Antiendomysial and antihuman recombinant tissue transglutaminase antibodies in the diagnosis of coeliac disease: a biopsy-proven European multicentre study

OBJECTIVE: To investigate the value of serum antitissue transglutaminase IgA antibodies (IgA-TTG) and IgA antiendomysial antibodies (IgA-EMA) in the diagnosis of coeliac disease in cohorts from different geographical areas in Europe. The setting allowed a further comparison between the antibody results and the conventional small-intestinal histology. METHODS: A total of 144 cases with coeliac disease [median age 19.5 years (range 0.9-81.4)], and 127 disease controls [median age 29.2 years (range 0.5-79.0)], were recruited, on the basis of biopsy, from 13 centres in nine countries. All biopsy specimens were re-evaluated and classified blindly a second time by two investigators. IgA-TTG were determined by ELISA with human recombinant antigen and IgA-EMA by an immunofluorescence test with human umbilical cord as antigen. RESULTS: The quality of the biopsy specimens was not acceptable in 29 (10.7%) of 271 cases and a reliable judgement could not be made, mainly due to poor orientation of the samples. The primary clinical diagnosis and the second classification of the biopsy specimens were divergent in nine cases, and one patient was initially enrolled in the wrong group. Thus, 126 coeliac patients and 106 controls, verified by biopsy, remained for final analysis. The sensitivity of IgA-TTG was 94% and IgA-EMA 89%, the specificity was 99% and 98%, respectively. CONCLUSIONS: Serum IgA-TTG measurement is effective and at least as good as IgA-EMA in the identification of coeliac disease. Due to a high percentage of poor histological specimens, the diagnosis of coeliac disease should not depend only on biopsy, but in addition the clinical picture and serology should be considered.     

Acquired prolactin deficiency indicates severe hypopituitarism in patients with disease of the hypothalamic-pituitary axis

OBJECTIVE: Prolactin deficiency has been the subject of many scientific studies, but there is a paucity of information regarding prolactin deficiency in humans. In this report, adults with disease of the hypothalamic-pituitary axis (HPA) were studied to determine the prevalence of severe acquired prolactin deficiency (APD) and the pathophysiological characteristics associated with it. PATIENTS AND METHODS: APD was defined as a serum prolactin level persistently below the detection limit of the assay, i.e. less than 50 mU/l (normal range: male 85-444, female 85-530). Patients with a diagnosis of acromegaly, prolactinoma or with congenital or drug induced prolactin deficiency were excluded. Three hundred and sixty-nine patients (190 women, age range 17-79 years) with disease of the HPA, meeting the specified criteria were identified. RESULTS: Twenty-two (13 women, age range 29-76 years), showed evidence of APD. Thirteen of the 22 patients with APD had been treated for Cushing's disease. In all, 62 patients treated for Cushing's disease were identified, resulting in a prevalence of APD in treated Cushing's disease of 20.97%. Excluding treated Cushing's disease, the prevalence of APD in the remainder of the cohort was 2.93%. Nineteen patients with APD (86.4%) and 183 without APD (52.7%) underwent surgery in the region of the HPA (P = 0.0042). In contrast, nine patients with APD (40.9%) and 283 without APD (80.4%) had received radiotherapy, with fields which included the HPA (P < 0.001). No patient with isolated APD was identified. All patients with APD had evidence of severe GH deficiency (GHD) with a peak GH response to provocative stimuli of < 1.6 mU/l and a median IGF-I standard deviation score (SDS) of -4.85 (quartiles -9.56 to -2.80). Of the 13 patients with APD and Cushing's disease, all were gonadotrophin and TSH-deficient, six were adrenocorticotropic hormone (ACTH)-deficient and six (46.1%) had cranial diabetes insipidus (CDI). Of the remaining nine patients with APD, total anterior pituitary hormone failure was present in all and CDI was present in two (22.2%). CONCLUSIONS: The presence of APD indicates severe hypopituitarism in adults with HPA disease. It is universally associated with severe GHD. It is more common after surgery to the HP region. It has a low overall prevalence except in patients surgically treated for Cushing's disease.     

In utero origin of t(8;21) AML1-ETO translocations in childhood acute myeloid leukemia

Recent reports have established the prenatal origin of leukemia translocations and resultant fusion genes in some patients, including MLL-AF4 translocations in infants and TEL-AML1 translocations in children. We now report evidence for the prenatal origin of a translocation in childhood acute myeloid leukemia (AML). The t(8;21) AML1-ETO translocations were sequenced at the genomic level in 10 diagnostic leukemia samples from children with available neonatal Guthrie blood spots. Clonotypic genomic AML1-ETO sequences were detected in the Guthrie spots for 5 individuals, providing unambiguous evidence of prenatal origin in these cases. Two of these patients were older than 10 years of age at diagnosis, indicative of a protracted postnatal latency. Three of the patients were assessed for the persistence of genomic fusion sequences in complete clinical remission samples and were found to be positive. These data indicate that t(8;21) in childhood AML can arise in utero, possibly as an initiating event in childhood AML, and may establish a long-lived or stable parental clone that requires additional secondary genetic alterations to cause leukemia.