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Secondary Causes of Dyslipidemia

      The causes of the lipid disorders in patients referred to specialty clinics for difficult-to-treat dyslipidemias are likely multifactorial. However, the importance of evaluating for secondary causes is unclear. The investigators performed a chart review of new patients referred to the University of Michigan Lipid Clinic from January 2004 to June 2011 (n = 824) to evaluate for the prevalence of several secondary causes of dyslipidemia. In addition to lipoproteins, new patients were assessed for secondary dyslipidemias by a standardized protocol consisting of laboratory testing, a nutritional evaluation, and medical history. These data were evaluated to determine the prevalence of several secondary causes of dyslipidemia. A total of 363 separate factors were identified in the 824 patients that were thought to be potential secondary causes of dyslipidemia. Because some patients (n = 83 [10%]) had multiple conditions, there were 230 (28% of the cohort) with ≥1 potential secondary dyslipidemias. The most common conditions were excessive alcohol intake (n = 82 [10%]), uncontrolled diabetes mellitus (n = 68 [8%]), and overt albuminuria. Although other causes occurred less frequently (each individually found in <5% of patients), altogether they were present in a substantial portion of patients (n = 102 [12%]). In conclusion, nearly 1/3 of patients referred to a specialty clinic had identifiable secondary conditions plausibly contributing to their dyslipidemia. Numerous disorders were identified, with diabetes mellitus and excessive alcohol being the most common.
      Current guidelines for hyperlipidemia state that clinicians should evaluate for underlying conditions that could be causing or exacerbating dyslipidemias before initiating or intensifying treatment in their patients.
      Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
      Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).
      • Catapano A.L.
      • Reiner Z.
      • De Backer G.
      • Graham I.
      • Taskinen M.R.
      • Wiklund O.
      • Agewall S.
      • Alegria E.
      • Chapman M.J.
      • Durrington P.
      • Erdine S.
      • Halcox J.
      • Hobbs R.
      • Kjekshus J.
      • Perrone Filardi P.
      • Riccardi G.
      • Storey R.F.
      • Wood D.
      ESC Committee for Practice Guidelines 2008-2010 and 2010-2012 Committees
      ESC/EAS guidelines for the management of dyslipidemias The Task Force for the Management of Dyslipidemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS).
      • Genest J.
      • McPherson R.
      • Frohlich J.
      • Anderson T.
      • Campbell N.
      • Carpentier A.
      • Couture P.
      • Dufour R.
      • Fodor G.
      • Francis G.A.
      • Grover S.
      • Gupta M.
      • Hegele R.A.
      • Lau D.C.
      • Leiter L.
      • Lewis G.F.
      • Lonn E.
      • Mancini G.B.
      • Ng D.
      • Pearson G.J.
      • Sniderman A.
      • Stone J.A.
      • Ur E.
      2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult—2009 recommendations.
      These conditions are referred to as “secondary causes” of dyslipidemia and are important to identify for several reasons.
      • Elisaf M.
      • Tsimihodimos V.
      Editorial: secondary dyslipidemias.
      Some associated diseases are important health issues to recognize per se (e.g., chronic kidney disease, diabetes mellitus [DM]), and the dyslipidemia may be 1 of the first clues to the diagnosis. Treatment of the underlying condition may also improve the dyslipidemia, potentially reducing the need for therapy. Recognizing the co-morbidity may alter subsequent treatment decisions (e.g., identifying potential drug interactions, diagnosing hypothyroidism, which may increase the risk for statin-related myopathy). Finally, some dyslipidemias can appear to be refractory to drug treatment in the presence of an ongoing unrecognized secondary cause. For example, untreated DM or excessive alcohol intake can render medical therapy of hypertriglyceridemia much less effective. Although numerous factors have been linked to adverse lipoprotein changes,
      • Elisaf M.
      • Tsimihodimos V.
      Editorial: secondary dyslipidemias.
      their prevalence and clinical importance remain poorly described. Hence, we evaluated the characteristics of secondary causes of dyslipidemia in patients referred to our lipid clinic.

      Methods

      This study was approved by the University of Michigan institutional review board. We performed a retrospective chart review of the electronic medical records of all patients referred to the tertiary care lipid management clinic at the University of Michigan from January 2004 to June 2011. As part of the initial visit, patients were seen by a dietician for nutrition assessment. In addition, laboratory testing was performed to assess lipoproteins, cardiovascular risk factors and a standard screening protocol for secondary dyslipidemias. Afterward, the patients were evaluated by 1 of 2 physicians specializing in the treatment of complex lipid disorders.
      Patient information from the dietician, physician history, and initial visit laboratory was entered into a database (Table 1). The results were checked by 1 of the physicians for accuracy. The presence of a specific set of secondary causes of dyslipidemia was evaluated for in each patient from a list of factors that were uniformly measured on all patients during laboratory testing or assessed on first dietician and physician visits (disorders listed in Table 2). Next, we determined if the disorder was an “active condition,” defined as being present by self-report or associated with pertinent laboratory abnormalities at the first visit as defined in Table 2. Thereafter, it was assessed if the active condition was contributing to the related dyslipidemia (i.e., a “true secondary dyslipidemia”). This scenario was met when the active condition was associated with lipid abnormalities, either an elevation in triglycerides >150 mg/dl or low-density lipoprotein cholesterol >130 mg/dl alone or together, in a manner known to be induced by the specific disorder.
      Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
      Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).
      • Catapano A.L.
      • Reiner Z.
      • De Backer G.
      • Graham I.
      • Taskinen M.R.
      • Wiklund O.
      • Agewall S.
      • Alegria E.
      • Chapman M.J.
      • Durrington P.
      • Erdine S.
      • Halcox J.
      • Hobbs R.
      • Kjekshus J.
      • Perrone Filardi P.
      • Riccardi G.
      • Storey R.F.
      • Wood D.
      ESC Committee for Practice Guidelines 2008-2010 and 2010-2012 Committees
      ESC/EAS guidelines for the management of dyslipidemias The Task Force for the Management of Dyslipidemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS).
      • Genest J.
      • McPherson R.
      • Frohlich J.
      • Anderson T.
      • Campbell N.
      • Carpentier A.
      • Couture P.
      • Dufour R.
      • Fodor G.
      • Francis G.A.
      • Grover S.
      • Gupta M.
      • Hegele R.A.
      • Lau D.C.
      • Leiter L.
      • Lewis G.F.
      • Lonn E.
      • Mancini G.B.
      • Ng D.
      • Pearson G.J.
      • Sniderman A.
      • Stone J.A.
      • Ur E.
      2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult—2009 recommendations.
      Table 1Patient characteristics
      VariableTotal Patients
      (n = 824)
      Age (years)52 ± 14
      Men460 (56%)
      Race/ethnicity
       Asian36 (4%)
       African American45 (5%)
       Caucasian692 (84%)
       Hispanic11 (1%)
       Native American1 (<1%)
       Multiple race2 (<1%)
       Unknown or not reported32 (4%)
      Systolic blood pressure (mm Hg)117 ± 16
      Diastolic blood pressure (mm Hg)69 ± 10
      Body mass index (kg/m2)29.64 ± 6.26
      Current smokers (any cigarettes in past month)97 (12%)
      Previous smokers (no cigarettes in past month)282 (34%)
      Family history of early coronary heart disease297 (36%)
      Personal history of coronary heart disease220 (27%)
      Triglycerides (mg/dl)304 ± 462
      Total cholesterol (mg/dl)242 ± 82
      High-density lipoprotein-cholesterol (mg/dl)44 ± 19
      Low-density lipoprotein-cholesterol (mg/dl)144 ± 67
      Total cholesterol/high-density lipoprotein cholesterol (mg/dl)6.3 ± 4
      Non-high-density lipoprotein cholesterol (mg/dl)197 ± 80
      Lipoprotein(a) (mg/dl)37 ± 43
      Apolipoprotein A (mg/dl)140 ± 35
      Apolipoprotein B (mg/dl)118 ± 38
      Medications
       Statins32%
       Ezetimibe14%
       Niacin12%
       Bile acid resin4%
       Fibrates17%
       Fish oil34%
      Data are expressed as mean ± SD or as number (percentage).
      Table 2Secondary causes of dyslipidemia
      DisordersHistory of Condition
      See “Methods” for definition. The number reported represents the number of secondary dyslipidemia conditions found, which is identical to the number of patients with the condition. The percentage reported represents the rounded nearest percentage of patients with the secondary dyslipidemia condition.
      Active Condition at First Visit
      See “Methods” for definition. The number reported represents the number of secondary dyslipidemia conditions found, which is identical to the number of patients with the condition. The percentage reported represents the rounded nearest percentage of patients with the secondary dyslipidemia condition.
      ,
      A condition was deemed active when occurring with abnormal laboratory values, defined as alkaline phosphatase >130 IU/L, glycosylated hemoglobin >7.0%, and thyroid-stimulating hormone >5.6 mIU/L. Excessive alcohol intake was defined as >2 standard drinks on most days of the week, as assessed by a dietician and a food frequency questionnaire.
      True Secondary Dyslipidemia
      See “Methods” for definition. The number reported represents the number of secondary dyslipidemia conditions found, which is identical to the number of patients with the condition. The percentage reported represents the rounded nearest percentage of patients with the secondary dyslipidemia condition.
      DM170 (21%)85 (10%)68 (8%)
      Hypothyroidism111 (13%)20 (2%)8 (<1%)
      Liver disease58 (7%)2 (<1%)0 (0%)
       High alkaline phosphatase25 (3%)13 (<1%)1 (<1%)
       Primary biliary cirrhosis4 (<1%)4 (<1%)4 (<1%)
      Excessive alcohol intake123 (15%)123 (15%)82 (10%)
      Lupus4 (<1%)4 (<1%)3 (<1%)
      Multiple myeloma or gammopathy1 + 2 (<1%)3 (<1%)3 (<1%)
      Chronic kidney disease46 (6%)
       eGFR (0–15 ml/min)4 (<1%)3 (<1%)
       eGFR (16–23 ml/min)7 (<1%)5 (<1%)
       eGFR (31–60 ml/min)78 (9%)20 (2%)
      Proteinuria89 (11%)
       UMA (30–299 mg/g)75 (9%)64 (8%)
       UMA (300–999 mg/g)8 (<1%)6 (<1%)
       UMA (>999 mg/g)6 (<1%)6 (<1%)
      Medications
       Estrogen oral contraceptives16 (2%)16 (2%)8 (<1%)
       Estrogen replacement therapy18 (2%)18 (2%)10 (1%)
       Human immunodeficiency virus therapy
      Use of anti–human immunodeficiency virus medications that can alter lipoproteins.
      3 (<1%)3 (<1%)3 (<1%)
       Antipsychotic medications28 (3%)28 (3%)26 (3%)
       Steroids
      Anabolic or glucocorticoid steroid use that can alter lipoproteins.
      25 (3%)25 (3%)20 (2%)
       Oral retinoids1 (<1%)1 (<1%)1 (<1%)
       Immunosuppressive agents
      Use of medications (e.g., cyclosporine) that can alter lipoproteins.
      22 (3%)22 (3%)22 (3%)
       Total number
      Because there may be >1 secondary condition in a single patient, the number at the bottom of each column represents the total number of conditions, not the number of patients with a condition.
      743543363
      eGFR = estimated glomerular filtration rate; UMA = spot urine microalbuminuria/creatinine ratio.
      low asterisk See “Methods” for definition. The number reported represents the number of secondary dyslipidemia conditions found, which is identical to the number of patients with the condition. The percentage reported represents the rounded nearest percentage of patients with the secondary dyslipidemia condition.
      A condition was deemed active when occurring with abnormal laboratory values, defined as alkaline phosphatase >130 IU/L, glycosylated hemoglobin >7.0%, and thyroid-stimulating hormone >5.6 mIU/L. Excessive alcohol intake was defined as >2 standard drinks on most days of the week, as assessed by a dietician and a food frequency questionnaire.
      Use of anti–human immunodeficiency virus medications that can alter lipoproteins.
      § Anabolic or glucocorticoid steroid use that can alter lipoproteins.
      Use of medications (e.g., cyclosporine) that can alter lipoproteins.
      Because there may be >1 secondary condition in a single patient, the number at the bottom of each column represents the total number of conditions, not the number of patients with a condition.

      Results

      We found 824 patients who had all the necessary information (Table 1). We identified 363 factors among the 824 patients that were thought to be true secondary causes of dyslipidemia (Table 2). The most common conditions were DM and excessive alcohol intake. Numerous other factors were identified; however, each condition occurred in <5% of patients.
      Many patients had >1 possible underlying secondary cause (n = 83 [10%]). One hundred eighty-three, 35, 8, and 4 patients had 1, 2, 3, and 4 identified secondary conditions, respectively. Taking this into account, we identified 230 patients (28% of the cohort) with ≥1 possible secondary dyslipidemias. This main result of 230 patients included only patients with ≥1 g of albuminuria on spot urine testing, because lower levels do not always have a relevant impact on lipoproteins. Including all levels of albuminuria listed in Table 2 had a modest effect on the results, leading to 255 patients (31%) having secondary causes. Although conditions other than DM, excessive alcohol intake, and any degree of albuminuria each occurred separately only infrequently (e.g., hypothyroidism, multiple myeloma, biliary obstructive diseases, lupus, adverse medication effects), when taken in sum, they were present altogether in a substantial number of patients (n = 102 patients [12% of the cohort]).

      Discussion

      We found that a considerable portion of patients (28%) had underlying potential secondary dyslipidemias upon their referral to our tertiary care lipid clinic. Moreover, 10% of the cohort had >1 plausible contributing factor. Even after excluding the most common conditions (DM, excessive alcohol intake, and any albuminuria), roughly 12% of our patients were affected. These findings support the guideline recommendations that clinicians should evaluate for underlying conditions that may be causing or exacerbating dyslipidemias.
      Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
      Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).
      • Catapano A.L.
      • Reiner Z.
      • De Backer G.
      • Graham I.
      • Taskinen M.R.
      • Wiklund O.
      • Agewall S.
      • Alegria E.
      • Chapman M.J.
      • Durrington P.
      • Erdine S.
      • Halcox J.
      • Hobbs R.
      • Kjekshus J.
      • Perrone Filardi P.
      • Riccardi G.
      • Storey R.F.
      • Wood D.
      ESC Committee for Practice Guidelines 2008-2010 and 2010-2012 Committees
      ESC/EAS guidelines for the management of dyslipidemias The Task Force for the Management of Dyslipidemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS).
      • Genest J.
      • McPherson R.
      • Frohlich J.
      • Anderson T.
      • Campbell N.
      • Carpentier A.
      • Couture P.
      • Dufour R.
      • Fodor G.
      • Francis G.A.
      • Grover S.
      • Gupta M.
      • Hegele R.A.
      • Lau D.C.
      • Leiter L.
      • Lewis G.F.
      • Lonn E.
      • Mancini G.B.
      • Ng D.
      • Pearson G.J.
      • Sniderman A.
      • Stone J.A.
      • Ur E.
      2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult—2009 recommendations.
      We are not aware of any previous study that reported the prevalence of secondary causes underlying multiple dyslipidemia phenotypes in a single population. Hence, our findings provide important insights for clinical practice. Because most patients were sent for consultation because of the inability to control their dyslipidemia, this study assessed the prevalence of secondary dyslipidemias in patients deemed difficult to manage. The true prevalence of secondary dyslipidemias within the general population is unknown and likely varies depending on many factors considered.
      • Elisaf M.
      • Tsimihodimos V.
      Editorial: secondary dyslipidemias.
      Strictly speaking, a condition can be a secondary dyslipidemia only if it is treated and the lipoprotein abnormalities are diminished without other intervention. This “gold standard” criterion is extremely difficult to apply in an unbiased manner. In our cohort, many therapeutic recommendations were made on the first visit, and hence we could not assess if solely addressing the secondary cause ameliorated the dyslipidemia. Nonetheless, we believe the methods used (using a uniform screening protocol and the process of defining the presence of a true secondary dyslipidemia) provided an accurate estimate of secondary causes of dyslipidemia in our cohort.
      Numerous patients were already receiving lipid-lowering medications on referral (Table 1). Hence, it is likely that many of the conditions we identified were not previously recognized by the referring physicians to be remediable and causally related to the dyslipidemia. In contrast, it is also possible that the factor was recognized but not treated or adequately addressed. Regardless, we believe these observations provide even more support for the importance of educating health care providers about the existence of secondary dyslipidemias and the importance of screening for them before starting medications or intensifying existing lipid-lowering therapy among difficult or “refractory” cases.
      We recognize a few study limitations. Obesity and poor diet were not included as “secondary dyslipidemias” per se, because they were extremely prevalent (288 additional cases of body mass index > 30 kg/m2) and thought to play a role in the origin of “primary polygenic-environmental dyslipidemia.” We also only recorded relatively common secondary causes for which we could uniformly evaluate among our new patients. Infrequent conditions (e.g., Cushing syndrome) may have been overlooked. Certain cardiovascular medications that can affect lipids (e.g., β blockers) were often needed for other reasons; hence, we did not include these as secondary causes, because they could not be stopped. We also restricted this analysis to low-density lipoprotein cholesterol and triglycerides and did not assess secondary causes of isolated low high-density lipoprotein cholesterol. Some rare conditions, such as vanishing high-density lipoprotein cholesterol syndrome due to fibrate therapy (which we know occurred in a few of our patients) were likely overlooked when they were not accompanied by elevated triglycerides. Together, most of these limitations suggest that our findings actually under-represent the prevalence of secondary causes of dyslipidemia. Future larger scale studies are warranted to corroborate our observations and assess the prevalence and characteristic of secondary causes of dyslipidemia in the general population.
      Preexisting secondary causes of dyslipidemia were common in patients referred to our tertiary care lipid clinic. We believe our findings support national guidelines that clinicians should be aware of these conditions and routinely screen for them, particularly DM and excessive alcohol intake, when managing patients with complex cases of dyslipidemia.

      References

        • Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
        Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).
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        • Catapano A.L.
        • Reiner Z.
        • De Backer G.
        • Graham I.
        • Taskinen M.R.
        • Wiklund O.
        • Agewall S.
        • Alegria E.
        • Chapman M.J.
        • Durrington P.
        • Erdine S.
        • Halcox J.
        • Hobbs R.
        • Kjekshus J.
        • Perrone Filardi P.
        • Riccardi G.
        • Storey R.F.
        • Wood D.
        • ESC Committee for Practice Guidelines 2008-2010 and 2010-2012 Committees
        ESC/EAS guidelines for the management of dyslipidemias.
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        • Genest J.
        • McPherson R.
        • Frohlich J.
        • Anderson T.
        • Campbell N.
        • Carpentier A.
        • Couture P.
        • Dufour R.
        • Fodor G.
        • Francis G.A.
        • Grover S.
        • Gupta M.
        • Hegele R.A.
        • Lau D.C.
        • Leiter L.
        • Lewis G.F.
        • Lonn E.
        • Mancini G.B.
        • Ng D.
        • Pearson G.J.
        • Sniderman A.
        • Stone J.A.
        • Ur E.
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        • Tsimihodimos V.
        Editorial: secondary dyslipidemias.
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        (Accessed April 22, 2012)