Familial hypercholesterolaemia (FH): laboratory contributions to management
Hapizah Mohd Nawawi1,2
1Department of Pathology, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh Campus, Selangor, Malaysia; 2Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Universiti Teknologi MARA, Sungai Buloh Campus, Selangor, Malaysia
FH is a serious, potentially treatable and the most common autosomal dominant disorder affecting mankind, mainly caused by mutations in the low-density lipoprotein receptor, and other FH-candidate genes, resulting in lifelong hypercholesterolaemia, leading to increased risk for premature atherosclerotic cardiovascular disease (pASCVD). Globally, FH is under-diagnosed and under-treated, resulting in missed opportunities for pASCVD prevention. Lipid profiles and laboratory investigations to exclude secondary hypercholesterolaemia are important to screen for primary hypercholesterolaemia. Diagnosis can be confirmed clinically with/without genetic testing, using various FH diagnositc criteria including the most widely utilised Dutch Lipid Clinic Network criteria, incorporating a scoring system based on family and personal history, presence of lipid stigmata, pre-treatment LDL-C and genetic analysis. Probands should be identified according to the following criteria:(a)pre-treatment TC>8mmol/L and/or LDL-C>5.0mmol/L; (b)premature ASCVD; (c)tendon xanthomas in the patient or family members; or (d)sudden premature cardiac death in a family member. Family cascade screening of a proband allows efficient identification of new cases, with TC or LDL-C analysis, but genetic testing is recommended when the causative mutation is known. The diagnosis can be verified by showing pathogenic variants (PV) in the candidate genes. However, the frequency of detectable PV in patients with clinically potential FH is between 60-80%, suggesting that a proportion of FH patients have either polygenic hypercholesterolaemia or that other genes involved are yet to be identified. FH patients are in the very-high or high-risk categories due to presence/absence of prior ASCVD/another major risk factor, respectively. Risk categorisation is important to determine target LDL-C levels. The laboratories also contribute to assessment of other co-existing risk factors, including lipoprotein(a), monitoring achievement of target LDL-C levels, and side effects. In conclusion, laboratories have significant contributions to FH management in terms of screening and diagnosis, family cascade screening, risk categorisation, monitoring response to treatment and side effects.
Laboratory Role in Osteoporosis
Subashini C. Thambiah
Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia
Osteoporosis is a disease characterised by low bone mass and microarchitectural deterioration of bone tissue leading to enhanced bone fragility and a consequent increase in fracture risk. First- line laboratory investigations in patients with osteoporosis aim to identify its common aetiologies. Further selected investigations may be performed if clinically indicated. As parathyroid hormone and vitamin D are important regulators of calcium and phosphate homeostasis, issues with these assays will be highlighted. The International Osteoporosis Foundation and the International Federation of Clinical Chemistry and Laboratory Medicine recommend serum/plasma procollagen type I N propeptide (PINP) and C-terminal cross-linking telopeptide of type I collagen (CTX) to be used as reference markers and measured by standardised assays in clinical studies to help resolve uncertainties over their clinical use. The role of P1NP and CTX in osteoporosis will be emphasised in this talk.
Lp(a) as cardiovascular risk biomarker
Aw Tar Choon
Department of Laboratory Medicine, Changi General Hospital, Singapore
Each Lp(a) particle comprises apo(a) attached to apoB-100. The apo(a) chain contains five cysteine-rich domains known as “kringles”. Apo(a) kringle IV has 10 variants (KIV1 to KIV10); all are present in one copy while KIV2 is highly variable in number and determine the size of the Lp(a) isoform. Apo(a) isoform size are inversely correlated to Lp(a) levels. Lp(a) is excreted by the liver and partly by the kidneys. Lp(a) has prothrombotic, proinflammatory and proatherogenic properties. Elevated Lp(a) is present in premature atherosclerotic cardiovascular disease (ASCVD). Lp(a) particles are more easily taken up by macrophage scavenger receptors and preferentially sequestrated into the arterial walls than LDL. Lp(a) concentrations are genetically determined. Indians have higher Lp(a) than Chinese and Malays (Pathology1999;31:225) and thus more ASCVD and myocardial infarction in an angiographic study (Atherosclerosis 2022). Lp(a) measurements are confounded by variations in KIV2, assay calibrator target value assignments and assessment of Lp(a) mass (mg/dL) versus particle number (nmol/L). Lp(a) mass includes apo(a), apoB-100, cholesterol, phospholipids, cholesteryl esters and triglycerides. Heterogeneity of apo(a) and KIV2 impacts standardization of Lp(a) calibrators; more KIV2 repeats over-estimate while less under-estimate Lp(a). Conversion factors for Lp(a) (2.4nmol/L:1mg/dL) are not recommended. The Denka Seiken assay reports Lp(a) in nmol/L and is referenced to WHO/IFCC reference materials.A single Lp(a) measurement suffices and repeat testing is reserved for identifying secondary causes of elevated Lp(a) or monitoring treatment response. The 2019 European Atherosclerosis Society and European Society of Cardiology guidelines endorse screening to identify those with very high Lp(a) levels >180mg/dL (>430nmol/L). The National Lipid Association (NLA) and HEART UK advocate measuring Lp(a) amongst those with a personal/family history of premature ASCVD and those with LDL-C ≥190mg/dL; Lp(a) >125 nmol/L (>50mg/dL) are deemed high risk. Lp(a) measurements have improved and new efficacious therapies (e.g. antisense agents) are in clinical trials.