Professor Apostolos Hatzitolios, 1st Medical Propedeutic Department, AHEPA Hospital, Aristotle University of Thessaloniki, G. Stavrou 4, T.K. 54623, Thessaloniki, Greece. Email: firstname.lastname@example.org
Malnutrition has increasingly been acknowledged as an important prognostic factor which can influence the clinical outcome of patients suffering from end-stage liver disease (ESLD). Despite the fact that malnutrition is not included in the Child–Pugh classification, its presence should alert clinicians to the same extent as do other complications, such as ascites and hepatic encephalopathy. The pathophysiological mechanisms and the clinical conditions that drive cirrhotic patients to an ill-balanced metabolic state are multiple and they intertwine. Inadequate offer of nutrients, the hypermetabolic state in cirrhosis, the diminished synthetic capacity of the liver and the impaired absorption of nutrients are the main reasons that disrupt the metabolic balance in ESLD. Identifying patients that are approaching the state of malnutrition by simple and easily applied methods is necessary in order to provide nutritional support to those that need it most. According to the European Society for Clinical Nutrition and Metabolism, simple bedside methods such as Subjective Global Assessment and anthropometric parameters are reliable in assessing the nutritional state of cirrhotic patients. Correcting the nutrient deficit of the affected patients is mandatory. Avoidance of alcohol and excess fat and ingestion of 4–6 meals/day containing carbohydrates and protein are the most common recommendations. In severe malnutrition, initiation of enteral feeding and/or use of special formulae such as branched-chain amino acid-enriched nutrient mixtures are often recommended. Enteral nutrition improves nutritional status and liver function, reduces complications, prolongs survival and is therefore indicated.
Malnutrition is by far considered one of the most important prognostic factors in liver cirrhosis and should alert clinicians to the same extent as the presence of other common complications of cirrhosis such as hepatic encephalopathy or ascites.1,2 The original Child-Turcotte1 classification, which was used up to 1973 to assess the prognosis in end-stage liver disease (ESLD), included the nutritional status in its criteria, whereas the modified Child–Pugh classification has replaced it with prothrombin time.
Malnutrition has been found to be as common as 80%3 among cirrhotic patients but the most astonishing finding in several clinical trials is that even in patients classified as Child–Pugh class A the prevalence of malnutrition was as high as 25%.4 The clinical importance of these ongoing studies is that malnourished patients have considerably higher prevalence in morbidity and mortality3,5,6 and early intervention in replenishing the nutrient deficit can prolong life expectancy, ameliorate quality of life, diminish complications and prepare them for a more successful liver transplantation.5,7
Unfortunately, one should keep in mind that the assessment of malnutrition on everyday clinical practice is quite difficult because of the objectiveness of the methods used and the tendency of fluid retention in cirrhosis which may alter the results.6 Therefore, different parameters in assessing the nutritional status have been used and evaluated, and some of them are quite useful and easy to perform not only by experts.
In January 2006 the European Society for Clinical Nutrition and Metabolism (ESPEN) issued specific guidelines on enteral nutrition in liver disease which can be easily applied in both inpatients and outpatients.8 The guidelines recommend the use of simple bedside methods such as the Subjective Global Assessment (SGA) or anthropometry to identify patients at high risk of undernutrition.9 In order to quantitate undernutrition, the use of phase angle or body mass cell measured by bioelectric impedance analysis (BIA) has been used.6,9 In the ESPEN guidelines it is stressed that identifying those cirrhotic patients that are truly malnourished is of great clinical importance because ‘enteral nutrition improves nutritional status and liver function, reduces complications and prolongs survival and is therefore recommended’.1,9
Causes of malnutrition in liver cirrhosis
Diminished nutrient intake
The majority of cirrhotic patients unintentionally follow a low caloric diet, a fact that is attributed to various side-effects observed in cirrhosis. Loss of appetite, which is currently attributed to the presence of cytokines such as tumor necrosis factor α (TNF- α),10 or alcohol-induced anorexia, are the most common reasons. Also, early satiety due to impaired gastric accommodation11,12 and impaired expansion capacity of the stomach due to the presence of clinically evident ascites10 quite often lead to an inadequate nutrient intake.
Patients with chronic liver diseases experience abdominal pain, nausea and bloating3 and are found to have altered gut motility,13 all of which lead to the development of functional dyspepsia. As is excellently stressed by Kalaitzakis et al.,3 there is an increased severity of gastrointestinal symptoms associated with recent weight loss and impaired health-related quality of life and the severity of liver disease.
One other important factor is the presence of impaired digestion and nutrient absorption due to portal hypertension, suggesting that controlling the pressure in the portal vein either by transjugular intrahepatic portocaval shunts (TIPS) or medication could improve the patients' nutritional status.10 Cholestatic liver disease is another reason for impaired absorption, especially of fat-soluble vitamins such as A,D,E and K, due to the reduced intraluminal bile salt concentrations.14,15
Furthermore, conditions such as bacterial overgrowth, coexistent small intestinal disease (inflammatory bowel disease, celiac sprue), pancreatic insufficiency, mucosal congestion and villus atrophy contribute to the impaired absorption and utilization of nutrients.
Unfortunately, we should keep in mind that too many physicians tend to prescribe a low protein diet in order to avoid hepatic encephalopathy leading to poorer nutritional status. Other iatrogenic causes for protein and caloric loss include the multiple hospitalizations which may lead to loss of regular meals for reasons of pending examinations and procedures.10
The well-recognized hyperdynamic circulation in cirrhosis leads to a systematic vasodilatation and to an expanded intravascular blood volume. As a direct effect, a higher heart blood volume and therefore a greater use of macro- and micronutrients is one of the most common causes of high energy expenditure and demand.
Among cirrhotic patients, 34% are considered hypermetabolic16 with a resting energy expenditure 120% of the expected value.1 Elevated pro-inflammatory and anti-inflammatory cytokine levels17,18 point to a cytokine-driven hypermetabolism in cirrhosis.
On various occasions, patients are driven from a normometabolic state to a speeding catabolic state without any obvious reason. One should keep in mind, however, that compromised gut barrier function in affected patients results in bacterial translocation. Possible effects of this are a spontaneous bacterial peritonitis, deterioration in hepatic encephalopathy or the presence of fever of unknown origin, complications that promote the increased degradation of protein and energy expenditure. In these circumstances, patients may experience deterioration in their general health and nutritional status and may shift to a higher grade in the Child–Pugh classification.10
Inadequate synthesis or absorption of micro- and macronutrients
Other important factors in the loss of body protein are the inadequate synthesis of various proteins from the affected liver, the diminished storage capacity of the cirrhotic liver and the affected enterohepatic circle. If we add to these conditions, the portal hypertensive enteropathy which leads to an impaired absorption of nutrients we can easily come to the conclusion that providing the cirrhotic patient with the proper amount of energy is far from easy.
It has been observed that among cirrhotic patients, after an overnight fast, an early switch to gluconeogenesis from amino acids originating from body proteins is often the rule. The lack of sufficient amounts of hepatic glycogen reserves, due to the impaired synthetic capacity of hepatic cells, results in the mobilization of amino acids from the skeletal muscles so that the proper amount of glucose is provided. This condition is observed in healthy individuals after a fasting period of approximately 3 days19,20 depicting the great amount of hepatic damage that cirrhotic patients suffer.
Furthermore, deficiency in vitamins and trace minerals is often observed in liver cirrhosis. As has been mentioned earlier, cholestasis and portal hypertensive enteropathy may cause impaired absorption of fat and fat-soluble vitamins. This can result in specific deficiencies such as vitamin A deficiency, osteoporosis as a result of calcium loss and vitamin D malabsorption, deficiencies in folate, riboflavin, nicotinamide, pantothenic acid, pyroxidine, vitamin B12 and thiamine.14,15 Decreased levels of zinc, magnesium, sodium and phosphorus are not rare.1,14 It is worth mentioning that zinc deficiency impairs wound healing, immune reaction, protein metabolism and alters appetite and taste.15
Loss of protein and minerals is a common clinical condition in ESLD resulting from complications of cirrhosis or iatrogenic interventions. The most common iatrogenic interventions are the use of diuretics in order to cope with ascites and fluid retention, the quite often prescribed lactulose which is used in order to alter the intestinal flora, and the performance of multiple paracentesis. Last but not least, the occult or overt blood loss from esophageal and gastric varices and the intestinal lumen due to ulcerations or portal enteropathy are some of the main reasons for protein loss1
Apart from the established portal hypertensive enteropathy, other conditions such as altered intestinal flora and lesser synthesis and secretion of bile salts and pancreatic enzymes are also significant causes of nutrient loss.
Assessment of malnutrition
The need for a proper classification which would differentiate the patients with compensated and uncompensated liver cirrhosis and would classify them according to their prognosis and life expectancy has arisen some time ago. A simple and easy to memorize method is the key to a quick assessment of patients suffering from ESLD in order to plan the proper interventions and long-term follow up.
By far the easiest and globally recognized methods for assessing the clinical status and severity of disease in patients with liver cirrhosis are the Child–Pugh classification5 and the model for end stage liver disease (MELD).21–24
The Child–Pugh classification was the evolution of the Child-Turcotte classification21 which was used up to the early seventies and recognizes five factors that can affect prognosis and survival. These five factors are ascites, hepatic encephalopathy, and the levels of bilirubin, albumin and prothrombin time. Unfortunately, nutritional status, which is a well-recognized factor in affecting prognosis and survival, is not included in the Child–Pugh classification. Apart from this, the major criticism of the classification was its subjectiveness in evaluating the grade of hepatic encephalopathy or even ascites, which may lead to controversial results among different clinicians. Nevertheless, it is the most common and feasible method in categorizing cirrhotic patients.
The MELD classification is certainly more difficult to apply for every patient but it is widely used and is generally accepted among physicians.
Nevertheless, the previously mentioned methods have omitted undernutrition from their scoring systems, neglecting the fact that undernutrition and malnutrition play a major role in overall morbidity and mortality in cirrhosis. The methods which are universally used to evaluate the nutritional status and to detect the presence of malnutrition are SGA and anthropometric parameters.9
SGA is recommended by ESPEN as a practical bedside method in assessing undernourished patients and has the benefit of precluding the use of subjective measurements.9 SGA collects clinical information through history-taking and physical examination. As it entails and calculates recent weight loss or gain, it is considered reliable, as it is not affected by fluid retention or the formation of ascites.5
Apart from the data which are collected by the SGA questionnaire, the ESPEN guidelines recommend the use of simple anthropometric parameters in evaluating malnutrition which are also not affected by the presence of ascites and peripheral edema.5,9 These parameters consist of mid-arm muscle circumference (MAMC) or mid-arm circumference (MAC) and triceps skin fold thickness (TST). It is suggested, however, that they should be performed by experienced clinicians in order to avoid intra- and interobserver variabilities. Diagnosis of malnutrition is established on values of MAMC and/or TST below the 5th percentile in patients aged 18–74 years, or the 10th percentile in patients aged over 74 years.6
The need for a simpler method in evaluating malnutrition in ESLD is still a challenge. In a study by Campillo et al. the use of body mass index (BMI) proved to be a reliable parameter for the detection of malnutrition using different BMI cut-off values depending on the presence and severity of ascites.6 In particular, patients with a BMI below 22 with no ascites, 23 with mild ascites and 25 with tense ascites were considered malnourished.
Hand-grip examination by dynamometer was used by Alvares-da-Silva and Reverbel da Silveira25 as a simple method to detect malnutrition among patients with nutritional risk. By comparing their results with the standard SGA, they have concluded that hand-grip examination can be considered a reliable method and is easy to perform.
In another study by Gunsar et al. of the Royal Free Hospital in London, a modified SGA has been evaluated.5 The Royal Free Hospital-Subjective Global Assessment combines a subjective assessment of nutritional status with BMI, TST, MAMC and a subjective override26 and has proved to be significantly associated with mortality. (Fig. 1) There are, of course, more sophisticated methods for the analysis of body composition such as bioelectrical impedance analysis and dual-energy X-ray absorptiometry which are only used in special centers and are certainly not as cost-effective as the methods previously reported.
Energy and protein requirements
The primary goal for a patient suffering from ESLD should be to maintain their weight, avoid by all means possible intentional or unintentional weight loss and sustain a diet rich in macro- and micronutrients. For reasons mentioned earlier, this effort may be considered a mission impossible.
Patients with liver cirrhosis should receive 35–40 kcal/kg per day9 with a protein intake up to 1.6 g/kg per day.1,9 For those with compensated liver cirrhosis this goal can be achieved with a normal diet without any restrictions in carbohydrates, proteins or fat. In the case of uncompensated liver cirrhosis supplementary meals are often recommended and prescribed.27
According to the ESPEN consensus report in 2006,9 low-grade hepatic encephalopathy (grades I and II) is not regarded a reason for diet or protein restriction, pointing to the fact that malnutrition is certainly considered a negative prognostic factor. There is an exception, however, for those patients with severe hepatic encephalopathy (grades III and IV) who should be deprived of protein intake.1 The above negates the longstanding belief that protein intake can easily deteriorate hepatic encephalopathy. Perhaps overuse of this restriction has been, up to now, unjustified. Two recently conducted studies in Australia in New South Wales and the Australian Capital Territory have surprisingly depicted that 58% and 36%, respectively, of the dieticians questioned continued to restrict protein intake in patients with hepatic encephalopathy one year after the 2006 ESPEN guidelines.28 Apart from this, deprivation of food intake for long periods of time during hospitalization with the exceptions of variceal bleeding and severe hepatic encephalopathy should be avoided. Early enteral feeding should be started.2 Physicians should also keep in mind not to deprive patients of regular meals and should organize examinations and procedures in a way that will not keep their patients starving for long. These patients are quite often hospitalized and this risk is real.
In ESLD, the liver has lost some of its capacity to synthesize and metabolize protein, glycogen and very low-density lipoprotein (VLDL). As a consequence, the liver can no longer regulate metabolism and therefore a continuous offer of nutrients is mandatory. Owen et al. have shown that an overnight fast in cirrhotic patients has lead to a metabolic state similar to that of healthy individuals after a 3-day fast.19,20 This study is very interesting because it shows that hepatic glycogen reserves are extremely low in the affected liver and, as a consequence, an early switch to gluconeogenesis from amino acids originating from body protein is a status quo in cirrhosis. This means that in order to maintain proper body composition, the patient should receive a late evening snack to compensate for the overnight fasting period and to avoid gluconeogenesis.29–32 Regular meals are mandatory and a program with specific meals is advisable.
Energy requirements consist of 35–40 kcal/kg per day9 with a protein intake of up to 1.2–1.6 g/kg per day.1,9 This means that a 75 kg patient should ingest 2625–3000 kcal per day with approximately 90–120 g protein per day, which means that 360–480 kcal of the total amount of energy should be of protein origin. The exact amount of protein recommended depends on the severity of malnutrition and the compliance of the affected patients. Of course, the role of the physician is to lead his patient to an anabolic state.
Carbohydrates and fat
In the prescribed diets there should be no restriction on carbohydrate intake,14 even in patients that suffer from diabetes mellitus or belong to the subgroup of patients with insulin resistance. This situation is not rare. In fact, 40–50% of all patients with ESLD suffer from insulin-resistant diabetes mellitus.14,33 The exact causes differ from patient to patient with the most prominent being chronic hyperinsulinemia, an affected pancreas due to alcohol toxicity, diminished glycogen storage capacity of the liver, and impaired glucose uptake from the skeletal muscles.14 When cirrhosis reaches levels at which 80% of hepatocytes are dysfunctional, hypoglycemia is a frequent event due to hyperinsulinemia. However, correction of hypoglycemia with glucose administration can lead to resistant hyperglycemia.33
Therefore, multiple meals are required in order to provide a continuous and regulated flow of nutrients. Four to six meals containing food rich in carbohydrates are recommended.27
Further nutritional support is needed in cirrhotic patients with ongoing alcohol abuse because of the danger of hypoglycemia due to the alcohol-induced restriction in gluconeogenesis. It is important to state that alcohol abstinence should be seriously considered. Alcohol intake not only aggravates liver function but has a potential negative role in deteriorating malnutrition. Alcohol-induced anorexia, the ingestion of empty calories, and the loss of meals are some of the reasons that alcohol should be banned for life in patients with liver diseases.
An increased absorption of fat in patients with impaired liver function can aggravate the hepatic inflammation and fibrogenesis. Fat is absorbed through the portal route34 and consequently is directed to the liver. The rich offer of fat in combination with an impaired hepatic VLDL release can result in an increased hepatic fat storage and an already suffering liver cannot tolerate an excess fat inflow.
Enteral versus parenteral feeding
Another issue that should be discussed is the method of feeding cirrhotic patients who are hospitalized. Enteral nutrition via a nasogastric tube, parenteral feeding and oral intake are used in severely ill patients with ESLD. The majority of attending physicians don't initiate enteral feeding promptly on the grounds that many of the patients start spontaneous dietary intake with amelioration of general health and liver function after a few days. Oral feeding with the addition of oral supplements is generally the rule in many hospital units as far as cirrhotic patients are concerned. As was shown by the study of Campillo et al., oral dietary intake improved after a long hospital stay with oral nutritional support and the help of a dietician within a period of 2–3 weeks in the majority of patients.35
However, in severely ill patients, supplemental enteral nutrition is advisable. According to the ESPEN recommendations, patients that cannot meet their caloric requirements through oral food intake, despite adequate individualized nutritional support, are candidates for supplemental enteral nutrition. Tube feeding even in the presence of esophageal varices is suggested. In patients with ascites the use of whole protein formulae and concentrated high energy formulae is recommended. Branched chain amino acid (BCAA)-enriched formulae are used in patients with hepatic encephalopathy arising during enteral nutrition.9
When deciding between enteral or parenteral nutrition in critically ill patients the risk of repeated vomiting or diarrhea and bronchopulmonary aspiration during feeding through a nasogastric tube4 must be weighed against the complications of parenteral feeding. Septic complications and a supply of an excessive fluid load are often observed during total parenteral feeding.36
Vitamin and mineral requirements
It is not generally advised to provide supplementation of vitamins and minerals in patients with ESLD, but, at times, emerging complications of deficiencies in various minerals and vitamins justify individualized nutritional support. Therefore, the prescription of supplements in the presence of clinical symptoms of various deficiencies is indicated.14
One of the most common complications of ESLD is osteoporosis. In particular, patients with risk factors such as previous smoking habits, older age and a history of fractures are candidates for supplementation. Prescription of 1200–1500 mg calcium and 400–800 IU vitamin D, especially in patients with cholestasis, is advised. In the presence of osteoporosis the addition of biphosphonates is also recommended.14 Lack of vitamin A results in nyctalopia and dry cornea and so the use of 100.000–200.000 IU every 4 weeks is advisable.14
Supplementation of vitamin K in conditions with high risk of bleeding such as the presence of impaired prothrombin time and esophageal varices is quite often the case. Parenteral administration of 10 mg vitamin K every 4 weeks is recommended.14
A diet low in sodium of less than 2–3 g NaCl/day is generally advised in ESLD among patients with ascites and fluid retention. These diets often fail due to the lack of compliance among the affected patients, as they omit numerous food categories and are difficult to follow.
According to the nutritional guidelines of the ESPEN consensus report, the use of supplemental enteral nutrition is advisable when patients cannot meet their caloric requirements through food intake despite individualized nutritional advice. If cirrhotic patients are not able to maintain adequate oral intake from food, the use of oral nutritional supplements or tube feeding is required. The use of whole protein formulae in malnourished patients and the intake of more concentrated high-energy formulae in patients with ascites are recommended.9 A more novel approach to malnutrition is the ongoing use of BCAA-enriched nutrient mixtures in patients with hepatic encephalopathy arising during enteral nutrition or, in general, in patients with advanced cirrhosis.9 Oral BCAA formulae contain isoleucine, leucine and valine amino acids and nutrients such as glucose and lipids, offering a rich essential nutrients meal.27
Several studies have investigated the benefits of the addition of BCAA in the recommended oral diets in ESLD. The results are controversial,34 but the majority of authors tend to recognize that BCAA can improve the clinical outcome if prescribed to patients with established nutritional deficit.9,27,37
The first and most well-accepted clinical condition in which BCAA are recommended is in patients with hepatic encephalopathy with intolerance to enteral protein as it is stated in the ESPEN guidelines. The exact role of BCAA in patients with hepatic encephalopathy can be explained by their pathophysiological role in the blood–brain barrier. The brain uptake of tryptophan in patients with hepatic encephalopathy is increased due to the decreased ratio of endogenous BCAA/tryptophan in cirrhosis. The actual cause of this is the effect of hyperinsulinemia and the decreased postabsorptive removal of non-BCAA by the affected liver. As BCAA compete with tryptophan for the same amino acid transporter in the blood–brain barrier, the decreased ratio leads to an easier passage of tryptophan in the brain circulation.38,39
A study that was designed to prove the efficacy of BCAA in protein-intolerant patients with hepatic encephalopathy has enrolled patients who could not ingest more than 40 g protein without deterioration of hepatic encephalopathy. They were given 70 g protein either in the form of casein or BCAA supplement. A deterioration of encephalopathy was observed in almost half of the patients in the casein group and in only one in the BCAA group.40 This study gives basis to the ESPEN recommendations about the use of BCAA formulae.
BCAA have an additional role in energy metabolism. They are not only used as substrates in protein synthesis but they regulate protein synthesis and consequently keep the skeletal muscles intact. The long-term use of BCAA in liver cirrhosis leads to an increase of serum protein of approximately 10% if given before bedtime.38
In liver cirrhosis the increased prevalence of hyperinsulinemia leads to an increase uptake of endogenous BCAA by skeletal muscle for use as energy substrates.41,42 BCAA are also the source of ammonia degradation in the skeletal muscles of the patients. As a consequence, low levels of circulating BCAA result in the destruction of skeletal muscles and the impaired synthesis of protein. One can easily draw the conclusion that supplementing BCAA through oral intake helps energy metabolism of cirrhotic patients to shift from catabolic to anabolic.
In a study conducted by Nakaya et al., the long-term use of BCAA mixtures has proved more beneficial than a late evening snack in terms of improving the serum albumin levels and the metabolic state in cirrhotic patients.27 In particular, the investigators have concluded that the catabolic state of their patients has improved and the prevalence of anorexia has decreased, but the study failed to establish an overall improvement in the quality of life of the patients that were enrolled in the study. Unfortunately, non-compliance and withdrawals from the study were attributed to the bad taste of the supplements.
In another study, treatment with BCAA has proved to reduce average hospital admission rates, stabilize or even better improve nutritional parameters, liver function tests, quality of life and anorexia. In the same study, the Child–Pugh score in several patients decreased.37 The unpalatability of the formulae was the main reason for the poor long-term compliance. For this reason, the use of BCAA supplements are not widely used because some physicians avoid prescribing an expensive and bad-tasting therapy in their patients before receiving more evidence of their benefit.
In both studies, BCAA were given before bedtime in order to help patients avoid the catabolic state of the overnight fasting period, providing them with the proper nutrients. Furthermore, it is already established that nocturnal BCAA administration may stimulate hepatic albumin synthesis.27 On the contrary, when used during the daytime27 or twice a day (after breakfast and at night)43 the majority of BCAA are used for energy formation and not for albumin synthesis with a clearer benefit of the late-night administration.
Over the past years, the role of nutrition as one of the most important factors that can influence overall mortality and morbidity in ESLD has been well understood and appreciated. Without any doubt, liver cirrhosis drives the patients to a catabolic state depriving them of essential nutrients through mechanisms that need to be well understood by attending physicians so that proper actions are taken. Identifying the patients that are approaching the state of malnutrition by simple and easily applied methods is necessary in order to provide nutritional support to those that need it the most. Correction of the nutrient deficit can improve the clinical outcome. Therefore, nutritional advice by dieticians and supplementation of nutrients through oral feeding, enteral feeding, and/or administration of specially designed formulae should be undertaken. The use of BCAA formulae in protein-intolerant patients and in severe cases of malnutrition has given hope, despite the dispute over them.