and pulmonary vascular resistance¹¹. These results suggest that patients with NASH have lower exercise capacity than age-matched healthy adults and moreover impaired dynamic respiratory gas exchange and pulmonary capacitance during exercise contribute largely to redu-ced exercise capacity. There may be several factors that can elicit impairments in respiratory gas exchange and pulmonary capa-citance in this type of liver disease; however, it can be speculated that increased pulmonary inflammation⁶ and altered pulmonary vascular tone¹² have pivotal roles.

Except for spirometry-measured pulmonary function, there is still a lack of clinical insight into more in-depth pulmonary patho-physiology in NASH. In clinical practice, more specific pulmonary pathophysiology needs to be evaluated via multi-dimensional assessments. Although the present study reports preliminary data, the results may provide future directions to improve the therapeutic approach and help guide decision-making. However, this requires further studies with larger sample sizes to investigate clinical insights.

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