Sarcopenia

Sarcopenia is defined as the loss of muscle mass, strength, and function leading to adverse health outcomes [29]. Cirrhosis-induced sarcopenia affects 30–50% of end-stage liver disease patients [30–33] and is most prevalent in those with advanced disease [34, 35]. As detailed in previous chapters, the pathology inherent with liver disease directly leads to impaired protein synthesis and muscle contractility as well as increased muscle breakdown. Changes in muscle mass are predictive of mortality, independent of the Model for End-Stage Liver Disease (MELD) score [34]. Evidence suggests that sarcopenia may be reversible in patients with cirrhosis after exercise rehabilitation [36–40].

Frailty

In cirrhosis, physical frailty is characterized by sarcopenia, malnutrition, and physical deconditioning [7]. Frailty is defined in many ways, but for cirrhosis patients, it is likely best defined as a low physiologic reserve and decreased functional status [4], which leaves patients vulnerable to health stressors, leading to physical dependency and death [41]. Roughly 20% of patients with cirrhosis are classified as frail, while 40% are functionally limited [42]. Patients are at an increased risk for falls, fractures, hospitalization, and limited recovery from health complications [42, 43]. Tests of frailty have been correlated with poor clinical outcomes in the cirrhosis population. Newly developed indices of frailty can improve the prognostic ability of conventional status scores including the Model for End-Stage Liver Disease (MELD) and Child-Pugh [42, 44]. Given that frailty in cirrhosis is characterized by declines in multiple systems, the benefits of exercise are of clinical interest to guard against health declines and to improve overall health.

Rationale for Exercise Training

Physical inactivity and sedentary behaviour are strong predictors of poor health outcomes, such as cardiovascular disease, malignancy, musculoskeletal disease, and metabolic disorders [45]. In cirrhosis, physical inactivity exacerbates other existing poor health conditions, such as decreased protein synthesis, hypermetabolism, increased inflammatory cytokines, hyperammonemia, and low testosterone levels [7, 46]. Together, these factors lead to cardiovascular and skeletal muscle deconditioning, characterized by sarcopenia and frailty. Exercise improves skeletal muscle mass, strength, endurance, and cardiopulmonary function. Given that cirrhosis-related impairment is founded on muscle dysfunction and cardiopulmonary deconditioning, exercise is a promising therapy for patients living with liver disease. In other chronic disease populations, exercise-related benefits have been noted independent of the degree of physical deconditioning [47]. As the majority of studies in cirrhosis have been performed in patients with compensated disease, the degree of response expected across the strata of disease severity and physical deconditioning in cirrhosis remains to be evaluated [7, 12].

Safety Concerns

A major concern regarding exercise in cirrhosis is a rise in the hepatic venous pressure gradient (HVPG), an accurate surrogate measure of portal hypertension. Rises in the HVPG put patients at risk for variceal bleeding [48, 49]. An early study found that the HVPG increased in patients with cirrhosis and portal hypertension during exercise [49]. However, a follow-up study showed that, with the use of non-selective beta-blocker medication, a decrease in the HVPG occurs during exercise [48]. Further, evidence from more recent years has failed to prove that patients with cirrhosis and portal hypertension are at increased risk for adverse events when performing exercise [50–52]. Indeed, a randomized controlled trial combining moderate aerobic and resistance exercise training resulted in decreases in the HVPG over the long term [53]. A subsequent randomized controlled trial confirmed this finding using a lifestyle intervention which involved both light-moderate exercise training and diet modification in cirrhosis patients with portal hypertension [36].

Effects on Sarcopenia and Frailty

Sarcopenia can be assessed by measuring muscle mass using computed tomography (CT) scan, DEXA, or ultrasound each with their inherent advantages and disadvantages. It can also be indirectly measured using bioelectrical impedance or measures of muscle strength, like handgrip strength. Although no studies have evaluated the effects of exercise on muscle mass using cross-sectional imaging (CT or MRI scans), several studies have shown improvements in both muscle mass and strength through supervised and home-based exercise training [50, 51, 55–57]. Improvements in muscle mass can also be complemented by decreases in fat mass [36, 52, 56, 58].

Cardiopulmonary endurance/function is often assessed by either cardiopulmonary exercise testing or the 6-minute walk test. Frailty can be assessed by composite tests, including the Short Physical Performance Battery (comprised of gait speed, balance, and repeated sit to stand) or the Liver Frailty Index (including balance, repeated sit to stand, and handgrip strength tests). Trials in cirrhosis have shown that exercise training can reduce the risk of falls [56], decrease fatigue [50], and improve exercise capacity as well as physiologic reserve [36, 50–53, 55, 56]. Further research is required to explore the effects of exercise training on additional frailty metrics.

Although the evidence supports the use of exercise training to attenuate sarcopenia and frailty in patients with liver disease, there is much variability in the frequency, intensity, time, and type of exercise showing effects in the literature. Trials have ranged from progressive step goals for aerobic exercise to supervised randomized controlled trials using both aerobic and resistance exercise [Table 7.1]. The exercise parameters vary considerably, yet it is clear that both resistance and aerobic exercise show promise in targeting sarcopenia and frailty in this population.

Cirrhosis-Related Safety Considerations

The 2015 Baveno VI Consensus recommends that patients with a FibroScan score ≥20 kPa or platelet count ≤150,000/μl be screened for varices [59]. Thrombocytopenia (low platelet count) is not a contraindication to exercise per se, but exercises with high risk of injury or falling should be avoided, particularly when platelets are <20,000/μl. In this situation, it is recommended that the patient is prescribed exercises that incorporate a stable support surface. Patients with high-risk varices or those who have had a previous variceal bleed should be on primary or secondary variceal prophylaxis prior to exercise initiation [60].

Beyond varices, no other cirrhosis-related considerations are absolute contraindications to activity that is low-moderate intensity. However, a number of other complications can impact exercise tolerability, adherence, and efficacy [2]. These include large volume ascites, pedal oedema, and hepatic encephalopathy. Patients with ascites typically experience impaired exercise capacity, and it may be challenging to perform certain exercises. Exercises should be progressed on days where ascites accumulation is minimal. Exercises where pressure is put on the abdomen (i.e. prone exercise or straining abdominal exercises) should be avoided. For patients with overt hepatic encephalopathy, their readiness to engage, understand, and perform exercise directions should be considered. At the very least, a caregiver should be present during exercise sessions. Finally, patients on diuretic therapy may be at risk of volume depletion or hypotension following exercise. These patients should consume water during their exercise sessions, monitor symptoms of dizziness [61], and end the exercise session immediately if they feel faint.

Cardiopulmonary Safety Screening

Prevalence of cardiovascular risk factors in the liver disease population is high, but the link between these factors and events is low. The current American College of Sports Medicine (ACSM) guidelines recommends “medical clearance” for those starting a moderate intensity programme with signs, symptoms, or a history of cardiovascular, metabolic, or renal disease. Medical clearance should be obtained if the patient presents with any of the following signs or symptoms: chest discomfort with exertion, unreasonable breathlessness, dizziness, fainting, blackouts, heart palpitations, lower limb claudication, or heart murmur [62]. Likewise, medical clearance should be obtained if the patient has a history of the following: heart attack, heart surgery, cardiac catheterization or coronary angioplasty, pacemaker, heart valve disease, heart failure, heart transplantation, congenital heart disease, diabetes, or renal disease. The procedure for medical clearance is left up to the clinician.

ACSM defines moderate intensity as 40–59% heart rate reserve, a VO₂ reserve of 3.0–5.9 metabolic equivalent (METs), or a rating of perceived exertion (RPE) of 12–13 on the 6–20 Borg scale or 5–6 on the 0–10 scale.

In our opinions, asymptomatic patients wanting to pursue low-moderate activity should adhere to a “start low and progress slow” approach to training [7] and do not require a pre-participation cardiac clearance [63]. In symptomatic patients, it may be beneficial to conduct additional testing, including cardiopulmonary exercise testing. At the very least, approval for participation should be obtained from the patient’s clinician prior to exercise training initiation.

Other Safety Considerations

Patients should be asked if they experience exertional symptoms that limit their activities of daily living. This can help identify factors (e.g. muscle cramping, claudication, joint pain, restricted range of motion) that may require exercise programme modification or additional therapeutic intervention before exercise initiation [19]. During physical performance assessments, fall risk can be assessed using balance testing included in the Short Performance Physical Battery or Liver Frailty Index . Those at high risk of falling should perform supported activity (e.g. seated or standing with a support). Caregiver supervision is also recommended. If the patient has additional comorbidities, the recent ACSM guidelines should be consulted for safety implications [19]. Lastly, for patients who are identified as having an increased risk of falling, careful consideration is needed before progressing the patient to unsupported exercises.

Encourage Non-exercise Activity Thermogenesis (NEAT)

Describing the simple principles of NEAT to patients is a way to encourage them to increase the amount of physical activity that they do outside of scheduled exercise programming. NEAT activities involve making the “less convenient” choice, with a goal to increase activity, for example, stepping in place while watching TV instead of sitting on the couch, climbing stairs instead of taking the elevator, or parking in a spot further away from their destination instead of the closest spot [64].

Scheduled Exercise Programming

On the basis of the available literature, 30- to 60-minute sessions of both aerobic and resistance training are recommended with the goal being to achieve 150+ minutes/week of moderate intensity exercise. For an exercise training programme to be effective, it should last at least 3 months to facilitate physiological gains [65]. Resistance exercise should always be prescribed as it has an important role in preventing or attenuating muscle loss. Aerobic exercise compounds the effects of resistance exercise by improving physiological reserve and functioning of patients. Flexibility and balance exercise can complement these two primary training modes by maintaining joint function and balance. Table 7.2 outlines the ideal frequency, intensity, time (duration), and type of exercise that are effective in targeting sarcopenia and frailty and explain how exercise can be progressed for patients with liver disease. These recommendations are adapted from Tandon et al. [12].

Table 7.2

Aerobic and resistance exercise training recommendations

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