Improved Efficiency of the Clinical Diagnostic Criteria for Familial Hypercholesterolemia in Children: A Comparison of the Japan Atherosclerosis Society Guidelines of 2017 and 2022.

AIMS: Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels, which increases the risk of premature coronary artery disease. Early detection and treatment are vital, especially in children. To improve FH diagnosis in children, the Japan Atherosclerosis Society (JAS) released new guidelines in July 2022. This study assessed and compared the sensitivity and specificity of the clinical diagnostic criteria from the JAS pediatric FH guidelines of 2017 and 2022. METHODS: From September 2020 to March 2023, 69 children with elevated plasma LDL-C levels (≥ 140 mg/dL) were included in a pediatric FH screening project in Kagawa. The children were evaluated using genetic testing alongside the clinical diagnostic criteria from the JAS pediatric FH guidelines of 2017 and 2022. RESULTS: Using the JAS pediatric FH 2017 criteria, eight children were diagnosed as FH-positive and 61 children as FH-negative. The JAS pediatric FH 2022 criteria identified 15 children with definite FH, 31 with probable FH, and 23 with possible FH. Genetic testing detected FH pathogenic variants in 24 children. The sensitivity and specificity for the JAS pediatric FH 2017 criteria were 0.292 and 0.978, respectively. For the JAS pediatric FH 2022 criteria, the sensitivity was 0.542 for definite FH with a specificity of 0.956, and 0.917 for probable FH with a specificity of 0.467. CONCLUSION: The clinical diagnostic criteria of the JAS pediatric FH 2022 guidelines demonstrated improved diagnostic efficiency compared with those of 2017, as evidenced by the increased sensitivity while preserving specificity.

Universal Screening for Familial Hypercholesterolemia in Children in Kagawa, Japan.

AIM: Familial hypercholesterolemia (FH) is an underdiagnosed autosomal dominant genetic disorder characterized by high levels of plasma low-density lipoprotein cholesterol (LDL-C) from birth. This study aimed to assess the genetic identification of FH in children with high LDL-C levels who are identified in a universal pediatric FH screening in Kagawa, Japan. METHOD: In 2018 and 2019, 15,665 children aged 9 or 10 years underwent the universal lipid screening as part of the annual health checkups for the prevention of lifestyle-related diseases in the Kagawa prefecture. After excluding secondary hyper-LDL cholesterolemia at the local medical institutions, 67 children with LDL-C levels of ≥ 140 mg/dL underwent genetic testing to detect FH causative mutations at four designated hospitals. RESULTS: The LDL-C levels of 140 and 180 mg/dL in 15,665 children corresponded to the 96.3 and 99.7 percentile values, respectively. Among 67 children who underwent genetic testing, 41 had FH causative mutations (36 in the LDL-receptor, 4 in proprotein convertase subtilisin/kexin type 9, and 1 in apolipoprotein B). The area under the curve of receiver operating characteristic curve predicting the presence of FH causative mutation by LDL-C level was 0.705, and FH causative mutations were found in all children with LDL-C levels of ≥ 250 mg/dL. CONCLUSION: FH causative mutations were confirmed in almost 60% of the referred children, who were identified through the combination of the lipid universal screening as a part of the health checkup system and the exclusion of secondary hyper-LDL cholesterolemia at the local medical institutions.

The prevalence of Helicobacter pylori in Japanese children with gastritis or peptic ulcer disease.

BACKGROUND: Although Helicobacter pylori infection is typically acquired in childhood, the role of H. pylori infection in gastroduodenal diseases in childhood remains to be defined. The purpose of this study was to evaluate the prevalence of H. pylori infection in children with gastritis, duodenal ulcer, and gastric ulcer. METHODS: This was a retrospective analysis of 283 Japanese children (mean age, 11.5 years) with non-nodular gastritis ( n = 73), nodular gastritis ( n = 67), duodenal ulcer ( n = 100), and gastric ulcer ( n = 43). H. pylori status was based on biopsy tests. Clinical symptoms at the time of endoscopy were analyzed with regard to a possible association with the infection. RESULTS: The prevalence of H. pylori in non-nodular gastritis, nodular gastritis, duodenal ulcer, and gastric ulcer was 28.8%, 98.5%, 83.0%, and 44.2%, respectively. H. pylori was significantly linked to duodenal ulcer and gastric ulcers in the age group of 10-16 years, but not in the age group of 9 years and under. In children with H. pylori infection, nodular gastritis was observed in 26.3% of gastric ulcer patients and in 74.7% of duodenal ulcer patients ( P < 0.001). H. pylori infection was significantly associated with the prevalence of anemia ( P < 0.05). CONCLUSIONS: H. pylori is the most important causal factor for the development of duodenal ulcer in childhood. While H. pylori infection appears to be a risk factor in gastric ulcer, other causes are responsible for most cases. Nodular gastritis is the most common type of H. pylori gastritis in childhood. Chronic infection with H. pylori is associated with anemia.

Efficacy of interferon-alpha treatment in Japanese children with chronic hepatitis C.

BACKGROUND: We investigated the efficacy of natural interferon (IFN)-alpha treatment in 34 Japanese children with chronic hepatitis C. METHODS: Thirty-four children completed 6 months of therapy with natural IFN-alpha and were followed for 12 months or longer. We examined the serum hepatitis C virus (HCV) RNA titer and liver histology before, during, and after IFN treatment. RESULTS: At 6 months after the cessation of IFN-alpha treatment, 16 patients (47%) had normal serum alanine aminotransferase concentration and no detectable serum HCV RNA. There were no major side-effects, excluding some influenza-like symptoms during the IFN-alpha treatment. Most genotype 2a patients had a complete response (80%). Moreover, patients who had a low HCV RNA titer (<102 copies/mL) after 1 month of IFN-alpha treatment became complete responders at 6 months after the cessation of treatment. Histological improvement was observed in almost all patients after IFN-alpha treatment. CONCLUSION: Interferon-alpha treatment is safe and effective for children with chronic hepatitis C and has no serious side-effects. A HCV RNA concentration of <102 copies/mL after 1 month of IFN-alpha treatment and genotype 2a may be useful predictors of long-term IFN efficacy.

Accuracy of the stool antigen test for the diagnosis of childhood Helicobacter pylori infection: a multicenter Japanese study.

OBJECTIVE: The (13)C-urea breath test (UBT) has been accepted as a reliable noninvasive test for detecting Helicobacter pylori infection. Recently, another noninvasive test, a new enzyme immunoassay for H. pylori antigens in stool, has been widely investigated for its clinical usefulness. The purpose of this multicenter study was to evaluate the diagnostic accuracy of the stool antigen test in Japanese children. METHODS: A total of 264 children (148 male and 116 female; mean age 9.2 yr, range 2-17 yr) who underwent (13)C-UBT and the stool antigen test were studied. The diagnosis in these patients was gastritis (n = 49), gastric ulcer (n = 4), duodenal ulcer (n = 24), recurrent abdominal pain (n = 43), and other conditions (n = 144). The stool antigen test was performed using the HpSA ELISA (Premier Platinum HpSA, Meridian Diagnostics). According to manufacturer's instructions, an absorbance at 450/630 nm of <0.100, > or =0.120, and 0.100-0.119 was defined as negative, positive, and indeterminate, respectively. Based on the (13)C-UBT with a cutoff value of 3.5 per mil, the performance of HpSA was studied. In 21 patients who received eradication therapy, the HpSA was performed at baseline and at 1, 2, and 6 months after completion of therapy. Eradication of H. pylori was confirmed by (13)C-UBT at 2 or 3 months of follow-up. RESULTS: (13)C-UBT showed that 76 children were infected with H. pylori and 188 were not infected. In these same children, HpSA results were positive in 77 children, negative in 183, and indeterminate in four. The overall sensitivity, specificity, and accuracy of the test were 96.0% (95% CI = 88.6-99.2%), 96.8% (95% CI = 94.2-99.3%), and 96.5% (95% CI = 94.3-98.8%), respectively. There were no significant differences in these results among age groups of < or =5, 6-10, and > or =11 yr. Receiver operating characteristic curve analysis demonstrated that the best cutoff value of absorbance at 450/630 nm was 0.110. When a single cutoff value of 0.110 without indeterminate results was used, the sensitivity, specificity, and accuracy were 96.1% (95% CI = 90.8-99.7%), 96.3% (95% CI = 93.6-99.0%), and 96.2% (95% CI = 93.9-98.5%), respectively. In 19 patients in whom H. pylori was successfully eradicated, HpSA results were negative at 1 month of follow-up and remained negative through 6 months. CONCLUSIONS: The HpSA is an accurate test for the detection of H. pylori infection in all age groups of children.

Helicobacter pylori and TT virus prevalence in Japanese children.

BACKGROUND: The major transmission route of Helicobacter pylori, oral-oral or fecal-oral, remains to be established. TT virus (TTV), a recently discovered microbe that is prevalent in healthy persons, is believed to be mainly transmitted by nonparenteral routes. The purpose of this study was to test the hypothesis that these two microorganisms have a common mode of transmission. METHODS: We investigated the seroprevalence of H. pylori and TTV in a cross-sectional study of 454 healthy Japanese children from birth to age 15 years, living in five different geographic areas. Determination of H. pylori status was based on the presence of specific serum IgG and IgA antibodies, determined using enzyme immunoassays. TTV DNA was detected and the titer was determined using semiquantitative polymerase chain reaction with heminested primers. RESULTS: The overall prevalences of H. pylori and TTV were 12.2% and 21.6%, respectively. An age-related increase of prevalence was shown for H. pylori ( P < 0.001), but not for TTV ( P = 0.23). Titers of TTV DNA significantly decreased with age (P = 0.02). There were significant geographic differences in TTV prevalence ( P < 0.001), but not in H. pylori seroprevalence (P = 0.33). There was no true correlation between the prevalence of these two organisms (Phi coefficient = -0.02 and P = 0.66). CONCLUSIONS: Although Japanese children frequently acquire both H. pylori and TTV, especially in early childhood, their acquisition appears to be independent.

Diagnostic accuracy of the 13C-urea breath test for childhood Helicobacter pylori infection: a multicenter Japanese study.

OBJECTIVES: In adults, the 13C-urea breath test (UBT) has been widely used as a noninvasive test of Helicobacter pylori infection because of its high sensitivity and specificity. However, this test is less well established in pediatric practice. The optimum cutoff value and test protocol of the 13C-UBT remains to be established in the pediatric population. The primary purpose of this study was to evaluate diagnostic accuracy of the 13C-UBT for children and to determine its optimum cutoff value. METHODS: A total of 220 Japanese children aged 2-16 yr (mean = 11.9) who underwent upper GI endoscopy and gastric biopsies were finally studied. Endoscopic diagnoses included gastritis (n = 131), gastric ulcer (n = 15), duodenal ulcer (n = 72), and combined ulcer (n = 2). H. pylori infection status was confirmed by biopsy tests including histology, urease test, and culture. With the 13C-UBT, breath samples were obtained at baseline and at 20 min after ingestion of 13C-urea without a test meal and were analyzed by isotope ratio mass spectrometry. Based on biopsy tests, a cutoff value was determined using a receiver operating characteristic curve. In 26 children (seven children infected and 19 noninfected), paired breath samples were also measured by nondispersive infrared spectometry (NDIRS). RESULTS: Biopsy tests demonstrated that 89 children (40%) were infected with H. pylori and 131 children were not infected. There were no statistical differences in mean delta 13C values at 20 min between male and female H. pylori-infected and noninfected patients. A receiver operating characteristic analysis defined the best cutoff value as 3.5 per thousand. The overall sensitivity and specificity at a cutoff value of 3.5 per thousand were 97.8% (95% CI = 92.1-99.7%) and 98.5% (95% CI = 96.4-100%), respectively: high sensitivity and specificity were demonstrated in all three age groups (< or =5, 6-10, and > or = 11 yr). There was a close correlation between the values with isotope ratio mass spectrometry and NDIRS methods (r = 0.998, p < 0.001). CONCLUSIONS: The 13C-UBT with a cutoff value of 3.5 per thousand is an accurate diagnostic method for active H. pylori infection. The test with the NDIRS method is inexpensive and might be widely applied in clinical practice.