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"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

Much of the risk from hypercholesterolemia can be prevented if elevated low density lipoprotein (LDL) and other atherosclerotic forms of cholesterol are mitigated with attention to lifestyle measures and medication. However, this requires screening and diagnosis.

Given the high risk of genetic familial hypercholesterolemia for early cardiovascular disease and premature mortality, National Heart, Lung, and Blood Institute (NHLBI) recommend screening in childhood at age 9 to 11 years in the general population or as early as age 2 if there is a family history of high blood cholesterol, heart attack, or stroke that increases the likelihood of an inherited cholesterol disorder. Family history is particularly relevant if a first degree relative was diagnosed with coronary artery disease before age 55 (men) or 65 (women). But, the hasn't recommended screening asymptomatic youth due to insufficient evidence.

Then for young adulthood, the NHLBI recommends that screening start around age 20 and be repeated every 5 years. For men starting at age 45 and women at 55, screening should increase in frequency to every 1-2 years. After age 65, annual screening is recommended.

More frequent screening might also be prompted by known coronary artery disease risk factors, such as:

• Family history of hypercholesterolemia or heart attacks

• Overweight or obesity

• Physical inactivity

• Diabetes

• Unhealthy diet

• Tobacco use

Screening blood tests can be performed with fasting or nonfasting measurement of lipids. "For general risk screening, non-fasting samples seem to have at least the same prognostic value as fasting samples," the European Society of Cardiology (ESC) note. Non-fasting samples have better patient acceptability but calculated levels should be "interpreted with caution" in patients with metabolic syndrome, diabetes mellitus, or hypertriglyceridemia, the guidelines add.

Diagnostic Levels

How much cholesterol is acceptable varies. High density lipoprotein (HDL) cholesterol should ideally be above 60 mg/dL. For most people, an LDL of 100 mg/dL or greater and total cholesterol of 200 mg/dL or above is considered hypercholesterolemia. However, for people who have coronary artery disease -- including a history of heart attacks, angina, stents, or coronary bypass -- the LDL threshold is below 70 mg/dL.

Primary severe hypercholesterolemia is defined by LDL cholesterol of 190 mg/dL or greater. This threshold can also point to familial hypercholesterolemia.

While ESC guidelines are more supportive of testing apolipoprotein B and lipoprotein-a, or Lp(a), American Heart Association/American College of Cardiology (AHA/ACC) note that Lp(a) of 50 mg/dL or higher may be considered a risk-enhancing factor, but "should be considered in women only in the presence of hypercholesterolemia and with the understanding that the improvement in risk prediction in adult women in a large clinical trial was minimal."

If screening points to high cholesterol, the test should ideally be repeated within 2 weeks to confirm the diagnosis.

Of course, hypercholesterolemia is largely diagnosed in the context of atherosclerotic cardiovascular disease risk, as the AHA/ACC base lipid-lowering treatment on risk calculation, and use those therapies to target LDL percentage reduction. Risk calculation and treatment thresholds will be covered in the next installment of this Medical Journey series.

Secondary Causes of Hypercholesterolemia

Certain medical conditions can interfere with cholesterol metabolism and lead to secondary hypercholesterolemia.

For example, thyroid hormone stimulates LDL cholesterol degradation. Thus, with clinically low thyroid hormone levels can lead to up to 30% elevations in LDL cholesterol as well as increases in apolipoprotein B and Lp(a). A showed that after more than 6 months of thyroid hormone replacement therapy, LDL cholesterol declined along with reduced intima-medial thickness in patients with subclinical hypothyroidism.

Nephrotic syndrome can cause high LDL through excess urinary protein loss-induced hepatic overproduction of LDL and very low-density lipoprotein, reduced clearance of triglyceride-rich lipoproteins due to decreased enzyme activity, and impaired maturation of HDL.

Other secondary causes include:

• Primary biliary cholangitis

• Obstructive jaundice

• Diabetes

• Cushing's syndrome

• Pheochromocytoma

The physical exam can help rule these out by looking for bradycardia, dry skin, and delayed reflexes as signs of hypothyroidism; edema and ascites as signs of nephrotic syndrome; and jaundice and hepatomegaly as signs of cholestasis. Blood tests to check for secondary causes can include thyroid stimulating hormone to evaluate for hypothyroidism, fasting plasma glucose to check for diabetes, urinalysis and serum albumin to look for nephrotic syndrome, and bilirubin and alkaline phosphatase to check for cholestasis.

Medications that interfere with lipid metabolism and can increase LDL cholesterol include hormonal birth control, retinoids, corticosteroids, antivirals, anticonvulsants, and some medications for high blood pressure, such as diuretics and older forms of beta-blockers.

The differential diagnosis might also consider and , which have been linked to higher LDL cholesterol in some studies.

Read previous installments in this series:

Part 1: Hypercholesterolemia: A Complex System

Part 2: Consequences of Hypercholesterolemia

Part 3: Genetics of Hypercholesterolemia

Part 4: Case Study: High Lipoprotein(a) Levels in Younger Patients Are Not So Clear Cut

Part 5: The Shifting Epidemiology of Hypercholesterolemia

Up next: Primary Prevention in Hypercholesterolemia