Rex Brown, PharmD
Coordinator of Nutrition Support Services at Regional Medical Center at Memphis/University of Tennessee Bowld Hospital Memphis,Tennessee

Parenteral nutrition (PN) is indicated in acute and chronic care settings when the gastrointestinal tract is neither accessible nor functional. Catheter-related sepsis, metabolic bone disease, and hepatic dysfunction are common problems in patients receiving long-term PN.¹ This article will address the issue of hepatic cholestasis in patients receiving chronic PN.

Shortly after the introduction of PN in the late 1960s and early 1970s, reports of elevations in transaminases, alkaline phosphatase, and occasionally total bilirubin began to be reported in adults. Frank cholestasis was reported in children following the administration of PN. This can be particularly problematic in patients receiving long-term PN. Cholestasis has been reported in 25% to 95% of children receiving long-term PN.^2,3 The incidence of chronic liver disease has been reported to be between 15% and 40% in adults receiving long-term PN. One case reported an adult patient who developed hepatic steatosis leading to progressive steatosis, hepatic fibrosis, and eventually micronodular cirrhosis during long-term administration of PN. These findings were documented by serial liver biopsies over many years.⁴

Pathogenesis

To date, it is still not evident whether the hepatic complications secondary to PN in adults and children follow similar mechanisms. Many adults demonstrate transient rises in transaminase and alkaline phosphatase during PN that resolve without treatment. This is presumed to be hepatic steatosis. Children, on the other hand, are more prone to develop cholestasis that may be accompanied by steatohepatitis. For these reasons, the 2 populations will be considered separately.



Children

Cholestasis with micro- and macrovesicular steatosis has been reported most frequently in neonates and children receiving long-term PN. Associated etiologies with this disorder include prematurity, immature enterohepatic circulation, length of time receiving PN, length of time of gastrointestinal rest, underlying disease, number of infections, bacterial overgrowth, surgeries, and blood transfusions.^2,3 Other possible etiologies include deficiencies in taurine, choline, methionine, essential fatty acids, and carnitine. Nutrient excesses that have been associated with cholestasis include aluminum, manganese, phytosterols from intravenous fat emulsion, and tryptophan.^2,3 There is also substantial evidence that hepatic complications accompany many disease states (eg, major enterectomy in Crohn’s disease), so it is unclear if the administration of PN is a cause or associated cause of hepatic abnormalities. To further complicate the pathogenesis, etiologic factors that were more prevalent in the 1970s are less significant today. For instance, enteral gut stimulation was often deferred for many weeks after major enterectomy. Today, these patients receive early gut stimulation through modest enteral intakes that would minimize the duration of bowel rest as a major risk factor for hepatic cholestasis. The aluminum content delivered to patients was much higher when protein hydrolysates were used as the protein component of PN. Today, crystalline amino acids are used and provide much less aluminum to the patient.

Adults

Hepatic steatosis is common in adults receiving PN, even when the PN is administered for relatively short time periods.⁵ In most cases, the hepatic steatosis is self-limiting, whether the PN is discontinued or not. Some adult patients on long-term PN demonstrate steatohepatitis that eventually results in fibrosis/cirrhosis leading to cholestasis. Many of the etiologies that have been suggested as a cause of PN-associated hepatic complications in pediatrics are also considerations in adult patients. Giving nutrients intravenously instead of via the gastrointestinal tract, nutrient excesses/ deficiencies, decreased enterohepatic circulation, decreased gall bladder motility, abnormal bile acid metabolism, and multiple episodes of sepsis have all been suggested as causes of these complications in adults. Similar to cases in pediatrics, etiologic factors that were widespread in the 1970s are less significant today. For instance, many adults receiving PN in the past were overfed, especially with glucose. This clearly led to fat synthesis in the liver (ie, de novo lipogenesis) with concurrently elevated insulin concentrations resulting in hepatic steatosis. In the last decade, there has been a major emphasis on feeding fewer calories to patients receiving PN.

Prevention

There are a number of measures that every clinician involved in managing long-term PN patients can follow to prevent hepatic complications. First, adult patients should receive conservative doses of glucose (approximately 15 kcal/kg/d) and intravenous lipid (approximately 1 g/kg/d).⁶ These doses can be decreased as oral absorption improves following gut hypertrophy. It has been shown in pediatric patients that lower doses of lipids appear to prevent the onset of cholestatsis in these patients when receiving PN.⁷ Administration of PN should be cycled to allow insulin concentrations to decrease and allow synthesized fat to be mobilized out of the liver.² Patients should be allowed some oral intake with low residue nutrition. This causes gut stimulation resulting in secretion of digestive enzymes into the gut lumen and contraction of the gall bladder. Minimizing the intake of aluminum can be achieved by using components of PN that contain the lowest amount of aluminum contamination.⁸ Since the number of septic episodes is associated with hepatic complications of PN, adherence to a rigid protocol of catheter care would be beneficial.⁹ There are now data suggesting a requirement for choline in the diet.¹⁰ In fact, a deficiency in choline leads to decreased synthesis of very low density lipoprotein and hepatic steatosis in some patients. Patients on long-term PN with severe malabsorption should be considered for intravenous choline supplementation; however, this product is not commercially available yet so patients would have to be enrolled in a clinical trial where they could receive a sterile product. Otherwise an oral form could be used if the patient were taking some PO nutrition. The absorption would be unknown in patients with profound malabsorption. The role of choline in adults continues to be actively investigated.