Parenteral Nutrition–Associated Liver Disease

Short abstract

http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/15-2-reading-nowak a video presentation of this article

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Abbreviations

IV

intravenous

PN

parenteral nutrition

PNALD

parenteral nutrition–associated liver disease

SIBO

small‐bowel bacterial overgrowth

Types of Parenteral Nutrition–Associated Liver Disease

Parenteral nutrition (PN)‐associated liver disease (PNALD) refers to liver dysfunction caused by intestinal failure, or inability to digest and absorb nutrients, that occurs in the setting of PN use. There are three primary types of PNALD: steatosis, cholestasis, and gallbladder sludge/stones. Patients may have one of these disorders or a combination of the three.1 Details of each of these diseases are described in the following subsections and in Table 1.

Table 1.

Types of PNALD2, 3, 4

Type of PNALD	Typical Population	Cause	Presentation	Severity
Steatosis	Adults	Overfeeding	Mild to moderately elevated	Benign, although can progress to fibrosis or cirrhosis in patients receiving long‐term PN
			Serum aminotransferase levels Slightly elevated Alkaline phosphatase Total bilirubin
Cholestasis	Children or adults receiving long‐term PN	Multifactorial	Elevated	Serious and can progress to cirrhosis and liver failure
			Alkaline phosphatase γ‐Glutamyl transpeptidase Conjugated (direct) bilirubin (>2 mg/dL)
Gallbladder sludge/stones	Children or adults	Lack of enteral stimulation	No specific laboratory parameters	Typically benign

Steatosis

Steatosis is the accumulation of fat in the liver usually caused by overfeeding or providing excess calories in PN. This disease is more commonly seen in adults than in the pediatric population. On presentation, serum aminotransferase concentrations are slightly elevated, although patients are typically asymptomatic. This presentation typically occurs within 2 weeks of PN initiation, and levels can return to baseline even when PN is continued.2 The presentation of steatosis is usually benign, although it can progress to fibrosis or cirrhosis in patients who are receiving long‐term PN.3

Cholestasis

Cholestasis is caused by impaired secretion of bile or a biliary obstruction. This is typically seen in pediatric patients or adults who are receiving long‐term PN therapy. On presentation, alkaline phosphatase, γ‐glutamyl transpeptidase, and conjugated (direct) bilirubin levels are elevated. Conjugated bilirubin levels >2 mg/dL are the main indicator that cholestasis is present. Cholestasis caused by long‐term PN therapy is a serious complication that can lead to cirrhosis and liver failure.2

Gallbladder Sludge/Stones

Gallbladder stasis can lead to gallstone formation or gallbladder sludge development, resulting in inflammation. Rather than being a direct result of the PN infusion, lack of enteral stimulation leads to decreased cholecystokinin production, which impairs bile flow and gallbladder contractility. Biliary sludge can be produced and causes inflammation of the gallbladder without gallstone formation. Biliary sludge production is associated with duration of PN therapy.2, 4

Risk Factors

There are multiple risk factors for development of PNALD. Some of these are related to the nutrient composition of the PN solution, whereas others are unrelated to PN use. Medical risk factors include intestinal failure/resection, bacterial or fungal infections, sepsis, or small‐bowel bacterial overgrowth (SIBO).2, 3 These risk factors are described in more detail in Table 2.

Table 2.

Risk Factors for Development of PNALD1, 4

Medical Risk Factors	Result in:
Intestinal failure/resection	Interruption of enterohepatic circulation Alterations in bile acid metabolism and excretion
Bacterial or fungal infections/sepsis	Systemic inflammation Release of proinflammatory cytokines that alter membrane function and reduce bile flow
SIBO	Anaerobic bacteria producing hepatotoxins that lead to injury to the liver

Nutrition Risk Factors	Result in:
Excess calories	Steatosis or fat deposition in the liver from increased insulin production Promotion of lipogenesis and inhibition of fatty acid oxidation
Excess carbohydrate administration	Excess carbohydrates depositing in the liver as fat
Excess lipid administration	Excess lipids depositing in the liver as fat when the infusion rate of IV lipids exceeds the liver's ability to clear phospholipids and fatty acids
Soybean oil lipid emulsions	Liver dysfunction caused by the proinflammatory effect of ω‐6 fatty acids Impaired bile flow and biliary sludge/stones related to high phytosterol content
Lack of enteral stimulation	Reduced gallbladder contractility Biliary sludge development impairing bile flow and enterohepatic circulation and bile acid secretion/absorption Mucosal atrophy and potential for bacterial translocation
Continuous PN infusion	Hyperinsulinemia Fat deposition in the liver

Nutrition‐Related Risk Factors

Nutrition‐related risk factors specifically associated with PN infusions are also described in Table 2. The first of these is overfeeding or providing excessive energy that can lead to steatosis or fat deposition in the liver. This is caused by increased insulin release in relation to the excess calorie load, which promotes lipogenesis and inhibits fatty acid oxidation.1 Another risk factor is excessive carbohydrate or lipid administration. High doses of dextrose can deposit in the liver as fat and cause steatosis. High doses of lipids can also lead to steatosis when the infusion rate of intravenous (IV) lipids exceeds the liver's ability to clear phospholipids and fatty acids. High rates of IV lipid administration, especially in long‐term PN use, have also been associated with cholestasis. Finding the ideal ratio of carbohydrate and lipid administration for PN solutions is vital because under provision of lipids it can lead to essential fatty acid deficiency, which can also lead to steatosis secondary to impaired lipoprotein formation and triglyceride secretion.2 Specific recommendations for carbohydrate and lipid administration in PN solutions can be found in Table 3. Providing appropriate amounts of dextrose and lipids in PN solutions can reduce risk for steatosis by decreasing hepatic triglyceride uptake and increasing fatty acid oxidation.1

Table 3.

Ideal PN Solution Recommendations for Carbohydrates and Lipids9, 11

Macronutrient	Current Recommendation
Carbohydrate	70‐85% of nonprotein energy Dextrose infusion rate ≤7 g/kg/day
Lipids	15‐30% of nonprotein energy <2.5 g/kg/day in adults and children <3 g/kg/day in preterm infants Lipid infusion rate ≤1 g/kg/day in patients who experience development of PNALD

IV Lipids

IV lipid source can also have a significant effect on development of PNALD. The most commonly used lipid emulsion in the United States is soybean oil based and contains high doses of ω‐6 fatty acids and large amounts of phytosterols. These ω‐6 fatty acids are proinflammatory and can suppress the immune system.5 Phytosterols are plant‐based cholesterol‐like compounds that can impair flow of bile and cause biliary sludge/stones due to inefficient metabolism in the liver to bile acids. The combination of these ω‐6 fatty acids and phytosterols can contribute to hepatotoxic effects seen in PNALD, especially for patients receiving long‐term PN therapy with soybean oil–based lipid emulsions.2

Newer lipid emulsions are becoming available in the United States. One of these emulsions is a fish oil–based lipid composed of ω‐3 fatty acids with minimal phytosterols. This specific emulsion has been shown to reverse PNALD in pediatric patients when used in place of a soybean oil–based emulsion.6, 7 Further research is needed to determine whether this lipid emulsion should be used routinely to prevent PNALD. Another lipid emulsion containing soybean, coconut, olive, and fish oils has recently become available for use in the United States. This lipid emulsion contains anti‐inflammatory ω‐3 fatty acids, along with ω‐6 fatty acids, which could potentially decrease the risk for development of PNALD or provide treatment for those with preexisting PNALD, although more research is needed to confirm these potential benefits.8

Reducing Risk for Development of PNALD

As discussed earlier, preventing excessive total caloric administration and providing the appropriate ratio of calories from dextrose and lipid is vital in preventing PNALD. There are other modifications that can be made to reduce risk for development of PNALD. Intestinal stimulation in the form of oral or enteral nutrition can drastically reduce the risk for PNALD. This stimulation can promote enterohepatic circulation of bile acids, reducing risk for hepatobiliary complications seen in long‐term PN use.2 Lack of enteral stimulation can impair enterohepatic circulation and bile acid secretion and absorption, which in turn can lead to gut mucosal atrophy and increased risk for bacterial translocation.9 Providing PN infusions over less than 24 hours, also referred to as cycling, is another important intervention to reduce risk for PNALD. A continuous infusion of PN can result in excess insulin production in relation to glucose levels, leading to fat deposition in the liver. Providing patients with time off of PN has been shown to decrease serum liver enzyme and conjugated bilirubin concentrations, resulting in decreased risk for development of PNALD, especially in patients with long‐term PN.10 Interventions to reduce risk for development of PNALD are described in Table 4.

Table 4.

Interventions to Decrease Risk for Development of PNALD2, 4

Intervention	Mechanism
Prevent excess calorie administration	Reduces risk for development of steatosis caused by excessive calories depositing in the liver
Appropriate ratio of dextrose to fat	Decreases the incidence of steatosis by decreasing hepatic triglyceride uptake and promoting fatty acid oxidation
Introducing oral or enteral nutrition	Promotes enterohepatic circulation of bile acids
Cycled infusions (PN infusion less than 24 hours, generally 8‐12 hours)	Reduces serum liver enzymes and conjugated bilirubin

Summary

In summary, there are three major types of PNALD: steatosis, cholestasis, and gallbladder sludge/stones. Numerous factors can contribute to risk for development of these three types of PNALD. It is important to modify PN prescriptions, especially in those patients who require long‐term PN therapy, to minimize the risk for development of these complications.