Hepatobiliary Manifestations of Short Bowel Syndrome and Intestinal Failure–Associated Liver Disease

Watch a video presentation of this article

Abbreviations

cILE

combination intravenous lipid emulsion

FGF

fibroblast growth factor

FO‐ILE

fish oil intravenous lipid emulsion

IF

intestinal failure

IFALD

intestinal failure–associated liver disease

ILE

intravenous lipid emulsion

PN

parenteral nutrition

SIBO

small‐intestinal bacterial overgrowth

SO‐ILE

soybean oil–based intravenous lipid emulsion

TGR5

Takeda G protein receptor 5

Patients with intestinal failure (IF) who require long‐term parenteral nutrition (PN) are at risk for development of hepatobiliary complications. Approximately 20% to 30% of patients with IF who are receiving prolonged PN will experience progressive liver disease, referred to as intestinal failure–associated liver disease (IFALD). ¹ Currently, IFALD lacks a consensus diagnostic definition and generally refers to liver injury secondary to IF and associated PN therapy, in the absence of other causes of liver disease.

PN support commonly leads to abnormalities in liver tests, with transient fluctuations in aspartate aminotransferase and alanine aminotransferase most commonly reported in the early weeks of PN support. With prolonged use of PN, the most common biochemical abnormality is a rise in serum alkaline phosphatase. Consequently, cholestasis (elevated bilirubin or alkaline phosphatase and γ‐glutamyl transpeptidase > 1.5 times the normal upper limit) has become a commonly recognized endpoint definition in the study of IFALD. ² In children, cholestasis is the predominant histopathological feature, whereas steatosis progressing to fibrosis is more commonly seen in adult patients (Fig. 1). ³ Khalaf and Sokol ⁴ recently described a conceptual model categorizing IFALD in children into two phases. Phase I is associated with cholestasis and hepatic inflammation, which usually resolves once PN is discontinued. Phase II is characterized by steatosis and fibrosis, which may persist for years and can be independent of PN use. ⁴ The underlying mechanisms and predictive factors for development of IFALD are unclear, although both PN‐related factors and clinical characteristics likely play a role.

FIG 1.

Histological features of IFALD. (A) Phase 1 IFALD with cholestasis (red arrows) in the hepatic lobules. (B) Phase 2 IFALD (fibrosis and steatosis) with micronodules showing inflamed portal areas/fibrous septae with a bile ductular reaction, as well as hepatocellular ballooning in the lobules (red arrows). Photomicrographs are courtesy of Lindsay Alpert, M.D., Department of Pathology, University of Chicago, Chicago, IL.

A number of noninvasive markers of liver fibrosis and steatosis to include FibroScan, Fibrosis‐4 index, and magnetic resonance spectroscopy have recently been explored and correlated to traditional risk factors for the development of IFALD in an attempt to better define the prevalence and risk factors for disease development. ⁵ However, none of the noninvasive markers have been applied broadly enough to be incorporated into the diagnosis of IFALD, and liver biopsy remains the gold standard.

Using definitions of chronic cholestasis, a number of clinical risk factors have been associated with the development of liver disease, broadly categorized as either PN or patient related (Fig. 2). The rate of progression to fibrosis and cirrhosis varies between patients and is likely influenced by age, genetics, intestinal anatomy, duration of PN exposure, and the intestinal microbiome.

FIG 2.

Risk factors for development of IFALD.

PN‐Related Factors

The amount and provision of intravenous lipid emulsions (ILEs) are primary factors in the development of IFALD. Intake of soybean oil–based ILE (SO‐ILE) of greater than 1 g/kg/day has been shown to be an independent risk factor for development of chronic cholestasis. ⁶ Soybean oil contains a high amount of proinflammatory omega‐6‐polyunsaturated fatty acids, as well as hepatotoxic phytosterols. In mouse models, phytosterols promote cholestasis and liver injury by antagonizing the nuclear hormone receptor farnesoid X receptor in hepatocytes, resulting in downregulation of bile acid transporters and activation of hepatic macrophages. ⁷ In contrast, primary fish oil ILEs (FO‐ILE) contain omega‐3 fatty acids that have anti‐inflammatory effects and no phytosterols. Case series have demonstrated reversal of cholestasis in infants transitioned from SO‐ILE to FO‐ILE. ⁸ Combination ILEs (c‐ILEs) containing a mixture of lipid sources with a reduced omega‐6/omega‐3 ratio have since been developed with promising evidence for reduction in biochemical abnormalities. ⁹

Central to the caloric support in PN, continuous infusion of dextrose leads to hyperinsulinemia and hepatic lipogenesis, increasing the risk for steatosis. Limiting the infusion rate of dextrose and reducing the PN delivery time allows for periods of fasting, which decreases steatosis by increasing fatty acid oxidation. ¹⁰

In contrast with excess lipid and caloric supplementation, deficiencies in essential nutrients that play a key role in fatty acid metabolism, such as choline, carnitine, and taurine, have also been demonstrated to result in hepatic steatosis and chronic cholestasis. ⁵ Sufficient quantities of these nutrients are unstable in PN solution and would require additional parenteral or oral supplementation, providing a potential avenue for formal studies in the prevention or resolution of IFALD.

Patient‐Related Factors

Recent studies have demonstrated that a remaining small‐bowel length of <50‐100 cm independently predicts the development of IFALD. ¹¹ The small bowel is a rich source of enteral hormones, which when disrupted impair the gut‐liver axis. Bile acids stimulate ileal enterocytes to secrete fibroblast growth factor 19 (FGF19), which, in turn, binds the FGF receptor 4 on hepatocytes, providing negative feedback for bile acid synthesis. In patients with extensive ileal resection, the marked reduction in serum FGF19 has been associated with a cholestatic liver injury. ¹² Alternative bile acid signaling pathways, such as signaling through the Takeda G protein receptor 5 (TGR5) on intestinal enteroendocrine cells and cholangiocytes, appears to reduce cholestasis associated with PN. ¹³ Impaired TGR5 signaling has also been associated with reduced gallbladder contractility and formation of gallstones. Other factors that contribute to cholelithiasis include reduction in cholecystokinin secretion because of lack of enteral feeding, which promotes biliary stasis, as well as cholesterol supersaturation from loss of bile salts after ileal resection.

Small‐intestinal bacterial overgrowth (SIBO) and sepsis are commonly encountered complications in the management of IF secondary to altered intestinal anatomy and the need for indwelling catheters, respectively. The resulting inflammation has been postulated to cause hepatic injury via bacterial translocation and activation of proinflammatory cytokines, which interfere with biliary transport, particularly in children with cholestsis. ¹⁴

Treatment Options

Progression of liver fibrosis to cirrhosis and development of portal hypertension is a serious complication of IFALD that often necessitates intestinal/multivisceral transplantation. ² In cases of early hepatic fibrosis and well‐compensated cirrhosis without portal hypertension, isolated intestinal transplantation has been shown to improve or reverse fibrosis without the need for concurrent liver transplantation. ¹⁵ The key to the prevention of progression to end‐stage liver disease is early recognition and mitigation of risk factors of IFALD, especially in individuals who require prolonged PN.

Switching lipid emulsions from SO‐ILE to FO‐ILE or c‐ILE has been successfully done in the reversal of phase I IFALD in clinical practice. ⁴ Recently, a pure FO‐ILE (Omegavan; Fresenius Kabi, Bad Homburg, Germany) was approved by the US Food and Drug Administration for reversal of IFALD in children. Although less data are present on the prevention of IFALD with alternative lipid emulsions, a c‐ILE (SMOF‐Lipid; Fresenius Kabi) was demonstrated to reduce the onset of cholestasis in preterm neonates when compared with an olive oil/soybean oil lipid emulsion (ClinOleic; Baxter, Lessines, Belgium). ¹⁶

Other key factors in mitigating the risks for development of IFALD include limiting PN lipid delivery to <1 g/kg/day, reducing PN delivery time, minimizing caloric overfeeding, preventing catheter‐related infections, and preserving small‐bowel length/restoration of bowel continuity. In select patients for whom restoration of continuity cannot be achieved, intestinal lengthening procedures have also been shown to be beneficial in reversing liver disease. ¹⁷

Pharmacological options for IFALD are limited and are based on observational data. Use of ursodeoxycholic acid, choline, taurine, or carnitine supplementation has demonstrated some promising results, although more data are required before their use can be recommended in routine practice. ² Glucagon‐like peptide‐2 analogues have been shown to enhance gut absorption and reduce PN requirement in patients with IF, and their role in the development of IFALD is an active area of study.

Conclusion

Improvements in the delivery and management of home PN have resulted in overall reductions in PN complications. However, the development of IFALD remains a feared complication of prolonged PN support. PN‐based and surgical approaches aimed at reducing the risk factors for the development of IFALD are essential to improve patient outcomes and reduce the need for intestinal or multivisceral transplantation. Additional studies using pharmacological agents or supplementation of deficient micronutrients will be an exciting avenue in the prevention of IFALD in the future.