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How should you evaluate elevated calcium in an asymptomatic patient?
First, establish that true hypercalcemia exists by repeating the serum calcium and measuring or calculating the physiologically active serum calcium when abnormalities in blood pH or albumin are found (SOR: C, expert opinion). Patients with unexplained asymptomatic true hypercalcemia should be screened for primary hyperparathyroidism (PHPT) and malignancy using an intact parathyroid hormone (PTH) level by immunoradioassay (SOR: C, expert opinion). Other recommended tests that can distinguish PHPT from malignancy and familial hypocalciuric hypercalcemia, as well as help manage patients with PHPT include urinary 24-hour calcium and creatinine levels, parathyroid hormone related peptide (PTHrP), alkaline phosphatase, calcitriol, and bone densitometry (SOR: C, expert opinion).
Choose tests carefully to reduce false positives
Jon O. Neher, MD
Valley Family Medicine, Renton, Wash
Including serum calcium measurements in the chemistry panels that physicians use to manage common conditions such as hypertension has resulted in an epidemic of incidental hypercalcemia. Tempting as it may be to ignore these unexpected numbers, they point to a significant underlying condition in some patients. This puts the family physician in a familiar clinical position—having to worry a patient just enough to convince him to consent to a careful, stepwise evaluation while somehow reassuring him that usually no problem is found. The best solution is to order each test for a reason, which would reduce the number of false positives that we spend so much time chasing.
Evidence summary
Make sure it’s true hypercalcemia
Measuring calcium levels in asymptomatic patients often leads to false-positive elevations caused by random error or changes in the level of physiologically active calcium because of alterations in blood pH or serum albumin. Serum calcium levels between 10.0 and 12.0 mg/dL indicate mild hypercalcemia; levels >14.0 mg/dL are severe. Because changes in pH and serum albumin levels alter levels of physiologically active calcium, authoritative sources recommend measuring or calculating physiologically active calcium if blood pH or albumin is abnormal.1,2 To determine the level, use the equation [4.0 – (plasma albumin)] × 0.8 + (serum calcium) or measure serum ionized calcium.2 Normal levels of serum ionized calcium for adults older than 19 years are 1.13 to 1.32 mmol/L, although the exact range can vary from laboratory to laboratory. Elevated physiologically active calcium indicates true hypercalcemia.
Assess for the most common causes, PHPT and malignancy
Evaluation of the patient with true hypercalcemia should include a detailed history, physical examination, and assessment of risk factors for all causes of hypercalcemia.1,2 PHPT and malignancy are the two most common causes of asymptomatic true hypercalcemia (TABLE).2
Laboratory evaluation targeting these causes, beginning with an intact PTH level, is a logical first step.1,2 Persistent hypercalcemia in the presence of elevated or inappropriately normal PTH concentrations confirms the diagnosis of PHPT.3 When serum calcium rises, PTH is normally suppressed. Normal intact PTH and low 24-hour urinary calcium excretion distinguishes patients with PHPT from those with less common familial hypocalciuric hypercalcemia.1,2
Most patients with PHPT are asymptomatic, although some eventually develop bone loss, nephrolithiasis, and renal colic.4,5 A 10-year prospective cohort study of patients with PHPT found that 21% of asymptomatic patients developed decreased bone density at one or more sites.6 None acquired kidney stones, but hypercalcemia and hypercalciuria did worsen in 10 of 52 patients. A guideline and a review on PHPT recommend measuring creatinine clearance and obtaining a bone densitometry study of the distal third of the radius, hip, and lumbar spine to assess for end-organ changes related to the condition; declining renal function and osteoporosis may be indications for surgery.3,5
Malignancy is the most common cause of low intact PTH and true hypercalcemia, especially when the calcium level is >14 mg/dL.1 A PTHrP >1.0 pmol/L is highly specific for malignancy because this level does not occur in healthy people.1 In a prospective case series of patients with hypercalcemia and malignancy, 54% had elevated PTHrP levels.7 The authors found that an elevated PTHrP in patients younger than 65 years of age doubles the risk of death from malignancy compared to patients the same age with normal PTHrP (hazard ratio=1.9; 95% CI, 1.1-3.4).
TABLE
Causes of hypercalcemia
| Primary hyperparathyroidism |
Malignancy
|
| Chronic renal failure |
| Endocrine disorders (hyperthyroidism, pheochromocytoma, Addison’s disease) |
| Familial hypocalciuric hypercalcemia |
| Immobilization |
| Laboratory artifact resulting from altered albumin concentration or pH |
| Medications (vitamin A toxicity [dietary fads, isotretinoin overdose], estrogens, antiestrogens, thiazides, lithium) |
| Milk alkali syndrome |
| Vitamin D toxicity (granulomatous disease [sarcoidosis, tuberculosis], vitamin D supplementation) |
| Based on Hutton E,1 and Carroll MF et al.2 |
Identify less common causes
Serum calcitriol in association with a low intact PTH level and elevated calcium lower than 14 mg/dL helps differentiate the less common causes of hypercalcemia. Calcitriol is high in granulomatous diseases such as sarcoidosis, tuberculosis, and histoplasmosis, and normal in hyperthyroidism and Addison’s disease.1
Immobilization as a cause of hypercalcemia can be distinguished from PHPT by history and normal PTH levels and from malignancy by a normal alkaline phosphatase level.1
Recommendations
In addition to the recommendations discussed previously, Williams Textbook of Endocrinology advises repeating the initial calcium level twice and measuring serum BUN, creatinine, electrolytes, albumin, globulin, and phosphate.8 The authors recommend a generalized work-up for malignancy, including mammography, chest radiography with or without CT, abdominal CT, serum and urine immunoelectrophoresis, and temporary discontinuation of lithium for patients taking the drug. They also recommend using PTHrP only when PTH is suppressed but an underlying malignancy can’t be found.
1. Hutton E. Evaluation and management of hypercalcemia. JAAPA. 2005;18(6):30-35.
2. Carroll MF, Schade DS. A practical approach to hypercalcemia. Am Fam Physician. 2003;67:1959-1966.
3. Belezikian JP, Potts JT, Fuleihan GE, et al. Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century. J Clin Endocrinol Metab. 2002;87:5353-5361.
4. AACE/AAES task force on primary hyperparathyroidism. The American Association of Clinical endocrinologists and the American Association of endocrine surgeons position statement on the diagnosis and management of primary hyperparathyroidism. Endocr Pract. 2005;11(1):49-54.
5. Silverberg SJ, Bilezikian JP. The diagnosis and management of asympyomatic primary hyperparathyroidism. Nat Clin Pract Endocrinol Metab. 2006;2:494-503.
6. Silverberg SJ, Shane E, Jacobs TP, et al. A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N Engl J Med. 1999;341:1249-1255.
7. Truong NU, deB Edwards MD, Papavacillicu V, et al. Parathyroid hormone related peptide and survival of patients with cancer and hypercalcemia. Am J Med. 2003;115:115-121.
8. Bringhurst FR, Dernay MB, Kronenberg HM. Approach to the hypercalcemic patient. In: Williams RH, Larsen PR. Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders;2003:1336-1339.
First, establish that true hypercalcemia exists by repeating the serum calcium and measuring or calculating the physiologically active serum calcium when abnormalities in blood pH or albumin are found (SOR: C, expert opinion). Patients with unexplained asymptomatic true hypercalcemia should be screened for primary hyperparathyroidism (PHPT) and malignancy using an intact parathyroid hormone (PTH) level by immunoradioassay (SOR: C, expert opinion). Other recommended tests that can distinguish PHPT from malignancy and familial hypocalciuric hypercalcemia, as well as help manage patients with PHPT include urinary 24-hour calcium and creatinine levels, parathyroid hormone related peptide (PTHrP), alkaline phosphatase, calcitriol, and bone densitometry (SOR: C, expert opinion).
Choose tests carefully to reduce false positives
Jon O. Neher, MD
Valley Family Medicine, Renton, Wash
Including serum calcium measurements in the chemistry panels that physicians use to manage common conditions such as hypertension has resulted in an epidemic of incidental hypercalcemia. Tempting as it may be to ignore these unexpected numbers, they point to a significant underlying condition in some patients. This puts the family physician in a familiar clinical position—having to worry a patient just enough to convince him to consent to a careful, stepwise evaluation while somehow reassuring him that usually no problem is found. The best solution is to order each test for a reason, which would reduce the number of false positives that we spend so much time chasing.
Evidence summary
Make sure it’s true hypercalcemia
Measuring calcium levels in asymptomatic patients often leads to false-positive elevations caused by random error or changes in the level of physiologically active calcium because of alterations in blood pH or serum albumin. Serum calcium levels between 10.0 and 12.0 mg/dL indicate mild hypercalcemia; levels >14.0 mg/dL are severe. Because changes in pH and serum albumin levels alter levels of physiologically active calcium, authoritative sources recommend measuring or calculating physiologically active calcium if blood pH or albumin is abnormal.1,2 To determine the level, use the equation [4.0 – (plasma albumin)] × 0.8 + (serum calcium) or measure serum ionized calcium.2 Normal levels of serum ionized calcium for adults older than 19 years are 1.13 to 1.32 mmol/L, although the exact range can vary from laboratory to laboratory. Elevated physiologically active calcium indicates true hypercalcemia.
Assess for the most common causes, PHPT and malignancy
Evaluation of the patient with true hypercalcemia should include a detailed history, physical examination, and assessment of risk factors for all causes of hypercalcemia.1,2 PHPT and malignancy are the two most common causes of asymptomatic true hypercalcemia (TABLE).2
Laboratory evaluation targeting these causes, beginning with an intact PTH level, is a logical first step.1,2 Persistent hypercalcemia in the presence of elevated or inappropriately normal PTH concentrations confirms the diagnosis of PHPT.3 When serum calcium rises, PTH is normally suppressed. Normal intact PTH and low 24-hour urinary calcium excretion distinguishes patients with PHPT from those with less common familial hypocalciuric hypercalcemia.1,2
Most patients with PHPT are asymptomatic, although some eventually develop bone loss, nephrolithiasis, and renal colic.4,5 A 10-year prospective cohort study of patients with PHPT found that 21% of asymptomatic patients developed decreased bone density at one or more sites.6 None acquired kidney stones, but hypercalcemia and hypercalciuria did worsen in 10 of 52 patients. A guideline and a review on PHPT recommend measuring creatinine clearance and obtaining a bone densitometry study of the distal third of the radius, hip, and lumbar spine to assess for end-organ changes related to the condition; declining renal function and osteoporosis may be indications for surgery.3,5
Malignancy is the most common cause of low intact PTH and true hypercalcemia, especially when the calcium level is >14 mg/dL.1 A PTHrP >1.0 pmol/L is highly specific for malignancy because this level does not occur in healthy people.1 In a prospective case series of patients with hypercalcemia and malignancy, 54% had elevated PTHrP levels.7 The authors found that an elevated PTHrP in patients younger than 65 years of age doubles the risk of death from malignancy compared to patients the same age with normal PTHrP (hazard ratio=1.9; 95% CI, 1.1-3.4).
TABLE
Causes of hypercalcemia
| Primary hyperparathyroidism |
Malignancy
|
| Chronic renal failure |
| Endocrine disorders (hyperthyroidism, pheochromocytoma, Addison’s disease) |
| Familial hypocalciuric hypercalcemia |
| Immobilization |
| Laboratory artifact resulting from altered albumin concentration or pH |
| Medications (vitamin A toxicity [dietary fads, isotretinoin overdose], estrogens, antiestrogens, thiazides, lithium) |
| Milk alkali syndrome |
| Vitamin D toxicity (granulomatous disease [sarcoidosis, tuberculosis], vitamin D supplementation) |
| Based on Hutton E,1 and Carroll MF et al.2 |
Identify less common causes
Serum calcitriol in association with a low intact PTH level and elevated calcium lower than 14 mg/dL helps differentiate the less common causes of hypercalcemia. Calcitriol is high in granulomatous diseases such as sarcoidosis, tuberculosis, and histoplasmosis, and normal in hyperthyroidism and Addison’s disease.1
Immobilization as a cause of hypercalcemia can be distinguished from PHPT by history and normal PTH levels and from malignancy by a normal alkaline phosphatase level.1
Recommendations
In addition to the recommendations discussed previously, Williams Textbook of Endocrinology advises repeating the initial calcium level twice and measuring serum BUN, creatinine, electrolytes, albumin, globulin, and phosphate.8 The authors recommend a generalized work-up for malignancy, including mammography, chest radiography with or without CT, abdominal CT, serum and urine immunoelectrophoresis, and temporary discontinuation of lithium for patients taking the drug. They also recommend using PTHrP only when PTH is suppressed but an underlying malignancy can’t be found.
First, establish that true hypercalcemia exists by repeating the serum calcium and measuring or calculating the physiologically active serum calcium when abnormalities in blood pH or albumin are found (SOR: C, expert opinion). Patients with unexplained asymptomatic true hypercalcemia should be screened for primary hyperparathyroidism (PHPT) and malignancy using an intact parathyroid hormone (PTH) level by immunoradioassay (SOR: C, expert opinion). Other recommended tests that can distinguish PHPT from malignancy and familial hypocalciuric hypercalcemia, as well as help manage patients with PHPT include urinary 24-hour calcium and creatinine levels, parathyroid hormone related peptide (PTHrP), alkaline phosphatase, calcitriol, and bone densitometry (SOR: C, expert opinion).
Choose tests carefully to reduce false positives
Jon O. Neher, MD
Valley Family Medicine, Renton, Wash
Including serum calcium measurements in the chemistry panels that physicians use to manage common conditions such as hypertension has resulted in an epidemic of incidental hypercalcemia. Tempting as it may be to ignore these unexpected numbers, they point to a significant underlying condition in some patients. This puts the family physician in a familiar clinical position—having to worry a patient just enough to convince him to consent to a careful, stepwise evaluation while somehow reassuring him that usually no problem is found. The best solution is to order each test for a reason, which would reduce the number of false positives that we spend so much time chasing.
Evidence summary
Make sure it’s true hypercalcemia
Measuring calcium levels in asymptomatic patients often leads to false-positive elevations caused by random error or changes in the level of physiologically active calcium because of alterations in blood pH or serum albumin. Serum calcium levels between 10.0 and 12.0 mg/dL indicate mild hypercalcemia; levels >14.0 mg/dL are severe. Because changes in pH and serum albumin levels alter levels of physiologically active calcium, authoritative sources recommend measuring or calculating physiologically active calcium if blood pH or albumin is abnormal.1,2 To determine the level, use the equation [4.0 – (plasma albumin)] × 0.8 + (serum calcium) or measure serum ionized calcium.2 Normal levels of serum ionized calcium for adults older than 19 years are 1.13 to 1.32 mmol/L, although the exact range can vary from laboratory to laboratory. Elevated physiologically active calcium indicates true hypercalcemia.
Assess for the most common causes, PHPT and malignancy
Evaluation of the patient with true hypercalcemia should include a detailed history, physical examination, and assessment of risk factors for all causes of hypercalcemia.1,2 PHPT and malignancy are the two most common causes of asymptomatic true hypercalcemia (TABLE).2
Laboratory evaluation targeting these causes, beginning with an intact PTH level, is a logical first step.1,2 Persistent hypercalcemia in the presence of elevated or inappropriately normal PTH concentrations confirms the diagnosis of PHPT.3 When serum calcium rises, PTH is normally suppressed. Normal intact PTH and low 24-hour urinary calcium excretion distinguishes patients with PHPT from those with less common familial hypocalciuric hypercalcemia.1,2
Most patients with PHPT are asymptomatic, although some eventually develop bone loss, nephrolithiasis, and renal colic.4,5 A 10-year prospective cohort study of patients with PHPT found that 21% of asymptomatic patients developed decreased bone density at one or more sites.6 None acquired kidney stones, but hypercalcemia and hypercalciuria did worsen in 10 of 52 patients. A guideline and a review on PHPT recommend measuring creatinine clearance and obtaining a bone densitometry study of the distal third of the radius, hip, and lumbar spine to assess for end-organ changes related to the condition; declining renal function and osteoporosis may be indications for surgery.3,5
Malignancy is the most common cause of low intact PTH and true hypercalcemia, especially when the calcium level is >14 mg/dL.1 A PTHrP >1.0 pmol/L is highly specific for malignancy because this level does not occur in healthy people.1 In a prospective case series of patients with hypercalcemia and malignancy, 54% had elevated PTHrP levels.7 The authors found that an elevated PTHrP in patients younger than 65 years of age doubles the risk of death from malignancy compared to patients the same age with normal PTHrP (hazard ratio=1.9; 95% CI, 1.1-3.4).
TABLE
Causes of hypercalcemia
| Primary hyperparathyroidism |
Malignancy
|
| Chronic renal failure |
| Endocrine disorders (hyperthyroidism, pheochromocytoma, Addison’s disease) |
| Familial hypocalciuric hypercalcemia |
| Immobilization |
| Laboratory artifact resulting from altered albumin concentration or pH |
| Medications (vitamin A toxicity [dietary fads, isotretinoin overdose], estrogens, antiestrogens, thiazides, lithium) |
| Milk alkali syndrome |
| Vitamin D toxicity (granulomatous disease [sarcoidosis, tuberculosis], vitamin D supplementation) |
| Based on Hutton E,1 and Carroll MF et al.2 |
Identify less common causes
Serum calcitriol in association with a low intact PTH level and elevated calcium lower than 14 mg/dL helps differentiate the less common causes of hypercalcemia. Calcitriol is high in granulomatous diseases such as sarcoidosis, tuberculosis, and histoplasmosis, and normal in hyperthyroidism and Addison’s disease.1
Immobilization as a cause of hypercalcemia can be distinguished from PHPT by history and normal PTH levels and from malignancy by a normal alkaline phosphatase level.1
Recommendations
In addition to the recommendations discussed previously, Williams Textbook of Endocrinology advises repeating the initial calcium level twice and measuring serum BUN, creatinine, electrolytes, albumin, globulin, and phosphate.8 The authors recommend a generalized work-up for malignancy, including mammography, chest radiography with or without CT, abdominal CT, serum and urine immunoelectrophoresis, and temporary discontinuation of lithium for patients taking the drug. They also recommend using PTHrP only when PTH is suppressed but an underlying malignancy can’t be found.
1. Hutton E. Evaluation and management of hypercalcemia. JAAPA. 2005;18(6):30-35.
2. Carroll MF, Schade DS. A practical approach to hypercalcemia. Am Fam Physician. 2003;67:1959-1966.
3. Belezikian JP, Potts JT, Fuleihan GE, et al. Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century. J Clin Endocrinol Metab. 2002;87:5353-5361.
4. AACE/AAES task force on primary hyperparathyroidism. The American Association of Clinical endocrinologists and the American Association of endocrine surgeons position statement on the diagnosis and management of primary hyperparathyroidism. Endocr Pract. 2005;11(1):49-54.
5. Silverberg SJ, Bilezikian JP. The diagnosis and management of asympyomatic primary hyperparathyroidism. Nat Clin Pract Endocrinol Metab. 2006;2:494-503.
6. Silverberg SJ, Shane E, Jacobs TP, et al. A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N Engl J Med. 1999;341:1249-1255.
7. Truong NU, deB Edwards MD, Papavacillicu V, et al. Parathyroid hormone related peptide and survival of patients with cancer and hypercalcemia. Am J Med. 2003;115:115-121.
8. Bringhurst FR, Dernay MB, Kronenberg HM. Approach to the hypercalcemic patient. In: Williams RH, Larsen PR. Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders;2003:1336-1339.
1. Hutton E. Evaluation and management of hypercalcemia. JAAPA. 2005;18(6):30-35.
2. Carroll MF, Schade DS. A practical approach to hypercalcemia. Am Fam Physician. 2003;67:1959-1966.
3. Belezikian JP, Potts JT, Fuleihan GE, et al. Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century. J Clin Endocrinol Metab. 2002;87:5353-5361.
4. AACE/AAES task force on primary hyperparathyroidism. The American Association of Clinical endocrinologists and the American Association of endocrine surgeons position statement on the diagnosis and management of primary hyperparathyroidism. Endocr Pract. 2005;11(1):49-54.
5. Silverberg SJ, Bilezikian JP. The diagnosis and management of asympyomatic primary hyperparathyroidism. Nat Clin Pract Endocrinol Metab. 2006;2:494-503.
6. Silverberg SJ, Shane E, Jacobs TP, et al. A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N Engl J Med. 1999;341:1249-1255.
7. Truong NU, deB Edwards MD, Papavacillicu V, et al. Parathyroid hormone related peptide and survival of patients with cancer and hypercalcemia. Am J Med. 2003;115:115-121.
8. Bringhurst FR, Dernay MB, Kronenberg HM. Approach to the hypercalcemic patient. In: Williams RH, Larsen PR. Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders;2003:1336-1339.
Evidence-based answers from the Family Physicians Inquiries Network
When should we screen children for hyperlipidemia?
Children should be screened for hyperlipidemia when there is a history of familial hypercholesterolemia (strength of recommendation [SOR]: C).
No clear evidence supports screening all children or just those with family history of cardiovascular disease (CVD) or hyperlipidemia (SOR: C).
With no clear medical treatment for childhood dyslipidemia, screening provides little help
Walter Foliaco, MD
Chesterfield Family Practice, Midlothian, Va
There is no clear evidence to support screening children with or without familial hypercholesterolemia for hypercholesterolemia. In an era where judicious use of medical dollars is a must, screening for hypercholesterolemia would also be cost-prohibitive. Other than stressing exercise and nutrition, there is no clear medical treatment that is FDA-approved for dyslipidemia among children, so screening would provide very little help in the management of this population.
Patients with a strong family history of lipid disorders or familial hypercholesterolemia should have more directed education on cholesterol and their need to treat in early adulthood; however, at this time there is very little evidence to support screening in this population. Aggressive promotion of age-appropriate exercise and a healthy lifestyle should be the thrust of our intervention until more evidence-based information shows that screening and treatment improves morbidity and mortality.
This Clinical Inquiry emphasizes the need to do more research in pediatric hypercholesterolemia, to better counsel our patients not only in screening but ultimately in earlier medical intervention.
Evidence summary
Screening for hyperlipidemia using total cholesterol and low-density lipoprotein (LDL) cholesterol is recommended for adults after the age of 35 years for men and 45 years for women.1 Younger adults (men aged 20–35 and women aged 20–45) should be screened for lipid disorders if they have other risk factors for CVD.1
Children with heterozygous familial hypercholesterolemia, an autosomal dominant disorder with a prevalence of 1 in 500, are at increased risk of cardiovascular morbidity and mortality in adulthood. One quarter of males with familial hyper-cholesterolemia suffer fatal coronary heart disease (CHD) by age 50 years.2
The use of statins by children with familial hypercholesterolemia for up to 2 years is safe and lowers LDL cholesterol.3 Longer use by children has not been studied, so no comment can be made about long-term safety and decreased CHD morbidity and mortality.
One systematic review and cost-effectiveness analysis investigated the appropriateness and cost-effectiveness of screening methods for familial hypercholesterolemia beginning at the age of 16 years.4 The authors identified potential screening strategies from 6 cross-sectional studies and applied these to a decision analysis. Screening of first-degree relatives of those with familial hypercholesterolemia was most effective in detecting cases of familial hypercholesterolemia (number needed to screen [NNS]=3; cost per case detected=$232; cost per life-year gained=$5397).
Universal screening of all 16-year-olds was also cost-effective (cost per life-year gained=$4839), but resulted in a much larger NNS and cost of detection (NNS=1365, cost per case detected=$16,999). The authors concluded that case finding through screening of first-degree relatives was the most cost-effective strategy overall.
In contrast to children affected with familial hypercholesterolemia, the relationship of blood cholesterol levels in children without familial hypercholesterolemia to CHD later in life has not been established. A paucity of data exists that links lowering of cholesterol in childhood with reduced CHD morbidity and mortality in adulthood. Therefore, the benefits of detecting and treating childhood hyperlipidemia without familial hypercholesterolemia are not known. Despite the lack of patient-oriented outcomes research in this area, 2 guidelines recommend screening all children for hyperlipidemia.5,9
Three studies investigated the use of various recommended screening indicators in identifying children with hyperlipidemia. The first was a control cohort from a case-control study that applied the National Cholesterol Education Program (NCEP) guidelines for screening in children5 to 501 US males less than 20 years old, and examined the effectiveness of using the recommended 2 major screening indicators (family history of premature cardiovascular disease and parent cholesterol >240 mg/dL) plus 5 discretionary indicators (high-fat/high-cholesterol diet, hypertension, obesity, smoker, steroid/medication).6 If all major and discretionary indicators were applied to the cohort, 96% of the children with LDL greater than 130 mg/dL were identified. However, the individual positive predictive values (PPV; probability of having LDL >130 when a child had a screening indicator) ranged from 6.8% to 20.6%.
The 2 other studies used a cross-sectional design to evaluate family history of premature cardiovascular disease and hyperlipidemia screening indicators in 4183 grade-school children in Taiwan7 and 2217 youths in Quebec.8 Family history performed poorly as a mechanism for identifying children with hypercholesterolemia (total cholesterol >200 mg/dL; LDL >130 mg/dL) (PPV <12.5%7, PPV=7.7%8). More than 75% of the children in the Taiwan study would have been missed using family history as a screen. Both studies concluded that family history as a screening indicator is insensitive and inaccurate, and no more useful than general population screening.
Recommendations from others
Neither the American Academy of Family Physicians or the US Preventive Services Task Force makes a recommendation about screening for hyperlipidemia in this age group.
The American Academy of Pediatrics recommends screening children aged 2 years or older whose parents or grandparents had coronary atherosclerosis at age 55 or younger (defined by diagnostic coronary arteriography, myocardial infarction, angina pectoris, peripheral vascular disease, cerebrovascular disease, or sudden cardiac death). They also advocate screening children of a parent with an elevated blood cholesterol level (total cholesterolra 240 mg/dL or higher) and those whose parental history is unobtainable.9
1. US Preventive Services Task Force. Screening for lipid disorders in adults. Release date: 2001. Available at: www.ahrq.gov/clinic/uspstf/uspschol.htm. Accessed on July 6, 2006.
2. Stein E. Statins in children. Why and when. Nutr Metab Cardiovasc Dis 2001;11(Suppl 5):24-29.
3. Rodenburg J, Vissers MN, Trip MD, Wiegman A, Bakker HD, Kastelein JJ. The spectrum of statin therapy in hyperlipidemic children. Semin Vasc Med 2004;4:313-320.
4. Marks D, Wonderling D, Thorogood M, Lambert H, Humphries SE, Neil HA. Screening for hypercholesterolaemia versus case finding for familial hypercholesterolaemia: a systematic review and cost-effectiveness analysis. Health Technol Assess 2000;4:1-123.
5. National Cholesterol Education Program. Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents (National Institutes of Health Pub. No. 91-2732.) Bethesda, Md: US Dept of Health and Human Services, Public Health Service, National Institutes of Health, September 1991:1-119.
6. Diller PM, Huster GA, Leach AD, Laskarzewski PM, Sprecher DL. Definition and application of the discretionary screening indicators according to the National Cholesterol Education Program for Children and Adolescents. J Pediatr 1995;126:345-352.
7. Liu CS, Lin CC, Shih HC, Li TC. The advisability of implementing cholesterol screening in school-age children and adolescents with a family history of cardiovascular disease and hyperlipidemia. Fam Pract 1999;16:501-505.
8. O’Loughlin J, Lauzon B, Paradis G, et al. Usefulness of the American Academy of Pediatrics recommendations for identifying youths with hypercholesterolemia. Pediatrics 2004;113:1723-1727.
9. American Academy of Pediatrics, Committee on Nutrition. Cholesterol in Childhood Pediatrics 1998;101:141-147.
Children should be screened for hyperlipidemia when there is a history of familial hypercholesterolemia (strength of recommendation [SOR]: C).
No clear evidence supports screening all children or just those with family history of cardiovascular disease (CVD) or hyperlipidemia (SOR: C).
With no clear medical treatment for childhood dyslipidemia, screening provides little help
Walter Foliaco, MD
Chesterfield Family Practice, Midlothian, Va
There is no clear evidence to support screening children with or without familial hypercholesterolemia for hypercholesterolemia. In an era where judicious use of medical dollars is a must, screening for hypercholesterolemia would also be cost-prohibitive. Other than stressing exercise and nutrition, there is no clear medical treatment that is FDA-approved for dyslipidemia among children, so screening would provide very little help in the management of this population.
Patients with a strong family history of lipid disorders or familial hypercholesterolemia should have more directed education on cholesterol and their need to treat in early adulthood; however, at this time there is very little evidence to support screening in this population. Aggressive promotion of age-appropriate exercise and a healthy lifestyle should be the thrust of our intervention until more evidence-based information shows that screening and treatment improves morbidity and mortality.
This Clinical Inquiry emphasizes the need to do more research in pediatric hypercholesterolemia, to better counsel our patients not only in screening but ultimately in earlier medical intervention.
Evidence summary
Screening for hyperlipidemia using total cholesterol and low-density lipoprotein (LDL) cholesterol is recommended for adults after the age of 35 years for men and 45 years for women.1 Younger adults (men aged 20–35 and women aged 20–45) should be screened for lipid disorders if they have other risk factors for CVD.1
Children with heterozygous familial hypercholesterolemia, an autosomal dominant disorder with a prevalence of 1 in 500, are at increased risk of cardiovascular morbidity and mortality in adulthood. One quarter of males with familial hyper-cholesterolemia suffer fatal coronary heart disease (CHD) by age 50 years.2
The use of statins by children with familial hypercholesterolemia for up to 2 years is safe and lowers LDL cholesterol.3 Longer use by children has not been studied, so no comment can be made about long-term safety and decreased CHD morbidity and mortality.
One systematic review and cost-effectiveness analysis investigated the appropriateness and cost-effectiveness of screening methods for familial hypercholesterolemia beginning at the age of 16 years.4 The authors identified potential screening strategies from 6 cross-sectional studies and applied these to a decision analysis. Screening of first-degree relatives of those with familial hypercholesterolemia was most effective in detecting cases of familial hypercholesterolemia (number needed to screen [NNS]=3; cost per case detected=$232; cost per life-year gained=$5397).
Universal screening of all 16-year-olds was also cost-effective (cost per life-year gained=$4839), but resulted in a much larger NNS and cost of detection (NNS=1365, cost per case detected=$16,999). The authors concluded that case finding through screening of first-degree relatives was the most cost-effective strategy overall.
In contrast to children affected with familial hypercholesterolemia, the relationship of blood cholesterol levels in children without familial hypercholesterolemia to CHD later in life has not been established. A paucity of data exists that links lowering of cholesterol in childhood with reduced CHD morbidity and mortality in adulthood. Therefore, the benefits of detecting and treating childhood hyperlipidemia without familial hypercholesterolemia are not known. Despite the lack of patient-oriented outcomes research in this area, 2 guidelines recommend screening all children for hyperlipidemia.5,9
Three studies investigated the use of various recommended screening indicators in identifying children with hyperlipidemia. The first was a control cohort from a case-control study that applied the National Cholesterol Education Program (NCEP) guidelines for screening in children5 to 501 US males less than 20 years old, and examined the effectiveness of using the recommended 2 major screening indicators (family history of premature cardiovascular disease and parent cholesterol >240 mg/dL) plus 5 discretionary indicators (high-fat/high-cholesterol diet, hypertension, obesity, smoker, steroid/medication).6 If all major and discretionary indicators were applied to the cohort, 96% of the children with LDL greater than 130 mg/dL were identified. However, the individual positive predictive values (PPV; probability of having LDL >130 when a child had a screening indicator) ranged from 6.8% to 20.6%.
The 2 other studies used a cross-sectional design to evaluate family history of premature cardiovascular disease and hyperlipidemia screening indicators in 4183 grade-school children in Taiwan7 and 2217 youths in Quebec.8 Family history performed poorly as a mechanism for identifying children with hypercholesterolemia (total cholesterol >200 mg/dL; LDL >130 mg/dL) (PPV <12.5%7, PPV=7.7%8). More than 75% of the children in the Taiwan study would have been missed using family history as a screen. Both studies concluded that family history as a screening indicator is insensitive and inaccurate, and no more useful than general population screening.
Recommendations from others
Neither the American Academy of Family Physicians or the US Preventive Services Task Force makes a recommendation about screening for hyperlipidemia in this age group.
The American Academy of Pediatrics recommends screening children aged 2 years or older whose parents or grandparents had coronary atherosclerosis at age 55 or younger (defined by diagnostic coronary arteriography, myocardial infarction, angina pectoris, peripheral vascular disease, cerebrovascular disease, or sudden cardiac death). They also advocate screening children of a parent with an elevated blood cholesterol level (total cholesterolra 240 mg/dL or higher) and those whose parental history is unobtainable.9
Children should be screened for hyperlipidemia when there is a history of familial hypercholesterolemia (strength of recommendation [SOR]: C).
No clear evidence supports screening all children or just those with family history of cardiovascular disease (CVD) or hyperlipidemia (SOR: C).
With no clear medical treatment for childhood dyslipidemia, screening provides little help
Walter Foliaco, MD
Chesterfield Family Practice, Midlothian, Va
There is no clear evidence to support screening children with or without familial hypercholesterolemia for hypercholesterolemia. In an era where judicious use of medical dollars is a must, screening for hypercholesterolemia would also be cost-prohibitive. Other than stressing exercise and nutrition, there is no clear medical treatment that is FDA-approved for dyslipidemia among children, so screening would provide very little help in the management of this population.
Patients with a strong family history of lipid disorders or familial hypercholesterolemia should have more directed education on cholesterol and their need to treat in early adulthood; however, at this time there is very little evidence to support screening in this population. Aggressive promotion of age-appropriate exercise and a healthy lifestyle should be the thrust of our intervention until more evidence-based information shows that screening and treatment improves morbidity and mortality.
This Clinical Inquiry emphasizes the need to do more research in pediatric hypercholesterolemia, to better counsel our patients not only in screening but ultimately in earlier medical intervention.
Evidence summary
Screening for hyperlipidemia using total cholesterol and low-density lipoprotein (LDL) cholesterol is recommended for adults after the age of 35 years for men and 45 years for women.1 Younger adults (men aged 20–35 and women aged 20–45) should be screened for lipid disorders if they have other risk factors for CVD.1
Children with heterozygous familial hypercholesterolemia, an autosomal dominant disorder with a prevalence of 1 in 500, are at increased risk of cardiovascular morbidity and mortality in adulthood. One quarter of males with familial hyper-cholesterolemia suffer fatal coronary heart disease (CHD) by age 50 years.2
The use of statins by children with familial hypercholesterolemia for up to 2 years is safe and lowers LDL cholesterol.3 Longer use by children has not been studied, so no comment can be made about long-term safety and decreased CHD morbidity and mortality.
One systematic review and cost-effectiveness analysis investigated the appropriateness and cost-effectiveness of screening methods for familial hypercholesterolemia beginning at the age of 16 years.4 The authors identified potential screening strategies from 6 cross-sectional studies and applied these to a decision analysis. Screening of first-degree relatives of those with familial hypercholesterolemia was most effective in detecting cases of familial hypercholesterolemia (number needed to screen [NNS]=3; cost per case detected=$232; cost per life-year gained=$5397).
Universal screening of all 16-year-olds was also cost-effective (cost per life-year gained=$4839), but resulted in a much larger NNS and cost of detection (NNS=1365, cost per case detected=$16,999). The authors concluded that case finding through screening of first-degree relatives was the most cost-effective strategy overall.
In contrast to children affected with familial hypercholesterolemia, the relationship of blood cholesterol levels in children without familial hypercholesterolemia to CHD later in life has not been established. A paucity of data exists that links lowering of cholesterol in childhood with reduced CHD morbidity and mortality in adulthood. Therefore, the benefits of detecting and treating childhood hyperlipidemia without familial hypercholesterolemia are not known. Despite the lack of patient-oriented outcomes research in this area, 2 guidelines recommend screening all children for hyperlipidemia.5,9
Three studies investigated the use of various recommended screening indicators in identifying children with hyperlipidemia. The first was a control cohort from a case-control study that applied the National Cholesterol Education Program (NCEP) guidelines for screening in children5 to 501 US males less than 20 years old, and examined the effectiveness of using the recommended 2 major screening indicators (family history of premature cardiovascular disease and parent cholesterol >240 mg/dL) plus 5 discretionary indicators (high-fat/high-cholesterol diet, hypertension, obesity, smoker, steroid/medication).6 If all major and discretionary indicators were applied to the cohort, 96% of the children with LDL greater than 130 mg/dL were identified. However, the individual positive predictive values (PPV; probability of having LDL >130 when a child had a screening indicator) ranged from 6.8% to 20.6%.
The 2 other studies used a cross-sectional design to evaluate family history of premature cardiovascular disease and hyperlipidemia screening indicators in 4183 grade-school children in Taiwan7 and 2217 youths in Quebec.8 Family history performed poorly as a mechanism for identifying children with hypercholesterolemia (total cholesterol >200 mg/dL; LDL >130 mg/dL) (PPV <12.5%7, PPV=7.7%8). More than 75% of the children in the Taiwan study would have been missed using family history as a screen. Both studies concluded that family history as a screening indicator is insensitive and inaccurate, and no more useful than general population screening.
Recommendations from others
Neither the American Academy of Family Physicians or the US Preventive Services Task Force makes a recommendation about screening for hyperlipidemia in this age group.
The American Academy of Pediatrics recommends screening children aged 2 years or older whose parents or grandparents had coronary atherosclerosis at age 55 or younger (defined by diagnostic coronary arteriography, myocardial infarction, angina pectoris, peripheral vascular disease, cerebrovascular disease, or sudden cardiac death). They also advocate screening children of a parent with an elevated blood cholesterol level (total cholesterolra 240 mg/dL or higher) and those whose parental history is unobtainable.9
1. US Preventive Services Task Force. Screening for lipid disorders in adults. Release date: 2001. Available at: www.ahrq.gov/clinic/uspstf/uspschol.htm. Accessed on July 6, 2006.
2. Stein E. Statins in children. Why and when. Nutr Metab Cardiovasc Dis 2001;11(Suppl 5):24-29.
3. Rodenburg J, Vissers MN, Trip MD, Wiegman A, Bakker HD, Kastelein JJ. The spectrum of statin therapy in hyperlipidemic children. Semin Vasc Med 2004;4:313-320.
4. Marks D, Wonderling D, Thorogood M, Lambert H, Humphries SE, Neil HA. Screening for hypercholesterolaemia versus case finding for familial hypercholesterolaemia: a systematic review and cost-effectiveness analysis. Health Technol Assess 2000;4:1-123.
5. National Cholesterol Education Program. Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents (National Institutes of Health Pub. No. 91-2732.) Bethesda, Md: US Dept of Health and Human Services, Public Health Service, National Institutes of Health, September 1991:1-119.
6. Diller PM, Huster GA, Leach AD, Laskarzewski PM, Sprecher DL. Definition and application of the discretionary screening indicators according to the National Cholesterol Education Program for Children and Adolescents. J Pediatr 1995;126:345-352.
7. Liu CS, Lin CC, Shih HC, Li TC. The advisability of implementing cholesterol screening in school-age children and adolescents with a family history of cardiovascular disease and hyperlipidemia. Fam Pract 1999;16:501-505.
8. O’Loughlin J, Lauzon B, Paradis G, et al. Usefulness of the American Academy of Pediatrics recommendations for identifying youths with hypercholesterolemia. Pediatrics 2004;113:1723-1727.
9. American Academy of Pediatrics, Committee on Nutrition. Cholesterol in Childhood Pediatrics 1998;101:141-147.
1. US Preventive Services Task Force. Screening for lipid disorders in adults. Release date: 2001. Available at: www.ahrq.gov/clinic/uspstf/uspschol.htm. Accessed on July 6, 2006.
2. Stein E. Statins in children. Why and when. Nutr Metab Cardiovasc Dis 2001;11(Suppl 5):24-29.
3. Rodenburg J, Vissers MN, Trip MD, Wiegman A, Bakker HD, Kastelein JJ. The spectrum of statin therapy in hyperlipidemic children. Semin Vasc Med 2004;4:313-320.
4. Marks D, Wonderling D, Thorogood M, Lambert H, Humphries SE, Neil HA. Screening for hypercholesterolaemia versus case finding for familial hypercholesterolaemia: a systematic review and cost-effectiveness analysis. Health Technol Assess 2000;4:1-123.
5. National Cholesterol Education Program. Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents (National Institutes of Health Pub. No. 91-2732.) Bethesda, Md: US Dept of Health and Human Services, Public Health Service, National Institutes of Health, September 1991:1-119.
6. Diller PM, Huster GA, Leach AD, Laskarzewski PM, Sprecher DL. Definition and application of the discretionary screening indicators according to the National Cholesterol Education Program for Children and Adolescents. J Pediatr 1995;126:345-352.
7. Liu CS, Lin CC, Shih HC, Li TC. The advisability of implementing cholesterol screening in school-age children and adolescents with a family history of cardiovascular disease and hyperlipidemia. Fam Pract 1999;16:501-505.
8. O’Loughlin J, Lauzon B, Paradis G, et al. Usefulness of the American Academy of Pediatrics recommendations for identifying youths with hypercholesterolemia. Pediatrics 2004;113:1723-1727.
9. American Academy of Pediatrics, Committee on Nutrition. Cholesterol in Childhood Pediatrics 1998;101:141-147.
Evidence-based answers from the Family Physicians Inquiries Network