diagnosis of FH

Last edited 05/2021 and last reviewed 05/2021

• a family history of premature coronary heart disease should always be assessed in a person being considered for a diagnosis of FH
• with respect to children at risk of FH because of one affected parent
  • NICE suggest the following diagnostic tests should be carried out by the age of 10 years or at the earliest opportunity thereafter
    • a DNA test if the family mutation is known
    • LDL-C concentration measurement if the family mutation is not known
    • when excluding a diagnosis of FH a further LDL-C measurement should be repeated after puberty because LDL-C concentrations change during puberty
• consider the possibility of FH in adults with raised cholesterol (total cholesterol typically greater than 7.5 mmol/l), especially when there is a personal or a family history of premature coronary heart disease
  • exclude secondary causes of hypercholesterolaemia before a diagnosis of FH is considered
  • diagnosis of FH should be made using the Simon Broome criteria, which include a combination of family history, clinical signs (specifically tendon xanthomata), cholesterol concentration and DNA testing

    • Simon Broome diagnostic criteria for index individuals (probands)

      • definite familial hypercholesterolaemia (FH) if patient has:
        • cholesterol concentrations as defined in table below and tendon xanthomas, or evidence of these signs in first- or second-degree relative

          Cholesterol levels to be used as diagnostic criteria for the index individual

          	Total cholesterol	LDL-C
          Child/young person	> 6.7 mmol/l	> 4.0 mmol/l
          Adult	> 7.5 mmol/l	> 4.9 mmol/l

          or

        • DNA-based evidence of an LDL-receptor mutation, familial defective apo B-100, or a PCSK9 mutation
          • for molecular studies of patients with suspected FH a standard PCR assay that can pick up mutations in the PCSK9 gene (D374Y), apoB gene (R3500Q) and LDL-R gene (18 most common mutations ). These are the 20 most common mutations observed in the UK population
          • test can detect 50-80% of FH gene mutation carriers depending on the population tested
            
            
      • possible FH if patient has cholesterol concentrations as defined in table and at least one of the following
    • Family history of myocardial infarction: aged younger than 50 years in second-degree relative or aged younger than 60 years in first-degree relative
    • Family history of raised total cholesterol: greater than 7.5 mmol/l in adult first- or second-degree relative or greater than 6.7 mmol/l in child, brother or sister aged younger than 16 years

     

  • consider a clinical diagnosis of homozygous FH in adults with a low-density lipoprotein cholesterol (LDL-C) concentration greater than 13 mmol/l and in children/young people with an LDL-C concentration greater than 11 mmol/l. All people with a clinical diagnosis of homozygous FH should be offered referral to a specialist centre
    
    
• to confirm a diagnosis of FH, healthcare professionals should undertake two measurements of LDL-C concentration because biological and analytical variability occurs
  
• absence of clinical signs (for example, tendon xanthomata) in adults and children/young people does not exclude a diagnosis of FH
  
  
• when considering a diagnosis of FH, healthcare professionals with expertise in FH should use standardised pedigree terminology to document, when possible, at least a three-generation pedigree
• should include relatives' age of onset of coronary heart disease, lipid concentrations and smoking history. For deceased relatives, the age and cause of death, and smoking history should be documented. If possible, the index individual should verify this information with other family members
• ultrasonography of the Achilles tendon is not recommended in the diagnosis of FH
  
  
• FH Testing in children:
  • in children aged 0-10 years at risk of FH because of 1 affected parent, offer a DNA test at the earliest opportunity. If testing of a child at risk has not been undertaken by the age of 10 years, offer an additional opportunity for a DNA test
  • in children at risk of homozygous FH because of two affected parents or because of the presence of clinical signs, for example, cutaneous lipid deposits (xanthomata), LDL-C concentration should be measured before the age of 5 years or at the earliest opportunity thereafter. If the LDL-C concentration is greater than 11 mmol/l then a clinical diagnosis of homozygous FH should be considered

Suspect familial hypercholesterolaemia (FH) as a possible diagnosis in adults with (1):

• a total cholesterol level greater than 7.5mmol/l and/or
• a personal or family history of premature coronary heart disease (an event before 60 years in an index individual or first-degree relative)

Systematically search primary care records for people (1):

• younger than 30 years, with a total cholesterol concentration greater than 7.5 mmol/l and
• 30 years or older, with a total cholesterol concentration greater than 9.0 mmol/l
• as these are the people who are at highest risk of FH

Use the Simon Broome or Dutch Lipid Clinic Network (DLCN) criteria to make a clinical diagnosis of FH in primary care settings (1)

Refer the person to an FH specialist service for DNA testing if they meet the Simon Broome criteria for possible or definite FH, or they have a DLCN score greater than 5.

Inform all people who have an identified mutation diagnostic of FH that they have an unequivocal diagnosis of FH even if their LDL-C concentration does not meet the diagnostic criteria

American Heart Association propsed diagnostic criteria for FH (3)

• in the absence of genetic testing, heterozygous FH (HeFH) is diagnosed
  • if LDL-C is >= 160 mg/dL (4.1 mmol/L) in a child or >=190 mg/dL (4.9 mmol/L) in an adult confirmed on 2 occasions,with a first-degree relative similarly affected, or with premature coronary artery disease (CAD), or with an FH-causing mutation
    
    
• homozygous FH (HoFH) is diagnosed
  • if LDL-C > 400 mg/dL (10 mmol/L) and 1 or both parents have FH diagnosed clinically or by genetic testing
    
    
  • if an individual has an untreated LDL-C is >560 mg/dL (14 mmol/L) or if LDL-C is >400 mg/dL (10 mmol/L) with aortic valve disease or xanthomata before age 20 years, HoFH is highly likely

Notes:

• coronary heart disease risk estimation tools such as those based on the Framingham algorithm should not be used because people with FH are already at a high risk of premature coronary heart disease

Reference:

• (1) NICE (November 2017). Identification and management of familial hypercholesterolaemia
• (2) JBS2: Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice. Heart 2005; 91 (Supp 5).
• (3) Gidding SS, et al.; American Heart Association Atherosclerosis, Hypertension, and Obesity in Young Committee of Council on Cardiovascular Disease in Young, Council on Cardiovascular and Stroke Nursing, Council on Functional Genomics and Translational Biology, and Council on Lifestyle and Cardiometabolic Health . The agenda for familial hypercholesterolemia: a scientific statement from the American Heart Association. Circulation. 2015;132(22):2167-2192.