Measurement practices of alanine aminotransferase in children: Temporal changes and etiology for increased values.

Data on alanine aminotransferase (ALT) measurement practices and diagnoses associated with increased values are limited. We evaluated these issues by collecting ALT measurements from 1- to 16-year-old patients investigated in 1992-2018 in a tertiary center. Diagnoses were gathered in 2008-2018. Altogether 145,092 measurements from 28,118 children were taken 42% undergoing repeated testing. Testing increased from 21/1000 to 81/1000 children and the prevalence of elevated values fluctuated between 18% and 26%. An increase was seen especially in emergency care and departments of rheumatology, gastroenterology, hemato-oncology, and psychiatry. Common acute causes associated with elevated ALT were infections (45%), hemato-oncologic conditions (17%), and external reasons (13%), whereas autoimmune diseases (28%), psychiatric conditions (14%), and metabolic-dysfunction associated steatotic liver disease (10%) were common chronic causes. In conclusion, ALT testing increased 3.9-fold while the proportion of increased values remained stable, indicating that increased testing was justified. However, in some departments the testing efficiency was low.

Alanine aminotransferase cutoffs for the pediatric fatty liver disease: Major impact of the reference population.

OBJECTIVES AND STUDY: The often-recommended alanine aminotransferase (ALT) cutoffs (girls 21 U/l, boys 25 U/l) are based on a NHANES cohort. A novel concept of metabolic dysfunction associated steatotic liver disease (MASLD) emphasizes the role of ALT. We tested the prevalence of increased ALT and MASLD in children with overweight or obesity applying population-based and NHANES-based cut-offs. METHODS: Six- to seventeen-year-old children underwent data collection in a prospective Physical Activity and Nutrition in Children (PANIC) study. ALT 95th percentiles were calculated from 1167 separate measurements considering various confounders. Test cohort comprised 1044 children with overweight/obesity. RESULTS: ALT values increased at puberty onset (p = 0.031) and correlated negatively with age in girls (r = -0.222, p < 0.001). Particularly overall and central obesity increased ALT, whereas underweight or metabolic abnormalities had smaller effect. After applying the tested exclusions, the age-related ALT 95th percentiles were 24-29 U/l for girls and 29-32 U/l for boys. In 6-8-year-old children with overweight/obesity, the prevalence of increased ALT and MASLD were 21.6% and 2.4% with age-specific PANIC cutoffs. In older children, when NHANES-based cutoffs were used, there was a trend for higher prevalence of increased ALT and MASLD in all age groups for both sexes, reaching significance for increased ALT in 12-16-year-old boys (NHANES 63.5%, 95% confidence interval [CI]: 56.4%-70.0% vs. PANIC 47.1%, 95% CI [40.1%-54.2%]) and 9-11-year-old girls (60.0% [49.4%-69.8%] vs. 31.8% [22.8%-42.3%]), respectively. Increased ALT/MASLD were more common in boys than in girls, and in boys these increased with age, whereas in girls these peaked at age 9-12 years. CONCLUSION: A reference population impacts on the prevalence of increased ALT and MASLD. Considering this help optimizing screening while avoiding unnecessary investigations and surveillance. The prospective part of this study is registered in clinicaltrials.gov; identifier NCT01803776.

Measured levels of positive transglutaminase 2 antibodies are not associated with presentation or incidental endoscopic findings at celiac disease diagnosis.

OBJECTIVES: It has been suggested that celiac disease could be diagnosed non-invasively in adults with transglutaminase antibody (TGA) levels >10x upper limit of normal (ULN). It is, however, unclear if high values signify more advanced disease and higher risk of co-morbidities. We investigated the association between the TGA levels, clinical characteristics and non-celiac endoscopic findings. METHODS: Medical data on 450 celiac disease patients at diagnosis were collected. They were further divided into those with high positive (>10x ULN, n = 164), moderately positive (1-10x ULN, n = 219), and negative (n = 67) TGA. RESULTS: Median age of patients was 50 years and 60% were women. Patients with negative TGA were older (median age 58 vs. 51 vs. 46 years respectively, p = 0.002) and had more often weight loss (27% vs. 10% vs. 9%, p < 0.001) and abdominal pain or dyspepsia (40% vs 27% vs. 22%, p = 0.017) than did those with moderately positive/high TGA. The groups did not differ in sex, BMI, or other symptoms. Major endoscopic findings included one esophageal adenocarcinoma presenting with dysphagia, six esophagitis, three gastric ulcers, and 39 H. Pylori or other active gastritis. High, moderately positive or negative TGA levels were not associated with these findings in crude or age-adjusted analyses. CONCLUSIONS: Presentation was similar in patients with moderate or high levels of TGA, whereas patients with negative TGA were different. The level of TGA was not associated with incidental endoscopic findings and the only malignancy presented with an alarm symptom atypical to celiac disease.

Prevalence of vomiting and nausea and associated factors after chronic and acute gluten exposure in celiac disease.

BACKGROUND: Vomiting and nausea seem to be relatively specific symptoms related to gluten ingestion in treated celiac disease. However, the overall prevalence and associated factors of these symptoms after chronic gluten exposure at celiac disease diagnosis and acute re-exposure during gluten challenge remain obscure. METHODS: Medical data on 815 adult celiac disease patients were collected at diagnosis from the medical records and through supplementary interviews. An additional 74 patients underwent a three-day (10 g/day) gluten challenge (wheat, barley, rye or a combination of the three grains) while in remission. Prevalence of vomiting/nausea and associated factors were evaluated in both cohorts. A literature review was conducted to summarize earlier studies. RESULTS: Twenty-eight (3%) patients presented with vomiting at diagnosis. They were less often screen-detected and suffered from extra-intestinal symptoms, and had more often abdominal pain (71% vs. 49%, p = 0.021), diarrhea (61% vs. 40%, p = 0.031), weight loss (36% vs. 17%, p = 0.019) and childhood symptoms (61% vs. 33%, p = 0.002) than those without vomiting (n = 787). The groups were comparable in other clinical-demographic data and in genetic, serological, and histological findings. Short-term gluten challenge provoked vomiting/nausea in 14/74 (19%) patients. They consumed gluten-free oats less often than those without these symptoms (64% vs. 92%, p = 0.017), whereas the groups did not differ in clinical-demographic features at diagnosis, presence of comorbidities, duration of gluten-free diet, or in other symptoms or grain used ingested during the challenge. According to the literature, prevalence of vomiting/nausea at celiac disease diagnosis has varied 3-46% and during gluten challenge 13-61%. CONCLUSIONS: In chronic gluten exposure at celiac disease diagnosis, vomiting was associated with other gastrointestinal symptoms and onset of symptoms already in childhood, whereas regular consumption of oats may increase the tolerance against vomiting/nausea after acute re-exposure in treated celiac disease.

Prevalence and associated factors of metabolic-associated fatty liver disease in overweight Finnish children and adolescents.

Introduction: Data on the prevalence of pediatric fatty liver disease remain limited, partly due to challenges in diagnosis. A novel concept of metabolic-associated fatty liver disease (MAFLD) makes it possible to establish the diagnosis in overweight children with sufficiently elevated alanine aminotransferase (ALT). We investigated the prevalence, risk factors, and metabolic co-morbidities of MAFLD in a large group of overweight children. Methods: Data on 703 patients aged 2-16 years examined due to overweight in different levels of healthcare in 2002-2020 were collected retrospectively from patient records. MAFLD was here defined as ALT >2x reference (>44 U/l in girls and >50 U/l in boys) in overweight children according to recently updated definition. Patients with MAFLD and without it were compared, and subgroup analyses were conducted among boys and girls. Results: Median age was 11.5 years, and 43% were girls. Altogether 11% were overweight, 42% obese and 47% severely obese. Abnormal glucose metabolism was present in 44%, dyslipidemia in 51%, hypertension in 48% and type 2 diabetes (T2D) in 2%. MAFLD prevalence varied between 14-20% in examined years without significant change (p=0.878). The pooled prevalence over the years was 15% (boys 18%, girls 11%; p=0.018), peaking in girls at early puberty and increasing in boys with age and puberty. Associated factors in boys were T2D (OR 7.55, 95% CI 1.23-46.2), postpubertal stage (5.39, 2.26-12.8), increased fasting insulin (3.20, 1.44-7.10), hypertriglyceridemia (2.97, 1.67-5.30), hyperglycemia (2.88, 1.64-5.07), decreased high-density lipoprotein (HDL) cholesterol (2.16, 1.18-3.99), older age (1.28, 1.15-1.42) and higher body-mass-index (1.01, 1.05-1.15), and in girls T2D (18.1, 3.16-103), hypertriglyceridemia (4.28, 1.99-9.21), and decreased HDL (4.06, 1.87-8.79). Conclusion: Prevalence of MAFLD was 15%, with no statistically significant increase in the 2000s. The condition was associated in general with male gender, puberty stage and disturbances in glucose and lipid metabolism, and higher age and BMI in boys.

Association of concomitant autoimmunity with the disease features and long-term treatment and health outcomes in Celiac disease.

Background: Celiac disease (CeD) is often accompanied by other autoimmune diseases (AID). However, the association of co-existing autoimmunity with the presentation and treatment success in CeD is unclear. We investigated these issues with a large and well-defined cohort of Finnish patients. Methods: Adult CeD patients (n = 806) were collected from multiple heath care sites via nationwide recruitment. They were interviewed, underwent measurement of CeD autoantibodies, and filled out questionnaires to ascertain quality of life (PGWB) and gastrointestinal symptoms (GSRS) after a median of 9.7 years on a gluten-free diet. Data were supplemented retrospectively from patient records. The results were compared between CeD patients with and without a coexisting AID. Results: Altogether 185 patients had CeD+AID and 621 had CeD only. At CeD diagnosis, patients with CeD+AID were older (median 42 vs. 36 years, p = 0.010) and had more joint symptoms (9.1 vs. 4.2%, p = 0.011), whereas the groups were comparable in sex, family history of CeD, other presenting symptoms, proportion of screen-detected subjects, and severity of duodenal lesion. During follow-up on gluten-free diet, CeD+AID patients experienced poorer general health (median score 12 vs. 14, p < 0.001) in PGWB, more overall gastrointestinal symptoms (2.1 vs. 1.9, p = 0.001), and constipation (2.0 vs. 1.7, p < 0.001) in GSRS, whereas there was no difference in histological and serological recovery, dietary adherence, use of gluten-free oats, smoking, and presence of regular follow-up. Conclusions: Co-existing AID was not significantly associated with the baseline features or with most long-term outcomes in CeD. However, the increased prevalence of gastrointestinal symptoms and reduced poorer self-perceived health during treatment indicates these patients' need for special support.

Differential diagnosis and long-term outcomes of non-atrophic duodenal changes in children.

Objectives and study: Gastrointestinal endoscopy is often performed when investigating abdominal complaints in children. While atrophic changes of the duodenal mucosa are usually caused by celiac disease, the prevalence and clinical significance of non-atrophic duodenal changes are less clear. We studied these issues in a large pediatric endoscopic cohort. Methods: Comprehensive data on clinical features, diagnostic findings and long-term outcomes of children who had undergone upper gastrointestinal endoscopy with systematic duodenal sampling were collected. Study variables were compared between children with non-atrophic changes and normal histology, and between those with non-atrophic changes who did and did not receive a diagnosis. Results: The study comprised 1,170 consecutive children, of whom 51 (4.4%) had non-atrophic and 315 (26.9%) atrophic duodenal changes and 804 (68.7%) normal histology. The most common non-atrophic findings were non-specific inflammation (n = 19) and intraepithelial lymphocytosis (n = 14). Patients with non-atrophic changes presented more often with blood in stools (23.5 vs. 11.3%; p = 0.009), anemia (43.2 vs. 36.5%; p = 0.028) and positive celiac serology (34.3 vs. 12.9%; p < 0.001) than those with a normal duodenum. Twenty-four (44%) of those with non-atrophic changes received an initial diagnosis, the most common of which were inflammatory bowel disease (IBD) (n = 8), Helicobacter pylori infection (n = 3) and food allergy (n = 3). The prevalence of the diagnoses did not differ from those with a normal duodenum. Those who received a diagnosis had more often blood in stools (37.5 vs. 11.1%; p = 0.027), anemia (70.6 vs. 20.0%; p = 0.002) and negative celiac serology (50.0 vs. 7.7%; p = 0.013) than those without diagnosis. During a follow-up of 6.1-13.3 years, five of the 12 initially undiagnosed seropositive patients developed celiac disease, and one patient also developed ulcerative colitis. Conclusion: Non-atrophic duodenal changes are relatively common and associated with anemia, blood in stools, and positive celiac disease serology. Excluding potential celiac disease, those without an initial diagnosis have a favorable long-term prognosis.

Significance of low ferritin without anaemia in screen-detected, adult coeliac disease patients.

BACKGROUND: Low ferritin without anaemia has been linked to adverse health effects. OBJECTIVES: To investigate the prevalence and clinical significance of low ferritin in screen-detected coeliac disease. METHODS: Seventy-six screen-detected coeliac disease patients were enrolled in the prospective collection of comprehensive clinical, laboratory and histological data at diagnosis and after 1-2 years on a gluten-free diet (GFD). All variables were compared between patients with different ferritin levels. RESULTS: At coeliac disease diagnosis, six patients had anaemia. Of the 70 nonanaemic patients, ferritin levels were <15 µg/L in 21%, 15-29 µg/L in 19%, 30-99 µg/L in 36% and ≥100 µg/L in 24%. Those with lower ferritin were more often females, had lower body mass index, haemoglobin and villous height-crypt depth ratio and also had higher intra-epithelial lymphocyte CD3+ levels in duodenal biopsies. The groups did not differ in neurological or gastrointestinal symptoms, health-related quality of life, bone mineral density, liver values, vitamin, albumin or coeliac autoantibody levels or the prevalence of comorbidities. Median ferritin levels increased from 41.5 µg/L to 86.0 µg/L on GFD (p < 0.001). Ferritin remained <30 µg/L in 21% of patients but was not associated with dietary compliance, nor was any correlation between changes in ferritin and quality of life, gastrointestinal symptoms, autoantibody levels or degree of histological damage detected. CONCLUSION: Decreased ferritin is a frequent finding in screen-detected coeliac disease and may not be fully restored on a GFD. However, low ferritin levels are not associated with more severe symptoms or poorer quality of life.

Review article: Systemic consequences of coeliac disease.

BACKGROUND: The best-known symptoms of coeliac disease are related to the gastrointestinal tract, but the disease may also present with various systemic manifestations outside the intestine. Some of these consequences may remain permanent in undiagnosed individuals or if the diagnostic delay is prolonged. However, for many of the systemic manifestations, the scientific evidence remains scant and contradictory. AIMS AND METHODS: We conducted a narrative review of the most thoroughly studied and clinically relevant systemic consequences of coeliac disease, especially those that could be prevented or alleviated by early diagnosis. The review is intended particularly for physicians encountering these patients in daily clinical practice. RESULTS: The possible systemic consequences of coeliac disease extend to multiple organ systems, the best studied of which are related to skeletal, reproductive, cardiovascular and neurological systems. Furthermore, the disease is associated with an elevated risk of psychiatric comorbidities, non-Hodgkin lymphomas and intestinal adenocarcinoma. CONCLUSIONS: The various systemic consequences of coeliac disease play a significant role in the overall health of patients. Early diagnosis and treatment with a gluten-free diet appear to be beneficial for most, but not all of these conditions. The possible negative metabolic and psychosocial effects of the diet should be acknowledged during follow-up.

Persistent symptoms are diverse and associated with health concerns and impaired quality of life in patients with paediatric coeliac disease diagnosis after transition to adulthood.

OBJECTIVE: To investigate the prevalence and associated factors of persistent symptoms despite a strict gluten-free diet in adult patients with coeliac disease diagnosed in childhood. DESIGN: Medical data on 239 currently adult patients with paediatric diagnosis were collected from patient records. Also, patients completed structured study questionnaire. All variables were compared between those with and without persistent symptoms. RESULTS: Altogether 180 patients reported adhering to a strict gluten-free diet. Of these, 18% experienced persistent symptoms, including various gastrointestinal symptoms (73%), arthralgia (39%), fatigue (39%), skin symptoms (12%) and depression (6%). Those reporting persistent symptoms had more often gastrointestinal comorbidities (19% vs 6%, p=0.023), health concerns (30% vs 12%, p=0.006) and experiences of restrictions on daily life (64% vs 43%, p=0.028) than the asymptomatic subjects. The patients with symptoms had poorer general health (median score 13 vs 14, p=0.040) and vitality (15 vs 18, p=0.015) based on a validated Psychological General Well-Being Questionnaire and more severe symptoms on a Gastrointestinal Symptom Rating Scale scale (total score 2.1 vs 1.7, p<0.001). Except for general health, these differences remained significant after adjusting for comorbidities. The groups were comparable in current sociodemographic characteristics. Furthermore, none of the childhood features, including clinical, serological and histological presentation at diagnosis, and adherence and response to the diet after 6-24 months predicted symptom persistence in adulthood. CONCLUSION: Almost one-fifth of adult patients diagnosed in childhood reported persistent symptoms despite a strict gluten-free diet. The ongoing symptoms were associated with health concerns and impaired quality of life.

Coexisting Type 1 Diabetes, Persistent Symptoms, and Financial Issues Associate With Poorer Adherence to a Gluten-Free Diet in Celiac Disease After Transition From Pediatrics to Adult Care.

Purpose: We evaluated adherence to a gluten-free diet and associated factors in adult celiac disease patients diagnosed in childhood. Methods: Comprehensive medical data on 955 pediatric celiac disease patients was collected and study questionnaires sent to 559 who were now adults. All variables were compared between strictly adherent and non-adherent patients. Results: Altogether 237 adults (median age 27 years, 69% women) responded to the questionnaires a median of 18 (range 3-51) years after the childhood diagnosis. Altogether 78% were reportedly adherent and 22% non-adherent. The non-adherent patients had more concomitant type 1 diabetes (18% vs. 4%, p = 0.003), whereas the groups did not differ in demographic data or clinical and histological features at diagnosis, or in short-term dietary adherence. In adulthood, non-adherent patients found gluten-free diet more challenging (39% vs. 17%, p < 0.001) and had higher prevalence (39% vs. 19%, p = 0.004) and severity of symptoms. The main motivation factors for dietary adherence were attempts to avoid symptoms and complications, but these were considered less important and price of gluten-free products more important among non-adherent patients. Adherent and non-adherent patients did not differ in socioeconomic or lifestyle factors, comorbidities other than type 1 diabetes, self-reported general health, health concerns, follow-up, or in quality of life. Conclusion: Most originally pediatric celiac disease patients reported strict dietary adherence in adulthood. However, particularly those with concomitant type 1 diabetes, persistent symptoms or financial issues may require attention during the transition from pediatric to adult care.

Frequency and clinical significance of histologic upper gastrointestinal tract findings in children with inflammatory bowel disease.

OBJECTIVE: Assessment of the upper gastrointestinal tract (UGI) may enable more personalized treatment strategies in pediatric inflammatory bowel disease (IBD). However, data on the frequency and significance of these findings remain limited. METHODS: Data on 132 pediatric IBD patients with systematic UGI sampling were collected and the baseline characteristics and presence of complications compared between those with and without histological UGI findings. The control group comprised 162 children who received no diagnoses. RESULTS: Seventy-six children had ulcerative colitis (UC), 47 Crohn's disease (CD) and nine IBD unclassified. UGI findings were more common in IBD patients than controls (69.7% vs. 30.9%, respectively, p < .001), particularly in the stomach (62.1% vs. 16.8%; p < .001). Among IBD patients, findings were more common in CD than in UC (80.9% vs. 63.2%; p = .038), particularly in the duodenum (21.3% vs. 2.6%, p = .001). Four patients had UGI granulomas consistent with CD. Hypoalbuminemia (OR 3.22; 95% CI 1.18-8.79) and failure to thrive (2.82; 1.17-6.78) increased the likelihood of UGI findings in IBD. In CD, perianal morbidity was less common in those with than in those without UGI findings (13.2% vs. 44.4%; p = .032) whereas in UC, UGI findings increased the risk for co-morbidities (18.8% vs. 3.6%; p = .059). The long-term outcomes did not differ between patients with or without UGI findings. CONCLUSIONS: Histologic UGI findings were more common in children with IBD than in children with no gastrointestinal diagnoses. In CD, UGI findings were more frequent than in UC, especially in the duodenum. In UC, UGI findings were associated with more complex disease.

Prevalence and Clinical Significance of Helicobacter Pylori-negative Chronic Gastritis in Children.

OBJECTIVES: The clinical significance of Helicobacter pylori-negative chronic gastritis (HPNCG) in children is unclear. We examined this issue in patients who had undergone esophagogastroduodenoscopy with systematic gastric sampling. METHODS: Data of 1178 consecutive children who underwent diagnostic esophagogastroduodenoscopy were collected. Baseline characteristics and long-term outcomes were compared between children with active and inactive HPNCG and those with normal gastric histology. Follow-up data were available for up to 13 years. RESULTS: Altogether 24 (2.0%) children had active and 235 (19.9%) inactive HPNCG, 27 (2.3%) were Hpylori-positive, 46 (3.9%) had other gastric pathology, and 846 (71.8%) normal histology. Diarrhea (31.3% vs 25.1%, P  = 0.033), poor growth (23.6% vs 14.7%, P  < 0.001), bloody stools (13.9% vs 7.2%, P < 0.001), anemia (46.5% vs 23.4%, P < 0.001), hypersedimentation (39.7% vs 21.4%, P < 0.001), hypoalbuminemia (40.4% vs 16.2%, P < 0.001), and elevated fecal calprotectin (62.4% vs 31.5%, P < 0.001) were more common and heartburn (13.9% vs 22.9%, P = 0.002) less common in the HPNCG group than in the controls. Both active (OR 3.64,95% CI 1.35-9.82) andinactive (2.98, 2.18-4.08) HPNCG predicted a diagnosis in the initial investigations. Crohn disease (41.7%) was the most common diagnosis in active HPNCG and celiac disease (37.4%) in inactive HPNCG. During follow-up, 7 (9.9%) of the 71 initially nondiagnosed HPNCG children received a diagnosis. CONCLUSIONS: HPNCG is a frequent finding in children undergoing EGD, the active form being associated especially with Crohn disease and the inactive with celiac disease. The long-term prognosis of patients with HPNCG who do not receive an initial diagnosis is good.

Presence of high-risk HLA genotype is the most important individual risk factor for coeliac disease among at-risk relatives.

BACKGROUND: Family screening has been advocated as a means to reduce the major underdiagnosis of coeliac disease. However, the precise risk of the disease in relatives and the impact of patient- and relative-related individual factors remain obscure. AIMS: To investigate the individual risk of coeliac disease among patients' relatives. METHODS: Altogether 2943 relatives of 624 index patients were assessed for the presence of previous coeliac disease diagnosis, or were screened for the disease. Coeliac disease-associated human leucocyte antigen (HLA) genotype was determined from all participants. The association between individual factors and new screening positivity was assessed by logistic regression. RESULTS: There were 229 previously diagnosed non-index relatives with coeliac disease and 2714 non-affected (2067 first-degree, 647 more distant) relatives. Of these 2714 relatives, 129 (4.8%) were screening-positive (first-degree 5.1%, second-degree 3.6%, more distant 3.5%). The combined prevalence of the previously diagnosed and now detected cases in relatives was 12.2% (6.3% clinically detected, 5.9% screen-detected). In univariate analysis, age <18 years at diagnosis (odds ratio 1.60, 95% CI 1.04-2.45) in index, and age 41-60 years (1.73, 1.10-2.73), being a sibling (1.65, 1.06-2.59) and having the high-risk genotype (3.22, 2.01-5.15 DQ2.5/2.5 or DQ2.5/2.2 vs other risk alleles) in relatives were associated with screening positivity. Only high-risk HLA remained significant (2.94, 1.80-4.78) in multivariable analysis. CONCLUSIONS: Unrecognised coeliac disease was common among at-risk relatives even in a country with an active case-finding policy, and also in relatives more distant than first-degree. The presence of a high-risk genotype was the most important predictor for screening positivity. ClinicalTrials.gov identifier NCT03136731.

Nonbiopsy Approach for Celiac Disease Is Accurate When Using Exact Duodenal Histomorphometry: Prospective Study in 2 Countries.

GOALS: To test the accuracy of serology-based criteria for diagnosing celiac disease utilizing quantitative histomorphometry. BACKGROUND: The revised European pediatric guidelines allow noninvasive celiac disease diagnosis for a subgroup of children. However, in some of the studies on this issue, the positive predictive value (PPV) of serology has remained suboptimal, possibly because of challenges of histopathology as the reference standard. STUDY: Prospectively enrolled children with transglutaminase 2 antibodies (TGA) above the upper limit of normal (ULN) underwent blood sampling and duodenal biopsy in Finland and Romania. Those with TGA ≥10× ULN, positive endomysium antibodies (EmA), and disease-associated genetics were considered to fulfill triple criteria for celiac disease. Initial histopathologic analysis was conducted using grouped classification, whereupon centralized morphometry was performed. RESULTS: Altogether 88 (54%) children were triple positive. In local evaluation, 99% of triple-positive children and 73% of children with TGA <10× ULN had celiac disease. These figures increased to 100% and 85% after more precise morphometric analysis. Triple-positive children had more anemia and higher median EmA and liver enzyme values than those with TGA<10× ULN; the groups were comparable in other clinical features and laboratory parameters. CONCLUSIONS: When applied as recommended, the nonbiopsy strategy had already yielded excellent PPV regardless of the site of diagnosis or clinical presentation in the local analysis. PPV further increased to 100% with standardized duodenal morphometry.

Current and emerging therapies for coeliac disease.

Coeliac disease is a common enteropathy that occurs in genetically susceptible individuals in response to the ingestion of gluten proteins present in wheat, rye and barley. Currently, the only available treatment for the condition is a strict, life-long gluten-free diet that, despite being safe and often effective, is associated with several challenges. Due to the high cost, particularly restrictive nature and perception of decreased quality of life associated with the diet, some patients are continuously exposed to gluten, which prevents an adequate disease control. Moreover, a subgroup of patients does not respond to the diet adequately, and healing of the small-bowel mucosa can be incomplete. Thus, there is a need for alternative treatment forms. The increasingly understood pathogenetic process of coeliac disease has enabled the identification of various targets for future therapies. Multiple investigational therapies ranging from tolerogenic to immunological approaches are in the pipeline, and several drug candidates have entered phase II/III clinical trials. This Review gives a broad overview of the different investigative treatment modalities for coeliac disease and summarizes the latest advances in this field.

Type 1 tyrosinemia in Finland: a nationwide study.

BACKGROUND: Introduction of nitisinone and newborn screening (NBS) have transformed the treatment of type 1 tyrosinemia, but the effects of these changes on the long-term outcomes remain obscure. Also, the predictors for later complications, the significance of drug levels and the normalization of laboratory and imaging findings are poorly known. We investigated these issues in a nationwide study. RESULTS: Type 1 tyrosinemia was diagnosed in 22 children in 1978-2019 in Finland. Incidence was 1/90,102, with a significant enrichment in South Ostrobothnia (1/9990). Median age at diagnosis was 5 (range 0.5-36) months, 55% were girls and 13 had homozygotic Trp262X mutation. Four patients were detected through screening and 18 clinically, their main findings being liver failure (50% vs. 100%, respectively, p = 0.026), ascites (0% vs. 53%, p = 0.104), renal tubulopathy (0% vs. 65%, p = 0.035), rickets (25% vs. 65%, p = 0.272), growth failure (0% vs. 66%, p = 0.029), thrombocytopenia (25% vs. 88%, p = 0.028) and anaemia (0% vs. 47%, p = 0.131). One patient was treated with diet, seven with transplantation and 14 with nitisinone. Three late-diagnosed (6-33 months) nitisinone treated patients needed transplantation later. Kidney dysfunction (86% vs. 7%, p = 0.001), hypertension (57% vs. 7%, p = 0.025) and osteopenia/osteoporosis (71% vs. 14%, p = 0.017) were more frequent in transplanted than nitisinone-treated patients. Blood/serum alpha-fetoprotein decreased rapidly on nitisinone in all but one patient, who later developed intrahepatic hepatocellular carcinoma. Liver values normalized in 31 months and other laboratory values except thrombocytopenia within 18 months. Imaging findings normalized in 3-56 months excluding five patients with liver or splenic abnormalities. Low mean nitisinone concentration was associated with higher risk of severe complications (r = 0.758, p = 0.003) despite undetectable urine succinylacetone. CONCLUSIONS: Prognosis of type 1 tyrosinemia has improved in the era of nitisinone, and NBS seems to provide further benefits. Nevertheless, the long-term risk for complications remains, particularly in the case of late diagnosis and/or insufficient nitisinone levels.

Clinical characteristics and long-term health in celiac disease patients diagnosed in early childhood: Large cohort study.

BACKGROUND: Early detection of celiac disease could theoretically prevent most of the disease-associated complications, but long-term effects of this approach are unclear. AIMS: To investigate features at diagnosis and adulthood health in celiac disease patients diagnosed in early childhood in 1965-2014. METHODS: Medical data on 978 pediatric patients were collected and study questionnaires sent to 559 adult patients who were diagnosed in childhood. Results were compared between patients diagnosed in early (≤3.0 years) and later (3.1-17.9 years) childhood. RESULTS: Early diagnosed patients (n=131) had more often total villous atrophy (37% vs 25%, p=0.001), gastrointestinal presentation (61% vs 47%, p<0.001), growth disturbances (70% vs 32%, p=0.001) and severe symptoms (30% vs 9%, p<0.001) and were less often screen-detected (10% vs 27%, p<0.001) at diagnosis than those diagnosed later (n=847). Among 239 adult responders, early diagnosed patients (n=36) had fewer comorbidities (33% vs 53%, p=0.034) but considered their health less often good/excellent (69% vs 84%, p=0.029). The groups were comparable in current age, dietary adherence, symptoms and health-related quality of life. CONCLUSION: Despite more severe initial presentation, the long-term health in early diagnosed patients was mostly comparable or even better to those diagnosed later in childhood. Poorer self-perceived health suggests a need for support during the transition to adulthood care.