Liver Transplantation for Primary Sclerosing Cholangitis (PSC) With or Without Inflammatory Bowel Disease (IBD)-A European Society of Organ Transplantation (ESOT) Consensus Statement.

Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of inflammatory bowel disease (IBD) and a lead indication for liver transplantation (LT) in the western world. In this article, we present a Consensus Statement on LT practice, developed by a dedicated Guidelines' Taskforce of the European Society of Organ Transplantation (ESOT). The overarching goal is to provide practical guidance on commonly debated topics, including indications and timing of LT, management of bile duct stenosis in patients on the transplant waiting list, technical aspects of transplantation, immunosuppressive strategies post-transplant, timing and extension of intestinal resection and futility criteria for re-transplantation.

Regulation of bile acid metabolism in biliary atresia: reduction of FGF19 by Kasai portoenterostomy and possible relation to early outcome.

BACKGROUND: Fibroblast growth factor 19 (FGF19) is produced in the small intestine and is involved in suppression of hepatic bile acid (BA) synthesis. FGF19 is also expressed in the liver and serum levels are elevated in adults with cholestatic liver disease. This may reflect a rescue mechanism to dampen liver injury caused by increased intrahepatic BAs. OBJECTIVES: To examine circulating FGF19 at early stages of biliary atresia and at short-term follow-up post-Kasai portoenterostomy (KPE) in relation to noncholestatic infants. The relationship between FGF19, BAs and markers for BA synthesis and hepatic gene expression of factors involved in BA metabolism were also evaluated. METHODS: Liver tissue, portal and peripheral blood samples were obtained from fifteen patients at KPE; additional blood was collected 4-6 months after surgery. Two control groups were included; to examine possible changes related to surgery and to compare FGF19 in biliary atresia to noncholestatic infants. RESULTS: Circulating FGF19 levels correlated to its hepatic gene expression at time of KPE in biliary atresia and levels were elevated compared to noncholestatic infants. At follow-up, FGF19 levels were markedly reduced, and the decline coincided with reductions in bilirubin and conjugated chenodeoxycholic acid and with increased levels of the BA synthesis marker C4. CONCLUSION: Elevated circulating FGF19 in biliary atresia is of hepatic origin and reduced following KPE. Changes in serum FGF19 may reflect the level of restoration of the enterohepatic circulation, and this warrants further long-term studies on the role of FGF19 in the cholestatic liver.

Impaired intention-to-treat survival after listing for liver transplantation in children with biliary atresia compared to other chronic liver diseases: 20 years' experience from the Nordic countries.

Biliary atresia (BA) is the most common indication for LT in children. We investigated whether this diagnosis per se, compared to other chronic liver diseases (OCLD), had an influence on patient survival. Data from 421 Scandinavian children, 194 with BA and 227 with OCLD, listed for LT between 1990 and 2010 were analyzed. The intention-to-treat survival and influencing risk factors were studied. Patients with BA had higher risk of death after listing than patients with OCLD. The youngest (<1 year) and smallest (<10 kg) children with the highest bilirubin (>510 µmol/L), highest INR (>1.6), and highest PELD score (>20) listed during 1990s had the worst outcome. Given the same PELD score, patients with BA had higher risk of death than patients with OCLD. For adolescents, low weight/BMI was the only prognostic marker. Impaired intention-to-treat survival in patients with BA was mainly explained by more advanced liver disease in younger ages and higher proportion of young children in the BA group rather than diagnosis per se. PELD score predicted death, but seemed to underestimate the severity of liver disease in patients with BA. Poor nutritional status and severe cholestasis had negative impact on survival, supporting the "sickest children first" allocation policy and correction of malnutrition before surgery.

De Novo Donor-Specific HLA Antibody Formation in Two Patients With Crigler-Najjar Syndrome Type I Following Human Hepatocyte Transplantation With Partial Hepatectomy Preconditioning.

Clinical hepatocyte transplantation is hampered by low engraftment rates and gradual loss of function resulting in incomplete correction of the underlying disease. Preconditioning with partial hepatectomy improves engraftment in animal studies. Our aim was to study safety and efficacy of partial hepatectomy preconditioning in clinical hepatocyte transplantation. Two patients with Crigler-Najjar syndrome type I underwent liver resection followed by hepatocyte transplantation. A transient increase of hepatocyte growth factor was seen, suggesting that this procedure provides a regenerative stimulus. Serum bilirubin was decreased by 50%, and presence of bilirubin glucuronides in bile confirmed graft function in both cases; however, graft function was lost due to discontinuation of immunosuppressive therapy in one patient. In the other patient, serum bilirubin gradually increased to pretransplant concentrations after ≈600 days. In both cases, loss of graft function was temporally associated with emergence of human leukocyte antigen donor-specific antibodies (DSAs). In conclusion, partial hepatectomy in combination with hepatocyte transplantation was safe and induced a robust release of hepatocyte growth factor, but its efficacy on hepatocyte engraftment needs to be evaluated with additional studies. To our knowledge, this study provides the first description of de novo DSAs after hepatocyte transplantation associated with graft loss.

Maternal and fetal outcome in Swedish women with erythropoietic protoporphyria.

BACKGROUND: Painful photosensitivity is characteristic of erythropoietic protoporphyria (EPP). In women, symptoms may be affected by menstrual cycle and pregnancy but very little is known about maternal and fetal outcome. OBJECTIVES: To investigate the impact of menstruation, pregnancy and breast-feeding on photosensitivity and possible effects of EPP on maternal, fetal and neonatal outcome. METHODS: Retrospective study screening all 20 Swedish women alive and older than 18 years diagnosed with EPP with a total of 33 deliveries. Data were retrieved for 19 women and 32 deliveries in medical records and completed by a questionnaire sent to the patients. RESULTS: Photosensitivity worsened in five of 19 (26%) women around menstruation whereas amelioration was reported in 17 of 32 (53%) pregnancies and during 11 of 32 (34%) breast-feeding periods. Fertility rate was normal and there were no maternal or fetal complications apart from minor arterial hypertension in one woman. CONCLUSIONS: The study confirms changes in photosensitivity during menstruation and pregnancy. Amelioration during breast-feeding is a new finding. Pregnancy appears safe without increased risks of pregnancy complications or adverse effects on fetal or neonatal health.

Hepatocyte transplantation for inherited metabolic diseases of the liver.

Inherited metabolic diseases of the liver are characterized by deficiency of a hepatic enzyme or protein often resulting in life-threatening disease. The remaining liver function is usually normal. For most patients, treatment consists of supportive therapy, and the only curative option is liver transplantation. Hepatocyte transplantation is a promising therapy for patients with inherited metabolic liver diseases, which offers a less invasive and fully reversible approach. Procedure-related complications are rare. Here, we review the experience of hepatocyte transplantation for metabolic liver diseases and discuss the major obstacles that need to be overcome to establish hepatocyte transplantation as a reliable treatment option in the clinic.

Determinants of symptoms in functional dyspepsia: gastric sensorimotor function, psychosocial factors or somatisation?

BACKGROUND: Gastric sensorimotor dysfunction, psychosocial factors and somatisation are all implicated in symptom generation in functional dyspepsia (FD). AIM: To determine the relative contribution of each of these factors to overall dyspeptic symptom severity and weight loss in FD. METHODS: In 201 consecutive tertiary care patients with FD (mean age 40.1 (SD 12.6) years), gastric sensorimotor function was studied using barostat (sensitivity, compliance and accommodation). Psychosocial factors (depression and anxiety disorders, positive and negative affect, perceived stress, alexithymia and history of abuse), somatisation and co-morbid irritable bowel syndrome (IBS) and chronic fatigue symptoms were assessed using self-report questionnaires. Variables were correlated with dyspepsia symptom severity (DSS) and weight loss. Hierarchical multiple linear regression was used to identify determinants of DSS and weight loss. RESULTS: Multiple linear regression identified the following determinants of DSS: gastric sensitivity (beta = 0.77, p = 0.25), depression (beta = 0.12, p = 0.06) and somatisation (beta = 0.48, p<0.0001) (controlling for age and occupation, R(2) = 0.29, p<0.0001). The effect of depression on DSS is partially mediated by somatisation. Gastric sensitivity (beta = 2.87, p = 0.08), history of childhood sexual abuse (beta = 9.37, p = 0.0006), depression (beta = 0.19, p = 0.24) and somatisation (beta = 0.67, p = 0.01) are independent determinants of weight loss (controlling for gender and occupation, R(2) = 0.42, p<0.0001). The effect of depression on weight loss is fully mediated by somatisation. CONCLUSION: Symptom severity and weight loss in FD are determined by psychosocial factors (depression, abuse history) and somatisation, and only to a lesser extent by gastric sensorimotor function. The importance of psychosocial factors and somatisation compared to gastric sensorimotor function is most pronounced in hypersensitive patients.

Prevalence and impact of self-reported irritable bowel symptoms in the general population.

Background and aims: The symptom-based diagnostic criteria for irritable bowel syndrome (IBS) have recently been revised in the Rome IV consensus. On the other hand, with rising public awareness of IBS, self-diagnosis and self-management is also increasing. We compared the prevalence and impact of Rome IV-based IBS vs self-diagnosed IBS in the general population. Methods: An internet panel filled out an online survey on bowel symptoms and their impact on health care utilization and daily activities. Results: A representative internet panel of 1012 individuals completed the online survey. Bowel symptoms were present in 68.6% of the population. Of these, 21% consulted a physician for these symptoms in the last year and 42% earlier. Rome IV IBS criteria were fulfilled by 5.5%, and these were younger and more likely to be female. In this subset, 37% had consulted a physician for IBS symptoms in the preceding year and 29% had done so earlier. A colonoscopy had been performed in 22%. Based on a brief description, 17.6% of the population self-identified as suffering from IBS (p < 0.001 compared to Rome IV IBS prevalence), and these were more likely to be female. Concordance with the Rome IV criteria was only 25%, but except for a lower reporting of pain, the symptom pattern, severity, impact on daily life, inability to work and health care utilization were similar to the Rome IV group. A total of 134 days of absence from work were attributed to bowel symptoms in those self-reporting with IBS. Conclusion: In the general population, bowel symptoms are highly prevalent, and the self-reported "IBS" is three times more prevalent than according to Rome IV criteria. Self-reported IBS is associated with a similar impact on health care utilization and quality of life but a higher impact on absence from work.

Influence of citalopram, a selective serotonin reuptake inhibitor, on oesophageal hypersensitivity: a double-blind, placebo-controlled study.

Background Tricyclic antidepressants, which have multiple pharmacological influences, have a therapeutic effect in non-cardiac chest pain, but selective serotonin reuptake inhibitors have a single pharmacological effect. Aim To evaluate the acute effect of citalopram on oesophageal hypersensitivity. Methods On two separate occasions, 10 healthy subjects (seven men, mean age 25 years) with established oesophageal hypersensitivity, underwent oesophageal manometry with evaluation of mechanical and chemical sensitivity. Subjects received placebo or citalopram 20 mg i.v. in a randomized, crossover, double-blind fashion. Results Citalopram did not alter oesophageal motility. Citalopram significantly increased the threshold inducing first perception (4.6+/-0.3 vs. 6.7+/-0.4 mL, P<0.005) and discomfort (8.6+/-0.4 vs. 9.9+/-0.6 mL, P<0.01) during balloon distention. It also significantly prolonged the acid perfusion time to induce perception of heartburn (6.0+/-0.9 vs. 10.7+/-0.6 min, P<0.005) and discomfort (12.2+/-0.8 vs. 16.7+/-0.7 mL, P<0.001). Seven subjects experienced a retrosternal sensation during edrophonium provocation with placebo, and this was reduced to two of 10 after citalopram (P=0.02). Conclusions Acute administration of citalopram significantly lowers chemical and mechanical oesophageal sensitivity in oesophageal hypersensitivity, without altering the motility.

Influence of acute serotonin reuptake inhibition on colonic sensorimotor function in man.

BACKGROUND: It is unclear whether decreased serotonin transporter function contributes to sensorimotor abnormalities in irritable bowel syndrome. AIM: To study the influence of acute serotonin transporter inhibition on colonic sensorimotor function in man. METHODS: Ten healthy subjects (five men, aged 20-29 years) underwent a combined manometry/barostat study of the descending colon on two occasions. Stepwise distentions by 2 mmHg increments were performed until discomfort. Subsequently, placebo or citalopram 20 mg were administered i.v. over 20 min and distentions were repeated. Afterwards, isobaric tone measurements were performed 30 min before and 90 min after ingestion of a meal. High-amplitude propagated contractions, colonic motility index, colonic compliance, sensitivity and colonic response to a meal after placebo or citalopram were compared by t-test and two-way ANOVA. RESULTS: Citalopram induced a significant increase in colonic motility index (5.6 +/- 0.9 to 0.8 +/- 1.9 mL*min, P < 0.005) and high-amplitude propagated contractions (32 after citalopram vs. 2 after placebo, P < 0.05), which were associated with abdominal cramping. Administration of citalopram increased colonic compliance (10.3 +/- 1.5 vs. 14.5 +/- 2.2 mL/mmHg, P < 0.01) and inhibited colonic response to a meal (volume decrease 48 +/- 12 vs. 16 +/- 12 mL, P < 0.01). CONCLUSIONS: Acute serotonin transporter inhibition in man increases colonic phasic contractility and the occurrence of high-amplitude propagated contractions, increases colonic compliance and suppresses the colonic tonic response to a meal. These data suggest that both release and elimination of 5-hydroxytryptamine by serotonin transporter are involved in the control of colonic motility in man.

The impact of major depressive disorder on the short- and long-term outcome of Crohn's disease treatment with infliximab.

BACKGROUND: Major depressive disorder is the most common psychiatric diagnosis in Crohn's disease. In other chronic diseases, evidence suggests that depression influences the course of the disease. Strong evidence of such a mediating role of major depressive disorder in Crohn's disease has never been found. AIM: To assess the relationship between major depressive disorder and outcome of treatment of luminal Crohn's disease with infliximab. METHODS: In this prospective study, 100 consecutive unselected patients underwent assessment of psychosocial, demographical disease-related biological and clinical parameters at baseline and at 4 weeks after infliximab. Major depressive disorder was diagnosed using the Patient Health Questionnaire. Subsequently, the patients were followed up clinically until the next flare or during 9 months. RESULTS: The Crohn's disease responded in 75% of the patients, and remission was achieved in 60%. The presence of major depressive disorder at baseline predicted a lower remission rate (OR = 0.166, 95% CI = 0.049-0.567, P = 0.004). At follow-up, 88% of the patients needed retreatment. At univariate regression analysis, major depressive disorder significantly decreased time to retreatment (P = 0.001). Multivariate Cox regression confirmed major depressive disorder as an independent determinant of active disease both at baseline and at re-evaluation (hazard ratio = 2.271, 95% CI: 1.36-3.79, P = 0.002). CONCLUSION: Major depressive disorder is a risk factor for failure to achieve remission with infliximab and for earlier retreatment in patients with active luminal Crohn's disease. Assessment and management of major depressive disorder should be part of the clinical approach to patients with Crohn's disease.

Review of clinical and psychobiological dimensions of the chronic fatigue syndrome: differentiation from depression and contribution of sleep dysfunctions.

Chronic fatigue syndrome (CFS) is a disabling condition characterized by subjective fatigue, mental and physical fatigability, a whole range of somatic symptoms and a poor quality of sleep. Its physiopathology is largely unknown. Several clinical and biological differences were observed between CFS and major depression. A classical conceptualization of masked (or somatized expression of) depression is therefore no longer tenable. Sleep anomalies were reported in all studies published to date. However, these sleep anomalies do not seem to explain a major part of the symptomatology of CFS. The contribution of sleep abnormalities to the development and chronicity of CFS should be further studied. CFS can be considered as a somatoform condition. CFS is like most functional disorders a clinically and biologically heterogeneous condition. The best available treatment to date is cognitive-behavioural therapy.

Influence of the selective serotonin re-uptake inhibitor, paroxetine, on gastric sensorimotor function in humans.

BACKGROUND: The role of 5-hydroxytryptamine in the control of gastric fundus tone in humans is still unknown. Selective 5-hydroxytryptamine re-uptake inhibitors act both centrally and peripherally to enhance the availability of physiologically released 5-hydroxytryptamine. AIM: To study the influence of a selective 5-hydroxytryptamine re-uptake inhibitor, paroxetine, on gastric fundus tone, on the perception to gastric distension and on gastric accommodation to a meal. METHODS: Sixteen healthy volunteers underwent a gastric barostat study on two occasions, after pre-treatment with placebo or paroxetine, 20 mg/day. Graded isobaric and isovolumetric distensions were performed and perception was scored by a questionnaire. Subsequently, the amplitude of the gastric accommodation to a mixed liquid meal was also measured. RESULTS: Pre-treatment with paroxetine did not alter the thresholds for perception and discomfort during isobaric (4.7 +/- 2.3 vs. 4.0 +/- 2.0 mmHg and 13.3 +/- 3.1 vs. 12.7 +/- 2.3 mmHg above the minimum intragastric distending pressure, N.S.) and isovolumetric (307 +/- 90 vs. 417 +/- 114 mL and 772 +/- 74 vs. 750 +/- 76 mL, N.S.) distensions. Paroxetine significantly enhanced the amplitude of the meal-induced fundus relaxation (136 +/- 51 vs. 255 +/- 43 mL, P < 0.05). CONCLUSIONS: Pre-treatment with paroxetine enhances gastric accommodation to a meal. These data suggest that the release of 5-hydroxytryptamine, probably at the level of the enteric nervous system, is involved in the control of the accommodation reflex in humans, and that paroxetine may be beneficial to patients with impaired post-prandial fundus relaxation.

A nurse-led interdisciplinary intervention program for delirium in elderly hip-fracture patients.

OBJECTIVES: To develop and test the effect of a nurse-led interdisciplinary intervention program for delirium on the incidence and course (severity and duration) of delirium, cognitive functioning, functional rehabilitation, mortality, and length of stay in older hip-fracture patients. DESIGN: Longitudinal prospective before/after design (sequential design). SETTING: The emergency room and two traumatological units of an academic medical center located in an urban area in Belgium. PARTICIPANTS: 60 patients in an intervention cohort (81.7% females, median age = 82, interquartile range (IQR) = 13) and another 60 patients in a usual care/nonintervention cohort (80% females, median age = 80, IQR = 12). INTERVENTION: (1) Education of nursing staff, (2) systematic cognitive screening, (3) consultative services by a delirium resource nurse, a geriatric nurse specialist, or a psychogeriatrician, and (4) use of a scheduled pain protocol. MEASUREMENTS: All patients were monitored for signs of delirium, as measured by the Confusion Assessment Method (CAM). Severity of delirium was assessed using a variant of the CAM. Cognitive and functional status were measured by the Mini-Mental State Examination (MMSE) (including subscales of memory, linguistic ability, concentration, and psychomotor executive skills) and the Katz Index of activities of daily living (ADLs), respectively. RESULTS: Although there was no significant effect on the incidence of delirium (23.3% in the control vs 20.0% in the intervention cohort; P =.82), duration of delirium was shorter (P =.03) and severity of delirium was less (P =.0049) in the intervention cohort. Further, clinically higher cognitive functioning was observed for the delirious patients in the intervention cohort compared with the nonintervention cohort. Additionally, a trend toward decreased length of stay postoperatively was noted for the delirious patients in the intervention cohort. Despite these positive intervention effects, no effect on ADL rehabilitation was found. Results for risk of mortality were inconclusive. CONCLUSIONS: This study demonstrated the beneficial effects of an intervention program focusing on early recognition and treatment of delirium in older hip-fracture patients and confirms the reversibility of the syndrome in view of the delirium's duration and severity.

Immune changes induced by electroconvulsive therapy (ECT).

There is a significant increase in the percentage and absolute number of activated lymphocytes (OKT10+, IL2R1+) after ECT treatment of major depressive disorder. There is an acute decrease in the absolute number of total lymphocytes, T8+ and Leu11+ cells one hour after a single ECT.

Physical fatigability and exercise capacity in chronic fatigue syndrome: association with disability, somatization and psychopathology.

Physical fatigability and avoidance of physically demanding tasks in chronic fatigue syndrome (CFS) were assessed by the achievement or nonachievement of 85% of age-predicted maximal heart rate (target heart rate, THR) during incremental exercise. The association with functional status impairment, somatization, and psychopathology was examined. A statistically significant association was demonstrated between this physical fatigability variable and impairment, and a trend was found for an association with somatization. No association was demonstrated with psychopathology. These results are in accordance with the cognitive-behavioral model of CFS, suggesting a major contribution of avoidance behavior to functional status impairment; however, neither anxiety nor depression seem to be involved in the avoidance behavior. Aerobic work capacity was compared between CFS and healthy controls achieving THR. Physical deconditioning with early involvement of anaerobic metabolism was demonstrated in this CFS subgroup. Half of the CFS patients who did not achieve THR did not reach the anaerobic threshold. This finding argues against an association in CFS between avoidance of physically demanding tasks and early anaerobic metabolism during effort.

Cytomegalovirus DNA detection on Guthrie cards in patients with neonatal cholestasis.

AIM: To time the onset of cytomegalovirus (CMV) infection in patients (n = 39) with CMV associated neonatal cholestasis by analysing CMV DNA on Guthrie cards sampled at 3 days of age. METHODS: CMV infection was diagnosed by serology/urine isolation or by CMV DNA detection (polymerase chain reaction) in liver biopsy specimens. In order to time the infection dry blood filter paper discs were punched out from stored Guthrie cards. After phenol-choloroform extraction CMV DNA was detected by nested polymerase chain reaction. RESULTS: All cards from control children (n = 8) with congenital CMV tested positive; none of the negative controls (n = 4) did so. Two of 39 cholestatic infants were CMV DNA positive; their mothers had serological signs compatible with infection during the second half of the pregnancy. All other cholestatic infants tested negative. CONCLUSIONS: CMV DNA was not detected in most of the children using Guthrie cards, suggesting that infection developed at or soon after birth.

Immune dysfunction associated with chronic professional stress in nurses.

The relationship between chronic professional stress in nurses and immunity as well as the possible impact of psychopathology upon this relationship have been examined. Sixty subjects were selected on the basis of high/low scores on professional stress and psychopathology. Chronic professional stress appeared to be associated with immune dysfunction including signs of immune activation (increased numbers of cells expressing the interleukin-2 receptor, especially CD4+CD25+ cells) and possibly immune suppression (decrease in percentage of natural killer cells). The increase in activation markers, CD3+CD16CD56+ cells and serum neopterin was most pronounced in the group with high stress/low psychopathology whereas the decrease in CD8+CD11b+ cells was most pronounced in the group with high stress/high psychopathology. It is hypothesized that in the presence of chronic stress distinct psychological mechanisms are associated with specific immune dysfunctions.

The Coca-Cola incident in Belgium, June 1999.

The present paper describes the outbreak of health complaints that occurred in Belgium, in June 1999, among schoolchildren and members of the general public in relation to the consumption of Coca-Cola and other soft drinks. The outbreak took place in the wake of a major food crisis, caused by PCB/dioxin contamination of animal feed, that had erupted shortly before. The clinical features (absence of serious poisoning) and epidemiological characteristics of the Coca-Cola outbreak pointed to mass sociogenic illness, and no subsequent toxicological or other data have refuted this hypothesis.

Psychosocial and behavioral selection criteria for solid organ transplantation.

An evidence-based selection process for organ transplantation may be a valuable approach to improve posttransplant outcomes. This paper reviews state-of-the-art psychosocial and behavioral selection criteria and assesses their validity in view of predicting outcomes after transplantation. Psychosocial factors addressed are psychiatric disorders, mental retardation, irreversible cognitive dysfunction, and lack of social support. Behavioral selection criteria discussed are alcoholism, smoking, drug abuse, and obesity. This review reveals that the evidence concerning these selection criteria in scarce. There is a definite need for more longitudinal research to strengthen the scientific basis of the psychosocial and behavioral dimension of transplantation.