Chronic illness accounts for 75% of health care costs (1). In the United States alone 750,000 adults have cirrhosis (1). The time frame from diagnosis to death averages 10 years and approximately 20% of patients with cirrhosis will be hospitalized within 1 year (2). Rates of readmission to hospital increase in decompensated cirrhosis due to ascites, spontaneous bacterial peritonitis, variceal hemorrhage, hepatic encephalopathy (HE) and compromised renal function (3). Frequent readmissions are not only costly to the healthcare system (approximately $20,000 per admission) but also to patients as they are often deconditioned from their hospital stay (3).
Complications related to disease progression may result in changes in treatment modalities. Patients have multiple physicians involved in their care and subsequently may receive conflicting advice (3). Of concern, is patients are coming for liver transplant (LT) assessment following low-protein diets on advice from their family physicians and medical specialists. The intent of this review is to address protein and energy requirements throughout the transplant process and offer strategies to preserve lean tissue and mitigate excessive weight gain.
Nutritional status pre-LT
Malnutrition is prevalent among patients with end-stage liver disease (ESLD) and has been reported in 20–100% of all patients (4-7). The cause of malnutrition is multifactorial. Inadequate dietary intake may occur from nausea, vomiting, early satiety, delayed gastric emptying, ascites, HE and frequent hospitalizations (8,9). Impaired digestion and absorption from bile salt deficiency, altered motility, and bacterial overgrowth may cause nutrient loss (10,11). Altered metabolism may occur from accelerated starvation (protein and lipids are used as an energy source as carbohydrate stores are diminished), insulin resistance and reduced synthesis of hepatic proteins (8,12). Patients with malnutrition have longer hospital stays, increased incidence of ascites and hepatorenal syndrome, as well as increased mortality (13,14).
Body mass index (BMI)
BMI is calculated by using the following formula W/H2 where W represents weight in kilograms and H represents height in meters. From the Global BMI Mortality Collaboration Study of over 10 million participants, all-cause mortality in the BMI range of 20 to below 25 kg/m2 was minimal however, mortality increased significantly for BMIs below 20 kg/m2 and for BMIs of 25 or greater (15). BMI is considered a simple tool to detect malnutrition in patients with cirrhosis (16). Dick and colleagues reviewed the United Network for Organ Sharing (UNOS) database (1987–2007) and found that patients at the extremes of the BMI range, underweight (<18.5 kg/m2) and severely obese (>40 kg/m2), had significantly lower survival. The underweight patients had more hemorrhagic complications and the severely obese had more infections and cerebral vascular accidents (17). A low BMI (<18.5 kg/m2) was associated with increased mortality in the surgical intensive care unit mainly due to more pulmonary complications (18). The impact of BMI in the context of the model for ESLD (MELD) was investigated using the UNOS database from 2002 to 2011. Overweight or obese recipients did not have an increased risk for graft loss or death regardless of MELD but underweight patients were at increased risk for poor outcomes. Interestingly, the underweight recipients with low MELD scores had an increased risk for both graft loss and death (19).
From the starvation/famine literature, fat rather than lean tissue is used as an energy source. Females have a greater amount of adipose tissue which may be one reason why women withstand starvation to a lower BMI level than men. A BMI level of 13 in males and 11 in females may be the lowest limit for survival (20). In the hunger strikers, a weight loss of 40–50% of body weight with a BMI of 10 kg/m2 was not compatible with life (21). Patients undergoing assessment for LT with low BMIs warrant a detailed review of comorbid conditions and functional status (19). Is the patient able to improve nutritional status through optimal nutrition therapy and exercise? If not, what is the lowest BMI acceptable for LT? As BMI does not differentiate between fat and lean body tissue, is there a critical amount of lean tissue necessary to withstand the surgery and post-transplant complications?
Muscle mass is an objective tool utilized to predict LT outcomes (22). Healthy adults lose 1% of muscle mass every year after the age of 30 (22). Sarcopenia (age related muscle loss) may be defined as 2 or more standard deviations below the mean muscle of healthy young adults (23,24). The prevalence of sarcopenia in adults older than 60 years ranges from 7–50% (22-24) and greater than 50% in those over 80 years (23). The overall presence of sarcopenia was 40% in patients being evaluated for LT and the mortality risk was 2-fold higher in the patients with sarcopenia (25,26). Sarcopenia in cirrhosis presents earlier in men than women and it appears men are more susceptible to sarcopenia than women (50% vs. 18%) (25,26).
Sarcopenia can be defined by total abdominal muscle mass on computed tomography (CT) at the level of the third lumbar vertebrae (L3) (25). With appropriate software (SliceOmatic V4.3, Tomovision, Montreal, Quebec, Canada), muscle and adipose tissue can be quantified and normalized for stature. The L3 skeletal muscle index (SMI) was expressed as muscle area (cm2)/height (m2). The cutoffs for sarcopenia were L3 SMI of 38.5 cm2/m2 or less for women and 52.4 cm2/m2 or less for men (25). LT candidates with sarcopenia have a higher wait list mortality and patients are more likely to die of sepsis (25,26). In patients with sarcopenia measured by the total psoas area (TPA) on CT scan at L4, increased morbidity and mortality was found post LT (27) as well as an increased risk of infection (28). Sarcopenia may also occur in obese individuals and is a better predictor of abnormalities in physical function (gait, balance, and falls) then in either sarcopenia or obesity alone (29). In the New Mexico Elder Health Survey, two or greater self-reported physical disabilities odds ratio in men for sarcopenic obesity was 8.72 compared to 3.78 for sarcopenia alone or 1.34 for only obesity (29).
Cirrhotic patients require routine imaging for surveillance of hepatocellular cancer (HCC) therefore, with appropriate software, an objective level of muscle mass can then be determined without additional exposure (22).
Sinclair and colleagues investigated the impact of frailty on number of hospital days in patients waitlisted for LT (30). The Fried Frailty Index was used which consists of handgrip strength (HGS), unintentional weight loss, exhaustion, gait speed, and physical activity (31). The results demonstrated that physical frailty is associated with an increased number of days in hospital independent of disease severity as determined by the MELD score (30). Functional decline in LT candidates is associated with increased risk of death and delisting (32,33). Functional tests such as HGS and gait speed, can be done quickly, are economical and practical in a clinical setting and do not require imaging (34). Canadian reference values for grip strength for ages 6–79 are available from Statistics Canada (35).
As both low muscle mass and low muscle function predict morbidity and mortality, the European Working Group on Sarcopenia in Older People recommend the definition of sarcopenia to include both low muscle mass and muscle function (34). In 2011 the Society of Sarcopenia, Cachexia and Wasting Disorders added walking speed less than 1 meter/second or distance walked during the 6-minute walk test (less than 400 meters) to a definition of sarcopenia with limited mobility (36).
Obesity is becoming one of the most serious health problems globally (37). Canadian 2015 statistics reported that 28.1% of Canadians are obese (BMI >30 kg/m2) (38). Obesity is associated with diabetes, hypertension, hyperlipidemia, coronary artery disease, compromised pulmonary function, liver disease [mainly non-alcoholic steatohepatitis (NASH)], and recurrent disease post LT (NASH, HCC) (37,39-41). Obesity is associated with surgical complications (infection, wound dehiscence) (42) and long-term mortality (37).
Weight loss is recommended for all obese patients waiting for LT, especially those with a BMI above 35 kg/m2 to a weight target below 30 kg/m2 (37). A BMI of greater than 30 kg/m2 before transplantation is a strong predictor of BMI above 30 kg/m2 at 3 years after LT (43).
Malnutrition, sarcopenia, frailty, and obesity all affect pre- and post-transplant morbidity and mortality. This underscores the pivotal role of nutrition assessment and intervention in LT patients.
Nutrition assessment is critical in identifying malnourished patients. An accurate height and weight should be obtained. An estimated dry weight can be determined by subtracting the volume of ascites reported on imaging (3–5 kg for small ascites, 7–9 kg for moderate, 14–15 kg for large) from the actual weight (44). Previous paracentesis and amount removed is helpful but generally not all ascites is removed. Of note, ascites itself can increase the relative risk for post-LT mortality. In a study of over 1,300 patients, ascites volume increased relative risk for mortality by 7% [hazard ratio (HR), 1.07] for each liter of ascites removed at transplant and graft failure by 6% (HR, 1.06) (45). Edema must be estimated and deducted from the weight (1 kg for mild edema, 5 kg for moderate, 10 kg for severe) (43). An estimation of dry weight is subjective but it is better than gross overestimation, especially in assessing energy and protein requirements and in refeeding the malnourished patient. BMI can then be determined using the estimated dry weight.
The Subjective Global Assessment (SGA) method developed by Detsky and colleagues in Toronto, Canada in the 1980’s (46) is considered a gold standard for bedside nutrition assessment and is universally utilized (47-50). SGA consists of a medical/nutritional history including weight change over time, dietary intake compared to usual intake, gastrointestinal symptoms lasting longer than 2 weeks and functional status. The physical exam component of the SGA includes subcutaneous fat loss (triceps, biceps, orbital fat pads, mid axillary line, back), muscle wasting (temple, clavicle, shoulder, scapula, and quadriceps) and fluid retention (edema, ascites). The medical diagnosis and the effect on metabolic stress are considered. The patient is then classified as A—well nourished, B—mild to moderately malnourished and C—severely malnourished (46). SGA is a predictor of outcomes after LT. Malnourished patients (SGA B and C) required prolonged ventilator support, increased ICU days, increased incidence of tracheostomies (4) and longer hospital stays (5).
Nutrition assessment is performed with the intent of optimizing patient outcomes. Nutrition goals are to provide adequate protein and calories via the oral, enteral or parenteral route to optimize nutritional status, increase or at least preserve lean body mass, and help modulate inflammation and the immune response (51). As there is such a variation in energy needs due to disease severity, muscle mass and other comorbidities, indirect calorimetry (IC) is the best tool for assessing resting energy expenditure (REE) but is not available in all settings. For predictive equations, the Harris Benedict Equation (HBE) using an estimated dry weight plus a 20% stress factor is reasonable (52,53). One can adjust calorie level for weight loss, weight gain and activity level. European guidelines recommend 35–40 kcals/kg dry weight/day for patients with cirrhosis (49). Critical care guidelines recommend 25–30 kcals/kg dry weight/day (51,54). Refer to Table 1 for recommended energy and protein requirements.
Protein intake should not be restricted in patients with cirrhosis. Historically there were concerns that a high protein intake would contribute to HE. Cordoba and colleagues randomized patients with episodic HE to receive different amounts of protein. The incidence of HE was not significantly different between the two groups. The lower protein group had higher protein breakdown which disappeared when both groups were at 1.2 g/kg/day (55). Inadequate protein intake less than 0.8 g/kg/day was associated with increased mortality in cirrhotic patients awaiting LT (56). Recommended protein needs are 1.2–1.5 g/kg dry weight/day (54). Critical care guidelines recommend protein levels of 1.2–2.0 g/kg dry weight/day (51). Medical therapy with Lactulose and antibiotics may be required for persistent HE (51,54).
A diet of small frequent meals (6–10 a day) is recommended to optimize intake and reduce symptoms of bloating, fullness, nausea and vomiting (57). Cirrhotic patients will lose as much in an overnight fast as healthy volunteers will lose in 2–3 days of fasting due to increased fat oxidation and early onset gluconeogenesis (58). A late evening meal improves nitrogen retention (59). A bedtime snack of about 50 g of carbohydrate (two slices of bread and jam) shortened nocturnal fasting and diminished fat and protein oxidation (12). The Association for the Study of Liver Diseases (AASLD) guidelines recommend multiple feedings with emphasis on a nighttime snack and breakfast feeding to improve nitrogen balance (60).
If oral intake is not adequate within 5–7 days of admission, enteral nutrition (EN) via a tube feed is recommended (61,62). There is often patient resistance to having a tube placed but once the tube is in and the patient feels better from being adequately fed, the benefits of tube feeding become apparent to the patient. In addition, it takes the pressure off the patient of having to “push” oral intake to try and meet their nutritional goals.
In patients with an upper gastrointestinal bleed (GIB) it is recommended to wait 24–48 hours after the resolution of the bleed prior to feeding tube placement (61). Coagulopathy may be a risk for tube placement. The patient may require platelet transfusion, fresh frozen plasma or vitamin K to improve the international normalized ratio (INR) and platelet count (61). Percutaneous endoscopic gastrostomy (PEG) placement is contraindicated in decompensated cirrhosis because of risk of ascites, peritonitis, variceal puncture and coagulopathy (63-65).
A standard feeding formula is generally used. Branched chain amino acid supplements in decompensated cirrhosis have not been shown to reduce HE recurrence or survival (66). Immune modulation nutrition (IMN) products containing some combinations of fish oils, arginine, nucleic acids and antioxidants have shown reduced infectious complications and reduced ventilator days in the general post-operative patients but no change in mortality (67). Plank and colleagues randomized 120 patients waitlisted for LT to receive IMN enriched with omega 3 fatty acids, arginine, and nucleotides (Impact) or an isocaloric control. Perioperative IMN did not demonstrate significant benefits in terms of nutritional status pre-operatively or post-operative outcome (68).
If the patient is fluid overloaded a concentrated formula is more suitable. For patients at refeeding risk, starting at 15–20 kcals/kg and advancing slowly is recommended. Glucose, potassium, magnesium and phosphate levels should be checked daily until goal nutrition is reached and bloodwork is within normal limits (61). If cyclic EN is warranted, nocturnal tube feeding has been demonstrated to result in protein accretion and is better than daytime feeding in increasing lean tissue (69). For prolonged tube feeding of greater than 4–6 weeks, it is recommended the tube be placed in the other nostril (62).
Parenteral nutrition (PN) may be required in the severely malnourished patient where there is a contraindication to tube placement or an inability to use the gastrointestinal tract.
Early post-transplant phase (0–3 months)
If there are no contraindications, a regular diet may be initiated in the first 24 hours. Traditionally the diet progression was clear fluid, full fluid and then regular diet however giving a regular diet as the first post-operative meal does not increase morbidity or mortality (67). Clear liquids may actually increase risk of aspiration when compared to solid foods as liquids are more easily aspirated (70). The occurrence of nausea is about 20% whether the patients are given clear liquids or solids (71).
Early feeding by oral or tube feeding within the first 24 hours results in better outcome as it maintains gut integrity, modulates the immune response, stress response, and attenuates disease severity (72,73). In cases of severe sepsis, shock or severe malabsorption, EN may be feasible in the first 24–36 hours once the patient has stabilized. Intraluminal nutrients help to reverse mucosal hypo-perfusion from shock (74). EN may not be feasible if there is bowel discontinuity, risk of bowel ischemia, obstruction or ongoing peritonitis. If unable to establish oral or EN in the severely malnourished patient by post-operative day 5, PN is warranted.
As malnourished LT patients tend to have more infectious complications (viral, bacterial, fungal), increased requirements for ventilator support, increased incidence of tracheostomy, and longer hospital stays, it is critical to provide adequate nutrition (4-6,51,75).
Plank and colleagues quantified the sequential changes in energy expenditure and body composition in the first year post LT (76). Before transplant patients were significantly protein depleted (82% of total body protein compared to pre-illness) and lost an additional 1% (approximately 1 kg) of total body protein within 10 days post LT (mainly from skeletal muscle) (76). Protein requirements are l.5 g/kg dry weight/day (77,78). In patients on continuous renal replacement therapy (CRRT), an additional 10–15 g of protein is lost daily. In CRRT, protein requirements are 1.5–2.5 g/kg/dry weight/day (51). In patients with an open abdomen, 15–30 g of protein/liter of exudate is lost in the drains and should be replaced to mitigate loss of lean tissue. Patients with an open abdomen can be fed safely if there is no bowel injury. EN [when compared to nil per os (NPO)] was shown to decrease time to facial closure, pneumonia, abdominal complications and mortality (79-82).
Some patients develop persistent inflammation, immunosuppression and catabolic syndrome (PICS) and experience persistent cachexia. Provision of at least 1.5 g protein/kg/day is recommended to help with anabolic resistance (83).
Ferreira and colleagues measured REE before LT and at 5 intervals during the first year after LT (84). Energy requirements were elevated post LT reaching 42% above predicted values by post-operative day 10 and remained elevated for 3 months. Measured REE was higher than predicted REE and no patients were hypo-metabolic at 3 months post LT (84).
Generally, patients are able to be discharged within 2–3 weeks post LT. Some patients may benefit from inpatient rehabilitation which has been shown to decrease 30-day readmission rate (85).
Late post-transplant phase >3 months
Hyper-metabolism is still present at 6 months post LT but reaches predicted values by 12 months (76). Hyper-metabolism before LT is associated with hyper-metabolism after LT. Higher levels of fat mass prior to LT are associated with hypo-metabolism after LT (84).
Just over half of protein lost is restored by 12 months however body fat is restored by 12 months (76). Over hydration of fat free mass (total body weight minus total body fat) evident in the pre-transplant phase is still present at 12 months post LT (76). Respiratory muscle strength does improve but it is significantly lower than predicted values at 12 months (76,86).
Sarcopenic obesity begins in the first month post LT (87). The liver is a metabolic sensor that relays information (humoral and neural) via the brainstem to the hypothalamus (controller of feeding behavior) (88). In LT the normal hepatic innervations (afferent and efferent neural limbs) are lost which may affect energy metabolism and thus contribute to weight gain (88). Oral intake improves post LT contributing to a positive energy balance. Prednisone, in addition to steroid induced diabetes, is associated with weight gain by increasing appetite, decreasing fat oxidation and increasing fat deposition (84). Prednisone is also associated with increased proteolysis and decreased protein synthesis (89). Calcineurin inhibitors, tacrolimus and cyclosporine, may contribute to impaired muscle growth and regeneration as calcineurin has an effect on skeletal muscle differentiation and hypertrophy. Sirolimus and everolimus inhibit rapamycin complex involved in protein synthesis (89).
Obesity (BMI >30 kg/m2) is present in 36% of patients at 3 years post LT (43). The greatest weight gain appears to occur after the first 6 months (43). Of the patients who were not obese pre-transplant, 31% became obese by 3 years post LT (43). Obesity can lead to metabolic syndrome which is reported to range from 43% to 58% post LT compared to 24% in the general population (90). Cardiovascular risk is associated with metabolic syndrome and cardiovascular complications are the primary non-graft related cause of death in LT (91). Treatment goals include optimal blood glucose control, fast tapering of steroids, lipid normalization, weight reduction and increased physical activity (92).
Although physical activity generally increases after LT more than 75% of patients remain sedentary (84). LT recipients have impaired peak physical exercise performance that is approximately 40–50% below age-related values (93,94); however, improvement can be achieved with diet modification and exercise (95). Regular exercise can optimize functioning after LT and intensive training can reach normal levels or even higher levels of VO2peak (oxygen uptake at the highest tolerable level of exercise) (95). Regular exercise training should optimally begin in the pre-transplant setting as improvements in aerobic capacity and muscle strength can be achieved (96).
Chronic disease care-management programs such as the one described by Morando and colleagues are cost effective and improve 12-month survival (97). In this model, patients with cirrhosis and ascites are seen by a team (hepatologists, physicians in training, nurses) while having access to a day hospital for paracentesis, transfusions, and bandings. Addition of a dietitian and physiotherapist to this model would add a “pre-habilitation” component to optimize nutritional status and physical functioning to mitigate/improve sarcopenia, frailty, and obesity even before referral for LT.
Sarcopenia is already present in 10% of Child Pugh Class A cirrhosis patients (26) therefore, early screening is of benefit. Adequate protein intake, a high complex carbohydrate bedtime snack, and breakfast feeding are critical in the pre-transplant phase for mitigating loss of muscle tissue. Providing 25–30 g/meal of high quality protein (meat, fish, poultry, eggs, and dairy) is recommended to maximally stimulate muscle protein synthesis (98). In patients with sarcopenia, BCAA supplementation (leucine 7.5 g, isoleucine 3.75 g and valine 3.75 g) dissolved in a carbonated beverage may help to reduce proteolysis and activate muscle protein synthesis (99). Anabolic therapies known to increase muscle mass such as testosterone and growth hormone may be useful in some patients (99,100). Exercise guidelines of 20–30 minutes of aerobic activity and 20–30 minutes of resistance training 3 times a week are recommended (99,100).
For older and/or deconditioned patients, exercises for improving flexibility, strength and balance are illustrated at www.nhs.uk/exercises-for-older-people. Inpatient rehabilitation, both pre- and post-transplant is of benefit in the severely debilitated patient. Older adults (greater than 65 years of age) require protein intakes of 1.0–1.2 g/kg and very active older adults require 1.2–1.5 g/kg/day secondary to changes in protein metabolism that occur with aging (101).
Obese patients are advised to lose weight pre-transplant. A restricted energy intake to provide for a weight loss of 0.5 kg a week is considered safe weight loss. Adequate protein intake and exercise are advised to mitigate loss of muscle tissue, promote muscle synthesis while decreasing excess adipose reserve.
Regular monitoring of nutritional status and timely intervention in the post-transplant setting is necessary to help correct malnutrition and prevent metabolic syndrome. A healthy diet and regular exercise both aerobic and resistance training is strongly emphasized. The Mediterranean diet (olive oil, high intake of vegetables, fruits, legumes, moderate intake of fish, white meat, low intake of high fat dairy, red meats, homemade sweets) is considered one of the healthiest diets, has a positive influence on cardiovascular disease, improves the clinical profile of patients with fatty liver disease when combined with an active lifestyle, and is both palatable and sustainable (102).
LT requires a high resource allocation. A long-term commitment to optimize body composition, physical functioning, and attenuate co-morbidities is warranted (93).
Conflicts of Interest: The author has no conflicts of interest to declare.
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Cite this article as: Fortier L. Malnutrition, frailty, sarcopenia, obesity—optimizing nutrition care in liver transplantation. AME Med J 2018;3:22.