Intestinal Failure–Associated Liver Disease: What Do We Know Today?

doi:10.1053/j.gastro.2005.10.066

Gastroenterology

Volume 130, Issue 2, Supplement, February 2006, Pages S70-S77

https://doi.org/10.1053/j.gastro.2005.10.066 Get rights and content

Intestinal failure–associated liver disease develops in 40% to 60% of infants who require long-term total parenteral nutrition (TPN) for intestinal failure and 15% to 40% of adults on home parenteral nutrition. The clinical spectrum includes hepatic steatosis, cholestasis, cholelithiasis, and hepatic fibrosis. Progression to biliary cirrhosis and the development of portal hypertension and liver failure occurs in a minority but is more common in infants and neonates than in adults. The pathogenesis is multifactorial. In infants it is related to prematurity, low birth weight, duration of PN, short bowel syndrome requiring multiple laparotomies, and recurrent sepsis. Other important mechanisms include lack of enteral feeding, which leads to reduced gut hormone secretion; reduction of bile flow and biliary stasis, which leads to the development of cholestasis; and biliary sludge and gallstones, which exacerbate hepatic dysfunction. In adults, IFALD is less common and related to age, length of time on PN, total caloric intake, and lipid or glucose overload. In preterm infants, a deficiency of taurine or cysteine may play a role, whereas in both adults and children, choline deficiency may exacerbate IFALD. Lipid emulsions, choline deficiency, and manganese toxicity are associated with both hepatic steatosis and cholestasis in adults and children. Management strategies for the prevention of intestinal failure–induced liver disease include early enteral feeding, a multidisciplinary approach to the management of parenteral nutrition, and aseptic catheter techniques to reduce sepsis. The addition of choline, taurine, and cysteine to PN solutions may also play a role. Oral administration of ursodeoxycholic acid may improve bile flow and reduce gallbladder stasis. Survival after either isolated small bowel or combined liver and small bowel transplantation is approximately 50% at 5 years, making this an acceptable therapeutic option in adults and children with irreversible liver and intestinal failure.

Section snippets

Hepatic Steatosis

Hepatic steatosis is associated with hepatic accumulation of lipid or glycogen from excess calories (>8–12 mg/kg/d of glucose).¹² It is thought that parenteral carbohydrate calories are converted to triglyceride, perhaps by stimulating insulin release or by lipogenesis and the sythesis of acylglycerol from glucose as shown in rats.¹³ Histology of the liver reveals fatty infiltration of hepatocytes, which is reversible after reduction of calories.¹⁴ Hepatitic steatosis may also be related to

Cholestasis

The development of cholestasis is related to a number of factors. In infants, it is associated with prematurity, recurrent sepsis, lipid emulsions, and possibly lack of enteral feeding.3, 19, 20, 21, 22, 23, 24 It is also associated with the number of laparotomies, number of days on antibiotics, and delayed start to enteral feeding.²⁵

The earliest clinical sign is a rise in conjugated bilirubin particularly during episodes of intercurrent sepsis²³ associated with an increase in alkaline

Lack of Enteral Intake

The inability to establish enteral feeding is common in children requiring parenteral nutrition and is one of the main indications for TPN. IFALD appears to develop more frequently in those children who are unable to tolerate any enteral feeding compared with those who are partially enteral fed, although more recent studies suggest that recurrent sepsis may be a more important mechanism.3, 21, 23

Experimental studies have shown that short-term fasting has several metabolic and endocrine

Sepsis

IFALD is more common in neonates who have recurrent episodes of sepsis whether this is related to central line infections or bacterial translocation from bacterial overgrowth.19, 20, 22, 23, 41 Bacterial overgrowth from intestinal stasis has been related to the development of IFALD possibly because of the combination of the reduction in bile flow, the production of secondary bile salts, and sepsis from bacterial translocation. A review of 8 fatal cases of progressive liver failure in surgical

Components of TPN

IFALD may be related either to a deficiency or excess of amino acids or lipid in the TPN solutions. It is possible that hepatotoxicity may be caused by a deficiency of taurine or cysteine, which are conditional essential amino acids in neonates because of the low levels of hepatic cystathionase and cysteine sulfinic decarboxylase.⁴³ In older infants and adults, cysteine and taurine are synthesized from methionine but this production is diminished in premature infants.⁴⁴ Not only is taurine one

Toxic Components of TPN

Historically, the degradation of tryptophan in TPN solutions contaminated by sodium bisulphate was thought to produce cholestatic metabolites, but this does not occur with modern solutions. Although aluminium toxicity is well recognized in TPN and may lead to bone disease, there is no evidence that it is implicated in TPN liver disease.47, 48

Chromium toxicity, secondary to TPN, has been reported in animals. Both serum and urine chromium concentration levels are higher in children on long-term

Manganese Toxicity

A number of recent studies have reported the effects of manganese toxicity in children on long-term TPN.51, 52 Fifty-seven children receiving long-term TPN including the multitrace element solutions of Pedel or Addamel (KabiVitrum, UK) were studied.⁵² Forty-five children (79%) had whole-blood manganese concentrations above the reference range. Children with impaired liver function had the highest manganese levels, and there was a significant correlation between whole-blood manganese levels,

Lipid Emulsions

There is now some evidence that lipid emulsions induce cholestasis as well as steatosis. It has been accepted that excess lipid calories (the lipid overload syndrome) may lead to hepatic steatosis, hyperlipidemia, and thrombocytopenia and that close monitoring of triglyceride levels was necessary to monitor lipemia in both adults and neonates with hepatic dysfunction.7, 54

More recently, Colomb et al⁵⁵ correlated episodes of cholestasis in 23 infants with alteration in lipid concentration,

Summary

IFALD is more common in infants and children than in adults. Important mechanisms in infants include prematurity, length of remaining bowel, and recurrent sepsis, whereas in adults it is related to the length of time on PN and excess caloric intake of glucose and lipids. Despite recent advances in management and administration of PN, much more still needs to be learned to prevent the development of life-threatening liver disease.

References (82)

A. Van Gossum et al.
Clinical, social and rehabilitation status of long-term home parenteral nutrition patientsresults of a European multicentre survey
Clin Nutr
(2001)
D.J. Andorsky et al.
Nutritional and other postoperative management of neonates with short bowel syndrome correlates with clinical outcomes
J Pediatr
(2001)
L. Pironi et al.
Safety and efficacy of home parenteral nutrition for chronic intestinal failurea 16-year experience at a single centre
Dig Liver Dis
(2003)
S. Chan et al.
Incidence, prognosis and etiology of end-stage liver disease in patients receiving home total parenteral nutrition
Surgery
(1999)
W. Luman et al.
Prevalence, outcome and associated factors of deranged liver function tests in patients on home parenteral nutrition
Clin Nutr
(2002)
S.V. Beath et al.
Parenteral nutrition-related cholestasis in postsurgical neonatesmultivariate analysis of risk factors
J Pediatr Surg
(1996)
J.B. Watkins et al.
Bile salt metabolism in the human premature infant
Gastroenterology
(1975)
P.T. Clayton et al.
The role of phytosterols in the pathogenesis of liver complications of pediatric parenteral nutrition
Nutrition
(1998)
G. Greenberg et al.
Effect of total parenteral nutrition on gut hormone release in human
Gastroenterology
(1981)
J.E. Hodes et al.
Hepatic failure in infants on total parenteral nutrition (TPN) clinical and histophathologic observations
J Pediatr Surg
(1982)

J.M.E. Fell et al.

Manganese toxicity in children receiving long-term parenteral nutrition

Lancet

(1996)

B. Messing et al.

Does total parenteral nutrition induce gallbladder sludge formation and lithiasis?

Gastroenterology

(1983)

S.V. Beath et al.

Clinical features and prognosis of children assessed for isolated small bowel (ISBTx) or combined small bowel and liver transplantation (CSBLTx)

J Pediatr Surg

(1997)

B.B. Dahms et al.

Serial liver biopsies in parenteral nutrition associated cholestasis in early infancy

Gastroenterology

(1981)

J.A. Alverdy et al.

The effect of glutamine-enriched TPN on gut immune cellularity

J Surg Res

(1992)

W.W. Souba et al.

The role of glutamine in maintaining a healthy gut and supporting the metabolic response to injury and infection

J Surg Res

(1990)

J. Neu et al.

Enteral glutamine supplementation for very low birth weight infants decreases morbidity

J Pediatr

(1997)

S.C. Donnell et al.

Infection rates in surgical neonates and infants receiving parenteral nutritiona five-year prospective study

J Hosp Infect

(2002)

M.I. Spagnuolo et al.

Urosodeoxycholic acid for treatment of cholestasis in children on long-term total parenteral nutritiona pilot study

Gastroenterology

(1996)

P. Beau et al.

Is ursodeoxycholic acid an effective therapy for total parenteral nutrition related liver disease?

J Hepatol

(1994)

T.R. Weber et al.

Adverse effects of liver dysfunction and portal hypertension on intestinal adaptation in short bowel syndrome in children

Am J Surg

(2002)

D.L. Sudan et al.

Isolated intestinal transplantation for intestinal failure

Am J Gastroenterol

(2000)

J.W.L. Puntis

Nutritional support at home and in the community

Arch Dis Child

(2001)

J.W.L. Puntis et al.

Staff traininga key factor in reducing intravascular catheter sepsis

Arch Dis Child

(1991)

F.W. Guglielmi et al.

Hepatobiliary complications of long-term home parenteral nutrition

Clin Nutr

(2000)

M. Cavicchi et al.

Prevalence of liver disease and permanent intestinal failure

Ann Intern Med

(2000)

I.F. Btaiche et al.

Parenteral nutrition-associated liver complications in children

Pharmacotherarpy

(2002)

A. Buchman

Total parenteral nutrition-associated liver disease

JPEN J Parenter Enteral Nutr

(2002)

N. Zaman et al.

Effects of intravenous lipid as a source of energy in parenteral nutrition associated hepatic dysfunction and lidocaine eliminationa study using isolated rat liver perfusion

Biopharm Drug Dispos

(1997)

M.M. Meguid et al.

Effects of continuous graded total parenteral nutrition on feeding indexes and metabolic concomitants in rats

Am J Physiol

(1991)

I. Tulikoura et al.

Morphological fatty changes and function of the liver, serum free fatty acids and triglycerides during parenteral nutrition

Scand J Gastroenterol

(1982)

A. Vromen et al.

Pentoxifyline and thalidomide fail to reduce hepatic steatosis during total parenteral nutrition and bowel rest in the rat

JPEN J Parenter Enteral Nutr

(1997)

E.P. Shronts

Essential nature of choline with implications for total parenteral nutrition

J Am Diet Assoc

(1997)

R.J. Sokol et al.

Hepatic oxidant injury and glutathione depletion during total parenteral nutrition in weanling rats

Am J Physiol

(1996)

P. Chessex et al.

Photooxidation of parenteral multivitamins induces hepatic steatosis in a neonatal guinea pig model of intreavenous nutrition

Paediatr Res

(2002)

R.G. Heine et al.

New approaches to parenteral nutrition in infants and children

J Paediatr Child Health

(2002)

M. Candusson et al.

Outcome and quality of life in paediatric home pareneteral nutrition

Curr Opin Clin Nutr Metab Care

(2002)

S.S. Kaufman

Prevention of parenteral nutrition-associated liver disease in children

Pediatr Transplant

(2002)

J. Bueno et al.

Analysis of patients with longitudinal intestinal lengthening procedure referred for intestinal transplantation

J Pediatr Surg

(2001)

V. Colomb et al.

Liver disease associated with long-term parenteral nutrition in children

Transplant Proc

(1994)

R.A. Drongowski et al.

An analysis of factors contributing to the development of total parenteral nutrition induced cholestasis

JPEN J Parenter Enteral Nutr

(1989)

Cited by (329)

Approximately 50% of acute intestinal failure (AIF) patients on short-term parenteral nutrition (PN) have intestinal failure-associated liver disease (IFALD) without effect on hospital length of stay and mortality
2024, Clinical Nutrition ESPEN
Patients with intestinal failure (IF) are often dependent on PN for provision of calories and nutrients for survival. Similar to chronic intestinal failure (CIF) patients, those who have AIF are also at risk of IFALD, which is a poorly understood but potentially fatal condition. The local incidence of IFALD amongst AIF patients is not known.
The primary objective of this study was to determine the incidence of IFALD in AIF patients on short-term PN. Secondary objectives were to analyse patient and PN risk factors of IFALD, and clinical outcomes of length of stay (LOS) and inpatient mortality.
This was a retrospective cross-sectional cohort study of hospitalised adult patients with AIF prescribed with short-term PN. All adult patients aged 21 years and above who received PN for at least 5 consecutive days and had normal liver function tests (LFTs) at the time of PN initiation were included in this study.
A total of 171 patients were enrolled in this study, with 77 (45%) having deranged LFTs at the end of PN therapy and categorised under the IFLAD group. The patient cohort was predominantly male (92 [54%]) and had a median age of 68 years (IQR 59–76). Patients with IFALD at the end of PN therapy had higher diabetes prevalence (36% vs 26%, p = 0.2) and were on PN for a longer duration (median [IQR]: 12 [8–17] vs 8 [6–15] days, p = 0.003) than those without IFALD. There were no significant differences in patient and PN characteristics between the IFLAD and non-IFALD group. The multivariable models showed that the IFALD cohort had longer hospital stays (HR 0.90, 95% CI 0.65–1.23) and lower odds of inpatient death (OR 0.75, 95% CI 0.12–4.60), though both findings are not statistically significant (p = 0.5, 0.7).
In this study, IFALD is a common phenomenon in AIF and the incidence was found to be an estimated 50% amongst patients on short-term PN with similar clinical outcomes between the two groups.
ESPEN guideline on chronic intestinal failure in adults – Update 2023
2023, Clinical Nutrition
In 2016, ESPEN published the guideline for Chronic Intestinal Failure (CIF) in adults. An updated version of ESPEN guidelines on CIF due to benign disease in adults was devised in order to incorporate new evidence since the publication of the previous ESPEN guidelines.
The grading system of the Scottish Intercollegiate Guidelines Network (SIGN) was used to grade the literature. Recommendations were graded according to the levels of evidence available as A (strong), B (conditional), 0 (weak) and Good practice points (GPP). The recommendations of the 2016 guideline (graded using the GRADE system) which were still valid, because no studies supporting an update were retrieved, were reworded and re-graded accordingly.
The recommendations of the 2016 guideline were reviewed, particularly focusing on definitions, and new chapters were included to devise recommendations on IF centers, chronic enterocutaneous fistulas, costs of IF, caring for CIF patients during pregnancy, transition of patients from pediatric to adult centers. The new guideline consist of 149 recommendations and 16 statements which were voted for consensus by ESPEN members, online in July 2022 and at conference during the annual Congress in September 2022. The Grade of recommendation is GPP for 96 (64.4%) of the recommendations, 0 for 29 (19.5%), B for 19 (12.7%), and A for only five (3.4%). The grade of consensus is “strong consensus” for 148 (99.3%) and “consensus” for one (0.7%) recommendation. The grade of consensus for the statements is “strong consensus” for 14 (87.5%) and “consensus” for two (12.5%).
It is confirmed that CIF management requires complex technologies, multidisciplinary and multiprofessional activity, and expertise to care for the underlying gastrointestinal disease and to provide HPN support. Most of the recommendations were graded as GPP, but almost all received a strong consensus.
Enteral and parenteral nutrition
2023, Encyclopedia of Human Nutrition: Volume 1-4, Fourth Edition
Nutritional support refers to the provision of nutrients to individuals who are unable to maintain adequate nutritional status due to derangements in nutritional intake, malabsorption, or altered metabolism. The nutrition assessment process is a critical step in identifying patients who are at nutritional risk. It incorporates both subjective (medical and nutrition histories) as well as objective (physical examination, anthropometric measurements, laboratory tests, etc.) parameters to determine those in whom nutritional support would be beneficial. Nutritional support can be in the form of oral, enteral, or parenteral administration of nutrients.
Enteral Nutrition (EN) is the preferred method of feeding patients who cannot eat, absorb, or use a normal diet in the presence of a useable GI tract. The route of delivery of EN varies from nasogastric, nasoenteric, gastrostomy or jejunostomy. A wide selection of EN formulas is commercially available depending on the needs of the patient. Enteral feedings are administered via pump assist devices or using gravity drip or manual bolus (syringe). If managed properly, enteral feeding is associated with improved clinical outcomes and reduced infectious complications and is the preferred form of nutritional support.
Parenteral nutrition (PN), which is a compounded formulation of crystalline amino acids, dextrose, fats, electrolytes, vitamins, and minerals, is utilized in situations where the gastrointestinal tract is not functioning or cannot be accessed or in those cases where adequate nutrition cannot be attained by enteral or oral means alone. The advent of parenteral nutrition has revolutionized the management of very ill patients who are unable to maintain adequate nutritional intake.
A case of intestinal failure associated with meconium peritonitis requiring transanal decompression using a Kangaroo New Enteral Feeding Tube
2022, Journal of Pediatric Surgery Case Reports
Meconium peritonitis is a congenital disorder characterized by intestinal perforation in utero and presents as sterile chemical peritonitis. When intraabdominal chemical inflammation is severe, intestinal decompression may be required to control intestinal failure due to severe adhesions. In this case, we safely controlled intestinal failure by transanal decompression using a Kangaroo New Enteral Feeding Tube (EF tube) because oral intestinal adhesions were severe and conventional transoral decompression was not feasible. Given the risk of anastomotic leakage and the potential time needed to improve intestinal failure, transanal decompression by EF tube should be considered when transoral decompression proves difficult.
Hepatic complications of parenteral nutrition in adults in 2022: From monitoring to treatment
2022, Nutrition Clinique et Metabolisme
L’hépatopathie liée à la nutrition parentérale impacte négativement le pronostic des patients insuffisants intestinaux, par son évolution possible vers la cirrhose et l’insuffisance hépatique. Ses facteurs de risque sont multiples, mais la composition de la nutrition parentérale et l’insuffisance intestinale sous-jacente jouent probablement un rôle majeur. Cette complication est très certainement sous-diagnostiquée, et il n’existe pas à ce jour de définition consensuelle de cette pathologie. Actuellement, son diagnostic repose essentiellement sur un faisceau d’arguments biologiques, radiologiques et/ou histologiques, en absence de diagnostic différentiel. Son traitement est majoritairement fondé sur la prévention, en repérant les patients à risque, notamment les patients ayant un syndrome de grêle court ; en adaptant les apports glucido-lipidiques et la composition des émulsions lipidiques ; et en traitant précocement les complications infectieuses, qu’elles soient liées aux accès veineux ou à une translocation bactérienne. À l’avenir, des études supplémentaires sont nécessaires pour mieux comprendre les mécanismes physiopathologiques de cette complication, proposer une stratégie diagnostique, un suivi adapté et des axes thérapeutiques préventifs et curatifs innovants.
Hepatopathy related to parenteral nutrition, because of its possible evolution towards cirrhosis and liver failure, has a negative impact on the prognosis of patients with intestinal failure. The pathogenesis of this complication is multifactorial, ranging from the composition of the parenteral nutrition to the length of the remaining small intestine, and to date there is no consensual definition. Its diagnosis is essentially based on a range of biological, radiological and/or histological arguments. Its treatment is based on prevention, identification of risk factors, adaptation of carbohydrate-lipid intake and the composition of lipid emulsions and the earliest possible management of any sepsis, related to venous access or bacterial translocation. In the future, additional studies are needed to better understand the pathophysiological mechanisms of this complication, to propose a diagnostic strategy, adapted follow-up and innovative preventive and curative therapies.
Parenteral Nutrition
2022, Medical Clinics of North America

View all citing articles on Scopus

View full text

Original ArticleIntestinal Failure–Associated Liver Disease: What Do We Know Today?

Section snippets

Hepatic Steatosis

Cholestasis

Lack of Enteral Intake

Sepsis

Components of TPN

Toxic Components of TPN

Manganese Toxicity

Lipid Emulsions

Summary

Clin Nutr

J Pediatr

Dig Liver Dis

Surgery

Clin Nutr

J Pediatr Surg

Gastroenterology

Nutrition

Gastroenterology

J Pediatr Surg

Lancet

Gastroenterology

J Pediatr Surg

Gastroenterology

J Surg Res

J Surg Res

J Pediatr

J Hosp Infect

Gastroenterology

J Hepatol

Am J Surg

Am J Gastroenterol

Nutritional support at home and in the community

Arch Dis Child

Staff traininga key factor in reducing intravascular catheter sepsis

Arch Dis Child

Hepatobiliary complications of long-term home parenteral nutrition

Clin Nutr

Prevalence of liver disease and permanent intestinal failure

Ann Intern Med

Parenteral nutrition-associated liver complications in children

Pharmacotherarpy

Total parenteral nutrition-associated liver disease

JPEN J Parenter Enteral Nutr

Effects of intravenous lipid as a source of energy in parenteral nutrition associated hepatic dysfunction and lidocaine eliminationa study using isolated rat liver perfusion

Biopharm Drug Dispos

Effects of continuous graded total parenteral nutrition on feeding indexes and metabolic concomitants in rats

Am J Physiol

Morphological fatty changes and function of the liver, serum free fatty acids and triglycerides during parenteral nutrition

Scand J Gastroenterol

Pentoxifyline and thalidomide fail to reduce hepatic steatosis during total parenteral nutrition and bowel rest in the rat

JPEN J Parenter Enteral Nutr

Essential nature of choline with implications for total parenteral nutrition

J Am Diet Assoc

Hepatic oxidant injury and glutathione depletion during total parenteral nutrition in weanling rats

Am J Physiol

Photooxidation of parenteral multivitamins induces hepatic steatosis in a neonatal guinea pig model of intreavenous nutrition

Paediatr Res

New approaches to parenteral nutrition in infants and children

J Paediatr Child Health

Outcome and quality of life in paediatric home pareneteral nutrition

Curr Opin Clin Nutr Metab Care

Prevention of parenteral nutrition-associated liver disease in children

Pediatr Transplant

Analysis of patients with longitudinal intestinal lengthening procedure referred for intestinal transplantation

J Pediatr Surg

Liver disease associated with long-term parenteral nutrition in children

Transplant Proc

An analysis of factors contributing to the development of total parenteral nutrition induced cholestasis

JPEN J Parenter Enteral Nutr

Original Article
Intestinal Failure–Associated Liver Disease: What Do We Know Today?