Digestive and Liver Disease
Volume 38, Issue 9 , Pages 623-642, September 2006

Total parenteral nutrition-related gastroenterological complications☆

Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy

Received 29 November 2005; accepted 6 April 2006.

Article Outline

Abstract 

Total parenteral nutrition is a life saving therapy for patients with chronic gastrointestinal failure, being an effective method for supplying energy and nutrients when oral or enteral feeding is impossible or contraindicated. Clinical epidemiological data indicate that total parenteral nutrition may be associated with a variety of problems. Herein we reviewed data on the gastroenterological tract regarding: (i) total parenteral nutrition-related hepatobiliary complications; and (ii) total parenteral nutrition-related intestinal complications. In the first group, complications may vary from mildly elevated liver enzyme values to steatosis, steatohepatitis, cholestasis, fibrosis and cirrhosis. In particular, total parenteral nutrition is considered to be an absolute risk factor for the development of biliary sludge and gallstones and is often associated with hepatic steatosis and intrahepatic cholestasis. In general, the incidence of total parenteral nutrition-related hepatobiliary complications has been reported to be very high, ranging from 20 to 75% in adults. All these hepatobiliary complications are more likely to occur after long-term total parenteral nutrition, but they seem to be less frequent, and/or less severe in patients who are also receiving oral feeding. In addition, end-stage liver disease has been described in approximately 15–20% of patients receiving prolonged total parenteral nutrition. Total parenteral nutrition-related intestinal complications have not yet been adequately defined and described. Epidemiological studies intended to define the incidence of these complications, are still ongoing. Recent papers confirm that in both animals and humans, total parenteral nutrition-related intestinal complications are induced by the lack of enteral stimulation and are characterised by changes in the structure and function of the gut. Preventive suggestions and therapies for both these gastroenterological complications are reviewed and reported in the present review.

Keywords: Cholelitiasis, Colestasis, End-stage liver disease, Liver cirrhosis, Steatohepatitis, Steatosis, Total parenteral nutrition

 

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1. Introduction 

Total Parenteral Nutrition (TPN) has been widely applied to patients who are temporarily or permanently unable to receive sufficient nutrition by enteral intake because of the presence of Intestinal Failure (IF). In this last case TPN must be considered a ‘life saving therapy’, although in long-term users it can cause a variety of problems. In the last decade, gastroenterologists have frequently been involved in the management of patients requiring TPN, so it is necessary for them to know not only the indications but also the limitations and potential complications of this treatment. Herein we reviewed and report data regarding possible gastroenterological problems, subdivided into two categories: (i) TPN-related hepatobiliary complications; and (ii) TPN-related intestinal complications. As it is also desirable for gastroenterologists to be familiar with the treatment of TPN-related complications, all preventive suggestions and medical/surgical therapies for gastroenterological complications are taken into account in this review.

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2. The incidence of TPN-related gastroenterological complications 

2.1. TPN-related hepatobiliary complications 

Hepatic complications are common in both infants and adults receiving TPN, even if no underlying liver disease is present. In the paediatric age group the prevalence has been reported to be from 20 to 90% whereas in adults a broad spectrum of various liver function derangements have been reported in 15–85% of patients undergoing all types and regimens of TPN [1]. The wide spectrum of clinical, biochemical and pathological manifestations may include any combination, ranging from transient benign increases in liver enzymes to liver disease histologically characterised by centrilobular, intrahepatic cholestasis, portal fibrosis, reactive bile duct proliferation, non-specific portal and periportal inflammation, and hepatic steatosis. Cholestasis is the most frequent TPN-related hepatic dysfunction occurring in children [2], [3], [4]. In early studies the incidence of intrahepatic cholestasis in small infants undergoing TPN regimens was reported to range from 7.4 to 84% [2], [3], [5], [6]. In a European survey including 53 centres, liver histological findings ranged from 0 to 40% for fatty liver and 0 to 25% for cirrhosis [7]. Approximately 15–20% of patients who receive prolonged TPN develop end-stage liver disease (ESDL), featuring a high rate of morbidity and mortality [8].

Biliary sludge is the most frequent and transient event. In a series of 23 patients undergoing TPN, Messing et al. [9] observed the development of sludge in 50% of cases after 4–6 weeks of TPN and the formation of gallstones in six patients (23%). In a further study in patients after TPN withdrawal, biliary sludge was still present in 88% of cases after 1–3 weeks, but in none after more than 4 weeks. Gallstones are common in patients with acute and chronic IF, occurring in 45% of patients with a short bowel and in 25% of patients with Crohn's disease [10], [11], [12]. Gallstones are more common in men than women [13].

2.2. TPN-related intestinal complications 

No data are currently available describing the epidemiology and incidence of TPN-related intestinal complications in patients temporarily or permanently unable to receive sufficient nutrition by enteral intake because of the presence of IF.

In Table 1 we summarise data regarding the incidence of TPN-related hepatobiliary and intestinal complications, in adult and in paediatric populations.

Table 1. Incidences of TPN-related gastroenterological complications
Adult patients [references]Paediatric patients [references]
TPN-related hepatobiliary complications
Siderosis15–100% [73], [74]n.a.
Steatosis0–40% [7]29% [75]

Cholestasis55% at 2 years [85]7.4–84% [2], [3], [5], [6]
64% at 4 yearsn.a.
72% at 6 yearsn.a.

Cirrhosis0–25% [7]13% [75]
ESDLa10–15% [8]Occasionally [8]

Biliary sludge6% after 3 weeks [9]n.a.
50% after 6 weeks [9]n.a.
100% after more of 6 weeks [9]n.a.

Gallstones23–40% [10], [12]n.a.

TPN-related intestinal complications
All typesn.a.n.a.

aPatients receiving prolonged TPN; n.a.: not available.

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3. TPN-related hepatobiliary complications 

3.1. Steatosis and steatohepatitis 

The incidence of hepatic steatosis has decreased thanks to the improvements made of TPN solutions and technology, including modifications of the TPN regimen, such as a greater content of lipids and lesser content of glucose. However, hepatic steatosis still remains the most common complication of TPN [14]. Steatosis consists of a hepatic accumulation of micro- or macrovessicular fat associated with metabolic diseases, diabetes, obesity [15], drugs and toxins [16], surgical procedures, and parenteral nutrition (PN) [17], as well as non-alcoholic steatohepatitis, in which case oxidant stress is thought to play a pathogenic role [18].

3.1.1. Pathogenesis of TPN-associated hepatic steatosis 

The precise pathogenesis of TPN-associated hepatic steatosis is still unclear. TPN-related hepatic dysfunctions [19] have been linked to oxidant stress [20], [21] as well as to genetic [22], [23], nutritional, environmental and inflammatory factors [16]. More specifically, the following nutritional factors have been associated with steatosis and/or steatohepatitis: an excessive infusion of glucose [24] or lipids [25], a carbohydrate to nitrogen imbalance [26], [27], and the source of infused lipids [28], an amino acid imbalance [29], [30], enteral starvation [31], [32], photo-oxidised products of amino acids (AAs) [33], [34], [35].

3.1.1.1. Role of macronutrients 

TPN-associated hepatic steatosis may be related to a high concentration of dextrose or glucose in the regimen, and impaired triglyceride secretion by the liver. TPN relying on glucose or lipid emulsion as the energy source usually leads to more severe hepatic steatosis than if a combination of glucose and lipids is used [36]. The ingestion of excess carbohydrates stimulates hepatic acetyl-CoA carboxylase, resulting in a decreased rate of trygliceride secretion [37]. In humans, it has been shown that glucose infusion rates of more than 5mg/(kgmin) result in a fatty liver [38]. There are two mechanisms leading to hepatic lipogenesis and the subsequent increase in hepatic triglyceride formation. Firstly, at a high infusion rate, glucose is maximally utilised, which results in lipogenesis and an increase in triglyceride formation. Secondly, high plasma glucose levels result in increased plasma insulin levels, that again trigger hepatic lipogenesis. Insulin also stimulates glycolysis, fatty acid synthesis, glycogen synthesis, and fatty acid esterification while depressing fatty acid oxidation, glycogenolysis and gluconeogenesis [39].

This has been demonstrated even in the presence of adequate protein stores, stressing the pathogenic importance of excess glucose. Although the infusion of fat also results in steatosis [40], [41], the fat is typically seen in the Kupffer cells and the hepatic lysosomes [42].

Before the widespread use of lipid emulsion, patients developed essential fatty acid deficiency, which resulted in high plasma insulin levels and hepatic accumulation of lipoproteins.

3.1.1.2. Role of AAs 

An absolute or relative deficiency of carnitine is commonly postulated to be a factor contributing to the development of hepatic steatosis following TPN. Previous studies showed that patients on long-term TPN had carnitine deficiency [43], [44], [45], [46], but the prophylactic effects of carnitine supplementation on hepatic steatosis have not been well documented.

Carnitine is synthesised from both methionine and lysine, which are supplied in the TPN solution. However, there is some evidence that hepatic transulfuration pathways may be impaired in these patients, as shown by depressed levels of hepatic S-adenosylmethionine, which would metabolise methionine. When methionine is delivered systemically rather than through the portal system, methionine may be peripherally metabolised into mercaptans, rather than transulfuration products [47]. This would result in deficiencies of important sulfa-containing products such as carnitine, choline, lecithin, taurine and glutathione, which are metabolised through this pathway from methionine.

Among the nutritional factors contributing to steatosis, a carbohydrate to nitrogen imbalance might be implicated. In rats, choline-free diets are used to induce steatosis [48] and in humans, steatosis is corrected by giving choline [49]. Choline is an important component of phosphocholine, which is involved in lipid transport. Low serum levels of choline have been found in these patients, with a significant correlation between the serum-free choline levels, the degree of steatosis, and elevated levels of amino transferases [50], [51], [52], [53]. Steatosis occurs because choline is necessary to synthesise very low density lipoprotein (VLDL). With decreased VLDL, there is decreased transport of triglyceride from the liver and steatosis occurs.

3.1.1.3. Role of other factors 

Starvation, and possibly sepsis, may be the cause of the steatosis seen in these patients [51], [54]. Both states result in an increase in free fatty acids released from triglycerides and an increase in both triglyceride hepatic uptake and hepatic synthesis. This has been shown to occur in starving humans [55] and in animals after the infusion of endotoxin [56]. Moreover, these changes are partially reversed by the administration of antibiotics or tumour necrosis factor (TNF) antibodies in animals [57], [58]. Kaminski et al. [37] demonstrated that patients on TPN with chronic infections have an increased hepatic lipid content as opposed to those without chronic infections.

Exposure of TPN solutions to light is linked to alterations in hepatobiliary function and histology in a perfused liver model [59] as well as in vivo [60]. In the presence of light, reactions occur in the parenteral multivitamin preparation between oxygen and electron donors, resulting in the generation of peroxides. Hydrogen peroxide (H2O2), which is regarded as a key element in the oxygen toxicity of the cell, represents over 80% of the peroxides generated in multivitamins (MV) [61]. Organic peroxides have also been reported to contaminate PN solutions [62], [63], [64]. However, the antioxidant components of the parenteral MV would be expected to protect against the free radicals derived from peroxides generated in TPN solutions [34].

The aetiology of hepatic steatosis might be explained by infused oxidants increasing lipogenesis, or decreasing lipid transport [60] and oxidative metabolism [65], [66]. However, peroxides and/or free radical are not mediators of the induction of steatosis observed after infusion of photo-exposed MV, as there was no correspondence between histological findings and hepatic levels of isoprostane [67]. Starvation might account for the hepatic steatosis observed when glucose is the only source of energy provided with MV. TPN only partially prevents the steatosis induced by MV. This effect of TPN could be explained by an effect of the lipid emulsion acting either as a shield protecting the MV against the effect of light or as a substrate improving the nutritional status. Since the effect of light has also been observed with TPN, the latter explanation is more likely.

Photooxidation of MV might be the common link among reports involving AAs [35], lipids [28] and light exposure [59], [60] in the aetiology of hepatic complications of PN.

MV and H2O2 induce similar responses on markers of oxidation measured in the lungs [33], [68], whereas in the liver they induce separate effects on hepatic isoprostane levels and on steatosis. After infusion, MV and peroxides will transit through the lungs before reaching the liver. This could in part explain why the responses elicited in these tissues are different. However, this discrepancy is not due to peroxides being consumed before reaching the liver, as they have been shown to cause a marked increase in hepatic isoprostane levels.

However, the prophylactic effects of nitric oxide (NO) on hepatic steatosis have not been documented. Nitric oxide synthase (NOS), a site of superoxide synthesis, can catalyse NO synthesis, and can also generate superoxide [71]. The generation of superoxide would increase at suboptimal concentrations of arginine. Sokol et al. [21] reported that hepatic oxidant injury and glutathione depletion occurred during TPN.

NO produced by hepatic cells has many cytoprotective effects such as modulation of vascular smooth muscle tone, inhibition of leucocyte adhesion and platelet aggregation, and reduction of free radicals, and it may play an important pathophysiological role in hepatic diseases [69], [70]. Moreover, hepatic NO synthesis could be increased and NOS activity could be reduced by arginine, while hepatic steatosis was reported to improve. Exogenous arginine was effective in increasing hepatic membrane transport activity and the production of NO. Arginine could promote hepatic NO synthesis, improve hepatic microcirculation, provide feedback inhibiting NOS activity, reduce the generation of superoxide catalysed by NOS and decrease hepatic damage. N-nitro-l-arginine methyl ester (l-NAME) significantly decreased hepatic NO synthesis and induced much more severe hepatic steatosis [72]. The effects of l-NAME on hepatic NO synthesis, NOS activity and hepatic steatosis were reversed by arginine.

3.2. Hepatic siderosis during HPN 

Hepatic siderosis has been reported in histological findings of patients with non-alcoholic steatoepatitis [73]. In our experience of liver histology in eight patients (age, underlying diseases, duration treatment, liver function tests and underwent liver biopsy are reported in Table 2) submitted to biopsy because of abnormal liver function tests during short- or long-term HPN, siderosis was detected in 100% of patients. In all these patients, in fact, a different grade (mild and moderate) of siderosis (Fig. 1A and B) was reported together with mild, typical signs of steatosis (Fig. 1C) and/or fibrosis in liver specimens [74].

Table 2. Sex, age, underlying diseases, treatment duration, liver function tests and liver histology of eight patients treated with HPN
PatientsSexAge (years)Underlying diseaseDuration HPN (days)Liver testsaLiver histology
ALTASTγGtT. bilirubinSteatosisFibrosisSiderosis
A.A.M56Gardner's disease167×0.5×0.5×2.60.90FocalNoModerate
M.E.M28Crohn's disease1161×4×2.7×120.60NoModerateDiffuse, moderate
D.N.F23Intestinal lymphangectasia4381×1.5×1.5×1.70.27FocalModerateDiffuse, moderate
T.M.M67Mesenteric infartion550×1.2×1.3×0.61.04ModerateModerateDiffuse, moderate
C.C.F29Crohn's disease1326×0.7×0.6×0.31.45NoNoDiffuse, mild
M.C.F43Intestinal angiodysplasia2546×1.2×1.3×0.61.04Mild/moderateMildModerate
S.M.F38Crohn's disease1067×1.6×1.1×0.61.0MildMildModerate
L.R.M60Mesenteric infartion2300×2.3×2×10.8ModerateMildDiffuse

ALT: alanine amino transferase; AST: aspartate amino transferase; γGt: gamma glutamyl transpeptidase; T. bilirubin: total bilirubin; and HPN: home parenteral nutrition.

aValues are reported as multiples of the high normal values.

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  • Fig. 1. 

    Histology of liver specimens of patients on HPN; siderosis is observed, together with typical signs of steatosis. Perls's test: mild (A) and moderate (B) diffuse pattern of fine haemosiderin granules, zonal distribution in hepatocytes; Perls's test: mixed pattern of coarse haemosiderin granules in hepatocytes and Kupffer cells (C); EH: macrovacuolar perivenular steatosis (D).

3.3. Intrahepatic cholestasis 

The incidence of liver disease induced by TPN is higher in children than in adults [17] and cholestasis is the most frequent TPN-related hepatic dysfunction occurring in children [2], [3], [4]. The indication for TPN in paediatric patients is frequently a primary gastrointestinal disorder causing IF (congenital intestinal abnormalities, necrotising enterocolitis). The need for a prolonged TPN regimen in these small patients may trigger cholestasis, fibrosis and cirrhosis and even cause liver failure [5], [6]. Hepatobiliary complications of TPN therefore remain a serious threat in younger patients who need long-term TPN to survive.

A common definition of parenteral nutrition-associated cholestasis (PNAC) includes a rise in serum-conjugated bilirubin of 2mg/dl or more, which may be accompanied by increases in γ-glutamyl transpeptidase, alkaline phosphatase and serum transaminase. Extrahepatic causes of cholestasis need to be excluded and drugs with a possible hepatotoxic action suspended. In the great majority of patients, elevated bilirubin values are already observed after the first 2 weeks of TPN, although they may develop even months later. Histological examinations of liver biopsies performed at diagnosis generally reveal a mild to moderate cholestasis with scarce evidence of inflammation or necrosis and no evidence of fat accumulation. As the TPN regimen continues, however, severe cholestasis may occur, concomitantly with bile duct regeneration, portal inflammation and fibrosis. Progressively increasing severe histopathological changes have been reported to be directly related to the duration of TPN [75] and after a few months, cirrhosis may develop in some patients [76].

3.3.1. Risk factors 

The higher incidence of cholestasis in small infants as compared with adults reflects the coexistence of many risk factors in this population: prematurity and low birth weight may be associated with impaired immunity and a higher susceptibility to infections; limited oral intake and intestinal stasis may facilitate small bowel bacteria overgrowth. Risk factors found to be associated with the appearance of cholestasis include prematurity, low birth weight, sepsis, the presence of jejunostomy and the need for gastrointestinal surgery [2], [3], [4], [77], [78]. The duration of TPN and of enteral fasting are also positively correlated with PNAC [75].

3.3.2. The pathogenesis of PNAC 

Numerous studies have attempted to identify the pathogenesis of cholestasis and liver injury induced by TPN. While this complication probably has a multifactorial origin, a better knowledge of the risk factors has suggested new hypotheses regarding the mechanism involved in this complication. The high prevalence of PNAC in younger age groups is certainly conditioned by the relative immaturity of the biliary secretory system in neonates and, in particular, in premature versus full-term infants. Premature neonates have a decreased bile acid pool and an impaired hepatic mitochondrial function [79]. A transient immaturity of the enterohepatic circulation is also common in early life, causing an impairment in bile uptake, production and release [80]. Other pathogenetic factors involved in PNAC have been classified in three categories: (a) consequences of the lack of physiological enteral intake; (b) the toxicity of TPN components; and (c) causes related to the underlying disease necessitating TPN use [81].

3.3.2.1. Loss of physiologic enteral intake 

The lack of enteral stimulation by intraluminal nutrients during TPN is responsible for multiple changes ultimately contributing to PNAC [4], [79], [81], [82]. These changes include: (1) Lack of oral intake-induced release of the gastrointestinal hormones and growth factors (involved in enterocyte proliferation and maturation). (2) Lack of cholecystokinin (CCK) release and consequent decreased emptying of the gallbladder leading to bile stasis and depletion of the enterohepatic circulation. (3) Intestinal stasis, enterocyte hypoplasia and impaired gut immunity (decreased GALT function with reduced IgA secretion), favouring bacterial overgrowth. Bacterial overgrowth may contribute to the development of cholestasis by increasing bile acids deconjugation. Chenodeoxycholate is converted to lithocholate, which is known to induce cholestasis in experimental models. (4) Enterocyte hypoplasia, which may favour bacterial translocation (BT) and cause an activation of inflammatory pathways through an increase in portal endotoxins. The lipopolysaccharide component of endotoxins stimulates macrophages to release cytokines (interferon-γ (INF-γ), interleukin (IL)-1, IL-6, TNF and transforming growth factor (TGF)-β). TGF-β is known to trigger hepatic fibrosis and may contribute to cholestasis.

3.3.2.2. The toxicity of TPN components 

Many studies on the development of cholestasis have postulated the involvement of some factors inherent to nutrition itself. As previously reported, a calorie excess due to glucose and lipid overload may result in liver toxicity, thus causing hepatic steatosis and cholestasis [83], [84]. The amount of lipids infused, for doses higher than 1g/(kgday), also correlates with liver dysfunction [85], [86]. On the other hand, a small amount of lipids (0.5kg/day) should be included in TPN infusions to avoid PNAC [84]. The TPN protein content and the composition of AAs mixtures have been also advanced as possible factors inducing liver dysfunction. Cholestasis, in fact, develops earlier in patients receiving TPN formulations with a higher protein content [87]. As to AAs mixtures, based on the knowledge that the metabolism of some AAs is impaired in premature infants (methionine may accumulate due to a slower metabolism), while other AAs (such as taurine) are virtually essential in children and therefore need to be added [88], paediatric formulations have been developed. The possible toxic role of specific nutrients added to TPN – such as aluminum, copper and manganese [89] – has also been underlined; the administration of these elements is therefore commonly suspended in patients with either initial or overt evidence of liver dysfunction. A decrease in antioxidants such as Vitamin A, Vitamin E and selenium has also been reported in PNAC, although supplementation with antioxidants to normalise their levels does not guarantee a clinical improvement. Contaminants and other non-nutrient substances present in PN formulations have also been attributed a possible role as toxins causing liver damage. Among these, we can include phytosterols – derived from soy and present in many commercial lipid formulations – which may accumulate and cause an alteration in the bile flow [90], [91], and polysorbate [92], used as a TPN emulsifier, or Tween 80 (polyoxyethylene sorbitan mono-oleate) used as a surfactant.

3.3.2.3. Underlying disease which necessitates TPN use 

Since most patients who require TPN have a primary gastrointestinal disorder as well as other severe medical conditions, a contribution of the underlying disease to hepatobiliary alterations cannot be excluded. In patients with short bowel syndrome (SBS), who require chronic TPN treatment due to IF [93], the disease itself adds further risk factors such as malnutrition, failure to thrive, bacterial overgrowth and translocation, frequent infections, as well as repeated surgical procedures and the need for multiple therapies—which may include the administration of drugs with a potential cholestatic effect. All these factors may act synergically with TPN to cause liver dysfunction and intrahepatic cholestasis [94], [95].

3.4. Fibrosis, cirrhosis and ESDL 

In practice, these conditions trigger an irreversible process that is preceded by one or several of the above-mentioned histopathological features. Periportal fibrogenesis is usually caused by the stimulation of fibroblasts in the connective tissue in this area and is associated with acute cholangitis and pericholangitis. Panlobular fibrogenesis is more closely linked to cholestasis, steatohepatitis and necrosis brought on by the stimulation of Ito cells, via several molecular mechanisms, some of which have been previously referred by Shaffer and ESPEN-HAN Group [7]. The incidence and the severity of hepatic damage leading to steatohepatitis, cholestasis and other irreversible injury such as fibrogenesis and cirrhosis increases progressively if TPN is administered for a longer period or if the underlying disease is complicated by: (a) SBS; (b) frequent sepsis; (c) multisurgical procedures; and (d) Crohn's disease [2], [96], [97], [98], [99].

The development of ESLD has also been occasionally reported in children receiving HPN [100]. The combination of chronic inflammation and SBS and, perhaps, age, appears to be necessary to determine ESLD following prolonged home TPN. A few studies have suggested that patients with duodenocolostomies appeared to be at higher risk [101] than those with some residual in situ jejunum or ileum. The poor prognosis of ESLD strongly supports the need for active investigation of potential measures limiting severe hepatic injury.

3.5. Biliary sludge and gallstones 

The loss of enteric stimulation occurring during TPN impairs the gallbladder motor function, favouring the development of a sluggish gallbladder. This explains the frequent association of TPN with gallbladder dysfunction, including abnormal gallbladder dilatation and the development of acalculous cholecystitis, biliary sludge and gallstones.

3.5.1. Risk factors 

The biliary sludge and gallstones detected during TPN in IF patients may be due to risk factors directly related to TPN or to other indirect risk factors that could be present in the same patient (ileal disease or resection, surgery, rapid weight loss or drug treatments). Bacterial overgrowth has been proved to have a role [102].

3.5.1.1. Direct risk factors: TPN 

Bile is not supersaturated as a result of TPN [103], but bile flow is impaired [104] and gallbladder emptying is reduced during both continuous and cyclic infusions [105]. A medium/long-chain triglyceride mixture in a PN regimen may be more likely to cause biliary sludge than long-chain triglycerides alone [106].

3.5.1.2. Indirect risk factors: ileal disease or resection 

Gallstones often appear calcified on a plain abdominal radiograph [11]. They are more common in patients with ileitis than in those with ileo-colitis or colitis [107], and their likelihood may increase with the length of bowel resected [108], the duration of the disease, previous surgery and the patient's age [12], [109].

Disruption of the enterohepatic circulation and a consequent loss of bile salts should lead to an increase in cholesterol saturation (related to concentrations of cholesterol, bile salts and phospholipids); this was the case in some studies of patients with ‘ileal dysfunction or resection’ [110], [111] but not in others [110]. A reduced amount of deoxycholic acid and an increased amount of ursodeoxycholic acid (UDCA) (which helps to keep cholesterol soluble) are found in the bile of patients with ileal Crohn's disease [111], [112]. Bilirubin concentrations in bile are two- to three-fold higher in patients with ileal disease as compared to those without ileal disease [111], [112], while there is no difference in phosphatidylcholine levels [111]. The majority of patients (children and adults) who undergo ileal resection and require long-term TPN develop pigment gallstones [113]. Moreover, in patients with Crohn's disease it has been suggested that other mechanisms could play an important role. In fact, a significant reduction of gallbladder contractility has been demonstrated after a fatty meal [114], [115], which could contribute to the formation of biliary sludge.

3.5.1.3. Indirect risk factors: surgery 

Major abdominal surgery – not involving the biliary system – [116], cardiac valve replacement surgery [117], and a period of intensive care therapy [118] all predispose to gallstone development, with an equal incidence in both sexes. This is again likely to be due to bowel rest causing biliary stasis, biliary sludge and the formation of gallstones.

3.5.1.4. Indirect risk factors: rapid weight loss 

Cholesterol gallstones are common (40%) in morbidly obese patients, and this figure increases in cases of a diet causing rapid weight loss or after weight-reducing surgery [119]. Approximately 38% of patients undergoing gastric by-pass surgery developed gallstones [120], which formed during the time of maximal weight loss. Reduced gallbladder motility is likely the most important factor, but increased cholesterol saturation may also contribute [120]. A significant increase in the gallbladder volume occurred after 10 days in obese patients taking a low-energy, low fat diet [121], and could be secondary to minimal CCK secretion or to excess secretion of pancreatic polypeptide or somatostatin (gallbladder wall relaxants).

3.5.1.5. Indirect risk factors: drug treatments 

Octreotide, a long-acting somatostatin analogue used in the treatment of a high-output jejunostomy, increases the risk of cholelithiasis [122]. It reduces post-prandial gallbladder contractility [123] and slows intestinal transit; thus, secondary (more lithogenic) bile acids are formed by intestinal bacteria [124]. Opiate and anti-cholinergic drugs reduce gallbladder contractility, and may increase the risk of developing gallbladder disease.

3.5.2. Pathogenesis 

Bile supersaturation, nucleation and crystallisation, together with reduced gall bladder contractility, are traditionally the key factors that produce ‘lithogenic bile’. In patients with IF, the stones are of pigmented type, composed of calcium bilirubinate, and probably develop in biliary sludge which has formed due to gallbladder stasis. Biliary sludge contains calcium bilirubinate or unconjugated bilirubin, cholesterol monohydrate crystals and increased amounts of mucin glycoproteins [125]. Biliary sludge may disappear spontaneously, but frequently evolves into gallstones [126]. Sludge may persist or recur in 50% of cases, and gallstones may form in up to 14% of affected subjects over the age of 3 years [127].

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4. TPN-related intestinal complications 

4.1. Animal and human data in the non-critical setting 

In this part of the review, the experimental and human studies investigating intestinal alterations during TPN in the healthy state or in non-critical diseases are discussed. The vast majority of the information summarised below has been derived from animal models, while relatively little information is available from human studies.

TPN has been associated with changes in gut morphology, intestinal blood flow and in several intestinal functions: cell proliferation and apoptosis, enzymatic functions, immune defence, permeability, barrier integrity, motility and bacterial ecology.

It has not been clearly defined whether such intestinal changes are determined by the absence of luminal nutrient substrates or by TPN itself. The issue has been addressed in a recent study in a mouse model, which demonstrated that increased apoptosis of epithelial cells, changes in the phenotype and functions of the intraepithelial lymphocytes (IEL) and BT are caused by the lack of enteral feeding rather than by TPN [128].

4.1.1. Changes in gut mucosal morphology 
4.1.1.1. Animal studies 

It has been demonstrated [129], [130] that rats receiving 10–15 days of TPN exhibit a significant (p<.001) decrease in the jejunal mass, the jejunal and ileal length of villi, and in the perimeter length, mucosal thickness, villous area and villous surface in the distal ileum, compared with a control group fed chow. Recent studies in neonatal piglets have shown that in this model the gut alterations occur very early: by day 3 the ileal crypt depth, and by day 7 both jejunum villous height and crypt depth, were found to be significantly lower (p<.05) in TPN versus TEN-fed animals [131]. In similar experimental conditions, after 6 days of TPN, Burrin et al. [132] demonstrated a significantly (p<.001) lower small intestinal weight and protein and DNA content, while Niinikoski et al. [133] were able to show that similar changes (decreased total mucosal intestinal weight and jejunal mucosal weight, DNA mass, villous height, protein mass, crypt cell proliferation and mean number of crypt cells) can occur after only 48h of TPN. They also observed a higher rate of apoptosis in both the crypt and the villi (p<.05); interestingly, it was found that these changes are preceded by portal venous and superior mesenteric arterial blood flow suppression, that occurs rapidly (within 8h) after TPN; within 24h of TPN, inducible NOS decreases and mucosal atrophy develops. The authors hypothesised that the insufficient supply of oxygen and nutrients to the villous epithelial cells may induce hypoxia, oxidant stress, and eventually cell death and villous atrophy.

4.1.1.2. Human studies 

In the few human studies conducted, TPN-induced gut alterations were less marked and not consistently detected: no significant changes in villous height were observed in patients fed by TPN for 10 days before surgery [134], while in healthy volunteers 14-days TPN was associated with a significant decrease in mucosal thickness (p<.003) and in the number of villous cells (p<.03). However, the number of crypt cells and the microvillous height were not significantly affected [135].

4.1.2. Changes in digestive, absorption, metabolic and proliferative functions of the epithelial cells 
4.1.2.1. Animal studies 

Niinikoski et al. [133] were able to show that compared with enteral nutrition, 24h-TPN results in a significant decrease both of protein fraction synthesis and of crypt cells proliferation (p<.05) in the jejunum of neonatal piglets; further progression of these changes was observed after 48h. Burrin et al. [132] studied the effects of 6-days TPN, compared with EN in infant pigs: in animals pre-treated with TPN they observed a marked reduction in the net absorption of both glucose and galactose and a significant, but less pronounced, suppression of the absorption of lysine, threonine, isoleucine and arginine; the arterial utilisation and oxidation of leucine were also significantly lower. Therefore, it is possible to conclude that in infant animals TPN rapidly induces severe alterations in functional and proliferative activities.

4.1.2.2. Human studies 

The results obtained in human studies are reported in Table 3, although no conclusions can be drawn, because these studies were performed in heterogeneous clinical situations. It could be hypothesised that in humans damage to the functional and proliferative activities due to the lack of enteral nutrition might occur only when TPN is administered in subjects with a concomitant inflammatory status of the digestive tract [136], [137], [138], or in long-term TPN [139], while no alterations are induced by short-term (12–14 days) TPN in adult healthy subjects [135] or after neurosurgery [138] and by medium-term (30-days) TPN in IBD children [139].

Table 3. Enzymatic and proliferative activities during TPN: human studies
AuthorsNumber of patientsDuration of TPNObservations
Guedon et al. [136]Seven IBD adult patients21 days↓ Enzymatic activities of the brush border (p<.05)
↓ Peptidases (p<.05)

Inoue et al. [137]Six pre-operative adult patients7 days↓ Brush border transport of AAs (except GLN) by 26–44% (p>.05)
↓ Brush border transport of glucose (p>.05)

Rossi et al. [139]Three IBD children (9–17 years)1 month- Disaccharidase activities: no significant changes
Four SBS children (7–54 months)>9 months↓ Disaccharidases (p<.05)
↓ Thymidine incorporation (p<.001)

Wicks et al. [138]Twenty-four adult patients after liver transplant10 days↓Carbohydrates absorption (p<.05)

Buchmann et al. [135]Eight healthy adult volunteers14 days- Disaccharidase activities: no significant changes

Suchner et al. [140]Thirty-four adult patients after neurosurgery12 days↓ Vitamin A absorption (p<.05)
- d-xylose absorption: no significant changes
- Lactose tolerance: no significant changes

IBD: inflammatory bowel disease; and SBS: short bowel syndrome.

4.1.3. Changes in intestinal mucosal immunity and intestine-derived inflammatory responses 

Most of the currently available knowledge derives from experimental studies, in which the effects of malnutrition on gut immunity can be explored separately from those related to enteral nutrient deprivation.

4.1.3.1. Animal studies 

In mice it has been demonstrated that compared with a complex enteral diet (CED) and with chow, i.v.- and intragastric TPN (the last used as an enteral elements diet), induce an overall reduction of up to 50% in total lymphocytes (T and B cell populations), in the whole small intestine, both in Peyer's patches and in the lamina propria, together with a significant reduction in CD4+ cells and in the CD4:CD8 ratio in the lamina propria [140], [141] these changes occur rapidly, reaching a maximum within 3 days of TPN [142], and are reversed equally rapidly by the resumption of the chow diet [143]. It was also shown that TPN impairs the mitogenic responses of the gut lymphoid populations [144], and decreases the number of biliary secretory IgA, of IgA plasma cells in the terminal ileum [18] and the overall secretion of intestinal IgA [141]. A parallel reduction of respiratory mucosal IgA was also documented [142], demonstrating that the lack of luminal nutrient stimulation of the gastrointestinal (GI) tract may cause the suppression of extraintestinal mucosal immunity. Enteral stimulation of the GI tract is also essential to maintain pre-established respiratory mucosal immunity against viruses and bacteria: 50% of TPN-fed mice lost their pre-acquired protection against the APR/8 Haemophilus influenza virus, whereas all animals fed via the gastrointestinal tract were able to clear the virus [145], [146]. Similarly, after immunisation with the Pseudomonas antigen, animals undergoing TPN lost their respiratory immunity to the bacterial challenge after five days, whereas animals fed chow or by CED maintained their immunity intact [147].

The TPN-induced reduction in the lamina propria CD4:CD8 ratio [147] leads to a change in the balance maintained under normal conditions between Th2 IgA stimulating cytokines (IL-4, IL-5, IL-6, IL-10 and IL-13) and Th1 IgA inhibiting cytokines. The lack of enteral feeding reduces the former but has no effect on the latter [148]; this imbalance accounts for a drop in IgA by approximately 50% and upregulates the inflammatory response in the intestine and other organs. In fact, it has been observed that TPN induces a significant increase in the expression of the intercellular adhesion molecule-1 (ICAM-1) in the intestine and lung [149], of P-selectin in the intestine and of E-selectin in the pulmonary vasculature [150], in conjunction with increased intestinal levels of myeloperoxidase, a marker of polymorphonuclear neutrophils accumulation. These phenomena have been hypothesised to act as a diet-induced “first hit” to the intestine; in turn this can affect the response to subsequent injuries such as ischaemia/reperfusion. In fact, mice pre-treated with TPN suffered 80% mortality after 30min of gut ischaemia, versus 10–15% mortality in chow and CED-fed animals [151].

4.1.3.2. Human studies 

In adult healthy volunteers, 2 weeks of TPN did not affect the intestinal immune function, measured by the number of IgA-, IgM- and IgG-producing cells, T and B cells, and the intraepithelial and lamina propria lymphocyte counts [152]. In a recent meta-analysis of clinical studies in which enteral nutrition was compared to PN, Braunschweig et al. [153] found that tube feeding was associated with a lower risk of infection than PN, and the effect remained in the subgroup analyses including the presence of cancer, the nutritional status, the year of publication of the study and the study quality score.

It is not possible to ascertain from the results of the metanalysis whether enteral nutrition has a specific protective role on mucosal immunity, although this cannot be excluded. However, the higher rate of infection with TPN, that persists even after removing the effect of catheter sepsis, seems to be due, at least in part, to factors specifically related to TPN, like hyperglycaemia.

In human infants a reduction in intestinal IgA immunocytes was documented when PN was started [154]; in children, a 50% decrease in IgA immunocytes has been observed in defunctioning colostomies within 2–11 months of surgery [155].

In conclusion, in animals there is no doubt that the lack of enteral nutrition is associated with derangements of intestinal and extraintestinal immunity; in adult humans, the effect has not been clearly demonstrated, even though enteral nutrition is associated with a lower risk of infection than PN; in infants and children the lack of enteral nutrition induces a decrease of IgA immunocytes.

4.1.4. Changes in intestinal permeability; BT 
4.1.4.1. Animal studies 

Several experimental studies have demonstrated that TPN alters intestinal permeability, while BT (the passage of intact, viable bacteria from the bowel lumen to the mesenteric lymph nodes) has occasionally been reported [72], [129], [156], [157], [158], [159], [160].

4.1.4.2. Human studies 

In human beings, elevated gut permeability has frequently but not always been found; however, in the only study that addressed the issue [134], it was observed that BT is unaffected by TPN. Moreover, O’ Boyle et al. [156] did not find any relationship between BT and either intestinal permeability or the index of villous atrophy [161], [162], [163].

The results of experimental and human studies are reported in Table 4.

Table 4. Intestinal permeability and BT during TPN: experimental and human studies
AuthorsAnimals/patientsDuration of TPN (days)Method (for gut permeability)Intestinal permeabilityBT
Experimental studies
Alverdy et al. [157]Rats14 n.a.+
Illig et al. [129]Rats10Lactulose+n.s.
Haskel et al. [158]Rats7 n.a.+
Mosenthal et al. [159]Rats7Ex vivo using chamber system++
Kansagra et al. [160]Piglets6Mannitol, lactulose, PEG 4000+n.s.
Zheng et al. [72]Rats7 +

Human studies
Van der Hulst et al. [161]IBD, cancer10–14Lactulose/mannitol+n.a.
Buchmann et al. [135]Healthy volunteers14Lactulose/mannitol+n.a.
Sedman et al. [134]Pre-op10 n.s.
Carr et al. [162]Post-op6Lactulose/mannitol+n.a.
Reynolds et al. [163]Post-op7Lactulose/mannitoln.s.n.a.

n.a.: not available; n.s.: no significant difference from control; IBD: inflammatory bowel disease; pre-op: pre-operative findings; and post-op: post-gastrointestinal surgery findings.

4.1.5. Changes in intestinal motility 
4.1.5.1. Animal studies 

The effect of TPN has been studied experimentally in dogs, using regimens containing only glucose and AAs [164], or the usual clinical solutions of glucose, AAs and lipids [39]. It was found that neither TPN regimen altered phase III of the migrating motor complex (MMC) either in a jejunoileum site [164] or at the midpoint of the duodenum, at the jejunum 10cm distal to the ligament of Treitz, at the midpoint of the small intestine between the jejunum and ileum, and at a point 15cm proximal to the ileocolic junction [165]. The transit time during fasting was also unaltered [164]. However, during complete TPN, the MMC lasted longer and phase III less long, in the stomach, duodenum and gallbladder; a prolongation of phase II was also observed in the stomach and duodenum [165].

4.1.5.2. Human studies 

In humans it has been clearly demonstrated that gallbladder motility is impaired by complete TPN [166], [167]. Intravenous glucose reduces gastric motility; the inhibitory effect is related to the degree of hyperglycaemia and may result from suppression of the activity of the vagal-cholinergic nerve system and the reduction of motilin [168]. Lipids infusion causes delayed gastric emptying [169] and, at a high infusion rate, reduces the duration of phase III in the jejunum [170]. However, i.v. administration of high doses of AAs stimulates gastric acid secretion [171], and gallbladder contraction [172]; both effects are antagonised by the concomitant infusion of glucose [173] and of lipids [171]. During infusion of AAs, the intestinal transit time is significantly prolonged, the recurrence of phase III is accelerated and phase II is suppressed.

4.1.6. Changes in the intestinal bacterial ecosystem 
4.1.6.1. Animal studies 

Several studies in rats have demonstrated that after 7–10 days of TPN, the caecal [129], [158], and ileal [174] bacterial content greatly increases, while only minimal changes are observed in the jejunum. Anaerobes and Gram-negative enteric bacteria entirely account for the increase. In piglets undergoing TPN the ileum bacterial content grew rapidly with mucin (mucin-associated bacteria), and in particular the content of Clostridium perfringens, was significantly higher compared with that of TEN-fed animals [175]. C. perfringens is an opportunistic pathogen that may contribute to the induction of necrotising enterocolitis in low birth infants, of infectious diarrhoea and of enteritis necroticans.

4.1.7. Changes in blood flow 
4.1.7.1. Animal studies 

Interestingly, a recent study on 3-week-old piglets demonstrated that after 8h of TPN both the portal and the superior mesenteric artery blood flow decreased by 30% compared with the flow in enteral feeding; this change preceded morpho-functional alterations, that appeared after 24h (villous atrophy and the suppression of protein synthesis) and after 48h (decrease in cell proliferation and rise in apoptosis) from the onset of TPN [133].

4.2. Animal and human data in the critically ill setting 

Despite being clinically beneficial in critically ill patients, TPN causes the lack of enteral stimulation and is associated in these patients with additional intestinal changes in structure and function: gut barrier damage, upregulation of SIRS, impaired mucosal immunity.

4.2.1. Gut barrier damage 
4.2.1.1. Animal studies 

Recently, in rat models of surgical trauma and infection, Ding et al. [176] explored additional gut damage of TPN and sepsis in these critical conditions. After one week of PN, TPN-fed rats demonstrated extreme atrophy of the intestinal mucosa and impairment of the intestinal barrier function when compared to controls and to EN-fed rats. Intraperitoneally injected LPS resulted in further damage in TPN rats compared with much less marked damage in EN rats. The increased impairment of the mucosal barrier function might be related to NO, after LPS injection. The L/M ratio also increased progressively in all rats except controls.

The cellular mechanisms involved in the increased permeability observed during TPN have not been completely established; cultured epithelial cells have been shown to lose tight junction integrity with the addition of INF-γ, a reaction which may be blocked by TGF-β.

Because IEL are a rich source of these cytokines in the epithelium, Kiristioglu and Teitelbaum [177] hypothesised that in mice receiving TPN, changes in the IEL might be responsible for the mediation of such cytokine responses. He found a 40 and 12.5% incidence of BT to mesenteric lymph nodes in the TPN and Control groups, respectively. TPN led to statistically significant decreases in the CD4+, CD8−; CD4+, CD8+; and the CD8+, CD44+ IEL subpopulations (p<.05); mRNA expression for INF-γ was increased by 53% (p<.05), and TGF-β1 mRNA expression decreased by 75% (p=.1) in the IEL of TPN-fed mice as compared to controls.

However, gut inflammation may play a role. In rodents, Fukatsu et al. [149] found that myeloperoxidase activity was increased in animals fed TPN. Furthermore, they found an increase in ICAM-1 expression in the intestinal tissue of the TPN-fed animals. The significant increase in myeloperoxidase activity in the proximal small bowel, which could be a marker of polymorphonuclear leucocyte (PMN) infiltration or inflammation, might be linked to the increased permeability.

Kansagra et al. [160] focused their attention on alterations in the TJ in TPN and EN-fed piglets. In the TPN group there was a notably increased content of the TJ protein claudin-1. This was an unexpected finding, given that paracellular permeability was increased in this group. Investigators have suggested that TJ fibrils are heteropolymeric, so that differing claudin superfamily subtypes combine to form varying degrees of ‘adhesiveness’. Moreover, TJ strands are repeatedly broken and reannealed to give the junction a certain tightness. Despite no difference in the quantities present, the remaining proteins may change their localisation.

Most interestingly, in the small intestine of neonatal piglets, goblet cell expansion occurred independently of overt inflammation but in association with parenteral feeding [131]. These data support the hypothesis that goblet cell expansion represents an initial defence mechanism triggered by reduced epithelial renewal, serving to prevent intestinal barrier failure.

This mechanism helps to maintain mucosal barrier homeostasis by enriching the epithelial monolayer with longer-lived, apoptosis-resistant cells, which contribute sulfomucins that resist bacterial enzymatic degradation.

Given these changes in the villus architecture and goblet-cell phenotype, it may be hypothesised that TPN, and hence the absence of exogenous nutrients, alters the qualitative nature of the microbial population, bringing about a selective enrichment of mucolytic bacteria, i.e. bacteria that are able to grow within the mucus layer by degrading and fermenting mucins. In piglets the bacterial community structure was equally complex in the ileum of TEN and TPN-fed animals, but the profiles clustered according to the nutrition mode. In TPN, 62% of the total mucus-associated bacteria grew on mucin, compared with 33% of mucus-associated bacteria in TEN ileal samples. Bacteria capable of using sulphated monosaccharides were also enriched in TPN samples. C. perfrigens, an opportunistic pathogen, was specifically enriched in the TPN ileum [175]. Similar enrichment processes may occur in humans nourished by TPN and may thereby contribute to intestinal dysfunction.

4.2.1.2. Human studies 

In critically ill patients, after short enteral fasting (7 days) Hernandez et al. [178] found gut mucosal atrophy, expressed as a decrease in villus height and crypt depth, compared with controls. The patients also exhibited an abnormal lactulose-mannitol test. The morphometric changes did not correlate with permeability. Furthermore, he found no correlation between clinical data and the results of the lactulose-mannitol test and of mucosal morphometry.

Hadfield et al. [179] measured GIT absorption (on the basis of urinary recovery of d-xylose and 3-O-methyl-d-glucose) and GIT mucosal permeability (on the basis of the ratio between urinary recovery of lactulose and l-rhamnose) in TPN and EN-fed critically ill patients and in controls. Measurements were performed at entry to the study and on every third day thereafter. Baseline recovery of d-xylose and 3-O-MG was significantly lower than in controls. The baseline L/R ratio was increased compared with the EN group and the controls. In the EN group, the L/R ratio declined progressively and significantly, whereas in the TPN group, no significant change in the L/R ratio was observed. This study demonstrates that GIT dysfunction is evident in critically ill patients and suggests that loss of GIT mucosal integrity is reversed by the institution of EN.

4.2.2. Upregulation of SIRS 

As compared to EN, TPN increases the expression of P-selectin in the GI tract and of E-selectin in the lungs; this triggers leucocyte rolling along the endothelium of post-capillary venules and induces priming of PMNs by overexpression of ICAM-1, induced by the reduction of IL-4 and IL-10 levels in the small bowel.

4.2.2.1. Animal studies 

TPN constitutes a ‘first hit’ in rats and upregulates intestinal, hepatic and pulmonary SIRS to a second injury (i.e. ischaemia); mortality was significantly higher in the PN group than in the enteral nutrition group (40% versus 10%). Both intestinal ICAM-1 and MPO levels return to normal within 4 days after reinstitution of an oral diet or after glutamine (GLN) supplementation [149].

4.2.3. Impaired mucosal immunity 
4.2.3.1. Animal studies 

In mouse, the lack of EN leads to reductions in PP, LP (by 55–66% in B and 40% in T lymphocytes) and IEL, partly due to a rapid reduction in the PP mucosa addressin adhesion molecule-1 (MAdCAM-1), that regulates the traffic of naïve lymphocytes to the PP and of activated lymphocytes to the LP [141]. TPN decreases the CD4:CD8 ratio by reducing the number of CD4 cells and therefore reduces the stimulatory effects of IL-4 and IL-10 on plasma cells IgA production [148]. TPN decreases selective transport of IgA into the lumen by reducing the cellular basolateral SC receptors due to its effect on Il-4 levels [180].

Experimental studies in mice showed decreases in both intestinal and nasotracheal IgA levels within 3 days [148]. These data could explain the increased mortality rate in previously immunised mice and the higher susceptibility to pneumonia of TPN-fed patients.

In a recent work, Wildhaber et al. [128] concluded that the changes observed during TPN administration are caused by the lack of enteral feeding, and not by the TPN solution itself. In TPN-fed mice the addition of oral feeding reverses the TPN-associated GALT impairment and significantly reduces BT, restoring control group levels.

In rat models of surgical trauma and infection, impaired mucosal immunity and BT are higher in TPN-fed septic animals than in EN-fed ‘critically ill’ animals [176].

BT does occur in critically ill patients. There is good evidence to show that translocation is associated with an increased incidence of septic complications but not with mortality [180].

BT has been suggested to be promoted by three factors: alterations in the physical properties of the intestinal barrier, and in gut ecology, as well as decreased host immune defences.

4.2.3.2. Human studies 

Nevertheless, despite extensive corroboratory evidence from animal studies, there is as yet insufficient evidence to conclude that BT is either a promoter or an initiator of septic morbidity in critically ill patients receiving TPN.

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5. Preventive suggestions and therapy 

5.1. Prevention and treatment of hepatobiliary complications 

Prevention of gallbladder stasis is based on stimulation of CCK secretion, gallbladder contraction and bile flow, on decreasing the lithogenicity of bile and on avoiding drugs which decrease gallbladder contractility and slow small bowel transit (Table 5).

Table 5. Prevention of biliary sludge and stones in patients on PN
Aim [references]TreatmentResults in humans/comments
Simulation of CCK secretion [181], [182], [183], [184]Minimal oral intake of food (proteins and long-chain triglycerides)/enteral nutritionDecreased secretion of CCK in ultra-short bowel
Rapid i.v. infusions of AAs: 2.5g in 5min of an amino acid solution enriched with BCAA (volume 200ml)Efficacy demostrated in one study

Stimulation of gallbladder contraction [185], [186], [187], [188]i.v. CCK-octapeptide:Efficacy demonstrated in two studies; frequent side effects: nausea, vomiting and abdominal pain
Adults: 50ng/kg body weight
Children: 20–40ng/kg body weight
i.v. erythromycin:No studies in patients on PN
≤7mg/kg body weight
Oral indomethacinNo studies in patients on PN

Increasing bile flow [189], [190]Sphincterotomy (sphincter of Oddi)No studies in humans
Prophylactic cholecystectomy in patients with short bowelNo studies in humans

Decreasing the lithogenicity of bile [191], [192], [193]Oral metronidazoleMetronidazole decreases the production of secondary bile acids (e.g. lithocholic acid) by preventing/treating small bowel bacteria overgrowth: efficacy demonstrated in a study of patients with Crohn's disease
UDCAUDCA reduces cholesterol crystallisation

Avoiding drugs [189], [17]Octreotide, opiate and anti-cholinergic drugs: decreased gallbladder contractility and slow small bowel transitOctreotide is used in the treatment of a high-output jejunostomy

The oral/enteral intake of small amounts of food containing proteins and long-chain triglycerides stimulates CCK secretion, which in turn causes gallbladder contraction. The CCK response to oral feeding may be decreased in patients with a very short residual small bowel [181], [182]. CCK release and gallbladder contraction have been observed after rapid intravenous infusions of AAs [183], [184]. Gallbladder contraction can be obtained by means of intravenous infusion of CCK-octapeptide or of erythromycin, a macrolide antibiotic with a prokinetic effect, and by oral intake of therapeutic doses of indomethacin [185], [186], [187], [188]. Sphincterotomy (the sphincter of Oddi) may favour bile flow, and prophylactic cholecystectomy has been proposed in patients with a short bowel [189], [190].

Metronidazole may have a role in preventing cholestasis [191]. It suppresses the overgrowth of anaerobic bacteria in the intestinal lumen, responsible for the production of secondary bile acids (i.e. lithocholic acid). UDCA, a secondary bile acid that reduces cholesterol crystallisation by reducing the concentrations of promoting factors, has also been shown to be effective in reducing PN-related intrahepatic cholestasis [192], [193].

Protection against, or treatment of, liver disease in patients undergoing PN must take into account pathogenetic factors related both to the underlying disease and to the PN.

The prevention and treatment of small bowel bacterial overgrowth, intestinal inflammation and mucosal damage, intestinal hypoperfusion or hypoxia and sepsis are mandatory in patients on PN, as these conditions play a major role in causing liver disease. Drug hepatotoxicity must also be considered [189], [5].

Table 6 shows the treatment options for the PN factors. PN macronutrient overfeeding can be avoided by optimising the infusion of dextrose, lipids and AAs [5], [83], [85], [194], [195]. Insulin secretion can be decreased by replacing 30% of the dextrose energy with lipids in the PN formula and by cycling the PN infusion with an 8h break during the day [196], [197]. The amounts of ω6 polyunsaturated fatty acids, phospholipids and phytosterols infused with the lipid emulsions can be reduced by using a mixture of long and medium chain triglycerides or oleic acid based emulsions [13], [198], [199], [200]. In neonates, intravenous taurine promotes bile flow and limits the synthesis of bile acids secondary to hepatotoxicity. Taurine is the principal bile acid conjugate in neonates, who may not be able to make taurine from methionine and cysteine. Bile flow can also be promoted by maintaining some enteral feeding, while UDCA is a choleretic agent which replaces bile acids that are toxic to the liver [192], [193], [201], [202]. Choline supplementation, a precursor of phospholipid synthesis, may decrease liver steatosis by promoting VLDL secretion [39], [203]. Carnitine supplementation may stimulate fatty acids oxidation, but its addition to a PN regimen was not able to improve the liver alterations [204]. A deficiency of some micronutrients may be implicated in the development of liver steatosis and cholestasis in patients on PN. [5], [189], [205], [206]. Copper and manganese are excreted in bile, therefore they should be removed from the PN solution of patients with cholestasis. [5], [189]. Finally, patients with ESLD should be referred for combined small bowel and liver transplantation. Due to the high rate of death of these patients on the waiting list, early referral is mandatory [200], [207].

Table 6. Preventing and treating PN-related liver disease
Aim [references]TreatmentResults in humans/comments
Avoiding PN macronutrient overfeeding [17], [194], [83], [85], [87], [195]Dextrose:
<7g/(kgday) (<5mg/(kgmin))Dosage in non-catabolic patients
<5g/(kgday) (<3.5mg/(kgmin))Dosage in patients with severe catabolism
Lipids (as a 20% lipid emulsion rich in ω6 polyunsaturated fatty acids):
<2g/(kgday)Dosage in short-term PN
<1g/(kgday)Dosage in long-term PN
AAs:
<2g/(kgday)

Decreasing insulin secretion [196], [197]Substitute lipids for 30% of energy from dextroseContinuous PN results in hyperinsulinism and high rates of lipogenesis; cyclic PN results in lower insulin levels
Cyclic PN (stop for 8h)

Decreasing pro-inflammatory lipids (ω6 PUFA), phospholipids and phytosterols [25], [198], [199], [200]Lipid emulsions based on mixture of long- and medium-chain triglycerides or ω9 monounsaturated fatty acidLower serum bilirubin levels in patients with cholestasis have been reported using long- and medium-chain triglyceride emulsion
No data on ω9 monounsaturated fatty acid emulsion in patients on PN and cholestasis

Promoting bile flow, decrease synthesis of secondary bile acids (i.e. lithocolic acid) [192], [193], [201], [202]i.v. taurineTaurine, more useful in neonates, who may not be able to make taurine from methionine and cysteine
Oral and enteral nutrition whenever possibleEnteral nutrition improves glucose tolerance
Oral UDCA: 20–30mg/(kgday)Efficacy of UDCA demonstrated in one study of PN patients with cholestasis

Increasing VLDL synthesis by the liver [203], [50]Choline:Efficacy demonstrated for both oral lecithin and i.v. choline;
As oral lecithin: 20g b.i.d.
As i.v. choline: 2g/dayi.v. choline not available

Increasing long-chain fatty acid oxidation [204]i.v. carnitine: 2g/dayOne study in four patients on HPN: no effects

Avoiding/treating micronutrient deficiency [189], [17], [199], [205], [206]PhosphateLow serum phosphate can worse hepatic hypoxia
Essential fatty acids: 2–4% of non-protein calories such as linoleic acid are recommended
MethionineMethionine is the only sulphur-containing amino acid in most parenteral formulations; hepatic transsulfuration to S-adenosylmethionine may be low in PN patients
MolybdenumMolybdenum deficiency has been associated with cholestasis
Anti-oxidants (Vitamin E, selenium)Peroxidative free radical damage can be caused by PU-related deficiencies of Vitamin E and selenium

Avoiding/treating microelement overload [189], [17]Remove copper and manganese from the PN solution of patients with cholestasisCopper and manganese are excreted in bile
Transplantation [200], [207]Combined small bowel and liver transplantationEarly referral for transplantation is recommended for patients with progressive liver disease, because of the high rate of death on the waiting list

5.2. The prevention and treatment of intestinal complications 

The preventive and therapeutic options available for TPN-related intestinal complications appear insufficient. The few data on this issue described in the literature are reported below.

5.2.1. Prevention 

It has been claimed that even a low quantity of enteral feeding can protect the gut from TPN-dependent alterations. The question is: how much is the ‘minimum enteral feeding’ required to avoid intestinal complications? Searching for an answer to this question, we have found only the data discussed below.

5.2.1.1. Animal studies 

Experimental studies in rats have shown that BT progressively decreases with increased oral feeding; a 20–25% of calories given as chow is considered sufficient to reduce the number of bacteria-positive mesenteric lymph nodes to a safe level (∼10%) [208], [209], but these same amounts do not improve intestinal permeability and immunity [209], [210]. However, higher enteral intakes are necessary in piglets to increase the jejunum protein mass and villus height (>40%), the ileal protein mass (>60%), to sustain normal mucosal proliferation and growth (>60%) and to increase total lactase activity [211] in both the proximal jejunum and the ileum (>80%).

5.2.2. Treatment 

A number of agents, including biologically active peptides, have been demonstrated to enhance the intestinal function parameters and morphology in animal models and in human patients [212]. Growth hormone (GH) is the most important endocrine peptide that seems to have a role on intestinal morphology and function.

GH administration has been shown to have no acute effect on intestinal water, electrolytes or xylose absorption in vivo [213], while its administration for 3 days preoperatively increased intestinal amino acid, but not glucose, absorption in surgical patients undergoing intestinal resection [214]. Ellgard et al. [215] demonstrated that low doses of GH did not increase intestinal water or protein absorption, whereas Byrne et al. [216] found, in eight patients, that co-administration of GH (0.14mg/(kgday)) with GLN and a modified diet increased intestinal protein and glucose absorption, decreased stool loss, and increased body weight. This data was not confirmed in other studies of similar therapeutic regimens [217], [218]. Another randomised, double-blind, placebo-controlled, crossover study [219] detected no increases in intestinal absorption of carbohydrate, fat, nitrogen and electrolytes, measured 5 days after a 4-week treatment period with GH and GLN. Finally, in a more recent randomised, double-blind, placebo-controlled, crossover study [220], 3 weeks of low dose GH significantly improved intestinal absorption in HPN-dependent SBS patients receiving a hyperphagic western diet.

As we have shown, the currently available therapeutic options for NPT-related intestinal complications and for IF are not clearly defined. Maybe differences in the therapeutic approach have to be considered in acute and in chronic disorders, such as in patients in intensive care and those affected by chronic IF.

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6. Conclusions 

Clinical epidemiological data indicate that TPN may be associated with TPN-related hepatobiliary complications (mild liver enzyme elevations, steatosis, steatohepatitis, cholestasis, fibrosis and cirrhosis) and TPN-related intestinal complications (changes in gut morphology, intestinal blood flow, cell proliferation, apoptosis, enzymatic functions, immune defence, permeability, barrier integrity, motility, bacterial ecology) that very frequently have negative effects on the morbidity rate and quality of life of patients undergoing home PN. The incidence of gastroenterological complications could be significantly reduced by carefully following the preventive measures reported in the SINPE guidelines [221], [222]. While therapeutic interventions for TPN-related hepatobiliary complications have been well defined, therapeutic options for TPN-related intestinal complications still lack clinical importance and require further scientific confirmation.

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Conflict of interest statement 

None declared.

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Acknowledgement 

We are grateful for the helpful contribution of the SINPE (Italian Society of Parenteral and Enteral Nutrition).

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References 

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☆ This paper includes data based on the detailed reports of all the speakers invited to the Joint Meeting AIGO-SIGE-SINPE ‘Patenteral Nutrition: Gastroenterological Complications’ held in Genoa on the 15th of March, 2005 during the XI National Congress of Digestive Disease.

PII: S1590-8658(06)00150-2

doi:10.1016/j.dld.2006.04.002

Digestive and Liver Disease
Volume 38, Issue 9 , Pages 623-642, September 2006

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