The Differentiation of Intestinal-Failure-Associated Liver Disease from Nonalcoholic Fatty Liver and Nonalcoholic Steatohepatitis.

Intestinal failure-associated liver disease (IFALD), formerly known as parenteral nutrition-associated liver disease has often been listed in textbooks as an example of nonalcoholic fatty liver disease (NAFLD). However, the etiology, pathophysiology, epidemiology, histology, and progression differ substantially between the conditions defined as NAFLD and the disease, IFALD. Therefore, IFALD should not be defined or considered as a type or a cause of nonalcoholic fatty liver or nonalcoholic steatohepatitis, but rather as a distinct disease.

Management and Complications of Short Bowel Syndrome: an Updated Review.

Short bowel syndrome (SBS) is defined as loss of bowel mass from surgical resection, congenital defects, or disease. Intestinal failure (IF) includes the subset of SBS unable to meet nutrition needs with enteral supplements and requires parenteral nutrition (PN). The parenteral treatment of SBS is now a half-century old. Recent pharmacologic treatment (GLP-2 analogues) has begun to make a significant impact in the care and ultimate management of these patients such that the possibility of reducing PN requirements in formerly PN-dependent patients is a now a real possibility. Finally, newer understanding and possible treatment for some of the complications related to IF have more recently evolved and will be an emphasis of this report. This review will focus on developments over the last 10 years with the goal of updating the reader to new advances in our understanding of the care and feeding of the SBS patient.

Neopterin concentration as an index of disease activity in Crohn's disease and ulcerative colitis.

BACKGROUND: Neopterin, a pyrazino-[2,3-d]-pyrimidine compound, is a metabolite of cyclic guanosine monophosphate that is released by activated T lymphocytes and macrophages after induction by γ interferon. We sought to determine whether neopterin concentration in stool, serum, or urine is a useful marker of disease activity in patients with Crohn's disease or ulcerative colitis. METHODS: We prospectively studied 70 outpatients (33 M, 37 F, aged 39.2 ± 14.0 y) with Crohn's disease (33 clinically in remission, 37 active), 52 outpatients (29 M, 23 F, aged 39.8 ± 12.2 y) with ulcerative colitis (29 clinically in remission, 23 active), and 141 healthy control subjects. Fecal, serum, and urine samples were analyzed for neopterin concentration and other analytes of interest. The following clinical indices were calculated at enrollment: for Crohn's disease, the Capetown Index and Harvey Bradshaw Index; for ulcerative colitis, Simple Clinical Colitis Activity Index, Disease Activity Index, and endoscopic disease severity (rated on a scale of 0 to 3). Crohn's disease was considered active if the Harvey Bradshaw Index was ≥ 5, and ulcerative colitis was considered active if the Simple Clinical Colitis Activity Index was >3. RESULTS: Among Crohn's disease patients, fecal neopterin was higher in those with either clinically active (96.0 ng/g) or inactive (87.2 ng/g) disease than in control subjects (12.0 ng/g; P<0.05; inactive or active disease vs. controls). For ulcerative colitis patients, fecal neopterin concentration was higher in those with active (135.2 ng/g) disease than in those with inactive disease (62.7 ng/g; P<0.05) or healthy controls (12.0 ng/g; P<0.05). Neither serum nor urine neopterin concentrations were increased in patients with active inflammatory bowel disease. Nonsignificant trends toward greater fecal neopterin concentration were observed with increased colonic disease involvement, although not with endoscopic severity or clinical disease activity indices. CONCLUSIONS: Fecal neopterin concentration is increased in patients with clinically active or inactive Crohn's disease and in patients with clinically active ulcerative colitis when compared with controls, and therefore represents a new biomarker for disease activity.

Plasma citrulline concentration as a marker for disease activity in patients with Crohn's disease.

BACKGROUND: Citrulline is a nitrogen end product produced from the intermediary metabolism of glutamine through the enzymatically mediated urea cycle, almost exclusively in the enterocytes of small intestinal epithelium, with some synthesis in colonocytes. Intestinal dysfunction resulting from intestinal diseases or injuries affects intermediary metabolism, which includes citrulline synthesis. We sought to determine whether plasma citrulline was a biomarker for disease activity in patients with Crohn's disease with the hypothesis that citrulline concentration would be reduced during active disease. METHODS: A total of 81 outpatients aged 18 to 65 years (mean, 40.6±15.4 y) with a known history of Crohn's disease were studied prospectively. Patients with prior small intestinal resection, or renal or hepatic insufficiency were excluded. Crohn's disease activity was measured by Harvey-Bradshaw Index (HBI) and was correlated to the plasma citrulline concentration measured simultaneously (ion chromatography). Spearman correlation coefficients were used to assess for an association between the 2 variables. Subgroup analyses of patients with isolated small intestinal disease and endoscopically or radiologic verified disease activity were also performed. RESULTS: Twenty-two patients had isolated colonic disease and 59 had small intestinal involvement. Twenty-six of these patients had concurrent endoscopy and/or computed tomography or magnetic resonance imaging. On the basis of HBI scores, 32 patients had active disease (HBI ≥5) and 49 patients had inactive disease. The mean HBI scores were 4.8±5.5. The mean plasma citrulline concentration was normal, although was below normal in some patients. However, it failed to distinguish between active and inactive patients based on the HBI (active 27.8±8.8 µmol/L, inactive 27.8±11.1 µmol/L, P=0.991). There was no significant linear association between the ranks of citrulline and ranks of HBI (rs=0.012, P=0.915). Of the 59 patients with isolated small intestinal disease, there was no association between plasma citrulline concentration and the HBI (Spearman correlation coefficient, 0.073; P=0.583). There was no difference in plasma citrulline concentrations among those with confirmed inflammation by imaging or endoscopy (confirmed, 26.2±11.8; negative, 28.0±10.0; independent t test P=0.583). CONCLUSIONS: Plasma citrulline concentration was not a marker of disease activity in patients with Crohn's disease. However, all patients studied were outpatients and it is possible that plasma citrulline concentration may be depressed only in patients with more severe disease or extensive small bowel involvement. In addition, plasma citrulline may be increased in the postabsorptional state, and for the most part, our patients were nonfasting. More studies are needed to further elucidate the role of citrulline as a marker of disease activity in patients with Crohn's disease. The possibility also exists that citrulline may be a better marker in patients with previous resection, and this group will require specific evaluation.

Adult-Onset Primary Intestinal Lymphangiectasia With Liver Enzymes Elevation.

Primary intestinal lymphangiectasia is a rare disorder that may result in protein-losing enteropathy. We report a 21-year-old man with malabsorption syndrome, an unintentional weight loss of 30 kg over 10 months, lymphocytopenia, and hepatic aminotransferase elevation. His diagnosis was established by a combination of enteroscopy, histopathology, and secondary etiology exclusion. Institution of parenteral nutrition, followed by a low-fat diet, medium-chain triglycerides, and octreotide, resulted in the resolution of his symptoms and laboratory abnormalities and led to weight gain. Aminotransferase abnormalities are an atypical finding in primary intestinal lymphangiectasia and were most likely due to nonalcohol steatohepatitis after rapid weight loss. Primary intestinal lymphangiectasia should be considered in patients with protein-losing enteropathy and lymphocytopenia.

A randomised placebo-controlled multicentre trial of intravenous semapimod HCl for moderate to severe Crohn's disease.

OBJECTIVE: Semapimod, a small molecule known to inhibit proinflammatory cytokine activity, was studied to determine the optimal dose necessary to achieve a response in patients with moderate to severe Crohn's disease (CD). METHODS: A randomised, double-blind, placebo-controlled trial (CD04) was carried out followed by an open-label extension study (CD05). The trial was conducted in international multicentre outpatient clinics and included patients with moderate to severe CD (Crohn's Disease Activity Index (CDAI) 250-400). Placebo was administered for 3 days; 60 mg semapimod intravenously for 1 day with placebo for 2 days; or 60 mg semapimod intravenously for 3 days. Participants who completed CD04 could participate in the open-label extension study, CD05, to receive up to five additional semapimod HCl 60 mg daily doses three times every 6-8 weeks. The main outcome measures were CDAI, Inflammatory Bowel Disease Questionnaire (IBDQ), Crohn's Disease Endoscopic Inflammation Score (CDEIS) and serum C-reactive protein (CRP) concentration. RESULTS: 152 patients were randomised in CD04. Responses for 1 and 3 day regimens were similar to placebo for CDAI (p=0.82), IBDQ (p=0.85), CDEIS (p=0.57) and CRP (p=0.40). The only noteworthy treatment-related safety finding was infusion reaction (phlebitis): 7.3, 34.8 and 62.7% for the placebo and 1 and 3 day semapimod treatment groups, respectively (p<0.001). In the open-label CD05 study (included=119 patients) a posthoc analysis showed that the mean CDAI improved in patients receiving 6 compared with < or = 3 cumulative doses (204.1+/-83 vs 251.4+/-103.05, p=0.006). CONCLUSIONS: Single and 3 day dosing of semapimod (< or = 180 mg) was ineffective for the treatment of moderate to severe CD. However, cumulative dosing > or = 360 mg was associated with decreased CDAI in a limited number of patients.

The addition of choline to parenteral nutrition.

Choline is a quaternary amine endogenously synthesized from the amino acid methionine or absorbed via the portal circulation. It is ubiquitous in the diet, although it has a greater presence in organ meats. Choline is an essential component of all cell membranes, and has been considered a required dietary nutrient since 1998 by the US Institute of Medicine's Food and Nutrition Board. Choline is necessary for DNA repair, mediated by its role as a methyl donor. It also serves as the precursor for the neurotransmitter acetylcholine. Evidence has accumulated that hepatic steatosis, which occurs during parenteral nutrition therapy, develops as a result of choline deficiency because endogenous production of choline from parenterally infused methionine is deficient. In addition, memory deficits and skeletal muscle abnormalities have been described, and choline deficiency appears to activate cellular apoptosis. Provision of intravenous choline ameliorates hepatic steatosis associated with parenteral nutrition infusion.

Micronutrients in parenteral nutrition: too little or too much? The past, present, and recommendations for the future.

This research workshop in 2009 grew out of a concern in the United States, Europe, and other countries with advanced medicine that it was time to revisit the parenteral requirements for a number of micronutrients. Critical questions sought to be answered included the following: Were there micronutrients not routinely added that should be part of a parenteral nutrition (PN) formula? Were other micronutrients present but in inappropriate amounts? How are various micronutrient requirements altered in the critically or chronically ill?

Development of Crohn's disease in patients with intestinal failure: a role for bacteria?

We present 3 cases of Crohn's disease that developed in patients with previously diagnosed short bowel syndrome from another cause. There are characteristics unique to patients with short bowel syndrome that may increase their likelihood to develop Crohn's disease, based on current concepts of the pathophysiology of inflammatory bowel disease. These patients may have a higher than average prevalence of small intestinal bacterial overgrowth. This may lead to an increase in bacterial translocation and dysregulation of the intestinal immune response. In addition, these patients often require parenteral nutrition (PN) because of macronutrient and micronutrient deficiencies. Some patients receiving PN, particularly those with bowel obstructions, may be at risk for septicemia due to bacterial translocation. It is thought that PN may enhance intestinal dysmotility and impair gut immunity, contributing further to an antigenic immune response in the intestinal immune system, although supporting data is lacking. Finally, studies have demonstrated that patient's with Crohn's disease have a shorter bowel length before any intestinal resections and not related to disease activity. Although the significance of this is unclear, a shorter bowel length may potentially predispose people to the development of Crohn's disease via an alteration of intestinal motility and intestinal flora.

Serum B12 concentration is elevated in patients receiving chronic parenteral nutrition, but is not a marker of intestinal failure-associated liver disease.

BACKGROUND: Cobalamin is released during hepatic cytolysis associated with liver injury. Serum B12 concentration is frequently elevated in patients that receive long-term parenteral nutrition (PN). We hypothesized that serum B12 concentration would become elevated in intestinal failure-associated liver disease and would reflect in disease severity. METHODS: We retrospectively evaluated 13 patients with short bowel syndrome (<200 cm residual small intestine) that included complete terminal ileum resection (3 male and 10 female, aged 42 to 78 y) that had received parenteral nutrition (PN) 6.1+/-3 years. All 13 patients had received at least 1 liver biopsy for presumed intestinal failure-associated liver disease. At the time of biopsy, patients had received PN between 2 and 7 days a week (4.7+/-1.9 d). The liver biopsies were evaluated and prospectively scored for pathology using 3 independent scoring systems validated for nonalcoholic steatohepatitis and nonalcoholic fatty liver disease [Brunt, NAFLD activity score (NAS) and Dixon methods], whereby numeric values were assigned to degrees of steatosis, inflammation, and fibrosis. Serum B12 concentration and hepatic chemistries (aspartate transaminase, alanine transaminase, alkaline phosphatase, and bilirubin) were recorded within 1 week of the biopsies. RESULTS: Thirteen biopsies were available for analysis. Serum B12 concentration and hepatic chemistries were available for all biopsy times. The mean serum B12 concentration was 619+/-222 pg/mL. The mean daily parenteral B12 dose was 3.3+/-1.3 mcg. Mean NAS, Brunt, and Dixon scores were 2, 1, and 1, respectively. The Spearman correlation coefficients between serum B12 concentration and liver biopsy scores were 0.15, 0.1, and 0.1 for the NAS, Brunt, and Dixon scores, respectively, indicating that there was no correlation between serum B12 concentration and liver pathology. The Spearman correlation coefficient between the NAS inflammation subscore and serum B12 concentration was 0.02. B12 concentration also failed to correlate with hepatic chemistries. There was surprisingly little correlation between serum B12 concentration and exogenous B12 daily dose through PN (r=0.19, P=0.45). CONCLUSIONS: Elevated serum B12 concentration is commonly encountered in patients who receive long-term parenteral nutrition. This does not seem to be an indicator of hepatic pathology; rather it may reflect the provision of excessive intravenous vitamin B12 and other as yet unknown factors.

Whole-blood-free choline and choline metabolites in infants who require chronic parenteral nutrition therapy.

BACKGROUND AND AIM: Choline deficiency is associated with hepatic dysfunction. Parenteral nutrition (PN) and lipid emulsions contain phosphatidylcholine (PtdCho) but insignificant free choline (FCho). PtdCho is sequentially degraded to glycerolphosphocholine (GPCho), phosphocholine (PCho), and finally to FCho. Biosynthesis of FCho may be insufficient during PN therapy. The aim of the study was to examine the status of FCho and related metabolites in infants on prolonged (> or =4 weeks) PN. METHODS: Whole blood concentrations of FCho, PtdCho, GPCho, and PCho were measured and compared in infants on PN and infants on enteral feeds (controls). RESULTS: Infants on PN (n = 14) had higher birth weight but same postnatal age as controls (n = 14) (mean +/- standard deviation) 8.3 +/- 3.9 versus 7.4 +/- 3.6 weeks. Parenteral nutrition was associated with increased PtdCho 1761 +/- 452 versus 1471 +/- 221 nmol/mL, P = 0.04. Mean whole blood FCho, GPCho, and PCho concentrations did not differ significantly in PN versus controls: 40.0 +/- 15.4 versus 50.8 +/- 49.7, 16.4 +/- 14.5 versus 25.2 +/- 29.3, and 15.3 +/- 13.5 versus 22.0 +/- 14.8 nmol/mL, respectively. However, PCho was positively correlated with GPCho in controls (r = 0.91, P < 0.01) but not PN (r = 0.24, P = NS), and infants receiving >90% of daily energy intake from PN (n = 6) had decreased PCho, 5.7 +/- 4.1 nmol/mL, compared with those receiving <90% of daily energy intake (n = 8) 22.5 +/- 13.7 nmol/mL, P < 0.05, and controls, 22.0 +/- 14.8 nmol/mL, P < 0.01. CONCLUSIONS: Decreased whole-blood concentrations of choline suggest possible evidence of choline deficiency as illustrated by decreased whole-blood PCho. Choline supplementation should be investigated in infants who require prolonged PN, and whole-blood PCho can be used to monitor response.

Oral rehydration solutions in non-cholera diarrhea: a review.

The use of oral rehydration solution (ORS) has revolutionized the management of acute diarrhea. The implementation of the standard World Health Organization ORS (WHO-ORS) has resulted in decreased mortality associated with acute diarrheal illnesses in children, although in general stool volume and diarrhea durations are not reduced. Decreased morbidity and mortality have occurred because of improved hydration status. Decreased morbidity has also been described in adults who used this therapy. Various modifications to the standard ORS have been derived. These modifications have included hypo-osmolar or hyperosmolar solutions, use of rice-based ORS, zinc supplementation, and the use of amino acids, including glycine, alanine, and glutamine. Some of these variations have been successful, some have not, and others are still under investigation. ORS has been used for travelers' diarrhea and to decrease intravenous (IV) fluid requirements in patients with short bowel syndrome (SBS) who require parenteral nutrition (PN). This paper reviews the standard WHO-ORS and its mechanism of action, followed by more contemporary reduced osmolarity ORS and rice-based ORS in non-cholera diarrhea. Various modifications to improve ORS are also discussed.

An evaluation of the model for end-stage liver disease and serum C-reactive protein as prognostic markers in intestinal failure patients on parenteral nutrition.

BACKGROUND: Intestinal failure (IF) patients require parenteral nutrition (PN) to avoid malnutrition and death. However, they face complications of recurrent sepsis and liver failure. By the time liver failure is discovered, it is often too late for intervention and prognosis on the waiting list is grim. The Model for End-Stage Liver Disease (MELD) has traditionally been used to predict mortality in patients with liver failure but has never been analyzed in IF patients who are at risk for liver complications. C-reactive protein (CRP) is an acute inflammatory marker that has been shown to reflect disease progression in nonalcoholic steatohepatitis, a disease that in many ways resembles PN-associated liver disease. MELD and CRP are promising clinical markers of disease progression in IF patients on PN. METHODS: The authors performed a retrospective, case-control study to compare levels of MELD and CRP within the entire population of 133 adult patients referred to Northwestern Memorial Hospital for IF from 1999 to 2006. RESULTS: Elevated MELD score is strongly predictive of increased mortality over the subsequent 6 months. Elevated CRP is strongly predictive over a smaller 3-month window. One-year mortality was significantly greater in patients who have either elevated MELD scores or serum CRP levels. CONCLUSIONS: In this study, the authors evaluated for the first time use of MELD and serum CRP as predictive markers of mortality in IF patients. Both seem to be promising clinical tools to identify which patients are at highest risk for complication.

Clinical spectrum of vulva metastatic Crohn's disease.

Crohn's disease is a chronic granulomatous disorder that may involve any segment of the gastrointestinal tract. Extraintestinal manifestations of Crohn's disease such as erythema nodosum and pyoderma gangrenosum are well recognized and appreciated. However, metastatic Crohn's disease (MCD), defined as the same granulomatous inflammation seen in Crohn's disease but at a skin site distant to the gastrointestinal tract, is less well recognized. We report three cases of MCD involving the perianal and vulvar skin that initially presented with vulvar pain.

Efficacy and safety of tacrolimus in refractory ulcerative colitis and Crohn's disease: a single-center experience.

BACKGROUND: The published experience regarding the use of tacrolimus in Crohn's disease (CD) and ulcerative colitis (UC) refractory to more commonly used medical therapy has been fairly limited. Our objective was to describe our experience with its use in a cohort of patients which, to our knowledge, represents the largest North American cohort described to date. METHODS: This was a retrospective, single-center chart analysis. Patients were identified by compiling all hospital discharges with principle diagnoses of ICD-9 codes for 555.0-555.9 (regional enteritis) and 556.0-556.9 (ulcerative colitis) from January 1, 2000, to October 31, 2005, and then cross-referencing the electronic charts for tacrolimus serum concentrations ordered during this time period. Additional patients were identified through verbal communication with participating clinicians. Information abstracted included proportion with clinical response and remission (using a modified disease activity index), ability to wean from steroids, need for surgery / time to surgery, and side-effect profile. RESULTS: In all, 32 UC patients and 15 CD patients were identified. The mean disease duration was: UC 81 months (range, 1 month to 37 years), CD 100 months (range, 1 month to 35 years). The disease distribution for UC was: pancolitis 12 (37.5%), extensive colitis 6 (18.8%), left-sided 11 (34.4%), and proctitis 3(9.4%). For CD this was: TI 2 (13.3%), small bowel 2 (13.3%), colonic 3 (20.7%), ileocolonic 7(46.7%), and perianal 1 (6.7%). The duration of tacrolimus treatment for UC was mean, 29 weeks. For CD it was mean, 9.9 weeks. In all, 30/32 UC and 7/15 CD patients were on steroids; 4/30 UC and 0/7 CD patients were able to subsequently wean off steroids. In all, 12/32 UC patients proceeded to colectomy. Mean time to colectomy was 28 weeks and 6/15 CD patients proceeded to a resective surgery. The mean time to surgery was 22 weeks. In all, 22/32 UC patients achieved a clinical response; 3/32 achieved remission and 8/15 CD patients achieved a clinical response; 1/15 achieved remission. Adverse reactions were generally mild. In 6 patients the drug had to be discontinued because of an adverse reaction. There were no opportunistic infections identified, no cases of renal insufficiency related to drug administration, and no deaths while on the medicine. CONCLUSIONS: Our experience with tacrolimus in UC and CD indicates that it is safe and relatively well tolerated, although its clinical efficacy is quite variable. More prospective studies assessing its use are necessary.