Parenteral Nutrition-associated Liver Disease Research Articles

Nutritional Risk Factors in the Pathogenesis of Parenteral Nutrition-Associated Liver Disease

Parenteral nutrition has been a lifesaving therapy for individuals who cannot sustain adequate oral or enteral nutrient intake to maintain fluid, electrolyte, and nutrient balance. Nonetheless, parenteral nutrition can lead to an increased risk of complications, such as parenteral nutrition-associated liver disease (PNALD). The pathogenesis of PNALD has been associated with multiple risk factors, such as longer duration, reduced small bowel length, decreased enteral intake, and bacterial infections. Nutritional risk factors also play an important role in the development of PNALD. This review presents several nutrient deficiencies and excesses that have been associated with PNALD. Deficiencies in certain nutrients (amino acids, essential fatty acids, enteral intake), excesses of certain nutrients (calories, carbohydrates, lipids), types of lipid emulsions, and mineral toxicities (aluminum, copper, manganese) have been associated with PNALD. Strategies to address PNALD require correction of these risk factors. The use of newer mixed lipid emulsions (including soybean, medium-chain triglycerides, olive oil, and fish oil) may also have less hepatotoxicity than traditional soybean oil-based lipid emulsions. Knowledge of nutritional risk factors for PNALD will help the clinician in the systematic evaluation and treatment of these specific risk factors. Moreover, an understanding of their effects guides the balance between addressing the patient’s nutritional needs and reducing the risk of PNALD.

Parenteral Nutrition-associated Liver Disease

Parenteral Nutrition-associated Liver Disease

Influence of Fish Oil-Containing Lipid Emulsions on Parenteral Nutrition-Associated Liver Disease in Neonates

This study is a comparative evaluation of the incidence of parenteral nutrition-associated liver disease (PNALD) when administering intravenous fat emulsions containing fish oil.

Hyperinsulinemic Hypoglycemia in Patients with Intestinal Failure Receiving Parenteral Nutrition with a High Glucose Infusion Rate

Management of persistent hyperinsulinemic hypoglycemia in infant and neonatal patients remains controversial. Prolonged hyperinsulinemic hypoglycemia is generally responsive to a high glucose infusion rate (GIR), however the long term adverse effects of providing a high GIR are not well described in the literature. Patients with intestinal failure who develop parenteral nutrition associated liver disease also require a high GIR to meet nutrition needs during lipid minimization. Here we present two cases of confirmed hyperinsulinemic hypoglycemia that developed in pediatric patients with intestinal failure who received a high GIR due to lipid minimization. Our first patient presented to our clinic as a parenteral nutrition dependent four year old female with a history of gastroschisis and jejunal atresia with resultant short bowel syndrome (based on outside records, she was noted to have lost 87% of her small bowel but had 2/3 of her colon) and chronic kidney disease. Her parenteral nutrition utilized lipid minimization, providing her with 1 g/kg/day of lipids and a GIR of 14.1 mg/kg/min. She was diagnosed with hyperinsulinemic hypoglycemia and was started on treatment with diazoxide. Our second patient presented to the intensive care nursery as a three month old female with a history of type IIIB ileal atresia (status post repair on day 3 of life) and failure to thrive. Subsequently, she had multiple bowel resections with lysis of adhesions and a right hemicolectomy, with 63 centimeters of remaining small bowel noted. In the intensive care nursery, she was receiving lipid minimization with a GIR of 26.25 mg/kg/min and 1 g/kg/day of lipids. She was diagnosed with hyperinsulinemic hypoglycemia and was started on treatment with diazoxide. Non-genetic risk factors for hyperinsulinemic hypoglycemia are not well established. From these cases, we postulate that providing high amounts of glucose through a high GIR during lipid minimization in parenteral nutrition alters the pancreatic beta cell regulatory mechanism for insulin release, leading to hyperinsulinism. To our knowledge, this is the first report of this association in the literature in the intestinal failure patient population.

An Observational Study of SMOFlipid® Versus Intralipid® on the Evolution of Parenteral Nutrition Associated Liver Disease in Neonates with Intestinal Failure

An Observational Study of SMOFlipid® Versus Intralipid® on the Evolution of Parenteral Nutrition Associated Liver Disease in Neonates with Intestinal Failure

Alterations in intestinal microbiota relate to intestinal failure-associated liver disease and central line infections

BackgroundThe gut microbiota plays a vital role in modulating the metabolic and immune functions of the intestines. We aimed to analyze the dysbiosis of microbiota in infants with short bowel syndrome (SBS) with different complications. ProcedureWe included 26 fecal samples from 18 infants with SBS during parenteral nutrition. The samples were categorized into three groups: asymptomatic, parenteral nutrition-associated liver disease (PNALD), and central line-associated bloodstream infection (CLABSI). Seven healthy infants were enrolled as controls. Fecal microbiota, secretory IgA, calprotectin, bile acids, and short chain fatty acids were detected. ResultsThe bacterial diversity of the Asymptomatic and Control Groups was significantly higher than that in the PNALD and CLABSI Groups. Proteobacteria was the most pronounced phylum in the PNALD and CLABSI Groups. Decreased acetate was observed in all SBS samples; however, fecal secretory IgA and calprotectin and the proportion of primary and secondary bile acids did not differ from those in healthy controls. ConclusionsMarked alterations of the intestinal microbiota with decreased level of acetate were shown in SBS patients compared with healthy controls. Over-abundance of Proteobacteria (especially Enterobacteriaceae) was found in the samples from the PNALD and CLABSI Groups. Level of evidencePrognosis Study, Level I.

Phytosterols Have Limited Direct Effect on Hepatocyte Transporter Expression but Synergize with Endotoxin to Enhance Kupffer Cell Inflammatory Response

Phytosterols, non‐nutritive components of soybean oil‐based lipid emulsions (SO), have been implicated in the development of parenteral nutrition associated liver disease (PNALD). Phytosterols may drive the pathogenesis of PNALD through a two‐hit mechanism: suppression of hepatic bile clearance through downregulation of the bile salt export pump (BSEP) and increased hepatic inflammation. Inflammation can further suppress BSEP and potentially the ATP‐binding cassette transporters ABCG5/8, the hepatic phytosterol clearance transporter, creating a feed‐forward loop leading to further hepatic injury. Two nuclear hormone receptors, Farnesoid X Receptor (FXR) and Liver X Receptor (LXR) regulate bile acid metabolism and have been shown to suppress the inflammatory response. The aim of our study was to first, determine if the hepatic transport dysfunction and inflammatory response is hepatocyte independent or requires activation of the resident macrophages, Kupffer cells; second, determine if ligand‐mediated activation of FXR and LXR can restore inflammation‐induced suppression of transporter function. Preterm piglets were administered parenteral nutrition for 10 d containing SO lipid emulsion. On day 10, piglets were given an 8‐h infusion of saline or LPS (10 μg*kg−1*h−1). In a separate experiment, primary hepatocytes and Kupffer cells were isolated from neonatal piglets. Cells were treated with media supplemented with 1% SO with or without the addition of a phytosterol mixture containing β‐sitosterol, stigmasterol, and campesterol. After incubation for 24 h, cells were additionally treated with FXR ligand Obeticholic acid (OCA), or LXR ligand GW3694 in the presence or absence of 50 ng/mL LPS or 10 ng/mL IL‐1β for 24 h. In piglets, administration of LPS lead to a significant suppression of BSEP and ABCG5/8 expression compared to saline infused piglets. In cell culture, administration of IL‐1β, but not LPS or phytosterols, led to suppression of both BSEP and ABCG5/8. In hepatocytes co‐treated with IL‐1β and OCA or GW3694, only BSEP expression was rescued. In Kupffer cells, phytosterols alone failed to activate expression of cytokines, however, when treated with both LPS and phytosterols increased cytokine expression significantly more than with LPS alone. From this study, we conclude inflammation can suppress the transporters for bile acid and phytosterol clearance. Our in vitro data shows that Kupffer cells are susceptible to enhanced activation of cytokine expression by phytosterols when cells are primed with LPS. These results suggest that phytosterols may contribute to the progression of liver disease through inflammation.Support or Funding InformationAmerican Society of Parenteral and Enteral Nutrition Rhoads Research Foundation, National Institute of Health Grant DK‐094616

Ileal atresia and multiple jejunal perforations in a premature neonate with gestational alloimmune liver disease

Abstract Recovery after surgical repair of an ileal atresia with or without intestinal perforation requires prolonged exposure to parenteral nutrition (PN) that may lead to PN-associated liver disease. Early liver failure and cholestasis out of proportion for PN exposure may be a harbinger for gestational alloimmune liver disease (GALD), a potentially life-threatening condition that often requires liver transplant if not treated in a timely manner. This case report presents a premature neonate with ileal atresia and multiple jejunal perforations who developed liver failure and was later determined to have GALD. Recognition of clinical and laboratory findings consistent with GALD is essential to promote early treatment, which can enhance neonatal outcomes and impact future pregnancies.

The Differentiation of Intestinal-Failure-Associated Liver Disease from Nonalcoholic Fatty Liver and Nonalcoholic Steatohepatitis.

Intestinal failure-associated liver disease (IFALD), formerly known as parenteral nutrition-associated liver disease has often been listed in textbooks as an example of nonalcoholic fatty liver disease (NAFLD). However, the etiology, pathophysiology, epidemiology, histology, and progression differ substantially between the conditions defined as NAFLD and the disease, IFALD. Therefore, IFALD should not be defined or considered as a type or a cause of nonalcoholic fatty liver or nonalcoholic steatohepatitis, but rather as a distinct disease.

Effects unrelated to anti-inflammation of lipid emulsions containing fish oil in parenteral nutrition for adult patients.

Several reviews and meta-analyses on modulated inflammatory and immunologic responses after the administration of omega-3 polyunsaturated fatty acids (PUFAs) in different diseases and conditions have been published. However, omega-3 PUFAs exert several other actions which are not directly related to immunologic or inflammatory responses. The aim of this paper was to review the effects which are not directly related to immunologic and inflammatory responses of intravenous lipid emulsions (IVLEs) containing fish oil (FO) in parenteral nutrition (PN) for adult patients. IVLEs containing FO could have a role in the prevention of alterations in liver enzyme tests (LETs) or PN-associated liver disease (PNALD). Studies using FO doses of ≥ 0.150 mg/kg/day or IVLEs with high FO concentration reported more positive results than those with lower doses. Once PNALD was developed, the use of IVLEs exclusively composed of FO at doses of 0.25-1 g of FO/kg/day for several weeks could attenuate or even eradicate cholestasis and liver alteration. IVLEs containing FO seemed to have faster blood clearance, and this could be beneficial for some patients. Some studies also suggested a possible improvement of respiratory function by the administration of these IVLEs. In general, IVLEs containing FO were safe. Their use did not increase oxidative stress but, in contrast, increased plasma tocopherol content. They did not alter insulin sensitivity or glycemic control, and studies have found no relevant clinical effect on platelet aggregation or hemostasis. In conclusion, the use of IVLEs containing FO in PN may be beneficial with regard to older IVLEs, in addition to the modulation of systemic inflammation response.

The Effect of Fish Oil-Based Versus Soybean Oil-Based Fat Emulsion in the Occurrence of Parenteral Nutrition-Associated Liver Disease in Premature Infants

The Effect of Fish Oil-Based Versus Soybean Oil-Based Fat Emulsion in the Occurrence of Parenteral Nutrition-Associated Liver Disease in Premature Infants

Stomatocytosis and spherocytosis in a patient with novel heterozygous novel mutation in the erythrocyte protein 4.2 gene and parenteral nutrition-associated liver disease

Stomatocytosis and spherocytosis in a patient with novel heterozygous novel mutation in the erythrocyte protein 4.2 gene and parenteral nutrition-associated liver disease

Pediatric Parenteral Nutrition-Associated Liver Disease.

Pediatric parenteral nutrition-associated liver disease (PNALD) is typically defined as a decrease in bile flow that is independent of a mechanical obstruction and of any other underlying liver disease. It is most often seen in pediatric patients receiving parenteral nutrition support. Up to 50% to 66% of children receiving long-term parenteral nutrition are reported to be diagnosed with PNALD. The goal of treatment for PNALD is advancement to full enteral nutrition and elimination of dependence on parenteral nutrition support. Achieving this goal is not always possible, especially in patients with short bowel syndrome. The following review article highlights some of the current treatment strategies focused on prevention or correction of PNALD as noted in current American Society for Parenteral and Enteral Nutrition guidelines.

Fish oil-based lipid emulsions versus standard lipid emulsions for prevention of parenteral nutrition-associated liver disease in children

Fish oil-based lipid emulsions versus standard lipid emulsions for prevention of parenteral nutrition-associated liver disease in children

Parenteral nutrition dysregulates bile salt homeostasis in a rat model of parenteral nutrition-associated liver disease

Parenteral nutrition (PN), a lifesaving therapy in patients with intestinal failure, has been associated with hepatobiliary complications including steatosis, cholestasis and fibrosis, collectively known as parenteral nutrition-associated liver disease (PNALD). To date, the pathogenesis of PNALD is poorly understood and therapeutic options are limited. Impaired bile salt homeostasis has been proposed to contribute PNALD. The objective of this study was to establish a PNALD model in rats and to evaluate the effects of continuous parenteral nutrition (PN) on bile salt homeostasis. Rats received either PN via the jugular vein or received normal diet for 3, 7 or 14 days. Serum biochemistry, hepatic triglycerides, circulating bile salts and C4, IL-6 and TNF-alpha, and lipogenic and bile salt homeostatic gene expression in liver and ileum were assessed. PN increased hepatic triglycerides already after 3 days of administration, and resulted in conjugated bilirubin elevation after 7 or more days. This indicates PN-induced steatosis and impaired canalicular secretion of bilirubin, the latter which is in line with reduced hepatic expression of Mrp2 mRNA. There was no histological evidence for liver inflammation after PN administration, and circulating levels of pro-inflammatory cytokines IL-6 and TNF-α, were comparable in all groups. Hepatic expression of Fxr mRNA was decreased after 7 days of PN, without apparent effect on expression of Fxr targets Bsep and Shp. Nonetheless, Cyp7a1 expression was reduced after 7 days of PN, indicative for lowered bile salt synthesis. Circulating levels of C4 (marker of bile salt synthesis) were also decreased after 3, 7 and 14 days of PN. Levels of circulating bile salts were not affected by PN. This study showed that PN in rats caused early mild steatosis and cholestasis, while hepatic and systemic inflammation were not present. The onset of these abnormalities was associated with alterations in bile salt synthesis and transport. This animal model serves as an experimental model to further investigate the pathogenesis of PNALD inflicted by steatosis and cholestasis.

Fish oil-based lipid emulsions versus standard lipid emulsions for treatment of parenteral nutrition-associated liver disease in children

Fish oil-based lipid emulsions versus standard lipid emulsions for treatment of parenteral nutrition-associated liver disease in children

Management of Parenteral Nutrition in Hospitalized Adult Patients

Despite the high prevalence of malnutrition in adult hospitalized patients, surveys continue to report that many clinicians are undertrained in clinical nutrition, making targeted nutrition education for clinicians essential for best patient care. Clinical practice models also continue to evolve, with more disciplines prescribing parenteral nutrition (PN) or managing the cases of patients who are receiving it, further adding to the need for proficiency in general PN skills. This tutorial focuses on the daily management of adult hospitalized patients already receiving PN and reviews the following topics: (1) PN basics, including the determination of energy and volume requirements; (2) PN macronutrient content (protein, dextrose, and intravenous fat emulsion); (3) PN micronutrient content (electrolytes, minerals, vitamins, and trace elements); (4) alteration of PN for special situations, such as obesity, hyperglycemia, hypertriglyceridemia, refeeding, and hepatic/renal disease; (5) daily monitoring and adjustment of PN formula; and (6) PN-related complications (PN-associated liver disease and catheter-related complications).

OR03: MIR122 as a Potential Marker of Home Parenteral Nutrition-Associated Liver Disease in Adult Patients: Pilot Study

OR03: MIR122 as a Potential Marker of Home Parenteral Nutrition-Associated Liver Disease in Adult Patients: Pilot Study

Lipid Emulsion Formulation of Parenteral Nutrition Affects Intestinal Microbiota and Host Responses in Neonatal Piglets.

Total parenteral nutrition (TPN) is a cause of intestinal microbial dysbiosis and impaired gut barrier function. This may contribute to life-threatening parenteral nutrition-associated liver disease and sepsis in infants. We compared the effects of a lipid emulsion containing long-chain ω-3 polyunsaturated fatty acids (PUFAs; SMOFlipid) and a predominantly ω-6 PUFA emulsion (Intralipid) on microbial composition and host response at the mucosal surface. Neonatal piglets were provided isocaloric, isonitrogenous TPN for 14 days versus sow-fed (SF) controls. Equivalent lipid doses (10 g/kg/d) were given of either SMOFlipid (ML; n = 10) or Intralipid (SO; n = 9). Ileal segments and mucosal scrapings were used to characterize microbial composition by 16S rRNA gene sequencing and quantitative gene expression of tight junction proteins, mucins, antimicrobial peptides, and inflammatory cytokines. The microbial composition of TPN piglets differed from SF, while ML and SO differed from each other (analysis of molecular variance; P < .05); ML piglets were more similar to SF, as indicated by UniFrac distance ( P < .05). SO piglets showed a specific and dramatic increase in Parabacteroides ( P < .05), while ML showed an increase in Enterobacteriaceae ( P < .05). Gene expression of mucin, claudin 1, β-defensin 2, and interleukin 8 were higher in TPN; overall increases were significantly less in ML versus SO ( P < .05). The formulation of parenteral lipid is associated with differences in the gut microbiota and host response of TPN-fed neonatal piglets. Inclusion of ω-3 long-chain PUFAs appears to improve host-microbial interactions at the mucosal surface, although mechanisms are yet to be defined.

ESPGHAN Committee on Nutrition Position Paper. Intravenous Lipid Emulsions and Risk of Hepatotoxicity in Infants and Children: a Systematic Review and Meta-analysis.

The aim of the present article was to perform a systematic review with meta-analysis of available scientific evidence regarding the role of different intravenous lipid emulsions (ILE) in the pathogenesis of cholestasis and parenteral nutrition-associated liver disease. A systematic review of the literature (up to March 2015) identified 23 randomized controlled trials (RCTs). Of these, 17 were performed in preterm infants or critically ill neonates with a short duration of intervention, 2 in older children with short-term use (following surgery or bone marrow transplantation), 1 in neonates with long-term use, and 3 in infants and children receiving long-term parenteral nutrition (PN). Meta-analysis showed no differences in the rate of cholestasis or bilirubin levels associated with short-term use of different ILEs. Because of high heterogeneity of the long-term studies no meta-analysis could be performed. Available studies found that the use of multicomponent fish oil (FO)-containing ILE compared with pure soya bean oil (SO), ILE-reduced liver enzymes, and bilirubin levels in noncholestatic children on long-term PN and one other RCT found that FO-based ILE-reversed cholestasis in a proportion of patients. The ESPGHAN Committee on Nutrition concludes that there is no evidence of a difference in rates of cholestasis or bilirubin levels between different ILE for short-term use in neonates. The use of multicomponent FO-containing ILE may contribute to a decrease in total bilirubin levels in children with IF on prolonged PN. Well-designed RCTs are, however, lacking and long-term effects have not been determined.