Sarcopenia in cirrhosis: a clinical practice review

Introduction

Cirrhosis is the end stage of any chronic liver disease and globally accounts for two million deaths annually (1). The disease process is the result of chronic liver injury leading to progressive scarring, or fibrosis. Etiologies include chronic alcohol use, metabolic dysfunction associated steatotic liver disease (MASLD)—formerly known as non-alcoholic fatty liver disease (NAFLD), hepatitis B or C virus infection, genetic conditions and autoimmune diseases. Liver function is initially preserved; however, if left untreated, ongoing fibrosis leads to disarray in hepatic architecture and nodule formation with gradual impairment of hepatic function (2).

Compensated cirrhosis is primarily asymptomatic, without significant biochemical or anatomic complications. Decompensated cirrhosis is characterized by the deterioration in liver function with the development of jaundice, esophageal variceal bleeding, hepatic encephalopathy (HE) and ascites (3). The Child-Pugh scoring system is a tool initially designed to predict mortality and categorize the severity of portal hypertension. The five components of the Child-Pugh score include subjective parameters along with objective laboratory data indicating liver function: (I) degree of HE, (II) severity of ascites, (III) bilirubin, (IV) albumin and (V) prothrombin time, which is often substituted by international normalized ratio (INR) (4). Cirrhosis is one of the most significant predisposing factors in developing malnutrition, frailty, and sarcopenia (5). These conditions directly correlate to morbidity, mortality, and overall poorer outcomes in patients with end-stage liver disease (ESLD) and liver transplant recipients (6). In this review article, we highlight the current understanding of malnutrition, frailty, and sarcopenia with a focus on assessments and interventions in the setting of cirrhosis.

Malnutrition

In the clinical setting, the terms malnutrition, frailty and sarcopenia are often used interchangeably. However, frailty and sarcopenia are distinct clinical manifestations of malnutrition. A corollary to this ideology is in patients with metabolic syndrome and diabetes who develop physical manifestations of insulin resistance, such as acanthosis nigricans.

Malnutrition is a clinical syndrome related to the imbalance (deficiency or excess) of nutrients and impaired nutrient utilization that is associated with measurable adverse effects on function and clinical outcome (7,8). The reported prevalence of malnutrition in patients with cirrhosis ranges from 50% to 90% and increases with the severity of disease (9-11). Malnutrition is one of the most impactful independent prognostic factors in cirrhosis outcomes, hospital length of stay and mortality (9). In a cross-sectional study evaluating nutritional status, major complications such as uncontrolled ascites, HE, spontaneous bacterial peritonitis (SBP), and hepatorenal syndrome (HRS) developed in 65.5% of malnourished patients vs. 11.8% of well-nourished ones (P<0.05) (12). In a prospective study of 212 hospitalized patients with cirrhosis who were followed clinically for two years or until death, the prevalence of severe malnutrition in those with Child-Pugh class A, B and C were 12.5% (P<0.001), 35.2% (P<0.01) and 45.5%, respectively (13). Malnutrition is highly prevalent amongst patients on the waiting list for liver transplantation (14). By not meeting nutritional requirements, the patients are in a vicious cycle of progressive cirrhosis and deranged nutritional status.

The etiology for malnutrition is multifactorial, but reduced oral intake plays a significant role. Illness, dietary restrictions, fasting periods, hospitalization and symptoms of cirrhosis, including anorexia, nausea, and vomiting all have an impact on malnutrition. Decompensations further exacerbate poor daily food intake. In those with ascites, compression of the stomach leads to loss of appetite and early satiety. In those with HE, preparing meals or consuming food is often not feasible. Nutritional intake in patients with cirrhosis is characterized by low overall energy, protein intake and inadequate food composition (15). Limited access to food due to socioeconomic factors and selection of nutritious foods due to low health literacy also play a role in inadequate macro- and micronutrient intake (16).

Chronic liver disease and inflammation affect impaired macro- and micronutrients. In alcohol-associated liver disease, common deficiencies include folate, thiamine, zinc, selenium, vitamin D and vitamin E (17). Fat-soluble vitamin (A, D and E) deficiencies are commonly seen in cholestatic liver diseases due to the disruption of enterohepatic circulation of bile salts leading to maldigestion and malabsorption (18). Vitamin D directly results in decreased muscle contractility leading to frailty and sarcopenia (19). In a study of 33 patients with chronic liver disease who were treated with oral vitamin D3 at a dose of 2,000 IU once a daily for 12 months compared to control, the prevalence of sarcopenia decreased from 80.0% to 33.3% (P=0.025) demonstrating vitamin D restores skeletal muscle volume and strength (20). MASLD pathophysiology is linked to metabolic risk factors including elevated fasting plasma glucose, hypertriglyceridemia and obesity, which increases risk for sarcopenic obesity (SO).

The liver plays a key role in nutritional metabolism. The development of cirrhosis leads to an increased catabolic state. Glucose uptake in both hepatic and skeletal tissue results in impaired glucose homeostasis (21). Hepatic glucose metabolism is thus altered. Net hepatic glycogenolysis is 3.5 fold lower (P=0.01) and gluconeogenesis is markedly higher (P=0.03) in patients with cirrhosis when compared with no cirrhosis (22). Imbalances in synthesis and storage result in a state of accelerated starvation and increased protein breakdown. The inappropriate dependency on gluconeogenesis diverts amino acids from skeletal muscle exacerbating sarcopenia (23,24).

Altered protein metabolism leading to reduction of plasma free branched-chain amino acids (BCAA) affects extrahepatic ammonia detoxification and results in accelerated muscle breakdown (25). Approximately 33% of patients with cirrhosis develop a hypercatabolic state in which proteolysis outpaces protein synthesis (26). Resting energy expenditure (REE) is also increased in patients with cirrhosis. Hypermetabolism, the state of increased energy expenditure, is prevalent in patients with cirrhosis requiring higher caloric intake compared to the general population (26).

Protein homeostasis is further disturbed in cirrhosis due to factors such as hyperammonemia. Ammonia is derived from the breakdown of proteins and under normal physiologic conditions, the liver plays a central role in ammonia detoxification. Cirrhosis and portosystemic shunting result in inadequate ammonia detoxification and hyperammonemia results in ammonia toxicity, most notably neurotoxicity (24). Hyperammonemia can lead to increased mitochondrial free radical production, causing abnormal oxidative stress and autophagy of skeletal muscle, leading to loss of muscle mass/sarcopenia (27,28). Increased ammonia levels crossing the blood-brain barrier can result in HE, a common neuropsychiatric complication of cirrhosis marked by confusion, psychiatric abnormalities, memory loss and in severe situations, coma. Skeletal muscle plays a role in extrahepatic ammonia detoxification thus decreased muscle mass reciprocally causes hyperammonemia perpetuating a negatively symbiotic relationship (27).

Gastrointestinal dysfunction in cirrhosis can be either anatomical in the setting of tense ascites negatively impacting meal-induced accommodation of the stomach or functional as cirrhosis has been shown to prolong gastric emptying and small bowel transit (29-31). Dysbiosis, characterized by an imbalance in the gut microbiota, leads to an increased intestinal permeability and bacterial translocation (32). This process is driven by the disruption of the intestinal barrier, which allows bacteria and their products to enter the systemic circulation. Systemic inflammation is thus further promoted, decreasing micronutrient production by the gut microbiota and affecting muscle mass and metabolism (33,34). Additionally, portosystemic shunting, pancreatic enzyme deficiency, bacterial overgrowth, and altered intestinal flora contribute to malabsorption. Dysbiosis in cirrhosis is also associated with small intestinal bacterial overgrowth (SIBO), which can impair nutrient absorption and digestion, contributing to malnutrition (35).

Hormonal and cytokine abnormalities also contribute to malnutrition. Cytokines, specifically tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6), along with “hepatokines”, which are liver-specific cytokines, perpetuate the inflammatory process, hepatocyte necrosis and progressive fibrosis (24,36). The pathophysiology of malnutrition in cirrhosis involves several interrelated mechanisms, including that ultimately lead to a catastrophic result (Figure 1).

Figure 1 Contributing factors in cirrhosis leading to frailty and sarcopenia.

Frailty and sarcopenia

Frailty is the clinical state of increased vulnerability to health stressors in the setting of decreased physiologic reserve that leads to adverse health outcomes (7,37,38). Phenotypically, frailty is represented by impaired muscle contractile function. The prevalence of frailty in cirrhosis is 17–43% in the ambulatory setting and 38% in the inpatient setting with concomitant HE (5,39). Physical frailty is the primary manifestation of impaired muscle contraction; this has multiple implications, including disability, decreased physical function, and decreased functional performance (40). This is especially evident in cirrhosis patients as it impairs their overall physical function/performance and compounds on their baseline nutritional and muscular pathophysiology. Progressive immobility, often in the setting of worsening volume overload, episodic or uncontrolled HE and periods of hospitalization for acute decompensations contribute to frailty in patients with cirrhosis. A bidirectional relationship whereby factors that occur with decompensation and acute on chronic liver failure, such as anorexia, ascites and inflammatory cytokine release result in physical inactivity and reduced caloric intake.

Sarcopenia was initially used to describe the loss of muscle in the elderly population; however, it is now acknowledged in an array of chronic diseases, including cirrhosis (1). Classically defined as the age-related, progressive decline in skeletal muscle mass and function, sarcopenia is seen in 40–70% of cirrhosis patients, with severity and prevalence increasing in worsening liver disease (13). Sarcopenia is intrinsic to the aging process but is accelerated by factors such as inflammation, chronic illness, inactivity, and malnutrition. In a prospective study of 1,200 patients, it was determined that age >60 negatively impacted the skeletal muscle index (SMI) (P<0.001) (6). Sarcopenia appears to be more common in men than women with cirrhosis and is associated with an approximately 2-fold higher risk of death (41,42). In a meta-analysis of 8,945 patients with cirrhosis, sarcopenia emerged as a significant risk factor for mortality [hazard ratio (HR) 2.13, 95% confidence interval (CI): 1.86–2.44, P<0.001] (43).

SO is the co-existence of excess adiposity, or obesity [body mass index (BMI) >30 kg/m²], and decreased skeletal muscle mass and function. Prevalence of SO has been reported as high as 42% in patients with cirrhosis (44). Obesity can independently lead to sarcopenia due to the negative impact of adipose tissue-dependent metabolic derangements including oxidative stress, inflammation and insulin resistance (45). Obesity can also mask muscle wasting in patients with cirrhosis thus sarcopenia can go underrecognized in the absence of measures of physical function. The landscape of chronic liver disease has shifted dramatically in recent years with a notable increase in the incidence of MASLD and patients with liver disease are presenting with obesity. Obesity and insulin resistance are closely associated factors with metabolic syndrome, so SO is often seen in patients with cirrhosis due to MASLD. Like sarcopenia, SO is associated with high morbidity and mortality.

Assessment of frailty and sarcopenia

Early detection to allow for immediate intervention is imperative to improve the overall prognosis in patients with disease-related frailty and sarcopenia due to liver disease. Clinicians often utilize subjective frailty measurements in clinical decision-making. The Eyeball test, an assessment in which the physician makes a determination based on patient history and exam, the clinician’s knowledge of comorbidities and intuition can be an accurate method to rule out frailty. The Eyeball test was compared against the Fried test in 300 patients with cardiovascular disease and identified 41% (compared to 36%) of patients as frail with 86% sensitivity and 82% specificity, area under the curve (AUC) 0.82 for diagnosing frailty (46). Subjective assessments including frailty surveys and self-reported physical activity levels inherently lack objectivity, consistency, reproducibility, and meaningful serial variability.

Single objective metrics of frailty commonly used in the clinical setting include assessment of activities of daily living (ADL), and the 6-minute walk test (6MWT). ADL was evaluated in an observational study of 734 inpatients with decompensated cirrhosis which found that the odds ratio (OR) for ADL score of less than 12 of 15 on mortality was 1.83 (95% CI: 1.05–3.20) (47). In a study of 250 patients with chronic liver disease, of which 98 subjects had cirrhosis, 6MWT was found to be an independent predictor of survival (P=0.024) while Child-Pugh score was found to negatively correlate with the 6 minute walk distance (6MWD) (R=−0.328, P<0.01) (48). Patient participation is required in these metrics thus feasibility may be severely limited in acutely ill patients or those with significant decompensations.

The Fried Frailty Index (FFI) is a 5-point score that encompasses reported subjective measures—exhaustion, unintentional weight loss, and low physical activity, and objective measures—walk speed, and hand grip strength (49). Patients are scored between 0 (not frail) and 5 (most frail). FFI ≥3 is consistent with decreased independent ADL and increased risk of falls (50). In a single-center study of 267 liver transplant waitlist patients, frailty defined by FFI was more significantly associated with removal from the waitlist or waitlist mortality, compared with patients who were not frail (22% vs. 10%, P=0.03) (6). Every 1 unit increase in FFI corresponds to a 50% increase in liver transplant waitlist mortality (HR 1.50, P=0.01) (5). While FFI provides a good overview of frailty, the index does not incorporate important factors such as age and medical comorbidities or cirrhosis-specific factors such as malnutrition, liver failure and HE.

The Clinical Frailty Scale (CFS) is a 1-minute bedside clinical assessment that incorporates comorbidities, level of daily physical activity, dependence for ADLs and life expectancy less than 6 months (51). The index is divided into nine categories ranging from “severely frail” to “very fit” with CFS of 4 indicating the patient is pre-frail. Frailty, CFS >4, is associated with hospitalization or death (OR 3.6, P=0.008) in a study of patients with cirrhosis (51). In a validation study of 299 outpatients/inpatients, for every 1 unit increase in CFS score, there was an independent association with mortality in the outpatient cohort (HR 1.534, P=0.007) while a CFS >4 was found to be an independent predictor of 28-day mortality (OR 4.627, P=0.045) (52). CFS limitations include providing only a snapshot of frailty and inability to identify specific areas of frailty.

The Liver Frailty Index (LFI) combines three objective performance-based tests—hand grip strength, time to complete five chair stands (seconds), and time holding three balance positions (feet side by side, tandem, and semi tandem)—to provide a score that categorizes patients with cirrhosis in the ambulatory setting as robust, pre-frail, or frail (index <3.2; 3.2–4.5, and >4.5, respectively) (53). LFI is well-studied in patients with cirrhosis and a multicenter study of 1,044 patients frailty, ascites, and HE were significantly associated with waitlist mortality sub-hazard ratio (sHR) 2.38 (95% CI: 1.77–3.20, P<0.001), 1.52 (95% CI: 1.14–2.05, P=0.004), and 1.84 (95% CI: 1.38–2.45, P<0.001), respectively (39). In adjusted multivariable models only frailty by LFI was significantly associated with waitlist mortality (sHR 1.82, 95% CI: 1.31–2.52, P<0.001) (39). LFI is inexpensive, easy to administer, quick to complete and most importantly, liver-specific. In a study of 529 patients awaiting liver transplantation, addition of LFI to clinician assessment, compared to clinical assessment alone, significantly improved predicting risk of mortality (0.74 vs. 0.68, P=0.02) (54). A summary of the three validated assessments to evaluate frailty in patients with advanced liver disease is provided in Table 1. Patients with cirrhosis should be assessed for frailty with a standardized tool at baseline and longitudinally.

There is significant heterogeneity in the evaluation of sarcopenia in patients with cirrhosis. Several indirect and direct modalities exist for muscle quantification including anthropometry, ultrasound, bioelectrical impedance analysis (BIA), dual-energy X-ray absorptiometry (DEXA), computed tomography (CT) and magnetic resonance imaging (MRI). Traditional anthropometric measures such as weight and BMI have fallen out of favor due to their inability to correctly distinguish between fat and muscle. Mid-arm muscle circumference (MAMC, in cm) is a safe and inexpensive method that estimates the skeletal muscle mass and can avoid confounding from fluid overload. Proposed MAMC cutoff points for severe and moderate depletion of muscle mass were ≤21.5 cm and ≤24.2 cm; ≤20.9 cm and ≤22.9 cm for women and men, respectively (55).

BIA estimates body fat and muscle mass through a weak electrical current that flows through the body (56). Muscle mass loss is diagnosed by BIA <7.0 kg/m² for men and <5.7 kg/m² for women (57). BIA for the measurement of body composition is a quick, noninvasive and reliable study (58). However, fluid retention, specifically ascites in patients with cirrhosis, affects the reliability of lean body mass assessment (59). BIA devices are not readily available in clinical practice and are also not well-validated in patients with cirrhosis.

Of the quantitative measures, ultrasound technology is the simplest, cheapest tool that can be employed to assess muscle mass. A transducer produces ultrasound waves that provide a noninvasive image of the targeted muscle (or muscle group). Quadriceps muscle thickness and quality showed concordance with CT for identifying patients with sarcopenia. Ultrasound measurement of thigh muscle thickness in combination with BMI is able to identify men and women with sarcopenia, AUC 0.78 and 0.89, respectively, when compared with CT imaging (60). Ultrasound measurement of the psoas muscle was significantly related to hospitalization and mortality (HR 0.881, 95% CI: 0.836–0.929, P<0.0001, and HR 0.930, 95% CI: 0.876–0.987, P=0.017, respectively) (61). Although readily available and non-invasive, ultrasound for sarcopenia assessment is not well validated in decompensated cirrhosis patients.

DEXA is a compartmentalized 3-dimensional whole-body scan with an emitting X-ray source that allows the measurement of lean mass (LM), fat mass (FM), and bone mineral content (BMC) (62). Muscle mass loss is diagnosed by DEXA at <7.0 kg/m² for males and <5.4 kg/m² for females (57). Appendicular LM assessed by DEXA in men with cirrhosis is strongly associated with mortality [HR 0.78 (0.62; 0.98), P=0.03] (63). However, accuracy may be restricted. In a study of 1,587 community-dwelling older adults evaluating sarcopenia via appendicular skeletal muscle mass by BIA and DEXA, BIA overestimated muscle mass compared with DEXA (2.89±0.38 vs. 2.97±0.45 kg/m², P<0.005) (64). One major limitation of DEXA is the overestimation of muscle mass in patients with extracellular fluid accumulation due to its inability to differentiate between water and bone-free LM (65).

Cross-sectional imaging is by far the most widely used and current gold standard for detecting sarcopenia in cirrhosis. The L3 SMI is a well-validated tool that requires specialized software and expertise to diagnose muscle wasting. The area of skeletal muscle (measured in cm²/m²) at the lumbar vertebra, L3, is quantified by cross-sectional imaging utilizing body segmentation analysis and further stratified based on sex-specific cutoffs SMI ≤52–55 cm²/m² for males and SMI ≤39–41 cm²/m² for females (66,67). In a study of 149 patients with cirrhosis, the degree of cirrhosis categorized by Child-Pugh class A, B and C, was associated with changes in skeletal muscle area per year, –1.3%, –3.5% and –6.1%, respectively (68). CT is straightforward, replicable and minimally affected by fluid retention. A single-center observational cohort study of 145 men with cirrhosis demonstrated prevalence of sarcopenia differed between CT and DEXA, 70.3% and 38.7%, respectively (69). While CT imaging is the preferred modality, cost and radiation exposure limit its practical use for the sole purpose of detecting sarcopenia (70). Table 1 compares the utility, strengths and limitations of the three major modalities used in assessing sarcopenia.

Outcomes

Frailty and sarcopenia are associated with increased risk of adverse outcomes including falls, fractures, disability, hospitalizations and mortality. In a study of 734 hospitalized patients with cirrhosis, disability defined by need for some assistance with ≥3 ADLs, was associated with a nearly 2-fold increased 90-day mortality (OR 1.83; 95% CI: 1.05–3.20) (47). In the ambulatory setting, physical frailty (LFI ≥4.5) was associated with a 1.9× increased risk of waitlist mortality when compared to non-frail patients (sHR 1.82; 95% CI: 1.31–2.52) (39). Changes in frailty over time also informs mortality risk. In a study of 1,093 patients with cirrhosis, a 0.1 unit increase in LFI every 3 months was associated with a 2-fold increased risk of waitlist death (HR 2.04; 95% CI: 1.35–3.09) (54). Outpatient assessments including clinical frailty scale, Fried frailty phenotype, frailty index, and short gait speed also correlate with both incidence and length of hospitalization (50,71,72). Two metrics of physical frailty/performance, the Karnofsky performance status (KPS) and ADL, have data from hospitalized cohorts. Loss of ADL was associated with adjusted risk of 90-day mortality after discharge (HR 1.83, 95% CI: 1.05–3.20) and for every 10-points of improvement in KPS score there was a 30% reduction in odds of 30 days death on discharge (95% CI: 20–40%) (47,73).

Sarcopenia and cirrhosis are bidirectional. Sarcopenia increases the incidence of HE (OR 2.42, P=0.001) and is significantly associated with mortality (HR 2.15; 95% CI: 1.52–3.05, P<0.001) (74). A prospective study of 911 patients with cirrhosis demonstrated that overall survival was significantly lower in cirrhosis patients with sarcopenia compared with those without sarcopenia [risk ratio (RR) 2.643, 95% CI: 1.646–4.244, P<0.001] (6). Median survival was shorter in patients with cirrhosis and sarcopenia when compared to non-sarcopenic patients (20±3 vs. 95±24 months, P<0.001) (75).

Patients with cirrhosis and sarcopenia were found to have increased cumulative incidence of ascites (RR 1.827, 95% CI: 1.259–2.651, P=0.002), SBP (RR 3.331, 95% CI: 1.404–7.903, P=0.006), HE (RR 1.962, 95% CI: 1.070–3.600, P=0.029) and gastrointestinal varices (RR 2.138, 95% CI: 1.319–3.466, P=0.002) (6). Aside from worsening complications of cirrhosis, sarcopenia was found to be an independent predictor of mortality (HR 2.36, 95% CI: 1.23–4.53) (72). Median survival time for cirrhosis patients with sarcopenia compared with no sarcopenia was 19±6 vs. 34±11 months (P=0.005) (41). In a study with a median follow-up period of 46.2 months (range, 3.4–87.6 months), cumulative mortality was significantly higher in patients with changes in skeletal muscle area per year <−2.4% vs. ≥−2.4% (P<0.001) (76).

Sarcopenia is a powerful predictor of waitlist mortality. More severe sarcopenia is associated with higher rates of delisting on the waitlist and waitlist mortality in 396 patients with cirrhosis awaiting liver transplantation (45.6 cm²/m², 95% CI: 38.5–50.8 cm²/m² compared with 48.5 cm²/m², 95% CI: 42.4–54.9 cm²/m², respectively, P<0.001) (77). In liver transplant recipients, sarcopenic patients had longer hospital stays when compared with nonsarcopenic patients (40±4 vs. 25±3 d; P=0.005) (78). Sarcopenia is a predictor of pre- and post-liver transplant mortality (79,80).

Interventions

Nutrition

Effective management of nutrition in patients with cirrhosis is a vital aspect of treatment. Interventions that address these nutritional deficits and counter the high metabolic demands of cirrhosis are essential. Determining a patient’s ideal caloric intake can be difficult. Indirect calorimetry is a method used to measure energy expenditure by assessing respiratory gas exchange thereby estimating metabolic rate and substrate utilization (81). However, assessment requires specialized equipment and thus is not widely available. A second option is estimating caloric need via weight-based equations using estimated dry weight. In non-obese patients at least 35 kcal/kg daily and in obese patients a moderately hypocaloric (500–800 kcal/d deficit) diet is clinically applicable (82).

Protein intake of 1.2–1.5 g/(kg·d) is recommended for cirrhosis patients, with up to 2.0 g/(kg·d) allowance for critically ill patients (83,84). BCAA supplementation at 0.25 g/(kg·d) may be an add-on therapy if protein goals are not met. There is insufficient data for the use of BCAAs in critically ill patients (83). A multicenter, randomized controlled trial compared 12 g/d of BCAA over two years vs. a diet comprised of 1–1.4 g/kg protein daily and a minimal caloric threshold. The primary endpoints included death (regardless of cause), esophageal variceal bleed, hepatocellular carcinoma or progression of cirrhosis. All of these were decreased in the BCAA group (HR 0.67, 95% CI: 0.49–0.93; P=0.015) vs. the diet group (85).

The pattern of food intake is also important in patients with cirrhosis. A “nibbling” or “grazing” pattern characterized by a large number of small meals including a good breakfast and a late evening meal, improved energy metabolism and resulted in shorter episodes of catabolism, compared to a “gorging” pattern characterized by a small number of large meals (86). Timing of intake is of importance in cirrhosis with the goal of avoiding extended fasting intervals. An early breakfast with small meals every 3–4 waking hours followed by a late evening/nighttime snack is the optimal strategy (87). In a cohort of 103 patients with cirrhosis who received either daytime or nighttime supplementary nutrition there was an associated increase in total body protein in the nighttime group at 3 months (0.38±0.10 kg, P=0.0004), 6 months (0.48±0.13 kg, P=0.0007) and 12 months (0.53±0.17 kg, P=0.003) compared to baseline. No significant improvement was seen in the daytime group (87).

All cirrhosis patients also require dietary counseling and educational resources. The mortality benefit of inpatient nutritional assessment has been contentious due to the inconclusive data gathered thus far. However, this may be skewed due to the limited duration of intervention in hospitalized patients with cirrhosis (88). A recent study tracking inpatient nutrition consults and education in hospitalized patients with cirrhosis prospectively over 90 days demonstrated a 10% (39.4% vs. 28.4%; P=0.04) absolute reduction in hospital re-admission and increased outpatient nutrition follow-up (89).

Physical activity & exercise

Structured exercise improves muscle function and overall health outcomes. Resistance and endurance exercises help promote muscle protein synthesis by activating the mammalian target of rapamycin (mTOR) signaling pathways, which are essential for muscle growth and repair, reducing muscle degradation, enhancing mitochondrial function, and improving muscle perfusion. This effectively counteracts the progression of sarcopenia (72,90). The upregulation of the mTOR signaling pathway can be seen on immunofluorescence and in a prospective study of 17 patients (91,92). Protein synthesis after exercise increased by 52% in males and 47% in females (P<0.05). The phosphorylation of mTOR also increased in both groups (P<0.05) (92). Aerobic exercise, such as walking, is recommended 4–7 days a week for a total of 150 minutes. Resistance exercise, such as functional or progressive weight/band training is recommended 2–3 days a week with flexibility and balance exercises at similar intervals (93).

Hormonal therapy

Hormone supplementation with products such as testosterone has shown potential benefits in restoring muscle mass. However, these interventions are accompanied with various potential adverse effects, most significantly increased cardiovascular risk (94). Testosterone has anabolic activity which leads to increased overall skeletal muscle mass, plasma albumin level but lacks finite long-term utility data (24). In a 12-month, double-blind, placebo-controlled trial of intramuscular testosterone undecanoate administered to 101 men with established cirrhosis and low serum testosterone, primary outcome of appendicular LM was significantly higher in testosterone-treated men [mean adjusted difference (MAD) +1.69 kg, P=0.021] and secondary outcomes of total LM and femoral neck mineral density were higher in testosterone-treated men (94). Strict nutrition management, guided exercise programs, along with select pharmacological aids offer a multifaceted approach to sarcopenia management.

Interventions specific to cirrhosis

Cirrhotic patients who develop sarcopenia require strict targeted management of complications such as ascites, HE, and portal hypertension to improve patient outcomes and mitigate disease progression (91). Ascites, the accumulation of fluid in the abdominal cavity, is a consequence of cirrhosis and often exacerbates sarcopenia through decreased protein intake secondary to diminished appetite and the compressive effect of intra-abdominal fluid. Effective initial management includes sodium restriction with concomitant diuretic use to assist with hypervolemia (95). Diuretics must be used cautiously, particularly loop diuretics, as they can negatively impact muscle mass at higher doses and increase mortality (68). However, spironolactone and tolvaptan have both been shown to decrease progression of sarcopenia and can be beneficial adjuncts to loop diuretics (96,97).

Patients with HE benefit significantly from lactulose and rifaximin as these medications improve cognitive function and slow sarcopenic decline (93). Lactulose is a non-absorbable disaccharide that acidifies the gut upon its breakdown leading to increased conversion of NH₃ to NH₄. This increases the ammonium ions trapped in the gut for excretion on bowel movement, thereby decreasing total ammonia in the plasma. Rifaximin decreases the ammonia-producing bacteria population in the gut, although the mechanism of action is disputed. Fecal microbial transplantation (FMT) has been proposed as a method for restoring healthy microbial function, but there is insufficient evidence on its efficacy (24).

In patients with advanced portal hypertension, a transjugular intrahepatic portosystemic shunt (TIPS) procedure is a shunt that reduces pressure in the portal vein (98). TIPS can significantly improve symptoms of cirrhosis such as protein-wasting ascites and indirectly support muscle health (99). TIPS placement also addresses gastrointestinal edema associated with cirrhosis thus enhancing uptake of protein and fats leading to improved muscle synthesis (100). In advanced cirrhosis, liver transplantation may be the only definitive treatment, showing substantial improvement in muscle mass as it restores liver function thereby enhancing nutrient metabolism and decreasing muscle breakdown (99). For these transplant candidates, pre- and post-operative nutritional management, routine exercise therapy, and consistent ammonia-lowering interventions are crucial to maximize outcomes and long-term recovery (101).

Emerging interventions

The landscape of therapeutic targets for skeletal muscle modulation continues to evolve. Rifaximin and L-ornithine L-aspartate have been shown to reduce ammonia levels resulting in increased muscle mass (102). In an experimental model, rats given L-ornithine L-aspartate and rifaximin over 4 weeks showed an improvement in muscle fiber size (P<0.001) (103). BCAAs activate mTOR and supplementation improves muscle mass in cirrhotic patients with sarcopenia. In a study of 32 patients with cirrhosis and sarcopenia, 12 weeks of BCAA supplementation demonstrated improvement in muscle mass in the BCAA group when compared to placebo (83.3% vs. 46.7%; P=0.056) (104). Mitochondrial-targeted antioxidants are another category requiring further research as they may improve protein synthesis along with muscle mass (103).

Future research directions for sarcopenia in cirrhosis include exploring novel therapeutic approaches, however this necessitates further clarifying the mechanisms of muscle wasting in cirrhosis along with refining diagnostic tools.

Palliative care in cirrhosis and sarcopenia

As cirrhosis progresses, patients experience more decompensations due to increasing portal pressures. Such complications include the development and/or worsening of ascites, HE, gastroesophageal variceal bleeding, jaundice, renal damage, pulmonary complications, and hepatocellular carcinoma. More insidious and under-recognized are sarcopenia and frailty both of which confer high rates of morbidity and mortality. While liver transplantation may be curative for a majority of these decompensations, barriers including organ availability, financial or insurance-related limitations, and active substance use may preclude patients from timely transplantation. For patients affected by these barriers, palliative medicine can offer tremendous aid in the form of supportive physical and psychosocial care.

In patients with cirrhosis, managing symptoms such as pain, fatigue, and anorexia, factors that exacerbate malnutrition and sarcopenia, is essential for improving quality of life. Palliative care teams may provide a multidisciplinary approach to nutritional support, involving dietitians and other specialists to ensure adequate protein and calorie intake.

Palliative care plays a crucial role in the management of cirrhosis symptoms. Addressing symptom management helps improve quality of life. Despite its benefits, palliative care is often underutilized and introduced late in the disease course. Early integration of palliative care can lead to improved management of symptoms thus optimizing frailty and sarcopenia, reduced hospitalizations, and enhanced patient and caregiver satisfaction.

Conclusions

Malnutrition is a severe complication of chronic liver disease and cirrhosis. Frailty and sarcopenia often present simultaneously in patients with cirrhosis. This perpetuates further decompensations which adversely affect quality of life, overall mortality and transplant candidacy. In patients with cirrhosis, early recognition of frailty and sarcopenia, understanding the interplay between the two processes and providing timely interventions is imperative. While we have a robust understanding of the symptoms and complications of these disease processes, many questions remain. Clarification of optimal diagnostic tools, effective interventions, longitudinal evaluation and management are still topics requiring further investigation.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://apm.amegroups.com/article/view/10.21037/apm-24-173/rc

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