CLN - The Sample

Strategies for Better Identifying Familial Hypercholesterolemia

The Sample: May 2019

Three abstracts presented at the American College of Cardiology annual scientific session underscore the pervasive underdiagnosis and undertreatment of familial hypercholesterolemia (FH) but also point to strategies for better identifying and implementing therapies for this disease.

Researchers at Kaiser Permanente Northern California used an algorithm based on Make Early Diagnosis to Prevent Early Deaths (MEDPED) diagnostic criteria to screen 1.6 million individuals who had at least one low-density lipoprotein cholesterol (LDL-C) value and to identify those with a high likelihood of FH (!/5758 search 1134-442). The researchers calculated an overall prevalence of 0.45% (1:222) in this population. Of 64 patients evaluated in a specialty clinic, just 5% had previously been diagnosed with FH, 73% were younger than age 45, and 54% were not on lipid-lowering therapy. Cascade testing identified nine relatives with FH.

The investigators concluded that their approach was “highly effective for population-level identification and management of patients with FH.”

Researchers in Denmark used Dutch Lipid Clinic Network (DLCN) criteria for FH to screen from six general medical practices 9,669 patients with at least one elevated LDL-C level (1232-420). In all, 34 individuals with DLCN scores ≥5 were determined to have probable or definitive FH; a prevalence of 1:284. Just three individuals already had been diagnosed and treated.

These findings demonstrate “massive underdiagnosis of FH in general practice,” according to the researchers.

A research team in Belgium investigated a pilot project to implement cascade screening among relatives of patients with FH who met inclusion criteria for LDL-C levels >250 mg/dL or LDL-C levels >190 mg/dL plus one other criterion and DLCN score ≥6 (1232-421). These criteria identified 132 index patients, of whom 91 were diagnosed definitively with FH, and 41 identified as having probable FH.

Two field nurses subsequently visited 276 relatives of these FH patients to collect clinical data and blood specimens. Among these relatives, 96 were determined to have definitive or probable FH based on MEDPED criteria or DLCN score.

Based on this pilot and the suspected number of individuals with FH in Belgium, the researchers concluded “this strategy…will require the sustained and extended collaboration of all stakeholders to achieve a nearly complete identification of suspected FH patients in a relatively reasonable period of 10 years.”

Point-of-Care Test Outperforms Standard Urine, Serum Tests in Predicting Preeclampsia

A pilot project involving 346 consecutive pregnant women being evaluated for preeclampsia (PE) found that a paper-based point-of-care test that provides results in 3 minutes outperforms standard urine and serum tests in predicting PE (EClinicalMedicine 2019; This Congo Red Dye (CRD) Paper Test “is uniquely positioned to increase the effectiveness of the [PE] triage process and possibly reduce healthcare costs,” according to the Ohio State University-based researchers, who also created the test.

The CRD Paper Test builds on the researchers’ prior investigations that found the urine of women with PE displays congophilia—the affinity of misfolded proteins for the azo-dye CR. Prior investigations had validated the clinical usefulness of detecting congophilia in diagnosing PE via a research laboratory protocol the investigators developed that uses nitrocellulose.

CRD Paper Test kits include two reaction papers and a visual colorimetric scale showing strong positive, weak positive, and negative results, as well as a syringe prefilled with CRD. Operators mix 150 µL fresh urine with the CRD from the syringe, then after 1 minute place equal sized drops on the reaction papers.

Two board-certified maternal fetal medicine specialists adjudicated each case; patients’ clinical care occurred separately from the research protocol. The researchers compared CRD Paper Test in confirming and ruling-out PE against the reference standard of the physician-adjudicated cases.

The CRD Paper Test area under the receiver operating characteristic for predicting PE was 0.85 compared with 0.723, 0.678, and 0.765 for urine soluble fms-like tyrosine kinase-1 (sFlt-1), urine placental growth factor (PlGF), and urine sFlt-1/PlGF, respectively, and 0.809, 0.747, and 0.820 for serum sFlt-1, serum PlGF, and serum sFlt-1/PlGF, respectively.

Paired, Appropriately Timed IFA IgG Tests Crucial for Improved Spotted Fever Rickettsioses Surveillance

Of 16,807 case reports of spotted fever rickettsioses (SFR) submitted to the Centers for Disease Control and Prevention (CDC) between 2010 and 2015, just 1% met the criteria for confirmed SFR (MMWR Morb Mortal Wkly Rep 2019;18:243-6). The remaining 99% met the probable case definition, mostly because they involved only a single indirect immunofluorescence assay (IFA) result or did not use any type of molecular diagnostic test. “Increased use of molecular assays and use of paired and appropriately timed IFA [immunoglobulin G] IgG testing practices could improve understanding of SFR epidemiology and increase the accuracy of disease incidence estimates,” wrote the investigators.

Council of State and Territorial Epidemiologist laboratory criteria for confirmed SFR include four methods: 1) seroconversion by IFA—defined as fourfold change in anti-SFR IgG antibody titers from paired serum specimens taken during the first week of illness and 2-4 weeks later; 2) polymerase chain reaction (PCR); 3) immunohistochemistry (IHC); or 4) culture. Of the 167 confirmed cases, 102 reported seroconversion, 66 involved PCR, IHC, or culture, and one reported both seroconversion and PCR.

Having a second (convalescent) IFA result is crucial to confirming an SFR, the researchers emphasized, because “antibodies to spotted fever group Rickettsia can persist for months or years following infection, making a single antibody titer unreliable for diagnosing incident disease.”

Probable SFR criteria include detection of anti-SFR IgG antibody by IFA, enzyme-linked immunosorbent assay (ELISA), dot-ELISA, or latex agglutination. Of the 16,640 probable cases, the majority (81.5%) provided only a single positive IFA IgG titer, or provided paired IFA IgG tests but without evidence of seroconversion (1.3%) or not within the recommended date range (7.6%). Another 9.6% provided only IFA IgM, ELISA, dot-ELISA, or latex agglutination results, all of which offer “insufficient evidence to confirm a new SFR illness; use of such tests hinders full understanding of SFR epidemiology and the incidence of disease in the [U.S.],” according to the investigators.