The US MEDPED (Make Early Diagnosis to Prevent Early Death) diagnostic criteria represent a critical screening tool designed to facilitate the early identification of individuals with familial hypercholesterolemia (FH). This genetic disorder, characterized by significantly elevated low-density lipoprotein cholesterol (LDL-C) levels from birth, poses a substantial risk for premature cardiovascular disease if left undiagnosed and untreated. The MEDPED criteria were developed to address the significant underdiagnosis of FH, which affects approximately 1 in 250 individuals worldwide but remains largely unrecognized in clinical practice.

Familial hypercholesterolemia is an autosomal dominant genetic condition that results from mutations affecting the LDL receptor pathway. The most common mutations occur in genes encoding the LDL receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9), and LDL receptor adaptor protein 1 (LDLRAP1). These genetic alterations impair the body's ability to clear LDL cholesterol from the bloodstream, leading to lifelong elevation of cholesterol levels and dramatically increased risk of coronary artery disease, often manifesting in the third, fourth, or fifth decades of life.

Familial hypercholesterolemia represents one of the most common monogenic disorders affecting humans, with a prevalence of approximately 1 in 250 individuals in the general population. The condition exists in two primary forms: heterozygous FH (HeFH), which affects approximately 1 in 250 people, and homozygous FH (HoFH), which is much rarer, occurring in approximately 1 in 250,000 to 1 in 1,000,000 individuals. Heterozygous FH is the most clinically relevant form, as it is significantly more common and often goes undiagnosed until a cardiovascular event occurs.

Individuals with FH typically present with elevated total cholesterol and LDL-C levels that are present from birth. In untreated adults with heterozygous FH, total cholesterol levels typically range from 300 to 400 mg/dL (7.8 to 10.3 mmol/L), while LDL-C levels commonly exceed 190 mg/dL (4.9 mmol/L). These levels are substantially higher than those seen in the general population and persist throughout life without appropriate treatment. The genetic nature of the condition means that family members are also at risk, creating opportunities for cascade screening once an index case is identified.

The clinical significance of FH cannot be overstated. Without treatment, men with heterozygous FH have approximately a 50% risk of developing coronary artery disease by age 50, while women have approximately a 30% risk by age 60. These risks are dramatically higher than those in the general population, where coronary artery disease typically presents much later in life. Early diagnosis and aggressive lipid-lowering therapy can substantially reduce these risks, making screening tools like the MEDPED criteria critically important for public health.

The MEDPED Criteria: Development and Rationale

The MEDPED criteria were developed to address the critical need for early identification of individuals with FH. The acronym MEDPED stands for "Make Early Diagnosis to Prevent Early Death," reflecting the tool's primary purpose of facilitating early detection to prevent premature cardiovascular events. The criteria were designed to be practical and easy to apply in clinical settings, using readily available clinical information: total cholesterol levels, patient age, and family history of FH.

One of the key innovations of the MEDPED criteria is the use of age-adjusted cholesterol thresholds. This approach recognizes that cholesterol levels naturally increase with age in the general population, and therefore, the thresholds for diagnosing FH must be adjusted accordingly. Lower thresholds are used for younger patients, allowing for earlier detection when treatment can have the greatest impact on long-term outcomes. This age-adjusted approach improves both the sensitivity and specificity of the screening tool compared to using a single threshold for all ages.

The criteria also incorporate family history in a sophisticated manner, recognizing that the strength of family history affects the pre-test probability of FH. Patients with first-degree relatives (parents, siblings, or children) with FH have the highest likelihood of having the condition themselves, and therefore, lower cholesterol thresholds are used for diagnosis. As the degree of relationship becomes more distant (second-degree relatives such as grandparents, aunts, uncles, or half-siblings; third-degree relatives such as great-grandparents, great-aunts/uncles, or first cousins), the thresholds increase accordingly. For individuals without a known family history of FH (general population), the highest thresholds are used.

How the MEDPED Criteria Work

The MEDPED criteria function by comparing a patient's total cholesterol level to age- and family history-specific thresholds. The criteria divide patients into four age groups: less than 20 years, 20-29 years, 30-39 years, and 40 years or older. For each age group, different cholesterol thresholds are established based on the strength of family history. If a patient's total cholesterol meets or exceeds the threshold for their age group and family history category, they meet the MEDPED criteria for FH diagnosis.

For patients under 20 years of age, the thresholds range from 220 mg/dL (5.7 mmol/L) for those with a first-degree relative with FH to 270 mg/dL (7.0 mmol/L) for the general population. These relatively low thresholds reflect the fact that cholesterol levels in children and adolescents are typically much lower than in adults, and any significant elevation is highly suggestive of a genetic cause.

For patients aged 20-29 years, the thresholds increase to 240-290 mg/dL (6.2-7.5 mmol/L), reflecting the natural increase in cholesterol that occurs with age. Patients in this age group with FH often have cholesterol levels that are clearly abnormal but may not be as dramatically elevated as in older patients. Early detection in this age group is particularly important, as it allows for initiation of treatment before significant atherosclerosis has developed.

For patients aged 30-39 years, the thresholds range from 270-340 mg/dL (7.0-8.8 mmol/L). This age group represents a critical window for intervention, as many patients with FH will begin to experience cardiovascular events in their 30s and 40s if left untreated. Detection and treatment during this period can prevent or delay the onset of significant cardiovascular disease.

For patients 40 years and older, the thresholds are highest, ranging from 290-360 mg/dL (7.5-9.3 mmol/L). While these thresholds are higher, they still represent significant elevations above normal cholesterol levels. It is important to note that even in older patients, meeting MEDPED criteria suggests a genetic component to hypercholesterolemia, which may warrant more aggressive treatment and family screening.

Clinical Application and Interpretation

When applying the MEDPED criteria in clinical practice, several important considerations must be kept in mind. First, the criteria use total cholesterol rather than LDL-C, which makes them easier to apply in settings where a full lipid panel may not be immediately available. However, this also means that the criteria may be less specific than tools that use LDL-C directly, as total cholesterol can be influenced by other lipid fractions, particularly high-density lipoprotein cholesterol (HDL-C) and triglycerides.

Patients who meet MEDPED criteria should undergo further evaluation, including a complete lipid panel with LDL-C measurement, physical examination for stigmata of FH (such as tendon xanthomas, xanthelasmas, or corneal arcus), and detailed family history assessment. Genetic testing may be considered to confirm the diagnosis, particularly in cases where the diagnosis is uncertain or when cascade screening of family members is planned.

It is important to recognize that not meeting MEDPED criteria does not completely rule out FH. Some patients with FH, particularly those with milder mutations or those who have been partially treated, may have cholesterol levels below the MEDPED thresholds. Clinical judgment must always be used, and other factors such as physical findings, family history of premature cardiovascular disease, and LDL-C levels should be considered in the diagnostic evaluation.

Conversely, meeting MEDPED criteria does not definitively confirm FH, as other conditions can cause severe hypercholesterolemia. Secondary causes of hypercholesterolemia, such as hypothyroidism, nephrotic syndrome, obstructive liver disease, or certain medications, should be excluded before making a diagnosis of FH. Additionally, polygenic hypercholesterolemia, which results from the combined effect of multiple genetic variants, can sometimes produce cholesterol levels that meet MEDPED criteria, particularly in older patients.

Family History Assessment

Accurate assessment of family history is crucial for proper application of the MEDPED criteria. First-degree relatives include parents, siblings, and children. These individuals share approximately 50% of their genetic material with the patient, making them the most informative for genetic risk assessment. A confirmed diagnosis of FH in a first-degree relative significantly increases the likelihood that the patient also has the condition.

Second-degree relatives include grandparents, aunts, uncles, and half-siblings. These individuals share approximately 25% of their genetic material with the patient. While the genetic relationship is more distant, a family history of FH in second-degree relatives still provides important information about the likelihood of the condition.

Third-degree relatives include great-grandparents, great-aunts/uncles, and first cousins. These individuals share approximately 12.5% of their genetic material with the patient. While the relationship is more distant, a family history of FH in third-degree relatives can still be relevant, particularly in families with a strong history of premature cardiovascular disease.

When assessing family history, it is important to obtain as much detail as possible about relatives with hypercholesterolemia or premature cardiovascular disease. Ideally, cholesterol levels and age at diagnosis should be documented. However, in many cases, this information may not be available, and clinicians must work with the information that is available. A family history of premature myocardial infarction, stroke, or other cardiovascular events in the absence of known cholesterol levels may still be suggestive of FH and should prompt further evaluation.

Age-Adjusted Thresholds: Why They Matter

The use of age-adjusted thresholds in the MEDPED criteria represents a sophisticated approach to screening that recognizes the natural variation in cholesterol levels across the lifespan. In the general population, total cholesterol levels tend to increase with age, peaking in middle age before potentially declining slightly in older adults. This age-related increase reflects various factors, including changes in diet, physical activity, hormonal status, and metabolic function.

For patients with FH, cholesterol levels are elevated from birth, but the absolute levels may vary with age just as they do in the general population. However, the elevation relative to age-appropriate norms remains consistent. By using age-adjusted thresholds, the MEDPED criteria can identify patients with FH at any age, while maintaining appropriate specificity to avoid overdiagnosis.

The lower thresholds used for younger patients are particularly important because they allow for early detection when treatment can have the greatest impact. Children and young adults with FH who are identified and treated early can often achieve near-normal cardiovascular risk, while those who are diagnosed later may already have significant atherosclerosis. Early detection also allows for family screening, potentially identifying other affected relatives who can benefit from treatment.

The higher thresholds used for older patients reflect the natural increase in cholesterol with age, but they are still set at levels that represent significant elevation above normal. Even in older patients, meeting MEDPED criteria suggests a genetic component to hypercholesterolemia that may warrant more aggressive treatment and family screening.

Integration with Other Diagnostic Tools

While the MEDPED criteria are valuable screening tools, they should be used in conjunction with other diagnostic approaches rather than in isolation. The Dutch Lipid Clinic Network (DLCN) criteria and the Simon Broome criteria are other well-validated tools for diagnosing FH that incorporate additional factors such as physical findings, genetic test results, and LDL-C levels directly.

The DLCN criteria assign points based on family history, clinical history, physical examination findings, LDL-C levels, and genetic testing results. A score of 8 or more points indicates definite FH, while 6-8 points indicates probable FH. This scoring system provides a more comprehensive assessment but requires more detailed clinical information than the MEDPED criteria.

The Simon Broome criteria define definite FH as total cholesterol greater than 290 mg/dL (7.5 mmol/L) or LDL-C greater than 190 mg/dL (4.9 mmol/L) in adults, plus either tendon xanthomas in the patient or a first- or second-degree relative, or DNA-based evidence of an FH-causing mutation. Probable FH is defined similarly but without the requirement for physical findings or genetic confirmation.

Each of these diagnostic tools has strengths and limitations, and they may be used complementarily in clinical practice. The MEDPED criteria are particularly useful for initial screening because they are simple to apply and require only basic clinical information. Patients who meet MEDPED criteria should then undergo more comprehensive evaluation using additional tools and diagnostic tests.

Management Considerations

Patients who meet MEDPED criteria for FH require comprehensive management that goes beyond simple cholesterol lowering. The goal of treatment is to reduce LDL-C levels by at least 50% from baseline, with an ideal target of less than 100 mg/dL (2.6 mmol/L) in adults, or less than 70 mg/dL (1.8 mmol/L) in patients with established cardiovascular disease or very high risk.

Lifestyle modifications, including a heart-healthy diet, regular physical activity, and avoidance of tobacco products, form the foundation of FH management. However, lifestyle modifications alone are typically insufficient to achieve target LDL-C levels in patients with FH, and pharmacologic therapy is almost always necessary.

High-intensity statin therapy is the first-line pharmacologic treatment for FH. Statins work by inhibiting HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, leading to upregulation of LDL receptors and increased clearance of LDL-C from the bloodstream. In patients with FH, high-intensity statins (such as atorvastatin 40-80 mg daily or rosuvastatin 20-40 mg daily) are typically required to achieve adequate LDL-C reduction.

Many patients with FH will require additional lipid-lowering medications beyond statins. Ezetimibe, which inhibits cholesterol absorption in the intestine, can provide additional LDL-C reduction of approximately 15-20% when added to statin therapy. PCSK9 inhibitors, monoclonal antibodies that increase LDL receptor availability, can provide dramatic additional LDL-C reduction of 50-60% when added to maximally tolerated statin and ezetimibe therapy.

For patients with homozygous FH or severe heterozygous FH that is refractory to conventional therapy, additional treatments may be necessary. Lipoprotein apheresis, a procedure that physically removes LDL-C from the blood, may be required for patients with very high LDL-C levels or established cardiovascular disease. Emerging therapies, including gene therapy and other novel approaches, are being developed for the most severe cases.

Cascade Screening and Family Evaluation

One of the most important aspects of FH management is cascade screening, the systematic evaluation of family members of an index case. Because FH is an autosomal dominant condition, each first-degree relative of an affected individual has a 50% chance of having the condition. Cascade screening allows for early identification and treatment of affected family members, potentially preventing premature cardiovascular events.

Cascade screening typically begins with the identification of an index case, a patient who has been diagnosed with FH. Once an index case is identified, all first-degree relatives should be offered cholesterol screening. Those with elevated cholesterol should undergo further evaluation, and if they meet diagnostic criteria, they should be treated. The process then continues with screening of their first-degree relatives, creating a cascade effect that can identify multiple affected individuals within a family.

Genetic testing can facilitate cascade screening by allowing for more precise identification of affected family members. If a pathogenic mutation is identified in the index case, genetic testing can be offered to family members. Those who test positive for the mutation can be diagnosed with FH even if their cholesterol levels are not yet dramatically elevated, allowing for early intervention. Those who test negative can be reassured and do not require intensive lipid-lowering therapy.

Cascade screening has been shown to be highly cost-effective and can identify many previously undiagnosed cases of FH. However, it requires coordination and communication among family members, which can be challenging. Healthcare providers should be prepared to assist patients in communicating with family members about the importance of screening and should provide resources and support to facilitate the cascade screening process.

Pediatric Considerations

FH can and should be diagnosed in children, as early treatment can prevent or delay the development of atherosclerosis. The MEDPED criteria include thresholds for patients under 20 years of age, recognizing the importance of early detection. However, pediatric FH diagnosis and management require special considerations.

In children, cholesterol levels are typically lower than in adults, making the MEDPED thresholds for patients under 20 years of age particularly important. A total cholesterol level of 220 mg/dL (5.7 mmol/L) or higher in a child with a first-degree relative with FH is highly suggestive of the condition and warrants further evaluation.

Physical examination findings can be particularly helpful in pediatric FH diagnosis. Tendon xanthomas, while rare in children, are pathognomonic for FH when present. Corneal arcus in children or young adults (under 45 years of age) is also highly suggestive of FH. Xanthelasmas, while less specific, can also be a clue to the diagnosis.

Treatment of pediatric FH typically begins with lifestyle modifications, including a heart-healthy diet and regular physical activity. However, many children with FH will require pharmacologic therapy to achieve adequate LDL-C reduction. Statin therapy can be initiated in children as young as 8-10 years of age, depending on the severity of hypercholesterolemia and the presence of other risk factors.

Pediatric FH management requires a multidisciplinary approach involving pediatricians, lipid specialists, dietitians, and other healthcare providers. Family involvement is crucial, as parents and other family members may also be affected and require treatment. Regular monitoring of cholesterol levels, growth, and development is important to ensure both effective treatment and safety.

Limitations and Considerations

While the MEDPED criteria are valuable screening tools, they have several important limitations that clinicians must recognize. First, the criteria use total cholesterol rather than LDL-C, which is the primary atherogenic lipoprotein. Total cholesterol can be influenced by HDL-C and triglycerides, potentially leading to misclassification in some cases. Patients with very high HDL-C levels may have elevated total cholesterol without having elevated LDL-C, while patients with very high triglycerides may have elevated total cholesterol that is primarily due to triglyceride-rich lipoproteins rather than LDL-C.

Second, the criteria do not account for treatment effects. Patients who are already receiving lipid-lowering therapy may have cholesterol levels below the MEDPED thresholds even though they have FH. In such cases, the diagnosis should be based on pre-treatment cholesterol levels, family history, physical findings, or genetic testing results.

Third, the criteria may miss patients with milder forms of FH or those with polygenic hypercholesterolemia. Some patients with FH-causing mutations may have cholesterol levels that are elevated but do not meet the MEDPED thresholds, particularly if they have other factors that lower cholesterol (such as a very healthy lifestyle or certain medications).

Fourth, secondary causes of hypercholesterolemia must be excluded before making a diagnosis of FH. Conditions such as hypothyroidism, nephrotic syndrome, obstructive liver disease, and certain medications can cause severe hypercholesterolemia that may meet MEDPED criteria but is not due to FH. A thorough evaluation for secondary causes should be performed in all patients with elevated cholesterol.

Finally, the criteria are screening tools and should not be used as the sole basis for diagnosis. Clinical judgment, physical examination, detailed family history, LDL-C levels, and in some cases genetic testing should all be considered in making a definitive diagnosis of FH. The MEDPED criteria are most useful as an initial screening tool to identify patients who warrant further evaluation.

Public Health Implications

The underdiagnosis of FH represents a significant public health challenge. Despite affecting approximately 1 in 250 individuals, the vast majority of people with FH remain undiagnosed until they experience a cardiovascular event. This represents a missed opportunity for prevention, as early diagnosis and treatment can dramatically reduce cardiovascular risk.

Screening tools like the MEDPED criteria can help address this challenge by facilitating early identification of individuals with FH. However, effective screening requires awareness among healthcare providers, access to cholesterol testing, and systems to support cascade screening of family members. Public health initiatives aimed at increasing FH awareness and improving screening rates are important components of cardiovascular disease prevention efforts.

In some countries, universal cholesterol screening of children has been proposed as a strategy to identify FH early. While this approach has the potential to identify many cases, it also raises questions about cost-effectiveness, resource allocation, and the psychological impact of screening on children and families. Targeted screening of high-risk individuals, such as those with a family history of premature cardiovascular disease or hypercholesterolemia, may be a more practical approach in many settings.

Regardless of the screening strategy used, the goal remains the same: to identify individuals with FH early so that they can receive appropriate treatment to prevent premature cardiovascular events. The MEDPED criteria provide a practical tool to support this goal, but their effectiveness depends on proper implementation, interpretation, and integration with comprehensive clinical evaluation and management.