Review article: diagnosis and management of intestinal failure-associated liver disease in adults.

BACKGROUND: Hepatic disturbances in the context of intestinal failure and parenteral nutrition (PN) are frequently encountered and carry a significant burden of morbidity and sometimes mortality. The term intestinal failure-associated liver disease (IFALD) refers to liver injury due to intestinal failure and associated PN, in the absence of another evident cause of liver disease, encompassing a spectrum of conditions from deranged liver enzymes, steatosis/ steatohepatitis, cholestasis as well as progressive fibrosis, cirrhosis and end-stage liver disease. AIMS: To present an up to date perspective on the diagnosis/definition, aetiologies and subsequent management of IFALD and to explore future consideration for the condition, including pharmacological therapies RESULTS: In adults using long-term PN for benign chronic intestinal failure, 1%-4% of all deaths are attributed to IFALD. The aetiology of IFALD is multifactorial and can be broadly divided into nutritional factors (eg lipid emulsion type) and patient-related factors (eg remaining bowel anatomy). Given its multifaceted aetiology, the management of IFALD requires clinicians to investigate a number of factors simultaneously. Patients with progressive liver disease should be considered for combined liver-intestine transplantation, although multivisceral grafts have a worse prognosis. However, there is no established non-invasive method to identify progressive IFALD such that liver biopsy, where appropriate, remains the gold standard. CONCLUSION: A widely accepted definition of IFALD would aid in diagnosis, monitoring and subsequent management. Management can be complex with a number of factors to consider. In the future, dedicated pharmacological interventions may become more prominent in the management of IFALD.

Low circulating concentrations of citrulline and FGF19 predict chronic cholestasis and poor survival in adult patients with chronic intestinal failure: development of a Model for End-Stage Intestinal Failure (MESIF risk score).

BACKGROUND: Patients with chronic intestinal failure (CIF) often develop cholestatic liver injury, which may lead to liver failure and need for organ transplantation. OBJECTIVES: The aim of this study was to investigate whether citrulline (CIT) and the enterokine fibroblast growth factor 19 (FGF19) are associated with chronic cholestasis and survival in adult CIF patients, and to develop a risk score to predict their survival. METHODS: We studied 135 adult CIF patients on intravenous supplementation (>3 mo). Associations of plasma CIT and FGF19 with chronic cholestasis and survival were estimated by logistic and Cox regression models. A predictive risk score was developed and validated internally. RESULTS: Patients with chronic cholestasis (17%) had a reduced 5-y survival rate compared with patients without chronic cholestasis (38% and 62%, respectively). In multivariable analysis, low FGF19, low CIT, and female sex were associated with chronic cholestasis. Patients with low rather than high CIT or FGF19 also had reduced 5-y survival rates (29% compared with 69%; 54% compared with 66%, respectively). Risk factors identified in multivariable analysis of survival were low FGF19 (HR: 3.4), low CIT (HR: 3.3), and number of intravenous infusions per week (HR: 1.4). These 3 predictors were incorporated in a risk model of survival termed Model for End-Stage Intestinal Failure (MESIF) (C-statistic 0.78). The 5-y survival rates for patients with MESIF scores of 0 to <20 (n = 47), 20-40 (n = 75), and >40 (n = 13) were 80%, 58%, and 14%, respectively. CONCLUSIONS: CIT and FGF19 predict chronic cholestasis and survival in this cohort of adult CIF patients, and the derived MESIF score is associated with their survival. Pending external validation, the MESIF score may help to identify patients for closer clinical monitoring or earlier referral to intestinal transplantation centers.

Systematic Review: Noninvasive Assessments of Intestinal Failure-Associated Liver Disease in the Adult Population.

Chronic intestinal failure (CIF) patients are at risk for developing intestinal failure-associated liver disease (IFALD), which can progress to end-stage liver disease. Liver biopsy is the current reference standard to diagnose and monitor IFALD. However, due to its associated complications, biopsy is an unattractive tool in this respect. Our aim was to assess the evidence regarding non-invasive assessment of IFALD in the adult population and provide ideas to take this field further. We searched the PubMed, EMBASE and Web of Science databases in accordance with the PRISMA guideline. We included studies in the adult/mixed intestinal failure population, performing non-invasive diagnostic assessment of IFALD and using liver biopsy, 1H-MRS or MRI-PDFF as reference. Quality of the included studies was assessed using the QUADAS-2 tool. Four studies were included, assessing two serum (vitamin B12, FGF21) and two imaging tests (Fibroscan, CAUS). Three used liver biopsy as reference, all according to a different histological scoring system. One used 1H-MRS as reference. Vitamin B12 did not correlate with liver injury, Fibroscan did not correlate with fibrosis, but with cholestasis. FGF21 correlated with steatosis grade. Several CAUS parameters correlated with the degree of steatosis assessed by 1H-MRS. In conclusion, three tests show promise to non-invasively assess IFALD, but the limited data do not justify conclusions on the diagnostic value of the tested biomarkers. Hence, additional studies are needed. Identification of and validation for grading and staging of clinically relevant histomorphological parameters of IFALD is also crucial and a conceptual study set up is provided.

Noninvasive Quantitative Assessment of Hepatic Steatosis by Proton Magnetic Resonance Spectroscopy Among Adult Patients Receiving Home Parenteral Nutrition.

BACKGROUND: Intestinal failure-associated liver disease is a frequent complication in patients with chronic intestinal failure (CIF), with steatosis as a dominant feature in adults. Proton magnetic resonance spectroscopy (1H-MRS) is a noninvasive method to quantify liver fat content (LFC). In this study, LFC was assessed with 1H-MRS, taking into account the possible accumulation of paramagnetic components of home parenteral nutrition (HPN) that may disturb these measurements. METHODS: LFC was measured in 15 adult CIF patients who had been receiving HPN for >6 months. 1H-MR spectra were obtained with a 3 Tesla magnetic resonance (MR) system, with a method correcting for the presence of paramagnetic ions. Patients with low (<5%) versus high (≥5%, steatosis) LFC were compared with nonparametric statistical tests. RESULTS: 1H-MRS analysis revealed steatosis in 5 patients (median, 10.3%), while 10 patients had normal LFC (median, 0.9%). In all patients, the 1H-MRS results indicated the presence of various amounts of paramagnetic constituents in the liver. Patients with steatosis had higher alanine aminotransferase values than patients without steatosis (median, 60 vs 28 U/L). Unexpectedly, in the steatosis group, the frequency of HPN use was lower, with significant lower total HPN and carbohydrate calories. In 1 patient, MR spectra were of inferior quality, with broadened resonances after infusion with a ferric compound. CONCLUSION: 1H-MRS enables reliable noninvasive assessment of LFC in patients receiving long-term HPN, if correcting for possible accumulation of paramagnetic components in the liver. However, LFC determination by 1H-MRS is not recommended after a recent ferric compound infusion.

Role of genetic variants of autophagy genes in susceptibility for non-medullary thyroid cancer and patients outcome.

Autophagy is a central process in regulation of cell survival, cell death and proliferation and plays an important role in carcinogenesis, including thyroid carcinoma. Genetic variation in autophagy components has been demonstrated to influence the capacity to execute autophagy and is associated with disease susceptibility, progression and outcome. In the present study, we assessed whether genetic variation in autophagy genes contributes to susceptibility to develop thyroid carcinoma, disease progression and/or patient outcome. The results indicate that patients carrying the ATG5 single nucleotide polymorphisms rs2245214 have a higher probability to develop thyroid carcinoma (OR 1.85 (95% CI 1.04-3.23), P = 0.042). In contrast, no significant differences could be observed for the other genetic variants studied in terms of thyroid carcinoma susceptibility. Furthermore, none of the selected genetic variants were associated with clinical parameters of disease progression and outcome. In conclusion, genetic variation in ATG5, a central player in the autophagy process, is found to be associated with increased susceptibility for thyroid carcinoma, indicating a role for autophagy in thyroid carcinogenesis.

A promoter polymorphism in human interleukin-32 modulates its expression and influences the risk and the outcome of epithelial cell-derived thyroid carcinoma.

Interleukin (IL)-32 is an intracellular proinflammatory mediator that strongly modulates the inflammatory reaction. Recent studies have suggested the involvement of IL-32 in the pathogenesis of malignancies. We aimed to assess whether a known germ-line polymorphism in the IL32 promoter modulates IL-32 expression, and whether it influences susceptibility and/or outcome of epithelial cell-derived thyroid carcinoma (TC). In this study, IL32 genotype was assessed in 139 TC patients and 138 healthy controls and was correlated with TC susceptibility and clinical outcome. Furthermore, IL-32 messenger RNA expression and protein were assessed in TC tissues and functional consequences of genetic variants of IL32 were studied in a model of human primary immune cells. Results demonstrate substantial IL-32 expression in TC tumor tissue. Lipopolysaccharide (LPS) stimulation of primary immune cells revealed 2-fold higher expression of IL-32γ, but not IL-32ß, in cells homozygous for the ancient T allele. Furthermore, production of LPS-induced cytokines was increased in cells bearing this T allele. Genetic analysis revealed that the ancient T allele was overrepresented in TC patients with odds ratio (95% confidence interval) = 1.71 (1.06-2.75). In addition, the cumulative radioactive iodine (RAI) dose received after total thyroidectomy was significantly higher in TC patients bearing the ancient T allele. In conclusion, individuals bearing genetic variants of IL32 that lead to an increased IL-32γ gene expression and higher production of proinflammatory cytokines have higher risk for developing epithelial cell-derived TC. Subsequently, they require higher dosages of RAI to achieve successful tumor remission. These data suggest an important role of IL-32 in the pathogenesis of TC.

High level of distress in long-term survivors of thyroid carcinoma: results of rapid screening using the distress thermometer.

CONTEXT: Cancer patients are at increased risk for distress. The Distress Thermometer (DT) and problem list (PL) are short-tools validated and recommended for distress screening in cancer patients. OBJECTIVE: To investigate the level of distress and problems experienced by survivors of differentiated non-medullary thyroid carcinoma (DTC), using the DT and PL and whether this correlates with clinical and demographical variables. PARTICIPANTS, DESIGN AND SETTING: All 205 DTC patients, under follow-up at the outpatient clinic of our university hospital, were asked to fill in the DT and PL, hospital anxiety and depression scale (HADS), illness cognition questionnaire (ICQ) and an ad hoc questionnaire. Receiver Operator Characteristic analysis (ROC) was used to establish the optimal DT cut-off score according to HADS. Correlations of questionnaires scores with data on diagnosis, treatment and follow-up collected from medical records were analyzed. RESULTS: Of the 159 respondents, 145 agreed to participate [118 in remission, median follow-up 7.2 years (range 3 months-41 years)]. Of these, 34.3% rated their distress score ≥5, indicating clinically relevant distress according to ROC analysis. Patients reported physical (86%) over emotional problems (76%) as sources of distress. DT scores correlated with HADS scores and ICQ subscales. No significant correlations were found between DT scores and clinical or demographical characteristics except for employment status. CONCLUSION: Prevalence of distress is high among patients with DTC even after long-term remission and cannot be predicted by clinical and demographical characteristics. DT and PL are useful screening instruments for distress in DTC patients and could easily be incorporated into daily practice.

Isolation of human antibodies to tumor-associated endothelial cell markers by in vitro human endothelial cell selection with phage display libraries.

Human antibodies selectively targeting angiogenic vessels hold great promise for the immunotherapy of human malignancies and can help to elucidate the molecular mechanisms regulating angiogenesis. By selecting a large antibody phage display library on proliferating stimulated HUVEC, we have isolated 15 human antibodies that bind to HUVEC in flow cytometric analysis, 11 of which target the vasculature of colorectal carcinomas as demonstrated by immunohistochemical analysis. The four most specific antibodies, TEM-A, TEM-C, TEM-M and TEM-Q, also stain the vasculature of a series of carcinomas derived from liver, ovary, kidney, bladder, lung and breast, and either react weakly or not all with the vasculature of corresponding normal tissues. All four antibodies react with the vasculature of endometrium, but only TEM-M and TEM-Q react with the vasculature of placenta. As shown by non-reducing western blot analysis, 9/15 of the antibodies recognize either one or two distinct bands on HUVEC cell lysates, with molecular weights of 175 and/or 110-125 kDa. Antibodies identified by this approach may be used for the identification of new markers of angiogenesis and/or tumor vasculature. The selected antibodies may prove useful as new prognostic markers, for in vivo tumor imaging purposes and for further development of targeted therapies.