Issues of malnutrition and bone disease in patients with cirrhosis

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1 Blackwell Science, LtdOxford, UK JGHJournal of Gastroenterology and Hepatology Blackwell Science Asia Pty Ltd 174April Malnutrition and bone disease in cirrhosis patients A Donaghy /j x Review Article462466BEES SGML Journal of Gastroenterology and Hepatology (2002) 17, ADVANCES IN LIVER DISEASE: ALCOHOLIC HEPATITIS, NON-CIRRHOTIC PORTAL FIBROSIS AND COMPLICATIONS OF CIRRHOSIS Issues of malnutrition and bone disease in patients with cirrhosis ANTHONY DONAGHY AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, New South Wales, Australia Abstract Malnutrition is a frequent complication of cirrhosis, and many studies have demonstrated the adverse influence of malnutrition on clinical outcomes in patients with cirrhosis. The coexisting complications of fluid overload and ascites may mask the severity of malnutrition, particularly in the early stages of its development. During periods of decompensation, protein and energy requirements are higher, and many patients have inadequate nutritional intake at these times. Further, protein supplementation should not be restricted ad hoc in cirrhotic patients, as for the vast majority of patients dietary protein does not precipitate hepatic encephalopathy. The impairment of hepatic glycogen storage in cirrhotic patients effects a state of accelerated starvation with catabolism of fat and protein to provide substrates for gluconeogenesis. Recent studies have demonstrated the efficacy of nocturnal nutritional supplements in improving nitrogen balance. Resistance to the actions of the anabolic growth factors insulin and growth hormone (GH) is common in cirrhosis, and recent studies have shown that GH resistance, in particular, may be overcome with exogenous GH therapy. Hypermetabolism may be observed in up to one-third of cirrhotic patients. The recent exciting observation that beta-blocker therapy can decrease energy expenditure and catecholamine levels in these patients indicates the need for further intervention studies of beta-blockers as metabolic therapy in cirrhosis Blackwell Publishing Asia Pty Ltd Key words: body cell mass, cirrhosis, end-stage liver disease, liver transplantation, malnutrition, metabolic bone disease, nutritional assessment. PATHOPHYSIOLOGY AND ASSESSMENT OF MALNUTRITION Prevalence and prognosis Malnutrition is an extremely common finding in patients with cirrhosis; in studies of both non-alcoholic 1 and alcoholic liver diseases 2 the prevalence is up to 100%. Poor nutritional status exerts a serious adverse influence on clinical outcome. Malnutrition was first used as a prognostic indicator in the Child Turcotte classification for estimating mortality in patients having portocaval shunt surgery. 3 Later studies have confirmed its prognostic value in patients with cirrhosis who undergo abdominal surgery, and in those treated medically. 4 The evolution of liver transplantation as definitive therapy for end-stage liver disease has stimulated a number of studies that further demonstrate how nutritional status influences clinical outcome. Moukarzel et al. demonstrated that growth-retarded children had a higher incidence of post-transplant complications and overall mortality. 5 Shepherd showed a 20% decrease in one year actuarial transplant survival in children with diminished body cell mass. These authors also noted a deterioration in nutritional status in patients awaiting a suitable donor organ; the figure they reported of a 21% death rate on the transplant waiting list may well be exceeded in adults who must now wait up to months for a graft. In a large cohort of adult liver transplant recipients, Shaw et al. identified nutritional status as one of six variables that were highly correlated with patient survival. 6 They also emphasized that nutrition was the only variable not dependent on disease activity, and was therefore potentially reversible. In a later study, 7 Muller demonstrated a threefold increase in mortality after liver transplantation among 62 patients with Correspondence: Dr Anthony Donaghy, AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia. tdonaghy@med.usyd.edu.au

2 Malnutrition and bone disease in cirrhosis patients 463 severe malnutrition, compared to that observed in an age-matched group of better-nourished transplant recipients. Nutritional assessment of people with cirrhosis The accurate assessment of nutritional status in patients with cirrhosis has proven difficult, largely because of overlap with other complications such as fluid retention and hypoproteinemia. Thus, liver disease specifically affects such conventional nutritional markers of nutrition as serum levels of proteins synthesized by the liver (albumin, transferrin, retinol-binding protein), and tests of immunological dysfunction, irrespective of nutritional status. The cachexia of advancing liver disease is often masked by the development of ascites and edema; this causes inherent inaccurancies in techniques such as bioimpedance analysis (BIA) and dual photon X-ray absorptiometry. However, upper limb anthropometry (skin fold thickness) remains a valuable and reproducible bedside measure of nutritional status in patients with cirrhosis. Two recent studies have demonstrated that use of more sophisticated techniques can improve the accuracy of nutritional assessment. Prijatmoko et al. showed that, in subjects with alcoholic cirrhosis, anthropometry and BIA did not detect protein losses documented by in vivo neutron activation analysis of total body protein. 8 Crawford et al., using simultaneous measurements of total body potassium and water in patients with nonalcoholic cirrhosis, demonstrated a progressive loss of BCM and body fat with increasing disease severity. 9 Importantly, they also observed that significant losses were seen in 71% of patients with Child s A cirrhosis. Recent nutritional research has focused on the potential value of assessing muscle strength as a functional measure of nutritional status. Muscle force has been shown to be a good measure of clinical outcome, while other studies have also suggested that functional abnormalities may be a more sensitive and earlier indicator of nutritional depletion than measurable changes in body composition. 10 Pathophysiology of malnutrition in cirrhosis The pathophysiology of malnutrition in cirrhosis is complex. It includes diminished food intake, malabsorption, maldigestion and hypermetabolism, and an interaction with resistance to growth factors such as insulin and growth hormone (GH). 9 In healthy people, hepatic glycogen stores are adequate to meet glucose needs, primarily for the brain, for h during the fasting state. In contrast, the cirrhotic liver can provide glucose for only 6 8 h of fasting. This results in increased protein catabolism to provide free amino acids as substrate for gluconeogenesis, and there is preferential use of fat as an immediate energy source. 11,12 The impairment of hepatic glycogen storage capacity results in a metabolic profile that closely resembles that of starvation. Swart et al. have subsequently shown that, even in the short overnight fasting period, protein synthetic rates are decreased, compared to the fed state in patients with cirrhosis. 13 NUTRITIONAL THERAPIES FOR MALNUTRITION IN CIRRHOSIS The search for effective nutritional therapies in cirrhosis has not been rewarded with convincing findings of improved patient survival, although a small number of studies have demonstrated improvements in clinical indices and short-term outcomes. A number of newer approaches to the treatment of malnutrition in cirrhosis have been reported recently. Substrate availability Quantity There is considerable variance in the literature as to the adequacy of substrate intake in patients with cirrhosis. It does appear clear, however, that more severely ill patients may have significantly lower intakes of protein and total energy, particularly at times of disease complications such as infection, ascites, encephalopathy and bleeding. Among patients being assessed for liver transplantation in hospital, we have shown that protein and energy intake decline with increasing disease severity. Child s C category patients consumed a median of 50 g protein/day, and total energy intake was 88 kj/kg per day, levels well below those required to maintain positive nitrogen balance (A Donaghy, unpubl. data, 1994) (Table 1). Composition Swart et al. have demonstrated that more than 50 g protein/day is necessary to maintain positive nitrogen balance in cirrhosis. 13 In later studies, Kondrup et al. have demonstrated that the protein intake versus retention Table 1 Nutritional recommendations for patients with cirrhosis 1. Ensure adequate substrate intake Non-protein energy kj/kg per day Protein g/kg per day 2. Avoid protein restriction 3. Late evening feeding 4. Vigilance at times of clinical decompensation Frequent feeding Enteral sip feed supplements Continuous or overnight nasogastric feeding 5. Use exogenous growth factors to improve substrate utilization 6. Treat ascites aggressively to decrease higher energy expenditure

3 464 A Donaghy curve is significantly shifted to the right in patients with cirrhosis, emphasizing that they require a higher intake of protein to maintain nitrogen balance. 14 An important observation of the above study is that, in patients refed with a high protein intake, none developed hepatic encephalopathy. For many years, hepatology texts have recommended active protein restriction in cirrhotic patients for fear that dietary protein would induce hepatic encephalopathy. This dictum appeared to arise from the frequently observed development of hepatic encephalopathy in cirrhotic patients after portocaval shunt surgery. However, subsequent experience with TIPSS has suggested that hepatic encephalopathy is related more closely to the extent of portosystemic shunting than to hepatocyte dysfunction, and dietary protein-induced encephalopathy is very uncommon in cirrhosis. Thus, there is no evidence to support the notion of restricting protein intake ad hoc in cirrhotic patients, and it is important to avoid this unnecessary restriction because of the important nutritional implications. Alternative delivery patterns Two studies have targeted nutritional intakes to minimize the fasting period during which the metabolism, in order to maintain euglycemia, switches to fat and protein catabolism. Swart and Zillikens demonstrated that the spreading of food intakes to include a late evening meal significantly improved nitrogen balance when compared to an isonitrogenous and isocaloric diet of conventional pattern. 15 Zillikens et al. later demonstrated that this improvement could be attained with nocturnal polymeric glucose alone, indicating that the improved nitrogen economy was not dependent on protein delivery, but rather, on the replenishment of hepatic glycogen stores. 16 However, longer-term studies examining the effects of nocturnal supplementation on body composition and clinical outcomes have not yet been published. Substrate utilization Studies have demonstrated that some patients do not gain lean body mass with adequate provision of nutritional substrate. Many of these patients have developed acquired resistance to the dominant, potent anabolic growth factors, insulin and GH. In cirrhosis, insulin resistance appears multifactorial; there are contributions from high circulating levels of antagonist hormones, such as glucagon, cortisol and GH, in addition to a primary defect in non-oxidative glucose disposal in skeletal muscle. Liver transplantation reverses many of the features of insulin resistance, but few therapies have demonstrated efficacy in the pretransplant situation. Foods with low glycemic indices, and aerobic exercise, may improve insulin sensitivity. The somatomedin hypothesis of Salmon and Daughaday established that the majority of the growthpromoting effects of GH were mediated by the insulinlike growth factors (IGF). Growth hormone has been shown to actively stimulate protein synthesis in adults with GH deficiency, while IGF-I inhibits proteolysis in the postabsorptive state, but stimulates protein synthesis when adequate substrate is available. Many recent studies support the important role of the GH : IGF axis in the regulation of body composition in adults. Acquired GH resistance is a commonly recognized feature of protein catabolic states, in which breakdown of lean body mass results in altered body composition, loss of muscle strength, and impaired immune responses. In acquired GH resistance, it is apparent that there is a shift from the indirect growth-promoting actions of GH, which are largely mediated by IGF, to direct actions such as lipolysis and insulin antagonism. 17 In the setting of catabolism induced by injury or severe illness, these changes might provide substrates essential for short-term fuel needs. On the other hand, in the mid and longer term, with respect to the maintenance of body composition, they might be counterproductive. The liver has a central role in the GH : IGF axis. It is the major source of the circulating forms of IGF-I, IGFbinding proteins 1, 2 and 3, and the hepatocyte appears to be the only cell type that produces the acid-labile subunit, which is the third protein of the circulating ternary complex that regulates the bioavailability of IGF-I to its tissue receptors. The importance of the liver cell mass has been clearly demonstrated by the striking improvement in serum IGF-I levels seen in children after liver transplantation. 18 Chronic liver disease is characterized by severe GH resistance, and this is thought to underlie the pathogenesis of the state of protein catabolism so prevalent in these patients. 19 The pathophysiological mechanisms for the acquired GH resistance of cirrhosis remain incompletely understood. Our group has demonstrated in the cirrhotic human liver that there are significant decreases in expression of the genes for GH receptor, and for the GH-dependent proteins IGF-I and the ALS. Clinical studies have indicated that portosystemic shunting of insulin and other trophic factors away from functional liver mass is an important etiological factor. We showed in a short-term GH intervention study in cirrhosis that GH resistance can be overcome, at least partially. Thus, high-dose exogenous GHinduced small improvements in serum IGF-I, IGFBP-3 and ALS levels can effect a significant improvement in nitrogen balance. 20 Energy expenditure The recent superb study from Muller et al. has revealed that hypermetabolism is present in approximately 33% of patients with cirrhosis, while 63% are normometabolic and 3% hypometabolic. 21 Campillo et al. had previously recognized that hypometabolic patients had extremely poor clinical outcomes related to extreme resistance to nutritional intervention. 22 Muller et al. also demonstrated high plasma catecholamine levels in some of these patients, and showed that b-adrenergic receptor blockade could decrease these levels. 21 This

4 Malnutrition and bone disease in cirrhosis patients 465 exciting finding suggests a possible role for beta-blockers in decreasing energy expenditure, and thereby possibly improving nitrogen balance. METABOLIC BONE DISEASE IN PATIENTS WITH CIRRHOSIS Osteoporosis is a frequent complication of end-stage liver disease, irrespective of etiology. The prevalence varies between 9 60%, the highest being observed in cholestatic disorders and alcoholic liver disease. In these two groups, vitamin D malabsorption and the direct influence of alcohol on bone metabolism, respectively, are thought to be the most important pathogenic factors. A recent study has also noted that the prevalence of osteoporosis in patients with cirrhosis secondary to hepatitis B and hepatitis C was approximately 50%, indicating the central role of cirrhosis itself in the pathogenesis of osteoporosis in chronic liver disease. 23 Patients who proceed to liver transplantation suffer a further marked decrease in bone mass, which is most striking in the first few months post-transplant. In some patients, loss of up to 15 24% of bone mass within 3 6 months has been reported. This loss is associated with an increased risk of fractures, most commonly of the vertebrae and ribs; fractures occur in as many as 30 50% of patients within the first 12 months of a liver transplant. The use of high-dose immunosuppressive therapy, particularly glucocorticoids, following liver transplantation is a major factor contributing to the increased rate of bone loss. 24 The roles of cyclosporin and FK506 are controversial. There is conflicting evidence from both in vitro and in vivo studies, perhaps related to the steroid-sparing effect in vivo of these two agents. Additional factors may exacerbate bone loss during liver transplantation. These include suboptimal nutrition (possibly mediated through decreased IGF-I bioavailability), abnormalities in calcium and vitamin D metabolism, and prolonged immobilization. While the likely principal mechanism for osteoporosis in chronic liver disease is reduced bone formation and low bone turnover, 14 the predominant pathogenic mechanism causing the early and rapid loss of bone mass after liver transplantation appears to be increased bone resorption. This is consistent with the mechanism of glucocorticoid action on bone metabolism. It is also supported by measurements of biochemical markers of bone metabolism. 9,15 However, histomorphometric studies performed following liver transplantation have yielded conflicting results, 6,14 which may be in part due to the lack of correlation between the timing of the bone biopsy and the maximal resorptive effect. Over the past decade, bisphosphonate therapy has provided a significant clinical advance for the treatment of disorders of bone characterized by excessive bone resorption; examples include tumor-induced hypercalcemia, postmenopausal osteoporosis, Paget s disease, and bone lesions in multiple myeloma and metastatic breast cancer. Bisphosphonates have revolutionized the treatment of some rarer diseases like osteogenesis imperfecta, which have previously been untreatable. Their mechanism of action is direct inhibition of osteoclast activity and hence inhibition of bone resorption. Clinical trials are currently being conducted to assess the efficacy of potent bisphosphonate therapy in the prevention of bone mineral loss in the early period after liver transplantation. CONCLUSION The recent advances in the assessment of nutritional impairment in patients with cirrhosis are clarifying the extent of this problem. Newer approaches to enhance or improve nutritional status, as well as to ameliorate bone loss in the early stages after liver transplantation, carry the potential to improve the outcomes and quality of life of people in the advanced stages of chronic liver disease. REFERENCES 1 Di Cecco SR. Assessment of nutritional status of patients with end stage liver disease undergoing liver transplantation. Mayo Clin. Proc. 1989; 64: Mendenhall CL, Anderson S, Weesner RE, Goldberg SJ, Crolic KA. Protein calorie malnutrition associated with alcoholic hepatitis. Am. J. Med. 1984; 76: Child CG, Turcotte JG. Surgery and portal hypertension. In: Child C, ed. The Liver and Portal Hypertension, Vol. 50. Philadelphia: W.B. Saunders Co, Christensen E. Prognostic value of Child Turcotte Criteria in medically treated cirrhosis. Hepatology 1984; 4: Moukarzel AA, Najm I, Vargas J. Effect of nutritional status on outcome of orthotopic liver transplantation in paediatric patients. Transplant. Proc. 1990; 22: Shaw BW, Wood WP, Gordon RD. Influence of selected patient variables and operative blood loss on six month survival following liver transplantation. Semin. Liver. Dis. 1985; 5: Muller MJ. Hepatic energy and substrate metabolism: a possible metabolic basis for early nutritional support in cirrhotic patients. Nutrition 1998; 14: Prijatmoko D, Strauss BJ, Lambert JR et al. Early detection of protein depletion in alcoholic cirrhosis: role of body composition analysis [see comments]. Gastroenterology 1993; 105: Crawford DH, Cuneo RC, Shepherd RW. Pathogenesis and assessment of malnutrition in liver disease. J. Gastroenterol. Hepatol. 1993; 8: Jeejeebhoy K. Bulk or Bounce-The Object of Nutritional Support. J. Parenter. Enteral Nutr. 1988; 12: Owen OE, Trapp VE, Reichard GJ et al. Nature and quantity of fuels consumed in patients with alcoholic cirrhosis. J. Clin. Invest. 1983; 72: Krahenbuhl S, Weber FJ, Brass EP. Decreased hepatic glycogen content and accelerated response to starvation in rats with carbon tetrachloride-induced cirrhosis. Hepatology 1991; 14: Swart GR, van dbj, Wattimena JL, Rietveld T, van VJ, Frenkel M. Elevated protein requirements in cirrhosis of

5 466 A Donaghy the liver investigated by whole body protein turnover studies. Clin. Sci. 1988; 75: Kondrup J, Nielsen K, Juul A. Effect of long-term refeeding on protein metabolism in patients with cirrhosis of the liver. Br. J. Nutr. 1997; 77: Swart G, Zillikens M. Effect of a late evening meal on nitrogen balance in patients with cirrhosis of the liver. Br. Med. J. 1989; 299: Zillikens MC, van dbj, Wattimena JL, Rietveld T, Swart GR. Nocturnal oral glucose supplementation. The effects on protein metabolism in cirrhotic patients and in healthy controls. J. Hepatol. 1993; 17: Jenkins R, Ross R. Acquired growth hormone resistance in catabolic states. In: Ross R, Savage M, eds. Bailliere s Clinical Endocrinology and Metabolism, Vol. 10. London: Bailliere Tindall, 1996; Holt RI, Jones JS, Stone NM, Baker AJ, Miell JP. Sequential changes in insulin-like growth factor I (IGF-I) and IGF-binding proteins in children with end-stage liver disease before and after successful orthotopic liver transplantation. J. Clin. Endocrinol. Metab. 1996; 81: Donaghy A, Ross R, Gimson A, Hughes SC, Holly J, Williams R. Growth hormone, insulinlike growth factor- 1, and insulinlike growth factor binding proteins 1 and 3 in chronic liver disease. Hepatology 1995; 21: Donaghy A, Ross R, Wicks C et al. Growth hormone therapy in patients with cirrhosis: a pilot study of efficacy and safety. Gastroenterology 1997; 113: Muller MJ, Bottcher J, Selberg O et al. Hypermetabolism in clinically stable patients with liver cirrhosis. Am. J. Clin. Nutr. 1999; 69: Campillo B, Bories PN, Pornin B, Devanlay M. Influence of liver failure, ascites, and energy expenditure on the response to oral nutrition in alcoholic liver cirrhosis [see comments]. Nutrition 1997; 13: Gallego-Rojo F, Gonzalez-Calvin J, Munoz-Torres M et al. Bone mineral density, serum insulin-like growth factor- I and bone turnover markers in viral cirrhosis. Hepatology 1998; 28: McCaughan G, Feller R. Osteoporosis in chronic liver disease: pathogenesis, risk factors and management. Dig. Dis. Sci. 1994; 12:

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