The patients at intensive care unit (ICU) usually required one of two major nutritional supports enteral (EN) or parenteral therapy (PN) (1, 2, 3). Parenteral nutrition is a life-saving therapy that provides the necessary complete and balanced nutrition for patients who are unable to absorb sufficient nutrients due to intestinal abnormalities or in which there is a contraindication to use the gastrointestinal (GI) tract (insufficient intestinal length or function) (2). From the first time, in the 1960s, when the total parenteral nutrition was implemented many varies studies were conducted to estimate its application and possible side effects (1, 3, 4).

Clinical and epidemiological data indicate that total parenteral nutrition may be associated with a variety of problems. One of the major causes of morbidity and mortality of patients receiving long-term total parenteral nutrition are liver diseases (5). Hepatobiliary system can be affected and complications may vary from mildly elevated liver enzyme values to steatosis, steatohepatitis, cholestasis, cholelithiasis, fibrosis and cirrhosis (4, 6, 7). The most common of these is parenteral nutrition-associated cholestasis (PNAC), that may progress to liver failure (5, 6, 7).

Conversely to parenteral nutrition, enteral food supplying by means of oral nutritional supplements (ONS) and tube feeding (TF) offers the possibility to increase or to insure nutrient intake in case of insufficient oral food intake. This kind of nutritional therapy is indicated when patients cannot meet their caloric requirements through normal food and when there are no contraindications fromm gastrointestinal track (ex., ileus). Enteral nutrition, even not so often as parenteral nutrition, may cause also sides effects including liver damage (3).

The incidence of total parenteral nutrition-related hepatobiliary complications has been reported to be very high, ranging from 20 are to 75% in adults (4). Approximately 40-60% of children on long-term PN will develop hepatic dysfunction (8). In particular, total parenteral nutrition is considered to be an absolute nutrition-related risk factor for the development of biliary sludge and gallstones and is often associated with hepatic steatosis and intrahepatic cholestasis (4). Also hypertriglyceridemia is a common complication predisposing to hepatiobilary complications and it occurs in up to 33% of patients receiving PN (1).

Enteral and parenteral nutritional therapy may be related to transient elevations of liver enzyme concentrations, which return to normal level after parenteral nutrition is discontinued (3, 4). However, long-term use of PN is also associated with more deleterious sides effects including bloodstream infections and metabolic abnormalities. The most severe complication – end-stage liver disease has been described in approximately 15-20% of patients receiving prolonged total intra-venous nutrition (5).

Prolonged parenteral nutrition therapy associated with hepatobiliary disorders is commonly called parenteral nutrition associated liver disease – PNALD. It is the most prevalent and simultaneously most severe complication of intra-venous nutrition (1).

PNALD is characterized by elevations of serum aminotransferases, bilirubin, and alkaline phosphatase. Histologic alterations include steatosis, steatohepatitis, and cholestasis and, in some cases, progresses to fibrosis and cirrhosis (2). It is the most devastating complication of long-term parenteral nutrition therapy. The serum aminotransferase concentrations usually increases, however the increase is minor and does not require intervention (1). Unfortunately its progression is typically insidious causing the late diagnosis, when liver injury is irreversible. If the end-stage liver disease (ESLD) develops, medical treatment is usually futile, and only viable intervention in such stage is the transplantation of both an intestine and a liver (9, 10).

Although likely multifactorial in origin, the etiology of PNALD is poorly understood. A number of causes of PNALD have been proposed, including clinical intervention, nutrient deficiencies and excesses or individual features. Factors that contributes to PNALD include are presented in table 1.

Genetic factors should be also consider in the pathophysiological mechanism of PNALD. Multidrug resistance 1 gene (mdr1) and mdr2 seem to the main factor responsible for hepatobiliary condition. These genes encode P-glycoproteins that are bile canalicular transport proteins carrying bile components out of hepatocytes. In animal model the lack of mdr2 expression develop liver disease that appears similar to PNALD. Not only the decline in mdr2 but also the rise in mdr1 mRNA and protein expression with total parenteral nutrition administration occur before the development of liver injury (during an early state of cholestasis). This suggests that alterations in multidrug resistance genes expression may be a causative factor in the development of PNALD (11).

The possible cause of fatty liver development is a combination of various metabolic processes affecting lipid metabolism, such as increased mobilization from depot fat, augmented synthesis in liver, increased transport to liver, impaired transport from liver, and decreased oxidation of fatty acids (12). The histological examination reveal macro- or micro-vesicular hepatic steatosis with ballooned, fatty degeneration of hepatocytes (13).

Clinical and animal studies suggest that the development of steatosis associated with parenteral nutrition may be caused by apoptotic processes – the main mechanism stimulating fat deposition in the liver (2, 13, 14, 15, 16, 17, 18, 19). Apoptosis is activated through the Fas pathway. Fas is a transmembrane receptor protein belonging to the TNF receptor family and contains a death domain that signals via apoptotic pathways.

Increased levels of Fas in hepatocytes were recently reported in subjects with steatosis and impaired liver function (13, 18). Also lipids are a causative factors in oxidative stress, which are expressed via Fas-mediated apoptosis. In animal model Fas upregulation induced by PN were associated by other markers of hepatocytes apoptosis that included lower ATP concentration, accumulation of ubiquitin, activation of caspase-3 activity, and increased cleavage of poly-(ADP-ribose) polymerase, caspase-8, -9, and -7 (13).

Increased lipid peroxidation and apoptosis of hepatocytes may be caused by short-term as well as long-term PN (17). Continuous administration of PN may result in decreased oxidative phosphorylation in the hepatic mitochondria, leading to speculation that this deterioration in mitochondrial function may contribute to hepatic dysfunction (14). Lipids may also induces the mitochondrial-mediated apoptosis (Bcl-2 interactions) and seem to be a causative factor of fat accumulation in the hepatocytes. Bcl-2 and proliferating cell nuclear antigen expression are downregulated during this processes (13).

The fact that apoptotic changes of hepatocytes may induce the steatosis was also confirm in clinical conditions including nonalcoholic steatohepatitis (NASH) and alcoholic fatty liver disease (AFLD) (15, 16). Moreover, parenteral nutrition induced steatosis may also suppress the ability of hepatocytes to regenerate. It was proved that steatotic liver grafts are associated with a high incidence of primary non-function and initial poor function (19).

Parenteral nutrition-associated cholestasis is the most common complication of PN affecting hepatobiliary system. Bowel rest and bile stasis during parenteral nutrition lead to production of sludge, which can result in eventual gallstone formation (6, 20). The primary indicator of cholestasis is a serum conjugated bilirubin>2 mg/dl (1).

Whereas steatosis is relatively more common in adults, cholestasis is the most common and predictable parenteral nutrition-associated hepatobiliary dysfunction in children (2, 10). Nevertheless, pathologic background of PNAC is poorly understood. Its etiology is multifactorial and include excessive caloric administration, parenteral nutrition components, and nutritional deficiencies. Risk factors include prematurity, long duration of parenteral nutrition, sepsis, lack of bowel motility, and short bowel syndrome (2, 12).

The study of Messing et al. indicated that the percentage of sludge-positive patients during parenteral nutrition increased from 6% during the first three weeks to 50% after the fourth week in the group of 23 patients without hepatobiliary complication before nutritional treatment. Gallstone formation was observed only in sludge-forming patients but did not appeared in patients who were sludge-negative. Three of the 6 first stone-forming patients underwent cholecystectomy because of complications secondary to cholelithiasis after a mean 43-day course of parenteral nutrition. However the sludge positivity decreased during the first three weeks oral indicated refeeding (6).

Essential fatty acids (EFA) cannot be synthesized in human tissues and must be obtained from the diet. Many evidence indicates that unsaturated acids originating from plant oils in lipid emulsions may play a role in the onset of liver injury. The currently approved parenteral lipid emulsions contain safflower or soybean oils. Both oils are reach in omega -6 polyunsaturated fatty acids (PUFAs) that reveals potential proinflammatory effect (22). Omega-6 fatty acid presented in the commercial emulsions are not cleared and targeted similarly to enteral chylomicrons that are rapidly combined with apolipoproteins from HDL and transported to liver. Molecules formed during omega-6 fatty acids parenteral ingestion accumulate in the liver and are not so effective as in limiting de novo lipogenesis. This way they contribute to a steatosis of the liver that became more susceptible to oxidative injury (23).

Conversely to omega-6 fatty acids the omega-3 EFA reveal the antyinflammatory effect. This effect is mainly caused by the changes of the arachidonic acid pathway. Omega-3 polyunsaturated fatty acids displace arachidonic acid from tissue fatty acid pools and thereby reducing the substrate for eicosanoid-synthesizing enzymes and subsequent inflammation (24). They are especially beneficial in liver diseases (steathosis) because they participate in lipid metabolism and reduce elevated cholesterol and triglycerides. Deficiency can develop when intake of EFAs is insufficient (<1%-2% of total calories), that happened during the use of PN with inadequate fat intake (25).

The mechanism of omega-3 fatty acid clearance is independent from the route of administration (parenteral or enteral). Omega-3 fatty acid emulsions decrease lipogenesis de novo and prevent or ameliorate hepatosteatosis induced by parenteral nutrition in animal model. Especially eicosapentaenoic acid is one of the any fatty acid that reveals the greatest reduction of triglyceride production in the liver (21, 26).

Essential fatty acids deficiency (EFAD) is characterized by the decrease concentration of omega-3 and omega-6 fatty acids and is accompanied by a corresponding increase in the percentage of omega-9 fatty acids (mead acids). The deficiency of EFA is often accompanied by hypertriglyceridemia that a common complication in patients receiving parenteral nutrition (PN) predisposing to hepatiobilary complications (1).

Patients with EFAD may show adverse effects, including skin lesions, reproductive failure, growth retardation, reduced learning, impaired vision, and polydipsia, as well as susceptibility to infections. Mead acids are synthesized during the elongation and desaturation of oleic acid that is produced by de novo lipogenesis. The ratio of mead acids to arachidonic acids (the T:T ratio) is used as a diagnostic marker for EFAD. Plasma values of T:T above 0.2 is considered abnormal, whereas levels higher then 0.4 is considered diagnostic for EFAD. However, there are also suggestion that T:T ratios higher then 0.05 and mead acids to AA ratios crossing 0.2 are more reflective of EFAD (27).

Enteral nutrition is safe and effective in most critically ill patients (28, 29, 30, 31, 32, 33, 34). It has usually less side effects comparing with parenteral nutrition however gastrointestinal, mechanical, and metabolic complications may occur. Gastrointestinal complications of enteral nutrition include nausea and vomiting (approximately 20%), diarrhea (2% to 63% of patients) constipation and malabsorption.

Enteral nutrition in intensive care unit's patients may be also associated with alteration with liver dysfunction biomarkers such as enzyme and serum bilirubin. Hepatic dysfunction usually is related to a smaller extend to EN (comparing with PN) and may varied from elevated aminotransferases to steatosis, cholestasis, and gallstones (1, 28). The probable mechanism of liver dysfunction is connected with increased blood perfusion (caused by stimulation on the intestinal wall by EN) that accelerate the secretion of pancreas and biliary duct to prevent shrinking of gut mucosa (29).

It must be also underline that most patients who need EN are critically ill or have a primary severe gastrointestinal disorders (ex., disease short bowel syndrome, Crohn's disease). Thus clinical state is determined by disease-specific alterations which are seen in themselves as a risk factor for the development of liver dysfunction. Systemic inflammation due to the release of proinfalamatory cytokines, altered membrane function, limited antioxidative defense and bacterial overgrowth are risk factors of liver damage (35). An altered liver function defined as an elevation of the AST to more than twice the normal value or of the bilirubin above 2 mg/dl (36).

In the study of Richardson et al. the liver enzyme abnormalities was observed among enterally fed patients receiving a minimum of 1500 kcal/day for at least two weeks. From nineteen patients that fulfilled the study eleven developed abnormal liver function test, however there was no significant difference in the anthropometric measurements or serum albumin between patients with normal or elevated liver function tests. Authors of this study concluded that elevate liver enzymes are more likely to be due to associated clinical complications than the enteral nutritional support alone (31).

The possible modification of medical treatment should be undertaken to prevent hepatobiliary parenteral nutrition complications. Such changes should include avoiding sepsis, providing a balanced source of energy, avoiding overfeeding, weaning parenteral nutrition and starting enteral nutrition. Such modifications ought to be implemented as quick as possible to prevent the most deleterious side effects (3, 4). If a patient receiving PN develops liver complications, it is necessary to rule out all treatable causes and minimize other risk factors. Monitoring serum conjugated bilirubin level as the primary indicator of cholestasis and aminotranserases should be the first step during diagnosis and prevention of liver diseases (1).

To prevent PN-complication many different non-pharmacological therapy management strategies for PN-related liver diseases should be implemented. The change from parenteral to enteral nutrition is the best way in prevention and the fist step in treatment of PN-complications. It was proved that all the hepatobiliary complications are more likely to occur after long-term total parenteral nutrition, but the problem seem to be less frequent and less severe in patients who are also receiving oral feeding (4). If such modification can not be implemented, cyclic infusion should be consider. Interval treatment reduces the PNALD prevalence (1).

A balanced source of energy (with an avoidance of excess carbohydrate and lipid calories) should be of first importance. Lipids administration and amino acid dose should be modified and the dextrose-to-lipid ratio should be calculated. Taurine, carnitine and choline, deficiency should be avoided. Not only the excess of energy but also the nutrient deficiencies and nutrient toxicities should be consider during parenteral therapy (7).

The route of administration is important because the lipids are targeted differently. Lipids absorbed by the enterocyte in the digestive track form micelles are packaged into chylomicrons that are transported to the liver. Chylomicrons are connected with apolipoproteins from circulating high-density lipoproteins and are subsequently metabolized by the liver. Conversely to enteral nutrition, the emulsified particles formed during parenteral nutrition mimic the size and structure of chylomicrons but differ in their content (24, 37).

Substituting parenteral nutrition by enteral one protect against development of PNALD. Also cholestasis induced by parenteral nutrition may be reversed only when all or the majority of energy intake is enterally (10). The study of Javid et al. revealed that hyperbilirubinemia associated with PNALD permanently normalized after the start of full enteral nutrition and discontinuation of PN (30).

Lipid infusion rates – higher then 0.15 g/kg/h, can exceed the rate of metabolism and may lead to increase in serum triglycerides. It is also suggested that the energy supply should be limited together with the reduction of the dose of intra-venous fat emulsion that ought be lower then 1 g/kg/d (1). The accumulation of lipids in the hepatic Kupffer cells and hepatocytes may further impair liver function. Some authors recommend to temporarily stop lipid supply when cholestasis occurs (especially in the case of associated thrombocytopenia) (2). Regardless of these suggestions, such practice may be detrimental in infants, because their limited fat stores predispose to deficiency of essential fatty acids (2). Moreover, the compensation of limited calories from fat by increase amount of carbohydrates in the diet may augment the risk of fat accumulation in hepatocytes causing steatosis (23).

The lipid accumulation in hepatocytes and their impair during PNALD may be minimize by intra-venous fat emulsions consisting of fish oil that are high in eicosapentaenoic and docosahexaenoic acids that do not impair bile flow and may diminish fat accumulation in comparison to conventional fat emulsions (28).

One of the suggested cause of PNALD is the possibility of deficiency of essential fatty acids in conventional emulsions (38). This deficiency may be treated with oral or intra-venous therapy. The lipid intra-venous emulsion used in treatment of EFAD are rich in omega-6 fatty acids derived from soybean oil with or without safflower oils. An alternative lipid emulsion that may be used in the treatment of EFAD is fish oil that is rich in omega-3 fatty acids. This emulsion in is not intended to be used as monotherapy but rather as a supplement added to conventional lipid emulsions as an additional source of omega-3 fatty acids (5, 38). Some authors hypothesized that the administration of fat emulsion rich in fish oils in place of conventional emulsions would improve parenteral nutrition cholestasis in infants with short bowel syndrome and PNALD (38). Fish oil-based emulsion is hepatoprotective in a murine model of PNALD, and it appears to be safe and efficacious for the treatment of this type of liver disease in children (22).

Lipid moiety (soybean-or safflower based lipid emulsions) in commercially available solutions contains plant sterols that have been suggested to contribute to liver injury (38). An olive oil-based intra-venous fat emulsion with 80% olive oil, 20% soy oil and lower plant sterols causes the decrease in liver enzymes comparing to soy-based intra-venous fat emulsion (39).

Management of hypertriglyceridemia typically involves withholding the IV fat emulsion (IVFE) until serum triglyceride levels normalize. Gura et al. described the clinical improvement in EFAD and hypertriglyceridemia after three-weeks of the intra-venous fat emulsion (IVFE) derived from fish oils (40).

In most cases, the treatment for PN-induced hypertriglyceridemia is to reduce the dose or discontinue the IVFE infusion for 4-6 hours to allow for clearance. In some instances, the IVFE may be held for several days and only resumed to provide sufficient fat calories to prevent EFAD. PN therapy typically includes the avoidance of excessive carbohydrates; thus, optimum calories may not be administered if additional calories cannot be provided as fat. Further, the discontinuation of lipids for a prolonged period of time in response to hypertriglyceridemia can predispose patients to biochemical and clinical evidence of EFAD (41).

If the PNALD occurs, it is necessary to rule out all treatable causes and minimize other risk factors. First of all any potential hepatotoxic medications and herbal supplements must be eliminated. Early clinical intervention with a combination of nutritional, medical, hormonal, and surgical therapies can be effective in preventing liver disease progression. There are not specific pharmacological treatment of PN-complications.

The treatment with ursodeoxycholic acid together with an initiation of even small amounts of enteral nutrition may be beneficial in stimulating bile flow (1). UDCA has been shown to improve liver function by promoting bile flow, displacing toxic bile acids, providing chemoprotective effects on hepatocytes, reducing intestinal translocation of endotoxins and bacteria, and enhancing endotoxin biliary excretion (42). An antibiotic implementation should be considered to reduce the risk of bacterial overgrowth and translocation and sepsis (5).

If the non-pharmacological and pharmacological interventions fail, intestinal transplantation should be performed expeditiously before development of end-stage liver disease (9). Early referral for transplantation may be a solution in patients with severe and progressive liver disease. Also evidence of portal hypertension may be a recommendation to the graft. Sometimes combined transplantation of the liver and small bowel may be the only possibility for long-term survival for such patients with progressive liver disease (7). However, this combined procedure reveals usually relatively poor outcomes (9).

Even enteral nutrition has been proven to be an efficient nutritional support, which is prefer to parenteral nutrition, it is still important to thoroughly assess patients prior to initiation of tube feeding and to closely monitor them while they are receiving tube feedings in order to identify potential problems (34). Adequate energy supply and the quality of selected nutrients should be consider. The early initiation of oral nutrition may preserve mechanical and immunological gut barrier function, stimulating intestinal trophism, and reducing bacterial translocation and the incidence of sepsis and multisystem (32, 33, 34). The gut barrier plays a the major role in preventing bacteria translocation. Keeping the integrity of gut barrier is important to decrease the morbidity and mortality of the patients in intensive care units failure (32, 33).