Metabolic changes in cirrhosis

Figure 4.6.1 shows the major metabolic changes that occur in a person with cirrhosis and the connections between them.

Malnutrition in liver disease has been called a ‘glycogen storage disease’ as even in the fed state, glycogen stores remain low [14]. Hepatic glycogenolysis is also impaired, making glycogen a less suitable fuel for cirrhotic patients. To maintain blood glucose concentrations in the short term when there has been no recent intake of carbohydrate, there is an increase in gluconeogenesis from amino acids, resulting in protein depletion [15]. Petersen et al. compared gluconeogenesis and glycogenolysis rates in cirrhotic subjects and matched healthy controls using nuclear magnetic resonance spectroscopy and ²H₂O and found that they had similar rates of glucose production but the cirrhotic subjects had an increased rate of gluconeogenesis and decreased rate of glycogenolysis compared to the control subjects [16]. Fat is also used as an alternative fuel source [17]. However, the fat oxidation rates do return to normal after refeeding [18].

Using indirect calorimetry, the percentage of total energy from fat, carbohydrate and protein in control subjects after a 36–72-h fast were comparable to those found in cirrhotic patients after an overnight fast (10–12 h) [19]. These proportions were significantly different from overnight fasted control subjects. This indicates that cirrhotic patients reach a fasted state much more rapidly than healthy controls; cirrhosis has been termed a disease of accelerated starvation. Increased endogenous protein breakdown leads to increased protein turnover. However, the protein resynthesis rate does not increase and the capacity of the cirrhotic liver to synthesise and store proteins is reduced, leading to muscle wasting. The mechanism of this hypermetabolism is unclear but is thought to be extrahepatic as it persists for over a year following liver transplantation [20].

Not all cirrhotic patients are hypermetabolic; those that are have a similar percentage of muscle mass as normometabolic cirrhotic patients, but a reduced body cell mass [8]. They also have raised serum cytokines, indicating a potential role for the inflammatory response in the hypermetabolic state. Greco et al. showed hypermetabolism, increased lipid oxidation rates and insulin resistance after an overnight fast in Childs B cirrhotic patients when compared to matched healthy controls [20a]. The Body Mass Index (BMI), fat free mass and fat mass of the patients were not statistically significantly different from the healthy controls, suggesting that metabolic changes precede weight loss rather than being a consequence of it.

Muscle wasting can be a major feature of cirrhosis but with skilled nutritional assessment and therapy this can be prevented.

Nutritional assessment

Undernutrition can be present in the early stages of liver disease but is not always readily evident, especially in people who are overweight. Detailed nutritional assessment is needed to identify people who are undernourished or at risk of becoming so. Accurate assessment of nutritional status can be particularly difficult in patients with cirrhosis due to altered fluid homeostasis. Traditional nutritional assessment methods and nutrition screening tools are often based on weight and BMI changes but more specific measures of nutritional status are required for this patient group.

Nutritional assessment would include a review of symptoms, medical history, social history, assessment of body composition, biochemistry, detailed dietary intake and fluid restrictions. Symptoms such as nausea, anorexia, pain, fatigue and encephalopathy can reduce nutritional intake, as can any fluid restrictions. While constipation can lead people to be more likely to experience encephalopathy, diarrhoea reduces the absorption of nutrients and can also lead people to be less inclined to eat. Medical history including co-morbidities such as renal failure, hepatopulmonary syndrome or diabetes will potentially have an impact on patient nutritional status as well as the dietary counselling given. A person’s social situation including financial situation, living conditions, alcohol and illicit drug use will have an impact on their nutritional status. Changes in a patient’s liver function tests can give an indication of an improvement or decline in their condition; it is important to monitor electrolytes in potential refeeding syndrome patients and biochemistry can also be used to monitor conditions such as renal failure.

When taking a diet history, it is particularly important to note the pattern of nutritional intake as well as the nutritional content and portion sizes, looking out for the frequency and amount of carbohydrate and protein consumed in particular. As with any other patient group, it is important to take into account patient preferences and tolerances, daily pattern of activities and any concerns they have.

Upper arm anthropometry

Upper arm anthropometry, mid arm circumference (MAC), triceps skinfold thickness (TST) and mid arm muscle circumference (MAMC) are used in the clinic or ward setting to differentiate between fat and muscle stores. These measurements indicate a patient’s nutritional status compared to an expected population. Serial measurements in one patient every 3–8 weeks are most useful as body fat has to change by several kg before it is detectable by skinfold measurements [21]. It is important to be aware of inter- and intraobserver error. Reliability and accuracy can be improved by standardising the observer’s technique or by undertaking specialist anthropometry training.

Hand grip strength

Hand grip strength is measured using a dynamometer and is a measure of muscle function. Low handgrip strength has been shown to be a predictor of complications and poor clinical outcome in patients with cirrhosis [22]. Patients’ handgrip strength changes more rapidly than the measured change in muscle bulk and can be assessed weekly if required.

Nutrition screening

Tools that incorporate information from several sources to a patient in a structured way can be particularly helpful. The Royal Free Hospital Global Assessment (RFH-GA) which uses BMI (calculated using estimated dry body weight), MAMC, dietary intake and symptoms in an algorithm [23] has very good intra- and interobserver reproducibility and is validated in this patient group [24]. Accurate use of this assessment requires specialist training and can take an hour to complete. The Royal Free Hospital Nutritional Prioritising Tool (RFH-NPT) has recently been developed and validated. This has very good intra- and interobserver reproducibility, with a diagnostic sensitivity of 100% and specificity of 73% [25]. It takes 2–3 min and little training to complete but gives a less detailed assessment than the RFH-GA. This tool includes the presence/absence of ascites and/or oedema with different subsequent questions depending on this answer.

Dry weight

Table 4.6.2 can be used to estimate the weight of fluid and therefore to calculate dry weight. The estimated weight of ascites and peripheral oedema is subtracted from the patient’s ‘wet weight’. Patients may have ascitic volumes larger than 14 kg. Even in patients with no ascites or oedema, weight alone is a crude measure of nutritional status as it does not distinguish between fat and muscle stores. For patients with ascites who have regular paracentesis, it is useful to monitor how much fluid is removed during each paracentesis session, how much fluid is remaining after paracentesis, a typical postparacentesis weight and the duration since the last paracentesis, to individualise estimates of dry body weight.

Nutritional requirements

When gluconeogenesis rather than glycogenolysis is used to maintain hepatic glucose release there is an increase in both resting energy expenditure (REE) and protein requirements [19,27]. Gluconeogenesis uses more energy than glycogenolysis and requires amino acids as substrates, therefore both energy and protein requirements for cirrhotics are increased. People with liver disease can replete their stores with increased intakes [28,29]. The European Society of Parenteral and Enteral Nutrition (ESPEN) guidelines aim for 25–40 kcal/kg body weight but whether dry, actual or ideal body weight is used is not agreed (Table 4.6.3) [30]. If a patient is undernourished, unless they are overtly critically ill or septic, the addition of an extra 400–1000 kcal per day is encouraged to promote repletion of stores.

Protein stores of lean body mass (LBM) are depleted by the use of amino acids for glucose generation, therefore extra dietary protein is required to maintain and replete LBM. Swart et al. used radiolabelled [15 N]glycine to investigate rates of nitrogen flux, protein synthesis and protein breakdown in people with cirrhosis and healthy controls and suggested that cirrhotic patients require an increase in nitrogen intake to achieve a positive nitrogen balance due to their increase in gluconeogenesis [29]. Protein requirements are calculated based on the patient’s estimated dry weight and are shown in Table 4.6.3.

Patients, particularly if at home and mobile, may need to increase their intake beyond these calculated requirements in order to replete or maintain their muscle stores. It is important to monitor their nutritional status regularly and adjust their dietary recommendations accordingly.

In obese patients, protein and energy requirements are adjusted to account for increased body mass with a likely reduced percentage of metabolically active tissue. In the UK, protein and energy requirements are reduced by 25% and 400–1000 kcal per day respectively. When making any such adjustments, it is important that patients are regularly monitored so any decline in nutritional status can be identified and mitigated. Preservation of muscle function and a patient’s fitness take priority over any aim to reduce fat mass. ESPEN guidelines do not give guidance specifically for obese liver patients.

Fluid requirements are rarely estimated from predetermined calculations but assessed on an individual basis and dependent on the patient’s fluid status.

Disease-related anorexia and intake

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