Clinical Nutrition (2003) Supplement 2: S53–S56r 2003 ESPEN. Published by Elsevier Ltd. All rights reserved.doi:10.1016/S0261-5614(03)00150-X

Evolution of disease-oriented nutrition

G. GUARNIERI, R. SITULIN

Department of Clinical, Morphological andTechnological Sciences, Division of InternalMedicine, University ofTrieste, Italy(Correspondence to: GG)

Introduction

Over the past 30 years from the late 1960s to the presenttime there have been considerable advances in therationale and methods of nutritional support forpatients with organ insufficiencies. Deeper knowledgeof physiology, pathophysiology and metabolism hasled to approaches more and more closely tailored onthe disease characteristics. Historically, nutritionalinterventions were initially mainly directed towardssome nutrient intolerance causing clinically relevantsymptoms. Low protein diets, for example, were shownto be effective, in improving the clinical conditions ofseverely symptomatic patients with kidney or liverfailure, in the 1970s standardised method of nutritionalassessment became available and allowed deeper in-sights into the effects of different diseases on thenutritional status of the patients. A large number ofepidemiological studies showed high rates of proteinenergy malnutrition (PEM) in patients with organinsufficiencies. At the same time the specific nutritionalrequirements needed to maintain an adequate nutri-tional status were thoroughly investigated. Evidence wasproduced that the development of PEM was at timesiatrogenic. For example, overly restricted low proteindiets often associated with an insufficient energy supply,were found to be responsible for losses of functionalcapacities and wasting of tissue stores in patients withliver cirrhosis or chronic renal failure. These regimens,by favouring protein catabolism for energy production,increased the endogenous nitrogen load with the endresult of offsetting the effects of restricting the nitrogenintake. Previous nutritional interventions were thereforecriticised in the light of the new evidence. The emphasisfor nutritional interventions shifted from symptomcontrol to the prevention and treatment of malnutrition.Metabolic changes and intolerance to some nutrientswere of course still an issue to be taken into accountand the best way to feed the patients appeared at timesa dilemma. Later on, the nutritional support rationalebecome focused on the prevention or improvementof the functional and morphological changes of thefailing organs through early nutritional manipulationsor the administration of specific nutrients. Some

nutrients surged to an unforeseen pharmacological role.This development opened up new challenging chaptersin the field of nutrition and new windows on the future.It is certainly difficult to summarise in the short lengthof a paper the evolution of nutrition in patients withkidney, liver, lung and gut failure during the last 20years.

Kidney diseases

In the 1960s, nutritional interventions were mainlydirected toward the improvement of uremic symptomsassociated with increased levels of blood urea nitrogenand other toxic urea metabolites. Stringent proteinrestriction seemed to clear-cut way to control azotemiaand improve the well-being of patients with advancedrenal failure. Experimental observations showing higherrates of urea incorporation in the body proteins of ratsfed reduced amounts of mixtures of essential aminoacids (EAA) compared to animals fed with mixtures ofboth essential and non-essential amino acids gave wayto the hypothesis that the nitrogen needed to synthesisenon-essential amino acids by the liver could be derivedfrom urea hydrolysed to ammonia by bacteria in the gut.This supposed recycling of urea suggested that nitrogenintake could be further lowered by giving to patientswith kidney failure a prevalence of high biological value(HBW) proteins or mixture of only EAA. Early in the1960s Giordano and Giovannetti published their dataon the effects of very low amounts of EAA as the onlynitrogen source in advanced chronic renal failure (CRF)patients. BUN levels were reduced and uremic symp-toms improved. It was later demonstrated however thatthe urea recycling was really a limited process,inadequate to maintain the concentrations of all aminoacids. These results posed the bases for the prescriptionof low HBV, protein regimens (40 g/day) to CRFpatients with GFR around 10–15ml/min or of verylow protein diets (with no limitation on quality)supplemented with 15–20 g/day of essential amino acidsincluding histidine (which has been shown to be essentialin uremic patients) or their ketoanalogues to those withGFR o5ml/min. In the second ESPEN Congress held

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at Newcastle on Tyne in 1980 the main indications forprotein restriction were listed as follows:

(1) Recognition of severely compromised renal func-tions; (2) the possibility of ameliorating uremic andsymptoms; and (3) the possibility of improving uremi-cally induced symptomatic anemia. In the 1980s manyefforts were directed to the design of suitable amino acidformulas—either balanced (according the Rose formulafor healthy subjects) or unbalanced (to take into accountthe reported abnormalities of amino acid patterns inplasma and in skeletal muscle cells). The nitrogen-freeketo- and hydroxy-analogues of the essential aminoacids (with the exception of threonine and lysine)became also available. Analogue formulas were de-signed both as calcium and basic amino acid (lysine,ornithine and histidine) salts and were mostly unba-lanced. Since the analogues are transaminatcd in thebody to the corresponding EAA, the assumptionunderlying their use was to further reduce the supplyof total nitrogen. Furthermore, it was thought that theymight have a specific anabolic role and perhaps also oneffect on slowing the rate of deterioration of renalfunction. In time it appeared that the best way to ensure,an adequate protein synthesis was to supply a combina-tion of essential and non-essential AA.

In the 1980s the slowing of the progress of renalfailure, through long-term protein restriction startingearly in the course of the disease became a newambitious rationale for low protein diets even inproteinuric patients. The risk of developing PEM fromthese regimens which often were associated with aspontaneous lowering of energy intake, together withthe problem of the patient’s long-term compliance to thelow protein diets prompted large trials to test theirefficacy on the progression of renal failure. PEM wasoften associated with a negative prognosis. PEM was tobe taken seriously into account since its effects wereshown to be carried over to the dialysis phase withnegative prognostic effects. In the 1990s some evidenceof possible beneficial effects on progression wasproduced and it was also concluded that low proteindiets might be useful even in patients with diabeticnephropathy. To date, however, there is no definitive orgeneral consensus on the level of protein restriction andon the values of GFR below which it is useful to restrictprotein intake (G. Toigo et al. Expert working groupreport on nutrition in adult patients with renalinsufficiency. Accepted for publication on ClinicalNutrition 2000). The most recent indications recom-mend a restriction of protein intake tuned on the levelsof residual renal function and aimed at maintaining thelevels of urea at 25–30mmol/l. For patients onhemodialysis or CAPD a general agreement for theneed of higher than normal protein intake was reachedin the 1980s. The prognostic relevance of the nutritionalstate of patients on sostitutive therapy has also beenconfirmed in recent studies. Intradialytic and intraper-itoneal nutrition have been recently found to improve

the nutritional status and therefore seems to be apromising approach to the patient’s nutritional manage-ment. To achieve a neutral or positive nitrogen balancekidney patients need an energy intake of at least 35 kcal/kg body weight/day (or lower if the patient is over-weight). Despite careful instruction and considerableeffort, it is often very difficult to achieve an optimalenergy intake most likely because patients have difficul-ties in meeting the multiple diet modification prescribed(i.e. protein, phosphate, calcium). Even though todaygreater attention is given to the diet composition,chronically uremic patients might develop water solublevitamin deficiencies. Recent studies have confirmed theneed for supplementation. The prescription of vitaminD analogues is limited to patients with clinical evidenceof a deficiency.

Liver failure

In patterns with liver insufficiency nutritional Interven-tions were at first limited to cases complicated withencephalopathy. The patients were clearly malnourishedand wasted but their protein supply was limited as a wayto control the encephalopathy. Protein restriction toabout 40 g/day (about 0.6 g/kg/day or lower) wascommon clinical practice. The encephalopathy wasthought to result from the production of excessiveamounts of ammonia or some other nitrogenous wastesor short chain fatty acids and mercaptans by theintestinal flora (neurotoxic hypothesis). The availabilityof neomycin and lactulose allowed a bettor control ofencephalopathy. A further breakthrough in nutritionalinterventions has been the development of anotherhypothesis (‘false neurotransmitters’ hypothesis) whichrelated the pathogenesis of liver encephalopathy to analtered ratio of branched chain amino acid (BCAA) toaromatic amino acids leading to changes in theneurotransmitter in the CNS. Between the end of the1970s and the beginning 1980s many studies assessed thechanges of the amino acid metabolism in liver failure.They were extensively reviewed at the 2nd (1980) and the4th (1982) ESPEN Congresses. These studies promptednutritional interventions aimed at normalising thealtered plasma amino acid pattern with the rationaleof improving both the encephalopathy and the nutri-tional state. Mixtures of amino acids enriched withBCAAs; and with a reduced content of aromatic aminoacids became available and were administered orally orintravenously in an attempt to solve the dilemmabetween protein intolerance and negative nitrogenbalance. Other available formulas were the so-called‘coma solutions’ (containing only BCAA) and solutionsbased on pharmacokinetic criteria. Numerous investiga-tions were carried out to evaluate the effects of theseamino acid preparations which were administeredparenterally, eternally or orally to patients with differentlevels of encephalopathy. The TPN solutions enriched

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with BCAA were tested against the administration oflactulose or neomycin and dextrose as the only source ofnutrients. These studies were, however quite, incon-sistent, making it difficult to draw definitive conclusions.A meta-analysis concluded that the BCAA Supplementsimproved slightly but significantly the encephalopathy,but failed to improve mortality rates. The trials on oralsupplementation of the unbalanced amino acid mixturein patients with chronic encephalopathy and intolerantto proteins were able to show a near equivalence in themaintenance of a positive nitrogen balance between thesupplements and an equivalent amount of proteins.With the former, however, encephalopathy was lessfrequently induced. Long-term enteral supplementationof BCAA compared to isonitrogenous casein haveshown improvement of both encephalopathy andnitrogen balance. At the end of this long debate it wasconcluded that hepatic encephalopathy can be counter-acted by an adequate nutrition and BCAA are nowrecommended only in selected cases of proven proteinintolerance (ESPEN consensus group, 1997). Anotherless debated area of investigation in liver failure hascentred on the comparison of different qualities ofproteins (vegetable vs animal). In dogs with Eck fistulas,neurological symptoms were shown to develop withmeat but not with milk proteins. Some studies reportedbeneficial effects with vegetarian diets: mental stateimproved, urinary nitrogen output was lower; insulin toglucagon ratio were reduced. Multiple mechanisms forthese effects have been hypothesised, including a higherfaecal loss of nitrogen, but not clearly demonstrated.Furthermore often only small numbers of patients havebeen studied and only on a short-term basis. Otherstudies have addressed the effects of parenteral orenteral nutrition on the nutritional status of patientswith alcoholic liver cirrhosis or hepatitis. In conclusion,in the past 20 years nutritional interventions in liverfailure patients have evolved from strict protein restric-tion to extensive efforts to preserve, the nutritionalstatus by constant and careful monitoring. Malnutritionhas been continued to have a significant prognosticmeaning in advanced cirrhosis and ways to supplyartificial nutrition and its effects on outcome need to befurther investigated. The decreased levels of antioxi-dants (zinc, selenium and vitamin E) in liver failurepatients may warrant future considerations. Guidelinesfor liver disease patient nutrition have been recentlystated in the 1997 ESPEN consensus group. Recom-mendation are given according to the various clinicalconditions. Specific requirements are defined for com-pensated cirrhosis, for complications such as malnutri-tion and/or encephalopathy and for the phase aftermajor surgery including liver transplantation. Further-more in the consensus there has been an effort to definethe ways to assess the nutritional status, the tools andstrategies that can be used to influence the nutritionalstatus and the effects of nutritional interventions on theoutcome.

Lung disease

Nutritional interventions in lung failure have also gonethrough considerable changes in perspective. Malnutri-tion and weight loss in COPD patients were at firstconsidered to be part of an adaptive mechanismfinalised to reduce the oxygen consumption and it wasthought that respiratory muscle masses were sparedfrom wasting. Later however, it appeared clear thatPEM had relevant consequences on the respiratorymuscle mass and functions (inspiratory and expiratorypressures, maximal voluntary ventilation and vitalcapacity) and also on the respiratory epitheliumstructure and physiology (ciliary movement or synthesisand secretion of pulmonary surfactant). Furthermore,the PEM related impairment of immunocompetence wasassociated to an increased risk of lung infections. Therationale of nutritional interventions in COPD patientswas aimed at improving the nutritional status to obtainpositive effects both on the respiratory functions and onclinical outcome. Carbon dioxide production appearedto be influenced by both the type of nutrients and theamount of energy supplied. Glucose administrationincreased carbon dioxide production, minute ventilationand the ventilatory response to hypoxia. There hadbeen reports of worsening of respiratory failure or ofdifficulties in weaning from the ventilator with excessiveglucose intake. Enteral formula with a high fat anda low carbohydrate content became available. Sometheoretical grounds were criticised. Furthermore, resultsabout the use of these products in clinical trials were notunequivocally confirmed. It was concluded that feedingin COPD patients needs to be finely tuned to theventilatory demands of the single patient, and avoidingenergy overfeeding without changing the proportionsbetween fat and carbohydrates is now considered to bethe best policy. The need for modified products mightbe still indicated in patients with very compromisedpulmonary functions and marginal ventilatory reserve.Future developments might stem from the modulationof the inflammatory response through the administra-tion of different types and ratios of fatty acid precursorsof different prostaglandins involved in the inflammatoryand immune response and in the regulation of lungfunctions.

Prevention of gut malfunction

An editorial review of Clinical Nutrition issued inDecember 1984 and entitled ‘Disuse atrophy of theintestinal tract’ clearly underlined the essentiality offood for the maintenance of an healthy intestinalmucosa and for the adaptive hyperplasia that compen-sates for the loss of functioning bowel. Various studieshad shown that prolonged fasting or feeding by totalparenteral nutrition or the surgical bypass of someenteral segments caused villous atrophy and loss of gut

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functions. Elemental diets were observed to preserve themorphology and the functions of the small intestine butto cause also atrophy in the more distal color most likelyfrom the absence of residual bulk. The effects of fibre orother fermentable products were yet unknown. Thegastrointestinal tract functions were then further de-fined. The gut has been shown to have importantmetabolic, immune and barrier functions. The last twoallow a defence against antigens and bacteria both inphysiological and pathological conditions. Bacterialtranslocation or the passage of viable bacteria fromthe gut to the mesenteric lymph nodes, the liver and thespleen was hypothesised to be the motor of MOP orSIRS in trauma or sepsis. The possible protective role ofenteral feeding and the supply of selected gut nutrientsbegan to be assessed. Enteral feeding is now consideredfundamental to preserve gut functions. Furthermore,numerous nutrients such as glutamine, arginine or otheramino acids, nucleotides, short chain fatty acids fromfibre or other substrates including fructo-oligosacchar-ides fermented by the intestinal bacteria or omega-3fatty acids have been shown to have a specific role inmaintaining the gut structure and in enhancing itsfunctions. Multiple advantageous rationales for theutilisation of glutamine in the small intestine weresuggested such as the transport of sodium, the trophiceffect, the stimulation of local immunity. Glutamine canbe supplied to the intestine through both the parenteraland the enteral route. TPN enriched formulas hadpositive effects in the gut such as an increased villousheight and an improvement, in permeability. Enteralglutamine in healthy subjects has improved the structur-al and functional gut changes secondary to 2 weeks ofTPN. In the gut arginine can be converted to ornithineand citrulline. The activity of the enzyme ornithinedecarboxylase, the key enzyme for polyamine synthesisis very high in enterocytes both in the mature villi and inthe crypts. The endoluminal administration of ornithinein starved rats improved villous height and intestinalabsorption. However the role of arginine or ornithine aspolyamine precursors in the gut has not been yet clearlydefined. In animal models TPN supplemented withnucleotides showed trophic effects on the gut mucosaand improved intestinal functions. Fibre is the precursorof short chain fatty acids (SCFA) produced in the colonby bacterial fermentation. SCFA appeared to beimportant not only as fuel but also because of theirmultiple roles in regulating sodium absorption, colon-cyte proliferation, enteral blood flow, nervous systemfunction and hormone secretion. The relevance of

fructoligosaccharides as a source of SCFA as well asprebiotics and products such as yoghurt rich ofSaccharolytic bacteria (Bifidobacterium e Lactobacilli)have recently been investigated for their positive effectson the intestine.

Gut diseases

Short bowel syndrome (SBS) and inflammatory boweldisease (IBD) are two area where major progress andimprovement have been achieved. SBS were at firsttreated by TPN but the understanding of the role ofenteral nutrition in favouring the adaptation of theremaining bowel established the rationale for enteralsupport in many patients who would otherwise bedependent on long-term TPN for their survival. The useof gut specific nutrients in enhancing intestinal adapta-tion is still in the clinical experimental phase but it isconsidered promising. The evolution of nutritionalinterventions in patients with IBD reflects the changein perspective that paralleled the improvement ofknowledge on gut physiology and specific requirement.20 years ago nutrients were kept out of the gut byfeeding the patients through TPN. This approach wasthought to allow a beneficial and therapeutical ‘bowelrest’. The TPN regimens allowed remission rates thataveraged 60%, but relapses were also frequent. Theenteral route was tried but elemental diets were thoughtto be the best approach since they allowed a partialbowel rest. Remission rates were as high as 80%. Thechemically defined diets appeared to have the sameefficacy as prednisolone in symptomatic patients withCrohn’s disease. Furthermore, TEN allowed an im-provement of the nutritional status of the patients. Thehigh price and low palatability of the elemental dietsprompted trials to compare the effects of polymeric dietsto chemically defined products or to standard pharma-cological therapy. Results were conflicting but twoseparate meta-analysis showed no difference in theremission or relapse rates of Crohn’s disease betweenthe two dietary regimens, both of which were, however,less efficient than standard treatments. Immunonutri-tion has found a rationale in Crohn’s disease andulcerative colitis. The administration of n-3 rich fish oilmay have a modulatory effect on the immune andinflammatory response by lowering the synthesis of IL-1, IL-2 and TNF. Remission at 1 year was higher inpatients taking fish oil compared to those given theplacebo.

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