Guidance for the diagnosis and treatment of hypolipidemia disorders.

The Abetalipoproteinemia and Related Disorders Foundation was established in 2019 to provide guidance and support for the life-long management of inherited hypocholesterolemia disorders. Our mission is "to improve the lives of individuals and families affected by abetalipoproteinemia and related disorders". This review explains the molecular mechanisms behind the monogenic hypobetalipoproteinemia disorders and details their specific pathophysiology, clinical presentation and management throughout the lifespan. In this review, we focus on abetalipoproteinemia, homozygous hypobetalipoproteinemia and chylomicron retention disease; rare genetic conditions that manifest early in life and cause severe complications without appropriate treatment. Absent to low plasma lipid levels, in particular cholesterol and triglyceride, along with malabsorption of fat and fat-soluble vitamins are characteristic features of these diseases. We summarize the genetic basis of these disorders, provide guidance in their diagnosis and suggest treatment regimens including high dose fat-soluble vitamins as therapeutics. A section on preconception counseling and other special considerations pertaining to pregnancy is included. This information may be useful for patients, caregivers, physicians and insurance agencies involved in the management and support of affected individuals.

Is there a difference in breast milk fatty acid composition of mothers of preterm and term infants?

OBJECTIVE: Arachidonic acid (ARA) (c20:4 w6) and docosahexanoic acid (DHA) (c22:6 w3) are of major importance for neural maturation and retinal function in infancy. Requirements in preterm infants are increased due to accelerated growth and limited body stores. Data regarding human milk fatty acid composition after preterm and full-term delivery is inconsistent. This study compared fatty acid composition in breast milk from full-term and preterm infants. Findings were correlated with maternal dietary intake. METHODS: Human milk was obtained 4-5 days after full-term delivery (20 infants) and 4-5, 10-11 and 14-15 days after preterm delivery (21 infants, of whom 6 were born before 30 weeks). For fatty acid analysis, lipids were extracted, transesterified and separated by gas liquid chromatography. RESULTS: Total fat content was similar in the two groups. FA composition including LCPUFA and specifically ARA & DHA were similar in full-term and preterm infants and in the sub-set born before 30 weeks. In preterm infants, postnatal age did not influence LCPUFA content. CONCLUSIONS: This study did not detect any effect of gestational age or postnatal age on milk LCPUFA content. Accordingly, the increased demand for LCPUFA and specifically DHA in preterm infants need to be met by other supplementation.

Homozygous deletion of TRMT10A as part of a contiguous gene deletion in a syndrome of failure to thrive, delayed puberty, intellectual disability and diabetes mellitus.

Two recent reports describe a new syndrome of intellectual disability, short stature, microcephaly, and young onset diabetes or disturbed glucose metabolism in association with inactivating mutations in the TRMT10A gene. We investigated the clinical spectrum presented by a 17-year-old female with a homozygous contiguous gene deletion involving the TRMT10A gene. From infancy, she presented with failure to thrive and microcephaly. Puberty was characterized by a slow and an inconsistent course of progression. Concomitantly, gonadotropin levels fluctuated between low and high levels which were compatible with gonadal failure. Unlike the previous reports, the patient had ketoacidosis at onset of diabetes and islet cell autoantibodies. Nevertheless, glycemic control was excellent (HbA1C 5.0%-6.2%). RT-PCR and Western blot analysis demonstrated a complete abolishment of TRMT10A mRNA and its translated protein. In order to elucidate the nature of diabetes in this patient, endogenous insulin secretion and glycemic control were evaluated by a glucagon stimulation test and continuous glucose monitoring both during insulin treatment and off therapy. Endogenous insulin secretion still persisted 22 months after onset of diabetes and relatively normal glucose levels were kept over 3 days without insulin treatment. The fluctuating course of puberty and diabetes may reflect intermittent apoptotic damages due to sensitization of the relevant cells to various stress agents in the absence of functional TRMT10A.

Improvement in allergic and nonallergic rhinitis: A secondary benefit of adenoidectomy in children.

Chronic rhinitis (CR) is a common disorder in children. Allergic rhinitis (AR) is a risk factor for CR, and children with AR tend to suffer more from hypertrophic adenoids than do patients with nonallergic rhinitis (NAR). Few studies have addressed the issue of alleviating symptoms of pediatric CR or AR following adenoidectomy alone. We conducted a retrospective chart review to determine whether CR in children improves after adenoidectomy and whether children with AR will benefit more than those with NAR. Charts of 47 children who had undergone adenoidectomy for nasal obstruction and chronic middle ear effusion were reviewed. AR and NAR subgroups were classified based on symptoms, signs, blood IgE, and nasal smear (allergic criteria). Hypertrophic adenoids were graded using the adenoid-to-nasopharyngeal ratio (ANr >0.8). A questionnaire was used to assess the change in chronic rhinitis postoperatively. Improvement in CR was reported in 37 of 47 (79%) children. Patients with AR improved to a higher extent than those with NAR (12 of 14 [86%] vs. 25 of 33 [76%], respectively), but the difference was not statistically significant. A total of 41 lateral postoperative nasopharyngeal x-rays were obtained. The x-rays revealed that 20 of 26 (77%) of patients with ANr >0.8 had complete and 4 of 26 (15%) had partial resolution of symptoms of CR for a total resolution rate of 92%, compared to only a 53% resolution in the ANr <0.8 subgroup (6 of 15 and 2 of 15 patients, respectively [p <0.05]). The correlation between adenoid size and resolution of CR was not related to any of the AR/NAR subgroups. We conclude that symptoms of CR may improve after adenoidectomy in children who are experiencing nasal obstruction and chronic otitis media with effusion. Clinical improvement did not differ between AR and NAR patients, and was more prominent in children with hypertrophic adenoids (ANr >0.8).

Hepatitis C Virus in Children: Deferring Treatment in Expectation of Direct-Acting Antiviral Agents.

The major route of hepatitis C virus (HCV) infection in the pediatric age group is vertical, with infection occurring in up to 5% of infants born to mothers positive for HCV-RNA. The natural course of pediatric HCV infection is characterized by a high rate of spontaneous clearance, an asymptomatic clinical course, and normal or mild histologic changes. Cirrhosis is reported in 1-2% of children, and progression to severe chronic liver disease and HCC occurs 20-30 years after infection. Treatment with pegylated interferon (Peg-IFN) + ribavirin results in a sustained viral response (SVR) reaching 100% in children with HCV genotypes 2 or 3 but only 45-55% in those infected with genotypes 1 or 4. Treatment is associated with adverse effects ranging from flu-like symptoms, myalgia, anemia and thrombocytopenia, to less commonly observed thyroid-related symptoms, alopecia, neuropsychiatric manifestations and possible long-term effects on growth. Ongoing trials with direct-acting antiviral agents in adults show promising results with treatment regimens of shorter duration and high tolerance. The next few years will likely see these advances introduced to the pediatric population as well. In the meantime, in children with HCV an expectant approach is advocated and treatment should be offered only to those at high risk for more severe, progressive disease.

Continuous 13C-methacetin breath test differentiates biliary atresia from other causes of neonatal cholestasis.

BACKGROUND AND AIM: Distinguishing biliary atresia (BA) from other causes of neonatal cholestasis (NC) is challenging. Continuous BreathID C-methacetin breath test (MBT) is a novel method that determines liver function. Methacetin is metabolized uniquely by the liver and CO2 is measured passively, through a nasal cannula in the exhaled breath. The aim of this study was to assess the ability of MBT to differentiate BA from other causes of NC. METHODS: MBT was performed in infants with NC before any invasive procedure. Percent dose recovered (PDR) peak and time to peak (TTPP) of C recovered were correlated with blood test results and degree of fibrosis on liver biopsy. RESULTS: Fifteen infants were enrolled in the study. Eight were eventually diagnosed as having BA. MBT showed that infants with NC from various causes reached the PDR peak after 44.5 ± 6.7 minutes, whereas infants with BA reached the PDR peak value after 54.7 ± 4.3 minutes (P < 0.005). This suggested low cytochrome P450 1A2 activity in the BA group. The area under the curve (AUC) was 0.95 (95% confidence interval [CI] 0.83-1), sensitivity of 88%, and specificity of 100%. CONCLUSIONS: This pilot study shows that MBT can differentiate between BA and other causes of NC by time to peak of methacetin metabolism. The results suggest that MBT may be used as part of the diagnostic algorithm in infants with liver disease. Larger-scale studies should be conducted to confirm these initial observations.

DHA supplementation during pregnancy and lactation affects infants' cellular but not humoral immune response.

BACKGROUND: It is currently recommended that diet of pregnant mothers contain 200-300 mg DHA/day. Aim. To determine whether DHA supplementation during pregnancy and lactation affects infants' immune response. METHODS: 60 women in ≥3rd pregnancy studied; 30 randomly assigned to receive DHA 400 mg/day from 12th week gestation until 4 months postpartum. From breast-fed infants, blood obtained for anti-HBs antibodies, immunoglobulins, lymphocyte subset phenotyping, and intracellular cytokine production. RESULTS: CD4+ lymphocytes did not differ between groups, but CD4CD45RA/CD4 (naïve cells) significantly higher in infants in DHA+ group. Proportion of CD4 and CD8 cells producing IFN(γ) significantly lower in DHA+ group, with no differences in proportion of IL4-producing cells. Immunoglobulins and anti-HBs levels did not differ between groups. CONCLUSIONS: In infants of mothers receiving DHA supplementation, a higher percentage of CD4 naïve cells and decreased CD4 and CD8 IFN(γ) production is compatible with attenuation of a proinflammatory response.

Serum transaminases as a prognostic factor in children post cardiac surgery.

BACKGROUND: Elevated serum transaminases that are often observed in critically ill children are frequently attributed to liver injury. Indeed, hypoperfused or hypoxemic livers will produce sudden and marked elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). The aim of this study was to determine the frequency and consequences of elevated serum transaminases in children following cardiac surgery. METHODS: Charts of all children admitted to the Pediatric Intensive Care Unit following cardiac surgery over a 10-year period were retrospectively analyzed. RESULTS: Of the 384 children studied, 46 (11.9%) had elevated transaminases. Extreme ALT and AST levels (≥20-fold elevations over the upper limit of normal) were found in 3.4% and 4.7% of the children, respectively. Tetralogy of Fallot and double outlet right ventricle were significantly more common (P < 0.001) among the elevated transaminases group (26% and 13% vs 17% and 2.5%, respectively). A significant difference (P < 0.001) was noted between overall mortality among 384 patients studied: 15.8%, versus a mortality of 43.4% among children who manifested elevated transaminases levels following cardiac surgery. AST, ALT and lactate dehydrogenase peak levels were significantly higher in the group of children who died in comparison to the survivors (P < 0.05). Kaplan-Meier survival analysis demonstrated lower survival among the patients who had extreme ALT elevations (P < 0.05). CONCLUSIONS: Elevation of transaminases following cardiac surgery occurs more frequently than previously reported, particularly in the setting of right-sided heart failure. Extreme elevation of ALT, AST and lactate dehydrogenase correlated with decreased postoperative survival and places these children in a high-risk category, requiring closer, more stringent monitoring.

Helicobacter pylori infection in young children detected by a monoclonal stool antigen immunoassay.

The prevalence of Helicobacter pylori infection in young children attending day care facilities was studied using a monoclonal stool antigen test. Of 316 samples, 78 (24.7%) were positive. Only 7/98 (7.1%) of the 3- to 12-month-old infants tested positive compared with 71/218 (32.5%) of the 13- to 60-month-old group. We conclude that approximately 30% of infants may become infected with H. pylori after the first year of life.

Look-back study of Hepatitis C in teenagers after blood transfusions as neonates.

AIM: To conduct a single-centre "look-back" study of the prevalence of hepatitis C in teenagers who had received blood products as newborns, prior to hepatitis C virus (HCV) blood donor screening. METHODS: Using blood bank records, we identified 732 surviving teenagers aged 14-18 years who had received blood products as neonates during 1986-1990. Letters recommending HCV antibody testing were sent to 732 surviving teenagers; 581 recipients were contacted and invited to undergo testing, and, of these, 429 consented (59% of the survivors). HCV antibody testing was performed on all and HCV-RNA was tested on those who were antibody positive. RESULTS: Three teenagers (0.7%, 95% CI 0.54-0.86) tested positive for HCV antibodies and all three were HCV-RNA positive. There were no cases in which antibodies were detected and polymerase chain reaction (PCR) was negative. Two of the three had mildly elevated liver enzymes and all three had mild inflammatory activity and low fibrosis scores on liver biopsy. CONCLUSIONS: The look-back process, even in a single centre with a stable urban population, is relatively inefficient in screening at-risk populations. Although the prevalence of hepatitis C in this sample was relatively low, paediatricians should offer screening to teenagers and young adults who received blood products in the neonatal period.

A community-based behavior modification intervention for childhood obesity.

Childhood obesity, caused by reduced physical activity and increased food consumption, has reached epidemic proportions. We hypothesized that a single practitioner could enable a child to reduce BMI by educating towards a healthier lifestyle and then reinforcing the message in a structured manner. In this study, intervention group participants and their parents received a half-hour talk on exercise and diet, repeated after 3 months. They were instructed to fill weekly diaries and were called weekly by telephone. Controls received the initial instruction only. Twenty-seven (14 intervention) obese children were recruited. Anthropometric parameters, fitness and biochemical data were collected before intervention and after 6 months in both groups. Sustained but not statistically significant improvements in attitude, BMI SDS and LDL-cholesterol were noted in the intervention group. These promising results support a need for further work to evaluate the efficacy and applicability of our approach in the population at large.

Abetalipoproteinemia in Israel: evidence for a founder mutation in the Ashkenazi Jewish population and a contiguous gene deletion in an Arab patient.

Abetalipoproteinemia (ABL) is a rare autosomal recessive metabolic disorder, characterized by the absence of plasma apolipoprotein B-containing lipoproteins and very low levels of plasma triglycerides and cholesterol. ABL is caused by mutations of the MTP gene. We investigated the genetic basis for ABL in a cohort of Israeli families. In Ashkenazi Jewish patients we identified a conserved haplotype and a common MTP mutation, p.G865X, with a carrier frequency of 1:131 in this population. We also report the first case of ABL and additional abnormalities in a Muslim Arab patient, due to a homozygous contiguous gene deletion of approximately 481 kb, including MTP and eight other genes.

Should stored serum of patients previously tested for celiac disease serology be retested for transglutaminase antibodies?

INTRODUCTION: Tissue transglutaminase (tTG) antibodies are currently recognized as a highly sensitive indicator of celiac disease (CD). Although a high concordance rate between tTG antibodies and anti-endomysial antibodies (EMA) has been reported up to a third of known CD patients are positive for only one of these antibodies. AIM: To determine whether in laboratories in which serum samples previously examined for CD serology markers had not been discarded, these samples should be tested for tTG antibodies. METHODS: Fifty-eight stored (frozen at -70) serum samples of patients previously found to be EMA-negative but positive for one or more of the non-EMA markers: antigliadin antibodies (AGA)-IgA, AGA-IgG, antireticulin antibodies, were tested for anti-tTG antibodies (IMMCO Diagnostics). In patients found to be tTG positive, medical charts were reviewed and patients or their physicians contacted. RESULTS: Twelve of fifty-eight (20.7%) samples were found to be anti-tTG positive. These included: group A: 3/3 samples previously positive for AGA-IgA, AGA-IgG, and antireticulin antibodies. Group B: 3/16 samples positive for AGA-IgA and AGA-IgG. Group C: 3/4 samples positive for AGA-IgA and group D: 3/35 samples positive for AGA-IgG. Of the 12 positive patients, 1 was a 2-year-old boy, 5 were lost to follow up, and 7 underwent an intestinal biopsy. In 3 of these 7 patients, the biopsy was compatible with CD; 2 of these 3 patients were from group A and 1 from group B. CONCLUSIONS: In laboratories where stored serum samples are available, EMA-negative samples previously found to be positive for at least 2 other CD markers should be retested for tTG antibodies.

Cardiac function in children post-orthotopic liver transplantation: echocardiographic parameters and biochemical markers of subclinical cardiovascular damage.

Tacrolimus and cyclosporin A (CsA), the mainstay of preventive therapy for solid organ rejection, may cause various side-effects, such as hypertension and nephrotoxicity. Furthermore, tacrolimus is associated with cardiac hypertrophy. In the immediate post-transplant period, both drugs raise the levels of Endothelin-1 (ET), a potent vasoconstrictor; and of B-type Natriuretic Peptide (BNP), a sensitive marker of left ventricular volume overload, which may precede echocardiographic changes of cardiac dysfunction. The aim of the study was to investigate the presence of cardiac damage, by echocardiography and by the biochemical markers BNP and ET, in post-orthotopic liver transplantation (OLT) children, receiving long-term immunosuppressive therapy. ET (ELISA) and BNP (RIA) were measured in plasma of 18 children, post-OLT and 18 healthy controls. Children post-OLT were echocardiographically assessed for left ventricular mass (interventricular septum and posterior wall dimensions), systolic function (ejection fraction, fractional shortening) and diastolic parameters (mitral valve E and A waves, deceleration time, isovolumic relaxation time). None of the post-transplant recipients had a history or physical examination consistent with cardiac disease and all recipients were normotensive. Echocardiography revealed no systolic or diastolic dysfunction in any of the recipients. The mean ET and BNP levels tended to be higher among children post-liver transplant, compared with healthy controls (ET: 4.22 +/- 5.35 pg/mL vs. 2.1 +/- 2.0 pg/mL; BNP: 7.05 +/- 4.4 pg/mL vs. 5.87 +/- 2.0 pg/mL, respectively, mean +/- s.d.) although differences did not reach statistical significance. Three children (17%) had elevated BNP and/or ET levels. A strong correlation was observed between ET and BNP levels in post-OLT children (r = 0.79, p < or = 0.05). No correlation was found between ET or BNP levels and echocardiographic findings. In children receiving long-term immunosuppressive therapy post-OLT, although cardiac function is grossly preserved, ET and BNP levels tend to be higher than in healthy, age-matched children. Thus, elevated levels of BNP and/or ET may identify patients with early cardiac damage.

Oxidative stress in childhood--in health and disease states.

The accumulated information concerning the involvement of reactive oxygen species in many clinical disorders and disease states has led to the potential for intervention with antioxidants in these cases. There are currently numerous clinical trials involving administration of antioxidants in a variety of conditions such as coronary heart disease, cataract, cancer and neurodegenerative diseases. At the same time therapeutic trials aimed at preventing and delaying the aging process are also under investigation. Numerous disorders, in childhood, have also been linked to oxidative damage. The aim of this review is to provide an overview of oxidative stress, its mechanisms, targets and damage incurred, as pertaining specifically to clinical disorders during childhood. The defense mechanisms against oxidation; the enzymatic antioxidants and low molecular weight antioxidants are defined and a number of methods commonly used for evaluation of oxidative stress (methods for measurement of lipid and protein oxidation end products and methods for measurement of antioxidant defense capacity) described. Specific diseases related to oxidative stress in infancy and childhood are reviewed and the possible effect of nutritional intake on oxidative stress in the healthy child discussed. Other issues addressed include the ability of oxidative stress, as measured in plasma to reflect intratissue oxidation, the need for a simple laboratory method for characterization of an oxidative stress 'profile', the proposed role of oxidative stress in biological processes pertaining to growth and maturation and possible implications of unrestricted antioxidant supplementation.

Oxidative stress in abetalipoproteinemia patients receiving long-term vitamin E and vitamin A supplementation.

BACKGROUND: Patients with abetalipoproteinemia develop progressive ataxic neuropathy and retinopathy that are thought to be due, in part, to oxidative damage resulting from deficiencies of vitamins E and A. OBJECTIVE: The goal was to determine the degree of oxidative stress in abetalipoproteinemia patients who had received vitamin E (100 mg/kg) and vitamin A (10 000-15 000 IU/d) since infancy. DESIGN: Ten patients aged 3-25 y were studied. Assessed were plasma carbonyl concentrations as a marker of oxidative damage to proteins; total plasma oxidizability, which was used to evaluate the susceptibility of plasma lipoproteins to oxidation; and cyclic voltammetry, which represents the overall reducing and antioxidant capacity stemming from low-molecular-weight antioxidants in plasma. RESULTS: Concentrations of plasma carbonyls did not differ significantly between patients and control subjects ( +/- SE: 0.5670 +/- 0.031 and 0.5039 +/- 0.0134 nmol/mg protein, respectively). The lag phase of plasma oxidizability was 28.03 +/- 3.16 min in the patients and 24.0 +/- 2.79 min in healthy subjects in whom oxidizability of isolated HDL was measured (NS). Cyclic voltammetry showed a peak potential of 330 +/- 8.3 mV in all samples studied, denoting that the same antioxidants were present in the plasma of the patients and the control subjects. The anodic current of the samples, a measure of the concentration of hydrophilic low-molecular-weight antioxidants, was 5.227 +/- 0.25 and 5.38 +/- 0.20 micro A in the patients and the control subjects, respectively (NS). CONCLUSION: Enhanced oxidative stress is not apparent in the plasma of abetalipoproteinemia patients receiving long-term supplementation with vitamins E and A.

Medical treatment of recurrent intussusception associated with intestinal lymphoid hyperplasia.

Intestinal lymphoid hyperplasia (ILH) is an uncommon cause of recurrent intussusception in infants and young children. Surgical treatment has been suggested in the management of this disorder. We report 2 cases in which recurrent intussusception was associated with ILH. A short course of steroids resulted in resolution of both symptoms and hyperplasia. We conclude that when recurrent intussusception occurs in association with ILH, and no other lead point can be identified, it is important that treatment with steroids is considered before resorting to a more radical surgical approach.

An association between Helicobacter pylori infection and serum vitamin B12 levels in healthy adults.

GOALS: To determine whether serum vitamin B12 levels in non-vitamin B12 deficient healthy adults correlate with serological evidence of H. pylori infection. BACKGROUND: An association between H. pylori infection and vitamin B12 deficiency has been recently reported. STUDY: 133 adults, presenting to a community based primary care clinic who met the following exclusion criteria; history of H. pylori eradication or antacid use, liver disease, inflammatory bowel disease, previous gastrointestinal surgery, a vegetarian diet or multivitamin supplementation were studied. Blood was drawn for a complete blood count, serum vitamin B12, gastrin, folic acid and H. pylori IgG antibodies. Subjects with vitamin B12 < or = 145 ng/mL (deficient range) were excluded. RESULTS: Of 133 subjects 96 (72.2%) were seropositive for H. pylori IgG antibodies (HP+). Age of HP(+) subjects did not differ from that of seronegative subjects (HP-); 52.8 +/- 1.6 mean +/- SE versus 49.2 +/- 2.9 ( = NS). Prevalence of HP seropositivity was significantly higher among subjects with borderline (>145-180 pg/mL) or low normal (>180-250 pg/mL) vitamin B12 levels than among those with vitamin B12 > 250 pg/mL; among 25 subjects with vitamin B12 > 145-180 pg/mL 92% were seropositive and among 47 subjects with vitamin B12 > 180-250 pg/mL 89% were seropositive as compared with 31/61 (51%) of subjects with B12 > 250 pg/mL, Fisher exact test < 0.0001. Vitamin B12 levels did not correlate with age (r = -0.07). Gastrin levels (pg/mL) did not differ significantly between groups; 70.2 +/- 5.8 in HP(+) versus 56.0 +/- 12.4 in HP(-). CONCLUSIONS: The higher prevalence of H. pylori infection among subjects with serum vitamin B12 levels that are within the lower end of the normal range suggests a causal relationship between H pylori infection and vitamin B12 levels in healthy adults.