Michela Barollo

Diagnosis and management of Wilson's disease: results of a single center experience.

Aims To report on the diagnostic features, management, and clinical outcome after different treatments of Wilsons disease patients followed over a mean period of 15 years. Patients Thirty-five patients with Wilsons disease referred to the University of Padovas Department of Gastroenterology for diagnosis or treatment were observed for a mean 15 years. The diagnosis was based on clinical symptoms, laboratory tests (ceruloplasmin, urinary, and hepatic copper concentrations), and uptake of the radiostable isotope 65Cu into the plasma protein pool. Hepatic Cu content was measured by regular follow-up biopsies. Neurologic outcome after therapy was assessed using a newly developed scoring system. Results Twenty-three (65.7%) patients presented with liver disease; 12 (34.3%) had mixed neurologic and hepatic involvement. All patients had been initially treated with either penicillamine (23) or zinc sulfate (12). The neurologic symptoms became worse or remained stationary in 75% of those treated with penicillamine, whereas zinc treatment improved these symptoms in 90% of treated cases. Both treatments were effective in improving the hepatic symptoms. No differences in hepatic Cu content emerged between follow-up biopsies in either treatment group. Six patients (26%) had to abandon the penicillamine treatment due to side effects. In all, 4 patients underwent liver transplantation, which was successful in 3, with a mean survival after transplantation of 4.6 years; the fourth, who had a severe neurologic impairment, died of central pontine myelinolysis. Conclusions Penicillamine and zinc can effectively treat Wilsons disease, though the side effects of penicillamine may be severe enough to prompt its suspension. Liver transplantation remains the treatment of choice for end-stage liver disease.

Health-related quality of life after restorative proctocolectomy for ulcerative colitis: Long-term results

Restorative proctocolectomy (RPC) is the favorite operation for ulcerative colitis, but it may influence health-related quality of life (HRQL). Our aims were to determine the long-term HRQL of patients and its modifications after a 5-year follow-up and to identify any risk factor for a worse outcome. We enrolled 36 patients submitted to RPC (mean followup 8.4 ± 4.7 years), 36 ulcerative colitis (UC) patients, and 36 healthy subjects. We used a previously validated questionnaire that explored bowel symptoms, systemic symptoms, emotional function, and social function. A series of 17 patients had completed the same questionnaire 5 years earlier. Clinical and surgical factors were investigated. Statistical analysis was performed with Student’s t-test, Wilcoxon matched-pairs test, and Fisher’s exact test. The scores of the RPC patients were significantly better than those of moderate or severe UC patients, similar to those with remission/ mild UC, and higher than those of the controls. The scores of patients interviewed 5 years earlier did not change in the present study, except for patients during the first postoperative year, in whom the scores were now significantly better. The analysis of RPC patients in subgroups showed that the use of drugs, high stool frequency, pouchitis, pelvic complications, and younger age at UC diagnosis worsened the HRQL outcome. We concluded that RPC patients, after a long-term follow-up, had an HRQL similar to that of the remission/mild UC patients. Recently operated patients improved their quality of life mainly because of improved emotional function, and patients who had been operated on for a longer time maintained their HRQL. HRQL is influenced by drugs, stool frequency, pouchitis, postoperative pelvic complications, and age at diagnosis.RésuméLa coloprotectomie restauratrice (CPR) est l’intervention préférée dans la rectocolite ulcéro-hémorragique (RCUH), mais elle peut avoir un retentissement sur la qualité de vie (QV). Nos objectifs ont été de déterminer la QV des patients à long terme ainsi que leurs modifications après un suivi de 5 ans et d’identifier les facteurs de risque pour une évolution non favorable. Nous avons analysé les résultats concernant 36 patients ayant eu une CPR (suivi moyen: 8.4 ± 4.7 ans) pour avecRCUH 36 patients avec RCUH et 36 patients de contrôle. Nous avons utilisé un questionnaire validé antérieurement qui explore les symptômes intestinaux, les symptômes systémiques, les fonctions émotionnelle et sociale. Dix-sept patients avaient complété ce même questionnaire cinq ans plus tôt. On a également examiné les facteurs cliniques et chirurgicaux. L’analyse statistique a été réalisée par le test t de Student, de Wilcoxon pour les données appariées et le test exact de Fisher. Les patients CPR ont obtenu des scores significativement plus élevés que les patients présentant une RCUH modérée ou sévère, similaires à ceux présentant une RCUH en rémissionpeu sévère et plus élevés que les patients de contrôle. Les scores des patients interviewés cinq ans plus tôt n’ont pas changé sauf pour la première année postopératoire pendant laquelle il était significativement meilleur. L’analyse des sous-groupes de patients RCUH a montré que l’utilisation des medicaments, une fréquence élevée de l’évacuation, la pouchite, les complications pelviennes et un âge peu élevé au moment de l’intervention ou diagnostic a aggravé l’évolution de la QV. En conclusion, les patients ayant du eu une CPR au long cours jouissent d’une QV similaire à celle des patients en rémission ou avec une RCUH peu sévère. Les patients opérés récemment voient leur QV améliorée principalement en raison de leur fonction émotionnelle alors que les patients opérés il y a plus long temps gardent leur QV. La QV est influencée par l’utilisation des medicaments, la fréquence des selles, la pouchite, les complications postopératoires et l’âge au moment du diagnostic.ResumenLa proctocolectomía restaurativa (PCR) es el tipo de cirurgia en el tratamiento de la colitis ulcerativa, pero puede afectar la calidad de vida al comparla con el buen estado de salud (CVCS). Nuestro propósito fue determinar la CVCS a largo plazo y sus cambios después de S años de seguimiento, identificando factores de riesgo de empeoramiento. Se incorporaron 36 pacientes sometidos a PCR (promedio de seguimiento: 8.4 ± 4.7 años) 36 por colitis ulcerativa (CU), y 36 pacientes sanos. Se utilizó un cuestionario previamente validado para identificar síntomas intestinales, síntomas sistémicos, estado emocional y cualidad de vida en el ambito social. Diecisiete pacientes habían respondido el mismo cuestionario 5 años antes. Factores clínicos y quirúrgicos fueron investigados. Se hizo el análisis estadístico mediante la prueba de Student y las pruebas de apareamiento de Wilcoxon y de exactitud de Fischer. Los pacientes con PCR registraron valores significativamente mejores que los de los pacientes con colitis ulcerativa moderada o severa, una tasa similar a remisión de CU leve y más alta que la de los controles. Los valores de los pacientes entrevistados 5 años antes no mostraron cambio, y sólo aquellos en el primer año postoperatorio registraron ahora mejores valores. El análisis de los subgrupos de pacientes con PCR puso en evidencia que el requerimiento de drogas, la alta frecuencia en la defecatión, la “bolsitis” (pouchitis) las complicaciones pélvicas y la edad más joven en el momento del diagnóstico, desmejoraban la CVCS. En conclusión, los pacientes sometidos a PCR en el seguimiento a largo plazo logran una CVCS similar a la de aquellos con remisión de CU leve. Los pacientes recientemente operados mejoraron su calidad de vida principalmente por causa de un mejor estado emocional, en tanto que los operados con más anterioridad mantienen su CVCS. La CVCS se ve influenciada por el requerimiento de la droga, la frecuencia en la defecatión, la “bolsitis,” las complicaciones pélvicas postoperatorias y la edad en el momento del diagnóstico.

The role of CD40 in ulcerative colitis: histochemical analysis and clinical correlation.

Objectives CD40 co-stimulator seems to be implicated in the loss of tolerance against self-antigens in many autoimmune diseases. The evidence suggests that in the pathogenesis of ulcerative colitis there is an activity state against self-antigens of the gut wall and flora. The aim of this study was to analyse the expression of CD40 in ulcerative colitis, comparing it with Crohns disease and nonspecific inflammation of the colon and to determine whether there is a relationship between its expression and the activity stage of the disease. Methods The expression of CD40 in the colonic samples of 51 patients (30 ulcerative colitis, 9 Crohns disease and 12 nonspecific inflammation) was analysed by immunohistochemistry. Twenty-four patients with ulcerative colitis were scored according to clinical, endoscopic and histological classification. Results The mean percentage of CD40+ cells per field in the colonic mucosa was: ulcerative colitis 21 ± 11%, Crohns disease 24 ± 9%, nonspecific inflammation 7 ± 7%. The ulcerative colitis patients were statistically significantly different compared to the patients with nonspecific inflammation (P < 0.005), even when comparing the patients in remission (P < 0.05). The expression in Crohns disease was similar to that in ulcerative colitis. The expression of CD40 in ulcerative colitis was directly proportional to the state of activity of the disease according to the clinical (P < 0.02), endoscopic (P < 0.01) and histological (P < 0.02) criteria. Conclusions The expression of CD40 in the colonic mucosae of patients with ulcerative colitis is significantly increased and is proportional to the state of activity. The results seem to confirm the hypothesis that a loss of tolerance could be involved in the pathogenesis of this disease.

Effect of zinc supplementation on trace elements and intestinal metallothionein concentrations in experimental colitis in the rat

BACKGROUND AND AIM Zinc enhances cell protection against infection and injury and the healing processes themselves. We evaluated the effect of zinc supplementation at different doses on a model of experimental colitis in the rat. METHODS Colitis, induced by intra-rectal instillation of dinitrobenzen-sulphonic acid, was assessed at 1 week by examining: general outcome and macroscopic damage, myeloperoxidase activity, mucosal zinc, iron and metallothionein concentrations. Rats received zinc sulphate, 2 mg/kg or 30 mg/kg, twice a day by gavage for 9 days, starting 3 days before the induction of colitis, or intrarectal instillation of zinc (20 mg/kg) once daily starting 8 hours after the induction of colitis and for 6 days thereafter RESULTS Zinc-treated rats had less diarrhoea, higher body weight and lower colonic weight than untreated rats but no effect was observed on macroscopic inflammation, adhesions, colonic distension and neutrophil infiltration of the colonic mucosa. Zinc supplementation did not affect mucosal iron and zinc concentrations or plasma zinc levels in colitic rats. Metallothionein synthesis was induced in control rats and to a lesser extent in colitic rats. CONCLUSION Zinc administration induces metallothionein synthesis but has little effect on the short-term course of experimental colitis.

Effects of iron deprivation or chelation on DNA damage in experimental colitis

Background and aimsIn inflammatory bowel diseases iron contributes to the formation of DNA adducts through the production of hydroxyl radicals. The aim of our study was to evaluate the effects of dietary or pharmacological iron deprivation in an experimental model of colitis in the rat and its potential protective effect against DNA damage.MethodsColitis was induced in rats by intracolonic instillation of dinitrobenzene sulphonic acid. Rats were assigned to an iron-deprived diet or to desferrioxamine preceding the induction of colitis. The severity of colitis was assessed by the presence of bloody diarrhea, colonic macroscopic damage score, body-weight variations and the amount of DNA colonic adducts. Hepatic and colonic iron concentrations were measured.ResultsTreated rats experienced less diarrhea and did not lose weight in comparison to untreated animals. The macroscopic damage score was significantly reduced in the iron-deprived diet for the 5-week group (P=0.03). Liver and colonic iron levels were significantly more reduced in the iron-deprived groups than in the standard diet group (P<0.03 and P<0.01 after a 3- and 5-week iron-deprived diet, respectively). DNA adduct formation was significantly reduced in the groups deprived of iron for 5 weeks (P<0.001) or treated with desferrioxamine (P<0.01).ConclusionsThe degree of colitis caused by DNBS is macroscopically improved by dietary iron deprivation and to a lesser extent by pharmacological chelation; genomic damage is reduced by dietary iron deprivation or chelation, and this may have clinical implications on cancer prevention.

Antioxidative potential of a combined therapy of anti TNFα and Zn acetate in experimental colitis

AIM To evaluate whether combination therapy with anti-tumour necrosis factor α (TNFα) antibody and Zn acetate is beneficial in dextran sodium sulphate (DSS) colitis. METHODS Colitis was induced in CD1-Swiss mice with 5% DSS for 7 d. The experimental mice were then randomised into the following subgroups: standard diet + DSS treated (induced colitis group); standard diet + DSS + subcutaneous 25 μg anti-TNFα treated group; Zn acetate treated group + DSS + subcutaneous 25 μg anti-TNFα; standard diet + DSS + subcutaneous 6.25 μg anti-TNFα treated group and Zn acetate treated group + DSS + subcutaneous 6.25 μg anti-TNFα. Each group of mice was matched with a similar group of sham control animals. Macroscopic and histological features were scored blindly. Homogenates of the colonic mucosa were assessed for myeloperoxidase activity as a biochemical marker of inflammation and DNA adducts (8OH-dG) as a measure of oxidative damage. RESULTS DSS produced submucosal erosions, ulcers, inflammatory cell infiltration and cryptic abscesses which were reduced in both groups of mice receiving either anti-TNFα alone or combined with zinc. The effect was more pronounced in the latter group (vs Zn diet, P < 0.02). Myeloperoxidase activity (vs controls, P < 0.02) and DNA adducts, greatly elevated in the DSS fed colitis group (vs controls, P < 0.05), were significantly reduced in the treated groups, with a more remarkable effect in the group receiving combined therapy (vs standard diet, P < 0.04). CONCLUSION DSS induces colonic inflammation which is modulated by the administration of anti-TNFα. Combining anti-TNFα with Zn acetate offers marginal benefit in colitis severity.

Minimally invasive management of Crohn's disease complicated by ureteral stenosis

Ureteral involvement due to Crohns disease occurs in 3% to 6% of cases. Herein, we present a case of a 22-year-old woman with ileocolic Crohns disease with right hydronephrosis due to compression of the ureter that was resolved with a 3-stage, minimally invasive procedure (preoperative percutaneous nephrostomy, ureteral stent placement, and sequential laparoscopically assisted ileocolectomy). Percutaneous right nephrostomy drainage permitted us to prevent renal damage before surgery, and successive ureteral double-J catheter placement minimized the risk of ureteral damage during the laparoscopic procedure. The safety and feasibility of sequential minimally invasive management of ileocolonic Crohns disease involving the right ureter was assessed, and a good cosmetic result was achieved.

Expression of costimulatory molecule CD80 in colonic dysplasia in ulcerative colitis: an immunosurveillance mechanism against colorectal cancer?

Background and aimsUlcerative colitis is an established risk factor for colorectal cancer but dysplasia reports are much more frequent than invasive neoplasm diagnosis. The effective activation of T lymphocytes that provide antitumor surveillance requires the presence of costimulation molecules such as CD80 and CD86 on the surface of antigen-presenting cells. The aim of our study was to verify the presence of an in vivo immunosurveillance mechanism in the early stages of colon tumorigenesis.Patients and methodsExpression of CD80, CD86, and IFNγ in the colonic mucosa of 21 consecutive ulcerative colitis (UC) patients was quantified using reverse transcription polymerase chain reaction. After a 7-year follow-up period, we reviewed the histology of all surveillance colonoscopy specimens for colonic dysplasia. Correlation, frequency, and survival analyses were performed.ResultsCD80 was detectable in seven patients while expression of CD86 and IFNγ was evident in all patients. Histology confirmed the presence of dysplasia in eight patients. Patients who had dysplasia showed higher CD80 levels compared to those without dysplasia (p=0.02). Survival analysis demonstrated that cumulative dysplasia rates of CD80-positive patients were significantly higher than those of CD80-negative patients (p=0.04).ConclusionEven if partially limited by a relatively small sample size, our study seems to show an association between CD80 expression and colonic dysplasia in UC patients that may suggest a role for CD80 in the immunosurveillance against colorectal cancer in this early stage of tumorigenesis. On the contrary, CD86 seems to be involved in the inflammatory pathogenesis of UC.

The Role of Costimulatory Molecules CD80 and CD86 and IFNγ in the Pathogenesis of Ulcerative Colitis

Several studies showed that costimulatory signals on antigen presenting cells are up-regulated in inflammatory bowel disease. We quantified the expression of CD80, CD86, and IFNγ in colonic mucosa of patients affected by ulcerative colitis and correlated it with clinical and biochemical parameters to identify the context of this up regulation. We enrolled 21 patients affected by ulcerative colitis and 6 healthy subjects. We evaluated for each patient gender, age, duration of disease, clinical, endoscopic and histologic disease activity index, medical therapy, ESR, serum CRP, WBC, and serum αl-acid glycoprotein. CD80, CD86, and IFNγ expression in the colonic mucosa was quantified using reverse transcription polymerase chain reaction. Statistical analysis was performed using Mann–Whitney U test and Spearman’s rank correlation test. Significance was set at P &< 0.05. CD80 was detectable in seven patients, while CD86 and IFNγ expression was evident in all UC patients. CD80 and CD86 were not detectable in control specimens. Colonic CD80 expression was correlated to the age of the patients. CD86 expression showed an inverse correlation with duration of disease and a direct correlation with serum CRP levels and histologic grade of disease activity. IFNγ was not correlated with any of the examined parameter. Our study confirms a major role in ulcerative colitis pathogenesis for CD86 which correlates with histologic grade of disease and with serum CRP levels, and its up-regulation seems to be higher at the beginning of the disease. In “in vivo” conditions IFNγ may not be the only factor responsible for CD86 up-regulation in the ulcerative colitis colonic mucosa.

A gastrocolic fistula in Crohn's disease.

To the Editor: Gastrocolic fistulas are rare in Crohn’s disease. Only 37 cases have been described in the literature (1, 2). Typical features include diarrhea, abdominal pain, and weight loss but these alone are not sufficient to distinguish a fistula from active disease (3). Fecal vomiting is considered pathognomic but it is only present in one third of gastrocolic fistulas (4, 5). Case Report. A 26-year-old woman was referred to our institute with a 15-year history of Crohn’s disease for incoercible alimentary vomiting, crampiform abdominal pain, and weight loss. One year prior to admission a colonoscopy had shown a Crohn’s disease stenosis of the descending colon, while an upper endoscopy with biopsies had detected chronic gastritis and ruled out Crohn’s disease activity. One month prior to admission to our clinic an upper gastrointestinal (GI) series had revealed a fistulous tract between the inferior gastric margin and the transverse colon. This picture was definitely confirmed by a barium enema (Figure 1); the left colon showed Crohn’s disease as demonstrated by its cobblestone appearance and the segmental distribution of stenosis and dilatations. Unexpectedly, red blood cells, white blood cells, erythrocyte sedimentation rate, and C-reactive protein were normal, while albuminemia was slightly decreased. After initial medical therapy with mesalazine with no relief of symptoms and worsening of general conditions, the patient underwent left hemicolectomy and wedge resection of the stomach wall, followed by primary closure of the gastric defect. Histologic evidence demonstrated active Crohn’s disease of the whole colonic specimen, while the stomach was not primarily involved. The patient was discharged on the ninth postoperative day. Twenty months later she is asymptomatic, taking 5-aminosalicylate, 2.4 g orally daily. Discussion. Albrecht von Haller was the first to describe a gastrocolic fistula in 1775. Gastrocolic fistulas are usually due to colic or gastric tumors and gastric resections but are very rare in Crohn’s disease. Crohn’s disease is frequently complicated by internal or external fistulas. The most common types of internal fistulas in Crohn’s disease are enteroenteric, ileosigmoid, enterovaginal, or enterovesical. Fecal vomiting is considered pathognomonic of gastrocolic fistulas and is rarely present in patients with duodenal fistulas (6). Most gastric fistulas complicating Crohn’s disease arise from the transverse colon and extend by means of the gastrocolic ligament to involve the greater curvature of the stomach secondarily (7). The most reliable examination for the detection of fistulas is a barium enema, since it increases the intraluminal pressure within the bowel and leads to a better filling of the fistulous tracts (8). Initial medical therapy is recommended but when symptoms are uncontrollable, surgery is mandatory. Gastrocolic fistulas are treated successfully by resection of the diseased segment and primary closure of the gastric defect if the stomach is not involved by Crohn’s disease (2). In our case, because endoscopic biopsies 11 months earlier had shown only chronic gastritis, a barium meal was performed to investigate symptoms, exclude any functional disorder, and eventually localize Crohn’s disease in the upper GI tract. When the gastrocolic fistula was revealed the execution of a barium enema was then indispensable to define the lower GI tract involvement. An interesting point in our case was the low Crohn’s disease activity demonstrated by the normal inflammatory parameters, in contrast to the severe symptomatic picture, which was not typical. Since relevant diarrhea was absent, weight