Nutritional Management of a Liver Transplant Candidate

There are many NST available; however, their validity and prognostic accuracy in ESLD patients remains to be assessed prospectively in larger cohorts. Ney et al. recently systematically reviewed and meta-analyzed various nutritional screening and assessment tools in cirrhosis patients. Out of 47 studies (8850 patients), only 3 studies assessed NSTs. More than 32 definitions of malnutrition were utilized across the studies suggesting lack of consensus. Despite extremely limited and heterogenous data on NSTs, a clear association between malnutrition and waitlist mortality was reported.

Malnutrition screening tool, a community screening tool, and nutritional risk screening 2002 (NRS-2002), a hospital screening tool, are practical scores with good interrater correlation. However, both these scores do not take into account the effect of fluid collections such as ascites which are quite common in ESLD patients. Nutrition risk in critically ill score,^, which also incorporates acute physiology and chronic health evaluation (APACHE)-II and sequential organ failure assessment (SOFA) score within itself, has been validated in this population but requires interleukin-6 levels which limits its routine use.

Royal free hospital-nutrition prioritizing tool (RFH-NPT) is a cirrhosis specific tool and has been validated against RFH-subjective global assessment. RFH-NPT can be done quickly (takes <3 min) with minimal training. It includes variables such as presence of alcoholic hepatitis, need of tube feeding, third space fluid collections, BMI (if no ascites/edema), dietary pattern, recent weight loss, and presence of any acute illness. Score ranges from 0 to 7 with scores between 2 and 7 signifying high risk of malnutrition and need of detailed nutritional assessment and intervention. A prospective study, involving 84 ESLD patients in the study cohort and 64 patients in the validation cohort, compared RFH-NPT with NRS-2002 score. RFH-NPT independently correlated with clinical deterioration, severity of disease, and clinical outcomes such as ascites, HE, hepatorenal syndrome, and transplant-free survival. An improvement in RFH-NPT within 500 days was also associated with better survival.

The liver disease undernutrition screening tool (LDUST) is another cirrhosis-specific tool developed for ambulatory patients. LDUST uses six patient directed questions. Booi et al. in their 3-phase study showed more than 70% sensitivity and specificity of the tool with 93% positive predictive value to identify risk of malnutrition. However, the low negative predictive value (38%) exposed its inability to reliably rule-out undernutrition and need of further refinement and prospective validation. Wu et al. prospectively compared NRS-2002, RFH-NPT, malnutrition universal screening tool, and LDUST in 145 patients with cirrhosis. The RFH-NPT and NRS-2002 demonstrated higher sensitivities (64.8% and 52.4%) and specificities (60% and 70%) and RFH-NPT was the only score which independently predicted mortality. With the available evidence, guidance, and expert opinions, RFH-NPT appears to be the best NST in ESLD patients.^,

Inadequate dietary intake is a significant contributor to malnutrition.^, A 3-day recall diary is a better tool to assess macronutrient intake than a 24-h recall as covert memory impairments are common in ESLD patients.^, Apart from total calorie intake, special attention should be given to relative contribution by various macronutrients, type and quality of protein intake, and possible micronutrient deficiencies. Pattern of food intake (number of meals and gap between meals) and any recent change in amount of food intake must be inquired. Frequent day-time meals and a late-evening calorie-dense snack and protein should be ensured.^,, Further any barriers to inadequate dietary intake such as progressive ascites, dysgeusia, covert HE, constipation, self-imposed dietary restrictions, and socio-economic factors should be looked out for and addressed appropriately.^,,

Micronutrient deficiencies especially zinc, magnesium, vitamin A, and D are quite frequent in ESLD.^, Diuretics, laxatives, and frequent antibiotic use also contribute to these deficiencies apart from dietary insufficiency. Patients with cholestatic etiologies require regular assessment and supplementation with calcium and fat-soluble vitamins. Adequate supplementation and periodic reassessment should form a part of both outpatient and inpatient visits in pre and post-LT setting as well.^,

Sarcopenia is the “central component” of nutritional assessment in cirrhotic population. Unfortunately, standardized consensus-based universal definition of sarcopenia is still lacking. Overall, two-thirds of patients with ESLD have sarcopenia with significantly higher prevalence in males (51%) than females (21%).^,,, Females tend to lose more fat mass whereas males lose muscle mass more rapidly. Also, prevalence increases from compensated (20%) to decompensated cirrhosis (>50%).^, Older age of patients with cirrhosis further contributes to reduction in muscle mass (compound sarcopenia). Loss of muscle function usually commences before detectable sarcopenia and contributes to functional loss and poorer quality of life suggesting a non-linear relationship between muscle mass and muscle strength.^{,,  ,}  Consistent with current evidence, European working group on sarcopenia in older people incorporated diminished muscle function and performance also as a component of sarcopenia.^, However, most studies assessing the impact of sarcopenia on clinical outcomes in ESLD patients have used a static measure of muscle mass such as skeletal muscle index (SMI).

Sarcopenia has been found to be associated with increased cost of care, higher risk of developing new and progressive decompensations, greater risk of pre as well as post-LT infections, prolonged ICU stay, and mechanical ventilation requirement post-LT.^{,,,  ,  ,  ,,} Sarcopenia also predicts increased risk of HE after trans-jugular intra-hepatic portosystemic shunt (TIPS) and improvement in sarcopenia (>10%) post-TIPS reduces risk of post-TIPS HE.^, In a recent meta-analysis, the overall prevalence of sarcopenia among ESLD patients was 37.5% with higher prevalence in males, alcohol-related liver disease, and advanced cirrhosis. The cumulative survival was significantly less in sarcopenic patients at 1 year (76.6% vs 93.4%), 3-years (64.3% vs 82%), and 5-years (45.3% vs 74.2%). Every 1 cm²/m² increase in SMI at L3 and 1 mm/m increase in umbilicus-total psoas muscle thickness (TPMT) was associated with a 3% and 12% reduction in mortality risk, respectively.

Various direct and indirect tools like anthropometry, dual-energy X-ray absorptiometry (DEXA), bioelectrical impedance analysis (BIA), ultrasonography (USG), magnetic resonance imaging (MRI), and computed tomography (CT) have been studied to quantify muscle mass in ESLD.^,, Individual muscle and/or muscle groups such as SMI at 3rd lumber vertebra (L3), total psoas area, TPMT, psoas muscle index, and total skeletal muscle attenuation have been studied to assess muscle mass and quality.^,,

Mid-arm muscle circumference (MAMC), which requires triceps skin fold thickness (TSF), and mid-arm muscular area measurement, is the most frequently used anthropometric tool to assess sarcopenia.^,, These tools are simple, rapid, cheap, unaffected by fluid retention, and suitable for use in routine clinical practice. They show good intra- and inter-observer reproducibility when performed by trained individuals. MAMC has shown good correlation with CT SMI-L3 with an area under receiver operator curve of 0.75 for men and 0.84 for women.^, Both MAMC and TSF have a shown prognostic significance in ESLD patients with MAMC having an upper hand over TSF.

Body composition analysis to calculate total fat mass and fat-free mass (FFM) can be accomplished using BIA, air displacement plethysmography, DEXA, and magnetic resonance spectroscopy (MRS).^,, DEXA can additionally measure bone mineral density apart from estimation of the absolute skeletal muscle mass and/or appendicular skeletal muscle mass which can be adjusted for height or weight. DEXA has small-risk of radiation exposure which limits its routine use in community. BIA is portable, non-invasive tool with no radiation risk. However, accuracy of both DEXA and BIA is affected by hydration status, ascites, and presence of edema.^{,  ,  ,}

SMI at L3 assessed by CT is the most validated and frequently used tool.^{,  ,}  Total cross-sectional area of psoas, erector spinae, quadratus lumborum, transversus abdominis, external oblique, internal obliques, and rectus abdominis are calculated at L3 using various available and embedded software packages. It is then expressed as the total area of skeletal muscles at L3 vertebra (cm²) normalized to total body surface area (m²). In a North-American study done in LT-wait-listed patients with cirrhosis, cut-off values for the diagnosis of sarcopenia were suggested to be <50 cm²/m² and <39 cm²/m² for men and women, respectively. The mean muscle mass of Asians is about 15% less than that of Western population, even when corrected for height. Hence, it is imperative to establish, standardize, and validate criteria to diagnose sarcopenia in various ethnicities. A Japanese study suggested 42 cm²/m² (men) and 38 cm²/m² (women) as the optimal cut-off values for CT SMI-L3 to identify sarcopenia with 89% sensitivity and 57% specificity. Sidhu et al. assessed normative value of CT SMI-L3 in 3087 non-cirrhotic Indian patients (67% males) without cirrhosis who underwent CT for acute abdomen. They identified mean CT SMI-L3 of 44.33 ± 6.56 and 41.25 ± 4.42 in non-cirrhotic adult males and females, respectively. Another Indian study done in 2002 non-cirrhotic individuals (1308 males) suggested cut-off for sarcopenia as 39.59 cm²/m² and 31.83 cm²/m² in males and females, respectively. A CT SMI-L3 ≤ 21.2 cm²/m² was associated with increased 6-month mortality. Cut-offs suggested by various societies to diagnose sarcopenia using different assessment tools are summarized in Table 1.

MRI has also been used to assess muscle mass at various areas; however, data remain scarce and poorly validated.^,, Furthermore, availability, feasibility, and higher costs limit the use of MRI to solely assess sarcopenia. Tandon et al. evaluated the thigh muscle index during both compression and no compression at two predetermined points on the thigh via USG. They found that the average feather index (non-compression) was strongly associated with sarcopenia in ESLD patients. This safe and interesting modality requires further validation.

Baumgartner first defined SaO in the elderly population as co-existence of sarcopenia and obesity as measured by DEXA and associated it with decline in physical activity and performance. Clinically inconspicuous alterations in body composition such as increase in body fat with simultaneous reduction in muscle mass have been noted in the elderly population. A complex interplay of multiple pathophysiological pathways such as increased inflammatory cytokines milieu and oxidative stress, insulin resistance, hormonal imbalances, and reduced physical activity has been implicated in the development of SaO.^, With rising incidence and prevalence of NAFLD worldwide, increasing number of ESLD patients present with obesity. Currently available literature in ESLD patients suggests a wide prevalence range (2%–40%) of SaO likely due to heterogeneity in the definitions used. To diagnose SaO, sarcopenia is assessed using CT SMI-L3 and obesity is defined by dry BMI of >25 kg/m² for Asians or >30 kg/m² for Caucasians. SaO is diagnosed when both sarcopenia and obesity are present concurrently.^,,

Apart from reduction in muscle mass, there is simultaneous deterioration of muscle quality even in the apparently healthy elderly population. Muscle quality reduction is further accentuated in patients with chronic diseases such ESLD, malignancies, and so on in the form of pathological accumulation of fat in the skeletal muscle known as myosteatosis.^, Aberrant fat accumulation can occur within the muscular fibers (intramyocellular) or within the fascia (intermuscular). Myosteatosis has been linked to insulin resistance and enhanced inflammatory phenotype. It can be present even in the absence of sarcopenia and/or obesity. Myosteatosis is usually assessed via radiological tools such as CT, MRI, and MRS. Muscle attenuation on CT scan can indirectly assess muscle fat infiltration. Skeletal muscle is identified and quantified by Hounsfield units (HU) thresholds of −29 to +150. Similar to CT SMI-L3, mean muscle attenuation is reported for the entire muscle area at the L3. Using this method, mean muscle attenuation values of <41 HU in patients with a BMI ≤24.9 kg/m² and <33 HU in patients with a BMI ≥25 has been shown to be associated with increased mortality.^, In wait-listed ESLD patients, myosteatosis was documented in >50% cases and was associated with an increased risk of HE independent of liver function. In 678 (67% males) patients with cirrhosis, Montano-Loza et al. detected sarcopenia, SaO, and myosteatosis in 292 (43%), 135 (20%), and 353 (52%) patients, respectively, and all muscular abnormalities were associated with significantly reduced median survival. Kaibori et al. in their study done in patients undergoing hepatectomy for HCC showed reduced 5-year overall survival (46% vs 75%) and disease-free survival (18% vs 38%) in patients with intramuscular adipose tissue content. The presence of myosteatosis has been found to be independently associated with higher mortality (HR: 3.3), allograft failure (HR: 4.1), and longer hospital and ICU stay in LT recipients.^, Whether SaO independently exerts negative impact on post-LT outcomes compared to sarcopenia alone remains inconclusive; however, very limited evidence suggests that pre-LT SaO was associated with two times higher mortality at 1-year, 3-year, and 5-year after LT in a meta-analysis which may be attributed to higher incidence of PTMS in these patients.

Muscle strength and physical performance reflect a person's overall functional status and correlate more with overall outcomes than the muscle mass alone.^, Simple and cheap tools such as hand-grip strength (HGS), gait speed (GS), chair stand test, short physical performance battery (SPPB), and 6-min walk test (6-MWT) can be used to assess muscle strength and performance.^,,,, Apart from sex and ethnicity, measurement protocol and type of dynamometer used also affects HGS cut-off value. An HGS ≤25.3 kg-force was associated with increased mortality in an Asian study. The chair stand test assesses the strength of the lower extremities by measuring the time needed by the patient to rise from chair 5 times without using the arms. Short physical performance battery (SPPB) is a composite assessment of muscle strength, performance and frailty and consists of GS, chair stand test, and balance testing. Each tool is scored out of 4 with maximal score being 12. A score <10 increases mortality by 2.5 times.^, Cardiopulmonary exercise testing (CPET) is an advanced test to assess aerobic capacity but requires expensive equipment and is time consuming.^, Also, ESLD/ACLF patients may find it difficult to perform CPET. The cut-offs for above tools to assess muscle quality and performance vary depending on the sex, population, and ethnicity and are elaborated in Table 1.

Frailty extends beyond sarcopenia and was originally defined in the geriatric population as a distinct biologic syndrome of reduced physiologic reserve along with heightened susceptibility to health stressors.^,, Age-related frailty results from imbalances across multiple physiologic systems whereas liver-specific factors such as encephalopathy, variceal bleeding, sarcopenia, infections, proteostasis, repeated hospitalizations and psycho-social factors drive frailty in ESLD patients. Across multiple studies, frailty has been shown to be a strong independent predictor of waitlist drop-outs, repeated admissions, increased length of hospital stays, and post-LT mortality.^,,,

A wide range of tools to assess frailty have shown their prognostic utility especially in ambulatory patients. Activities of daily living (ADLs) and Karnofsky Performance Scale (KPS) have been shown to be valuable in prognosticating in-patients whereas most other tools such as 6-MWT, GS, HGS, Liver frailty index (LFI), and Clinical Frailty Scale (CFS) have been validated primarily in the ambulatory setting.^,, At least one frailty tool should be incorporated at initial evaluation and during longitudinal follow-up. LFI is an objective cirrhosis specific frailty assessment tool.^, It is simple and can be done in the outpatient setting and includes HGS, balance testing (assesses neuromuscular function), and chair stands. Formula to calculate LFI based on above parameters is available online at https://liverfrailtyindex.ucsf.edu. LFI score of ≥4.4 indicates frailty whereas prefrail status is indicated by LFI between 3.2-4.3. Longitudinal changes in frailty assessed by KPS and LFI scores also predict clinical outcomes in patients with ESLD.

Adequate management of primary disease improves all-cause mortality. It slows the progression and minimizes associated pathophysiological alterations that lead to sarcopenia and frailty.^,, Abstinence from alcohol, apart from removing the chronic hepatic insult, also improves alcohol-related myopathy and oral nutrient intake. Treatment of chronic hepatitic C has shown reduction in overall systemic inflammation. Similarly, interventions for NAFLD improve inflammation and insulin resistance. Furthermore, early resolution of HE and improvement in ascites improves oral intake and overall nutritional status.

Developing an individualized nutritional prescription requires calculation of the patient's resting energy expenditure^, (REE). Indirect calorimetry is the gold standard for determining actual REE but is limited by its availability. Inexpensive handheld calorimeters have now been validated in ESLD patients and can be used bedside. Sans indirect calorimetry, predictive equations such as Harris Benedict equation can be used to estimate REE but may be unreliable.^,, Patients with cirrhosis have been found to have REE 1.3–1.5 times that of general population.^, Studies have reported a total energy expenditure (TEE) between 28 and 38 kcal/kg/day in patients with cirrhosis.^,, Dry weight or ideal body weight can be used to estimate calories requirement depending on the scenario. Subjective estimation of the dry weight can be done by either considering the post-paracentesis weight or by subtracting 5%, 10%, 15% from actual body weight in patients with mild, moderate, or severe ascites, respectively. An additional 5% should be taken off if there is significant bilateral pedal edema. The European Society for Parenteral and Enteral Nutrition (ESPEN) recommends overall calorie intake of 35–40 kcal/kg/day and protein intake of 1.2–1.5 g/kg/day. Enteral nutrition via oral route is always preferable. Up to 50–60% calories should come from carbohydrates whereas 20–30% should come from fat in the diet.^, Moderate calorie deficit of approximately 500 Kcal per day may be considered in obese patients. International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) recommended stratification of 24-h energy requirement based on BMI. They suggested targets of 20–25 kcal/kg/day, 25–35 kcal/kg/day, and 35–40 kcal/kg/day for patients with BMI of >40 kg/m², 30–40 kg/m², and 20–30 kg/m², respectively, with the same protein requirement as ESPEN. ISHEN recommends using ideal body weight to calculate total energy and protein requisite.