Citation: Hidalgo-Blanco, M.Á.;
Lopez-Delgado, J.C.; Sarria-Guerrero,
J.A. Nutrition Therapy in Critically
Ill Patients with Liver Disease: A
Narrative Review. Livers 2023, 3,
529–544. https://doi.org/10.3390/
livers3030036
Academic Editor: Leonardo Baiocchi
Received: 31 July 2023
Revised: 10 September 2023
Accepted: 13 September 2023
Published: 21 September 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Review
Nutrition Therapy in Critically Ill Patients with Liver Disease:
A Narrative Review
Miguel Ángel Hidalgo-Blanco 1 , Juan Carlos Lopez-Delgado 1,2,* and José Antonio Sarria-Guerrero 1
1 Escola d’ Infermeria (Facultat de Medicina i Ciències de la Salut), Department d’ Infermeria Fonametal i
Medicoquirúrgica, University of Barcelona, C/Feixa Llarga, s/n, 08907 L’Hospitalet de Llobregat,
Barcelona, Spain; miguelhidalgo@ub.edu (M.Á.H.-B.); j.a.sarriaguerrero@ub.edu (J.A.S.-G.)
2 Hospital Clínic de Barcelona, Área de Vigilancia Intensiva (ICMiD), C/Villarroel, 170, 08036 Barcelona,
Barcelona, Spain
* Correspondence: juancarloslopezde@hotmail.com
Abstract: Nutrition therapy in critically ill patients with liver disease represents a challenge for
Intensive Care Units (ICUs). Nutritional status is correlated with the degree of hepatic dysfunction
and the presence of malnutrition worsens outcomes in these patients. The nutritional risk that
critically ill patients represent, together with the pathophysiological alterations of liver disease,
especially in terms of nutrition intake and protein depletion, leads to malnutrition and sarcopenia.
Nutrition therapy improves the survival of these patients; however, this is challenging since they
more frequently experience difficulties with nutrition delivery. In consequence, both evaluation of
nutritional status and an individualized approach seem mandatory for achieving nutrition objectives.
The present narrative review discusses the importance of nutrition therapy, the recommendations
of contemporary clinical practice guidelines, and a practical approach to provide the best possible
nutrition therapy in patients with liver disease admitted to ICUs.
Keywords: liver disease; nutrition therapy; intensive care unit; cirrhosis; malnutrition; acute liver
failure; acute-on-chronic liver failure
1. Introduction
The liver is a major organ involved in maintaining an appropriate nutritional sta-
tus with different roles that include the metabolism of proteins, carbohydrates, and fat;
malnutrition is the most common comorbidity associated with chronic liver disease [1].
Indeed, all patients with cirrhosis are malnourished to some degree due to changes in
nutrient ingestion, absorption, and utilization [2]. The severity of malnutrition correlates
with the degree of hepatic dysfunction and is associated with the presence of complications,
survival, and outcomes [2–5].
Patients with liver disease are admitted to an Intensive Care Unit (ICU) based on
the presence or absence of preexisting liver-related complications. However, the main
reasons for the ICU admission of these patients are liver related to a greater or lesser
extent: acute liver failure (ALF), acute-on-chronic liver failure (ACLF) (i.e., acute hepatic
decompensation, such as upper bleeding, in patients with preexisting chronic liver disease),
and liver transplantation [6]. The syndromes these patients develop are common to all
ICU patients (e.g., septic shock, bleeding, respiratory insufficiency, renal failure, etc.);
however, the etiology behind the specific reason for ICU admission is liver related from
a pathophysiological basis (e.g., immune dysfunction, portal hypertension, hepatorenal
syndrome) [5,6].
The prevalence of malnutrition in these patients is variable, with rates ranging from
24% to 66% of hospitalized patients with liver disease, depending on the method used to
estimate the nutritional status [2,3]. The prevalence also increases with the severity of the
liver disease, but it may occur even in early stages [4]. Chronic liver disease involves a
Livers 2023, 3, 529–544. https://doi.org/10.3390/livers3030036 https://www.mdpi.com/journal/livers
Livers 2023, 3 530
process of continuous inflammation and regeneration that eventually results in permanent
fibrosis and cirrhosis, where hepatitis C virus infection is the most common cause of this
condition [4]. Other common causes include alcoholic liver disease, non-alcoholic fatty
liver disease (NAFLD), and hepatitis B virus infection [7]. Chronic and acute inflammation
produced by liver disease affects gastrointestinal function, leading to malnutrition, and
malnutrition is more intense in the presence of alcohol as the etiological cause of liver
disease due to the poor oral intake and vitamin deficits of alcoholic patients [7].
Malnutrition in all forms of liver disease is associated with higher rates of mortality
and morbidity, yet it is often under-recognized and under-treated, even though appropriate
nutrition therapy can improve outcomes [8]. An example of this is the impact of malnutri-
tion on liver transplantation candidates: the degree of malnutrition itself has a significant
independent impact on outcomes after transplantation (e.g., postoperative complications,
length of hospital stay, and mortality) [5]. Patients suffering from chronic or acute liver
disease need to receive adequate metabolic and nutritional therapy to enhance their recov-
ery via control or reversal of the metabolic alterations (e.g., hypoalbuminemia) [9]. Indeed,
patients with ALF who exhibit a high nutritional risk (≈80%) and high rates of inadequate
nutritional therapy may improve their liver function (e.g., higher albumin levels, lower
prothrombin time, and lower bilirubin levels) and outcomes (e.g., 28-day mortality, length
of stay, nosocomial infections, and liver-related complications) with appropriate nutrition
therapy [10].
The application of nutritional assessment exhibits significant differences in the def-
inition and prevalence of malnutrition depending on the method used, which makes it
difficult to evaluate nutritional status in patients with liver disease admitted to an ICU.
In addition, nutrition therapy seems crucial, as ensuring adequate nutritional repletion,
as well as correcting vitamin and micronutrient deficiencies, is central to maintaining
the remaining hepatic function, thus improving the patient’s metabolic reserves and the
survival of these patients [9].
This narrative review discusses the impact of nutritional status and the importance
of nutrition medical therapy in liver disease based on the pathophysiological alterations
seen in these patients when admitted to an ICU. We also propose a practical approach for
adequate nutrition therapy in patients with liver disease.
2. Materials and Methods
The review of the indexed articles related to patients with liver disease in an ICU
was performed using the Ovid MEDLINE® interface until January 2023. The present
review aims to select manuscripts addressing malnutrition or the nutritional status of
patients with liver disease admitted to an ICU. The selection of articles focusing on the
pathophysiological characteristics of malnutrition or nutritional status in these patients
was performed based on scientific importance, the latest publication, and the citation of the
manuscripts based on the opinion of the present reviewers. The terms liver disease, ALF,
ACLF, and liver transplantation were selected to include those patients with a variable
spectrum of deteriorated liver function who were admitted to an ICU, and it also included
liver cirrhosis since it represents a stage of irreversible liver damage. Secondary liver injury
during ICU admission without previous liver disease, which represents a common cause of
cholestasis and liver damage (i.e., transaminitis), was not considered in the present review.
All manuscripts selected for the development of the present review have been included
and cited within the text.
3. Bidirectional Relationship between Liver Disease and Nutritional Status
Liver disease negatively affects metabolism and the patient’s nutritional status and,
simultaneously, a worsening of nutritional status could negatively affect the severity and
progression of liver disease. Malnutrition is frequently caused by a variety of factors,
including a decreased nutrient intake, gastrointestinal dysfunction leading to nutrient
Livers 2023, 3 531
malabsorption, and increased protein catabolism leading to sarcopenia [1–5]. In addition,
some cirrhotic patients (≈30%) have an increased resting energy expenditure (>120%) that
negatively affects nutritional status [11]. It has been hypothesized that the altered hyper-
metabolism is caused by chronic inflammation (e.g., increased blood levels of interleukin-1
and interleukin-6 (IL-6)) [12]. Thus, the hypercatabolic status of critical illness together with
this hypermetabolic status put the patient with liver disease at higher nutritional risk [5].
Patients with liver disease frequently experience symptoms that may contribute to-
ward a reduced nutrient intake, such as gastrointestinal effects (e.g., increased gastric
sensitivity to distension and delayed gut transit). Delayed gastric emptying has been
reported in patients with liver disease and has been associated with post-prandial fullness
and bloating [13]. These patients suffer from alterations in taste acuity, which has been
associated with deficiencies in trace elements including zinc, magnesium, and vitamin
A [14,15]. Appetite is also reduced due to increased inflammatory cytokines and alterations
in appetite-regulating hormones (i.e., leptin, ghrelin, peptide YY, and cholecystokinin) [16].
A decreased dietary intake in patients with liver disease enhances anorexia, which is also
affected by micronutrient deficiency (i.e., low zinc levels) and metabolic alterations, such
as hyperglycemia, that may contribute to increased inflammatory cytokine production
(e.g., Tumor Necrosis Factor (TNF-α) and IL-6) and leptin [17]. Functional problems such
as gastroparesis and delayed bowel transit time, which may induce bacterial overgrowth,
together with tense ascites, cause nausea and early satiety [18].
In addition, hormonal alterations and dysfunction negatively influence both nutrient
intake and metabolism. Increased insulin levels, caused by hyperinsulinemia and insulin re-
sistance, induce satiety [19]. Hyperglycemia may eventually contribute to the development
of autonomic neuropathy, which modifies gustatory sensation and dietary intake and may
also enhance the negative effect of liver disease on gastrointestinal functions, especially
regarding motility (e.g., gastric emptying) [20]. Another endocrine alteration is the lack of
response to high levels of ghrelin, a peripherally derived orexigenic hormone that normally
increases appetite and food intake. Despite the presence of high ghrelin levels in cirrhotic
patients, appetite is not increased [21].
In a patient with liver disease, the digestion, absorption, and metabolism of nutrients
are all also negatively affected. Fat and fat-soluble vitamin malabsorption due to impaired
bile acid metabolism is common [22]. A reduction in acid secretion in the stomach, or even
achlorhydria, may be present in patients with liver cirrhosis, regardless of Helicobacter
pylori infection, with a variable prevalence [18,23]. This may contribute to the impaired
digestion of macronutrients (e.g., proteins) and some micronutrients (e.g., vitamin B12
and iron), which may ultimately worsen their absorption and increase their deficit. Conse-
quently, this may also contribute to worsening clinical manifestations of nutrient deficiency
(e.g., anemia) [24].
Alcohol abuse, which is the most frequent cause of liver disease, may contribute
to the poor nutritional intake caused by the development of chronic pancreatitis, which
is per se associated with fat and micronutrient malabsorption and metabolic alterations
(e.g., hyperglycemia), which may produce liver damage [25]. Alcohol inhibits fatty acid
oxidation, leading to triglyceride accumulation in the liver and the development of fatty
liver disease or NAFLD [26].
The liver plays a central role in amino acid and protein metabolism, and a reduction
in blood levels is not surprising (e.g., hypoalbuminemia). Indeed, a reduction in branched
chained amino acid (BCAA) serum levels is associated with the occurrence of hepatic
encephalopathy [27]. Protein losses are caused by gastrointestinal bleeding and frequent
paracentesis, which may be further worsened by protein-losing enteropathy, contributing
to the development of hypoalbuminemia [28]. It is important to highlight that alterations
in carbohydrate metabolism also contribute to lower amino acid levels and protein deficit.
A decreased hepatic glucose production and lower hepatic glycogen reserves increase
Livers 2023, 3 532
gluconeogenesis from amino acids and even secondary protein breakdown from mus-
cle [29]. All these effects are enhanced by hypermetabolism accompanied by a reduced
food intake, leading to a negative caloric and protein balance, which is a vicious circle that
worsens the malnutrition and clinical manifestations of liver disease [30].
Some data suggest that preservation of the body’s lean mass is important during
the evolution of patients with liver disease since it is associated with fewer complica-
tions [31,32]. Muscle wasting or sarcopenia is the most objective feature of chronic protein
malnutrition in cirrhosis and is also an important predictor of survival in decompen-
sated liver disease, quality of life, and the ability to respond to stressors, such as surgery,
prolonged ventilator support, longer ICU and hospital stays, higher risk of infections,
mortality, and even lower survival chances during the perioperative course of liver trans-
plantation [31–35]. Testosterone, which plays an important role in protein synthesis, is
highly reduced (≈90% approximately) in cirrhosis and protein breakdown [36]. Despite
malnutrition not being a formal contraindication for liver transplantation, it is well known
that in candidates for liver transplantation, malnutrition adversely affects the perioperative
course, and nutritional status should be improved before surgery.
Some metabolic and nutritional factors related to the occurrence of malnutrition in
liver disease should be better elucidated; nevertheless, it is obvious that the metabolic
and nutritional status strongly impacts liver disease and vice versa. These pathophysio-
logical factors are common to all degrees of liver disease in patients admitted to the ICU
and vary depending on the severity of the liver failure. However, a reduced nutritional
intake (Figure 1) and protein depletion (Figure 2) both seem to play a key role in the
occurrence of malnutrition and sarcopenia in these patients, which ultimately strongly
influence outcomes.
Livers 2023, 2, FOR PEER REVIEW 4 
 
 
All these effects are enhanced by hypermetabolism accompanied by a reduced food in-
take, leading to a negative caloric and prot i  bala ce, which s a vicious circle that wors-
ens the malnutrition and clinical manifestations of liver disease [30]. 
Some data suggest that preservation of the body’s lean mass is important during the 
evolution of patients with liver disease since it is associated with fewer complications 
[31,32]. Muscle wasting or sarcopenia is the most objective feature of chronic protein mal-
nutrition in cirrhosis and is also an important predictor of survival in decompensated liver 
disease, quality of life, and the ability to respond to stressors, such as surgery, prolonged 
ventilator support, longer ICU and hospital stays, higher risk of infections, mortality, and 
even lower survival chances during the perioperative course of liver transplantation [31–
35]. Testosterone, which plays an important role in protein synthesis, is highly reduced 
(≈90% pproximately) in cirrhosis and protein breakdow  [36]. Despite mal utrition not 
being a formal contraindication for liver transplantation, it is well known that in candi-
dates fo  l ver transplantation, malnutrition adversely affects the perioperative course, 
and nutritional status should be improved before surgery. 
Some metabolic and nutritional factors related to the occurrence of malnutrition in 
liver disease should be better elucidated; nevertheless, it is obvious that the metabolic and 
nutritional status strongly impacts liver disease and vice versa. These pathophysiological 
factors are common to all degrees of liver disease in patients admitted to the ICU and vary 
depending on the severity of the liver failure. However, a reduced nutritional intake (Fig-
ure 1) and protein depletion (Figure 2) both seem to play a key role in the occurrence of 
malnutrition and sarcopenia in these patients, which ultimately strongly influence out-
comes. 
 
Figure 1. Factors associated with reduced nutrient intake in liver disease. Inflammatory factors neg-
atively influence appetite-regulating hormones. Simultaneously, both a lower taste acuity and some 
liver-related complications also negatively influence appetite. The latter is related to reduced motil-
ity (i.e., gastric emptying and bowel transit time), which may impact appetite and contribute to a 
reduced nutrient intake [13–21]. 
↓ Nutrient intake
MALNUTRITION
Nutrients deficiency
Delayed gastric emptying
Gastroparesis
Post-prandial fullness
↓ Appetite
↑ Inflammatory
Cytokines
(e.g., IL-6, TNFα)
IL: Interleukin; TNF: Tumor Necrosis Factor
↑: increase of ; ↓: decrease of
Appetite regulating hormones
(Leptin, ghrelin, peptide YY, cholecystokinin)
↓ Micronutrient levels
(e.g., Zinc, Magnesium, Vitamin A)
↓ Taste acuity
Ascites Bacterial overgrowth
↓ Bowel transit time
Figure 1. Factors associated with reduced nutrient intake in liver disease. Inflammatory factors
negatively influence appetite-regulating hormones. Simultaneously, both a lower taste acuity and
some liver-related complications also negatively influence appetite. The latter is related to reduced
motility (i.e., gastric emptying and bowel transit time), which may impact appetite and contribute to
a reduced nutrient intake [13–21].
Livers 2023, 3 533Livers 2023, 2, FOR PEER REVIEW 5  
 
 
Figure 2. Factors related to protein depletion in liver disease. Protein depletion and the development 
of sarcopenia are closely related to a reduced nutrient intake and the activation of mechanisms to 
guarantee the metabolic demands of carbohydrates. Liver-related insensitive protein losses and im-
paired protein digestion both negatively affect protein depletion, which also enhances the develop-
ment of liver-related complications (e.g., hepatic encephalopathy) [31–36]. 
4. Nutrition Management in Patients with Liver Disease 
Evidence for malnutrition as a prognostic indicator in patients with decompensated 
liver disease has mostly been derived from the liver transplantation population, in which 
severe malnutrition has been associated with higher perioperative mortality [13]. How-
ever, common models for determining the prognosis and degree of liver disease (i.e., 
model of end-stage liver disease and the Child–Pugh score) do not evaluate nutritional 
status. Identifying the degree of malnutrition in patients with liver disease is the first step 
toward addressing nutrition therapy in these patients. 
4.1. Evaluation of Nutritional Status in Patients with Liver Disease 
Evaluating nutritional status and the presence of malnutrition involves different pa-
rameters, such as physical examination, anthropometric measurements, laboratory tests, 
and instrumental examination, along with the determination of the patient’s functional 
capacity [9]. These parameters may be modified due to the inherent alterations associated 
with critical illness and liver disease (e.g., fluid overload and alterations in protein metab-
olism) which make it difficult to determine the nutritional status. 
Underweight (<18.5 kg/m2) and obesity (>30 kg/m2) are related to the presence of mal-
nutrition and sarcopenia in liver disease [37]. However, these measurements may be af-
fected by fluid overload, a frequent feature in these patients. Indeed, other anthropometric 
measurements, such as triceps skinfold and mid-arm muscle circumference, which assess 
subcutaneous fat and muscle mass, can also be affected by fluid overload when patients 
are admitted to an ICU [28]. Fluid overload may also affect both weight and laboratory 
biomarkers (e.g., albumin levels), which can be even lower due to impaired hepatic pro-
tein synthesis [38]. Despite this, laboratory markers may be helpful; serum protein levels 
(e.g., albumin, prealbumin, and transferrin), vitamin levels, and creatinine may be consid-
ered useful for nutritional assessment and can detect nutritional deficiencies in the ab-
sence of ideal biomarkers [5,7]. Prealbumin, also known as transthyretin, is a hepatic pro-
tein that correlates well with the body’s protein status and was found to be the best nutri-
tional predictor of survival in liver transplant patients in comparison with serum albumin, 
cholesterol, and creatinine [39,40]. 
Regarding nutritional scores, some have been evaluated in patients with liver disease. 
The subjective global assessment (SGA) has been used as a reference for the validation of 
Hormonal dysfunction 
(e.g., ↓ Testosterone levels)
SARCOPENIA
GI Bleeding
Paracentesis
↓Hepatic glycogen reserves
↓ Acid secretion of the stomach
GI: Gastro-intestinal; BCAA: Branched-chained amino acids
↑: increase of ; ↓: decrease of
↓ Digestion of proteins
GluconeogenesisHypoalbuminemiaAscites
Protein-losing
enteropathy
Protein
losses
↓ Nutrient intake
↓ Appetite
↓ Protein levels
(↓ BCAA)
Hepatic Encephalopathy
Iron deficiencyAnemia
↑ Muscle protein breakdown
& depletion
Figure 2. Factors related to protein depletion in liver disease. Protein depletion and the development
of sarcopenia are closely related to a reduced nutrient intake and the activation of mechanisms
to guarantee the metabolic demands of carbohydrates. Liver-related insensitive protein losses
and impaired protein digestion both negatively affect protein depletion, which also enhances the
development of liver-related complications (e.g., hepatic encephalopathy) [31–36].
4. Nutrition Management in Patie t i er isease
Evidence for malnutrition as a rog ostic indicator in patients with decompensated
liver disease has mostly been derived fro the liver transplantation population, in which
severe malnutrition has been associated with higher perioperative mortality [13]. However,
common models for determining the prognosis and degree of liver disease (i.e., model
of end-stage liver disease and the Child–Pugh score) do not evaluate nutritional status.
Identifying the degree of malnutrition in patients with liver disease is the first step toward
addressing nutrition therapy in these patients.
4.1. Evaluation of Nutritional Status in Patients with Liver Disease
Evaluating nutritional status and the presence of malnutrition involves different pa-
rameters, such as physic l examination, anthropometric measurements, laboratory t s s,
and instr mental examination, along with t e determination of the patient’s functional
capacity [9]. These parameters may be modified due to the inherent alterations associ-
ated with critical illness and liver disease (e.g., fluid overload and alterations in protein
metabolism) which make it difficult to determine the nutritional status.
Underweight (<18.5 kg/m2) and obesity (>30 kg/m2) are related to the presence of
malnutrition and sarcopenia in liver disease [37]. However, these measurements may be
affected by fluid overload, a frequent feature in these patients. Indeed, other anthropo-
metric measurements, such as triceps skinfold and mid-arm muscle circumference, which
assess subcutaneous fat and muscle mass, can also be affected by fluid overload when
patients are admitted to an ICU [28]. Fluid overload may also affect both weight and
laboratory biom rkers (e.g., albumin levels), which can e even l wer due to impaired
hepatic protein synthesis [38]. Despite this, labor tory markers may be helpful; serum
protein lev ls (e.g., albumin, prealbumin, d transferrin), vitamin levels, an creatinine
ma be considered useful for nutriti nal assessment and can detect nutritional deficie ci s
in the absence of ideal biomarkers [5,7]. Prealbumin, also known as transthyretin, is a
hepatic protein that correlates well with the body’s protein status and was found to be the
best nutritional predictor of survival in liver transplant patients in comparison with serum
albumin, cholesterol, and creatinine [39,40].
Livers 2023, 3 534
Regarding nutritional scores, some have been evaluated in patients with liver disease.
The subjective global assessment (SGA) has been used as a reference for the validation
of other malnutrition screening tools. It has been applied to this end in liver transplant
candidates with an overall fair to good inter-observer reproducibility rate [41]. Four features
of the medical history are elicited: weight loss in the previous six months, dietary intake in
relation to a patient’s usual pattern, the presence of significant gastrointestinal symptoms
(e.g., anorexia, nausea, vomiting, diarrhea, etc.), and patient’s functional capacity or energy
level (e.g., bedridden to full capacity) [42]. Patients are classified as well-nourished or with
mild, moderate, or severe malnutrition. Muscle wasting and fat depletion have both been
strongly associated with SGA scoring [41]. This test has shown a high specificity (96%)
with a very low sensitivity (22%) for diagnosing malnutrition in these patients, especially
in those with alcoholic liver disease [43]. Despite the limitations of the SGA, it has been the
reference screening tool for comparison with others in different studies.
The Mini-Nutritional Assessment (MNA) may also be an appropriate tool for nu-
tritional screening assessment in cirrhotic patients of any etiology [44]. It consists of six
preliminary questions with a total score of up to 30 points. Cases are defined as “malnour-
ished” (0–16 points), “at risk of malnutrition” (17–23.5 points), and “normal nutritional
status” (24–30 points). The MNA also correlates with representative nutrition-related
anthropometric parameters (e.g., percentage arm circumference, triceps skinfold, maxi-
mum grasp strength, and arm muscle circumference) and serum blood chemistry data
(i.e., albumin) [44]. The European Nutritional Risk Screening (NRS)-2002 is a suitable
screening tool for patients with early and mild liver disease; however, it is less accurate in
end-stage liver disease since it may promote false positives [45]. It identifies a nutritional
risk group with a score of three points or more and it was the first score to include disease
severity as a component of nutritional screening [45,46]. The Controlling Nutrition Status
(CONUT) score is an objective tool extensively used to evaluate nutritional status in various
diseases, which is based on three laboratory parameters (i.e., albumin, cholesterol, and
lymphocytes). It has been evaluated in adults with hepatitis C virus-related liver cirrhosis
reflecting liver functional reserves, which may potentially make the CONUT score a useful
marker of the presence of malnutrition in these patients [47]. The Malnutrition Universal
Screening Tool (MUST) was evaluated in cirrhotic patients. It evaluates body mass index
(BMI), percentage body weight loss, and acute or chronic disease. It is divided into three
stages, where patients scoring two points or more are classified as the high-risk group;
it is a relatively quick and easy screening tool. Unfortunately, MUST is less accurate in
patients with ascites/fluid retention, which makes it unreliable for identifying malnutrition
in patients with cirrhosis [48].
The Liver Disease Undernutrition Screening Tool (LDUST) has been validated as a
screening tool for malnutrition in ambulatory patients with liver disease [49]. It is based on
six parameters (i.e., recent oral intake, weight loss over 12 months, body fat loss, muscle loss,
fluid retention/ascites, and effects on daily activities) chosen by consensus and recognized
by the American Society for Parenteral and Enteral Nutrition (ASPEN) and the Academy
of Nutrition and Dietetics (AND) [50]. LDUST theoretically overcomes the ascites/fluid
retention limitations of MUST. Another specific screening tool validated for malnutrition
assessment in patients with liver cirrhosis, the Royal Free Hospital–Nutritional Prioritizing
Tool (RFH–NPT), also considers ascites/fluid retention [51]. It is included as part of
the algorithm to assess malnutrition in the clinical practice guidelines of the European
Association for the Study of the Liver (EASL) [52]. The RFH–NPT and LDUST are screening
tools that proved to be accurate in detecting malnutrition in cirrhotic patients [53].
Theoretically, a more objective way to diagnose malnutrition is using body composi-
tion assessment. Numerous indirect methods have been used to quantify body composition
in liver transplantation candidates, including total body electrical conductivity, bioelectrical
impedance analysis (BIA), dual-energy X-ray absorptiometry, air displacement plethysmog-
raphy, or magnetic resonance imaging (MRI) and computed tomography (CT) scans [54].
Unfortunately, like body weight and BMI, the accuracy of some body composition assess-
Livers 2023, 3 535
ment techniques is limited due to the presence of ascites/fluid retention, and their current
utility should be elucidated.
The annual rate of muscle loss increases with worsening liver reserves, and patients
with liver disease are more likely to present complications with sarcopenia. Sarcopenia
is prevalent in cirrhosis patients, with an incidence ranging from 30% to 70% [55]. This
wide range is related to the lack of standard diagnostic criteria for sarcopenia in cirrhosis,
the wide variability in etiology, the presence of comorbidities, the degree of liver dysfunc-
tion, and patient characteristics across different studies [54]. Low muscle mass or muscle
function have been identified as independent predictors of a poor quality of life associated
with a higher incidence of hepatic decompensation (i.e., ascites, hepatic encephalopathy,
and variceal bleeding) and mortality in patients with cirrhosis evaluated for liver trans-
plantation. The negative impact that sarcopenia has on patients with cirrhosis has been
demonstrated in several studies (Table 1).
Table 1. Studies describing the association of sarcopenia with outcomes in patients with liver disease.
Studies
(Year) n
Incidence of
Sarcopenia Main Results Related to the Occurrence of Sarcopenia
Merli et al. (2010) [56] 38 53% Increased LOS in the hospital and ICU and increased incidenceof perioperative infections in patients with sarcopenia
Englesbe et al. (2010) [57] 163 25% Higher mortality after LT
Montano-Loza et al. (2012) [58] 112 40% Sarcopenia was independently associated with mortality
Tandon et al. (2012) [59] 142 41% Sarcopenia was associated with increased mortality on the LTwaiting list
Meza-Junco et al. (2013) [60] 116 30% Sarcopenia was independently associated with mortality
Krell et al. (2013) [61] 207 33% Higher risk of infectious complications and mortality after LT
DiMartini et al. (2013) [62] 338 68% Muscle mass predicted longer LOS in ICU, total LOS, and alonger time on mechanical ventilation
Masuda et al. (2014) [63] 204 47% Sarcopenia was an independent prognostic factor for post-LTmortality and postoperative sepsis
LOS: length of stay; ICU: Intensive Care Unit; LT: liver transplantation.
Evaluation of physical activity in patients with liver disease may be mandatory as it is
both a mainstay of therapy for improving muscle mass and evaluating functional status
in patients with cirrhosis and liver disease. There are now several trials, predominantly
enrolling patients with compensated cirrhosis, which have evaluated the effects of exercise
therapy, reporting improvements in health-related quality of life (HRQoL), muscle mass,
exercise capacity, and even reductions in the hepatic venous pressure gradient [64–66].
However, it is important to underline that physical activity has been poorly studied until
recently because earlier studies associated physical activity with an increase in portal
pressure and, therefore, the risk of variceal bleeding [67]. However, these drawbacks have
not been detected in contemporary studies [64–66].
Deconditioning and fatigue are major issues for patients with cirrhosis, even those with
compensated liver disease, which may represent a significant barrier to physical activity.
Physical activity regimens, therefore, need to be adjusted to the patient’s level of baseline
function and carried out at their perceived level of effort [64]. For example, some very de-
conditioned patients may achieve a 7–8 out of 10 perceived exertions with just slow walking.
Despite there being no formal guidelines available for physical activity in cirrhosis, recog-
nizing the need to individualize prescribed physical activity in cirrhotic patients should be
mandatory due to the potential benefits that exercise entails. Further research is needed
regarding the optimal characteristics of physical activity/exercise (i.e., dose, duration,
frequency, intensity, type, etc.), not just for these patients but the entire ICU population.
As there is no gold standard, we recommend using a combination of different meth-
ods to evaluate and determine the extent of malnutrition in patients with liver disease.
Simultaneous evaluation of BMI and ascites/fluid retention together with the degree of
liver disease (i.e., the Child–Turcotte–Pugh score and Model for End-Stage Liver Disease
Livers 2023, 3 536
score) may be helpful for this purpose. The SGA, LDUST, and the RFH–NPT seem to be
the most suitable tools for screening malnutrition in these patients. Evaluating sarcopenia
and physical activity should be mandatory since these are considered surrogate markers of
nutritional and functional status irrespective of the degree of liver disease. Despite there
not being any gold standard or ideal tool in these patients, the presence of sarcopenia needs
to be evaluated (e.g., by CT scans, MRI, BIA, etc.). A summary detailing the nutritional
parameters for evaluating the metabolic and nutritional status in patients with liver disease
is provided in Table 2.
Table 2. Parameters to evaluate the metabolic and nutritional status in patients with liver disease
[36,37,41–43,49–54,64–67].
Type of Parameter Value Associated with the Presence of Malnutrition
Anthropometric
measurement BMI <18.5 kg/m
2 and >30 kg/m2
Laboratory biomarkers
Albumin <3 g/dL2
Prealbumin <160 mg/dL2
Vitamin levels Consider malnutrition in the presence of low levels
Nutrition Scores
SGA SGA B (mild) or C (severe)
LDUST ≥2 boxes in columns B or C
RFH–NPT Scores 1 and 2–7 correspond to moderate and high risk
Liver Scores CTP B (mild) or C (severe)
MELD >15
Muscle mass
BIA
Evaluate muscle mass and the presence of sarcopeniaCT scan
MRI
Physical activity HRQoL >3 reflects a poor quality of life
BMI: body mass index; SGA: Subjective Global Assessment; LDUST: Liver Disease Undernutrition Screening Tool;
RFH–NPT: Royal Free Hospital–Nutritional Prioritizing Tool; CTP: Child–Turcotte–Pugh score; MELD: Model for
End-Stage Liver Disease; BIA: bioelectrical impedance analysis; MRI: magnetic resonance imaging; CT: computed
tomography; HRQoL: health-related quality of life questionnaire.
4.2. What Do Clinical Practice Guidelines Recommend?
It is important to remark that most recommendations for nutrition therapy in patients
with liver disease arise from a pathophysiological basis and expert opinion or consensus;
the degree of evidence is moderate due to the lack of nutrition studies in this specific
population of ICU patients. As a result, there are few main contemporary international
guidelines available specifically addressing nutrition therapy in liver disease [5].
The EASL has published clinical practice guidelines on nutrition in advanced liver
disease, including how to recognize and assess nutritional problems and what the conse-
quences of malnutrition are and its correction, in addition to addressing different clinical
scenarios, such as hepatic encephalopathy and before/after transplantation [52]. The ES-
PEN guidelines on clinical nutrition in liver disease include recommendations on different
issues of nutritional management in various forms of liver disease (e.g., ALF, ACLF, cirrho-
sis, major liver surgery, or transplantation) [68]. Indeed, a recent ESPEN review underlined
the importance of sarcopenia in cirrhosis and made some recommendations for clinical
practice [69]. Table 3 summarizes these ESPEN guideline recommendations for nutrition
therapy in patients with liver disease.
It is important to note that none of these guidelines specifically address the population
admitted to the ICU with liver disease; the recommendations are selected and adapted
based on the characteristics of liver disease patients with critical illness. In consequence,
there are some concerns related to nutrition therapy and metabolic status in these patients
that are not emphasized in the guidelines and require careful attention. First, these patients
have major vitamin and trace element deficits, and identifying these deficits (if possible)
Livers 2023, 3 537
may be of crucial importance [24]. The routine administration of vitamins and trace element
supplementation may be considered when these patients are admitted to an ICU.
Table 3. Summary of recommendations for nutrition therapy in patients with liver disease in an
ICU [52,68,69].
Nutritional and metabolic assessment
Should be performed regularly in all patients to detect
malnutrition, especially those with acute liver failure
Evaluation should include measurement of weight, height, body mass
index (BMI), arm circumference, and serum albumin/prealbumin
Evaluate the occurrence of hypoglycemia in the setting of acute liver
failure
Screening of alcohol consumption Alcohol worsens liver disease and increases its associatedcomplications
Dietary advice
Patients at risk of or diagnosed with malnutrition Individualized dietary advice from a registered dietitian/nutritionist.
Nutrition medical therapy and nutritional considerations
Protein intake
High protein intake to avoid muscle loss and sarcopenia
Consider frequent monitoring of ammonia levels (i.e., 24–48 h) to
modulate protein intake
Energy intake
Adequate to maintain the patient’s nutritional status. In some cases, it
may be necessary to increase energy intake to compensate for increased
energy expenditure due to acute complications or malnutrition
Carbohydrates as the main source of energy
Fats should be limited to avoid liver damage from dyslipidemia
Consider nutritional supplements
To improve nutritional status or achieve nutritional requirements
Consumption of a snack at night (if possible oral route) with at least
50 g of carbohydrates
Careful sodium administration Adequate to avoid ascites/fluid retention
Metabolic disturbances
Careful control of acid–base balance Prevent complications such as lactic acidosis
Correction of electrolyte disturbances Hyponatremia, hypokalemia, and hypomagnesemia
Route of administration
Oral feeding Route of choice in the absence of severe HE
Enteral feeding by nasogastric tube
Insufficient oral intake or not tolerated due to complications such as
ascites or HE
Consider post-pyloric tube if high risk of bronchial aspiration
Consider parenteral nutrition Total or supplementary PN if they cannot tolerate enteral feedings or ifthey have compromised intestinal absorption.
Prevention and treatment of sarcopenia
Protein supplementation combined with physiotherapy
(e.g., resistance exercise training) Avoid muscle depletion
L-leucine Reverse the decrease in muscle protein balance due tohyperammonemia
Dietary recommendations
High protein diet (≈1.5 g/kg/day) with 30–40 kcal/kg/day
Consider nutritional supplements
Specific recommendations
Hepatic encephalopathy
Reduce protein intake to avoid worsening of hepatic encephalopathy
Consider supplementation with BCAAs
Caution with the enteral route due to the high risk of bronchial
aspiration (i.e., HE III–IV)
Bleeding complications Prevent (i.e., frequent screening of coagulation disorder) and treatcoagulopathy (i.e., vitamin K administration)
Liver-disease-related complications (i.e., portal
hypertension, hepatic encephalopathy, and ascites)
Prompt drug treatment to prevent or treat complications that ultimately
may affect the nutritional status
Vitamin D Correction of deficiency
HE: hepatic encephalopathy; PN: parenteral nutrition; BCAA: branched-chain amino acids.
Livers 2023, 3 538
Second, some patients develop a hypercatabolic status based on the metabolic charac-
teristics that liver disease entails; however, they are unable to tolerate full enteral nutrition
(EN) since they are critically ill (e.g., severe or prolonged shock) [10]. The hypercatabolic
status combined with the stress response of their critical status rapidly leads to malnutri-
tion because of the difficulty in achieving nutritional and metabolic requirements. Thus,
nutrition therapy should be individualized based on these considerations; nutrition therapy
should follow the recommendations for ICU patients (i.e., early and progressive adminis-
tration) and the specifications described above (e.g., reduce protein administration when
hepatic encephalopathy is present).
Third, enteral is the main administration route to maintain the integrity of the gastric
mucosa and gut barrier, yet patients frequently experience difficulties in achieving the
entire nutrition therapy volume because liver disease and ICU admission both entail
gastrointestinal dysfunction (e.g., delayed gastric emptying) [70]. We should follow prompt
strategies to optimize the enteral route during the first 72 h of ICU admission, such as
early use of prokinetics, and consider post-pyloric administration, especially if we suspect
previous malnutrition or chronic liver disease. In addition, the use of PN should be
considered early on (i.e., day 3–4 of ICU admission) to achieve nutritional targets and avoid
the occurrence or development of malnutrition [24]. Older patients (i.e., >50 years old)
under PN more frequently have ascites and a positive fluid balance; however, these patients
usually exhibit a higher risk of malnutrition compared with patients on EN [71]. Physicians
should be aware of the detrimental effects that a positive fluid balance caused by PN may
have on gastrointestinal function, which ultimately are related to worse outcomes [72]. EN,
even with minimal delivery, should be considered in combination with PN to maintain gut
structure and minimize the adverse effects (i.e., induced gut and liver inflammation) that
PN may entail [73]. It is important to remark that PN with a higher proportion of omega-3
polyunsaturated fatty acids (ω3-PUFA) may help minimize this adverse effect [74].
Finally, appropriate glycemic management may be an important metabolic target to
control. Glycemia may be monitored every 2 h with several objectives: to maintain glucose
levels between 150 and 180 mg/dL, avoid hypoglycemia, and detect hyperglycemia or high
glycemic variability during admission. It is important to remember that hyperglycemia
may exacerbate intracranial pressure when patients develop intracranial hypertension in
the setting of hepatic encephalopathy [75]. All these concerns should be considered for a
practical approach to nutrition therapy in these patients.
4.3. A Practical Approach to Nutrition Therapy in Patients with Liver Disease
We previously underlined that patients with cirrhosis may have a higher energy re-
quirement due to increased protein catabolism; however, we must balance this phenomenon
with nutrition tolerance, which is lower in the setting of critical illness and worsening liver
disease [5,33,52,68]. It is clear that an adequate protein intake is important to prevent
protein–calorie malnutrition and avoid sarcopenia [69]. The energy supply should be
mixed (i.e., carbohydrates and lipids) but limiting the lipid intake is recommended due to
the increased risk of hepatic steatosis or worsening of hypertriglyceridemia. The higher risk
of vitamin deficiencies due to intestinal malabsorption, higher energy demands, and previ-
ous deficits, mostly involving vitamins A, D, E, and K, as well as iron and zinc, should make
their routine administration necessary. According to general and specific guidelines for nu-
trition therapy in ICU patients, Table 4 summarizes the main points to consider for nutrition
therapy in patients with liver disease admitted to an ICU [5,33,52,54,65,68,69,76,77].
Some of the aforementioned recommendations may apply to patients with liver disease
who are not admitted to an ICU because the pathophysiological basis of liver disease
applies to all patients. However, the nutrition guidance provided cannot apply to all
patients with liver disease as ICU patients suffer from alterations that prevent adequate
nutrition therapy.
Livers 2023, 3 539
Table 4. Recommendations for nutrition status screening, management, and strategies to optimize
nutrition therapy in patients with liver disease admitted to an ICU [5,33,52,54,65,68,69,76,77].
Screening of nutrition status
• Evaluate the degree of liver disease (i.e., MELD and CTP scores).
• Measure BMI.
• Evaluate fluid status (e.g., ascites).
• Evaluate sarcopenia and functional status.
• Use a screening tool (i.e., SGA, LDUST, and/or RFH-NPS) to identify the occurrence of malnutrition or if the patient is
malnourished.
General considerations for the delivery of nutrition therapy
• Consider EN as the first choice for nutrition therapy if the oral route is not possible.
• Consider early PN (total or supplemental) when EN does not achieve the energy (<60%) and protein requirements.
• Consider nutritional supplements if the oral route does not achieve all the energy and protein requirements.
• More aggressive approach (e.g., early use of PN) in the presence of suspected malnutrition or nutritional risk (i.e., previous
liver disease or alcohol consumption).
Nutrition therapy route
EN
• Initiate early, within 24–48 h after ICU admission, when the patient is hemodynamically stable.
• EN should be initiated after correct resuscitation (i.e., stable dosage of vasopressors, normal or stable
arterial lactate levels, catecholamines, and/or mechanical circulatory support) in the presence of shock
or hemodynamic failure and in the absence of contraindications.
PN
Consider in the presence of absolute or relative contraindications for EN:
• Active gastrointestinal hemorrhage (absolute).
• Uncontrolled shock or hemodynamic failure (e.g., increasing dosage of vasopressors and/or greater
need for circulatory support), uncontrolled hypoxemia, hypercapnia, or acidosis (absolute).
• GRV > 500 mL every 6 h or inability to achieve energy requirements by the enteral route (relative).
• Suspected or diagnosed acute mesenteric ischemia, intestinal obstruction, or abdominal compartmental
syndrome (absolute).
Nutritional requirements
Energy 20–25 Kcal/Kg/day
Protein 1.2–2 g/Kg/day
Slowly increase EN rate considering clinical state and EN tolerance for 48–72 h
Strategies to optimize nutrition therapy and avoid complications
Recommended strategy Objective
Bed position > 30–45◦ Avoid regurgitation, vomiting, and aspiration
Prokinetic agents (i.e., Erythromycin
and/or Metoclopramide)
• Consider in the presence of gastric intolerance (GRV > 500 mL), regurgitation,
nausea, or vomiting.
• Optimize delivery of nutrition therapy.Post-pyloric NG tube placement
Optimize drugs that interfere with
gastrointestinal function (e.g., opioids)
• Avoid and prevent ileus and gastrointestinal failure.
• Optimize delivery of nutrition therapy.
Avoid fluid overload
Early mobilization and physiotherapy Avoid progression or development of sarcopenia
Vitamin and trace element
supplementation Avoid micronutrient deficiency
BMI: body mass index; SGA: Subjective Global Assessment; LDUST: Liver Disease Undernutrition Screening Tool;
RFH–NPT: Royal Free Hospital–Nutritional Prioritizing Tool; PN: parenteral nutrition; ICU: Intensive Care Unit;
EN: enteral nutrition; GRV: gastric residual volume; NG: nasogastric.
4.4. Considerations in the Perioperative Patient
Nutrition therapy improves outcomes (i.e., mortality, length of hospital stays, and
postoperative complications) in all types of perioperative scenarios in patients with liver
disease (i.e., liver transplantation, liver resections, and hepatocellular carcinoma) [70]. The
Livers 2023, 3 540
application of nutrition therapy in patients with severe nutritional risk (i.e., SGA C) is
recommended for 10–14 days before major surgery to optimize their nutritional status,
even if surgery must be delayed because of the presence of malnutrition [78]. This would
definitively positively affect the outcome of the patient, especially in terms of a lower
incidence of postoperative complications.
After surgery, especially after liver transplantation, enteral nutrient intake should
be started early in the postoperative period, even though transpyloric access and the
composition of the nutritional formula should be adapted to the patient’s metabolic stress.
The prevalence of sarcopenia does not seem to decrease, and although patients gain weight,
sarcopenic obesity may co-exist [79]. A greater food intake and physical inactivity are
responsible for the positive energy balance, which is observed in up to 88% of patients
after liver transplantation [80]. Several metabolic complications related to weight gain and
immunosuppression are developed in the long-term post-transplant. The risk of arterial
hypertension, dyslipidemia, and diabetes mellitus increases after surgery and impacts
outcomes as well as survival [81]. This set of metabolic disorders yields an increased risk
of metabolic syndrome, described in approximately half of liver transplant recipients [82].
Despite weight gain seeming positive for nutritional status after liver transplantation, this
is an additional risk factor for developing metabolic syndrome, which makes a nutritional
follow-up necessary.
5. Conclusions
In summary, nutrition therapy in critically ill patients with liver disease remains
difficult due to the pathophysiological alterations involved in these patients. Physicians face
both the nutritional risk that critically ill patients represent and changes in gastrointestinal
function associated with liver disease. Nutrition therapy clearly improves the survival of
these patients, especially in liver transplantation, and evaluation of the nutritional status is
mandatory to develop an individualized nutrition plan in the ICU. The delivery of nutrition
therapy should focus on avoiding the occurrence or development of malnutrition, and
strategies to optimize nutrition should be applied early on. PN during ICU admission
should be strongly considered to achieve nutrition delivery. Monitoring and detecting
nutrition-therapy-related and liver-related complications that may influence the tolerance of
nutrition therapy during an ICU stay are of notable importance. Adequate protein delivery
and physiotherapy may play a key role in the prevention and recovery of sarcopenia in
these patients.
Author Contributions: M.Á.H.-B., J.C.L.-D. and J.A.S.-G. conceived the present review and per-
formed a critical and concise review of the data retrieved from the selected manuscripts during
the review process. J.C.L.-D. put together the first draft of the manuscript but all authors were
involved in the writing of different versions of the manuscript. All the authors revised the manuscript
and approved the final version. All authors have read and agreed to the published version of
the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: All data reported in the present review comes from the manuscripts
cited among the text. There is not any specific dataset or specific data available.
Acknowledgments: We would like to thank the University of Barcelona and CERCA program of
Generalitat de Catalunya for institutional support.
Conflicts of Interest: The authors declare no conflict of interest.
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