Low density lipoprotein pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Environmental and genetic factors are involved in the pathophysiology of high LDL. Several conditions may contribute to the pathophysiology of high LDL, such as diet high in saturated fat, hypothyroidism, nephrotic syndrome, pregnancy, obesity, or medications such as amiodarone, cyclosporine, diuretics, and glucocorticoids.[1] Abnormally low LDL can occur, and they usually result from rare inherited conditions, such as familial hypobetalipoproteinemia, abetalipoproteinemia, Anderson's disease (chylomicron retention disease), familial combined hypolipidemia, and PCSK9 mutations.

Pathophysiology of High LDL

Familial Hypercholersterolemia

  • Contrary to other polygenic etiologies of elevated LDL, familial hypercholesterolemia (FH), also known as hyperlipidemia type II-A according to Fredrickson's classification, is a monogenic hypercholesterolemia due to deficiency of LDL receptors caused by a mutation of LDLR gene on chromosome 19. The disorder follows an autosomal co-dominant segregation pattern.[2]
  • Homozygous FH is a rare disorder; where individuals have extremely high levels of LDL, often > 1000 mg/dl in the presence of family history and cardiac or cutaneous symptoms, irrespective of other environmental factors, like diet, medications, or exercise.[3]
  • Patients with homozygous FH are very susceptible to early-onset cardiovascular disease along with cutaneous manifestations of abnormal lipid metabolism, such as eruptive xanthomas.
  • Goldstein and Brown described three cardinal features of FH:[4]
    • Selective elevation of LDL
    • Selective deposition of LDL-derived cholesterol into macrophages throughout the body but not in parenchyma
    • Inheritance as autosomal dominant trait with gene dosage effect
  • On the other hand, heterozygous FH, where only one mutated allele is present, has an incidence of 1 out of 500.[5] It is defined as any of the following:
    • LDL-C levels > 200 mg/dL + coronary heart disease/risk equivalents
    • LDL-C levels > 300 mg/dL regardless of disease or risk equivalents
  • Heterogeneous FH responds better to anti-lipidemics than the homogeneous counterpart.[2]

Diabetes Mellitus

  • Although plasma LDL concentration may be normal in patients with type II diabetes mellitus, several qualitative modifications aid in promoting atherosclerosis in this particular population.[6] The quantity of small dense triglyceride-rich LDL particles seem to be more abundant in patients with type II diabetes.[7]
  • Furthermore, patients with diabetes have increased LDL plasma residence time that contributes to increased arterial deposition of cholesterol and atherosclerosis.[6] Altered residence time is attributed to reduced LDL catabolism and decreased turnover,[6] probably due to decreased expression of LDL receptors.[8] The modification in LDL receptor have been attributed to diabetes that causes increased glycation of Apo-B within LDL altering adequate LDL receptor affinity and even worsening LDL oxidation.[9]
  • However, it is notable that insulin therapy targeting diabetes and anti-lipidemic treatment with statins have profound beneficial effects on the unfavorable LDL modifications present in diabetics. By inhibiting HMG-CoA reductase, statin therapy indirectly increases the expression of LDL receptors thus improving the abnormal affinity.[6]

Renal Disease

  • Renal disease causes a specific form of secondary dyslipidemia only when heavy proteinuria is present. Heavy proteinuria is required to exhibit decreased LDL receptor gene expression in hepatocytes, and alter gene expression of 2 key enzymes for LDL and cholesterol homeostasis: Increased activity of HMG-CoA reductase, the rate limiting enzyme for cholesterol synthesis, and reduced activity of 7α-hydroxylase, the rate limiting enzyme for cholesterol metabolism and bile acid synthesis.[10]
  • Similar to the pathogenesis observed in diabetic patients, nephrotic dyslipidemia also demonstrates changes in Apo-B that reduce LDL affinity to its receptor. The proportion of atherogenic small dense LDL particles is also increased.
  • Individuals undergoing dialysis also have abnormal LDL profiles. Patients on hemodialysis generally have normal LDL cholesterol but more concentrated small dense particules.[11] Specifically, patients on peritoneal dialysis generally have higher LDL and total cholesterol due to the considerable protein loss into the peritoneal dialysate that stimulates hepatic protein synthesis, including LDL and other lipoproteins.[12]

Liver Disease

  • Cholestatic liver disease is associated with marked hyperlipidemia and elevated LDL. It is hypothesized that because HDL is also elevated in these patients and is believed to play a protective role, cardiovascular disease does not seem to be increased in patients with cholestatic liver disease. Such outcomes, however, remain controversial.[15]

Thyroid Disease

  • Hypothyroidism is associated with marked elevations of LDL due to reduced LDL receptors that decrease LDL clearance. Since hypothyroidism also reduces oxygen consumption of cardiac myocytes, cardiac contractility is reduced and vascular resistance is increased.
  • Both vascular changes and LDL accumulation seen in hypothyroidism promote atherosclerosis.[16]

Obstructive Sleep Apnea

Oxidized LDL measured in patients with obstructive sleep apnea syndrome (OSAS) shows significant increase when compared to control groups.[17] This was believed to be due to the hypoxemia experienced by these patients that cause lipid peroxidation and an imbalance between reactive oxygen species and counteracting antioxidant reserve.[18] However, newer research findings have not entirely supported this theory; thus the exact mechanism that associates OSAS and elevated LDL remains controversial. Elevated LDL normalizes following appropriate continuous positive airway pressure (CPAP) therapy for patients with OSAS.

High LDL and Atherosclerosis

  • The term atherosclerosis was first introduced by Marchand to describe the association between fatty degeneration and medium to large-sized arterial sub-intimal thickening. Since the early 1980s, it has been emphasized that LDL oxidation is important for the development of atherosclerosis and coronary heart disease (CHD).[19] Atherosclerosis is considered the end-product and the most feared outcome of nearly all diseases that accompany an elevated LDL.
  • LDL undergoes oxidative modification in vivo by mechanisms that are still poorly understood. In-vitro studies have hypothesized the role of several enzymes in LDL oxidation, including 15-lipoxygenase, myeloperoxidase, xanthine oxidase, among several others.[20] It is believed that LDL oxidative modification accelerates accumulation of cholesterol within macrophages (foam cells) and initiate atherosclerotic lesions, called fatty streaks. Fatty streaks predispose to vascular disease and perturbation in endothelial function.
  • As a result, adhesive proteins such as ICAM-1 are overactivated allowing leukocytic and monocytic accumulation.[6] The latter plays a central role in the activation of inflammatory cascade and proliferation of smooth muscle cell and monocytes, further enhancing the inflammatory process and contributing to LDL oxidation and uptake by macrophages. Fatty streaks then evolve gradually into fibrous plaques, and subsequent lipid accumulation by LDL activity from the blood to the vessel wall leads to plaque instability and rupture resulting finally in thrombotic occlusion of the arterial bed. Oxidized LDL is considered significantly atherogenic and chemotactic for macrophages.
  • Once LDL moves from the blood to the vessel media, one of three outcomes will occur:
  1. LDL returns to blood causing regression of the lesion.
  2. LDL undergoes oxidation due to leukocytes and free radicals.
  3. LDL are taken up by scavenger receptors of macrophages that become foam cells. Scavenger receptors have particular recognition to LDL in oxidized form only.

Pathophysiology of Abnormally Low LDL

  • Familial hypobetalipoproteinemia is a rare autosomal dominant genetic disorder caused by apolipoprotein B mutations leading to loss of the ability to form lipoproteins in the liver and intestine.[21][22] Typically, plasma cholesterol levels will be in the range of 80-120 mg/dL, and LDL cholesterol will be in the range of 50-80 mg/dL.[22]
  • Abetalipoproteinemia is an autosomal recessive disorder that affects the absorption of dietary fats, cholesterol, and certain vitamins. People affected by this disorder are not able to make certain lipoproteins containing apo-B: chylomicrons, VLDL, and LDL. Two genes have been identified in which mutations are associated with this disorder: microsomal triglyceride transfer protein (MTTP) and apolipoprotein B (ApoB).[23]
  • Anderson's disease or chylomicron retention disease is an extremely rare disorder with approximately 50 cases reported. Patients with Anderson's disease have a mutated SAR1B protein in enterocytes. Although they are able to synthesize chylomicrons they are unable to transport them out of the enterocytes leading to accumulation.[24]
  • Familial combined hypolipidemia (FCH) is an inherited disorder due to a mutation in angiopoietin-like 3 (ANGPTL3). FCH leads to very low levels of LDL, HDL, triglycerides, and apo-B.[21]
  • Protein convertase subtilin/kexin type 9 (PCSK9) mutations lead to a gain of function that increases available LDL-C receptors on the surface of hepatocytes. Patients with PCSK9 mutations have LDL-C levels usually below 20 mg/dL with no other comorbidities observed and a very dramatic reduction in the incidence of cardiovascular disease. These patients were the basis for the development of PSCK9 blocking agents such as evolocumab, alirocumab, and bococizumab.[25]

References

  1. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH; et al. (2014). "2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.". J Am Coll Cardiol. 63 (25 Pt B): 2889–934. PMID 24239923. doi:10.1016/j.jacc.2013.11.002. 
  2. 2.0 2.1 Rader DJ, Cohen J, Hobbs HH (2003). "Monogenic hypercholesterolemia: new insights in pathogenesis and treatment.". J Clin Invest. 111 (12): 1795–803. PMC 161432Freely accessible. PMID 12813012. doi:10.1172/JCI18925. 
  3. Maiorana A, Nobili V, Calandra S, Francalanci P, Bernabei S, El Hachem M; et al. (2011). "Preemptive liver transplantation in a child with familial hypercholesterolemia.". Pediatr Transplant. 15 (2): E25–9. PMID 20846238. doi:10.1111/j.1399-3046.2010.01383.x. 
  4. Goldstein JL, Brown MS (1973). "Familial hypercholesterolemia: identification of a defect in the regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity associated with overproduction of cholesterol.". Proc Natl Acad Sci U S A. 70 (10): 2804–8. PMC 427113Freely accessible. PMID 4355366. 
  5. Nemati MH, Astaneh B (2010). "Optimal management of familial hypercholesterolemia: treatment and management strategies.". Vasc Health Risk Manag. 6: 1079–88. PMC 3004511Freely accessible. PMID 21191428. doi:10.2147/VHRM.S8283. 
  6. 6.0 6.1 6.2 6.3 6.4 Vergès B (2005). "New insight into the pathophysiology of lipid abnormalities in type 2 diabetes.". Diabetes Metab. 31 (5): 429–39. PMID 16357786. 
  7. Feingold KR, Grunfeld C, Pang M, Doerrler W, Krauss RM (1992). "LDL subclass phenotypes and triglyceride metabolism in non-insulin-dependent diabetes.". Arterioscler Thromb. 12 (12): 1496–502. PMID 1450181. 
  8. Duvillard L, Florentin E, Lizard G, Petit JM, Galland F, Monier S; et al. (2003). "Cell surface expression of LDL receptor is decreased in type 2 diabetic patients and is normalized by insulin therapy.". Diabetes Care. 26 (5): 1540–4. PMID 12716819. 
  9. Lyons TJ (1992). "Lipoprotein glycation and its metabolic consequences.". Diabetes. 41 Suppl 2: 67–73. PMID 1526339. 
  10. Liang K, Vaziri ND (1997). "Gene expression of LDL receptor, HMG-CoA reductase, and cholesterol-7 alpha-hydroxylase in chronic renal failure.". Nephrol Dial Transplant. 12 (7): 1381–6. PMID 9249773. 
  11. Kronenberg F, Lingenhel A, Neyer U, Lhotta K, König P, Auinger M; et al. (2003). "Prevalence of dyslipidemic risk factors in hemodialysis and CAPD patients.". Kidney Int Suppl (84): S113–6. PMID 12694323. 
  12. Wheeler DC (1996). "Abnormalities of lipoprotein metabolism in CAPD patients.". Kidney Int Suppl. 56: S41–6. PMID 8914053. 
  13. Day CP, James OF (1998). "Steatohepatitis: a tale of two "hits"?". Gastroenterology. 114 (4): 842–5. PMID 9547102. 
  14. Fon Tacer K, Rozman D (2011). "Nonalcoholic Fatty liver disease: focus on lipoprotein and lipid deregulation.". J Lipids. 2011: 783976. PMC 3136146Freely accessible. PMID 21773052. doi:10.1155/2011/783976. 
  15. Longo M, Crosignani A, Podda M (2001). "Hyperlipidemia in Chronic Cholestatic Liver Disease.". Curr Treat Options Gastroenterol. 4 (2): 111–114. PMID 11469968. 
  16. Duntas LH (2002). "Thyroid disease and lipids.". Thyroid. 12 (4): 287–93. PMID 12034052. doi:10.1089/10507250252949405. 
  17. Kizawa T, Nakamura Y, Takahashi S, Sakurai S, Yamauchi K, Inoue H (2009). "Pathogenic role of angiotensin II and oxidised LDL in obstructive sleep apnoea.". Eur Respir J. 34 (6): 1390–8. PMID 19574336. doi:10.1183/09031936.00009709. 
  18. Wali SO, Bahammam AS, Massaeli H, Pierce GN, Iliskovic N, Singal PK; et al. (1998). "Susceptibility of LDL to oxidative stress in obstructive sleep apnea.". Sleep. 21 (3): 290–6. PMID 9595608. 
  19. Steinbrecher UP, Parthasarathy S, Leake DS, Witztum JL, Steinberg D (1984). "Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids.". Proc Natl Acad Sci U S A. 81 (12): 3883–7. PMC 345326Freely accessible. PMID 6587396. 
  20. Segrest JP, Jones MK, De Loof H, Dashti N (2001). "Structure of apolipoprotein B-100 in low density lipoproteins.". J Lipid Res. 42 (9): 1346–67. PMID 11518754. 
  21. 21.0 21.1 Musunuru K, Pirruccello JP, Do R, Peloso GM, Guiducci C, Sougnez C; et al. (2010). "Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia.". N Engl J Med. 363 (23): 2220–7. PMC 3008575Freely accessible. PMID 20942659. doi:10.1056/NEJMoa1002926. 
  22. 22.0 22.1 Schonfeld G, Lin X, Yue P (2005). "Familial hypobetalipoproteinemia: genetics and metabolism.". Cell Mol Life Sci. 62 (12): 1372–8. PMID 15818469. doi:10.1007/s00018-005-4473-0. 
  23. Welty FK (2014). "Hypobetalipoproteinemia and abetalipoproteinemia.". Curr Opin Lipidol. 25 (3): 161–8. PMC 4465983Freely accessible. PMID 24751931. doi:10.1097/MOL.0000000000000072. 
  24. Okada T, Miyashita M, Fukuhara J, Sugitani M, Ueno T, Samson-Bouma ME; et al. (2011). "Anderson's disease/chylomicron retention disease in a Japanese patient with uniparental disomy 7 and a normal SAR1B gene protein coding sequence.". Orphanet J Rare Dis. 6: 78. PMC 3284428Freely accessible. PMID 22104167. doi:10.1186/1750-1172-6-78. 
  25. Mabuchi H, Nohara A, Noguchi T, Kobayashi J, Kawashiri MA, Inoue T; et al. (2014). "Genotypic and phenotypic features in homozygous familial hypercholesterolemia caused by proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutation.". Atherosclerosis. 236 (1): 54–61. PMID 25014035. doi:10.1016/j.atherosclerosis.2014.06.005. 




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