Pre-emptive transjugular intrahepatic portosystemic shunt in pediatric cystic fibrosis-related liver disease and portal hypertension: prospective long-term results.

PURPOSE: Portal hypertension (PHT) and its sequelae are the most clinically important manifestations in cystic fibrosis-related liver disease (CFLD). This paper aimed to evaluate the safety and efficacy of a pre-emptive transjugular intrahepatic portosystemic shunt (TIPS) to prevent PHT-related complications in pediatric patients with CFLD. METHODS: This was a prospective single-arm study on pediatric patients with CFLD, signs of PHT, and preserved liver function who underwent a pre-emptive TIPS in a single tertiary CF center between 2007 and 2012. The long-term safety and clinical efficacy were assessed. RESULTS: A pre-emptive TIPS was performed on seven patients with a mean age of 9.2 years (± standard deviation: 2.2). The procedure was technically successful in all patients, with an estimated median primary patency of 10.7 years [interquartile range (IQR) 0.5-10.7)]. No variceal bleeding was observed during the median follow-up of 9 years (IQR 8.1-12.9). In two patients with advanced PHT and rapidly progressive liver disease, severe thrombocytopenia could not be stopped. Subsequent liver transplantation revealed biliary cirrhosis in both patients. In the remaining patients with early PHT and milder porto-sinusoidal vascular disease, symptomatic hypersplenism did not occur, and liver function remained stable until the end of the follow-up. Inclusion for pre-emptive TIPS was discontinued in 2013 following an episode of severe hepatic encephalopathy. CONCLUSION: TIPS is a feasible treatment with encouraging long-term primary patency to avoid variceal bleeding in selected patients with CF and PHT. However, as the progression of liver fibrosis, thrombocytopenia, and splenomegaly is inevitable, the clinical benefits due to pre-emptive placement appear to be minor.

ESPEN-ESPGHAN-ECFS guidelines on nutrition care for infants, children, and adults with cystic fibrosis.

BACKGROUND: Malnutrition is both a frequent feature and a comorbidity of cystic fibrosis (CF), with nutritional status strongly associated with pulmonary function and survival. Nutritional management is therefore standard of care in CF patients. ESPEN, ESPGHAN and ECFS recommended guidelines to cover nutritional management of patients with CF. METHODS: The guidelines were developed by an international multidisciplinary working group in accordance with officially accepted standards. The GRADE system was used for determining grades of evidence and strength of recommendation. Statements were discussed, submitted to Delphi rounds, reviewed by ESPGHAN and ECFS and accepted in an online survey among ESPEN members. RESULTS: The Working Group recommends that initiation of nutritional management should begin as early as possible after diagnosis, with subsequent regular follow up and patient/family education. Exclusive breast feeding is recommended but if not possible a regular formula is to be used. Energy intake should be adapted to achieve normal weight and height for age. When indicated, pancreatic enzyme and fat soluble vitamin treatment should be introduced early and monitored regularly. Pancreatic sufficient patients should have an annual assessment including fecal pancreatic elastase measurement. Sodium supplementation is recommended and a urinary sodium:creatinine ratio should be measured, corresponding to the fractional excretion of sodium. If iron deficiency is suspected, the underlying inflammation should be addressed. Glucose tolerance testing should be introduced at 10 years of age. Bone mineral density examination should be performed from age 8-10 years. Oral nutritional supplements followed by polymeric enteral tube feeding are recommended when growth or nutritional status is impaired. Zinc supplementation may be considered according to the clinical situation. Further studies are required before essential fatty acids, anti-osteoporotic agents, growth hormone, appetite stimulants and probiotics can be recommended. CONCLUSION: Nutritional care and support should be an integral part of management of CF. Obtaining a normal growth pattern in children and maintaining an adequate nutritional status in adults are major goals of multidisciplinary cystic fibrosis centers.

International prospective study of distal intestinal obstruction syndrome in cystic fibrosis: Associated factors and outcome.

BACKGROUND: Distal intestinal obstruction syndrome (DIOS) is a specific complication of cystic fibrosis. METHODS: A study was performed in 10 countries to prospectively evaluate the incidence, associated factors, and treatment modalities in children and adults. RESULTS: 102 patients presented 112 episodes. The incidence of DIOS was similar in children and adults. Medical treatment failed only in cases of complete DIOS (11%). Children with meconium ileus had a higher rate of surgery for DIOS (15% vs. 2%, p=0.02). Complete DIOS entailed longer hospitalisation (4 [3; 7] days vs. 3 [1; 4], p=0.002). Delayed arrival at hospital and prior weight loss had a significant impact on the time needed for DIOS resolution. Associated CF co-morbidities for DIOS included meconium ileus (40% vs. 18%, p<0.0001), exocrine pancreatic insufficiency (92% vs. 84%, p=0.03), liver disease (22% vs. 12%, p=0.004), diabetes mellitus (49% vs. 25%, p=0.0003), and Pseudomonas aeruginosa (68% vs. 52%, p=0.01); low fibre intake and insufficient hydration were frequently observed. Female gender was associated with recurrent DIOS (75% vs. 52%, p=0.04), constipation with incomplete episodes (39% vs. 11%, p=0.03), and poor patient compliance in taking pancreatic enzyme therapy during complete episodes (25% vs. 3%, p=0.02). CONCLUSION: DIOS is a multifactorial condition having a similar incidence in children and adults. We show that delayed arrival at hospital after the initial symptoms causes significant morbidity. Early recognition and treatment would improve the prognosis.

Longitudinal Transient Elastography Measurements Used in Follow-up for Patients with Cystic Fibrosis.

Cystic fibrosis-related liver disease (CFLD) is diagnosed using a combination of criteria. Transient elastography (TE), an ultrasonographic method to evaluate liver stiffness, can differentiate patients with and without liver disease. This retrospective study (2007-2013) aimed to detect developing CFLD using consequent TE measurements. All cystic fibrosis patients with TE measurements between 2007 and 2013 (n = 150, median age 17 (9-24) y) were included, of which 118 had a median of three (range, 2-4) measurements with an interval of 1 (1-2) y. Twenty (14%) had CFLD at the first TE measurement; five (3%) developed CFLD during follow-up. The median TE value in CFLD was 14 kPa (8.7-32.2) compared with 5.3 (4.9-5.7) in cystic fibrosis patients without liver disease (CFnoLD; p = 0.0001). In CFnoLD, TE was correlated with age (p = 0.031). A TE result >6.8 kPa had a sensitivity of 91.5% and a specificity of 91.7% in predicting CFLD, according to the receiver operating characteristics analysis. It also has a positive predictive value of 88.6% and a negative predictive value of 86.9%, increasing to 91.7% and 98%, respectively, in patients at risk (<14 y) for developing CFLD. Patients with developing CFLD had progressively increasing consecutive TE measurements.

Nutrition and pancreatic enzyme intake in patients with cystic fibrosis with distal intestinal obstruction syndrome.

BACKGROUND: The etiology of distal intestinal obstruction syndrome (DIOS) remains unclear. Food intake and pancreatic enzyme replacement therapy (PERT) are often blamed for its occurrence. This study evaluates the nutrition intake and PERT of patients with cystic fibrosis (CF) at a first episode of DIOS. METHODS: All patients with CF perform annually a 3-day intake diary to evaluate their caloric, protein, fat, dietary fiber, liquid, and PERT intake. Patients diagnosed with a first episode of DIOS (n = 12) retrospectively completed an intake diary of the 3 days preceding the DIOS episode supervised by an expert dietitian. RESULTS were compared with those of 1 year before and also with 36 CF controls matched for age, sex, genotype, and disease severity. All were pancreatic insufficient. RESULTS: A first DIOS episode was diagnosed in 12 patients with CF. Only the absolute median fat intake (P = .015) and pancreatic enzyme intake (P = .035) were higher at the time of the DIOS attack in comparison to the preceding year. This could result from the difference in data collection or from the recommendations to increase fat intake and concomitant enzyme intake, since this trend was also found in the control group. The significant difference disappears when enzyme intake is expressed as units of lipase/g of fat. No other significant dietary differences were found. CONCLUSIONS: This study provides no indications for a potential role of nutrition factors or pancreatic enzymes in the first occurrence of DIOS.

Quantitative bone ultrasound at the distal radius in adults with cystic fibrosis.

It is of clinical importance to identify bone disease related to cystic fibrosis (CF) early in its course to allow therapeutic interventions that optimize bone health. To test the technical (precision) and clinical (percentage of abnormal results, correlation with clinical parameters) performance of a commercial quantitative ultrasound apparatus for radial measurements, speed of sound (SOS) was measured at the distal third of the left radius with the Omnisense 7000p apparatus (Sunlight Medical, Tel-Aviv, Israel) in a group of young adult CF patients with regular follow-up at the Brussels and Ghent University Hospital. Sixty-three (37 males) CF patients at a median (range) age of 23.5 y (18.1-39.9) were included. SOS, SOS z-score and SOS t-score were respectively 4017 ± 97 m/s, -0.31 ± 0.74 and -0.60 ± 0.78 in males and 4086 ± 97 m/s, -0.19 ± 0.75 and -0.51 ± 0.95 in females. Mean SOS t-score was significantly lower compared with the manufacturer's reference data for males (p < 0.0001) and females (p = 0.01). SOS z- and t-scores correlated with weight z-score and body mass index z-score in females. No significant correlation was found between SOS and forced expiratory volume in 1 s (%). Neither diabetes mellitus nor liver disease was found to influence SOS. Radial quantitative ultrasound has a precision of 0.55%. The SOS is in the low normal range in 14% of CF patients and is influenced by weight in female patients, but not by the severity of the lung disease.

Comparative bone status assessment by dual energy X-ray absorptiometry, peripheral quantitative computed tomography and quantitative ultrasound in adolescents and young adults with cystic fibrosis.

PURPOSE: Quantitative ultrasound bone sonometry (QUS) might be a promising screening method for cystic fibrosis (CF)-related bone disease, given its absence of radiation exposure, portability of the equipment and low cost.The value of axial transmission forearm QUS in detecting osteopenia in CF was therefore studied. METHODS: We investigated the application of QUS in the evaluation of bone status in a group of 64 adolescents (>12 years) and young adults (<40 years) with CF in a comparison with a dual X-ray absorptiometry (DXA) of the whole body and peripheral quantitative computed tomography (pQCT) of the radius at 4% and 66% sites. RESULTS: Mean (SD) Z-scores of speed of sound (SOS), whole body bone mineral content (BMC), radial trabecular bone mineral density (BMD), and radial cortical BMD were respectively -0.31 (0.78), -0.09 (1.28), 0.10 (1.16) and -0.62 (2.88). The pQCT determined bone geometry values (cortical bone area and cortical thickness) were more depressed than the BMD data. QUS had a sensitivity and specificity of respectively 0% and 96% for diagnosing osteopenia (based on a whole body BMC Z-score<-2). CONCLUSIONS: QUS cannot replace DXA, but can screen out patients with normal bone mass. Further and larger studies are needed to examine if QUS may reflect other aspects than bone mass, or if it is possible to improve its sensitivity by supplementing the SOS results with clinical risk factors.

Fatty acid composition of serum phospholipids in cystic fibrosis (CF) patients with or without CF related liver disease.

BACKGROUND: In cystic fibrosis (CF), changes in fatty acid (FA) composition of serum phospholipids (PL) and cell membranes can account, in part, for the inflammatory state of the disease. The severity of the genotype is known to correlate with the degree of FA changes. Liver diseases, such as cholestasis and cirrhosis are also known to influence FA status. Until now, there is no data on the influence of CF related liver disease (CFRLD) on the FA status of CF patients. The aim of this study was to evaluate, whether the presence of CFRLD influences FA status. METHODS: A fasting blood sample for the determination of serum vitamin E and PL-FA composition was collected from 79 CF patients with stable pulmonary disease and under good control in our CF centre. Patients with CFRLD (n=13) were compared to CF patients with the same severity of genotype (n=66) but without CFRLD. RESULTS: The CF patients with CFRLD had lower docosahexaenoic acid (DHA, 22:6n-3) and increased docosatetraenoic acid (22:4n-6). There were no significant differences in the precursors of these FAs. CONCLUSIONS: DHA concentration in patients with CFRLD is decreased more substantially compared with their genotype controls. The presence of CFRLD should be taken into account in future FA studies in CF patients.

Defining DIOS and constipation in cystic fibrosis with a multicentre study on the incidence, characteristics, and treatment of DIOS.

OBJECTIVES: Various definitions for distal intestinal obstruction syndrome (DIOS), meconium ileus equivalent, and constipation in patients with cystic fibrosis (CF) are used. However, an unequivocal definition for DIOS, meconium ileus equivalent, and constipation is preferred. The aims of this study were, therefore, to seek consensus on the definitions for DIOS and constipation in patients with CF and to determine the incidence, characteristics, and treatment of DIOS in a cohort of paediatric patients with CF. METHODS: During the 2005 European Society for Paediatric Gastroenterology, Hepatology, and Nutrition meeting in Porto a group of paediatric gastroenterologists discussed the definition of DIOS and constipation in CF. Subsequently, all patients younger than or equal to 18 years with complete DIOS according to the definition agreed upon and diagnosed during the years 2001 to 2005 in 8 CF centres were studied. RESULTS: Distal intestinal obstruction syndrome was defined as an acute complete or incomplete faecal obstruction in the ileocaecum, whereas constipation was defined as gradual faecal impaction of the total colon. Fifty-one episodes of DIOS in 39 patients were recorded, giving an overall incidence of 6.2 (95% confidence interval, 4.4-7.9) episodes per 1000 patient-years. Of the 39 patients with DIOS, 20% experienced a relapse, 92% were pancreatic insufficient, 44% had a history of meconium ileus at birth, and 82% had a severe genotype. Conservative treatment was effective in 49 of 51 DIOS episodes (96%). CONCLUSIONS: The European Society for Paediatric Gastroenterology, Hepatology, and Nutrition CF Working Group definitions of DIOS and constipation in CF are specific and make a clear distinction between these 2 entities. The incidence of DIOS in the present study was considerably higher than reported previously.

Vitamin D binding protein, a new nutritional marker in cystic fibrosis patients.

BACKGROUND: Vitamin D binding protein (DBP) is a multifunctional transport protein with a decreased serum concentration in cystic fibrosis (CF). The present study investigates the importance of DBP and its role as an alternative nutritional marker in CF. METHODS: DBP phenotypes of 116 CF patients were determined electrophoretically. Serum DBP was measured by immunonephelometry. Parathormone was assessed by an immunoradiometric assay. Serum 25OH vitamin D(3), 1,25(OH)(2) vitamin D(3) and leptin concentrations were determined by a radioimmunoassay. Serum alpha-tocopherol was measured by HPLC. Routine chemistry parameters were assessed using commercial methods. The Prognostic Inflammatory and Nutritional Index was calculated. RESULTS: Decreased serum DBP concentrations were observed in the CF group. Total cholesterol, low-density lipoprotein (LDL)-cholesterol, triglyceride concentration, alpha-tocopherol and a low nutritional status correlated positively with DBP. Lipoprotein precipitation demonstrated a partial presence of DBP in very-low-density lipoprotein and LDL. Furthermore, DBP was positively correlated with serum leptin concentration. CONCLUSIONS: The present study demonstrates a positive correlation between DBP and serum lipids. Serum DBP concentration can be considered as a nutritional marker (especially for lipids).

Relation between fatty acid composition and clinical status or genotype in cystic fibrosis patients.

OBJECTIVE: To evaluate the relation of clinical parameters and genotype with the serum phospholipid fatty acid (FA) composition in cystic fibrosis (CF) patients. METHODS: A blood sample was taken from CF patients with stable pulmonary disease for the determination of phospholipid FA composition and vitamin E concentration who had been followed for at least 6 months at our Cystic Fibrosis Centre. Genotype, age, pancreatic function, nutritional status, caloric intake, pulmonary function and presence of Pseudomonas colonization, liver disease or diabetes mellitus were recorded. Patients were divided into two groups according to their genotype (group A: mutation class I, II, or III, group B: mutation class IV, V). RESULTS: CF patients (group A and B together) have significantly lower docosahexaenoic acid (DHA) (p < 0.007) and linoleic acid (LA) (p < 0.0001) and higher dihomogammalinolenic acid (DHGLA) (p < 0.0001), oleic acid (OA) (p < 0.0001) and Mead acid (MA) (p < 0.0001), resulting in an increased ratio of arachidonic acid (AA)/DHA (p < 0.004), MA/AA (p < 0.0001) and OA/LA (p < 0.0001). Compared to group B, group A had a lower LA (p < 0.002) and a higher DHGLA (p < 0.002), 22:4omega-6 (p < 0.03), 22:5omega-6 (p < 0.03) and 20:3omega-9 (p < 0.04). There was however no significant difference between the groups for age, pulmonary function, nutritional status and vitamin E concentration. There was no relation of serum FA composition with nutritional status, caloric intake, pancreatic function, gender, pulmonary function, Pseudomonas colonization or diabetes mellitus. In CF with liver disease the DHA was lower than in the patients of the same genotype. CONCLUSION: FA disturbances are more pronounced in the severe CF genotypes and the presence of CF-related liver disease. Future studies on supplementation should take these parameters into account.

Outcome of total splenectomy with portosystemic shunt for massive splenomegaly and variceal bleeding in cystic fibrosis.

Multilobular biliary cirrhosis and portal hypertension are frequent complications of cystic fibrosis liver disease, leading to esophageal varices and splenomegaly. Therapy is focused on variceal bleeding control; however, reduction of spleen volume is also important to restore gastric volume and resolve invalidating abdominal discomfort. We report long-term follow up (median duration, 5.5 years; range, 14 months-21.5 years) of 6 patients with cystic fibrosis (4 men, 2 women; median age, 14 years; range, 8-18 years) who underwent splenectomy with a splenorenal shunt operation. Three patients received elective surgery for massive splenomegaly with important abdominal discomfort, recurrent variceal bleeding, and hypersplenism. Three were urgently treated to control variceal bleeding after several sessions of sclerotherapy. All but 2 received antipneumococcal vaccination before surgery. Four patients had a weight gain of 10% within 3 months of surgery, and 3 developed spontaneous puberty. Lung function remained stable, and there was an overall reduction of respiratory tract infections. The youngest patient, however, died of overwhelming septicemia during treatment with steroids. Although total splenectomy has important risks, in well-selected cases, it can have benefits. Immuno- and chemoprophylaxis, combined with patient awareness of supplementary risk of infections is indispensable to minimize septic complications.

Transient exocrine pancreatic insufficiency as a possible complication of an enterovirus infection.

UNLABELLED: Exocrine pancreatic insufficiency is an exceptional problem in children, mostly associated with diseases like cystic fibrosis, Shwachman-Diamond syndrome or chronic pancreatitis, as is the case in idiopathic fibrosing pancreatitis. Many viral infections are known to cause acute pancreatitis. Most of them, however, are transient with no remaining damage. The differential diagnosis of persisting diarrhoea after gastrointestinal infection does not routinely include a search for exocrine pancreatic insufficiency. CONCLUSION: This is the first description of a child with a transient but severe exocrine pancreatic insufficiency probably induced by an ordinary enterovirus infection

Colonic arteriovenous malformation in a child misinterpreted as an idiopathic colonic varicosis on angiography: remarks on current classification of childhood intestinal vascular malformations.

A case of lower gastrointestinal hemorrhage in a child caused by an arteriovenous malformation (AVM) of the colon is presented. On diagnostic angiography, the lesion was misinterpretated as an idiopathic colonic varicosis because none of the characteristic features of an AVM were present. The role of angiography and shortcomings in nomenclature and classification of intestinal vascular anomalies in childhood are discussed.