Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is an autoimmune liver disease that mostly affects women. A progressive disorder in the processes of bile secretion and enterohepatic bile salts circulation in patients with PBC already in its early stages, leading to an insufficient release of bile acids into the bowel and their entry into the systemic circulation. Insufficient bile acids released into the duodenum contributes to the development of malabsorption, energy malnutrition, and slowly progressive weight loss. The pathophysiological mechanisms of weight loss and its slow progression are associated with the deterioration of the fat emulsification processes and with the reduced absorption of hydrolyzed products, such as fatty acids and monoglycerides, with steatorrhea in patients with PBC, as well as in those with gut dysbiosis. Just in the early stages of the disease, this results in accelerated fatty acid β-oxidation that is aimed at compensating for progressive energy malnutrition. The entry of bile acids into the systemic circulation in PBC is accompanied by dyslipidemia. The mechanism of hyperlipidemia in patients with PBC differs from that in other conditions because along with an increase in total cholesterol (TC), there are elevated high-density lipoprotein levels and the appearance of unusual lipoprotein X (Lp-X). The appearance of Lp-X is most likely to be the body's protective reaction to inactivate the detergent effect of bile acids on the membrane structures of blood corpuscles and vascular endothelial cells. It is bile acids, rather than TC levels, that correlate with the content of Lp-X and determine its formation. Concomitant hypercholesterolemia in patients with PBC is also aimed at neutralizing the detergent effect of bile acids that have entered the systemic circulation and is most likely a compensatory reaction of the body. "Anomalous" hypercholesterolemia in PBC can serve as a model system for the search and development of new methods for the treatment of dyslipidemia since it occurs without an increase in the incidence of cardiovascular events.

N-nitroso compounds (NOCs) are among the most potent dietary carcinogens. N-nitrosodiethylamine (NDEA), N-nitrosodimethylamine (NDMA), and N-nitrosopiperidine (NPIP) are abundant in foods and carcinogenic to the liver. We investigated the relationship between dietary NOCs and HCC risk.

In this large, hospital-based, case-control study of 827 pathologically or radiologically confirmed HCC cases and 1,013 controls, NOC intake was calculated by linking food frequency questionnaire-derived dietary data with a comprehensive NOC concentration database. Multivariable-adjusted ORs and 95% CIs of HCC by quartiles of NOC consumption were estimated using logistic regression models, with the lowest quartile as the referent. We further investigated joint effects of consuming the highest quartile of NOCs that were associated with increased HCC risk and hepatitis, diabetes, or alcohol drinking on HCC risk. After adjustment for confounding factors, higher intake of NDEA from plant sources (ORQ4 vs. Q1  = 1.58; 95% CI = 1.03-2.41), NDMA from plant sources (ORQ4 vs. Q1  = 1.54; 95% CI = 1.01-2.34), and NPIP (ORQ4 vs. Q1  = 2.52; 95% CI = 1.62-3.94) was associated with increased HCC risk. No association was observed for nitrate or total NOC intake and HCC risk. Higher consumption of HCC-inducing NOCs and positive hepatitis virus status jointly increased the risk of developing HCC.

In conclusion, though some of our findings may indicate the presence of reverse causation owing to lower meat intake among cases with chronic liver diseases before HCC diagnosis, the potent dietary HCC carcinogens, NDEA, NDMA, and NPIP, and their enhanced carcinogenic effects among chronic carriers of hepatitis virus warrant further prospective investigation.

Acute post liver transplant (LT) phase is characterized by hypermetabolism and increased nutrient requirements. This study aimed to provide the cardinal data on nutrition progression in the management of acute post-LT patients.

This exploratory study recruited 54 adult acute post-LT recipients. The information regarding patient stay, weight status, biochemical parameters, and route of feeding was gathered. Recipients' dietary and nutrient intake was computed by 24-h dietary recall method.

The data exhibited a significant trend of lower hemoglobin, platelet, and albumin levels and increased bilirubin (T), alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase levels (P < 0.05). In acute post-LT patients, a significant decrease in weight status (P < 0.001*) was observed. The recipients' information on daily nutrition progression showed significantly lower intake of calorie, protein, fats, calcium (P < 0.05) and lower percentage adequacy of other nutrients as compared to the recommended guidelines. The energy and protein intake from the parenteral route of feeding significantly decreased and that of through oral route significantly increased (P < 0.05) from postoperative day (POD) 2 to POD 9 and POD 12.

There are scant data on nutrition management in acute post-LT phase. The present study provides the framework for the formulation of continuous, patient-centric, aggressive nutrition management interventions for acute post-LT recipients.

Measuring physical activity in people with rheumatoid arthritis (RA) is of great importance in light of the increased mortality in this population due to cardiovascular disease. Validation of activity monitors in specific populations is recommended to ensure the accuracy of physical activity measurement. Thus, the purpose of this study was to determine the validity of the SenseWear Pro3 Armband (SWA) as a measure of physical activity during activities of daily living (ADL) in people with RA.

Fourteen subjects (8 men and 6 women) with a diagnosis of RA were recruited from rheumatology clinics at the Mid-Western Regional Hospitals, Limerick, Ireland. Participants undertook a series of ADL of varying intensities. The SWA was compared to the criterion measures of the Oxycon Mobile indirect calorimetry system (energy expenditure in kJ) and of manual video observation (step count). Bland and Altman, intraclass correlation coefficient (ICC), and correlation analyses were done using SPSS, version 19.0.

The SWA showed substantial agreement (ICC 0.717, P < 0.001) and a strong relationship (Pearson's correlation coefficient = 0.852) compared with the criterion measure when estimating energy expenditure during ADL. However, it was found that the SWA overestimated energy expenditure, particularly at higher intensity levels. The ability of the SWA to estimate step counts during ADL was poor (ICC 0.304, P = 0.038).

The SWA can be considered a valid tool to estimate energy expenditure during ADL in the RA population; however, attention should be paid to its tendency to overestimate energy expenditure.

Infants with cholestatic liver disease are at risk of various nutritional deficiencies. They require regular review with appropriate interventions to prevent complications and ensure optimum possible status if liver transplantation becomes necessary. We propose evidence based and internationally agreed guidelines for their care with recommendations for therapeutic strategies and for service organization.

A subgroup of cirrhotic patients develop hypermetabolism, possibly mediated by increased sympathetic nervous system activity and increased cardiac output. The effect of hypermetabolism on prognosis in patients with cirrhosis has not been elucidated.

Resting energy expenditure (REE) was measured using indirect calorimetry in 256 cirrhotic patients with different etiologies and disease severity (165 men, 91 women; median age 49 y, age range 16-73 y; median model for end-stage liver disease [MELD] score 13, range 6-36; median Child-Pugh score 8, range 5-15). Measured and predicted values were compared using equations based on fat-free mass, total body protein (measured by neutron activation analysis), and the Harris-Benedict equations. Competing-risks Cox's proportional hazards analysis was performed to evaluate the influence of hypermetabolism and MELD or Child-Pugh scores on risk of death or liver transplantation.

Median follow-up was 49 mo (range 1-90 mo). Hypermetabolic patients had decreased transplant-free survival compared with non-hypermetabolic patients (9.7 versus 31.8 mo, P = 0.05). Increased REE, even within the normal range, was also associated with worse transplant-free survival (P = 0.001). Hypermetabolism was predictive of transplant-free survival independent of MELD and Child-Pugh scores (hazard ratio 1.19, 95% confidence interval 1.08-1.32, P = 0.0008; hazard ratio 1.13, 95% confidence interval 1.10-1.16, P < 0.0001; hazard ratio 1.38, 95% confidence interval 1.29-1.48, P < 0.0001; respectively). Patients on beta-blockers were more likely to be normometabolic (P = 0.035).

We found an inverse relation between REE and transplant-free survival in a large heterogeneous group of cirrhotic patients.

Most techniques for measuring body composition are based on 2-component models (2-CMs) and depend on assumptions relating to the constancy of the density (D(FFM)) and hydration fraction (HF(FFM)) of fat-free mass (FFM).

The objectives were to determine whether these assumptions are systematically violated in patients with cirrhosis and to assess the validity of the estimates of body composition obtained in these patients by using 2-CM techniques.

Body composition was assessed by using a 4-component model (4-CM), which was based on data obtained from densitometry, deuterium dilution, and dual-energy X-ray absorptiometry, in 20 patients with cirrhosis who had no evidence of fluid retention and in 20 pair-matched healthy control subjects. The results were compared with those obtained by using "reference" and "bedside" 2-CM techniques.

The mean (+/-SD) D(FFM) was significantly lower in the patients with cirrhosis (1.091 +/- 0.008 compared with 1.100 +/- 0.006 kg/L; P < 0.001); no significant difference in HF(FFM) was observed between the patients and control subjects (74.5 +/- 2.6 compared with 73.5 +/- 2.1), although there was greater variability in the patients. Significant differences were observed in the body-composition variables obtained by using the "reference" 2-CM techniques compared with the 4-CM-the 95% limits of agreement in the patients with cirrhosis exceeded 5% body fat and 3 kg FFM; the corresponding values for the "bedside" 2-CM techniques were 11% body fat and 7.5 kg FFM.

Assumptions relating to the constancy of the D(FFM) and HF(FFM) are violated in patients with cirrhosis. Thus, standard 2-CM techniques provide inaccurate body composition estimates in this patient population.

Malnutrition is common in liver cirrhosis patients. However, it is under-diagnosed because liver disease affects the traditional nutritional assessment. An understanding of changes in body composition and the establishment of the tissue-loss pattern in liver cirrhosis patients could help practitioners to better manage malnutrition in this setting. The aims of this study were: to quantify body composition changes, to determine tissue loss pattern, and to assess the relation of these to the severity of hepatic dysfunction.

Seventy-nine patients and 17 controls were studied. Total body water and extracellular water were measured using dilution techniques. Intracellular water and body cell mass were calculated from these parameters. Total body fat was obtained using absorptiometry.

Extracellular water was increased and intracellular water was decreased in patients. The two major compartments (body cell mass and body fat) were significantly reduced, mainly in patients with moderate and severe disease. However, significant losses occurred even in Child-Pugh class A patients. We established a tissue-loss pattern. In Child-Pugh class A patients body fat loss predominated. Child-Pugh class B patients had losses in at least one of the two compartments. Most Child-Pugh class C patients had simultaneous depletion in both compartments.

Liver cirrhosis was characterized by a significant reduction in body cell mass and body fat and by a redistribution of body water. Significant losses occurred even in patients with mild disease. There was a more pronounced loss of fat in the initial stages, followed by an accelerated loss of body cell mass in the advanced stages of liver cirrhosis.

To search for changes in body composition and energy metabolism associated with the repeatedly observed weight gain of cirrhotic patients after portosystemic shunting.

Twenty-one patients were studied prospectively before and 6 and 12 months after transjugular intrahepatic portosystemic shunt (TIPS) to assess body cell mass by two independent methods (total body potassium counting: body cell mass determined by TBP, BCMTBP, bioelectric impedance analysis: body cell mass determined by BIA, BCMBIA), muscle mass (anthropometry), resting energy expenditure (REECALO) by indirect calorimetry, and nutritional intake by dietary recall analysis.

Prior to TIPS patients were hypermetabolic in terms of measured vs. predicted REE (REECALO median 1423 (range 1164-1838) vs. REEPRED 1279 (1067-1687) kcal; P<0.05) and their body cell mass was lower (19.1 (10.9-33.4) vs. 31.7 (16.8-47.1) kg; P=0.001). After TIPS body cell mass (BCMBIA) increased to 23.5 (12.7-44.3) (P<0.025) and 25.7 (14.2-39.7) kg (P=0.05) at 6 and 12 months after TIPS and this was confirmed by total potassium counting (BCMTBP before TIPS: 18.8 (10.6-26.7) vs. 22.4 (12.9-28.5) kg at 6 months; P<0.01). Hypermetabolism persisted throughout the study period. Energy and protein intake increased significantly by 26 and 33%.

An increase of prognostically relevant variables body cell and muscle mass contributes to the weight gain after TIPS in malnourished patients with cirrhosis and hypermetabolism.

Patients with chronic liver disease exhibit a progressive loss of fat and muscle mass leading to mixed protein-energy malnutrition. The severe loss of muscle mass and body cell mass have convincingly been shown to carry a grave prognosis. Cachexia is likely to progress due to increased requirements as a consequence of hypermetabolism on the one hand and reduced volitional food intake and malabsorption on the other. Hypermetabolism may be mediated by factors such as frequent episodes of endotoxinemia, an activation of the inflammatory cytokine and/or the beta-adrenergic system. Some of these factors may also be responsible for reduced appetite. Obviously, these mechanisms may also be operative in other disease entities but clearly, portal hypertension and portosystemic shunting pose the cirrhotic patient at a particular risk for such disturbances including that of malabsorption. Apart from the established value of providing sufficient nutritious substrate to meet requirements the use of beta-adrenergic blocking agents and endotoxinemia lowering strategies seem worthwhile options that merit further clinical evaluation.

To quantify the sequential changes in the metabolic response occurring in patients with end-stage liver disease after orthotopic liver transplantation (OLT).

Detailed quantification of the changes in energy expenditure, body composition, and physiologic function that occur in patients after OLT has not been performed. Understanding these changes is essential for the optimal management of these patients.

Fourteen patients who underwent OLT for end-stage liver disease had measurements of resting energy expenditure, body composition, and physiologic function immediately before surgery and 5, 10, 15, 30, 90, 180, and 360 days later.

Resting energy expenditure was significantly elevated after surgery (24% above predicted), peaking around day 10 after OLT, when it averaged 42% above predicted. A significant degree of hypermetabolism was still present at 6 months, but at 12 months measured resting energy expenditure was close to predicted values. Before surgery, measured total body protein was 82% of estimated preillness total body protein. During the first 10 days after OLT, a further 1.0 kg (10%) of total body protein was lost, mostly from skeletal muscle. Only 54% of this loss was restored by 12 months. Significant overhydration of the fat-free body was seen before OLT, and it was still present 12 months later. Although significant losses of body fat and bone mineral occurred during the early postoperative period, only body fat stores were restored at 12 months. Both subjective fatigue score and voluntary hand grip strength improved rapidly after OLT to exceed preoperative levels at 3 months. At 12 months grip strength was close to values predicted for these patients when well. Respiratory muscle strength improved less markedly and was significantly lower than predicted normal levels at 12 months.

Before surgery, these patients were significantly protein-depleted, overhydrated, and hypermetabolic. After surgery, the period of hypermetabolism was prolonged, restoration of body protein stores was gradual and incomplete, and respiratory muscle strength failed to reach expected normal values. Our measurements indicate that OLT does not normalize body composition and function and imply that a continuing metabolic stress persists for at least 12 months after surgery.

Protein-calorie malnutrition is associated with poor prognosis in chronic liver disease, but reliable assessment is hampered by changes in body water. We prospectively evaluated the effect of fluid retention on bioelectrical impedance analysis (BIA) as a simple method for the estimation of body cell mass (BCM(BIA)) in 41 patients with cirrhosis (n = 20 with ascites; n = 21 without ascites) using total body potassium counting (BCM(TBP)) as a reference method. Arm muscle area and creatinine-derived lean body mass were compared with total body potassium data. In patients total body potassium was 24.4% lower than in controls and this loss was more severe in patients with ascites (-34.1%; P<.01). BCM(BIA) and BCM(TBP) were closely correlated in controls (r(2) =.87, P<.0001), patients without ascites (r(2) =.94, P <.0001) and patients with ascites (r(2) =.56, P<.0001). Removal of 6.2 +/- 3 L of ascites had only minor effects on BCM(BIA) (deviation of -0.18 kg/L ascites). Limits of agreement between both methods were wider in patients with ascites than in patients without (6.2 vs. 4.2 kg). In patients without ascites arm muscle area (r(2) =.64; P<.001) and lean body mass (r(2) =.55; P<.001) correlated significantly with total body potassium, but not in patients with ascites. For assessment of protein malnutrition in patients with cirrhosis, body cell mass determination by use of BIA offers a considerable advantage over other widely available but less accurate methods like anthropometry or the creatinine approach. Despite some limitations in patients with ascites, BIA is a reliable bedside tool for the determination of body cell mass in cirrhotic patients with and without ascites.

Poor nutritional status is common among patients awaiting orthotopic liver transplantation and is associated with poor outcome.

This prospective randomized controlled trial examined the effect of pretransplant nutritional supplementation on the outcome of patients undergoing liver transplantation. Of 82 consecutive patients with mid-arm muscle circumference <25th percentile, 42 received enteral supplementation, and the remainder acted as the control group. The supplemented group received a calorie-dense enteral feed taken daily (in addition to diet) until transplantation. Nutritional status was monitored by upper arm anthropometric measurements and handgrip strength. Dietary intake was calculated from 5-day food diaries.

Supplementation improved mid-arm circumference, mid-arm muscle circumference, and grip strength. Pretransplant nutritional status was not associated with posttransplant sepsis or major complications. Preoperative grip strength of <85% of normal values was predictive of increased incidence of posttransplant major complications. Supplementation did not affect outcome, although there were more deaths in the control group (seven deaths before and two deaths after transplant) than there were in the supplemented group (two deaths before and three deaths after transplant). There was no difference in overall survival (P = 0.075).

Enteral supplementation improved some parameters of nutritional status pretransplant. Dietary intake of patients in the two groups was similar at transplant. Nutritional supplementation has not increased nutritional intake, although this may reflect the importance of regular dietetic input and support, rather than suggesting that nutritional supplementation is ineffective. Supplementation had no effect on outcome of liver transplantation.

Measurements of resting energy expenditure (REE) can be used to determine energy requirements. Prediction formulae can be used to estimate REE but have not been validated in cirrhotic patients. REE was measured, by indirect calorimetry, in 100 cirrhotic patients and 41 comparable healthy volunteers, and the results compared with estimates predicted using the Harris-Benedict, Schofield, Mifflin, Cunningham, and Owen formulae, and the disease-specific Müller formula. The mean (+/- 1 SD) measured REE in the healthy volunteers (1,590 +/- 306 kcal/24 h) was significantly greater than the mean Harris-Benedict, Mifflin, Cunningham, and Owen predictions but comparable with the mean Schofield prediction; individual predicted values varied widely from measured values (95% limits of agreement, -460 to +424 kcal). The mean measured REE in the cirrhotic patients was significantly greater than in the healthy volunteers (23.2 +/- 3. 8 cf 21.9 +/- 2.9 kcal/kg/24 h; P <.05). The mean measured REE in the cirrhotic patients (1,660 +/- 337 kcal/24 h) was significantly different from mean predicted values (Harris-Benedict, 1,532 +/- 252 kcal/24 h, P <.0001; Schofield, 1,575 +/- 254 kcal/24 h, P <.0005; Mifflin, 1,460 +/- 254 kcal/24 h, P <.0001; Cunningham, 1,713 +/- 252 kcal/24 h, P <.05; Owen, 1,521 +/- 281 kcal/24 h, P <.0001; Müller, 1,783 +/- 204 kcal/24 h, P <.0001); individual predicted values varied widely from measured values (95% limits of agreement, -632 to +573 kcal). Simple regression analysis showed that fat-free mass (FFM) was the strongest predictor of measured REE in the cirrhotic patients, accounting for 52% of the variation observed. However, a population-specific prediction equation, derived using stepwise regression analysis, which incorporated FFM, age, and Pugh's score, accounted for only 61% of the observed variation in measured REE. REE should, therefore, be measured in cirrhotic patients, not predicted.

Malnutrition and micronutrient deficiencies are common in patients with liver diseases. The pathogenesis of protein-energy malnutrition in cirrhosis involves many factors, including poor oral intake, malabsorption, and metabolic abnormalities similar to stress. Encephalopathy may complicate cirrhosis but is usually not caused by diet. Protein restriction is only necessary in rare patients with refractory encephalopathy. The use of branched-chain amino-acid solutions is not supported by the literature. Chronic liver diseases without cirrhosis are not usually associated with protein-energy malnutrition, but vitamin and mineral deficiencies are common, especially with significant cholestasis. Fatty liver may result from excessive triglyceride uptake and production by the liver or by a secretory defect. Therapy for fatty liver depends on its cause. Chronic total parenteral nutrition may induce fatty liver and inflammation especially in patients with short-bowel syndrome. Deficiency of choline in parenteral nutrition has been proposed as the mechanism for liver disease. Acute liver diseases such as fulminant hepatic failure or alcoholic hepatitis are considered hypercatabolic diseases and thus require prompt nutritional intervention with a high-calorie enteral or parenteral formula. In fulminant hepatic failure, low-protein, fluid-restricted formulas are recommended.

Hypermetabolism has a negative effect on prognosis in patients with liver cirrhosis. Its exact prevalence and associations with clinical data, the nutritional state, and beta-adrenergic activity are unclear.

We investigated resting energy expenditure (REE) in 473 patients with biopsy-proven liver cirrhosis.

This was a cross-sectional study with a controlled intervention (beta-blockade) in a subgroup of patients.

Mean REE was 7.12 +/- 1.34 MJ/d and correlated closely with predicted values (r = 0.70, P < 0.0001). Hypermetabolism was seen in 160 patients with cirrhosis (33.8% of the study population). REE was > 30% above the predicted value in 41% of the hypermetabolic patients with cirrhosis. Hypermetabolism had no association with clinical or biochemical data on liver function. REE correlated with total body potassium content (TBP; r = 0.49, P < 0.0001). Hypermetabolic patients had lower than normal body weight and TBP (P < 0.05). About 47% of the variance in REE could be explained by body composition whereas clinical state could maximally explain 3%. Plasma epinephrine and norepinephrine concentrations were elevated in hypermetabolic cirrhotic patients (by 56% and 41%, respectively; P < 0.001 and 0.01). Differences in REE from predicted values were positively correlated with epinephrine concentration (r = 0.462, P < 0.001). Propranolol infusion resulted in a decrease in energy expenditure (by 5 +/- 3%; P < 0.05), heart rate (by 13 +/- 4%; P < 0.01), and plasma lactate concentrations (by 32 +/- 12%; P < 0.01); these effects were more pronounced in hypermetabolic patients (by 50%, 33%, and 68%, respectively; each P < 0.05).

Hypermetabolism has no association with clinical data and thus is an extrahepatic manifestation of liver disease. Increased beta-adrenergic activity may explain approximately 25% of hypermetabolism.

Nutritional intake in the patient with hepatobiliary disease provides the cornerstone of balanced medical care. Optimal recommendations require consideration of general nutritional principles, special species requirements and contemporary needs uniquely related to the patient's medical problem. Although general recommendations follow well-established guidelines developed to meet metabolic requirements for normal health, there is little information regarding altered requirements in animals that are ill. Consequently, recommendations for animals have been derived empirically from studies completed in humans, most work having been done in patients with end stage cirrhosis or liver failure complicated by hepatic encephalopathy. This is problematic because most veterinary patients with liver disease are not in hepatic failure and do not suffer from hepatic encephalopathy. Iatrogenic malnutrition can develop in patients when protein-restricted diets are inappropriately recommended. Insufficient energy intake and negative nitrogen balance can complicate a patient's condition, impairing tissue regeneration and recovery from disease. This paper reviews strategies that can be used to individualize nutritional management in small companion animals with hepatobiliary disease. Consideration is given to both the known and controversial issues regarding energy requirements, dietary energy distribution, vitamin and micronutrient supplementation, the special requirements of the cat with hepatic lipidosis, as well as strategies effective for palliation of hepatic encephalopathy.

In order to ascertain whether malnutrition is an early-onset feature of liver cirrhosis and whether the anabolic hormone insulin-like growth factor I (IGF-I) could be useful in the treatment of this complication, we analyzed the nutritional alterations present in rats with early-stage liver cirrhosis and the effects of IGF-I on nutritional parameters in these animals.

After a 24 h fast, a 15N-enriched diet was administered for 5 days to normal control rats and to cirrhotic rats receiving subcutaneous injections of vehicle (Group 1) or IGF-I, 2 micrograms.100 g bw-1.day-1, (Group 2) during the 5 experimental days. 15N, a stable N isotope, was measured in biological samples by mass spectrometry.

Compared with control rats, Group 1 animals showed significant reductions in N intake and food efficiency (p < 0.05, both). In addition, the weight of the gastrocnemius muscle, its total N content and the dietary N content of this muscle were significantly lower in Group 1 than in control animals (p < 0.05, all). In rats from Group 2, mean values of N intake, food efficiency, gastrocnemius N content and the amount of dietary N incorporated into this muscle were similar to those in control rats, and (with the exception of gastrocnemius N total content) significantly higher than those in non-treated cirrhotic rats (p < 0.05, all).

A variety of nutritional disturbances were detected in rats from the early stages of liver cirrhosis. Low doses of IGF-I were found to reverse most of these changes. These results stimulate further studies to determine whether IGF-I might be useful in the correction of the malnutrition present in patients with liver cirrhosis.

Very little information is available on body composition in patients with cirrhosis. Difficulties arise in studying these patients because they tend to retain fluid and this results in changes in tissue density and in the hydration fraction of fat-free mass. As the classic body composition techniques rely on the assumption that these variables remain constant, use of these methods will result in either under- or overestimates of body composition variables. Use of multicomponent models, employing two or more measurement techniques, will obviate the need for some of the assumptions inherent in the use of single techniques, thereby increasing the accuracy of the assessments without loss of precision. Dual-energy x-ray absorptiometry can be used to measure total body bone mineral, fat, and fat-free soft tissue mass. In healthy individuals excellent agreement is observed between data obtained using this technique and data obtained from the more established reference methods. However, the degree to which the absorptiometry measurements of soft tissue are sensitive to the hydration is not known. Thus, in order to assess this method of body composition analysis in patients with chronic liver disease, a multicomponent model must be devised which incorporates the absorptiometry technique and allows cross-validation of the individual component measures.

Very little information is available on body composition in patients with cirrhosis. Difficulties arise in studying these patients because they tend to retain fluid and this results in changes in tissue density and in the hydration fraction of fat-free mass. As the classic body composition techniques rely on the assumption that these variables remain constant, use of these methods will result in either under- or overestimates of body composition variables. Use of multi-component models, employing two or more measurement techniques, will obviate the need for some of the assumptions inherent in the use of single techniques, thereby increasing the accuracy of the assessments, without loss of precision.

Percentage body fat was determined by skinfold anthropometry and bioelectrical impedance analysis in 60 patients with cirrhosis, 30 of whom had overt fluid retention, and in 60 age- and sex-matched healthy volunteers. In the control population the mean +/- 1SD percentage body fat assessed using bioelectrical impedance analysis, 22.6 +/- 6.5%, and skinfold anthropometry, 22.5 +/- 6.9%, were comparable. However, there was considerable variation in individual values such that measurements made using bioelectrical impedance analysis could be from 9% less to 8% more than the corresponding anthropometric values. In patients with cirrhosis the mean percentage body fat assessed using bioelectrical impedance analysis, 24.4 +/- 8.9%, was significantly greater than the value obtained using skinfold anthropometry, 20.3 +/- 8.4% (p < 0.01) for the whole group and for the subgroup of patients with fluid retention, 24.5 +/- 8.5% cf. 18.4 +/- 7.1% (p < 0.005); estimates of body fat in the subgroup of patients without overt fluid retention were comparable between methods, 24.4 +/- 9.4% cf. 22.1 +/- 9.2%. In the whole patient group individual measurements made using bioelectrical impedance analysis could be from 10% less to 18% more than the corresponding anthropometric values; similar degrees of variation in individual values were observed in the two patient subgroups. Bioelectrical impedance analysis should not be used interchangeably with skinfold anthropometry for assessment of percentage body fat in patients with cirrhosis, irrespective of their state of hydration.

Previous studies of body composition in cirrhosis have either measured only one body compartment, used alcoholic subjects, or not corrected body composition for physical characteristics. The aim of this study was to perform a detailed analysis of body composition in subjects with nonalcoholic cirrhosis.

Simultaneous measurements of total body potassium and total body water were performed and values of body cell mass and body fat were corrected for physical characteristics.

Child's class C patients had a significantly lower mean total body potassium index (i.e., percent observed value/expected value) and body fat index than class A or B patients. Eighty-one percent of class C patients had simultaneous reductions in body fat and body cell mass, and 71% of patients with class A disease had a significant reduction in either or both compartments. Nine patients showed the pattern of tissue loss seen with short-term starvation. Fourteen patients showed the pattern of tissue loss seen in physiological stress.

Severe liver disease is characterized by significant reductions in body fat and body cell mass, most class A patients have a significant reduction in some nutritional compartments, and the pattern of tissue loss may reflect mechanisms of tissue wasting.

Conflicting data are available concerning energy metabolism in liver disease. Changes should be most pronounced in acute hepatic failure in which loss of 85% of liver cell mass is reported. Metabolic rate could be decreased due to impairment in liver mass but may also be increased as a result of systemic-mediator actions. To clarify this issue we studied energy metabolism in acute hepatic failure.

Energy metabolism was evaluated by indirect calorimetry in 12 patients with acute liver failure and 22 sex-, age-, and body size-matched healthy individuals. In controls and 5 patients, studies were performed in the postabsorptive state; the remaining 7 patients received glucose at a rate of 8 mumol/kg body weight.min to prevent hypoglycemia.

Resting energy expenditure was increased in acute liver failure compared with healthy controls (5.1 +/- 0.14 kJ.min-1 x 1.73 m-2 vs. 3.97 +/- 0.08 kJ.min-1 x 1.73 m-2; mean +/- SEM; P < 0.001). Respiratory quotient and oxidation rates for major fuels were not different between the total patient-group and controls. In patients without glucose supply, energy derived from fat was higher and from carbohydrate lower than in healthy controls and patients with glucose supply.

Energy expenditure is increased in acute liver failure. Altered substrate oxidation can be normalized by glucose supply.

Energy expenditure, whole body substrate oxidation rates and arterial substrate concentrations were measured in 14 patients with liver cirrhosis and 13 control subjects before and during sequential infusions of a long chain (LCT) or a medium chain triglyceride emulsion (MCT) without and with concomitant insulin plus glucose infusions. Resting energy expenditure, basal substrate oxidation rates and the arterial concentrations of glucose, lactate, triglycerides and ketones were normal, whereas plasma free fatty acids and glycerol were both increased in patients with liver cirrhosis. The arterial plasma triglyceride and free fatty acid concentrations as well as whole body lipid oxidation rate rose in response to LCT in both groups and the maximum lipid oxidation rate was 1.1 or 1.3 mg/kg fat free mass x min in controls and in cirrhotics, respectively (n.s.). Concomitantly, glucose oxidation rate fell to 65% of basal values in controls (p < 0.01), but remained nearly unchanged in the cirrhotic group (89% of the basal value; n.s.). The increase in plasma ketones was reduced to 67% of control values in liver cirrhosis (p < 0.01). Only a slight effect on energy expenditure was observed in both groups. When compared to controls, liver cirrhosis impaired insulin-induced increases in glucose disposal (-30%, p < 0.01) and in non oxidative glucose metabolism (-93%, p < 0.01). Concomitantly, normal increases in energy expenditure, glucose oxidation rate and the arterial plasma lactate concentrations and normal decreases in lipolysis, lipid oxidation and ketogenesis were observed in patients with liver cirrhosis. When lipids were given together with glucose, energy expenditure and lipid oxidation increased in controls, but glucose was the preferred fuel oxidised and lipid-induced thermogenesis was reduced in the cirrhotic group. Using a 50% MCT-emulsion, plasma free fatty acid concentrations further increased, but energy expenditure and lipid oxidation remained unchanged in both groups and further increases in plasma ketones were only observed in controls. Infusing glycerol in a subgroup of patients showed no thermogenic effect and a reduced glycerol clearance in liver cirrhosis.

The purpose of this article is to present detailed data on the nutritional assessment in cirrhotic patients. The exact frequency and types of malnutrition, its associations with the aetiology of liver disease, liver dysfunction and clinical staging in liver cirrhosis are unknown. A new classification system is presented which may help to suggest some interventional guidelines. Physical (anthropometry, 24-h urinary creatinine excretion, bioelectrical impedance analysis (BIA), total body potassium counting, ultrasound examination) and metabolic (indirect calorimetry) assessment of nutritional status was therefore performed in 123 patients with liver cirrhosis, who were considered as potential candidates for liver transplantation. Data were related to the clinical, biochemical, histological and prognostic data of liver disease. Of our patients 65% showed some signs of protein-calorie malnutrition as indicated by low body cell mass, reduced serum albumin concentrations or abnormal skinfold thickness. Of these 34% were considered as "kwashiorkor-like" (normal body composition, serum albumin less than 35 g/l), and 18% were "marastic" (reduced body weight, body cell mass, and fat mass). However, 49% of the malnourished group had reduced body cell mass in association with increased fat mass and frequently presented with a normal body weight ("mixed" or "obese" type). Protein-calorie malnutrition did not correlate with the aetiology of the disease and biochemical parameters of liver function. Malnutrition was observed at all clinical stages but was more frequently seen at advanced stages. We conclude that malnutrition associated with liver cirrhosis is not a clear phenomenon. Its clinical presentation is heterogenous and not reflected by the histological or biochemical parameters of liver disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin-induced glucose metabolism was investigated in 26 patients with biopsy-proven liver cirrhosis and 10 control subjects. Two glucose clamp protocols together with continuous indirect calorimetry were performed to examine whether reduced rates of glucose oxidation and/or nonoxidative glucose metabolism explain insulin resistance in liver cirrhosis. Using a 4-hour, two-step protocol (0-2 hours, plasma glucose 5.2 mmol/L, plasma insulin 92 mU/L to test the half-maximum response; 2-4 hours, hyperglycemia 10.0 mmol/L, plasma insulin 442 mU/L to test the maximum cellular glucose disposal) liver cirrhosis reduced glucose disposal to 45% and 60% of control values, respectively. Simultaneously, insulin-induced increases in glucose oxidation, plasma lactate levels, and lipogenesis were normal, whereas nonoxidative glucose metabolism was reduced (-82% and -47% of controls, respectively). To determine whether reduced nonoxidative glucose metabolism was caused by reduced glucose disposal, glucose disposal was "matched" to normal values in a subgroup of cirrhotic patients. Nonoxidative glucose metabolism values were normal, but plasma lactate concentrations disproportionally increased (+96%) after "matching" glucose disposal. Insulin resistance was independent of the etiology of the cirrhosis, the biochemical parameters of parenchymal cell damage and liver function, and the clinical and nutritional state of the patients. It is concluded that liver cirrhosis impairs insulin sensitivity and maximum cellular glucose disposal. Reduced glucose disposal is caused by defective glucose storage. Insulin resistance is independent of the etiology of liver cirrhosis and of the clinical and nutritional state of the patient.

Many clinicians subjectively feel that cirrhotic patients frequently have clinical signs of hypermetabolism. However, it is unknown whether hypermetabolism is a constant feature of chronic liver disease, corresponds to liver destruction and repair or is of prognostic value. This article is about resting energy expenditure and substrate oxidation rates in 123 patients with biopsy-proven cirrhosis differing with respect to cause, duration of the disease, biochemical parameters of parenchymal cell damage, cholestasis, liver function, number of complications, clinical staging and nutritional state. Resting energy expenditure varied between 1,090 and 2,300 kcal/day and differed from the predicted values in 70% of the patients. Resting energy expenditure was closely related to fat-free mass, and 52% of the variability could be explained by fat-free mass, age and sex. Of all the patients, 18% were hypermetabolic and 31% were hypometabolic. Hypermetabolism showed no strict association with the cause of cirrhosis, the duration of the disease, liver function, cholestasis, cell damage, clinical staging, blood hemoglobin, plasma thyroid hormone levels or human leukocyte antigens. An increased resting energy expenditure was associated with significant losses of muscle, body cell mass and extracellular mass at unchanged body fat, whereas fat and fat-free mass were increased in hypometabolic patients when compared with normometabolic patients. Lipid oxidation was increased, but glucose oxidation was reduced in nearly all patients with cirrhosis. This was most pronounced at advanced stages of liver disease. Although similar with respect to liver function and clinical staging, 76.2% of hypermetabolic patients had transplants within the observation period, compared with only 16.7% and 8.1% in the normometabolic group and hypometabolic group, respectively. Posttransplantation mortality was independent of pretransplantation resting energy expenditure, but it increased significantly in patients with losses in body cell mass. In conclusion, hypermetabolism is not a constant feature of cirrhosis and results more from extrahepatic than from hepatic factors. It may cause malnutrition and contributes to the clinical outcome of patients with chronic liver disease.

Using H2[18O] tracer isotope dilution and corrected bromide space as standard reference techniques, we determined total body water and extracellular water in cirrhotic patients with (four men and four women) and without (seven men and six women) ascites and compared them with a normal control group (eight men and six women). These results were then compared with calculations of total body and extracellular water determined by the bioelectrical impedance analysis technique. According to H2[18(O)] dilution, total body water was similar in cirrhotic patients without ascites and in controls (60.8% +/- 2.1% vs. 60.3% +/- 1.4% body wt), but was increased in patients with ascites (69.7% +/- 1.2% body wt; p less than 0.002). Correlation was excellent between the H2[18(O)] dilution and bioelectrical impedance measurements of total body water in controls and cirrhotic patients without ascites (r = 0.98; p less than 0.0001). However, this correlation was poor in cirrhotic patients with ascites (r = 0.17; not significant). According to the bromide space, extracellular water (expressed as a percentage of total body water) was increased in cirrhotic patients with (57.8% +/- 1.8%; p less than 0.001) and without (44.0% +/- 1.2%; p less than 0.001) ascites compared with controls (36.6% +/- 1.0%). A poor correlation (r = 0.41; p less than 0.13) was seen for extracellular water measurements between the bromide space method and the bioelectrical impedance method, which failed to detect the differences among the three groups observed with the bromide space technique. Furthermore, bioelectrical impedance failed to detect any change in total body or extracellular water after paracentesis, with a degree of inaccuracy that increased linearly as the amount of ascitic fluid removed increased (r = 0.97; p less than 0.001). All these intergroup comparisons remained the same, whether the analysis was of both men and women combined or for each gender individually. However, we saw differences between men and women in the control group and cirrhotic group without ascites. These results demonstrate that abnormalities in water homeostasis and compartmentalization between intracellular (the difference between total body and extracellular water fluid) and extracellular water may exist in cirrhosis whether or not fluid accumulation is clinically evident. These data further indicate that alterations in the metabolically active body cell mass (as represented by intracellular water) in cirrhosis may occur independently of total body water and calculated fat-free body mass. In addition, gender is an important variable to control for in studies of this type.(ABSTRACT TRUNCATED AT 400 WORDS)

While the rate of malnutrition is relatively modest in alcoholic patients without alcoholic liver disease, the rate of malnutrition is virtually 100% in patients with alcoholic hepatitis and/or alcoholic cirrhosis. The reasons for malnutrition in the alcoholic hepatitis patient include various factors such as anorexia, poor diet, malabsorption, and altered metabolic state. When the patient is hospitalized, the malnutrition frequently worsens because of fasting for tests, continued anorexia, and complications such as gastrointestinal bleeding. Patients with severe acute hepatitis appear to be both hypermetabolic and hypercatabolic, whereas data are much more conflicting concerning patients with more stable liver disease. Most studies suggest that patients with alcoholic liver disease require at least 60 g of protein per day to maintain positive nitrogen balance. Consistent alterations in plasma amino acid profiles occur in alcoholic liver disease, and specialized nutritional formulations have been devised to correct this amino acid profile with the intent of improving overall nutritional status, hepatic encephalopathy, and mortality. The effects of nutritional support (including use of specialized products) on outcome, on acute hepatic encephalopathy, and on chronic or latent portal systemic encephalopathy are reviewed.

Chronic liver failure is characterized by the appearance of jaundice, ascites, encephalopathy and/or gastrointestinal bleeding. Acute episodes of hepatic decompensation are frequently precipitated by additional events, e.g. septicaemia, diuretic therapy or excessive protein intake. Identification, correction and treatment of these precipitating factors are first steps in the management of chronic liver failure. Nutritional support is important in the treatment of cirrhotic patients, because malnutrition is one of the major determinants of patient outcome. Management of encephalopathy reduces the appearance of gut-derived nitrogenous toxins and corrects imbalances in amino acid metabolism. Treatment of ascites is salt restriction supported by gentle and incremental administration of diuretics. Ursodesoxycholic acid has become a new and promising modality in the management of cholestatic liver diseases. If conservative therapy fails to recompensate liver function, liver transplantation may be indicated.