Recurrent abdominal pain in 200 children: somatic causes and diagnostic criteria.

AIM: To establish to what extent somatic causes can be found in children referred to secondary care with recurrent abdominal pain. METHODS: For 2 years, all consecutive patients (age 4-16 years) fulfilling Apley criteria, referred to secondary care, were included. After a diagnostic work-up, stepwise therapeutic interventions were performed. A diagnosis was considered to be the cause of the pain when the patient became pain free following therapeutic intervention and remained so for at least 6 months. RESULTS: Two hundred and twenty children (128 F, 92 M; mean age 8.8 years) were enrolled, of which 20 were lost to follow-up. Spontaneous recovery was seen in 54 patients, (occult) constipation in 92 patients (of whom 18 also had a somatic cause), gastrointestinal infections in 40, food allergy in five, miscellaneous disorders in seven and uncertain diagnosis in 13. In five patients, stress most likely caused the pain. A total of 198 patients became pain free and remained so during follow-up (mean 18, range 6-60 months). CONCLUSION: In 200 children with recurrent abdominal pain, somatic causes were found in 26%. Laxative therapy was successful in 46%, resulting in nearly all patients with functional abdominal pain to become pain free. Eventually, 99% became pain free using a therapeutic intervention protocol.

The duration of effect of infliximab maintenance treatment in paediatric Crohn's disease is limited.

BACKGROUND: Infliximab is effective for induction and maintenance of remission in children with moderately to severely active Crohn's disease (CD). AIM: To evaluate the long-term efficacy of infliximab treatment in paediatric CD. METHODS: In this observational, multicentre study, all paediatric CD patients in The Netherlands treated with infliximab from October 1992 to November 2009 and with minimal follow-up of 3 months since start of infliximab, were studied. RESULTS: One hundred and fifty-two CD patients [81M; median age at start of infliximab 15.0 years (IQR 13.1-16.4)] received a median number of 10.5 infliximab infusions (IQR 6-21). Median follow-up after start of infliximab was 25 months (IQR 13-40). Kaplan-Meier analysis showed that the cumulative probability of losing response to infliximab in patients who initially required repeated infusions was 13%, 40% and 50% after 1, 3 and 5 years, respectively. Seventy-four patients (49%) needed dose adjustments, with a median time to any adjustment of 6 months. CONCLUSIONS: Duration of effect of infliximab is limited as 50% of patients on infliximab maintenance treatment lose their therapeutic response after 5 years. Dose adjustments after start of infliximab are frequently needed to regain therapeutic benefit. These findings emphasise the need for effective, long-term treatment strategies for paediatric CD.

Abnormal liver enzymes two years after haematopoietic stem cell transplantation in children: prevalence and risk factors.

To establish the prevalence of elevated liver enzymes in children transplanted in a Dutch haematopoietic stem cell transplantation (HSCT) centre, we retrospectively assessed AST and ALT values at 2 years after HSCT. Age, sex, diagnosis, type of transplant, conditioning regimen and early post-transplant complications involving the liver (veno-occlusive disease, acute GVHD, viral reactivation) were analysed as risk factors. AST and ALT values were available at 2 years after HSCT in 216 of 290 patients (75%) alive at that time and were above normal in 53 (25%) and at least twice normal in 17 (8%) patients. Older age at HSCT and a diagnosis of benign haematological disease are risk factors for abnormal liver enzymes late after HSCT. In half of the patients with benign haematological disease, iron overload is the most likely aetiological factor. Chronic hepatitis B or C is uncommon in our centre. In conclusion, the prevalence of abnormal liver enzymes late after HSCT in our centre is lower than reported in previous studies. Abnormal liver enzymes occur more often in children who are older at HSCT and transplanted for benign haematological disease. Long-term follow-up is crucial to establish if elevated liver enzymes precede clinical liver disease.

Coeliac disease in The Netherlands.

BACKGROUND: The prevalence of adult coeliac disease in The Netherlands was studied in the Dutch Coeliac Disease Society and in blood donors but not in the general population. We therefore studied the prevalence of recognized and unrecognized coeliac disease in a large cohort, representative of the adult Dutch general population. Blood samples were available for anonymous research, as well as data on dietary habits, self-reported physical characteristics, health problems, quality of life and socio-economic circumstances. METHODS: Subjects included 50,760 individuals who had previously participated in two large population-based studies on health status in relation to lifestyle factors. Recognized coeliac disease was studied in all subjects by identification of self-reported adherence to a gluten-free diet and subsequent confirmation of the diagnosis of coeliac disease. Unrecognized coeliac disease was studied in a random sample of 1440 out of the 50,760 subjects through serologic screening and human lymphocyte antigen (HLA) typing. RESULTS: The prevalence of recognized coeliac disease was 0.016% (95% confidence interval 0.008-0.031) and of unrecognized coeliac disease 0.35% (95% confidence interval 0.15-0.81). Menarcheal age was higher in women with recognized coeliac disease than in women without coeliac disease. CONCLUSIONS: The prevalence of adult recognized coeliac disease in The Netherlands is one of the lowest in Europe, while the prevalence of unrecognized coeliac disease is comparable with that in other European countries. Adult coeliac disease is strongly under diagnosed in The Netherlands. The higher menarcheal age in women with recognized coeliac disease may be explained by diagnostic delay.

Coeliac disease and (extra)intestinal T-cell lymphomas: definition, diagnosis and treatment.

Intestinal lymphomas encompass those lymphomas with a dominant or only localized occurrence in the intestinal tract. Coeliac disease is highly associated with enteropathy-associated T-cell lymphomas (EATLs). Coeliac disease-related lymphomas can appear at nodal or extranodal sites. EATL is often multifocal with ulcerative lesions, which explains the high perforation rate at presentation or during chemotherapy. Staging includes ear-nose-throat examination and CT scan of the chest and abdomen. Positron emission tomography (PET) scanning may be valuable. Accurate diagnosis based on endoscopic biopsies is preferable; if necessary, full thickness laparoscopic small-bowel biopsies are mandatory. Refractory coeliac disease (RCD) with aberrant T cells carries a high risk of development of EATLs. There is no satisfactory treatment for EATL, the only possibility of preventing EATL development in RCD being autologous bone marrow transplantation. EATLs can present in 20% of patients as extra-small-bowel T-cell lymphomas; such as subcutaneous panniculitis-like lymphoma, hepatosplenic gamma/delta lymphoma, nodal as well as sinus, gastric or colon disease and extraintestinal T-cell lymphomas. The majority of EATLs present as large cell lymphoma CD3+, CD8-, CD30+; however, they also present as small cell lymphoma CD3+, CD8+, CD30-. Sometimes gamma/delta lymphomas in CD are recognized. Work-up of EATL must include immunohistology, T-cell flow cytometry, T-cell rearrangement and adequate imaging with CT and PET scanning.

[Two children with severe recurrent infections and the X-linked hyper-IgM syndrome]. / Twee kinderen met ernstige, recidiverende infecties en het X-gebonden hyper-IgM-syndroom.

A boy suffered from severe recurrent intestinal infections from the age of 8 months onwards; investigation into an immune disorder ultimately resulted in the diagnosis of 'hyper-IgM syndrome'. He was treated successfully with bone marrow transplantation, using an HLA-matched donor. Another boy had severe recurrent respiratory tract infections from the age of 3 months onwards. At the age of 6.5 years, 'hyper-IgM syndrome' was diagnosed. No suitable donor was available. In addition, he developed sclerosing cholangitis and end-stage liver disease, making a combined bone marrow and liver transplantation too risky. He died at 10.5 years of age. X-linked hyper-IgM syndrome is a rare congenital immunodeficiency disorder, characterised by a defect in both humoral and cellular immune responses. Deficiency in the membrane glycoprotein CD40 ligand (expressed on activated T-cells) compromises T-cell interactions with antigen-presenting cells. In a child with severe recurrent infections, and with dysgammaglobulinaemia with a normal or increased IgM level, the diagnosis of 'X-linked hyper-IgM syndrome' should be considered.

Cancer in children with celiac disease: a survey of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition.

BACKGROUND: In adults, the relation between celiac disease (CD) and cancer has been long recognized. In children, only four cases of CD and cancer have been described in Europe. We made a new inventory of cases with CD and cancer in children that were known by the members of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition between 1989 and 1999. METHODS: Postal inquiry was made of all European Society for Paediatric Gastroenterology, Hepatology and Nutrition members mentioned on the society's web page. The members were asked if they had seen a child with CD and cancer between 1989 and 1999 and if so, to supply additional clinical data. Also, information on working place, experience, and number of celiac patients under their care was requested. RESULTS: Fifty-six percent of the members responded. Sixteen members reported 22 cases of cancer and CD in children. One case had been reported in the literature previously. The tumors that were reported originated from the brain, thyroid, larynx, liver, small bowel, adrenal, lymphoreticular system, and the musculoskeletal system. There were no differences between members reporting a case and those who did not. CONCLUSIONS: Twenty-one new cases of cancer and CD in children in Europe were found. Cancer and CD in children are underreported. A remarkable number of thyroid and small bowel cancers were found, suggesting a possible relation with CD. It is important to evaluate whether these findings are coincidental. All cases of cancer and CD in children should be reported to the literature.

[Acute gastric dilatation in Duchenne's muscular dystrophy]. / Acute maagdilatatie bij de ziekte van Duchenne.

A 15 year old boy with Duchenne muscular dystrophy had severe pain in the lower abdomen and complained of nausea and bilious vomiting. A physical examination and an abdominal X-ray indicated an acute gastric dilation. With a treatment policy of administering nothing orally, a downward-hanging stomach tube and the intravenous administration of fluid the symptoms subsided. In Duchenne muscular dystrophy there may also be atrophy of the smooth muscle layers, in addition to the known progressive atrophy of striated skeletal and cardiac muscle. This may cause clinical dysfunctioning of the gastro-intestinal tract in the second decade of life.

End-stage liver disease as the only consequence of a mitochondrial respiratory chain deficiency: no contra-indication for liver transplantation.

UNLABELLED: The prerequisite for liver transplantation as a therapeutic option for inherited metabolic diseases should be that the enzyme defect, being responsible for the major clinical (hepatic and/or extra-hepatic) abnormalities, is localised in the liver. Furthermore, no adequate dietary or pharmacological treatment should be available or such treatment should have an unacceptable influence on the quality of life. We report an infant, who developed end-stage liver disease with persistent lactic acidaemia in his first months of life. Analysis of the mitochondrial respiratory chain in liver tissue revealed a combined partial complex I and IV deficiency. No extra-hepatic involvement could be demonstrated by careful screening for multiple organ involvement, including analysis of the mitochondrial respiratory chain in muscle tissue and cultured skin fibroblasts. The boy received a reduced size liver graft at the age of 8 months. He recovered successfully. Almost 5 years after transplantation he is in good clinical condition. No clinical or biochemical signs of any organ dysfunction have been demonstrated. The considerations on which basis it was decided that there was no contra-indication to perform liver transplantation in this patient are discussed. CONCLUSION: The possibility of a mitochondrial respiratory chain deficiency should be considered in liver disease of unknown origin prior to liver transplantation. Liver transplantation is a therapeutic option in mitochondrial respiratory chain deficiency-based end-stage liver disease provided that extra-hepatic involvement is carefully excluded.

Hepatocellular carcinoma in glycogen storage disease type IV.

A 13 year old patient with juvenile type IV glycogen storage disease died of the complications of hepatocellular carcinoma. To our knowledge this is the first reported case of hepatocellular carcinoma in association with type IV glycogen storage disease.

[5 children with hypokalemia, hypomagnesemia and hypocalciuria (Gitelman syndrome) in one family]. / Vijf kinderen met hypokaliëmie, hypomagnesiëmie en hypocalciurie (Gitelman-syndroom) in één gezin.

Gitelman's syndrome was diagnosed in five siblings. The parents were relatives in the third remove. Gitelman's syndrome is a rare autosomal recessive hereditary magnesium reabsorption defect in the distal tubule. It is characterized by episodes of muscle weakness, usually accompanied by abdominal pain and vomiting. Tetany may occur during a febrile illness. Patients are of normal height and weight and have normal blood pressures. Sometimes eczematous skin lesions are found. Biochemically there is hypokalaemia, hypomagnesaemia and alkalosis. Urinary excretion rates of potassium and magnesium are elevated, the excretion of calcium is diminished. Treatment consists of oral suppletion of magnesium, sometimes also with oral potassium. A potassium-sparing diuretic may be used. The prognosis appears to be good.

Acute liver failure: spontaneous recovery or transplantation?

BACKGROUND: Decision-making in acute liver failure. Acute liver failure is a disease with multiple organ involvement and a high mortality rate. Conservative management alone will only partly influence the outcome. The option of emergency liver transplantation has greatly improved survival rates, but unables spontaneous recovery. A set of prognostic criteria enables selection of patients who will benefit the most from emergency liver transplantation. METHODS: Retrospective review and survey of the Groningen results. RESULTS: Of 52 patients (33 adults and 19 children) admitted for acute liver failure 2 were beyond recovery and died, 9 were treated conservatively and recovered and 41 were listed for emergency liver transplantation because of an estimated survival rate < 20%. Of these, 3 died and 1 recovered spontaneously while waiting and 37 were transplanted. Survival rate for 41 patients listed for transplantation was 23 (56%) and was similar for children and adults. CONCLUSIONS: In patients with acute liver failure, management and decision-making in a specialized liver unit with the possibility of emergency liver transplantation is mandatory.

Expression of HLA-DQ antigens in the small-intestinal mucosa of patients with coeliac disease.

Studies at the DNA and product level of B-cell lines of coeliac patients have shown a strong association between coeliac disease and the HLA-DQ alpha 2.3 and HLA-DQ beta 2.7 alleles. The monoclonal antisera SFR20-DQ alpha 5 and XIII-358.4, which specifically react with HLA-DQ alpha 2.3 and with HLA-DQ beta 2.3 and -DQ beta 2.7, respectively, have been used to detect the expression of these specificities in the small-intestinal mucosa of 7 coeliac patients and 11 non-coeliac persons. An immunoperoxidase technique on frozen tissue sections of jejunal biopsy specimens was used. Positive specimens showed immunoperoxidase staining of lymphocytes and histiocytes in the lamina propria. The epithelial cells showed no immunoperoxidase staining. Positive results at the intestinal level correlated with the HLA typing of the patients and controls. The distribution found for the HLA-DQ alleles in the intestinal mucosa makes the role of a HLA-DQ alpha/beta dimer as gliadin receptor at the epithelial cell less probable, but it is compatible with the hypothesis that these DQ molecules are involved in the regulation of the intestinal immune response to gluten.