Elsevier

Clinical Nutrition

Volume 27, Issue 3, June 2008, Pages 328-339
Clinical Nutrition

Review
Citrulline as a biomarker of intestinal failure due to enterocyte mass reduction☆

https://doi.org/10.1016/j.clnu.2008.02.005Get rights and content

Summary

Background & aims

In human, citrulline (plasma concentration about 40 μmol/L) is an amino acid involved in intermediary metabolism and that is not incorporated in proteins. Circulating citrulline is mainly produced by enterocytes of the small bowel. For this reason plasma or serum citrulline concentration has been proposed as a biomarker of remnant small bowel mass and function. This article reviews this concept and its metabolic basis.

Methods

Conditions in which there is a significantly reduced small bowel enterocyte mass and function and a plasma or serum citrulline were measured in adults and children. These studies included patients with a short bowel syndrome, villous atrophy states, Crohn's disease, during monitoring of digestive toxicity of chemotherapy and radiotherapy or follow-up of patients after small bowel transplantation.

Results

In all these situations, with more than 500 studied patients a decreased level of plasma citrulline correlated with the reduced enterocyte mass independently of nutritional and inflammatory status. A close correlation between small bowel remnant length and citrullinemia was found. In addition, diagnosis of intestinal failure was assessed through plasma citrulline levels in severe small bowel diseases in which there is a marked enterocyte mass reduction.

Discussion

The threshold for establishing a diagnosis of intestinal failure is lower in villous atrophy disease (10 μmol/L) than in short bowel syndrome (20 μmol/L). Compromised renal function is an important factor when considering plasma citrulline levels as a marker of intestinal failure as this potentially can increase circulating citrulline values.

Conclusions

Reduced plasma citrulline levels are an innovative quantitative biomarker of significantly reduced enterocyte mass and function in different disease states in humans.

Introduction

Intestinal architecture supports a complex absorptive function. This function interrelates with other complex gut functions, notably defensive (either specific by adaptive immunity or non-specific by physical barrier and innate immunity), endocrine and neuromotor. The intestine, and especially the small bowel, exerts a metabolic activity for apoprotein synthesis and amino acid metabolism and, in the colon, short chain fatty acid production and consumption. We hypothesize that the quantification of the active metabolic mass of the intestine, predominantly the small bowel, due to its high cellular and metabolic capacity, could correctly represent and “model” the overall absorptive capacity of the gut and intestine. Accordingly, we looked at citrulline, an amino acid not included in proteins but produced almost exclusively by enterocytes of the small bowel mucosa, as a candidate plasma/serum biomarker for intestinal enterocyte function.1, 2

Section snippets

Previous proposed biomarkers of gut/intestinal functions

Over the years several biomarkers have been proposed to access overall intestinal gut function, including diamine oxidase (DAO), apoprotein AIV,3 beta-carotene and permeability tests. The most widely studied marker was DAO. This enzyme is involved in the catabolism of polyamines and appears to be largely produced by tissues with high cell turnover, e.g. intestinal mucosa. Since a single blood determination was judged insufficiently sensitive, a dynamic study and sequential assay after injection

Metabolism of citrulline

Splanchnic territory, including gut and liver, has a long-standing recognized major role in macronutrient metabolism and in quantitative and qualitative metabolic exchange of amino acids. In the seventies, Felig9 established with multicatheterization studies in healthy humans, that the splanchnic area consumed a large amount of glutamine and alanine in the post-absorptive state. On the contrary, of all amino acids only citrulline was significantly produced.

Blood citrulline assay: analytical methods and interpretation

Citrulline can be sampled in tubes for serum or plasma collection with no significant difference in results or interpretation. Citrulline assay is unsuited to routine analysis in a clinical chemistry laboratory because it necessitates specialized techniques. The first step in the analytical process is the deproteinization of serum or plasma. The separation of amino acids requires liquid chromatography methods such as ion exchange chromatography with post-column detection with ninhydrin, HPLC

Clinical factors of variation of citrullinemia to be taken into account for data interpretation

The most important points to check in a practical approach to patient management in a clinical setting will be considered here. In Western countries 97.5% of healthy subjects and patients with normal intestinal mucosa function and no renal function impairment have post-absorptive plasma citrulline concentrations between 20 and 60 μmol/L, with a mean of 40 μmol/L.41 Most of the conditions, either pathological or not, in which citrulline has been studied in humans are depicted on Table 2.

Short bowel syndrome

Historically, after animal models, the short bowel syndrome (SBS) was the first to be studied in a clinical setting1, 2, 41 owing to the near-“experimental” situation created by the removal of a large amount of the anatomical and functional mass of the intestine with a well-documented and measurable reduction of the enterocyte mass. Early studies had shown that interorgan glutamine flux was reduced by 20% in these patients, whether adults60 or children.61 In stable SBS patients, amino acids

Perspectives and clinical outcome

Citrulline is at the present time the only biological tool used in a clinical setting to quantitatively investigate intestinal epithelial integrity at the enterocyte level. Different sites of reduction of the enterocyte mass (proximal in celiac villous atrophy, distal in most patients with SBS) as well as functional adaptive changes in SBS can give a partial explanation of differences between these two models of enterocyte mass reduction. For example it can be estimated with citrulline assay

Conclusions

Plasma citrulline concentration is a quantitative biomarker of the remnant metabolically active enterocyte mass that reflects the functional absorptive capacity of a remnant small bowel. This biomarker is not significantly influenced by nutritional or inflammatory status. A cut-off of 20 μmol/L serves as an objective measurement for quantifying the degree of intestinal failure in SBS, whether transient or permanent, and so helps to select and evaluate appropriate treatment. However, citrulline

Conflict of interest statement

None declared.

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    ☆

    This work was partly presented during the 28th ESPEN Congress in Istanbul, October 2006.

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