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Non-genetic influences on lipoprotein(a) concentrations

  • Byambaa Enkhmaa
    Correspondence
    Corresponding author. Department of Internal Medicine, Division of Endocrinology, Metabolism, and Diabetes School of Medicine, UC Davis, 451 East Health Sciences Drive, Suite 5404, Genome and Biomedical Sciences Facility, Davis, CA, 95616, USA.
    Affiliations
    Department of Internal Medicine, School of Medicine, University of California Davis, Davis, CA, USA

    Center for Precision Medicine and Data Sciences, School of Medicine, University of California Davis, Davis, CA, USA
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  • Lars Berglund
    Affiliations
    Department of Internal Medicine, School of Medicine, University of California Davis, Davis, CA, USA
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      Highlights

      • An elevated level of plasma Lp(a) is a risk factor for cardiovascular disease.
      • Lp(a) level is genetically regulated, but some non-genetic factors influence it.
      • Lp(a) levels decrease with saturated fat intake, sex hormones and liver disease.
      • Kidney disease increases Lp(a) levels with variability across apo(a) isoform size.

      Abstract

      An elevated level of lipoprotein(a) [Lp(a)] is a genetically regulated, independent, causal risk factor for cardiovascular disease. However, the extensive variability in Lp(a) levels between individuals and population groups cannot be fully explained by genetic factors, emphasizing a potential role for non-genetic factors. In this review, we provide an overview of current evidence on non-genetic factors influencing Lp(a) levels with a particular focus on diet, physical activity, hormones and certain pathological conditions. Findings from randomized controlled clinical trials show that diets lower in saturated fats modestly influence Lp(a) levels and often in the opposing direction to LDL cholesterol. Results from studies on physical activity/exercise have been inconsistent, ranging from no to minimal or moderate change in Lp(a) levels, potentially modulated by age and the type, intensity, and duration of exercise modality. Hormone replacement therapy (HRT) in postmenopausal women lowers Lp(a) levels with oral being more effective than transdermal estradiol; the type of HRT, dose of estrogen and addition of progestogen do not modify the Lp(a)-lowering effect of HRT. Kidney diseases result in marked elevations in Lp(a) levels, albeit dependent on disease stages, dialysis modalities and apolipoprotein(a) phenotypes. In contrast, Lp(a) levels are reduced in liver diseases in parallel with the disease progression, although population studies have yielded conflicting results on the associations between Lp(a) levels and non-alcoholic fatty liver disease. Overall, current evidence supports a role for diet, hormones and related conditions, and liver and kidney diseases in modifying Lp(a) levels.

      Graphical abstract

      Keywords

      1. Introduction

      It is well established that elevated Lp(a) levels are an independent casual risk factor for cardiovascular diseases (CVD), including coronary artery disease (CAD), myocardial infarction (MI), and aortic valve stenosis [
      • Reyes-Soffer G.
      • Ginsberg H.N.
      • Berglund L.
      • et al.
      Lipoprotein(a): a genetically determined, causal, and prevalent risk factor for atherosclerotic cardiovascular disease: a scientific statement from the American heart association.
      ]. This is discussed in detail by Arsenault and Kamstrup in another review of this series [
      • Arsenault B.
      • Kamstrup P.
      Lipoprotein(a) and cardiovascular and valvular diseases: a genetic epidemiological perspective.
      ]. In addition, recent studies indicated a role also in heart failure [
      • Steffen B.T.
      • Duprez D.
      • Bertoni A.G.
      • et al.
      Lp(a) [Lipoprotein(a)]-Related risk of heart failure is evident in whites but not in other racial/ethnic groups.
      ]. Lp(a) levels are strongly determined through genetic variants in the LPA gene, particularly by a size polymorphism in apolipoprotein(a) [apo(a)] as reviewed by Coassin and Kronenberg [
      • Coassin S.
      • Kronenberg F.
      Lipoprotein(a) beyond the kringle IV repeat polymorphism: the complexity of genetic variation in the LPA gene.
      ]. The present review will focus on the roles of non-genetic factors such as diet and physical activity (PA) and the influence by sex and hormones (Fig. 1). We will also summarize evidence on pathological conditions that modify Lp(a) levels, including kidney and liver diseases, emphasizing the magnitude and directionality of their effects as pertinent to cardiovascular risk as well as the apo(a) size polymorphism (for a summary, see Box 1).
      Fig. 1
      Fig. 1Non-genetic factors influencing plasma Lp(a) levels.
      Although plasma Lp(a) levels are mostly genetically determined, some evidence suggests that non-genetic factors may also influence Lp(a) levels. These include lifestyle factors such as diet. In particular, reduction in dietary saturated fat intake and exercise (A), hormones and associated conditions such as menopause (B) and chronic conditions such as liver and kidney diseases that impact synthesis and catabolism of Lp(a) (C). Other factors with a potential to influence Lp(a) levels remain to be identified (D).
      Non-genetic influences on Lp(a) concentrations.
      • While Lp(a) is under strong genetic regulation, a number of other factors, including some clinical conditions, influence levels.
      • Replacement of dietary saturated fat with protein, carbohydrates or unsaturated fat increases Lp(a) levels in the order of 10–15%.
      • Modulation of physical activity has not been shown to consistently affect Lp(a) levels.
      • In contrast to endogenous sex hormone levels, under non-pregnant conditions, exogenously administered androgens and estrogens impact Lp(a) levels.
      • Both hyper- and hypothyroid conditions modestly impact Lp(a) levels.
      • Lp(a) levels increase in chronic kidney disease and nephrotic syndrome – in the former, the increase is primarily limited to Lp(a) with larger size apo(a) isoforms. Baseline Lp(a) levels are largely restored after renal transplantation.
      • Lp(a) levels are associated with hepatocellular damage – a decrease is seen in relation to disease progression. Whether Lp(a) is influenced by non-alcoholic fatty liver disease remains to be clarified.

      2. Non-genetic factors and Lp(a) levels

      2.1 Diet

      One of the first human clinical trial evidence that diet may modulate Lp(a) concentration was reported by Hornstra et al. [
      • Hornstra G.
      • van Houwelingen A.C.
      • Kester A.D.
      • et al.
      A palm oil-enriched diet lowers serum lipoprotein(a) in normocholesterolemic volunteers.
      ] who observed a 10% reduction in Lp(a) concentration with a palm-oil enriched diet compared to a control Dutch diet. In further support of an impact of fat quality, a 23% increase in Lp(a) concentration was seen in response to a high oleic-acid diet with ∼10% compared to a diet with 19% of calories from saturated fatty acids ( SFA ) [
      • Mensink R.P.
      • Zock P.L.
      • Katan M.B.
      • et al.
      Effect of dietary cis and trans fatty acids on serum lipoprotein[a] levels in humans.
      ]. Notably, LDL-C levels decreased by 17%. Replacement of SFA with trans-monounsaturated fatty acids resulted in an even higher increase (73%) in Lp(a) level. Further, compared to a control high-SFA diet, diets lower in SFA and proportionately higher in monounsaturated fatty acids (MUFA) or polyunsaturated fatty acids (PUFA) tended to increase Lp(a) but the change was not significant [
      • Mensink R.P.
      • Zock P.L.
      • Katan M.B.
      • et al.
      Effect of dietary cis and trans fatty acids on serum lipoprotein[a] levels in humans.
      ].
      The two DELTA (Dietary Effects on Lipoproteins and Thrombogenic Activity) trials were the first randomized multicenter dietary studies in participants with differing metabolic profiles [
      • Ginsberg H.N.
      • Kris-Etherton P.
      • Dennis B.
      • et al.
      Effects of reducing dietary saturated fatty acids on plasma lipids and lipoproteins in healthy subjects: the DELTA Study, protocol 1.
      ,
      • Berglund L.
      • Lefevre M.
      • Ginsberg H.N.
      • et al.
      Comparison of monounsaturated fat with carbohydrates as a replacement for saturated fat in subjects with a high metabolic risk profile: studies in the fasting and postprandial states.
      ]. The DELTA 1 trial recruited healthy participants and demonstrated that lowering dietary SFA intake from 16% to 5% of calories with a proportionate increase in complex carbohydrate (CHO) increased Lp(a) levels by ∼15% [
      • Ginsberg H.N.
      • Kris-Etherton P.
      • Dennis B.
      • et al.
      Effects of reducing dietary saturated fatty acids on plasma lipids and lipoproteins in healthy subjects: the DELTA Study, protocol 1.
      ]. The DELTA 2 study undertaken in participants with a high-risk metabolic profile showed that isocaloric replacement of SFA with complex CHO or MUFA increased Lp(a) levels by 20% and 11%, respectively [
      • Berglund L.
      • Lefevre M.
      • Ginsberg H.N.
      • et al.
      Comparison of monounsaturated fat with carbohydrates as a replacement for saturated fat in subjects with a high metabolic risk profile: studies in the fasting and postprandial states.
      ]. In both DELTA trials, as expected, LDL-C was reduced by 7–11%. Collectively these two DELTA trials demonstrated opposite changes in Lp(a) and LDL-C in response to dietary SFA replacement [
      • Ginsberg H.N.
      • Kris-Etherton P.
      • Dennis B.
      • et al.
      Effects of reducing dietary saturated fatty acids on plasma lipids and lipoproteins in healthy subjects: the DELTA Study, protocol 1.
      ,
      • Berglund L.
      • Lefevre M.
      • Ginsberg H.N.
      • et al.
      Comparison of monounsaturated fat with carbohydrates as a replacement for saturated fat in subjects with a high metabolic risk profile: studies in the fasting and postprandial states.
      ]. Other studies have reported similar findings replacing SFA with MUFA, PUFA, or a combination of MUFA and PUFA [
      • Clevidence B.A.
      • Judd J.T.
      • Schaefer E.J.
      • et al.
      Plasma lipoprotein (a) levels in men and women consuming diets enriched in saturated, cis-, or trans-monounsaturated fatty acids.
      ,
      • Muller H.
      • Lindman A.S.
      • Blomfeldt A.
      • et al.
      A diet rich in coconut oil reduces diurnal postprandial variations in circulating tissue plasminogen activator antigen and fasting lipoprotein (a) compared with a diet rich in unsaturated fat in women.
      ,
      • Silaste M.L.
      • Rantala M.
      • Alfthan G.
      • et al.
      Changes in dietary fat intake alter plasma levels of oxidized low-density lipoprotein and lipoprotein(a).
      ].
      A large randomized crossover feeding trial in adults with prehypertension or stage 1 hypertension (The Omni Heart Trial) tested differences in Lp(a) responses to DASH (Dietary Approaches to Stop Hypertension)-style diets differing in macronutrient content (either rich in CHO, protein, or unsaturated fat) and analyzed the responses by race [
      • Haring B.
      • von Ballmoos M.C.
      • Appel L.J.
      • et al.
      Healthy dietary interventions and lipoprotein(a) plasma levels: results from the Omni Heart Trial.
      ]. All three diets increased Lp(a) level by ∼8–18% compared to baseline after six weeks; however, the diets rich in unsaturated fats increased Lp(a) less than diets rich in CHO or protein and greater changes were observed in Black participants than in White participants [
      • Haring B.
      • von Ballmoos M.C.
      • Appel L.J.
      • et al.
      Healthy dietary interventions and lipoprotein(a) plasma levels: results from the Omni Heart Trial.
      ]. In this cohort, LDL-C was reduced by 12–14 mg/dL across all three test diets [
      • Appel L.J.
      • Sacks F.M.
      • Carey V.J.
      • et al.
      Effects of protein, monounsaturated fat, and carbohydrate intake on blood pressure and serum lipids: results of the Omni Heart randomized trial.
      ].
      A few studies have examined the effect of low-fat, high-CHO (LFHC) diets compared to high-fat, low-CHO (HFLC) diets on Lp(a). Compared to a HFLC diet, a LFHC diet increased Lp(a) levels by ∼12% and lowered LDL-C by ∼7 mg/dL [
      • Faghihnia N.
      • Tsimikas S.
      • Miller E.R.
      • et al.
      Changes in lipoprotein(a), oxidized phospholipids, and LDL subclasses with a low-fat high-carbohydrate diet.
      ]. This study also showed increases in oxidized phospholipids (OxPL) per apolipoprotein (apo)B or apo(a) with the LFHC diets [
      • Faghihnia N.
      • Tsimikas S.
      • Miller E.R.
      • et al.
      Changes in lipoprotein(a), oxidized phospholipids, and LDL subclasses with a low-fat high-carbohydrate diet.
      ]. Diet-induced changes in Lp(a) concentration were strongly correlated with changes in OxPL per apoB. Lp(a) is the primary carrier of circulating OxPL and as the OxPL content is hypothesized to mediate its atherogenicity further studies on the impact of diet are warranted [
      • Bergmark C.
      • Dewan A.
      • Orsoni A.
      • et al.
      A novel function of lipoprotein[a] as a preferential carrier of oxidized phospholipids in human plasma.
      ,
      • Tsimikas S.
      • Witztum J.L.
      The role of oxidized phospholipids in mediating lipoprotein(a) atherogenicity.
      ]. The topic on OxPLs carried on Lp(a) is discussed in detail by Koschinsky and Boffa in this review series [
      • Koschinsky M.L.
      • Boffa M.B.
      Oxidized phospholipid modification of lipoprotein(a): epidemiology, biochemistry and pathophysiology.
      ].
      In a recent randomized feeding trial, after an initial 10–14% weight loss, three maintenance diets containing 20% protein and differing 3-fold in CHO and SFA as a proportion of energy were consumed for 20 weeks [
      • Ebbeling C.B.
      • Knapp A.
      • Johnson A.
      • et al.
      Effects of a low-carbohydrate diet on insulin-resistant dyslipoproteinemia-a randomized controlled feeding trial.
      ]. While Lp(a) levels decreased by ∼15% in the low-CHO/high SFA group, no changes were observed in the moderate-CHO and high-CHO groups [
      • Ebbeling C.B.
      • Knapp A.
      • Johnson A.
      • et al.
      Effects of a low-carbohydrate diet on insulin-resistant dyslipoproteinemia-a randomized controlled feeding trial.
      ]. Collectively, there is strong documentation that short-term dietary interventions to reduce SFA intake result in an increase in Lp(a) levels of 9–23%, while at the same time decreasing LDL-C levels by 7–17%, depending on the type of replacement strategy and cohort characteristics.
      The question whether fasting versus nonfasting conditions would impact Lp(a) levels was recently addressed and similar Lp(a) concentrations under both conditions were reported [
      • Langsted A.
      • Kamstrup P.R.
      • Nordestgaard B.G.
      Lipoprotein(a): fasting and nonfasting levels, inflammation, and cardiovascular risk.
      ]. A larger dietary change in the Lp(a) concentration was reported in a n = 1 case study of a male physician with a very high Lp(a) level who undertook changes in dietary CHO consumption [
      • Scholl J.G.
      Does a ketogenic diet lower a very high Lp(a)? A striking experiment in a male physician.
      ]. Lp(a) levels varied considerably depending on the diet regimen, with a decrease during a very-low CHO ketogenic diet followed by an increase in the Lp(a) level after two weeks of a very high-CHO (400 g/day) diet, again being reduced after three weeks of restarting the very-low CHO ketogenic diet [
      • Scholl J.G.
      Does a ketogenic diet lower a very high Lp(a)? A striking experiment in a male physician.
      ]. These observations are in line with the notion that substitution of SFA with unsaturated fat, but not with CHO, is a preferable regimen in terms of Lp(a) levels [
      • Haring B.
      • von Ballmoos M.C.
      • Appel L.J.
      • et al.
      Healthy dietary interventions and lipoprotein(a) plasma levels: results from the Omni Heart Trial.
      ]. The rapid onset of these changes indicates a flexible regulation of Lp(a) levels in response to diet modulation.
      On the other hand, some studies have not found an increase in Lp(a) levels with a reduction of dietary SFA. For example, a 12-week intervention with a Mediterranean-style low-glycemic-load diet with reduced energy intake from CHO and fat, replaced by protein, lowered Lp(a) concentration by ∼50% in women with the metabolic syndrome (MetS) [
      • Jones J.L.
      • Comperatore M.
      • Barona J.
      • et al.
      A Mediterranean-style, low-glycemic-load diet decreases atherogenic lipoproteins and reduces lipoprotein (a) and oxidized low-density lipoprotein in women with metabolic syndrome.
      ]. Furthermore, a randomized crossover controlled feeding trial among overweight and obese participants found a modest but significant decrease in Lp(a) levels when a low-fat diet (24% total fat; 7% SFA) was compared to an average American diet (AAD) (34% total fat; 13% SFA) [
      • Wang L.
      • Bordi P.L.
      • Fleming J.A.
      • et al.
      Effect of a moderate fat diet with and without avocados on lipoprotein particle number, size and subclasses in overweight and obese adults: a randomized, controlled trial.
      ]. More recently, a 6-week randomized crossover controlled feeding study among at risk individuals reported an ∼11% reduction in Lp(a) levels with a PUFA-enriched diet, while no change in Lp(a) levels was seen with a MUFA-enriched diet [
      • Tindall A.M.
      • Kris-Etherton P.M.
      • Petersen K.S.
      Replacing saturated fats with unsaturated fats from walnuts or vegetable oils lowers atherogenic lipoprotein classes without increasing lipoprotein(a).
      ]. The contrasting observations in these trials versus the other trials with regard to Lp(a) responses to SFA reduction (a decrease versus an increase) need to be further explored, although differences in Lp(a) measurement methodology, test diets or cohort characteristics might contribute. Notably, as the vertical auto profile (VAP) method uses an ultracentrifugation technique and relies on Lp(a) cholesterol rather than quantification of Lp(a) concentrations, a potential overlap of the Lp(a) fraction with other lipoprotein fractions cannot be excluded using this approach [
      • Wang L.
      • Bordi P.L.
      • Fleming J.A.
      • et al.
      Effect of a moderate fat diet with and without avocados on lipoprotein particle number, size and subclasses in overweight and obese adults: a randomized, controlled trial.
      ,
      • Tindall A.M.
      • Kris-Etherton P.M.
      • Petersen K.S.
      Replacing saturated fats with unsaturated fats from walnuts or vegetable oils lowers atherogenic lipoprotein classes without increasing lipoprotein(a).
      ,
      • Kulkarni K.R.
      Cholesterol profile measurement by vertical auto profile method.
      ,
      • Yeang C.
      • Clopton P.C.
      • Tsimikas S.
      Lipoprotein(a)-cholesterol levels estimated by vertical auto profile correlate poorly with Lp(a) mass in hyperlipidemic subjects: implications for clinical practice interpretation of Lp(a)-mediated risk.
      ].
      Beyond macronutrient changes, the potential effects on Lp(a) levels by diets enriched with nuts (walnuts [
      • Zambon D.
      • Sabate J.
      • Munoz S.
      • et al.
      Substituting walnuts for monounsaturated fat improves the serum lipid profile of hypercholesterolemic men and women. A randomized crossover trial.
      ], pecans [
      • Rajaram S.
      • Burke K.
      • Connell B.
      • et al.
      A monounsaturated fatty acid-rich pecan-enriched diet favorably alters the serum lipid profile of healthy men and women.
      ] or almonds [
      • Jenkins D.J.
      • Kendall C.W.
      • Marchie A.
      • et al.
      Dose response of almonds on coronary heart disease risk factors: blood lipids, oxidized low-density lipoproteins, lipoprotein(a), homocysteine, and pulmonary nitric oxide: a randomized, controlled, crossover trial.
      ,
      • Berryman C.E.
      • West S.G.
      • Fleming J.A.
      • et al.
      Effects of daily almond consumption on cardiometabolic risk and abdominal adiposity in healthy adults with elevated LDL-cholesterol: a randomized controlled trial.
      ,
      • Lee Y.
      • Berryman C.E.
      • West S.G.
      • et al.
      Effects of dark chocolate and almonds on cardiovascular risk factors in overweight and obese individuals: a randomized controlled-feeding trial.
      ,
      • Gulati S.
      • Misra A.
      • Pandey R.M.
      Effect of almond supplementation on glycemia and cardiovascular risk factors in Asian Indians in North India with type 2 diabetes mellitus: a 24-week study.
      ]) have been explored. While a modest reduction in levels (6–15%) was seen in randomized trials using diets enriched with walnuts (41–56 g/day) [
      • Zambon D.
      • Sabate J.
      • Munoz S.
      • et al.
      Substituting walnuts for monounsaturated fat improves the serum lipid profile of hypercholesterolemic men and women. A randomized crossover trial.
      ] or pecans (72 g/day) [
      • Rajaram S.
      • Burke K.
      • Connell B.
      • et al.
      A monounsaturated fatty acid-rich pecan-enriched diet favorably alters the serum lipid profile of healthy men and women.
      ], studies on almond-enriched diets report inconsistent findings [
      • Jenkins D.J.
      • Kendall C.W.
      • Marchie A.
      • et al.
      Dose response of almonds on coronary heart disease risk factors: blood lipids, oxidized low-density lipoproteins, lipoprotein(a), homocysteine, and pulmonary nitric oxide: a randomized, controlled, crossover trial.
      ,
      • Berryman C.E.
      • West S.G.
      • Fleming J.A.
      • et al.
      Effects of daily almond consumption on cardiometabolic risk and abdominal adiposity in healthy adults with elevated LDL-cholesterol: a randomized controlled trial.
      ,
      • Lee Y.
      • Berryman C.E.
      • West S.G.
      • et al.
      Effects of dark chocolate and almonds on cardiovascular risk factors in overweight and obese individuals: a randomized controlled-feeding trial.
      ,
      • Gulati S.
      • Misra A.
      • Pandey R.M.
      Effect of almond supplementation on glycemia and cardiovascular risk factors in Asian Indians in North India with type 2 diabetes mellitus: a 24-week study.
      ]. Further studies are needed to establish a role in particular for almonds with regard to dietary modulation of Lp(a) levels.
      Regarding the role of alcohol consumption in Lp(a) level, an analysis of a large European American sample found no association between alcohol consumption and Lp(a) level [
      • Vu K.N.
      • Ballantyne C.M.
      • Hoogeveen R.C.
      • et al.
      Causal role of alcohol consumption in an improved lipid profile: the atherosclerosis risk in communities (ARIC) study.
      ], while a large study in middle-aged Chinese individuals reported a slight decrease in Lp(a) levels in male heavy drinkers compared with abstainers [
      • Hao G.
      • Wang Z.
      • Zhang L.
      • et al.
      Relationship between alcohol consumption and serum lipid profiles among middle-aged population in China: a multiple-center cardiovascular epidemiological study.
      ]. In intervention studies using red wine, no change in patients with carotid atherosclerosis [
      • Droste D.W.
      • Iliescu C.
      • Vaillant M.
      • et al.
      A daily glass of red wine associated with lifestyle changes independently improves blood lipids in patients with carotid arteriosclerosis: results from a randomized controlled trial.
      ] or a decrease in men at high risk for CVD have been reported for Lp(a) levels [
      • Chiva-Blanch G.
      • Urpi-Sarda M.
      • Ros E.
      • et al.
      Effects of red wine polyphenols and alcohol on glucose metabolism and the lipid profile: a randomized clinical trial.
      ].
      As the present format does not permit an in-depth analysis of the impact of nutrients on Lp(a), a more detailed summary that included a tabulation of such studies was recently published [
      • Enkhmaa B.
      • Petersen K.S.
      • Kris-Etherton P.M.
      • et al.
      Diet and Lp(a): does dietary change modify residual cardiovascular risk conferred by Lp(a)?.
      ]. However, in summary, although the evidence from randomized controlled clinical trials during the last three decades on the dietary modulation of Lp(a) level is not fully consistent, an increasing body of evidence indicates that reductions in dietary SFA intake result in an increase in Lp(a) levels. The SFA replacement choice (CHO, MUFA, PUFA, or protein) and certain food/drink types (and the amount) in the diet beyond its macronutrient composition may also contribute to modulate Lp(a) levels. Notably, a dietary SFA reduction consistently decreased LDL-C, resulting in an opposite pattern compared to Lp(a) (Fig. 2). As proinflammatory and proatherogenic OxPLs may shuttle between Lp(a) and LDL-C particles, the diet-induced opposing changes in OxPLs’ plasma carriers merit further investigation and will help adopt precision nutrition approaches to reduce CVD risk.
      Fig. 2
      Fig. 2Opposite effects of reducing dietary saturated fat intake on Lp(a) and LDL-C concentrations and modulation of their risk mediating properties as well as impact by other factors.
      Reduction in dietary saturated fatty acid (SFA) intake can increase Lp(a) concentrations while inducing a consistent clinically meaningful reduction in LDL-C concentrations (A). Although the impact of dietary SFA reduction on LDL-C and its properties is well studied, limited data is available on its impact on Lp(a)s unique properties such as oxidized phospholipids (OxPLs) concentration or subspecies composition and any modulatory role by the apo(a) size polymorphism (B). Whether the responses to dietary SFA reduction in Lp(a) concentrations and properties would differ by an individual's racial/ethnic background or metabolic burden and SFA replacement regimens or other food components in the diet remain to be established (C).

      2.2 Physical activity, exercise, and cardiorespiratory fitness

      A potential role of PA and exercise in the modulation of Lp(a) levels has attracted interest. An early report of a Lp(a) decrease of ∼22% in healthy young- and middle-aged men after an 8-day cross-country skiing regimen (equivalent to a 10 h of heavy PA/day) [
      • Hellsten G.
      • Boman K.
      • Hallmans G.
      • et al.
      Lipids and endurance physical activity.
      ] indeed suggested an impact of PA. However, these results have been challenging to confirm as several studies have failed to find an association between Lp(a) levels and PA level or cardiorespiratory fitness [
      • Selby J.V.
      • Austin M.A.
      • Sandholzer C.
      • et al.
      Environmental and behavioral influences on plasma lipoprotein(a) concentration in women twins.
      ,
      • MacAuley D.
      • McCrum E.E.
      • Stott G.
      • et al.
      Physical activity, lipids, apolipoproteins, and Lp(a) in the Northern Ireland health and activity survey.
      ,
      • Israel R.G.
      • Sullivan M.J.
      • Marks R.H.
      • et al.
      Relationship between cardiorespiratory fitness and lipoprotein(a) in men and women.
      ,
      • Szymanski L.M.
      • Durstine J.L.
      • Davis P.G.
      • et al.
      Factors affecting fibrinolytic potential: cardiovascular fitness, body composition, and lipoprotein(a).
      ]. Moreover, Lp(a) levels did not differ significantly between male athletes and sedentary controls [
      • Oyelola O.O.
      • Rufai M.A.
      Plasma lipid, lipoprotein and apolipoprotein profiles in Nigerian university athletes and non-athletes.
      ,
      • Hubinger L.
      • Mackinnon L.T.
      • Lepre F.
      Lipoprotein(a) [Lp(a)] levels in middle-aged male runners and sedentary controls.
      ,
      • Halle M.
      • Berg A.
      • von Stein T.
      • et al.
      Lipoprotein(a) in endurance athletes, power athletes, and sedentary controls.
      ]. Also, a prospective data in postmenopausal women did not find any influence of exercise alone on Lp(a) levels [
      • Lobo R.A.
      • Notelovitz M.
      • Bernstein L.
      • et al.
      Lp(a) lipoprotein: relationship to cardiovascular disease risk factors, exercise, and estrogen.
      ].
      Neither has any significant impact by PA on Lp(a) levels been documented in short- or long-term interventional and prospective studies [
      • Hubinger L.
      • Mackinnon L.T.
      The effect of endurance training on lipoprotein(a) [Lp(a)] levels in middle-aged males.
      ,
      • Hubinger L.
      • Mackinnon L.T.
      • Barber L.
      • et al.
      Acute effects of treadmill running on lipoprotein(a) levels in males and females.
      ,
      • Haskell W.L.
      • Alderman E.L.
      • Fair J.M.
      • et al.
      Effects of intensive multiple risk factor reduction on coronary atherosclerosis and clinical cardiac events in men and women with coronary artery disease. The Stanford Coronary Risk Intervention Project (SCRIP).
      ,
      • Theodorou A.A.
      • Panayiotou G.
      • Volaklis K.A.
      • et al.
      Aerobic, resistance and combined training and detraining on body composition, muscle strength, lipid profile and inflammation in coronary artery disease patients.
      ]. Thus, while an intensive 4-year individualized risk reduction program, recommending a healthy diet, increased PA and an individualized endurance training program in men and women with CAD improved the overall lipid profile, reduced body weight, increased exercise capacity and reduced dietary fat intake, there was no change in the Lp(a) concentration [
      • Haskell W.L.
      • Alderman E.L.
      • Fair J.M.
      • et al.
      Effects of intensive multiple risk factor reduction on coronary atherosclerosis and clinical cardiac events in men and women with coronary artery disease. The Stanford Coronary Risk Intervention Project (SCRIP).
      ]. More recently, although an 8-month study to increase PA in middle-aged men and women with one or more traditional CVD risk factors reduced LDL-C, and increased HDL-C and proprotein convertase subtilisin/kexin type 9 (PCSK9) levels, the mean Lp(a) concentration was not significantly affected [
      • Sponder M.
      • Campean I.A.
      • Dalos D.
      • et al.
      Effect of long-term physical activity on PCSK9, high- and low-density lipoprotein cholesterol, and lipoprotein(a) levels: a prospective observational trial.
      ].
      In contrast, some observational studies in younger populations report an association between PA and Lp(a) levels. Among Finnish children and young-adults (9–24 years old), Lp(a) levels were inversely correlated with leisure time PA with a dose-response manner [
      • Taimela S.
      • Viikari J.S.
      • Porkka K.V.
      • et al.
      Lipoprotein (a) levels in children and young adults: the influence of physical activity. The Cardiovascular Risk in Young Finns Study.
      ]. Also, in young children and adolescents with type 1 diabetes mellitus, physical fitness was inversely associated with Lp(a) levels [
      • Austin A.
      • Warty V.
      • Janosky J.
      • et al.
      The relationship of physical fitness to lipid and lipoprotein(a) levels in adolescents with IDDM.
      ]. Furthermore, in younger men (23–33 years old), Lp(a) levels were higher and positively associated with the maximum aerobic capacity in long-distance runners and body builders with regular prolonged high-level exercise training compared to sedentary men [
      • Cardoso G.C.
      • Posadas C.
      • Orvananos O.O.
      • et al.
      Long distance runners and body-builders exhibit elevated plasma levels of lipoprotein(a).
      ]. In previously sedentary younger men and women (median age: <40 years), an intensive 9-month long-distance running exercise training program significantly increased Lp(a) levels with a nearly 2-fold increase in both men and women who completed a half-marathon [
      • Ponjee G.A.
      • Janssen E.M.
      • van Wersch J.W.
      Long-term physical exercise and lipoprotein(a) levels in a previously sedentary male and female population.
      ].
      Among men and women with type 1 and type 2 diabetes mellitus, Lp(a) concentration decreased (−13%) among those with higher baseline values (>30 mg/dL) after a 3-month individualized aerobic exercise program [
      • Rigla M.
      • Sanchez-Quesada J.L.
      • Ordonez-Llanos J.
      • et al.
      Effect of physical exercise on lipoprotein(a) and low-density lipoprotein modifications in type 1 and type 2 diabetic patients.
      ]. The change in Lp(a) levels was inversely correlated with baseline levels. Similarly, a small study in obese men and women with type 2 diabetes mellitus reported a significant decrease in Lp(a) levels following a 12-week low-intensity resistance training [
      • Hamasaki H.
      • Kawashima Y.
      • Tamada Y.
      • et al.
      Associations of low-intensity resistance training with body composition and lipid profile in obese patients with type 2 diabetes.
      ].
      In summary, most of the available evidence suggests that PA, intensive exercise training, increases in exercise or cardiorespiratory fitness have no or minimal impact on Lp(a) concentration, while significantly influencing concentrations of other lipids and lipoproteins. However, results of some studies, particularly those in younger or diabetic populations, deviate from this and suggest a possible Lp(a)-modulating effect by a prolonged high-level exercise training, aerobic exercise or low-intensity resistance training. Nevertheless, the magnitude of exercise-induced changes in Lp(a) levels has generally been modest and any impact related to major genetic regulators of Lp(a) concentration such as the apo(a) size polymorphism has not been addressed. Additionally, the lack of a control group in some studies [
      • Ponjee G.A.
      • Janssen E.M.
      • van Wersch J.W.
      Long-term physical exercise and lipoprotein(a) levels in a previously sedentary male and female population.
      ,
      • Rigla M.
      • Sanchez-Quesada J.L.
      • Ordonez-Llanos J.
      • et al.
      Effect of physical exercise on lipoprotein(a) and low-density lipoprotein modifications in type 1 and type 2 diabetic patients.
      ,
      • Hamasaki H.
      • Kawashima Y.
      • Tamada Y.
      • et al.
      Associations of low-intensity resistance training with body composition and lipid profile in obese patients with type 2 diabetes.
      ] may raise concerns about the quality of data as studies have suggested presence of a modest intra-individual temporal variability in mean Lp(a) levels [
      • Marcovina S.M.
      • Viney N.J.
      • Hughes S.G.
      • et al.
      Temporal variability in lipoprotein(a) levels in patients enrolled in the placebo arms of IONIS-APO(a)Rx and IONIS-APO(a)-LRx antisense oligonucleotide clinical trials.
      ]. Therefore, more studies with appropriate control groups are needed taking potential confounders such as apo(a) sizes and assay methodology into account.

      3. Sex-specific differences and hormones

      3.1 Sex-specific differences

      While many studies across population groups (Blacks and Whites [
      • Guyton J.R.
      • Dahlen G.H.
      • Patsch W.
      • et al.
      Relationship of plasma lipoprotein Lp(a) levels to race and to apolipoprotein B.
      ], Hungarians [
      • Csaszar A.
      • Romics L.
      • Lackner C.
      • et al.
      [Plasma concentration of lipoprotein(a) and distribution of its subtypes in the healthy population of Hungary].
      ], Germans, Ghanaians, and Sans [
      • Helmhold M.
      • Bigge J.
      • Muche R.
      • et al.
      Contribution of the apo[a] phenotype to plasma Lp[a] concentrations shows considerable ethnic variation.
      ], Caucasians [
      • Jenner J.L.
      • Ordovas J.M.
      • Lamon-Fava S.
      • et al.
      Effects of age, sex, and menopausal status on plasma lipoprotein(a) levels. The Framingham Offspring Study.
      ], Tibetans, Koreans, Chinese, Nigerians, and Belgians [
      • Cobbaert C.
      • Kesteloot H.
      Serum lipoprotein(a) levels in racially different populations.
      ], Blacks in the Seychelles [
      • Bovet P.
      • Rickenbach M.
      • Wietlisbach V.
      • et al.
      Comparison of serum lipoprotein(a) distribution and its correlates among black and white populations.
      ] or Italians [
      • Volpato S.
      • Vigna G.B.
      • McDermott M.M.
      • et al.
      Lipoprotein(a), inflammation, and peripheral arterial disease in a community-based sample of older men and women (the InCHIANTI study).
      ]) have found no sex-specific differences in Lp(a) levels, some studies report higher Lp(a) levels in females than males. Thus, among children and adolescents, Lp(a) levels were significantly higher in girls than in boys for both Blacks and Whites [
      • Srinivasan S.R.
      • Dahlen G.H.
      • Jarpa R.A.
      • et al.
      Racial (black-white) differences in serum lipoprotein (a) distribution and its relation to parental myocardial infarction in children.
      ] as well as for Arabs [
      • Akanji A.O.
      • Al-Isa A.N.
      • Thalib L.
      Determinants of blood levels of some thrombogenic biomarkers in healthy Arab adolescent subjects.
      ]. Another study reported higher Lp(a) levels in women than in men for Europeans [
      • Bovet P.
      • Rickenbach M.
      • Wietlisbach V.
      • et al.
      Comparison of serum lipoprotein(a) distribution and its correlates among black and white populations.
      ] and Japanese [
      • Nago N.
      • Kayaba K.
      • Hiraoka J.
      • et al.
      Lipoprotein(a) levels in the Japanese population: influence of age and sex, and relation to atherosclerotic risk factors. The Jichi Medical School Cohort Study.
      ], but not for Blacks in the Seychelles [
      • Bovet P.
      • Rickenbach M.
      • Wietlisbach V.
      • et al.
      Comparison of serum lipoprotein(a) distribution and its correlates among black and white populations.
      ]. Addressing the potential influence of CAD familial predisposition on such findings, Barra et al. [
      • Barra S.
      • Cuomo V.
      • Silvestri N.
      • et al.
      Lipoprotein(a) concentration does not differ between sexes in healthy offspring of patients with premature myocardial infarction.
      ] demonstrated no significant difference in Lp(a) levels between healthy teenage brothers and sisters with a positive parental history of premature MI. In Europeans with CAD, a 2-fold higher Lp(a) level was observed in women compared to men after adjusting for covariates; this sex-specific difference was not seen in those without CAD [
      • Frohlich J.
      • Dobiasova M.
      • Adler L.
      • et al.
      Gender differences in plasma levels of lipoprotein (a) in patients with angiographically proven coronary artery disease.
      ]. Another study in a multiethnic familial hypercholesterolemia (FH) cohort reported higher Lp(a) levels in women than in men with CVD, but not in those without CVD [
      • Allard M.D.
      • Saeedi R.
      • Yousefi M.
      • et al.
      Risk stratification of patients with familial hypercholesterolemia in a multi-ethnic cohort.
      ]. Also in FH, higher Lp(a) levels were reported among CVD-susceptible versus CVD-resistant women with FH [
      • Nenseter M.S.
      • Lindvig H.W.
      • Ueland T.
      • et al.
      Lipoprotein(a) levels in coronary heart disease-susceptible and -resistant patients with familial hypercholesterolemia.
      ]. The topic on Lp(a) and FH is discussed in detail by Chemello et al. in this Lp(a) review series [
      • Chemello K.
      • Chan D.C.
      • Lambert G.
      • et al.
      Recent advances in demystifying the metabolism of lipoprotein(a).
      ]. In a longitudinal report, Lp(a) levels were significantly higher in women than in men at baseline, however, the association between elevated Lp(a) levels and 10-year first fatal/non-fatal CVD was significant in men but not in women [
      • Kouvari M.
      • Panagiotakos D.B.
      • Chrysohoou C.
      • et al.
      Lipoprotein (a) and 10-year cardiovascular disease incidence in apparently healthy individuals: a sex-based sensitivity analysis from ATTICA cohort study.
      ]. In a large population study of Europeans, including Finns, female sex was associated with increased Lp(a) levels [
      • Erhart G.
      • Lamina C.
      • Lehtimaki T.
      • et al.
      Genetic factors explain a major fraction of the 50% lower lipoprotein(a) concentrations in Finns.
      ]. The studied genetic variants, as well as age, sex, and renal function, explained nearly 72% of the observed population differences in Lp(a) [
      • Erhart G.
      • Lamina C.
      • Lehtimaki T.
      • et al.
      Genetic factors explain a major fraction of the 50% lower lipoprotein(a) concentrations in Finns.
      ]. Among Europeans, Lp(a) levels were higher in women than in men regardless of type 2 diabetes mellitus status [
      • Markus M.R.P.
      • Ittermann T.
      • Schipf S.
      • et al.
      Association of sex-specific differences in lipoprotein(a) concentrations with cardiovascular mortality in individuals with type 2 diabetes mellitus.
      ]. A further adjustment for Lp(a) levels had no impact on the HR for CVD mortality comparing men versus women without type 2 diabetes mellitus; however, among those with type 2 diabetes mellitus, the adjustment resulted in an increased risk in men and a decreased risk in women for CVD mortality [
      • Markus M.R.P.
      • Ittermann T.
      • Schipf S.
      • et al.
      Association of sex-specific differences in lipoprotein(a) concentrations with cardiovascular mortality in individuals with type 2 diabetes mellitus.
      ]. In a recent large study of middle-aged >460,000 UK Biobank participants, Lp(a) levels were somewhat elevated in women than in men and in individuals who had established CVD at the time of enrollment [
      • Patel A.P.
      • Wang M.
      • Pirruccello J.P.
      • et al.
      Lp(a) (Lipoprotein[a]) concentrations and incident atherosclerotic cardiovascular disease: New insights from a large National Biobank.
      ]. While Lp(a) level predicted incident CVD in both men and women without any interaction, it was a stronger risk factor for CVD among those without diabetes mellitus than with diabetes mellitus [
      • Patel A.P.
      • Wang M.
      • Pirruccello J.P.
      • et al.
      Lp(a) (Lipoprotein[a]) concentrations and incident atherosclerotic cardiovascular disease: New insights from a large National Biobank.
      ]. More details on the relationship between Lp(a), diabetes mellitus, and CVD risk are provided by Lamina et al. of this Lp(a) review series [
      • Lamina C.
      • Ward N.C.
      Lp(a) and diabetes mellitus.
      ].
      Taken together, while some evidence indicates higher Lp(a) levels in females than in males, more studies are needed to establish any sex-specific differences in Lp(a) levels and relevance to CVD risk. Potential confounding effects by factors such as race/ethnicity, apo(a) size distribution, menopausal and disease status and Lp(a) measurement method should be carefully considered. Particularly, an impact of menopause on Lp(a) levels as contributory to the age-dependent relative difference between middle-aged to older men and women should be considered.

      3.2 Hormones

      3.2.1 Sex hormones

      Among healthy men, Lp(a) levels were not associated with endogenous testosterone, free testosterone, or sex-hormone binding globulin (SHBG) [
      • Haffner S.M.
      • Gruber K.K.
      • Morales P.A.
      • et al.
      Lipoprotein(a) concentrations in Mexican Americans and non-Hispanic whites: the san Antonio heart study.
      ,
      • Marcovina S.M.
      • Lippi G.
      • Bagatell C.J.
      • et al.
      Testosterone-induced suppression of lipoprotein(a) in normal men; relation to basal lipoprotein(a) level.
      ,
      • Denti L.
      • Pasolini G.
      • Ablondi F.
      • et al.
      Correlation between plasma lipoprotein Lp(a) and sex hormone concentrations: a cross-sectional study in healthy males.
      ]. However, contradictory results have been reported in two studies for the association between Lp(a) levels and dehydroepiandrosterone sulfate ester (DHEA-S) [
      • Haffner S.M.
      • Gruber K.K.
      • Morales P.A.
      • et al.
      Lipoprotein(a) concentrations in Mexican Americans and non-Hispanic whites: the san Antonio heart study.
      ,
      • Denti L.
      • Pasolini G.
      • Ablondi F.
      • et al.
      Correlation between plasma lipoprotein Lp(a) and sex hormone concentrations: a cross-sectional study in healthy males.
      ], one of the most abundant endogenous androgen steroids. Among men with CAD, Lp(a) levels were significantly negatively associated with free testosterone, but not with DHEA-S [
      • Davoodi G.
      • Amirezadegan A.
      • Borumand M.A.
      • et al.
      The relationship between level of androgenic hormones and coronary artery disease in men.
      ]. In healthy postmenopausal women, inconsistent findings have been reported for the association for Lp(a) with endogenous DHEA-S or testosterone [
      • Noyan V.
      • Yucel A.
      • Sagsoz N.
      The association of androgenic sex steroids with serum lipid levels in postmenopausal women.
      ,
      • Lambrinoudaki I.
      • Christodoulakos G.
      • Rizos D.
      • et al.
      Endogenous sex hormones and risk factors for atherosclerosis in healthy Greek postmenopausal women.
      ].
      Exogenously administered androgens and estrogens impact Lp(a) levels. Administration of testosterone significantly reduced Lp(a) levels in healthy men [
      • Marcovina S.M.
      • Lippi G.
      • Bagatell C.J.
      • et al.
      Testosterone-induced suppression of lipoprotein(a) in normal men; relation to basal lipoprotein(a) level.
      ,
      • Anderson R.A.
      • Wallace E.M.
      • Wu F.C.
      Effect of testosterone enanthate on serum lipoproteins in man.
      ,
      • Zmunda J.M.
      • Thompson P.D.
      • Dickenson R.
      • et al.
      Testosterone decreases lipoprotein(a) in men.
      ,
      • Berglund L.
      • Carlstrom K.
      • Stege R.
      • et al.
      Hormonal regulation of serum lipoprotein (a) levels: effects of parenteral administration of estrogen or testosterone in males.
      ], but not in healthy postmenopausal women [
      • Zang H.
      • Carlstrom K.
      • Arner P.
      • et al.
      Effects of treatment with testosterone alone or in combination with estrogen on insulin sensitivity in postmenopausal women.
      ], hypogonadal men [
      • Ozata M.
      • Yildirimkaya M.
      • Bulur M.
      • et al.
      Effects of gonadotropin and testosterone treatments on Lipoprotein(a), high density lipoprotein particles, and other lipoprotein levels in male hypogonadism.
      ] or oophorectomized women [
      • Floter A.
      • Nathorst-Boos J.
      • Carlstrom K.
      • et al.
      Serum lipids in oophorectomized women during estrogen and testosterone replacement therapy.
      ]. Significant reductions in Lp(a) levels were observed in perimenopausal women treated with DHEA (−18%) [
      • Barnhart K.T.
      • Freeman E.
      • Grisso J.A.
      • et al.
      The effect of dehydroepiandrosterone supplementation to symptomatic perimenopausal women on serum endocrine profiles, lipid parameters, and health-related quality of life.
      ], in postmenopausal osteoporotic women [
      • Albers J.J.
      • Taggart H.M.
      • Applebaum-Bowden D.
      • et al.
      Reduction of lecithin-cholesterol acyltransferase, apolipoprotein D and the Lp(a) lipoprotein with the anabolic steroid stanozolol.
      ] or premenopausal women with endometriosis [
      • Crook D.
      • Sidhu M.
      • Seed M.
      • et al.
      Lipoprotein Lp(a) levels are reduced by danazol, an anabolic steroid.
      ], both cases treated with stanozolol (a synthetic anabolic steroid), or in men undergoing hemodialysis treated with another anabolic steroid, nandrolone decanoate (>50% reduction at 6 months) [
      • Teruel J.L.
      • Lasuncion M.A.
      • Rivera M.
      • et al.
      Nandrolone decanoate reduces serum lipoprotein(a) concentrations in hemodialysis patients.
      ]. Among male body builders, the administration of anabolic androgen steroids was associated with a lower prevalence of elevated Lp(a) levels [
      • Cohen L.I.
      • Hartford C.G.
      • Rogers G.G.
      Lipoprotein (a) and cholesterol in body builders using anabolic androgenic steroids.
      ] and a significant reduction in Lp(a) levels [
      • Hislop M.S.
      • St Clair Gibson A.
      • Lambert M.I.
      • et al.
      Effects of androgen manipulation on postprandial triglyceridaemia, low-density lipoprotein particle size and lipoprotein(a) in men.
      ,
      • Hartgens F.
      • Rietjens G.
      • Keizer H.A.
      • et al.
      Effects of androgenic-anabolic steroids on apolipoproteins and lipoprotein(a).
      ].
      A large number of studies in postmenopausal women have evaluated the effects of estrogen treatment on lipids. Lp(a) levels were significantly reduced following treatments with norethisterone [
      • Farish E.
      • Rolton H.A.
      • Barnes J.F.
      • et al.
      Lipoprotein (a) concentrations in postmenopausal women taking norethisterone.
      ], estrogen-progestogen therapy [
      • Mendoza S.
      • Velazquez E.
      • Osona A.
      • et al.
      Postmenopausal cyclic estrogen-progestin therapy lowers lipoprotein[a].
      ], tamoxifen [
      • Shewmon D.A.
      • Stock J.L.
      • Rosen C.J.
      • et al.
      Tamoxifen and estrogen lower circulating lipoprotein(a) concentrations in healthy postmenopausal women.
      ] or hormone replacement therapy (HRT) [
      • Kim C.J.
      • Jang H.C.
      • Cho D.H.
      • et al.
      Effects of hormone replacement therapy on lipoprotein(a) and lipids in postmenopausal women.
      ,
      • Kim C.J.
      • Min Y.K.
      • Ryu W.S.
      • et al.
      Effect of hormone replacement therapy on lipoprotein(a) and lipid levels in postmenopausal women. Influence of various progestogens and duration of therapy.
      ]. Lp(a) levels were significantly lower in women receiving HRT versus not receiving HRT in the Women Twins Study [
      • Selby J.V.
      • Austin M.A.
      • Sandholzer C.
      • et al.
      Environmental and behavioral influences on plasma lipoprotein(a) concentration in women twins.
      ] and in the Women's Health Study [
      • Suk Danik J.
      • Rifai N.
      • Buring J.E.
      • et al.
      Lipoprotein(a), hormone replacement therapy, and risk of future cardiovascular events.
      ]. A meta-analysis of studies conducted during 1966–2004 quantifying the effect of HRT in postmenopausal women documented an average of 25% reduction in Lp(a) levels [
      • Salpeter S.R.
      • Walsh J.M.
      • Ormiston T.M.
      • et al.
      Meta-analysis: effect of hormone-replacement therapy on components of the metabolic syndrome in postmenopausal women.
      ]. In Japanese women, Lp(a) levels were significantly higher in postmenopausal than in pre- or perimenopausal women and HRT reduced Lp(a) by ∼19% which was retained for four years [
      • Ushioda M.
      • Makita K.
      • Takamatsu K.
      • et al.
      Serum lipoprotein(a) dynamics before/after menopause and long-term effects of hormone replacement therapy on lipoprotein(a) levels in middle-aged and older Japanese women.
      ]. Treatment with tibolone, a synthetic steroid with weak estrogenic, progestogenic, and androgenic activity, for a year in postmenopausal women resulted in a 28% reduction in Lp(a) levels [
      • Perrone G.
      • Capri O.
      • Galoppi P.
      • et al.
      Effects of either tibolone or continuous combined transdermal estradiol with medroxyprogesterone acetate on coagulatory factors and lipoprotein(a) in menopause.
      ].
      A meta-analysis based on 24 randomized controlled trials demonstrated that both HRT (mean relative difference: −20.4%) and tibolone (−25.3%) reduced Lp(a) concentrations in postmenopausal women [
      • Anagnostis P.
      • Galanis P.
      • Chatzistergiou V.
      • et al.
      The effect of hormone replacement therapy and tibolone on lipoprotein (a) concentrations in postmenopausal women: a systematic review and meta-analysis.
      ]. Although the effect was statistically significant only for HRT compared to placebo or no treatment groups, there was no significant difference between HRT and tibolone regarding Lp(a) levels. Oral estrogen resulted in a greater reduction in Lp(a) concentrations than transdermal estrogen, whereas there was no significant difference comparing continuous versus cyclic HRT, conventional with low-dose estrogen, or estrogen monotherapy with estrogen combined with progestogen [
      • Anagnostis P.
      • Galanis P.
      • Chatzistergiou V.
      • et al.
      The effect of hormone replacement therapy and tibolone on lipoprotein (a) concentrations in postmenopausal women: a systematic review and meta-analysis.
      ]. This meta-analysis concluded that HRT significantly reduces Lp(a) concentrations with oral being more effective than transdermal estradiol and that the type of HRT, dose of estrogen and addition of progestogen do not modify the Lp(a)-lowering effect of HRT [
      • Anagnostis P.
      • Galanis P.
      • Chatzistergiou V.
      • et al.
      The effect of hormone replacement therapy and tibolone on lipoprotein (a) concentrations in postmenopausal women: a systematic review and meta-analysis.
      ].

      3.2.2 Thyroid hormones

      Lp(a) levels are decreased in hyperthyroidism and increased in hypothyroidism [
      • Kotwal A.
      • Cortes T.
      • Genere N.
      • et al.
      Treatment of thyroid dysfunction and serum lipids: a systematic review and meta-analysis.
      ]. The use of eprotirome, a liver-selective TH (thyroid hormone) analog, resulted in a dose-dependent reduction in Lp(a) concentrations (−45–55%) in statin-treated patients [
      • Ladenson P.W.
      • Kristensen J.D.
      • Ridgway E.C.
      • et al.
      Use of the thyroid hormone analogue eprotirome in statin-treated dyslipidemia.
      ]. A similar dose-response relationship between Lp(a) reduction and eprotirome was observed in other randomized double-blind placebo-controlled trials in patients with FH [
      • Sjouke B.
      • Langslet G.
      • Ceska R.
      • et al.
      Eprotirome in patients with familial hypercholesterolaemia (the AKKA trial): a randomised, double-blind, placebo-controlled phase 3 study, the Lancet.
      ] or with primary hypercholesterolemia [
      • Angelin B.
      • Kristensen J.D.
      • Eriksson M.
      • et al.
      Reductions in serum levels of LDL cholesterol, apolipoprotein B, triglycerides and lipoprotein(a) in hypercholesterolaemic patients treated with the liver-selective thyroid hormone receptor agonist eprotirome.
      ]. Bonde et al. reported that both eprotirome and hyperthyroidism reduced concentrations of Lp(a), PCSK9, plasma cholesterol in all lipoprotein fractions, apoB and apoA-I, while cholesterol synthesis was stable [
      • Bonde Y.
      • Breuer O.
      • Lutjohann D.
      • et al.
      Thyroid hormone reduces PCSK9 and stimulates bile acid synthesis in humans.
      ]. TH-induced reductions in PCSK9 levels likely contributed to the lower LDL-C and Lp(a) levels in hyperthyroidism. However, significant side effects such as increases in liver enzymes and cartilage side effects in animals have been seen with eprotirome, limiting its clinical use [
      • Zucchi R.
      Thyroid hormone analogues: an update.
      ]. More details on the relationship between Lp(a) and PCSK9 and its inhibition are provided by Chemello et al. of this Lp(a) review series [
      • Chemello K.
      • Chan D.C.
      • Lambert G.
      • et al.
      Recent advances in demystifying the metabolism of lipoprotein(a).
      ].
      In hypothyroidism, Lp(a) levels decreased with a 6-month levothyroxine treatment (mean ± SD: 28 ± 19 mg/dL versus 18 ± 11 mg/dL) in women with primary hypothyroidism (n = 12) [
      • Deyneli O.
      • Akpinar I.N.
      • Mericliler O.S.
      • et al.
      Effects of levothyroxine treatment on insulin sensitivity, endothelial function and risk factors of atherosclerosis in hypothyroid women.
      ]; however, levels remained elevated compared to controls (14 ± 4 mg/dL) (n = 11). In a retrospective analysis, a small increase in Lp(a) concentrations was seen after injections of recombinant human thyrotropin on a background of a stable levothyroxine dose in thyroid cancer patients who had undergone total thyroidectomy [
      • Beukhof C.M.
      • Massolt E.T.
      • Visser T.J.
      • et al.
      Effects of thyrotropin on peripheral thyroid hormone metabolism and serum lipids.
      ]. Case-control studies have found higher Lp(a) levels in patients with Hashimoto thyroiditis [
      • Yetkin D.O.
      • Dogantekin B.
      The lipid parameters and lipoprotein(a) excess in Hashimoto thyroiditis.
      ] or hypothyroidism [
      • Bansal S.K.
      • Yadav R.
      A study of the extended lipid profile including oxidized LDL, small dense LDL, lipoprotein (a) and apolipoproteins in the assessment of cardiovascular risk in hypothyroid patients.
      ] compared to healthy controls.
      A recent systematic review and meta-analysis of 166 studies (23 randomized and 143 nonrandomized) conducted during 1970–2018 evaluated the impact of therapy for overt and subclinical hyper- and hypo-thyroidism on blood lipids [
      • Kotwal A.
      • Cortes T.
      • Genere N.
      • et al.
      Treatment of thyroid dysfunction and serum lipids: a systematic review and meta-analysis.
      ]. Treatment of overt hyperthyroidism resulted in significant increases in Lp(a) by 4.18 mg/dL (95% CI: 1.65, 6.71)., TC, LDL-C, HDL-C, apoA and apoB concentrations without affecting triglycerides [
      • Kotwal A.
      • Cortes T.
      • Genere N.
      • et al.
      Treatment of thyroid dysfunction and serum lipids: a systematic review and meta-analysis.
      ]. In contrast, no effect on lipid parameters was seen during treatment for subclinical hyperthyroidism. Levothyroxine in overt hypothyroidism significantly decreased Lp(a) by −5.6 mg/dL (95% CI: −9.06, −2.14) and induced moderate to large reductions in TC, LDL-C, HDL-C, triglycerides, apoA1, and apoB concentrations. Levothyroxine in subclinical hypothyroidism showed similar changes but with a smaller magnitude. A recent study reported elevated Lp(a) levels in patients with overt (n = 280) or subclinical (n = 272) hypothyroidism compared to healthy controls (n = 270) [
      • Kaftan A.N.
      • Naser F.H.
      • Enaya M.A.
      Changes of certain metabolic and cardiovascular markers Fructosamine, H-FABP and lipoprotein (a) in patients with hypothyroidism.
      ].

      3.2.3 Growth hormones

      Growth hormone (GH) replacement therapy increases Lp(a) levels. Among adults with adult-onset pituitary insufficiency, Lp(a) levels increased markedly during GH treatment and were about twice as high compared with pre-treatment levels [
      • Eden S.
      • Wiklund O.
      • Oscarsson J.
      • et al.
      Growth hormone treatment of growth hormone-deficient adults results in a marked increase in Lp(a) and HDL cholesterol concentrations.
      ]. Among adults with postoperative GH deficiency, recombinant human GH treatment increased significantly Lp(a) levels at 12 months posttreatment, independently of baseline Lp(a) levels and apo(a) isoforms [
      • Nolte W.
      • Radisch C.
      • Armstrong V.W.
      • et al.
      The effect of recombinant human GH replacement therapy on lipoprotein(a) and other lipid parameters in adults with acquired GH deficiency: results of a double-blind and placebo-controlled trial.
      ]. More recently, a prospective observational study demonstrated that a GH replacement therapy in men with GH deficiency resulted in a significant increase in Lp(a) levels (mean: from 27.4 nmol/L to 34.3 nmol/L) [
      • Glynn N.
      • Halsall D.J.
      • Boran G.
      • et al.
      Growth hormone replacement may influence the biological action of thyroid hormone on liver and bone tissue.
      ]. There were no correlations between baseline Lp(a) levels (or the increase) and concentrations of TH or insulin-like growth factor-1 [
      • Glynn N.
      • Halsall D.J.
      • Boran G.
      • et al.
      Growth hormone replacement may influence the biological action of thyroid hormone on liver and bone tissue.
      ].

      4. Pathologies that modify Lp(a) concentrations

      4.1 Kidney diseases

      The role of kidney diseases in impacting Lp(a) levels has been the subject of many studies. The effects have varied depending on the specific condition and disease stage, the amount of proteinuria, or treatment modalities. In patients with severe chronic kidney disease (CKD), i.e., end-stage renal disease (ESRD), Dieplinger et al. observed higher Lp(a) levels compared with healthy controls despite similar apo(a) isoforms distribution in both groups [
      • Dieplinger H.
      • Lackner C.
      • Kronenberg F.
      • et al.
      Elevated plasma concentrations of lipoprotein(a) in patients with end-stage renal disease are not related to the size polymorphism of apolipoprotein(a).
      ]. In a diverse group of CKD patients, Milionis et al. found significantly elevated Lp(a) levels in patients with mild to moderate chronic renal failure (CRF) and patients treated with hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD) compared with controls, a finding not explained by the apo(a) size variability [
      • Milionis H.J.
      • Elisaf M.S.
      • Tselepis A.
      • et al.
      Apolipoprotein(a) phenotypes and lipoprotein(a) concentrations in patients with renal failure.
      ]. In another study among CRF patients, Lp(a) levels were twice as high as in healthy controls and were influenced by nutritional status [
      • Stenvinkel P.
      • Heimburger O.
      • Tuck C.H.
      • et al.
      Apo(a)-isoform size, nutritional status and inflammatory markers in chronic renal failure.
      ]. Addressing a void regarding the changes in Lp(a) levels in early stages of kidney impairment, Kronenberg et al. conducted a detailed assessment of the relationship between Lp(a) levels, apo(a) sizes, and kidney function in 227 patients with non-nephrotic kidney disease (NNKD) with various stages of kidney impairment [
      • Kronenberg F.
      • Kuen E.
      • Ritz E.
      • et al.
      Lipoprotein(a) serum concentrations and apolipoprotein(a) phenotypes in mild and moderate renal failure.
      ]. The results confirmed higher Lp(a) levels in patients with NNKD compared with healthy controls. Of note, the median Lp(a) levels increased as the kidney function impaired (11.0 at GFR >90, 18.4 at GFR 45–90 and 24.4 mg/dL at GFR <45 mL/min/1.73 m2). These findings suggested that Lp(a) levels begin to increase even in early stages of kidney impairment [
      • Kronenberg F.
      • Kuen E.
      • Ritz E.
      • et al.
      Lipoprotein(a) serum concentrations and apolipoprotein(a) phenotypes in mild and moderate renal failure.
      ,
      • Kronenberg F.
      Causes and consequences of lipoprotein(a) abnormalities in kidney disease.
      ] and showed an inverse association between Lp(a) levels and kidney function [
      • Kronenberg F.
      Causes and consequences of lipoprotein(a) abnormalities in kidney disease.
      ,
      • Kronenberg F.
      • Konig P.
      • Neyer U.
      • et al.
      Multicenter study of lipoprotein(a) and apolipoprotein(a) phenotypes in patients with end-stage renal disease treated by hemodialysis or continuous ambulatory peritoneal dialysis.
      ].
      A common finding among CKD patients has been that the increase in Lp(a) levels varies across apo(a) sizes as only patients with large size apo(a) isoforms exhibited a 2- to 4-fold higher Lp(a) level compared with controls [
      • Dieplinger H.
      • Lackner C.
      • Kronenberg F.
      • et al.
      Elevated plasma concentrations of lipoprotein(a) in patients with end-stage renal disease are not related to the size polymorphism of apolipoprotein(a).
      ] (Fig. 3). When compared with apo(a) phenotype-matched controls, the significant association between Lp(a) levels and kidney function was seen in patients with large apo(a) isoforms, but not in patients with small isoforms [
      • Kronenberg F.
      • Kuen E.
      • Ritz E.
      • et al.
      Lipoprotein(a) serum concentrations and apolipoprotein(a) phenotypes in mild and moderate renal failure.
      ]. Thus, median Lp(a) levels in patients with large apo(a) isoforms were 6.2 mg/dL at GFR >90, 14.2 mg/dL at GFR 45–90, and 18.0 mg/dL at GFR <45 mL/min/1.73 m2, all of which were markedly elevated compared with the median level of 4.4 mg/dL in controls. Other studies have shown that the Lp(a) response was dependent on apo(a) sizes also during dialysis treatment. Apo(a) size specific increases in Lp(a) levels were seen among patients with NNKD or ESRD patients treated with HD [
      • Dieplinger H.
      • Lackner C.
      • Kronenberg F.
      • et al.
      Elevated plasma concentrations of lipoprotein(a) in patients with end-stage renal disease are not related to the size polymorphism of apolipoprotein(a).
      ,
      • Kronenberg F.
      • Konig P.
      • Neyer U.
      • et al.
      Multicenter study of lipoprotein(a) and apolipoprotein(a) phenotypes in patients with end-stage renal disease treated by hemodialysis or continuous ambulatory peritoneal dialysis.
      ,
      • Zimmermann J.
      • Herrlinger S.
      • Pruy A.
      • et al.
      Inflammation enhances cardiovascular risk and mortality in hemodialysis patients.
      ]. Thus, Lp(a) levels were higher in HD patients compared with healthy controls (13.6 versus 9.2 mg/dL) as was the prevalence of a high Lp(a) level (23% versus 12%), despite a similar distribution of apo(a) isoforms in both groups [
      • Zimmermann J.
      • Herrlinger S.
      • Pruy A.
      • et al.
      Inflammation enhances cardiovascular risk and mortality in hemodialysis patients.
      ]. Again, this rise in Lp(a) level in HD patients versus controls was limited to large apo(a) isoform group only (14 versus 8 mg/dL) and was associated with heightened inflammation [
      • Zimmermann J.
      • Herrlinger S.
      • Pruy A.
      • et al.
      Inflammation enhances cardiovascular risk and mortality in hemodialysis patients.
      ]. More details on the association of Lp(a) with inflammation are provided by Dzobo et al. of this Lp(a) review series [
      • Dzobo K.E.
      • Kraaijenhof J.M.
      • Stroes E.S.G.
      • et al.
      Lipoprotein(a): an underestimated inflammatory mastermind.
      ].
      Fig. 3
      Fig. 3Differences underlying increased Lp(a) levels in chronic kidney disease versus nephrotic syndrome in relation to homeostasis and genetically determined apolipoprotein(a) sizes.
      Kidney diseases influence Lp(a) levels. In patients with chronic kidney disease (upper panel), Lp(a) catabolism is decreased, resulting in apo(a)-phenotype specific increases in Lp(a) levels. Thus, the increase is largely due to increases in the large apo(a) isoform associated levels. In contrast, in patients with nephrotic syndrome (lower panel), Lp(a) synthesis is increased, resulting in simultaneous increases for both large and small apo(a) size associated levels.
      While the findings for HD have been consistent, some variability is reported for CAPD. In a large multicenter study of ESRD patients, Kronenberg et al. reported elevated Lp(a) levels in CAPD patients compared to HD patients (34.6 versus 23.4 mg/dL), while both were significantly higher compared to those of healthy controls (18.4 mg/dL) [
      • Kronenberg F.
      • Konig P.
      • Neyer U.
      • et al.
      Multicenter study of lipoprotein(a) and apolipoprotein(a) phenotypes in patients with end-stage renal disease treated by hemodialysis or continuous ambulatory peritoneal dialysis.
      ]. The higher Lp(a) levels in both patient groups (versus controls) were not explained by apo(a) size variability as all three groups had a similar frequency of small apo(a) isoforms. Lp(a) levels were significantly elevated for the large apo(a) isoforms in both patient groups (HD and CAPD) compared with controls [
      • Kronenberg F.
      • Konig P.
      • Neyer U.
      • et al.
      Multicenter study of lipoprotein(a) and apolipoprotein(a) phenotypes in patients with end-stage renal disease treated by hemodialysis or continuous ambulatory peritoneal dialysis.
      ]. Of note, CAPD patients had significantly higher Lp(a) levels than did the HD patients for large apo(a) isoforms (26.1 versus 17.2 mg/dL) [
      • Kronenberg F.
      • Konig P.
      • Neyer U.
      • et al.
      Multicenter study of lipoprotein(a) and apolipoprotein(a) phenotypes in patients with end-stage renal disease treated by hemodialysis or continuous ambulatory peritoneal dialysis.
      ]. However, an increase in Lp(a) levels for patients with small apo(a) isoforms also been reported among CAPD patients. Thus, in contrast to HD, CAPD has been associated with elevated Lp(a) levels regardless of apo(a) sizes [
      • Milionis H.J.
      • Elisaf M.S.
      • Tselepis A.
      • et al.
      Apolipoprotein(a) phenotypes and lipoprotein(a) concentrations in patients with renal failure.
      ]. Furthermore, a study in children treated with peritoneal dialysis reported higher Lp(a) levels compared to matched controls, but no apo(a) size data was available [
      • Bakkaloglu S.A.
      • Saygili A.
      • Sever L.
      • et al.
      Impact of peritoneal transport characteristics on cardiac function in paediatric peritoneal dialysis patients: a Turkish Pediatric Peritoneal Dialysis Study Group (TUPEPD) report.
      ]. On the other hand, some studies have found no relationship between Lp(a) levels, GFR and/or apo(a) isoforms. For example, in the Modification of Diet in Renal Disease Study enrolled 804 patients with CKD (stages 3–4 with a GFR range of 13–55 mL/min/1.73 m2), Lp(a) level was not associated with GFR [
      • Uhlig K.
      • Wang S.R.
      • Beck G.J.
      • et al.
      Factors associated with lipoprotein(a) in chronic kidney disease.
      ]. Among kidney donors whose GFR was reduced by ∼36% at 1 year post donation versus before donation, Lp(a) was not changed [
      • Doucet B.
      • Kostner K.
      • Kaiser O.
      • et al.
      Live donor study - implications of kidney donation on cardiovascular risk with a focus on lipid parameters including lipoprotein a.
      ].
      The higher Lp(a) level in CKD patients seen in many reports has stimulated studies of underlying mechanisms. In vivo turnover studies using stable isotopes in HD patients suggested that a reduced catabolic rate of Lp(a)-apoB and apo(a) was responsible for the Lp(a) elevation in CKD [
      • Frischmann M.E.
      • Kronenberg F.
      • Trenkwalder E.
      • et al.
      In vivo turnover study demonstrates diminished clearance of lipoprotein(a) in hemodialysis patients.
      ]. Given the differential increase in Lp(a) depending on apo(a) sizes, this finding brings up the interesting possibility that CKD might affect Lp(a) catabolism differently depending on apo(a) size properties. Thus, metabolic studies under CKD conditions taking apo(a) size into account could offer valuable insights into Lp(a) metabolic properties.
      In contrast to CKD conditions, pronounced increases in Lp(a) levels occur in all apo(a) size groups in patients with nephrotic syndrome (NS) [
      • Kronenberg F.
      Causes and consequences of lipoprotein(a) abnormalities in kidney disease.
      ,
      • Kronenberg F.
      • Utermann G.
      • Dieplinger H.
      Lipoprotein(a) in renal disease.
      ,
      • Wanner C.
      • Rader D.
      • Bartens W.
      • et al.
      Elevated plasma lipoprotein(a) in patients with the nephrotic syndrome.
      ,
      • Kronenberg F.
      • Lingenhel A.
      • Lhotta K.
      • et al.
      The apolipoprotein(a) size polymorphism is associated with nephrotic syndrome.
      ]. Wanner et al. demonstrated that Lp(a) levels were increased in patients with NS (diabetic and non-diabetic) compared with controls across the apo(a) size range [
      • Wanner C.
      • Rader D.
      • Bartens W.
      • et al.
      Elevated plasma lipoprotein(a) in patients with the nephrotic syndrome.
      ]. Moreover, a large decrease in Lp(a) levels was seen in non-diabetic NS patients following remission of the syndrome with immunosuppressive therapy [
      • Wanner C.
      • Rader D.
      • Bartens W.
      • et al.
      Elevated plasma lipoprotein(a) in patients with the nephrotic syndrome.
      ]. Similarly, Kronenberg et al. reported ∼5-fold elevated Lp(a) levels in patients with non-diabetic NS compared with controls [
      • Kronenberg F.
      • Lingenhel A.
      • Lhotta K.
      • et al.
      The apolipoprotein(a) size polymorphism is associated with nephrotic syndrome.
      ]. While the increase was partly explained by a different distribution of apo(a) size phenotypes in the patient group versus the control group, both small (40–75%) and large (100–500%) apo(a) isoforms were associated with significantly elevated Lp(a) levels in the patient group. Others have also found significantly higher Lp(a) levels in patients with NS (severe proteinuria) or chronic glomerulonephritis (moderate proteinuria) compared with healthy controls [
      • Hong S.Y.
      • Yang D.H.
      Lipoprotein(a) levels and fibrinolytic activity in patients with nephrotic syndrome.
      ] and a decrease in Lp(a) levels with the remission of the syndrome [
      • Joven J.
      • Simo J.M.
      • Vilella E.
      • et al.
      Accumulation of atherogenic remnants and lipoprotein(a) in the nephrotic syndrome: relation to remission of proteinuria.
      ]. Shedding light into mechanisms underlying the increased Lp(a) level in NS patients, a turnover study by van der Velden et al. [
      • De Sain-Van Der Velden M.G.
      • Reijngoud D.J.
      • Kaysen G.A.
      • et al.
      Evidence for increased synthesis of lipoprotein(a) in the nephrotic syndrome.
      ] showed that while the fractional catabolic rate of Lp(a) was comparable between NS patients and controls, the absolute synthesis rate of Lp(a) correlated with Lp(a) concentration in all participants. These data suggest a role for an increased synthesis, rather than a decreased catabolism, as a cause for elevated Lp(a) levels in NS. It has been proposed that in NS and probably also in CAPD, patients lose a significant amount of proteins by urine and dialysate, respectively, that the increased synthesis of Lp(a) might be a result of a counteraction to keep up the oncotic pressure and/or viscosity of blood [
      • Hong S.Y.
      • Yang D.H.
      Lipoprotein(a) levels and fibrinolytic activity in patients with nephrotic syndrome.
      ,
      • De Sain-Van Der Velden M.G.
      • Reijngoud D.J.
      • Kaysen G.A.
      • et al.
      Evidence for increased synthesis of lipoprotein(a) in the nephrotic syndrome.
      ,
      • Hopewell J.C.
      • Haynes R.
      • Baigent C.
      The role of lipoprotein(a) in chronic kidney disease.
      ] (Fig. 3).
      Renal transplantation results in significant reductions in Lp(a) levels consistent with the acquired nature of the Lp(a) abnormality [
      • Kronenberg F.
      Causes and consequences of lipoprotein(a) abnormalities in kidney disease.
      ,
      • Hopewell J.C.
      • Haynes R.
      • Baigent C.
      The role of lipoprotein(a) in chronic kidney disease.
      ]. Prospective studies with variable follow-up periods have shown substantial decreases in Lp(a) levels [
      • Kronenberg F.
      • Konig P.
      • Lhotta K.
      • et al.
      Apolipoprotein(a) phenotype-associated decrease in lipoprotein(a) plasma concentrations after renal transplantation.
      ,
      • Kronenberg F.
      • Lhotta K.
      • Konig P.
      • et al.
      Apolipoprotein(a) isoform-specific changes of lipoprotein(a) after kidney transplantation.
      ,
      • Kerschdorfer L.
      • Konig P.
      • Neyer U.
      • et al.
      Lipoprotein(a) plasma concentrations after renal transplantation: a prospective evaluation after 4 years of follow-up.
      ,
      • Rosas S.
      • Joffe M.
      • Wolfe M.
      • et al.
      Effects of renal replacement therapy on plasma lipoprotein(a) levels.
      ]. The decrease was observed only in patients with large apo(a) isoforms [
      • Kronenberg F.
      • Konig P.
      • Lhotta K.
      • et al.
      Apolipoprotein(a) phenotype-associated decrease in lipoprotein(a) plasma concentrations after renal transplantation.
      ] or linked to a reduced expression of large apo(a) isoforms [
      • Kronenberg F.
      • Lhotta K.
      • Konig P.
      • et al.
      Apolipoprotein(a) isoform-specific changes of lipoprotein(a) after kidney transplantation.
      ]. Rosas et al., observed a rapid decline in Lp(a) levels after renal transplantation reaching a 35% reduction at 2 weeks [
      • Rosas S.
      • Joffe M.
      • Wolfe M.
      • et al.
      Effects of renal replacement therapy on plasma lipoprotein(a) levels.
      ]. Each reduction of 50% in creatinine was associated with ∼11% reduction in Lp(a) levels. Among patients with a relapse and worsening kidney function, a marked increase of the large isoform-associated Lp(a) levels was noted [
      • Kronenberg F.
      • Lhotta K.
      • Konig P.
      • et al.
      Apolipoprotein(a) isoform-specific changes of lipoprotein(a) after kidney transplantation.
      ]. Consistent with the reports of higher Lp(a) levels in CAPD compared to HD, Kerschdorfer et al. found a large decrease post transplantation in CAPD-versus HD-treated patients [
      • Kerschdorfer L.
      • Konig P.
      • Neyer U.
      • et al.
      Lipoprotein(a) plasma concentrations after renal transplantation: a prospective evaluation after 4 years of follow-up.
      ]. Similarly, a larger decrease was seen among patients with higher Lp(a) levels before renal transplantation or patients with large apo(a) isoforms [
      • Kerschdorfer L.
      • Konig P.
      • Neyer U.
      • et al.
      Lipoprotein(a) plasma concentrations after renal transplantation: a prospective evaluation after 4 years of follow-up.
      ]. In contrast, variable results regarding Lp(a) have been observed in cross-sectional studies [
      • Heimann P.
      • Josephson M.A.
      • Fellner S.K.
      • et al.
      Elevated lipoprotein(a) levels in renal transplantation and hemodialysis patients.
      ,
      • Irish A.B.
      • Simons L.A.
      • Savdie E.
      • et al.
      Lipoprotein(a) levels in chronic renal disease states, dialysis and transplantation.
      ,
      • Azrolan N.
      • Brown C.D.
      • Thomas L.
      • et al.
      Cyclosporin A has divergent effects on plasma LDL cholesterol (LDL-C) and lipoprotein(a) [Lp(a)] levels in renal transplant recipients. Evidence for renal involvement in the maintenance of LDL-C and the elevation of Lp(a) concentrations in hemodialysis patients.
      ,
      • Brown J.H.
      • Anwar N.
      • Short C.D.
      • et al.
      Serum lipoprotein (a) in renal transplant recipients receiving cyclosporin monotherapy.
      ,
      • Barbagallo C.M.
      • Averna M.R.
      • Sparacino V.
      • et al.
      Lipoprotein (a) levels in end-stage renal failure and renal transplantation.
      ,
      • Wheeler D.C.
      • Morgan R.
      • Thomas D.M.
      • et al.
      Factors influencing plasma lipid profiles including lipoprotein (a) concentrations in renal transplant recipients.
      ].
      The influence of immunosuppressive therapies on Lp(a) levels in renal transplant recipients has also been explored. Higher Lp(a) levels have been reported in recipients treated with cyclosporin versus azathioprine or prednisolone [
      • Webb A.T.
      • Reaveley D.A.
      • O'Donnell M.
      • et al.
      Does cyclosporin increase lipoprotein(a) concentrations in renal transplant recipients?.
      ,
      • Hilbrands L.B.
      • Demacker P.N.
      • Hoitsma A.J.
      • et al.
      The effects of cyclosporine and prednisone on serum lipid and (apo)lipoprotein levels in renal transplant recipients.
      ,
      • Brown J.H.
      • Murphy B.G.
      • Douglas A.F.
      • et al.
      Influence of immunosuppressive therapy on lipoprotein(a) and other lipoproteins following renal transplantation.
      ] independently of apo(a) size variability [
      • Webb A.T.
      • Reaveley D.A.
      • O'Donnell M.
      • et al.
      Does cyclosporin increase lipoprotein(a) concentrations in renal transplant recipients?.
      ], while others have found no evidence for a role of immunosuppressive therapy [
      • Kronenberg F.
      • Konig P.
      • Lhotta K.
      • et al.
      Apolipoprotein(a) phenotype-associated decrease in lipoprotein(a) plasma concentrations after renal transplantation.
      ,
      • Kerschdorfer L.
      • Konig P.
      • Neyer U.
      • et al.
      Lipoprotein(a) plasma concentrations after renal transplantation: a prospective evaluation after 4 years of follow-up.
      ,
      • Azrolan N.
      • Brown C.D.
      • Thomas L.
      • et al.
      Cyclosporin A has divergent effects on plasma LDL cholesterol (LDL-C) and lipoprotein(a) [Lp(a)] levels in renal transplant recipients. Evidence for renal involvement in the maintenance of LDL-C and the elevation of Lp(a) concentrations in hemodialysis patients.
      ,
      • Wheeler D.C.
      • Morgan R.
      • Thomas D.M.
      • et al.
      Factors influencing plasma lipid profiles including lipoprotein (a) concentrations in renal transplant recipients.
      ,
      • Kronenberg F.
      • Konig P.
      • Lhotta K.
      • et al.
      Cyclosporin and serum lipids in renal transplant recipients.
      ,
      • Murphy B.G.
      • Yong A.
      • Brown J.H.
      • et al.
      Effect of immunosuppressive drug regime on cardiovascular risk profile following kidney transplantation.
      ]. A retrospective analysis showed that young (<35 years old) renal transplant recipients with small apo(a) isoforms had a significantly shorter long-term graft survival compared with those with large apo(a) isoforms, independent of the number of HLA mismatches, sex, or immunosuppressive therapy [
      • Wahn F.
      • Daniel V.
      • Kronenberg F.
      • et al.
      Impact of apolipoprotein(a) phenotypes on long-term renal transplant survival.
      ]. Overall, whether the reduction in Lp(a) levels after renal transplantation is influenced by immunosuppressive therapies remains to be seen [
      • Hopewell J.C.
      • Haynes R.
      • Baigent C.
      The role of lipoprotein(a) in chronic kidney disease.
      ,
      • Enkhmaa B.
      • Anuurad E.
      • Berglund L.
      Lipoprotein(a): impact by ethnicity and environmental and medical conditions.
      ].
      In summary, there is strong evidence to support a role of the kidney in impacting Lp(a) levels. Both the increase in Lp(a) levels in CKD and the decrease in Lp(a) levels after renal transplantation are likely related to the degree of kidney function impairment. In contrast, the increase in Lp(a) levels in NS appears to result from an increased production in response to proteinuria [
      • Hopewell J.C.
      • Haynes R.
      • Baigent C.
      The role of lipoprotein(a) in chronic kidney disease.
      ]. The potential roles of additional factors in influencing Lp(a) in CKD remain to be determined.

      4.2 Liver diseases

      As the concentration of Lp(a) is primarily regulated by the hepatic apo(a) synthetic rate, liver diseases have the potential to influence Lp(a) levels. In general, hepatocellular damage is associated with reduced Lp(a) levels, where the decrease in levels is in parallel with the disease progression [
      • Malaguarnera M.
      • Giugno I.
      • Trovato B.A.
      • et al.
      Lipoprotein(a) concentration in patients with chronic active hepatitis C before and after interferon treatment.
      ,
      • Gregory W.L.
      • Game F.L.
      • Farrer M.
      • et al.
      Reduced serum lipoprotein(a) levels in patients with primary biliary cirrhosis.
      ,
      • Jiang J.
      • Zhang X.
      • Wu C.
      • et al.
      Increased plasma apoM levels in the patients suffered from hepatocellular carcinoma and other chronic liver diseases.
      ]. Patients with liver cirrhosis [
      • Alessandri C.
      • Basili S.
      • Maurelli M.
      • et al.
      Relationship between lipoprotein(a) levels in serum and some indices of protein synthesis in liver cirrhosis.
      ] and hepatitis [
      • Malaguarnera M.
      • Giugno I.
      • Trovato B.A.
      • et al.
      Lipoprotein(a) concentration in patients with chronic active hepatitis C before and after interferon treatment.
      ,
      • Irshad M.
      Serum lipoprotein (a) levels in liver diseases caused by hepatitis.
      ,
      • Geiss H.C.
      • Ritter M.M.
      • Richter W.O.
      • et al.
      Low lipoprotein(a) levels during acute viral hepatitis.
      ] exhibited lower Lp(a) levels compared to healthy controls. Geiss et al. [
      • Geiss H.C.
      • Ritter M.M.
      • Richter W.O.
      • et al.
      Low lipoprotein(a) levels during acute viral hepatitis.
      ] observed a 41% reduction in Lp(a) level, independent of apo(a) isoform size, in patients with acute hepatitis A, B and C (HCV). Lp(a) levels were significantly lower in HCV core protein-positive patients compared to core-negative cases [
      • Irshad M.
      • Dhar I.
      • Gupta S.
      • et al.
      Correlation of serum HCV core concentration with blood level of lipid and antioxidants in various forms of liver diseases.
      ]. A significant increase in Lp(a) levels was seen in chronic active HCV patients with a complete response to a 6-month interferon treatment [
      • Malaguarnera M.
      • Giugno I.
      • Trovato B.A.
      • et al.
      Lipoprotein(a) concentration in patients with chronic active hepatitis C before and after interferon treatment.
      ]. Also in patients with chronic HCV (81% cirrhotic), where the majority (93%) achieved a sustained virological response with a 24-week direct acting antiviral treatment, Lp(a) levels rose by ∼2-fold [
      • Gitto S.
      • Cicero A.F.G.
      • Loggi E.
      • et al.
      Worsening of serum lipid profile after direct acting antiviral treatment.
      ].
      Studies in patients with nonalcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD) have shown variable results with regard to Lp(a). A study on NASH showed similar Lp(a) levels to those of healthy controls [
      • Koruk M.
      • Savas M.C.
      • Yilmaz O.
      • et al.
      Serum lipids, lipoproteins and apolipoproteins levels in patients with nonalcoholic steatohepatitis.
      ]. Several recent Asian population studies have reported on the association between Lp(a) levels and different stages of NAFLD. Among Korean adults, Lp(a) levels decreased with the severity of NAFLD and the prevalence of NAFLD decreased with the Lp(a) tertiles [
      • Nam J.S.
      • Jo S.
      • Kang S.
      • et al.
      Association between lipoprotein(a) and nonalcoholic fatty liver disease among Korean adults.
      ]. The inverse association between Lp(a) levels and NAFLD remained significant after multivariate adjustment, but was attenuated when taking insulin resistance into account [
      • Nam J.S.
      • Jo S.
      • Kang S.
      • et al.
      Association between lipoprotein(a) and nonalcoholic fatty liver disease among Korean adults.
      ]. A large cross-sectional study in Korean adults confirmed an inverse association of Lp(a) levels with NAFLD with significantly lower levels in the NAFLD group versus the control group [
      • Jung I.
      • Kwon H.
      • Park S.E.
      • et al.
      Serum lipoprotein(a) levels and insulin resistance have opposite effects on fatty liver disease.
      ]. The odds ratio for NAFLD was the lowest in the top Lp(a) quartile [
      • Jung I.
      • Kwon H.
      • Park S.E.
      • et al.
      Serum lipoprotein(a) levels and insulin resistance have opposite effects on fatty liver disease.
      ]. Among Japanese patients with biopsy-confirmed NAFLD, Lp(a) levels were lower in patients with advanced fibrosis and an inverse association between the advanced fibrosis, NASH and Lp(a) levels remained significant in multivariate models [
      • Konishi K.
      • Miyake T.
      • Furukawa S.
      • et al.
      Advanced fibrosis of non-alcoholic steatohepatitis affects the significance of lipoprotein(a) as a cardiovascular risk factor.
      ]. In contrast, in Chinese patients with NAFLD, concentrations of Lp(a) and liver enzymes increased with the disease severity [
      • Zhang Y.
      • He H.
      • Zeng Y.P.
      • et al.
      Lipoprotein A, combined with alanine aminotransferase and aspartate aminotransferase, contributes to predicting the occurrence of NASH: a cross-sectional study.
      ]. The odds ratio of Lp(a) levels for NASH was 1.61 and a combination of Lp(a) and liver enzymes improved the prediction for NASH [
      • Zhang Y.
      • He H.
      • Zeng Y.P.
      • et al.
      Lipoprotein A, combined with alanine aminotransferase and aspartate aminotransferase, contributes to predicting the occurrence of NASH: a cross-sectional study.
      ]. Among Malaysians, a recent cross-sectional study in a high CVD risk cohort (patients with obstructive sleep apnea) found 3.5-fold higher Lp(a) levels in patients with NAFLD compared with those without NAFLD [
      • Sukahri S.
      • Mohamed Shah F.Z.
      • Ismail A.I.
      • et al.
      Significantly higher atherosclerosis risks in patients with obstructive sleep apnea and non-alcoholic fatty liver disease.
      ]. A stepwise increase in Lp(a) levels as well as in carotid intima media thickness was observed with a worsening clinical condition [
      • Sukahri S.
      • Mohamed Shah F.Z.
      • Ismail A.I.
      • et al.
      Significantly higher atherosclerosis risks in patients with obstructive sleep apnea and non-alcoholic fatty liver disease.
      ]. The differences underlying these heterogenous associations between Lp(a) levels and NAFLD across population groups need to be elucidated in future studies using standardized measurement methodology as well as potential impact from accompanying metabolic conditions, age, gender and genetics.

      5. Conclusions

      The current evidence on non-genetic influences on Lp(a) concentration indicates a potential role for diet, hormones and liver and kidney diseases (Box 1). In particular, strong consistent evidence suggests an impact on Lp(a) concentration by reducing dietary saturated fat intake, sex hormones and hormone replacement therapies and kidney diseases and treatment modalities (Table 1). In contrast, more data is needed to firmly establish any potential role for PA/exercise and certain liver diseases in influencing Lp(a) concentration. The use of well-standardized assay methods for Lp(a) measurement is of paramount importance for studying non-genetic influences on Lp(a) as discussed by a further review of this series [
      • Kronenberg F.
      Lipoprotein(a) measurement issues: are we making a mountain out of a Molehill?.
      ]. Additional factors of consideration include large sufficiently powered sample sizes and potential confounders, including but not limited to, race/ethnicity, metabolic status and genetic variability. Research to elucidate mechanisms underlying the changes in Lp(a) concentration and the modulation of Lp(a) properties beyond its plasma level will help improve our understanding of non-genetic influences on Lp(a). Finally, the clinical significance of the changes in Lp(a) concentration and its risk mediating properties due to non-genetic factors, including lifestyle interventions, remains to be seen.
      Table 1A broad summary of non-genetic factors that may influence Lp(a) concentrations described in this review article.
      Interventions and conditionsAssociation with Lp(a) concentration [Reference]
      1Diet
      a. Replacement of dietary saturated fats with carbohydrate or unsaturated fats∼8–20% increase [
      • Ginsberg H.N.
      • Kris-Etherton P.
      • Dennis B.
      • et al.
      Effects of reducing dietary saturated fatty acids on plasma lipids and lipoproteins in healthy subjects: the DELTA Study, protocol 1.
      ,
      • Berglund L.
      • Lefevre M.
      • Ginsberg H.N.
      • et al.
      Comparison of monounsaturated fat with carbohydrates as a replacement for saturated fat in subjects with a high metabolic risk profile: studies in the fasting and postprandial states.
      ,
      • Clevidence B.A.
      • Judd J.T.
      • Schaefer E.J.
      • et al.
      Plasma lipoprotein (a) levels in men and women consuming diets enriched in saturated, cis-, or trans-monounsaturated fatty acids.
      ,
      • Muller H.
      • Lindman A.S.
      • Blomfeldt A.
      • et al.
      A diet rich in coconut oil reduces diurnal postprandial variations in circulating tissue plasminogen activator antigen and fasting lipoprotein (a) compared with a diet rich in unsaturated fat in women.
      ,
      • Silaste M.L.
      • Rantala M.
      • Alfthan G.
      • et al.
      Changes in dietary fat intake alter plasma levels of oxidized low-density lipoprotein and lipoprotein(a).
      ,
      • Haring B.
      • von Ballmoos M.C.
      • Appel L.J.
      • et al.
      Healthy dietary interventions and lipoprotein(a) plasma levels: results from the Omni Heart Trial.
      ,
      • Enkhmaa B.
      • Petersen K.S.
      • Kris-Etherton P.M.
      • et al.
      Diet and Lp(a): does dietary change modify residual cardiovascular risk conferred by Lp(a)?.
      ]
      b. Low-carbohydrate, high-saturated fat diet∼15% decrease [
      • Ebbeling C.B.
      • Knapp A.
      • Johnson A.
      • et al.
      Effects of a low-carbohydrate diet on insulin-resistant dyslipoproteinemia-a randomized controlled feeding trial.
      ,
      • Enkhmaa B.
      • Petersen K.S.
      • Kris-Etherton P.M.
      • et al.
      Diet and Lp(a): does dietary change modify residual cardiovascular risk conferred by Lp(a)?.
      ]
      c. Diets enriched with walnuts or pecans∼6–15% decrease [
      • Zambon D.
      • Sabate J.
      • Munoz S.
      • et al.
      Substituting walnuts for monounsaturated fat improves the serum lipid profile of hypercholesterolemic men and women. A randomized crossover trial.
      ,
      • Rajaram S.
      • Burke K.
      • Connell B.
      • et al.
      A monounsaturated fatty acid-rich pecan-enriched diet favorably alters the serum lipid profile of healthy men and women.
      ,
      • Enkhmaa B.
      • Petersen K.S.
      • Kris-Etherton P.M.
      • et al.
      Diet and Lp(a): does dietary change modify residual cardiovascular risk conferred by Lp(a)?.
      ]
      d. Alcohol consumptionNo association or minor decrease [
      • Vu K.N.
      • Ballantyne C.M.
      • Hoogeveen R.C.
      • et al.
      Causal role of alcohol consumption in an improved lipid profile: the atherosclerosis risk in communities (ARIC) study.
      ,
      • Hao G.
      • Wang Z.
      • Zhang L.
      • et al.
      Relationship between alcohol consumption and serum lipid profiles among middle-aged population in China: a multiple-center cardiovascular epidemiological study.
      ,
      • Droste D.W.
      • Iliescu C.
      • Vaillant M.
      • et al.
      A daily glass of red wine associated with lifestyle changes independently improves blood lipids in patients with carotid arteriosclerosis: results from a randomized controlled trial.
      ,
      • Chiva-Blanch G.
      • Urpi-Sarda M.
      • Ros E.
      • et al.
      Effects of red wine polyphenols and alcohol on glucose metabolism and the lipid profile: a randomized clinical trial.
      ]
      2Physical activity and & exerciseNo or minimal association [
      • Hubinger L.
      • Mackinnon L.T.
      The effect of endurance training on lipoprotein(a) [Lp(a)] levels in middle-aged males.
      ,
      • Hubinger L.
      • Mackinnon L.T.
      • Barber L.
      • et al.
      Acute effects of treadmill running on lipoprotein(a) levels in males and females.
      ,
      • Haskell W.L.
      • Alderman E.L.
      • Fair J.M.
      • et al.
      Effects of intensive multiple risk factor reduction on coronary atherosclerosis and clinical cardiac events in men and women with coronary artery disease. The Stanford Coronary Risk Intervention Project (SCRIP).
      ,
      • Theodorou A.A.
      • Panayiotou G.
      • Volaklis K.A.
      • et al.
      Aerobic, resistance and combined training and detraining on body composition, muscle strength, lipid profile and inflammation in coronary artery disease patients.
      ,
      • Sponder M.
      • Campean I.A.
      • Dalos D.
      • et al.
      Effect of long-term physical activity on PCSK9, high- and low-density lipoprotein cholesterol, and lipoprotein(a) levels: a prospective observational trial.
      ]
      3Sex, hormones and associated conditions
      a. SexNo association or higher levels in females than males [
      • Jenner J.L.
      • Ordovas J.M.
      • Lamon-Fava S.
      • et al.
      Effects of age, sex, and menopausal status on plasma lipoprotein(a) levels. The Framingham Offspring Study.
      ,
      • Cobbaert C.
      • Kesteloot H.
      Serum lipoprotein(a) levels in racially different populations.
      ,
      • Bovet P.
      • Rickenbach M.
      • Wietlisbach V.
      • et al.
      Comparison of serum lipoprotein(a) distribution and its correlates among black and white populations.
      ,
      • Nago N.
      • Kayaba K.
      • Hiraoka J.
      • et al.
      Lipoprotein(a) levels in the Japanese population: influence of age and sex, and relation to atherosclerotic risk factors. The Jichi Medical School Cohort Study.
      ,
      • Kouvari M.
      • Panagiotakos D.B.
      • Chrysohoou C.
      • et al.
      Lipoprotein (a) and 10-year cardiovascular disease incidence in apparently healthy individuals: a sex-based sensitivity analysis from ATTICA cohort study.
      ,
      • Erhart G.
      • Lamina C.
      • Lehtimaki T.
      • et al.
      Genetic factors explain a major fraction of the 50% lower lipoprotein(a) concentrations in Finns.
      ,
      • Markus M.R.P.
      • Ittermann T.
      • Schipf S.
      • et al.
      Association of sex-specific differences in lipoprotein(a) concentrations with cardiovascular mortality in individuals with type 2 diabetes mellitus.
      ,
      • Patel A.P.
      • Wang M.
      • Pirruccello J.P.
      • et al.
      Lp(a) (Lipoprotein[a]) concentrations and incident atherosclerotic cardiovascular disease: New insights from a large National Biobank.
      ]
      b. Sex hormones (endogenous)No or minor association [
      • Haffner S.M.
      • Gruber K.K.
      • Morales P.A.
      • et al.
      Lipoprotein(a) concentrations in Mexican Americans and non-Hispanic whites: the san Antonio heart study.
      ,
      • Marcovina S.M.
      • Lippi G.
      • Bagatell C.J.
      • et al.
      Testosterone-induced suppression of lipoprotein(a) in normal men; relation to basal lipoprotein(a) level.
      ,
      • Denti L.
      • Pasolini G.
      • Ablondi F.
      • et al.
      Correlation between plasma lipoprotein Lp(a) and sex hormone concentrations: a cross-sectional study in healthy males.
      ,
      • Davoodi G.
      • Amirezadegan A.
      • Borumand M.A.
      • et al.
      The relationship between level of androgenic hormones and coronary artery disease in men.
      ,
      • Noyan V.
      • Yucel A.
      • Sagsoz N.
      The association of androgenic sex steroids with serum lipid levels in postmenopausal women.
      ,
      • Lambrinoudaki I.
      • Christodoulakos G.
      • Rizos D.
      • et al.
      Endogenous sex hormones and risk factors for atherosclerosis in healthy Greek postmenopausal women.
      ]
      c. Postmenopausal hormone replacement therapy (HRT)∼20–25% decrease; a greater decrease with oral vs transdermal estrogen; no difference between continuous vs cyclic HRT [
      • Salpeter S.R.
      • Walsh J.M.
      • Ormiston T.M.
      • et al.
      Meta-analysis: effect of hormone-replacement therapy on components of the metabolic syndrome in postmenopausal women.
      ,
      • Anagnostis P.
      • Galanis P.
      • Chatzistergiou V.
      • et al.
      The effect of hormone replacement therapy and tibolone on lipoprotein (a) concentrations in postmenopausal women: a systematic review and meta-analysis.
      ]
      d. HyperthyroidismDecreased Lp(a); treatment of overt hyperthyroidism increased Lp(a) by 20–25% [
      • Kotwal A.
      • Cortes T.
      • Genere N.
      • et al.
      Treatment of thyroid dysfunction and serum lipids: a systematic review and meta-analysis.
      ,
      • Bonde Y.
      • Breuer O.
      • Lutjohann D.
      • et al.
      Thyroid hormone reduces PCSK9 and stimulates bile acid synthesis in humans.
      ]
      e. HypothyroidismElevated Lp(a); treatment of overt and subclinical hypothyroidism decreased Lp(a) by 5–20% [
      • Kotwal A.
      • Cortes T.
      • Genere N.
      • et al.
      Treatment of thyroid dysfunction and serum lipids: a systematic review and meta-analysis.
      ,
      • Deyneli O.
      • Akpinar I.N.
      • Mericliler O.S.
      • et al.
      Effects of levothyroxine treatment on insulin sensitivity, endothelial function and risk factors of atherosclerosis in hypothyroid women.
      ,
      • Bansal S.K.
      • Yadav R.
      A study of the extended lipid profile including oxidized LDL, small dense LDL, lipoprotein (a) and apolipoproteins in the assessment of cardiovascular risk in hypothyroid patients.
      ,
      • Kaftan A.N.
      • Naser F.H.
      • Enaya M.A.
      Changes of certain metabolic and cardiovascular markers Fructosamine, H-FABP and lipoprotein (a) in patients with hypothyroidism.
      ]
      f. Growth hormone replacement therapy∼25–100% increase [
      • Eden S.
      • Wiklund O.
      • Oscarsson J.
      • et al.
      Growth hormone treatment of growth hormone-deficient adults results in a marked increase in Lp(a) and HDL cholesterol concentrations.
      ,
      • Nolte W.
      • Radisch C.
      • Armstrong V.W.
      • et al.
      The effect of recombinant human GH replacement therapy on lipoprotein(a) and other lipid parameters in adults with acquired GH deficiency: results of a double-blind and placebo-controlled trial.
      ,
      • Glynn N.
      • Halsall D.J.
      • Boran G.
      • et al.
      Growth hormone replacement may influence the biological action of thyroid hormone on liver and bone tissue.
      ]
      4Chronic kidney disease
      a. Chronic kidney disease and hemodialysisElevated Lp(a); an inverse association with kidney function; a 2–4-fold higher level only in patients with large size apo(a) vs controls [
      • Dieplinger H.
      • Lackner C.
      • Kronenberg F.
      • et al.
      Elevated plasma concentrations of lipoprotein(a) in patients with end-stage renal disease are not related to the size polymorphism of apolipoprotein(a).
      ,
      • Milionis H.J.
      • Elisaf M.S.
      • Tselepis A.
      • et al.
      Apolipoprotein(a) phenotypes and lipoprotein(a) concentrations in patients with renal failure.
      ,
      • Kronenberg F.
      • Kuen E.
      • Ritz E.
      • et al.
      Lipoprotein(a) serum concentrations and apolipoprotein(a) phenotypes in mild and moderate renal failure.
      ,
      • Kronenberg F.
      Causes and consequences of lipoprotein(a) abnormalities in kidney disease.
      ,
      • Kronenberg F.
      • Konig P.
      • Neyer U.
      • et al.
      Multicenter study of lipoprotein(a) and apolipoprotein(a) phenotypes in patients with end-stage renal disease treated by hemodialysis or continuous ambulatory peritoneal dialysis.
      ,
      • Zimmermann J.
      • Herrlinger S.
      • Pruy A.
      • et al.
      Inflammation enhances cardiovascular risk and mortality in hemodialysis patients.
      ]
      b. Continuous ambulatory peritoneal dialysis∼2-fold elevated vs controls [
      • Milionis H.J.
      • Elisaf M.S.
      • Tselepis A.
      • et al.
      Apolipoprotein(a) phenotypes and lipoprotein(a) concentrations in patients with renal failure.
      ,
      • Kronenberg F.
      • Konig P.
      • Neyer U.
      • et al.
      Multicenter study of lipoprotein(a) and apolipoprotein(a) phenotypes in patients with end-stage renal disease treated by hemodialysis or continuous ambulatory peritoneal dialysis.
      ],
      c. Nephrotic syndrome∼3–5-fold increase compared to controls [
      • Kronenberg F.
      Causes and consequences of lipoprotein(a) abnormalities in kidney disease.
      ,
      • Kronenberg F.
      • Utermann G.
      • Dieplinger H.
      Lipoprotein(a) in renal disease.
      ,
      • Wanner C.
      • Rader D.
      • Bartens W.
      • et al.
      Elevated plasma lipoprotein(a) in patients with the nephrotic syndrome.
      ,
      • Kronenberg F.
      • Lingenhel A.
      • Lhotta K.
      • et al.
      The apolipoprotein(a) size polymorphism is associated with nephrotic syndrome.
      ]
      d. Kidney transplantationSignificant reduction; near normalization [
      • Kronenberg F.
      Causes and consequences of lipoprotein(a) abnormalities in kidney disease.
      ,
      • Hopewell J.C.
      • Haynes R.
      • Baigent C.
      The role of lipoprotein(a) in chronic kidney disease.
      ,
      • Kronenberg F.
      • Konig P.
      • Lhotta K.
      • et al.
      Apolipoprotein(a) phenotype-associated decrease in lipoprotein(a) plasma concentrations after renal transplantation.
      ,
      • Kronenberg F.
      • Lhotta K.
      • Konig P.
      • et al.
      Apolipoprotein(a) isoform-specific changes of lipoprotein(a) after kidney transplantation.
      ,
      • Kerschdorfer L.
      • Konig P.
      • Neyer U.
      • et al.
      Lipoprotein(a) plasma concentrations after renal transplantation: a prospective evaluation after 4 years of follow-up.
      ,
      • Rosas S.
      • Joffe M.
      • Wolfe M.
      • et al.
      Effects of renal replacement therapy on plasma lipoprotein(a) levels.
      ]
      5Liver disease
      a. Hepatocellular damageDecreased in parallel with the disease progression; >40% reduction in hepatitis; a 2-fold increase with antiviral treatment [
      • Malaguarnera M.
      • Giugno I.
      • Trovato B.A.
      • et al.
      Lipoprotein(a) concentration in patients with chronic active hepatitis C before and after interferon treatment.
      ,
      • Gregory W.L.
      • Game F.L.
      • Farrer M.
      • et al.
      Reduced serum lipoprotein(a) levels in patients with primary biliary cirrhosis.
      ,
      • Jiang J.
      • Zhang X.
      • Wu C.
      • et al.
      Increased plasma apoM levels in the patients suffered from hepatocellular carcinoma and other chronic liver diseases.
      ,
      • Alessandri C.
      • Basili S.
      • Maurelli M.
      • et al.
      Relationship between lipoprotein(a) levels in serum and some indices of protein synthesis in liver cirrhosis.
      ,
      • Irshad M.
      Serum lipoprotein (a) levels in liver diseases caused by hepatitis.
      ,
      • Geiss H.C.
      • Ritter M.M.
      • Richter W.O.
      • et al.
      Low lipoprotein(a) levels during acute viral hepatitis.
      ,
      • Irshad M.
      • Dhar I.
      • Gupta S.
      • et al.
      Correlation of serum HCV core concentration with blood level of lipid and antioxidants in various forms of liver diseases.
      ,
      • Gitto S.
      • Cicero A.F.G.
      • Loggi E.
      • et al.
      Worsening of serum lipid profile after direct acting antiviral treatment.
      ]
      b. Non-alcoholic fatty liver diseaseInconsistent association across population groups [
      • Nam J.S.
      • Jo S.
      • Kang S.
      • et al.
      Association between lipoprotein(a) and nonalcoholic fatty liver disease among Korean adults.
      ,
      • Jung I.
      • Kwon H.
      • Park S.E.
      • et al.
      Serum lipoprotein(a) levels and insulin resistance have opposite effects on fatty liver disease.
      ,
      • Konishi K.
      • Miyake T.
      • Furukawa S.
      • et al.
      Advanced fibrosis of non-alcoholic steatohepatitis affects the significance of lipoprotein(a) as a cardiovascular risk factor.
      ,
      • Zhang Y.
      • He H.
      • Zeng Y.P.
      • et al.
      Lipoprotein A, combined with alanine aminotransferase and aspartate aminotransferase, contributes to predicting the occurrence of NASH: a cross-sectional study.
      ,
      • Sukahri S.
      • Mohamed Shah F.Z.
      • Ismail A.I.
      • et al.
      Significantly higher atherosclerosis risks in patients with obstructive sleep apnea and non-alcoholic fatty liver disease.
      ]

      Financial support

      This work was supported by the National Heart, Lung, And Blood Institute of the National Institutes of Health under Award Number R01HL157535 (B.E.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

      Declaration of competing interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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