Predicting Liver Failure in Parenteral Nutrition-Dependent Short Bowel Syndrome of Infancy

doi:10.1016/j.jpeds.2009.11.002

The Journal of Pediatrics

Volume 156, Issue 4, April 2010, Pages 580-585.e1

Portions of this work were presented at the X International Small Bowel Transplant Symposium, Sep 5 to 8, 2007, Santa Monica, CA. The authors declare no conflicts of interest.

https://doi.org/10.1016/j.jpeds.2009.11.002 Get rights and content

Objectives

To test the hypothesis that early trends in common blood tests may delineate risks of liver failure (LF) in infants with parenteral nutrition-associated liver disease (PNALD) from short bowel syndrome and suggest criteria for transplant referral.

Study design

Total levels of bilirubin, gamma-glutamyl transferase, albumin, alanine aminotransferase, platelet count, and absolute neutrophil count were recorded every 3 months for 61 infants with PNALD who were being considered for intestinal transplant starting at age 3 months until death without transplant (n = 12), LF with transplant (n = 35), or liver recovery without transplant (n = 14). Probabilities of LF were determined with logistic regression.

Results

Independent predictors of LF were, in descending order, total bilirubin level (odds ratio [OR] = 1.195), platelet count (OR = 0.992), and albumin level (OR = 0.248). Predicted probabilities of eventual LF varied from 36% to 38% at ages 3 to 6 months when the total bilirubin level was 6.0 mg/dL, platelet count was 220 x 10³/μL, and albumin level was 3.5 g/dL to 83% to 84% when the total bilirubin level was 11.7 mg/dL, platelet count was 168 x 10³/μL, and albumin level was 3.0 g/dL.

Conclusions

Transplant referral for a total bilirubin level of 6 mg/dL between 3 to 6 months of age is appropriate, because the probability of LF is at least 36%.

Section snippets

Methods

A total of 84 patients with SBS, defined as a minimum PN requirement of 6 weeks after resection, and cholestasis² were examined between August 2003 and December 2007. Of these 84 patients, 61 in whom designated demographic and laboratory data could be collected were included in the investigation. Frequent multiple caregivers at multiple institutions before referral was the usual explanation for inadequate information leading to exclusion of patients, most of whom were in advanced LF at the time

Demographic and Anatomical Comparison of the LR and LF Groups

Of the 61 subjects, LF developed in 47; the remaining 14 patients later experienced hepatic recovery. As noted in Table I, the average age at initial examination of the 47 patients in whom LF developed was approximately 6 months; 41 of these patients (87%) were referred by other institutions. In contrast, 8 of 14 patients (57%) who experienced LR were referred from other institutions (P < .01, χ² test) and were on average approximately half the age of the other patients. No patient referred

Discussion

Reports from several intestinal transplant centers have described the frequently advanced character of PNALD in pediatric patients at presentation, resulting in high mortality rates before transplantation can be attempted.13, 14, 15 One factor contributing to late referral is a lack of detailed information on the natural history of PNALD. In this study, we sought to ascertain whether delineation of trends in laboratory abnormalities, particularly at an early stage of the disease, might be more

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Deciding which patients would benefit from intestinal transplantation (IT) remains an ethical/clinical dilemma. New criteria* were proposed in 2015: ≥2 intensive care unit (ICU) admissions, loss of ≥3 central venous catheter (CVC) sites, and persistently elevated conjugated bilirubin (CB ≥ 75 μmol/L) despite 6 weeks of lipid modification strategies. We performed a retrospective, international, multicenter validation study of 443 children (61% male, median gestational age 34 weeks [IQR 29–37]), diagnosed with IF between 2010 and 2015. Primary outcome measure was death or IT. Sensitivity, specificity, NPV, PPV, and probability of death/transplant (OR, 95% confidence intervals) were calculated for each criterion. Median age at IF diagnosis was 0.1 years (IQR 0.03–0.14) with median follow-up of 3.8 years (IQR 2.3–5.3). Forty of 443 (9%) patients died, 53 of 443 (12%) were transplanted; 11 died posttransplant. The validated criteria had a high predictive value of death/IT; ≥2 ICU admissions (p < .0001, OR 10.2, 95% CI 4.0–25.6), persistent CB ≥ 75 μmol/L (p < .0001, OR 8.2, 95% CI 4.8–13.9). and loss of ≥3 CVC sites (p = .0003, OR 5.7, 95% CI 2.2–14.7). This large, multicenter, international study in a contemporary cohort confirms the validity of the Toronto criteria. These validated criteria should guide listing decisions in pediatric IT.
Early predictors of liver injury in patients on parenteral nutrition
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Different studies with adult PNALD patients have shown elevated alkaline phosphatase being the most common abnormality [7]. Kaufman et al. in a cohort of infants proved that an increased platelet count and an increased albumin concentration predicted liver failure [8]. Since PNALD-related hepatitis may lead to progressive fibrosis and cirrhosis, and the available data on effective treatment are insufficient, it is reasonable to actively search for patients at high risk of liver injury.
Parenteral nutrition-associated liver disease (PNALD) is diagnosed after at least 2 weeks of total parenteral nutrition (PN). However, its symptoms may occur early during PN. The aim of this study was to determine the early biochemical predictors of PNALD.
This cross-sectional retrospective study included 160 patients on total parenteral nutrition. The clinical and laboratory data collected during parenteral nutrition were analyzed. Patients were assessed before the onset, on the 2nd, 7th and on the 14th day of PN according to the definition of PNALD and in search for predominant liver function tests findings.
Out of 160 patients, 21 fulfilled the laboratory criteria of PNALD on the 14th day of PN. In the group of patients with PNALD, 14 met these criteria on the 7th day of PN. In multivariate logistic analyses the laboratory criteria of PNALD met on the 7th day of PN (OR = 5637; 95%Cl: 1.162–33.578; p-value = .039) were found to be of predictive value for PNALD on the 14th day. In PNALD group the 1.5-fold elevation of GGTP activity above upper limit of norm was the most prominent laboratory finding during the fourteen-day course of PN. The percentage of patients with 1.5-fold increased activity of GGTP varied in time from 76.2% to 95.2% on the 2nd and 14th day of PN, respectively.
PNALD may be predicted by liver function monitoring after seven days of PN.
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Intestinal failure (IF) secondary to short bowel syndrome is a challenging and complex medical condition with significant risk for surgical and medical complications. Significant advancements in the care of this patient population have led to improved survival rates. Due to their intensive medical needs children with IF are at risk for long-term complications that require comprehensive management and close monitoring.
The purpose of this paper is to review the available literature emphasizing the surgical aspects of care for children with IF secondary to short bowel syndrome. A key priority in the surgical care of this patient population includes strategies to preserve available bowel and maximize its function. Utilization of novel surgical techniques and autologous bowel reconstruction can have a significant impact on children with IF secondary to short bowel syndrome related to the function of their bowel and ability to achieve enteral autonomy. It is also important to understand the potential long-term complications to ensure strategies are put in place to mitigate risk with early detection to improve long-term outcomes.
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In particular, the international normalised ratio (INR) is used to predict adverse haematological outcomes and is also used for prognosis through its incorporation into the paediatric end stage liver disease (PELD) and model for end stage liver disease (MELD) scores [7]. Despite its use to date to predict mortality, there is growing evidence that the INR is not reliable for the purpose of predicting adverse haematological outcomes in the setting of paediatric liver disease [8–17]. The thrombin generation assay (TGA) is increasingly being used to assess the coagulation profile in the setting of chronic liver disease [6,13,18].
Changes in the coagulation profile in children with liver disease and extrahepatic portal vein obstruction or shunt result in both bleeding and thrombosis. Routine coagulation tests do not accurately predict bleeding risk, as they are not sensitive to changes in anticoagulant factors. The thrombin generation assay could be suitable for describing the overall balance of coagulation in children with liver disease. This study aims to characterise the mechanism of thrombin generation in this population, focusing on prothrombin conversion and thrombin inhibition.
Patients were categorised as: severe (paediatric end stage liver disease score > 15) and mild disease, or portal vein obstruction or shunt. Age and gender matched healthy controls were used. The thrombin generation assay was performed in plasma samples from patients and controls with and without exogenous thrombomodulin and the results were further analysed with the computational thrombin dynamics method.
A total of 42 patients (severe, n = 5; mild, n = 29, obstruction/shunt, n = 8) and 20 controls were included in this study. The total prothrombin conversion, thrombin-antithrombin formation and the thrombin decay capacity, in the presence and absence of thrombomodulin were reduced in children with severe liver disease. The rate of prothrombin conversion was increased and thrombin decay capacity was decreased in patients with portal vein obstruction or shunt compared to controls.
This study demonstrates changes in the mechanism in thrombin generation seen in severe chronic liver disease. The changes vary in parenchymal versus non parenchymal liver disease and further study assessing the clinical significance of these variations in mechanism is required.
Short Bowel Syndrome
2020, Pediatric Gastrointestinal and Liver Disease, Sixth Edition
Short bowel syndrome (SBS) is an important chronic gastrointestinal disorder of infancy and childhood. Type and magnitude of intestinal loss influence pathophysiology, clinical management, and prognosis. Appropriate management requires an understanding of normal intestinal growth and regional intestinal function as well as parenteral nutrition (PN), fluid and electrolyte physiology, and intestinal microbiology. Optimal care of the patient with SBS occurs in the home setting, with family members operating as an integral part of the multidisciplinary health care team. Continuous reevaluation of the prognosis is essential, particularly during the phase of PN dependence, in order to guide modifications in medical management and surgical interventions. Intestinal transplantation should be pursued when a fatal outcome on PN appears likely.
Visceral transplantation in patients with intestinal-failure associated liver disease: Evolving indications, graft selection, and outcomes
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Intestinal failure (IF)-associated liver disease (IFALD) is widely recognized as a lethal complication of long-term parenteral nutrition. The pathophysiology of IFALD is poorly understood but appears to be multifactorial and related to the inflammatory state in the patient with IF. Visceral transplant for IFALD includes variants of intestine, liver, or combined liver–intestine allografts. Graft selection for an individual patient depends on the etiology of IF, abdominal and vascular anatomy, severity of IFALD, and potential for intestinal rehabilitation. The past decade has witnessed dramatic improvement in the management of IFALD, principally due to improved lipid emulsion formulations and the multidisciplinary care of the patient with IF. As the recognition and treatment of IFALD continue to improve, the requirement of liver-inclusive visceral grafts appears to be decreasing, representing a paradigm shift in the care of the patient with IF. This review highlights the current indications, graft selection, and outcomes of visceral transplantation for IFALD.

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Original ArticlePredicting Liver Failure in Parenteral Nutrition-Dependent Short Bowel Syndrome of Infancy

Objectives

Study design

Results

Conclusions

Section snippets

Methods

Demographic and Anatomical Comparison of the LR and LF Groups

Discussion

J Pediatr Surg

J Pediatr Surg

Gastroenterology

J Pediatr Surg

Liver Transpl

J Pediatr Surg

Liver Transpl

Gastrointest Endosc

Clin Gastroenterol Hepatol

J Pediatr Surg

Infection and cholestasis in neonates with intestinal resection and long-term parenteral nutrition

J Pediatr Gastroenterol Nutr

Pediatric short bowel syndrome: adaptation after massive small bowel resection

J Pediatr Gastroenterol Nutr

Collaborative strategies to reduce mortality and morbidity in patients with chronic intestinal failure including those who are referred for small bowel transplantation

Transplantation

Organ allocation for liver-intestine candidates

Liver Transpl

Original Article
Predicting Liver Failure in Parenteral Nutrition-Dependent Short Bowel Syndrome of Infancy