Guideline: Screen Obese Children for NAFLD With ALT

New guidance from the North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) recommends screening obese children for nonalcoholic fatty liver disease (NAFLD) starting between ages 9 and 11 by assessing their alanine aminotransferase (ALT) levels (J Pediatr Gastroenterol Nutr 2016; doi:10.1097/MPG.0000000000001482). NAFLD, the guideline notes, may occur in as many as 38% of obese children, and may “represent an aggressive phenotype of the disease” in comparison to that found in adults.

Early detection of NAFLD offers the opportunity for lifestyle modifications, including dietary changes and more physical activity, the recommended first-line treatment option for children.

The NASPGHAN panel recommended ALT testing beginning between ages 9 to 11 in obese children who have body mass index (BMI) ≥95th percentile. ALT testing also should be considered in overweight children with BMI ≥85th and <94th percentile who have other risk factors, like dyslipidemia, central adiposity, sleep apnea, or a family history of NAFLD or nonalcoholic steatohepatitis (NASH). Screening might be considered in even younger children who are severely obese, or who have hypopituitarism or a family history of NAFLD or NASH.

While the ALT assay has been standardized, normal value reporting has not been, according to the panel. They emphasized that test results should be interpreted based on sex-specific upper limits (U/L) of normal—22 U/L for girls and 26 U/L for boys—not individual laboratory U/Ls. Children with ALT levels elevated for at least 3 months should be evaluated further to determine whether they have NAFLD or some other type of liver condition.

Elevated ALT levels should be considered first in the context of a child’s clinical presentation. In addition, the panel recommended a variety of tests to explore other reasons for elevated ALT, including screening labs (aspartate aminotransferase (AST) and bilirubin); excluding infections (hepatitis A IgM, HCV antibody); excluding endocrine disorders (thyroid stimulating hormone); excluding autoimmune causes (total IgA, antinuclear antibody); and excluding genetic causes (ceruloplasmin, lysosomal acid lipase). Liver biopsy should be considered in children with NAFLD at increased risk for NASH by virtue of ALT >80 U/L, splenomegaly, or AST/ALT >1. 

Pre-analytical Factors in and Proposed Quality Indicators for Hemostasis Testing

Pre-analytical factors account for most laboratory errors, and hemostasis testing is “especially vulnerable” to these issues compared with clinical chemistry or clinical immunology testing because of the nature of the citrated plasma sample. As such, a trio of authors “strongly” recommends that labs establish a quality management system (QMS) with pre-analytical quality indicators (QI), and that they monitor these indicators on a regular basis (Clin Biochem 2016;49:1315–20).

Inappropriate sample processing for hemostasis testing causes a variety of problems. For example, refrigerating whole blood samples prior to centrifuging them can lead to false diagnosis of hemophilia or von Willebrand disease because of platelet activation and loss of Factor VIII (FVIII) and von Willebrand factor (VWF). Filtering plasma causes loss of fibrinogen, FVIII, and VWF, potentially leading to an incorrect diagnosis of dys- or hypofibrinogenemia.

Different types of samples also affect routine coagulation tests, factor assays, and other hemostasis tests. For instance, enediaminetetraacetic acid plasma samples prolong prothrombin time and activated partial thromboplastin time (APTT), and might influence fibrinogen and D-dimer assays. They also yield false low FVIII levels.

Ideally a sample for hemostasis testing will have been obtained without trauma during phlebotomy and with minimal tourniquet use. The sample also will have been drawn first with a 3.2% blue stopper tube, and had the tube filled adequately, mixed thoroughly with anticoagulant, transported promptly at room temperature, and centrifuged within 1 hour of phlebotomy.

The authors proposed four QIs for sample collection, including the number of samples for clot-based assays submitted that are not sodium citrate compared to the total number of samples requiring sodium citrate anticoagulant for testing. They also proposed two QIs for sample storage, including how many samples for APTT testing are on the bench >4 hours prior to testing compared to all APTT tests performed, and how many samples for FVIII testing are stored >2 weeks compared with all FVIII tests performed. 

Non-Albumin Proteinuria: Highly Prevalent but Often Missed Without Both Urine Total Protein and Urine Albumin Results

Laboratory Corporation of America (LabCorp) researchers found a “strikingly high prevalence” of non-albumin proteinuria (NAP) in a clinically indicated U.S. population that was being routinely tested for proteinuria (Clin Biochem 2016;
2016.11.030). Their findings suggest a “high risk” of missing the diagnosis of proteinuria in about 20% of patients when only random urine albumin is measured and in more than one-third with 24-hour urine testing. The authors suggested that clinicians need both urine albumin and urine total protein results to make the differential diagnosis for proteinuria type, to prevent misdiagnosis, and to improve clinical outcomes.

The researchers sought to develop a baseline understanding of NAP prevalence in a U.S. population undergoing routine testing for proteinuria. They accessed test results across LabCorp for 89,757 paired albumin-to-creatinine ratio (ACR) and total protein-to-creatinine ratio (PCR) test results, and for 16,946 paired 24-hour albumin excretion rate (AER) and 24-hour total protein excretion rate (PER) results.

The authors defined eight categories of NAP results based on the type of urine testing (random versus timed) and proteinuria thresholds by ACR, PCR, or AER. For example, for random urine collection samples they defined NAP as ACR <3 mg/mmol with PCR >14.9 mg/mmol, but for all timed results, they defined NAP as AER <30 mg/24h with PER >149 mg/24h.

The researchers found NAP prevalence among patients who provided random urine samples was 10.1%. Among patients with normal random albumin results, 20% had NAP. In contrast, NAP prevalence among patients who provided timed urine samples was 24.6%. Among patients with normal timed urine albumin results, 36.2% had NAP. The diagnosis of proteinuria and its underlying etiology would have been missed in the latter group of patients if only urine albumin measurements would have been performed. 

Guideline Proposes Four-Tier System for Calling Cancer Genetic Variants

A new guideline for interpreting and reporting sequence variants in cancer proposes a four-tier system to categorize somatic variations based on their clinical importance in diagnosis, prognosis, or treatments (J Mol Diagn 2017;19:4–23). The Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists issued the joint consensus recommendations in light of how next-generation sequencing (NGS) identifies a plethora of genetic variations in cancers crucial to optimal patient care. This explosion of NGS-based data makes it “imperative to unify the interpretation and reporting of molecular results among laboratories performing these tests,” according to the guideline authors.

The four-tier system the guideline recommends is as follows. Tier 1 includes variants with strong clinical—therapeutic, prognostic, and diagnostic—significance as demonstrated by Level A or Level B evidence. Level A evidence reflects biomarkers that predict response or resistance to Food and Drug Administration-approved therapies or that have been included in professional guidelines for specific types of tumors.

Tier 2 variants have potential clinical significance based on Level C or Level D evidence. The former includes biomarkers that predict response or resistance for different tumor types or have been shown to have significance in multiple small studies. Level D evidence comprises biomarkers that have been associated with targeted therapies in preclinical trials. Tier 3 variants are of unknown clinical significance, while Tier 4 variants have either been deemed benign or are likely benign.

The authors also urged labs to report variants in a format that enables integration with electronic health records (EHR). “An aesthetically beautiful report that must be scanned … into a patient’s chart is … less valuable for that patient than a report that can be integrated into the structured environment of an [EHR],” they wrote.