Emma M. Tillman

Review and Clinical Update on Parenteral Nutrition–Associated Liver Disease

Parenteral nutrition-associated liver disease (PNALD) is a complex disease that is diagnosed by clinical presentation, biochemical markers of liver injury, concurrent use of parenteral nutrition (PN), and negative workup for other causes of liver disease. Since the first case of PNALD was reported more than 30 years ago, clinicians have had few effective treatments for PNALD, and when disease progressed to liver cirrhosis, it was historically associated with poor outcomes. Within the past 5 years, there has been much excitement about new treatments for PNALD, including use of both parenteral and enteral ω-3 polyunsaturated long-chain fatty acids (ω-3 PUFA) as well as restricting dosing of ω-6 PUFA. Scientists are also interested in uncovering the mechanisms associated with liver injury seen in PNALD. This article reviews the recent literature relating to the pathophysiology and treatment of PNALD.

Enteral Fish Oil for Treatment of Parenteral Nutrition‐Associated Liver Disease in Six Infants with Short‐Bowel Syndrome

Study Objective. To evaluate the use of enteral fish oil for the treatment of parenteral nutrition‐associated liver disease (PNALD).

Home Parenteral Nutrition Safe Transition From Hospital to Home

Parenteral nutrition (PN) is a complex therapy that may result in serious harm if not properly prescribed, prepared, and administered. The patient who is discharged home on PN for the first time poses significant safety challenges and requires coordination of care between several healthcare disciplines within and outside the hospital. Use of an experienced prescriber and multidisciplinary team to oversee the home PN therapy is an important measure to optimize safety. Referrals should be made to home health and home infusion agencies with qualified staff; however, this may at times be difficult to assess. A safe discharge also requires transition of care between inpatient clinicians caring for the patient and designated outpatient follow-up. Home PN and lab orders upon discharge should be clear and comprehensive. The use of a standardized home PN order format is an important measure to ensure accuracy of the order. Patient and/or caregiver education is another vital component to safely providing PN in the home setting and should ideally be initiated prior to discharge. This should include instructions to the patient regarding self-monitoring and when to call if problems develop. Specific criteria should be identified for the patients regarding when and who to contact for problems that develop after they are discharged home.

Eicosapentaenoic acid and docosahexaenoic acid synergistically attenuate bile acid-induced hepatocellular apoptosis.

BACKGROUND Clinical studies have demonstrated improvement of parenteral nutrition (PN)-associated liver disease (PNALD) with ω3 polyunsaturated fatty acid (ω3PUFA) supplementation containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Experiments were designed to test the following hypotheses: (1) therapeutic effects of ω3PUFA are due to attenuation of cellular apoptosis induced by hydrophobic bile acid exposure, which occurs in cholestasis, and (2) attenuation of apoptosis by EPA and DHA is additive or synergistic. METHODS Cultured HepG2 cells were treated with 50-200 µM chenodeoxycholic acid (CDCA) in the presence and absence of EPA, DHA, or EPA + DHA. Apoptosis was evaluated using cell staining with fluorescence microscopy and the Apo-ONE Homogeneous Caspase-3/7 assay. Specific apoptotic mediators were evaluated with quantitative RT-PCR. RESULTS Treatment with EPA alone and DHA alone resulted in 22% and 9% attenuation of caspase-3/7 activity, respectively. Caspase-3/7 activity was attenuated by 52% when cells were treated with a combination of EPA and DHA (P = .0034). Treatment with EPA alone, DHA alone, and the combination of EPA and DHA all resulted in equal attenuation of apoptotic mediator gene expression. CONCLUSIONS The combination of EPA and DHA resulted in a synergistic attenuation of bile acid-induced hepatocellular apoptosis, as assessed by caspase-3/7 activity, compared to EPA and DHA separately. The combination of EPA and DHA did not result in a synergistic attenuation of the upregulation of Fas or TRAIL-R2. These data suggest that EPA and DHA may be working via multiple intracellular pathways to attenuate bile acid-induced apoptosis.

Treatment of Transient Neonatal Diabetes Mellitus with Subcutaneous Insulin Glargine in an Extremely Low Birth Weight Neonate

Neonatal diabetes mellitus (NDM) results from impaired insulin secretion. While rare, NDM presents complex challenges with regard to the management of glycemic control. NDM is classified as transient neonatal diabetes mellitus (TNDM) or permanent neonatal diabetes mellitus (PNDM). Determination of TNDM vs. PNDM is usually possible only after medical management has been initiated. Management of NDM begins with insulin; however, the correct dose, choice of formulation, and route of administration are complicated by the risk of neonatal hypoglycemia. For the first time, the successful management of TNDM in an extremely low birth weight (ELBW) neonate with the long-acting subcutaneous insulin analog, insulin glargine, is reported. In addition, potential pharmacokinetic barriers to treating ELBW neonates diagnosed with NDM with subcutaneous insulin products are discussed.

Plasma citrulline concentration as a biomarker for bowel loss and adaptation in hospitalized pediatric patients requiring parenteral nutrition.

BACKGROUND Citrulline is a nonessential amino acid produced solely in the enterocyte. Plasma citrulline concentration has been proposed as a noninvasive biomarker for bowel length, function, and dependency on parenteral nutrition (PN). The purpose of this study was to determine if citrulline concentrations differed between pediatric patients with and without small bowel loss requiring specialized nutrition support. METHODS This was a retrospective categorical analysis of citrulline concentrations from previously published studies. Patients were included if they were receiving PN, more than 30 days of age, and if they had at least 2 plasma citrulline concentrations. Patients with renal insufficiency and who received outpatient PN treatment were excluded. Patients were categorized as either having or not having small bowel loss. RESULTS Thirty-six patients were included for analysis (18 per category). The median citrulline concentration was significantly lower in the group with bowel loss, 8.4 µmol/L vs 10.5 µmol/L (P < .0005), and undetectable citrulline concentrations occurred more often in the bowel loss group, 40% vs 8% (P < .0005). In 13 patients who received enteral nutrition during the study periods, plasma citrulline concentrations increased only in patients without bowel loss. CONCLUSIONS These data confirm previous studies and identify decreased citrulline concentrations in pediatric patients with bowel dysfunction in the absence of bowel loss. These data also represent the first serial citrulline concentrations over a 21-day period. The increase in citrulline concentrations only in fed patients without bowel loss suggests that citrulline concentrations could provide a biomarker for bowel function and adaptation.

Supratherapeutic International Normalized Ratio Due to Reduced Vitamin K Intake Secondary to Prolonged Vomiting in a Patient on Warfarin

OBJECTIVE: To report a case of prolonged vomiting during warfarin therapy, leading to an elevated international normalized ratio (INR). CASE SUMMARY: A 32-year-old female with a history of cyclic vomiting syndrome since early childhood and bilateral pulmonary emboli diagnosed 4 months prior to this acute event presented to the clinic for routine monitoring of warfarin therapy. The warfarin dose had been maintained at 35 mg/wk for 3½ months (INR 2-3.5), but it was increased to 37.5 mg/wk because the INR had trended down to the low goal range over the preceding month. At presentation, the patient reported a 15-day history of vomiting with minimal oral intake that required intravenous fluids to prevent dehydration. The INR was 4.7; warfarin was withheld, and oral vitamin K 5 mg as well as subcutaneous vitamin K 10 mg was administered the following day. The INR then decreased to 1.3. Therapy was transitioned to subcutaneous enoxaparin 1 mg/kg every 12 hours for the duration of the patients anticoagulation therapy. DISCUSSION: Multiple reports have demonstrated malabsorption of warfarin and decreased INR response in the presence of underlying gastrointestinal disease. Despite a prolonged episode of cyclic vomiting syndrome, our patient had an elevated INR. In normal circumstances, warfarin is rapidly absorbed from the gastrointestinal tract and reaches maximum serum concentrations in approximately 90 minutes. Studies have shown that although the presence of food does not affect overall absorption of the medication, it can decrease the rate of absorption. Our patient was vomiting 20-30 minutes after oral dose administration. Because the patient was not consuming food, absorption of warfarin was potentially prompt, thus contributing to the elevated INR. The variability of vitamin K in the diet also can have significant impact on the response to warfarin. Our patients INR had been stable while she consumed 3 servings each week of foods rich in vitamin K. This consumption was abruptly discontinued with the onset of the cyclic vomiting syndrome. We believe that decreased intake and retention of oral vitamin K–containing foods from the diet due to the prolonged vomiting coupled with the rapid onset of absorption resulted in a notably increased INR and subsequent bruising in our patient. CONCLUSIONS: In the presence of prolonged vomiting, warfarin therapy requires more frequent monitoring than usual to detect fluctuations in INR that may increase the risk of adverse events.

Role of PPARα in the attenuation of bile acid-induced apoptosis by omega-3 long-chain polyunsaturated fatty acids in cultured hepatocytes

Background:Omega-3 long-chain polyunsaturated fatty acids (ω3PUFA) have been shown to be antiinflammatory in the attenuation of hepatocellular injury. Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor transcription factor that inhibits the activation of nuclear factor κB, thereby repressing inflammation, and ωPUFA are PPARα ligands. The purpose of this study was to determine if ω3PUFA attenuate bile acid-induced apoptosis via PPARα.Methods:Human hepatocellular carcinoma (HepG2) cells were treated with chenodeoxycholic acid (CDCA) ± ω3PUFA. Activation of PPARα was evaluated, and expression of PPARα, farnesoid X receptor, liver X receptor alpha (LXRα), and retinoid X receptor mRNA was evaluated by reverse-transcriptase PCR.Results:PPARα activation was increased in HepG2 cells treated with ω3PUFA, and decreased in the presence of CDCA when compared with untreated cells. PPARα mRNA was reduced by 67% with CDCA and restored to the level of control with ω3PUFA. LXRα mRNA increased twofold with CDCA treatment and was significantly reduced by ω3PUFA.Conclusion:Expression of PPARα, as well as LXRα mRNA levels, was reduced with CDCA treatment and restored with the addition of ω3PUFA. These results suggest that PPARα and LXRα may be mediators by which ω3PUFA attenuate bile acid-induced hepatocellular injury.

Hospital-Acquired Hyponatremia in Pediatric Patients: A Review of the Literature

Hypotonic intravenous (IV) fluids in children are a mainstay of therapy based on a recommendation made in 1957 by Holliday and Segar. Since that time, hospital-acquired hyponatremia caused by hypotonic IV fluids has been found to be an additional risk factor in the cause of death and neurological impairment in acutely ill children. This article reviews and critically evaluates the literature regarding the association of hyponatremia and hypotonic IV fluids in pediatric hospitalized, postoperative, and critical care patients.

Pharmacologic Treatment for Pediatric Gastroparesis: A Review of the Literature

There have been a number of agents that have been tried for treatment of gastroparesis over the past 3 decades, with varying levels of success. Guidelines exist for the management of gastroparesis in adults; however, even though the cause of gastroparesis in children is similar to that in adults, no guidelines exist for treating pediatric gastroparesis as studies on the topic are limited. With what little information we have on pediatric gastroparesis, medications used in childrens studies do not seem to demonstrate the same results as in adult patients with gastroparesis; thus, future studies of whether certain medications are effective for treating pediatric gastroparesis and at what dose still need to be conducted. Pharmacological treatment options for pediatric gastroparesis do not show a clear correlation of resolving or even maintaining gastroparesis-associated symptoms or disease state. This article reviews the available studies of drugs that have shown some efficacy, with an emphasis on pediatric studies.