Liver complications of total parenteral nutrition: the latest therapeutic strategies

Total parenteral nutrition (TPN) is a life-saving nutritional therapy when enteral nutrition is contraindicated or inadequate. The indications for total or partial parenteral nutrition cover a wide range of clinical conditions, such as: short bowel syndrome, intestinal failure caused by neoplastic diseases, inflammatory bowel diseases (Crohn's disease), and highly secreting enterocutaneous fistulas [1].

The spectrum of parenteral nutrition–associated liver diseases (PNALD) includes liver enzyme abnormalities, steatosis, fibrosis, and ultimately cirrhosis. The pathophysiology is presumed to be multifactorial. Diagnosis in adults is based primarily on the elimination of other causes of chronic liver disease or cirrhosis. [2,3,4].

Among patients on short-term parenteral nutrition, abnormal levels of liver enzymes occur in 30% to 43%. In patients on chronic parenteral nutrition, 68% can develop these complications [5].

The aim of the study was to discuss the mechanisms possibly contributing to liver dysfunction related to parenteral nutrition and to discuss potential methods of PNALD prevention.

Cholecystokinin (CCK) released from cells in the proximal part of the small intestine stimulates the secretion of digestive enzymes from the exocrine pancreas and enhances the secretion of bile from the gallbladder. The cycle of secretion and absorption stimulates the flow of bile into the intestine, causing the enterohepatic circulation of the bile acids. The lack of cholecystokinin release followed by reduced emptying of the gallbladder leads to bile stasis and disturbances in enterohepatic circulation [6,7,8]. Studies show that the lack of enteral food supply, and thus the lack of intestinal stimulation, may disturb the secretion of hormones, enterohepatic circulation, and the secretion and absorption of bile acids, which in turn may result in the atrophy of the intestinal mucosa and an increased risk of bacterial translocation [9,10].

Parenteral nutrition may cause insulin resistance and hyperglycemia, due to the intravenous administration of concentrated glucose [11,12,13]. In addition, in patients with short bowel syndrome, the production of incretins (a group of intestinal hormones that increase postprandial insulin secretion by pancreatic β cells) is reduced [8]. The release of GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide) is also reduced because the enteral route is bypassed. GLP-1 inhibits the production of glucose in the liver, promotes the translocation of the GLUT4 (glucose transporter type 4) in skeletal muscle, exerts a cardioprotective effect, and reduces oxidative stress in vascular tissues (insulinomimetic effect). Approximatly 50% to 70% of GLP-1 and GIP hormones are released in response to oral glucose intake. They support the uptake of glucose by the tissues and inhibit the secretion of glucagon by the A-cells of the pancreas [8,14,15].

Chronic delivery of lipids in nutritional mixtures leads to overloading of insulin-sensitive tissue cells with lipid intermediates (diacylglycerols) which disrupt insulin signaling and glucose digestion. The administration of lipid emulsions with the release of n-6 PUFA may cause lipid-induced insulin resistance and leads to changes in insulin secretion. On the other hand, insulin resistance after infusion of lipid emulsions based on fish oil – containing n-3 – is less clear-cut. This may be due to the fact that the clearance of fish oil–based lipid emulsions is less dependent on LPL activity and shows favorable uptake by peripheral tissue. Studies show that n-3 PUFA counteract the negative effects of saturated fatty acids on insulin sensitivity, inflammation, and immunosuppression [13].

The intestinal microbiota have great influence on the condition of the immune system. A healthy gut microbiome provides a physical barrier to pathogens and stimulates the body to produce anti-inflammatory compounds [16]. The lack of enteral nutrition may result in changes in the intestinal microbiome – loss of diversity and an increase in the number of enterobacteria and proteobacteria, combined with a reduction in the number of lactobacilli, and development of the microbiome towards Gram-negative bacteria, all of which promote the production of pro-inflammatory cytokines [17].

For example, Proteobacteria found in the gut of parenterally fed patients include the opportunistic pathogens E. coli, Salmonella, Yersinia, Helicobacter, and Vibrio, all of which are commonly associated with infection [18]. The new findings also show that not only the lack of enteral nutrition but also the phytosterols found in soybean oil–based lipid emulsions affect the intestinal microbiome and thus directly influence enteritis and activate hepatic Kupffer cells, triggering PNALD [19]. Importantly, bile acids affect the composition of the intestinal microbiome by shaping the intestinal immunity of the host, and changes in the composition of the microbiome affect the synthesis and absorption of these acids. Wildhaber et al. showed that restricted enteral nutrition (less than 25% of total caloric intake) completely reversed the unfavorable phenotype associated with parenteral nutrition (increased bacterial translocation, increased production of pro-inflammatory cytokines, representation of the T subpopulation in the intestinal epithelium) [20]. All of the above mechanisms affect liver function and promote PNALD.

An important group of innate immune cells are macrophages residing in the intestine, which play a key role in maintaining homeostasis in the gastrointestinal tract. Intestinal macrophages produce IL-10 (interleukin 10), one of the major anti-inflammatory cytokines. Parenteral food administration leads to a profound decrease in the number of IL-10–producing macrophages in the small intestine. The hindered replenishment of IL-10–producing macrophages together with a shift in the microbial composition towards a more immunogenic phenotype (Toll-like receptors, ligand-rich proteobacteria) may act in synergy to produce a pro-inflammatory state in the small intestine dependent on parenteral nutrition [21,22].

Lipid emulsions are added to PN solutions to provide essential fatty acids and are an excellent energy substrate. They are also components of cell membranes, secondary messengers in cell signaling cascades, precursors of inflammation and platelet function modulators, and serve as a substrate for de novo biosynthesis of cholesterol and endogenous steroids [24].

The first developed lipid emulsion available on the market was soybean oil, which contained a high concentration of PUFA, n-6 fatty acids, and phytosterols. Lipid emulsions were then developed by partially replacing soybean oil with other lipids such as olive oil and fish oil [25]. However, it is believed that lipid preparations, especially the phytosterols contained in them, are involved in the development of liver and biliary disease in patients receiving parenteral nutrition [26].

Phytosterols are not fully metabolized by the human body and must be excreted via the hepatobiliary system. Blood and tissue phytosterol levels can reach high levels during parenteral lipid administration and can be toxic to cells. Accumulating scientific evidence suggests that intravenous administration of high doses of phytosterol-rich lipids contributes to the development of parenteral nutrition–related liver disease.

Phytosterols can also directly activate macrophages to enhance the pro-inflammatory environment. One theory is that relatively high concentrations of n-6 PUFA in plant emulsions generate pro-inflammatory eicosanoids and contribute to hepatitis and cholestasis [25]. The European Society of Clinical Nutrition and Metabolism (ESPEN) states in the latest recommendations to avoid intravenous fat emulsions based only on soybean oil rich in 18-carbon n-6 PUFA due to their probable pro-inflammatory effects [27].

It was proved in studies on rats that the supply of parenteral nutrition caused a decrease in the oxidative metabolism of the liver and the enzymatic antioxidant defense of the organism. It may be related to the saturation of microsomal fatty acids in the liver [23].

Oral or enteral administration of food can significantly reduce the risk of PNALD. This significantly improves the enterohepatic circulation of bile acids and reduces the risk of hepatobiliary complications [25]. It is worth noting that the reduction of side effects can be effectively achieved by administering a part of the caloric requirement by the enteral route as a supplement to TPN. The combination of parenteral and enteral nutrition in patients is beneficial, especially in terms of glucose metabolism and GIP secretion [28].

The ideal goal should be to accelerate enteral nutrition and to sequentially reduce the volume of administered nutritional mixtures, so that the supply of parenteral nutrition can be completely abandoned [29]. Due to clinical conditions, not all patients have such a possibility.

Some authors suggested that 2- to –6-hour breaks in the supply of nutrition reduce the concentration of liver enzymes in the serum, and can also reduce conjugated bilirubin, which leads to a reduction in the risk of PNALD development [30,31]. In our opinion, this strategy is effective in HPN patients. Hospitalized patients require optimization of parenteral support – the provision of individualized nutritional mixtures and adjustment of the time of their supply to the patients' health conditions.

Given the fact that different lipid emulsions have different properties, it is suggested that hepatic complications may be lipid–source dependent. Current research focuses on a lipid emulsion containing fish oil, which may improve clinical outcomes compared to soybean oil–based emulsion and may lead to resolution or even reversal of cholestasis [10,32,33]. N-3 fatty acids have shown a beneficial effect on the intestinal microbiome and studies have shown that they help maintain the epithelial barrier function [25,32,34]. Intravenous administration of fish oil lowers the level of arachidonic acid substrates, as well as plasma tumor necrosis factor-α and interleukin-6 (IL-6), and improves both liver and pancreatic function [35]. N-3 has a positive effect on the intestinal microbiome and helps to maintain the epithelial barrier function. The positive effect of fish oil is mainly attributed to its n-3 content, especially docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). DHA and EPA have anti-inflammatory, immunomodulatory, and antioxidant properties. The introduction of fish oil–based lipid emulsions, which provide partial or complete lipid replacement therapy, resolved PNALD that was associated with soybean oil therapy [24,36,37].

A study conducted in a mouse model by El Kasmi et al. suggests that soybean oil–based lipid solutions cause liver damage and activation of liver macrophages, in contrast to fish oil–based solutions or the use of lipid-free mixtures, which prevent these processes [38].

The review by Mateu de Antonio and Florit-Surred shows that the use of fatty emulsions containing fish oil not only does not increase oxidative stress but may also reduce liver test results in parenterally nourished patients [39]. Studies have also shown that fish oil reverses fatty liver and reduces markers of inflammation in long-term PN patients [34].

Also, α-tocopherol contained in the fats added to nutritional mixtures prevented the increase in serum bile and liver markers and PNALD lipidemia in preterm piglets [40]. However, subsequent studies by the same scientists also suggest that it was not vitamin E, but rifampicin that led to a decrease in PNALD parameters, by increasing the concentration of FGF-19 in the serum and the synthesis of bile acid (hiocholic acid) [41].

In 1995, Buchman et al. carried out studies which resulted in the conclusion that supplemented choline in parenteral nutrition alleviates or even prevents fatty liver [42].

The hepatocyte growth factor (HGF) has a strong anti-inflammatory and antioxidant effect on hepatocytes. Studies in a rat model administered HGF intravenously along with parenteral nutrition attenuated the liver steatosis induced by the 7-day dose of TPN, depending on the dose [43].

The atrophy of intestinal mucosa cells was alleviated by the administration of glucagon-like peptide-2 (GLP-2) and epidermal growth factor (EGF) in mice. The researchers concluded that in the case of enteral nutrient deficiency, the exogenous supply of GLP-2 and EGF showed a strong correlation with the improvement of intestinal epithelial cell responses [44].

The farnesoid X receptor (FXR) has an enteroprotective role as a regulator of intestinal innate immunity and homeostasis. Ceulemans et al. investigated whether the administration of obeticholic acid (OCA), an FXR antagonist, can ameliorate intestinal damage associated with excessive permeability, bacterial translocation, and the occurrence of inflammation. The administration of OCA to mice improved the 7-day survival to 50%, which was associated with the prevention of epithelial damage. In addition, FXR agonism led to a reduction in the release of pro-inflammatory cytokines and an amelioration of the inhibition of autophagy.

In a similar study, tropifexor, a farnesoid X receptor agonist, was administered in a piglet model. There was no increase in pro-inflammatory factors and no oxidative stress in piglets administered PN and tropifexor. Tropifexor can prevent liver damage in newborn piglets receiving PN by altering the composition of the intestinal microbiome and bile acids. Tropifexor also soothes inflammation in the intestines and protects the intestinal barrier. These results turn FXR into a promising target for preventing complications of parenteral nutrition [45,46].

Morin et al. made observations by adding glutathione to parenteral nutrition. This prevented PN-induced oxidative stress in the lungs and muscles and promoted protein synthesis in the liver and muscles. Researchers believe that glutathione may act as a precursor to cysteine, which is deficient in patients with chronic parenteral nutrition [47].

Research indicates that carbamazepine (CBZ), an anti-epileptic drug, modulates liver fibrosis and liver cell damage in a variety of liver diseases. Song et al. hypothesized that this drug could also prevent the development of PNALD. A study on piglets was conducted and it was found that the administration of CBZ alleviated the severity of PNALD [48].

Subsequent studies showed that secretin, as a well-studied gastrointestinal hormone, has a choleretic effect in patients with intrahepatic cholestasis. In an animal research model, a positive effect of secretin was found by enhancing tubular transport, inhibiting the export of bile acids from the liver, and ultimately reducing the total level of bile acids in the liver, which resulted in inhibition of cholestasis. It follows that treatment with exogenous secretin has the potential to prevent and treat PNALD in patients with intestinal failure when long-term parenteral nutrition is provided [10].

This solution is still controversial, but it is advisable to consider bowel transplantation in patients with persistent or progressive hepatic impairment. Impending or overt hepatic failure is considered an indication for intestinal transplantation [49,50].

Implementation of an appropriate, tailored model for the prevention and treatment of PNALD can dramatically reduce the risk of liver disease associated with parenteral nutrition.

In recent years, many studies have been carried out to explain the mechanisms of side effects of parenteral nutrition related to liver dysfunction. This has to do with the growing understanding of PNALD pathogenesis. It has been shown that there is a relationship between the way of feeding, the intestinal microbiota, and the metabolism of the whole organism. Rapid diagnosis of patients at risk, avoidance of excess macronutrients, consideration of early enteral nutrition, use of specialized lipid emulsions can dramatically reduce the risk of PNALD. Taking into account the fact that many complications of parenteral nutrition are correlated with the administration of lipid emulsions, specific guidelines should be created regarding the selection of the composition of the nutritional mixture, with particular emphasis on the fat emulsion, adjusted individually for each patient.