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InternalMed_Harrison. Sepsis is a relatively common cause of hypoglycemia. Increased glucose utilization is induced by cytokine production in macrophage-rich tissues such as the liver, spleen, and lung. Hypoglycemia develops if glucose production fails to keep pace. Cytokine-induced inhibition of gluconeogenesis in the setting of nutritional glycogen depletion, in combination with hepatic and renal hypoperfusion, may also contribute to hypoglycemia. Hypoglycemia can be seen with starvation, perhaps because of loss of whole-body fat stores and subsequent depletion of gluconeogenic pre cursors (e.g., amino acids), necessitating increased glucose utilization.


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InternalMed_Harrison. Hormone Deficiencies Neither cortisol nor growth hormone is critical to the prevention of hypoglycemia, at least in adults. Nonetheless, hypoglycemia can occur with prolonged fasting in patients with primary adrenocortical failure (Addison’s disease) or hypopituitarism. Anorexia and weight loss are typical features of chronic cortisol deficiency and likely result in glycogen depletion. Cortisol deficiency is associated with impaired gluconeogenesis and low levels of gluconeogenic precursors; these associations suggest that substrate-limited gluconeogenesis, in the setting of glycogen depletion, is the cause of hypoglycemia. Growth hormone deficiency can cause hypoglycemia in young children. In addition to extended fasting, high rates of glucose utilization (e.g., during exercise or in pregnancy) or low rates of glucose production (e.g., after alcohol ingestion) can precipitate hypoglycemia in adults with previously unrecognized hypopituitarism.


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InternalMed_Harrison. Hypoglycemia is not a feature of the epinephrine-deficient state that results from bilateral adrenalectomy when glucocorticoid replacement is adequate, nor does it occur during pharmacologic adrenergic blockade when other glucoregulatory systems are intact. Combined deficiencies of glucagon and epinephrine play a key role in the pathogenesis of iatrogenic hypoglycemia in people with insulin-deficient diabetes, as discussed earlier. Otherwise, deficiencies of these hormones are not usually considered in the differential diagnosis of a hypoglycemic disorder.


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InternalMed_Harrison. Non-β-Cell Tumors Fasting hypoglycemia, often termed non–islet cell tumor hypoglycemia, occurs occasionally in patients with large mesenchymal or epithelial tumors (e.g., hepatomas, adrenocortical carcinomas, carcinoids). The glucose kinetic patterns resemble those of hyperinsulinism (see next), but insulin secretion is suppressed appropriately during hypoglycemia. In most instances, hypoglycemia is due to overproduction of an incompletely processed form of insulin-like growth factor II (“big IGF-II”) that does not complex normally with circulating binding proteins and thus more readily gains access to 2434 target tissues. The tumors are usually apparent clinically, plasma ratios of IGF-II to IGF-I are high, and free IGF-II levels (and levels of proIGF-II [1–21]) are elevated. Curative surgery is seldom possible, but reduction of tumor bulk may ameliorate hypoglycemia. Therapy with a glucocorticoid, a growth hormone, or both has also been reported to alleviate hypoglycemia.


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InternalMed_Harrison. surgery is seldom possible, but reduction of tumor bulk may ameliorate hypoglycemia. Therapy with a glucocorticoid, a growth hormone, or both has also been reported to alleviate hypoglycemia. Hypoglycemia attributed to ectopic IGF-I production has been reported but is rare.


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InternalMed_Harrison. Endogenous Hyperinsulinism Hypoglycemia due to endogenous hyperinsulinism can be caused by (1) a primary β-cell disorder—typically a β-cell tumor (insulinoma), sometimes multiple insulinomas, or a functional β-cell disorder with β-cell hypertrophy or hyperplasia; (2) an antibody to insulin or to the insulin receptor; (3) a β-cell secretagogue such as a sulfonylurea; or perhaps (4) ectopic insulin secretion, among other very rare mechanisms. None of these causes is common.


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InternalMed_Harrison. The fundamental pathophysiologic feature of endogenous hyperinsulinism caused by a primary β-cell disorder or an insulin secretagogue is the failure of insulin secretion to fall to very low levels during hypoglycemia. This feature is assessed by measurement of plasma insulin, C-peptide (the connecting peptide that is cleaved from proinsulin to produce insulin), proinsulin, and glucose concentrations during hypoglycemia. Insulin, C-peptide, and proinsulin levels need not be high relative to normal, euglycemic values; rather, they are inappropriately high in the setting of a low plasma glucose concentration. Critical diagnostic findings are a plasma insulin concentration ≥3 μU/mL (≥18 pmol/L), a plasma C-peptide concentration ≥0.6 ng/mL (≥0.2 nmol/L), and a plasma proinsulin concentration ≥5.0 pmol/L when the plasma glucose concentration is <55 mg/dL (<3.0 mmol/L) with symptoms of hypoglycemia. A low plasma β-hydroxybutyrate concentration (≤2.7 mmol/L) and an increment in plasma glucose


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InternalMed_Harrison. pmol/L when the plasma glucose concentration is <55 mg/dL (<3.0 mmol/L) with symptoms of hypoglycemia. A low plasma β-hydroxybutyrate concentration (≤2.7 mmol/L) and an increment in plasma glucose level of >25 mg/dL (>1.4 mmol/L) after IV administration of glucagon (1.0 mg) indicate increased insulin (or IGF) actions.


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InternalMed_Harrison. The diagnostic strategy is (1) to measure plasma glucose, insulin, C-peptide, proinsulin, and β-hydroxybutyrate concentrations and to screen for circulating oral hypoglycemic agents during an episode of hypoglycemia and (2) to assess symptoms during the episode and seek their resolution following correction of hypoglycemia by IV injection of glucagon (i.e., to document Whipple’s triad). This is straightforward if the patient is hypoglycemic when seen. Since endogenous hyperinsulinemic disorders usually, but not invariably, cause fasting hypoglycemia, a diagnostic episode may develop after a relatively short outpatient fast. Serial sampling during an inpatient diagnostic fast of up to 72 h or after a mixed meal is more problematic. An alternative is to give patients a detailed list of the required measurements and ask them to present to an emergency room, with the list, during a symptomatic episode. Obviously, a normal plasma glucose concentration during a symptomatic episode indicates


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InternalMed_Harrison. measurements and ask them to present to an emergency room, with the list, during a symptomatic episode. Obviously, a normal plasma glucose concentration during a symptomatic episode indicates that the symptoms are not the result of hypoglycemia.


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InternalMed_Harrison. An insulinoma—an insulin-secreting pancreatic islet β-cell tumor— is the prototypical cause of endogenous hyperinsulinism and therefore should be sought in patients with a compatible clinical syndrome. However, insulinoma is not the only cause of endogenous hyperinsulinism. Some patients with fasting endogenous hyperinsulinemic hypoglycemia have diffuse islet involvement with β-cell hypertrophy and sometimes hyperplasia. This pattern is commonly referred to as nesidioblastosis, although β-cells budding from ducts are not invariably found. Other patients have a similar islet pattern but with postprandial hypoglycemia, a disorder termed noninsulinoma pancreatogenous hypoglycemia. Postgastric bypass postprandial hypoglycemia, which most often follows Roux-en-Y gastric bypass, is also characterized by diffuse islet involvement and endogenous hyperinsulinism. Some have suggested that exaggerated GLP-1 responses to meals cause hyperinsulinemia and hypoglycemia, but the relevant pathogenesis


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InternalMed_Harrison. by diffuse islet involvement and endogenous hyperinsulinism. Some have suggested that exaggerated GLP-1 responses to meals cause hyperinsulinemia and hypoglycemia, but the relevant pathogenesis has not been clearly established. If medical treatments with agents such as an α-glucosidase inhibitor, diazoxide, or octreotide fail, partial pancreatectomy may be required. Autoimmune hypoglycemias include those caused by an antibody to insulin that binds post-meal insulin and then gradually disassociates, with consequent late postprandial hypoglycemia. Alternatively, an insulin receptor antibody can function as an agonist. The presence of an insulin secretagogue, such as a sulfonylurea or a glinide, results in a clinical and biochemical pattern similar to that of an insulinoma but can be distinguished by the presence of the circulating secretagogue. Finally, there are reports of very rare phenomena such as ectopic insulin secretion, a gain-of-function insulin receptor mutation, and


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InternalMed_Harrison. distinguished by the presence of the circulating secretagogue. Finally, there are reports of very rare phenomena such as ectopic insulin secretion, a gain-of-function insulin receptor mutation, and exercise-induced hyperinsulinemia.


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InternalMed_Harrison. Insulinomas are uncommon, with an estimated yearly incidence of 1 in 250, 000. Because more than 90% of insulinomas are benign, they are a treatable cause of potentially fatal hypoglycemia. The median age at presentation is 50 years in sporadic cases, but the tumor usually presents in the third decade when it is a component of multiple endocrine neoplasia type 1 (Chap. 408). More than 99% of insulinomas are within the substance of the pancreas, and the tumors are usually small (<2.0 cm in diameter in 90% of cases). Therefore, they come to clinical attention because of hypoglycemia rather than mass effects. CT or MRI detects ∼70–80% of insulinomas. These methods detect metastases in the roughly 10% of patients with a malignant insulinoma. Transabdominal ultrasound often identifies insulinomas, and endoscopic ultrasound has a sensitivity of ∼90%. Somatostatin receptor scintigraphy is thought to detect insulinomas in about half of patients. Selective pancreatic arterial calcium


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InternalMed_Harrison. insulinomas, and endoscopic ultrasound has a sensitivity of ∼90%. Somatostatin receptor scintigraphy is thought to detect insulinomas in about half of patients. Selective pancreatic arterial calcium injections, with the endpoint of a sharp increase in hepatic venous insulin levels, regionalize insulinomas with high sensitivity, but this invasive procedure is seldom necessary except to confirm endogenous hyperinsulinism in the diffuse islet disorders. Intraoperative pancreatic ultrasonography almost invariably localizes insulinomas that are not readily palpable by the surgeon. Surgical resection of a solitary insulinoma is generally curative. Diazoxide, which inhibits insulin secretion, or the somatostatin analogue octreotide can be used to treat hypoglycemia in patients with unresectable tumors; everolimus, an mTOR (mammalian target of rapamycin) inhibitor, is promising.


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InternalMed_Harrison. ACCIDENTAL, SURREPTITIOUS, OR MALICIOUS HYPOGLYCEMIA Accidental ingestion of an insulin secretagogue (e.g., as the result of a pharmacy or other medical error) or even accidental administration of insulin can occur. Factitious hypoglycemia, caused by surreptitious or even malicious administration of insulin or an insulin secretagogue, shares many clinical and laboratory features with insulinoma. It is most common among health care workers, patients with diabetes or their relatives, and people with a history of other factitious illnesses. However, it should be considered in all patients being evaluated for hypoglycemia of obscure cause. Ingestion of an insulin secretagogue causes hypoglycemia with increased C-peptide levels, whereas exogenous insulin causes hypoglycemia with low C-peptide levels reflecting suppression of insulin secretion.


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InternalMed_Harrison. Analytical error in the measurement of plasma glucose concentrations is rare. On the other hand, glucose monitors used to guide treatment of diabetes are not quantitative instruments, particularly at low glucose levels, and should not be used for the definitive diagnosis of hypoglycemia. Even with a quantitative method, low measured glucose concentrations can be artifactual—e.g., the result of continued glucose metabolism by the formed elements of the blood ex vivo, particularly in the presence of leukocytosis, erythrocytosis, or thrombocytosis or with delayed separation of the serum from the formed elements (pseudohypoglycemia). Nondiabetic hypoglycemia also results from inborn errors of metabolism. Such hypoglycemia most commonly occurs in infancy but can also occur in adulthood. Cases in adults can be classified into those resulting in fasting hypoglycemia, postprandial hypoglycemia, and exercise-induced hypoglycemia.


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InternalMed_Harrison. Fasting Hypoglycemia Although rare, disorders of glycogenolysis can result in fasting hypoglycemia. These disorders include glycogen storage disease (GSD) of types 0, I, III, and IV and Fanconi-Bickel syndrome (Chap. 433e). Patients with GSD types I and III characteristically have high blood lactate levels before and after meals, respectively. Both groups have hypertriglyceridemia, but ketones are high in GSD type III. Defects in fatty acid oxidation also result in fasting hypoglycemia. These defects can include (1) defects in the carnitine cycle; (2) fatty-acid β-oxidation disorders; (3) electron transfer disturbances; and (4) ketogenesis disorders. Finally, defects in gluconeogenesis (fructose-1, 6-biphosphatase) have been reported to result in recurrent hypoglycemia and lactic acidosis.


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InternalMed_Harrison. Postprandial Hypoglycemia Inborn errors of metabolism resulting in postprandial hypoglycemia are also rare. These errors include (1) glucokinase, SUR1, and Kir6.2 potassium channel mutations; (2) congenital disorders of glycosylation; and (3) inherited fructose intolerance. Exercise-Induced Hypoglycemia Exercise-induced hypoglycemia, by definition, follows exercise. It results in hyperinsulinemia caused by increased activity of monocarboxylate transporter 1 in β cells. APPROACH TO THE PATIENT: In addition to the recognition and documentation of hypoglycemia as well as its treatment (often on an urgent basis), diagnosis of the hypoglycemic mechanism is critical for the selection of therapy that prevents, or at least minimizes, recurrent hypoglycemia.


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InternalMed_Harrison. Hypoglycemia is suspected in patients with typical symptoms; in the presence of confusion, an altered level of consciousness, or a seizure; or in a clinical setting in which hypoglycemia is known to occur. Blood should be drawn, whenever possible, before the administration of glucose to allow documentation of a low plasma glucose concentration. Convincing documentation of hypoglycemia requires the fulfillment of Whipple’s triad. Thus, the ideal time to measure the plasma glucose level is during a symptomatic episode. A normal glucose level excludes hypoglycemia as the cause of the symptoms. A low glucose level confirms that hypoglycemia is the cause of the symptoms, provided the latter resolve after the glucose level is raised. When the cause of the hypoglycemic episode is obscure, additional measurements—made while the glucose level is low and before treatment—should include plasma insulin, C-peptide, proinsulin, and β-hydroxybutyrate levels; also critical are screening for


InternalMed_Harrison

InternalMed_Harrison. additional measurements—made while the glucose level is low and before treatment—should include plasma insulin, C-peptide, proinsulin, and β-hydroxybutyrate levels; also critical are screening for circulating oral hypoglycemic agents and assessment of symptoms before and after the plasma glucose concentration is raised.


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InternalMed_Harrison. When the history suggests prior hypoglycemia and no potential mechanism is apparent, the diagnostic strategy is to evaluate the patient as just described and assess for Whipple’s triad during and after an episode of hypoglycemia. On the other hand, while it cannot be ignored, a distinctly low plasma glucose concentration measured in a patient without corresponding symptoms raises the possibility of an artifact (pseudohypoglycemia).


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InternalMed_Harrison. In a patient with documented hypoglycemia, a plausible hypoglycemic mechanism can often be deduced from the history, physical examination, and available laboratory data (Table 420-1). Drugs, particularly alcohol or agents used to treat diabetes, should be the first consideration—even in the absence of known use of a relevant drug—given the possibility of surreptitious, accidental, or malicious drug administration. Other considerations include evidence of a relevant critical illness, hormone deficiencies (less commonly), and a non-β-cell tumor that can be pursued diagnostically (rarely). Absent one of these mechanisms in an otherwise seemingly well individual, the physician should consider endogenous hyperinsulinism and proceed with measurements and assessment of symptoms during spontaneous hypoglycemia or under conditions that might elicit hypoglycemia.


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InternalMed_Harrison. If the patient is able and willing, oral treatment with glucose tablets or glucose-containing fluids, candy, or food is appropriate. A reasonable initial dose is 20 g of glucose. If the patient is unable or unwilling (because of neuroglycopenia) to take carbohydrates orally, parenteral therapy is necessary. IV administration of glucose (25 g) should be followed by a glucose infusion guided by serial plasma glucose measurements. If IV therapy is not practical, SC or IM glucagon (1.0 mg in adults) can be used, particularly in patients with T1DM. Because it acts by stimulating glycogenolysis, glucagon is ineffective in glycogen-depleted individuals (e.g., those with alcohol-induced hypoglycemia). Glucagon also stimulates insulin secretion and is therefore less useful in T2DM. The somatostatin analogue octreotide can be used to suppress insulin secretion in sulfonylurea-induced hypoglycemia. These treatments raise plasma glucose concentrations only transiently, and patients should


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InternalMed_Harrison. analogue octreotide can be used to suppress insulin secretion in sulfonylurea-induced hypoglycemia. These treatments raise plasma glucose concentrations only transiently, and patients should therefore be urged to eat as soon as is practical to replete glycogen stores.


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InternalMed_Harrison. Prevention of recurrent hypoglycemia requires an understanding of the hypoglycemic mechanism. Offending drugs can be discontinued or their doses reduced. Hypoglycemia caused by a sulfonylurea can persist for hours or even days. Underlying critical illnesses can often be treated. Cortisol and growth hormone can be replaced if levels are deficient. Surgical, radiotherapeutic, or chemotherapeutic reduction of a non–islet cell tumor can alleviate hypoglycemia even if the tumor cannot be cured; glucocorticoid or growth hormone administration also may reduce hypoglycemic episodes in such patients. Surgical resection of an insulinoma is curative; medical therapy with diazoxide or octreotide can be used if resection is not possible and in patients with a nontumor β-cell disorder. Partial pancreatectomy may be necessary in the latter patients. The treatment of autoimmune hypoglycemia (e.g., with glucocorticoid or immunosuppressive drugs) is problematic, but these disorders are sometimes


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InternalMed_Harrison. may be necessary in the latter patients. The treatment of autoimmune hypoglycemia (e.g., with glucocorticoid or immunosuppressive drugs) is problematic, but these disorders are sometimes self-limited. Failing these treatments, frequent feedings and avoidance of fasting may be required. Administration of uncooked cornstarch at bedtime or even an overnight intragastric infusion of glucose may be necessary for some patients.


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InternalMed_Harrison. Disorders of lipoprotein Daniel J. Rader, Helen H. Hobbs


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InternalMed_Harrison. Lipoproteins are complexes of lipids and proteins that are essential for transport of cholesterol, triglycerides, and fat-soluble vitamins. Previously, lipoprotein disorders were the purview of specialized lipidologists, but the demonstration that lipid-lowering therapy significantly reduces the clinical complications of atherosclerotic cardiovascular disease (ASCVD) has brought the diagnosis and treatment of these disorders into the domain of the internist. The number of individuals who are candidates for lipid-lowering therapy continues to increase. Therefore, the appropriate diagnosis and management of lipoprotein disorders is of critical importance in the practice of medicine. This chapter reviews normal lipoprotein physiology, the pathophysiology of disorders of lipoprotein metabolism, the effects of diet and other environmental factors that influence lipoprotein metabolism, and the practical approaches to the diagnosis and management of lipoprotein disorders.


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InternalMed_Harrison. Lipoproteins are large macromolecular complexes composed of lipids and proteins that transport poorly soluble lipids (primarily triglycerides, cholesterol, and fat-soluble vitamins) through body fluids Disorders of Lipoprotein Metabolism Density, g/mL 0.95 1.006 1.02 FIGURE 421-1 The density and size distribution of the major classes of lipoprotein particles. Lipoproteins are classified by density and size, which are inversely related. HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein. (plasma, interstitial fluid, and lymph) to and from tissues. Lipoproteins play an essential role in the absorption of dietary cholesterol, long-chain fatty acids, and fat-soluble vitamins; the transport of triglycerides, cholesterol, and fat-soluble vitamins from the liver to peripheral tissues; and the transport of cholesterol from peripheral tissues to the liver and intestine.


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InternalMed_Harrison. Lipoproteins contain a core of hydrophobic lipids (triglycerides and cholesteryl esters) surrounded by a shell of hydrophilic lipids (phospholipids, unesterified cholesterol) and proteins (called apolipoproteins) that interact with body fluids. The plasma lipoproteins are divided into five major classes based on their relative density (Fig. 421-1 and Table 421-1): chylomicrons, very-low-density lipoproteins (VLDLs), intermediate-density lipoproteins (IDLs), low-density lipoproteins (LDLs), and high-density lipoproteins (HDLs). Each lipoprotein class comprises a family of particles that vary in density, size, and protein composition. Because lipid is less dense than water, the density of a lipoprotein particle is primarily determined by the amount of lipid per particle. Chylomicrons are the most lipid-rich and therefore least dense lipoprotein particles, whereas HDLs have the least lipid and are therefore the most dense lipoproteins. In addition to their density, lipoprotein particles


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InternalMed_Harrison. most lipid-rich and therefore least dense lipoprotein particles, whereas HDLs have the least lipid and are therefore the most dense lipoproteins. In addition to their density, lipoprotein particles can be classified according to their size, determined either by nondenaturing gel electrophoresis


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InternalMed_Harrison. ApoA-I Intestine, liver ApoA-IV Intestine, ApoC-I Liver ApoC-II Liver ApoC-III Liver, HDL, chylomicrons HDL, chylomicrons HDL, chylomicrons VLDL, chylomicrons Chylomicrons, chylomicron remnants VLDL, IDL, LDL, Lp(a) Chylomicrons, VLDL, HDL Chylomicrons, VLDL, HDL Chylomicrons, VLDL, HDL Chylomicron remnants, IDL, HDL Structural protein for HDL Structural protein for VLDL, LDL, IDL, Lp(a) Ligand for binding to LDL receptor Inhibits LPL activity and lipoprotein binding to receptors Ligand for binding to LDL receptor and other receptors Abbreviations: HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LCAT, lecithin-cholesterol acyltransferase; LDL, low-density lipoprotein; Lp(a), lipoprotein A; LPL, lipoprotein lipase; VLDL, very-low-density lipoprotein.


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InternalMed_Harrison. or by nuclear magnetic resonance profiling. There is a strong inverse relationship between density and size, with the largest particles being the most buoyant (chylomicrons) and the smallest particles being the most dense (HDL). The proteins associated with lipoproteins, called apolipoproteins (Table 421-2), are required for the assembly, structure, function, and metabolism of lipoproteins. Apolipoproteins activate enzymes important in lipoprotein metabolism and act as ligands for cell surface receptors. ApoB is a very large protein and is the major structural protein of chylomicrons, VLDLs, IDLs, and LDLs; one molecule Electrophoretic Lipoprotein Density, g/mLa Size, nmb Mobilityc Major Other Other Constituents Chylomicrons 0.930 75–1200 Origin ApoB-48 A-I, A-V, C-I, C-II, Retinyl esters C-III, E Chylomicron 0.930–1.006 30–80 Slow pre-β ApoB-48 A-I, A-V, C-I, C-II, Retinyl esters remnants C-III, E VLDL 0.930–1.006 30–80 Pre-β ApoB-100 A-I, A-II, A-V, C-I, C-II, Vitamin E


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InternalMed_Harrison. Chylomicron 0.930–1.006 30–80 Slow pre-β ApoB-48 A-I, A-V, C-I, C-II, Retinyl esters remnants C-III, E VLDL 0.930–1.006 30–80 Pre-β ApoB-100 A-I, A-II, A-V, C-I, C-II, Vitamin E C-III, E IDL 1.006–1.019 25–35 Slow pre-β ApoB-100 C-I, C-II, C-III, E Vitamin E LDL 1.019–1.063 18–25 β ApoB-100 HDL 1.063–1.210 5–12 α ApoA-I A-II, A-IV, A-V, C-III, E LCAT, CETP, paroxonase Lp(a) 1.050–1.120 25 Pre-β ApoB-100 Apo(a) Oxidized phospholipids aThe density of the particle is determined by ultracentrifugation. bThe size of the particle is measured using gel electrophoresis. cThe electrophoretic mobility of the particle on agarose gel electrophores reflects the size and surface charge of the particle, with β being the position of LDL and α being the position of HDL. Note: All of the lipoprotein classes contain phospholipids, esterified and unesterified cholesterol, and triglycerides to varying degrees.


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InternalMed_Harrison. Note: All of the lipoprotein classes contain phospholipids, esterified and unesterified cholesterol, and triglycerides to varying degrees. Abbreviations: CETP, cholesteryl ester transfer protein; HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LCAT, lecithin-cholesterol acyltransferase; LDL, low-density lipoprotein; Lp(a), lipoprotein A; VLDL, very-low-density lipoprotein.


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InternalMed_Harrison. of apoB, either apoB-48 (chylomicron) or apoB-100 (VLDL, IDL, or LDL), is present on each lipoprotein particle. The human liver synthesizes apoB-100, and the intestine makes apoB-48, which is derived from the same gene by mRNA editing. HDLs have different apolipoproteins that define this lipoprotein class, most importantly apoA-I, which is synthesized in the liver and intestine and is found on virtually all HDL particles. ApoA-II is the second most abundant HDL apolipoprotein and is on approximately two-thirds of the HDL particles. ApoC-I, apoC-II, and apoC-III participate in the metabolism of triglyceride-rich lipoproteins. ApoE also plays a critical role in the metabolism and clearance of triglyceride-rich particles. Most apolipoproteins, other than apoB, exchange actively among lipoprotein particles in the blood. Apolipoprotein(a) [apo(a)] is a distinctive apolipoprotein and is discussed more below.


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InternalMed_Harrison. One critical role of lipoproteins is the efficient transport of dietary lipids from the intestine to tissues that require fatty acids for energy or store and metabolize lipids (Fig. 421-2). Dietary triglycerides are hydrolyzed by lipases within the intestinal lumen and emulsified with bile acids to form micelles. Dietary cholesterol, fatty acids, and fat-soluble vitamins are absorbed in the proximal small intestine. Cholesterol and retinol are esterified (by the addition of a fatty acid) in the enterocyte to form cholesteryl esters and retinyl esters, respectively. Longer-chain fatty acids (>12 carbons) are incorporated into triglycerides and packaged with apoB-48, cholesteryl esters, retinyl esters, phospholipids, and cholesterol to form chylomicrons. Nascent chylomicrons are secreted into the intestinal lymph and delivered via the thoracic duct directly to the systemic circulation, where they are extensively processed by peripheral tissues before reaching the liver. The particles


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InternalMed_Harrison. into the intestinal lymph and delivered via the thoracic duct directly to the systemic circulation, where they are extensively processed by peripheral tissues before reaching the liver. The particles encounter lipoprotein lipase (LPL), which is anchored to a glycosylphosphatidylinositol-anchored protein, GPIHBP1, that 2437 is attached to the endothelial surfaces of capillaries in adipose tissue, heart, and skeletal muscle (Fig. 421-2). The triglycerides of chylomicrons are hydrolyzed by LPL, and free fatty acids are released. ApoC-II, which is transferred to circulating chylomicrons from HDL, acts as a required cofactor for LPL in this reaction. The released free fatty acids are taken up by adjacent myocytes or adipocytes and either oxidized to generate energy or reesterified and stored as triglyceride. Some of the released free fatty acids bind albumin before entering cells and are transported to other tissues, especially the liver. The chylomicron particle progressively shrinks in


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InternalMed_Harrison. as triglyceride. Some of the released free fatty acids bind albumin before entering cells and are transported to other tissues, especially the liver. The chylomicron particle progressively shrinks in size as the hydrophobic core is hydrolyzed and the hydrophilic lipids (cholesterol and phospholipids) and apolipoproteins on the particle surface are transferred to HDL, creating chylomicron remnants.


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InternalMed_Harrison. Chylomicron remnants are rapidly removed from the circulation by the liver through a process that requires apoE as a ligand for receptors in the liver. Consequently, few, if any, chylomicrons or chylomicron remnants are generally present in the blood after a 12-h fast, except in patients with certain disorders of lipoprotein metabolism.


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InternalMed_Harrison. Another key role of lipoproteins is the transport of hepatic lipids from the liver to the periphery (Fig. 421-2). VLDL particles resemble chylomicrons in protein composition but contain apoB-100 rather than apoB-48 and have a higher ratio of cholesterol to triglyceride (~1 mg of cholesterol for every 5 mg of triglyceride). The triglycerides of VLDL are derived predominantly from the esterification of long-chain fatty acids in the liver. The packaging of hepatic triglycerides with the other major components of the nascent VLDL particle (apoB-100, cholesteryl esters, phospholipids, and vitamin E) requires the action of the enzyme microsomal triglyceride transfer protein (MTP). After secretion into the plasma, VLDL acquires multiple copies of apoE and apolipoproteins of the C series by transfer from HDL. As with chylomicrons, the triglycerides of VLDL are hydrolyzed by LPL, especially in muscle, heart, and adipose tissue. After the VLDL remnants dissociate from LPL, they are referred to


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InternalMed_Harrison. from HDL. As with chylomicrons, the triglycerides of VLDL are hydrolyzed by LPL, especially in muscle, heart, and adipose tissue. After the VLDL remnants dissociate from LPL, they are referred to as IDLs, which contain roughly similar amounts of cholesterol and triglyceride. The liver removes approximately 40–60% of IDL by LDL receptor–mediated endocytosis via binding to apoE. The remainder of IDL is remodeled by hepatic lipase (HL) to form LDL. During this process, phospholipids and triglyceride in the particle are hydrolyzed, and all apolipoproteins except apoB-100 are transferred to other lipoproteins. Approximately 70% of LDL is removed from the circulation by the liver in a similar manner as IDL; however, in this case, apoB, rather than apoE, binds the LDL receptor.


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InternalMed_Harrison. Lp(a) is a lipoprotein similar to LDL in lipid and pro tein composition, but it contains an additional protein called apolipoprotein(a) [apo(a)]. Apo(a) is synthesized IDL in the liver and attached to apoB-100 by a disulfide link- Disorders of Lipoprotein Metabolism age. The major site of clearance of Lp(a) is the liver, but the uptake pathway is not known.


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InternalMed_Harrison. All nucleated cells synthesize cholesterol, but only hepatocytes and enterocytes can effectively excrete cholesterol from the body, into either the bile or the gut lumen. In the liver, cholesterol is secreted into the bile, either directly or after conversion to bile acids. Cholesterol in peripheral cells is transported from the plasma mem-FIGURE 421-2 The exogenous and endogenous lipoprotein metabolic path-branes of peripheral cells to the liver and intestine by ways. The exogenous pathway transports dietary lipids to the periphery and the a process termed “reverse cholesterol transport” that is liver. The endogenous pathway transports hepatic lipids to the periphery. FFA, free facilitated by HDL (Fig. 421-3). fatty acid; HL, hepatic lipase; IDL, intermediate-density lipoprotein; LDL, low-density Nascent HDL particles are synthesized by the intestine lipoprotein; LDLR, low-density lipoprotein receptor; LPL, lipoprotein lipase; VLDL, and the liver. Newly secreted apoA-I rapidly


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InternalMed_Harrison. low-density Nascent HDL particles are synthesized by the intestine lipoprotein; LDLR, low-density lipoprotein receptor; LPL, lipoprotein lipase; VLDL, and the liver. Newly secreted apoA-I rapidly acquires very-low-density lipoprotein. phospholipids and unesterified cholesterol from its site or drug). Many, but not all, patients with dyslipidemia are at increased risk for ASCVD, the primary reason for making the diagnosis, as intervention may reduce this risk. In addition, patients with substantially elevated levels of triglycerides may be at risk for acute pancreatitis and require intervention to reduce this risk.


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InternalMed_Harrison. Although literally hundreds of proteins influence lipoprotein metabolism and may interact to produce dyslipidemia in an individual patient, there are a limited number of discrete “nodes” that regulate lipoprotein metabolism. These include: (1) assembly and secretion of triglyceride-rich VLDLs by the liver; (2) lipolysis of triglyceride-rich lipoproteins by LPL; (3) receptor-mediated uptake of apoB-containing lipoproteins by the liver; (4) cellular cholesterol metabolism in the hepatocyte and the enterocyte; and (5) neutral lipid transfer and phospholipid hydrolysis in the plasma. The following discussion


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InternalMed_Harrison. FIGURE 421-3 High-density lipoprotein (HDL) metabolism and reverse choles-will focus on these regulatory nodes, recognizing thatterol transport. This pathway transports excess cholesterol from the periphery back in many cases these nodes interact with and influenceto the liver for excretion in the bile. The liver and the intestine produce nascent each other. HDLs. Free cholesterol is acquired from macrophages and other peripheral cells and esterified by lecithin-cholesterol acyltransferase (LCAT), forming mature HDLs. HDL DYSLIPIDEMIA CAUSED BY EXCESSIVE HEPATIC SECRETION cholesterol can be selectively taken up by the liver via SR-BI (scavenger receptor OF VLDL class BI). Alternatively, HDL cholesteryl ester can be transferred by cholesteryl ester Excessive production of VLDL by the liver is one of transfer protein (CETP) from HDLs to very-low-density lipoproteins (VLDLs) and chy-the most common causes of dyslipidemia. Individuals lomicrons, which can then be taken up by the liver.


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InternalMed_Harrison. is one of transfer protein (CETP) from HDLs to very-low-density lipoproteins (VLDLs) and chy-the most common causes of dyslipidemia. Individuals lomicrons, which can then be taken up by the liver. IDL, intermediate-density lipo-with excessive hepatic VLDL production usually have protein; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor. elevated fasting triglycerides and low levels of HDL cholesterol (HDL-C), with variable elevations in LDL cholesterol (LDL-C) but usually elevated plasma levels of synthesis (intestine or liver) via efflux promoted by the membrane of apoB. A cluster of other metabolic risk factors are often found protein ATP-binding cassette protein A1 (ABCA1). This process in association with VLDL overproduction, including obesity, gluresults in the formation of discoidal HDL particles, which then recruit cose intolerance, insulin resistance, and hypertension (the so-called additional unesterified cholesterol from cells or circulating


InternalMed_Harrison

InternalMed_Harrison. in the formation of discoidal HDL particles, which then recruit cose intolerance, insulin resistance, and hypertension (the so-called additional unesterified cholesterol from cells or circulating lipopro-metabolic syndrome, Chap. 422). Some of the major factors that teins. Within the HDL particle, the cholesterol is esterified by lecithin-drive hepatic VLDL secretion include obesity, insulin resistance, a cholesterol acyltransferase (LCAT), a plasma enzyme associated with high-carbohydrate diet, alcohol use, exogenous estrogens, and genetic HDL, and the more hydrophobic cholesteryl ester moves to the core of predisposition. the HDL particle. As HDL acquires more cholesteryl ester, it becomes


InternalMed_Harrison

InternalMed_Harrison. Secondary Causes of VLDL Overproduction • HigH-carboHydraTe dieT spherical, and additional apolipoproteins and lipids are transferred Dietary carbohydrates are converted to fatty acids in the liver. Some to the particles from the surfaces of chylomicrons and VLDLs during of the newly synthesized fatty acids are esterified forming triglycerideslipolysis. (TGs) and secreted as constituents of VLDL. Thus, excessive intake ofHDL cholesterol is transported to hepatocytes by both an indirect calories as carbohydrates, which is frequent in Western societies, leads and a direct pathway. HDL cholesteryl esters can be transferred to to increased hepatic VLDL-TG secretion.


InternalMed_Harrison

InternalMed_Harrison. apoB-containing lipoproteins in exchange for triglyceride by the cholesteryl ester transfer protein (CETP). The cholesteryl esters are then alcoHol Regular alcohol consumption inhibits hepatic oxidation removed from the circulation by LDL receptor–mediated endocytosis. of free fatty acids, thus promoting hepatic TG synthesis and VLDL HDL cholesterol can also be taken up directly by hepatocytes via the secretion. Regular alcohol use also raises plasma levels of HDL-C and scavenger receptor class B1 (SR-B1), a cell surface receptor that medi-should be considered in patients with the unusual combination of ates the selective transfer of lipids to cells. elevated TGs and elevated HDL-C.


InternalMed_Harrison

InternalMed_Harrison. HDL particles undergo extensive remodeling within the plasma oBeSity and inSulin reSiStance (See also Chaps. 416 and 417) Obesity compartment by a variety of lipid transfer proteins and lipases. The and insulin resistance are frequently accompanied by dyslipidemia phospholipid transfer protein (PLTP) transfers phospholipids from characterized by elevated plasma levels of TG, low HDL-C, variable other lipoproteins to HDL or among different classes of HDL particles. levels of LDL-C, and increased levels of small dense LDL. The increase After CETPand PLTP-mediated lipid exchange, the triglyceride-enriched HDL becomes a much better substrate for HL, which hydro-in adipocyte mass and accompanying decreased insulin sensitivity associated with obesity have multiple effects on lipid metabolism, with lyzes the triglycerides and phospholipids to generate smaller HDL one of the major effects being excessive hepatic VLDL production.


InternalMed_Harrison

InternalMed_Harrison. particles. A related enzyme called endothelial lipase hydrolyzes HDL More free fatty acids are delivered from the expanded and insulin phospholipids, generating smaller HDL particles that are catabolized resistant adipose tissue to the liver, where they are reesterified in faster. Remodeling of HDL influences the metabolism, function, and hepatocytes to form TGs, which are packaged into VLDLs for secretion plasma concentrations of HDL. into the circulation. In addition, the increased insulin levels promote DISORDERS OF ELEVATED CHOLESTEROL AND TRIGLYCERIDES increased fatty acid synthesis in the liver. In insulin-resistant patients who progress to type 2 diabetes mellitus, dyslipidemia remains com- Disorders of lipoprotein metabolism are collectively referred to as mon, even when the patient is under relatively good glycemic control.


InternalMed_Harrison

InternalMed_Harrison. Disorders of lipoprotein metabolism are collectively referred to as mon, even when the patient is under relatively good glycemic control. “dyslipidemias.” Dyslipidemias are generally characterized clinically In addition to increased VLDL production, insulin resistance can alsoby increased plasma levels of cholesterol, triglycerides, or both, variresult in decreased LPL activity, resulting in reduced catabolism ofably accompanied by reduced levels of HDL cholesterol. Because chylomicrons and VLDLs and more severe hypertriglyceridemia (seeplasma lipids are commonly screened (see below), dyslipidemia is below).


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InternalMed_Harrison. frequently seen in clinical practice. The majority of patients with dyslipidemia have some combination of genetic predisposition (often poly-nepHrotic Syndrome (See also Chap. 335) Nephrotic syndrome genic) and environmental contribution (lifestyle, medical condition, is a classic cause of excessive VLDL production. The molecular mechanism of VLDL overproduction remains poorly understood but has been attributed to the effects of hypoalbuminemia leading to increased hepatic protein synthesis. Effective treatment of the underlying renal disease often normalizes the lipid profile, but most patients with chronic nephrotic syndrome require lipid-lowering drug therapy.


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InternalMed_Harrison. cuSHinG’S Syndrome (See also Chap. 406) Endogenous or exogenous glucocorticoid excess is associated with increased VLDL synthesis and secretion and hypertriglyceridemia. Patients with Cushing’s syndrome frequently have dyslipidemia especially characterized by hypertriglyceridemia and low HDL-C, although elevations in plasma levels of LDL-C can also be seen. Primary (Genetic) Causes of VLDL Overproduction Genetic variation influences hepatic VLDL production. A number of genes have been identified in which common and low-frequency variants likely contribute to increased VLDL production, likely involving interactions with diet and other environmental factors. The best recognized inherited condition associated with VLDL overproduction is familial combined hyperlipidemia.


InternalMed_Harrison

InternalMed_Harrison. familial comBined Hyperlipidemia (fcHl) FCHL is generally characterized by elevations in plasma levels of TGs (VLDL) and LDL-C (including small dense LDL) and reduced plasma levels of HDL-C. It is estimated to occur in approximately 1 in 100–200 individuals and is an important cause of premature coronary heart disease (CHD); approximately 20% of patients who develop CHD under age 60 have FCHL. FCHL can manifest in childhood but is usually not fully expressed until adulthood. The disease clusters in families, with affected family members typically have one of three possible phenotypes: (1) elevated plasma levels of LDL-C, (2) elevated plasma levels of TGs due to elevation in VLDL, or (3) elevated plasma levels of both LDL-C and TG. The lipoprotein profile can switch among these three phenotypes in the same individual over time and may depend on factors such as diet, exercise, weight, and insulin sensitivity. Patients with FCHL almost always have significantly elevated plasma levels of


InternalMed_Harrison

InternalMed_Harrison. in the same individual over time and may depend on factors such as diet, exercise, weight, and insulin sensitivity. Patients with FCHL almost always have significantly elevated plasma levels of apoB. The levels of apoB are disproportionately high relative to the plasma LDL-C concentration, indicating the presence of small, dense LDL particles, which are characteristic of this syndrome.


InternalMed_Harrison

InternalMed_Harrison. Individuals with this phenotype generally share the same metabolic defect, namely overproduction of VLDL by the liver. The molecular etiology of this condition remains poorly understood, and no single gene has been identified in which mutations cause this disorder. It is likely that defects in a combination of genes can cause the condition, suggesting that a more appropriate term for the disorder might be polygenic combined hyperlipidemia.


InternalMed_Harrison

InternalMed_Harrison. The presence of a mixed dyslipidemia (plasma TG levels between 200 and 600 mg/dL and total cholesterol levels between 200 and 400 mg/dL, usually with HDL-C levels <40 mg/dL in men and <50 mg/dL in women) and a family history of mixed dyslipidemia and/or premature CHD strongly suggests the diagnosis. Individuals with this phenotype should be treated aggressively due to significantly increased risk of premature CHD. Decreased dietary intake of simple carbohydrates, aerobic exercise, and weight loss can all have beneficial effects on the lipid profile. Patients with diabetes should be aggressively treated to maintain good glucose control. Most patients with FCHL require lipid-lowering drug therapy, starting with statins, to reduce lipoprotein levels and lower the risk of cardiovascular disease.


InternalMed_Harrison

InternalMed_Harrison. lipodyStropHy Lipodystrophy is a condition in which the generation of adipose tissue generally or in certain fat depots is impaired. Lipodystrophies are often associated with insulin resistance and elevated plasma levels of VLDL and chylomicrons due to increased fatty acid synthesis and VLDL production, as well as reduced clearance of TG-rich particles. This disorder can be especially difficult to control. Patients with congenital generalized lipodystrophy are very rare and have nearly complete absence of subcutaneous fat, accompanied by profound insulin resistance and leptin deficiency, and accumulation of TGs in multiple tissues including the liver. Some patients with generalized lipodystrophy have been treated successfully with leptin administration. Partial lipodystrophy is somewhat more common and 2439 can be caused by mutations in several different genes, most notably lamin A. Partial lipodystrophy is usually characterized by increased truncal fat accompanied by markedly reduced


InternalMed_Harrison

InternalMed_Harrison. common and 2439 can be caused by mutations in several different genes, most notably lamin A. Partial lipodystrophy is usually characterized by increased truncal fat accompanied by markedly reduced or absent subcutaneous fat in the extremities and buttocks. These patients generally have insulin resistance, often quite severe, accompanied by type 2 diabetes, hepatosteatosis, and dyslipidemia. The dyslipidemia is usually characterized by elevated TGs and cholesterol and can be difficult to manage clinically. Patients with partial lipodystrophy are at substantially increased risk of atherosclerotic vascular disease and should therefore be treated aggressively for their dyslipidemia with statins and, if necessary, additional lipid-lowering therapies.


InternalMed_Harrison

InternalMed_Harrison. Impaired lipolysis of the TGs in TG-rich lipoproteins (TRLs) also commonly contributes to dyslipidemia. As noted above, LPL is the key enzyme responsible for hydrolyzing the TGs in chylomicrons and VLDL. LPL is synthesized and secreted into the extracellular space from adipocytes, myocytes, and cardiomyocytes. It is then transported from the subendothelial to the vascular endothelial surfaces by GPIHPB1. LPL is also synthesized in macrophages. Individuals with impaired LPL activity, whether secondary or due to a primary genetic disorder, have elevated fasting TGs and low levels of HDL-C, usually without elevation in LDL-C or apoB. Insulin resistance, in addition to causing excessive VLDL production, can also cause impaired LPL activity and lipolysis. A number of common and low-frequency genetic variants have been described that influence LPL activity, and single-gene Mendelian disorders that reduce LPL activity have also been described (Table 421-3).


InternalMed_Harrison

InternalMed_Harrison. Secondary Causes of Impaired Lipolysis of TRLs • obesiTy and insulin reSiStance (See also Chaps. 415e, 416, and 417) In addition to hepatic overproduction of VLDL, as discussed above, obesity, insulin resistance, and type 2 diabetes have been reported to be associated with variably reduced LPL activity. This may be due in part to the effects of tissue insulin resistance leading to reduced transcription of LPL in skeletal muscle and adipose, as well as to increased production of the LPL inhibitor apoC-III by the liver. This reduction in LPL activity often contributes to the dyslipidemia seen in these patients.


InternalMed_Harrison

InternalMed_Harrison. Primary (Genetic) Causes and Genetic Predisposition to Impaired Lipolysis of TRLs • familial cHylomicronemia syndrome As noted above, LPL is required for the hydrolysis of TGs in chylomicrons and VLDLs, and apoC-II is a cofactor for LPL. Genetic deficiency or inactivity of either protein results in impaired lipolysis and profound elevations in plasma chylomicrons. These patients can also have elevated plasma levels of VLDL, but chylomicronemia predominates. The fasting plasma is turbid, and if left at 4°C (39.2°F) for a few hours, the chylomicrons float to the top and form a creamy supernatant. In these disorders, collectively called the familial chylomicronemia syndrome, fasting TG levels are almost invariably >1000 mg/dL. Fasting cholesterol levels are also elevated but to a lesser degree.


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InternalMed_Harrison. LPL deficiency has autosomal recessive inheritance and has a frequency of approximately 1 in 1 million in the population. ApoC-II deficiency is also recessive in inheritance pattern and is even less common than LPL deficiency. Multiple different mutations in the LPL and APOC2 genes cause these diseases. Obligate LPL heterozygotes often have mild-to-moderate elevations in plasma TG levels, whereas individuals heterozygous for mutation in apoC-II do not have hypertriglyceridemia.


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InternalMed_Harrison. Both LPL and apoC-II deficiency usually present in childhood with recurrent episodes of severe abdominal pain due to acute pancreatitis. On funduscopic examination, the retinal blood vessels are opalescent (lipemia retinalis). Eruptive xanthomas, which are small, yellowish-white papules, often appear in clusters on the back, buttocks, and extensor surfaces of the arms and legs. These typically painless skin lesions may become pruritic. Hepatosplenomegaly results from the uptake of circulating chylomicrons by reticuloendothelial cells in the liver and spleen. For unknown reasons, some patients with persistent Disorders of Lipoprotein Metabolism Lipoprotein lipase deficiency LPL (LPL) Chylomicrons, VLDL Eruptive xanthomas, hepatosplenomegaly, AR ~1/1,000,000 pancreatitis Familial apoC-II deficiency ApoC-II (APOC2) Chylomicrons, VLDL Eruptive xanthomas, hepatosplenomegaly, AR <1/1,000,000 pancreatitis


InternalMed_Harrison

InternalMed_Harrison. Familial apoC-II deficiency ApoC-II (APOC2) Chylomicrons, VLDL Eruptive xanthomas, hepatosplenomegaly, AR <1/1,000,000 pancreatitis ApoA-V deficiency ApoA-V (APOA5) Chylomicrons, VLDL Eruptive xanthomas, hepatosplenomegaly, AR <1/1,000,000 pancreatitis GPIHBP1 deficiency GPIHBP1 Chylomicrons Eruptive xanthomas, pancreatitis AR <1/1,000,000 Familial hepatic lipase Hepatic lipase (LIPC) VLDL remnants, HDL Pancreatitis, CHD AR <1/1,000,000 deficiency Familial ApoE (APOE) Chylomicron remnants, Palmar and tuberoeruptive xanthomas, AR ~1/10,000 dysbetalipoproteinemia VLDL remnants CHD, PVD cholesterolemia, type 3 Tendon xanthomas, CHD Tendon xanthomas, CHD Tendon xanthomas, CHD Tendon xanthomas, CHD Tendon xanthomas, CHD AD ~1/250 to 1/500 AD <~1/1500 AD <1/1,000,000 AR <1/1,000,000 AR <1/1,000,000


InternalMed_Harrison

InternalMed_Harrison. Tendon xanthomas, CHD Tendon xanthomas, CHD Tendon xanthomas, CHD Tendon xanthomas, CHD Tendon xanthomas, CHD AD ~1/250 to 1/500 AD <~1/1500 AD <1/1,000,000 AR <1/1,000,000 AR <1/1,000,000 Abbreviations: AD, autosomal dominant; apo, apolipoprotein; AR, autosomal recessive; ARH, autosomal recessive hypercholesterolemia; CHD, coronary heart disease; LDL, low-density lipoprotein; LPL, lipoprotein lipase; PVD, peripheral vascular disease; VLDL, very-low density lipoprotein. and pronounced chylomicronemia never develop pancreatitis, eruptive xanthomas, or hepatosplenomegaly. Premature CHD is not generally a feature of familial chylomicronemia syndromes.


InternalMed_Harrison

InternalMed_Harrison. and pronounced chylomicronemia never develop pancreatitis, eruptive xanthomas, or hepatosplenomegaly. Premature CHD is not generally a feature of familial chylomicronemia syndromes. The diagnoses of LPL and apoC-II deficiency are established enzymatically in specialized laboratories by assaying TG lipolytic activity in postheparin plasma. Blood is sampled after an IV heparin injection to release the endothelial-bound LPL. LPL activity is profoundly reduced in both LPL and apoC-II deficiency; in patients with apoC-II deficiency, it normalizes after the addition of normal plasma (providing a source of apoC-II). Molecular sequencing of the genes can be used to confirm the diagnosis.


InternalMed_Harrison

InternalMed_Harrison. The major therapeutic intervention in familial chylomicronemia syndrome is dietary fat restriction (to as little as 15 g/d) with fat-soluble vitamin supplementation. Consultation with a registered dietician familiar with this disorder is essential. Caloric supplementation with medium-chain TGs, which are absorbed directly into the portal circulation, can be useful, but there is uncertainty about their hepatic safety with prolonged use. If dietary fat restriction alone is not successful in resolving the chylomicronemia, fish oils have been effective in some patients. In patients with apoC-II deficiency, apoC-II can be provided by infusing fresh-frozen plasma to resolve the chylomicronemia in the acute setting. Management of patients with familial chylomicronemia syndrome is particularly challenging during pregnancy when VLDL production is increased. A gene therapy approach, called alipogene tiparvovec, is approved for LPL deficiency in Europe; it involves multiple intramuscular


InternalMed_Harrison

InternalMed_Harrison. challenging during pregnancy when VLDL production is increased. A gene therapy approach, called alipogene tiparvovec, is approved for LPL deficiency in Europe; it involves multiple intramuscular injections of an adeno-associated viral vector encoding a gain-of-function LPL variant, leading to skeletal myocyte expression of LPL.


InternalMed_Harrison

InternalMed_Harrison. apoa-v deficiency Another apolipoprotein, ApoA-V, facilitates the association of VLDL and chylomicrons with LPL and promotes their hydrolysis. Individuals harboring loss-of-function mutations in both APOA5 alleles develop hyperchylomicronemia. Heterozygosity for variants in APOA5 that reduce its function contributes to the polygenic basis of hypertriglyceridemia. gPiHbP1 deficiency Homozygosity for mutations that interfere with GPIHBP1 synthesis or folding cause severe hypertriglyceridemia by compromising the transport of LPL to the vascular endothelium. The frequency of chylomicronemia due to mutations in GHIHBP1 has not been established but appears to be very rare.


InternalMed_Harrison

InternalMed_Harrison. familial HypertriGlyceridemia (fHtG) FHTG is characterized by elevated fasting TGs without a clear secondary cause, average to below average LDL-C levels, low HDL-C levels, and a family history of hypertriglyceridemia. Plasma LDL-C levels are often reduced due to defective conversion of TG-rich particles to LDL. In contrast to FCHL, apoB levels are not elevated. The identification of other first-degree relatives with hypertriglyceridemia is useful in making the diagnosis. Unlike in FCHL, this condition is not generally associated with a significantly increased risk of CHD. However, if the hypertriglyceridemia is exacerbated by environmental factors, medical conditions, or drugs, the TGs can rise to a level at which acute pancreatitis is a risk. Indeed, management of patients with this condition is mostly geared toward reduction of TGs to prevent pancreatitis.


InternalMed_Harrison

InternalMed_Harrison. Individuals with this phenotype generally have reduced lipolysis of TRLs, although overproduction of VLDL by the liver can also contribute. No single gene has been identified in which mutations cause this disorder, whereas combinations of gene variants have been shown to cause this phenotype. A more appropriate term for this condition might be polygenic hypertriglyceridemia.


InternalMed_Harrison

InternalMed_Harrison. It is important to consider and rule out secondary causes of the hypertriglyceridemia as discussed above. Increased intake of simple carbohydrates, obesity, insulin resistance, alcohol use, estrogen treatment, and certain medications can exacerbate this phenotype. Patients who are at high risk for CHD due to other risk factors should be treated with statin therapy. In patients who are otherwise not at high risk for CHD, lipid-lowering drug therapy can frequently be avoided with appropriate dietary and lifestyle changes. Patients with plasma TG levels >500 mg/ dL after a trial of diet and exercise should be considered for drug therapy with a fibrate or fish oil to reduce TGs in order to prevent pancreatitis.


InternalMed_Harrison

InternalMed_Harrison. Impaired uptake of LDL and remnant lipoproteins by the liver is another common cause of dyslipidemia. As discussed above, the LDL receptor is the major receptor responsible for uptake of LDL and remnant particles by the liver. Downregulation of LDL receptor activity or genetic variation that reduces the activity of the LDL receptor pathway leads to elevations in LDL-C. One major factor that reduces LDL receptor activity is a diet high in saturated and trans fats. Other medical conditions that reduce LDL receptor activity include hypothyroidism and estrogen deficiency. In addition, genetic variation in a number of genes influences LDL clearance, and mutations in some of these genes cause several discrete Mendelian disorders of elevated LDL-C (Table 421-3).


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InternalMed_Harrison. Secondary Causes of Impaired Hepatic Uptake of Lipoproteins • HyPo tHyroidiSm (See also Chap. 405) Hypothyroidism is associated with elevated plasma LDL-C levels due primarily to a reduction in hepatic LDL receptor function and delayed clearance of LDL. Thyroid hormone increases hepatic expression of the LDL receptor. Hypothyroid patients also frequently have increased levels of circulating IDL, and some patients with hypothyroidism also have mild hypertriglyceridemia. Because hypothyroidism is often subtle and therefore easily overlooked, all patients presenting with elevated plasma levels of LDL-C, especially if there has been an unexplained increase in LDL-C, should be screened for hypothyroidism. Thyroid replacement therapy usually ameliorates the hypercholesterolemia; if not, the patient probably has a primary lipoprotein disorder and may require lipid-lowering drug therapy with a statin.


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InternalMed_Harrison. cHronic Kidney diSeaSe (See also Chap. 335) Chronic kidney disease (CKD) is often associated with mild hypertriglyceridemia (<300 mg/ dL) due to the accumulation of VLDLs and remnant lipoproteins in the circulation. TG lipolysis and remnant clearance are both reduced in patients with renal failure. Because the risk of ASCVD is increased in end-stage renal disease, subjects with hyperlipidemia, they should usually be aggressively treated with lipid-lowering agents, even though there is inadequate data at present to indicate that this population benefits from LDL-lowering therapy. Patients with solid organ transplants often have increased lipid levels due to the effect of the drugs required for immunosuppression. These patients can present a difficult clinical management problem, since statins should be used cautiously in these patients due to untoward muscle-related side effects. Primary (Genetic) Causes of Impaired Hepatic Uptake of Lipoproteins


InternalMed_Harrison

InternalMed_Harrison. Genetic variation contributes substantially to elevated LDL-C levels in the general population. It has been estimated that at least 50% of variation in LDL-C is genetically determined. Many patients with elevated LDL-C have polygenic hypercholesterolemia characterized by hypercholesterolemia in the absence of secondary causes of hypercholesterolemia (other than dietary factors) or a primary Mendelian disorder. In patients who are genetically predisposed to higher LDL-C levels, diet plays a key role; indeed increased saturated and trans fats in the diet shifts the entire distribution of LDL levels in the population to the right. Inheritance of several variants that together elevate LDLC, coupled with diet, is generally the cause of this condition; <10% of first-degree relatives themselves have hypercholesterolemia. However, single-gene (Mendelian) causes of elevated LDL-C are relatively common and should be considered in the differential diagnosis of elevated LDL-C.


InternalMed_Harrison

InternalMed_Harrison. familial HypercHoleSterolemia (fH) FH, also known as autosomal dominant hypercholesterolemia (ADH) type 1, is an autosomal co-dominant disorder characterized by elevated plasma levels of LDL-C in the absence of hypertriglyceridemia. FH is caused by loss-of-function mutations in the gene encoding the LDL receptor. The reduction in LDL receptor activity in the liver results in a reduced rate of clearance of LDL from the circulation. The plasma level of LDL increases to a level such that the rate of LDL production equals the rate of LDL clearance by residual LDL receptor as well as non-LDL receptor mechanisms. More than 1600 different mutations have been reported in association with FH. The elevated levels of LDL-C in FH are primarily due to delayed removal of LDL from the blood; in addition, because the removal of IDL is also delayed, the production of LDL from IDL is also increased. Individuals with two mutated LDL receptor alleles (FH homozygotes, or compound heterozygotes) have much


InternalMed_Harrison

InternalMed_Harrison. because the removal of IDL is also delayed, the production of LDL from IDL is also increased. Individuals with two mutated LDL receptor alleles (FH homozygotes, or compound heterozygotes) have much higher LDL-C levels than those with one mutant allele (FH heterozygotes).


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InternalMed_Harrison. Heterozygous FH is caused by the inheritance of one mutant


InternalMed_Harrison

InternalMed_Harrison. LDL receptor allele. The population frequency of heterozy gous FH due to LDL receptor mutations was originally estimated to be 1 in 500 individuals, but recent data suggest it may be 2441 as high as approximately 1 in 250 individuals, making it one of the most common single-gene disorders in humans. FH has a higher prevalence in certain founder populations, such as South African Afrikaners, Christian Lebanese, and French Canadians. Heterozygous FH is characterized by elevated plasma levels of LDL-C (usually 200– 400 mg/dL) and normal levels of TGs. Patients with heterozygous FH have hypercholesterolemia from birth, and disease recognition is usually based on detection of hypercholesterolemia on routine screening, the appearance of tendon xanthomas, or the development of symptomatic cardiovascular disease. Inheritance is dominant, meaning that the condition was inherited from one parent and ~50% of the patient’s siblings can be expected to have hypercholesterolemia. The family history


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InternalMed_Harrison. disease. Inheritance is dominant, meaning that the condition was inherited from one parent and ~50% of the patient’s siblings can be expected to have hypercholesterolemia. The family history is frequently positive for premature CHD on the side of the family from which the mutation was inherited. Physical findings in many, but not all, patients with heterozygous FH include corneal arcus and tendon xanthomas particularly involving the dorsum of the hands and the Achilles tendons. Untreated heterozygous FH is associated with a markedly increased risk of cardiovascular disease. Untreated men with heterozygous FH have an ~50% chance of having a myocardial infarction before age 60 years, and women with heterozygous FH are at substantially increased risk as well. The age of onset of cardiovascular disease is highly variable and depends on the specific molecular defect, the level of LDL-C, and coexisting cardiovascular risk factors. FH heterozygotes with elevated plasma levels of Lp(a) (see


InternalMed_Harrison

InternalMed_Harrison. disease is highly variable and depends on the specific molecular defect, the level of LDL-C, and coexisting cardiovascular risk factors. FH heterozygotes with elevated plasma levels of Lp(a) (see below) appear to be at greater risk for cardiovascular disease.


InternalMed_Harrison

InternalMed_Harrison. No definitive diagnostic test for heterozygous FH is available, except in certain founder populations where selected mutations predominate. Most LDL receptor mutations are private and require sequencing of the LDL receptor gene for identification. Sequencing for clinical diagnosis is available but not standard of care and is rarely performed in the United States, because the clinical utility of identifying the specific mutation has not been demonstrated. A family history of hypercholesterolemia and/or premature coronary disease is supportive of the diagnosis. Secondary causes of significant hypercholesterolemia such as hypothyroidism, nephrotic syndrome, and obstructive liver disease should be excluded.


InternalMed_Harrison

InternalMed_Harrison. Heterozygous FH patients should be aggressively treated to lower plasma levels of LDL-C, starting in childhood. Initiation of a diet low in saturated and trans fats is recommended, but heterozygous FH patients virtually always require lipid-lowering drug therapy for effective control of their LDL-C levels. Statins are effective in heterozygous FH and are clearly the drug class of choice, and usually a more potent member of the class. However, some heterozygous FH patients cannot achieve adequate control of their LDL-C levels even with high-dose statin therapy and require additional drugs; a cholesterol absorption inhibitor and/or a bile acid sequestrant are the next-line classes of drugs. Currently, heterozygous FH patients whose LDL-C levels remain markedly elevated (>200 mg/dL with cardiovascular disease [CVD] or >300 mg/dL without CVD) on maximally tolerated drug therapy are candidates for LDL apheresis, a physical method of purging the blood of LDL in which the LDL particles are


InternalMed_Harrison

InternalMed_Harrison. disease [CVD] or >300 mg/dL without CVD) on maximally tolerated drug therapy are candidates for LDL apheresis, a physical method of purging the blood of LDL in which the LDL particles are selectively removed from the circulation; LDL apheresis is usually performed every 2 weeks. A new class of drugs known as PCSK9 inhibitors is under clinical development and has the potential to effectively control LDL-C levels in the vast majority of patients with heterozygous FH who are inadequately controlled on a statin alone or who are statin intolerant.


InternalMed_Harrison

InternalMed_Harrison. Homozygous FH is caused by mutations in both alleles of the LDL receptor and therefore much rarer than heterozygous FH. Patients with homozygous FH have been classified into those patients with virtually no detectable LDL receptor activity (receptor negative) and those patients with markedly reduced but detectable LDL receptor activity (receptor defective). LDL-C levels in patients with homozygous FH range from about 400 to >1000 mg/dL, with receptor-defective patients at the lower end and receptor-negative patients at the higher end of the range. TGs are usually normal. Many patients with homozygous FH, particularly receptor-negative patients, present in childhood with cutaneous xanthomas on the hands, wrists, elbows, knees, heels, or


InternalMed_Harrison

InternalMed_Harrison. Disorders of Lipoprotein Metabolism 2442 buttocks. The devastating consequence of homozygous FH is accelerated ASCVD, which often presents in childhood or early adulthood. Atherosclerosis often develops first in the aortic root, where it can cause aortic valvular or supravalvular stenosis, and typically extends into the coronary ostia, which become stenotic. Symptoms can be atypical, and sudden death is not uncommon. Untreated, receptor-negative patients with homozygous FH rarely survive beyond the second decade; patients with receptor-defective LDL receptor defects have a better prognosis but almost invariably develop clinically apparent atherosclerotic vascular disease by age 30, and often much sooner. Carotid and femoral disease develops later in life and is usually not clinically significant. Homozygous FH should be suspected in a child or young adult with LDL >400 mg/dL without secondary cause. Cutaneous xanthomas, evidence of CVD, and hypercholesterolemia in both parents all are


InternalMed_Harrison

InternalMed_Harrison. Homozygous FH should be suspected in a child or young adult with LDL >400 mg/dL without secondary cause. Cutaneous xanthomas, evidence of CVD, and hypercholesterolemia in both parents all are supportive of the diagnosis. Although the specific mutations in the LDL receptor can usually be identified by DNA sequencing, this is not generally performed, and the diagnosis is usually made on clinical grounds. Patients with homozygous FH must be treated aggressively to delay the onset and progression of CVD. Receptor defective patients sometimes respond to statins and other LDL-lowering drug classes such as a cholesterol absorption inhibitor or a bile acid sequestrant, which upregulate the LDL receptor activity. Two drugs that reduce the hepatic production of VLDL and thus LDL, a small-molecule inhibitor of the microsomal TG transfer protein (MTP) and an antisense oligonucleotide to apoB, are approved in the United States for the treatment of adults with homozygous FH and can be considered.


InternalMed_Harrison

InternalMed_Harrison. inhibitor of the microsomal TG transfer protein (MTP) and an antisense oligonucleotide to apoB, are approved in the United States for the treatment of adults with homozygous FH and can be considered. PCSK9 inhibitors, which work through increasing LDL receptor availability, appear to have some benefit in receptor-defective patients and are under clinical development. LDL apheresis is used to lower plasma LDL levels in these patients and can promote regression of xanthomas as well as slow the progression of atherosclerosis. Because the liver is quantitatively the most important tissue for removing circulating LDLs via the LDL receptor, liver transplantation is effective in decreasing plasma LDL-C levels in this disorder but is infrequently used because of the associated problems with immunosuppression.


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InternalMed_Harrison. familial defecTive aPob-100 (fdb) FDB, also known as autosomal dominant hypercholesterolemia (ADH) type 2, is a dominantly inherited disorder that clinically resembles heterozygous FH with elevated LDL-C levels and normal TGs. FDB is caused by mutations in the gene encoding apoB-100, specifically in LDL receptor–binding domain of apoB-100. Several different mutations have been identified, but a single mutation predominates: substitution of glutamine for arginine at position 3500. The mutation results in a reduction in the affinity of LDL binding to the LDL receptor, so LDL is removed from the circulation at a reduced rate. FDB is less common than FH but is more prevalent in individuals of central European descent; the Lancaster County (United States) Amish are a founder population in which the prevalence of FDB is as high as 1 in 10 individuals. FDB is characterized by elevated plasma LDL-C levels with normal TGs; tendon xanthomas can be seen, although not as frequently as in FH, and


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InternalMed_Harrison. the prevalence of FDB is as high as 1 in 10 individuals. FDB is characterized by elevated plasma LDL-C levels with normal TGs; tendon xanthomas can be seen, although not as frequently as in FH, and there is an associated increase in risk of CHD. Patients with FDB cannot be clinically distinguished from patients with heterozygous FH, although patients with FDB tend to have somewhat lower plasma levels of LDL-C than FH heterozygotes, presumably due to the fact that IDL clearance is not impaired in this disorder. Homozygotes for FDB mutations have higher LDL-C levels than FDB heterozygotes but are not as severely affected as homozygous FH patients. The apoB-100 gene mutations can be detected directly through sequencing of the receptor-binding region of the apoB gene or genotyping for the most common mutation, but genetic diagnosis is not generally performed because there is no direct implication for clinical management. As with FH, patients are treated with statins first and, if


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InternalMed_Harrison. the most common mutation, but genetic diagnosis is not generally performed because there is no direct implication for clinical management. As with FH, patients are treated with statins first and, if necessary, with additional classes of LDL-lowering drugs.


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InternalMed_Harrison. autoSomal dominant HypercHoleSterolemia due to mutationS in pcSK9 (adH-pcSK9 or adH3) ADH-PCSK9, also known as autosomal dominant hypercholesterolemia (ADH) type 3, is a very rare autosomal dominant disorder caused by gain-of-function mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 is a secreted protein that binds to the LDL receptor, targeting it for degradation. Normally, after LDL binds to the LDL receptor, it is internalized along with the receptor, and in the low pH of the endosome, the LDL receptor dissociates from the LDL and recycles to the cell surface. When PCSK9 binds the receptor, the complex is internalized and the receptor is directed to the lysosome, rather than to the cell surface. The missense mutations in PCSK9 that cause hypercholesterolemia enhance the activity of PCSK9. As a consequence, the number of hepatic LDL receptors is reduced. Patients with ADH-PCSK9 are similar clinically to patients with FH. They may be particularly responsive


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InternalMed_Harrison. the activity of PCSK9. As a consequence, the number of hepatic LDL receptors is reduced. Patients with ADH-PCSK9 are similar clinically to patients with FH. They may be particularly responsive to PCSK9 inhibitors in clinical development. Loss-of-function mutations in PCSK9 cause low LDL-C levels (see below).


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InternalMed_Harrison. autoSomal receSSive HypercHoleSterolemia (arH) ARH is a very rare disorder that is mostly seen in individuals of Sardinian descent. The disease is caused by mutations in a protein, ARH (also called LDLR adaptor protein, LDLRAP), which is required for LDL receptor–mediated endocytosis in the liver. ARH binds to the cytoplasmic domain of the LDL receptor and links the receptor to the endocytic machinery. In the absence of LDLRAP, LDL binds to the extracellular domain of the LDL receptor, but the lipoprotein-receptor complex fails to be internalized. ARH, like homozygous FH, is characterized by hypercholesterolemia, tendon xanthomas, and premature coronary artery disease (CAD). The levels of plasma LDL-C tend to be intermediate between the levels present in FH homozygotes and FH heterozygotes, and CAD is not usually symptomatic until the third decade. LDL receptor function in cultured fibroblasts is normal or only modestly reduced in ARH, whereas LDL receptor function in lymphocytes and


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InternalMed_Harrison. and CAD is not usually symptomatic until the third decade. LDL receptor function in cultured fibroblasts is normal or only modestly reduced in ARH, whereas LDL receptor function in lymphocytes and the liver is negligible. Unlike FH homozygotes, the hyperlipidemia responds to treatment with statins, but these patients usually require additional therapy to lower plasma LDL-C to acceptable levels.


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InternalMed_Harrison. SitoSterolemia Sitosterolemia is a rare autosomal recessive disease that can result in severe hypercholesterolemia, tendon xanthomas, and premature ASCVD. Sitosterolemia is caused by loss-of-function mutations in either of two members of the ATP-binding cassette (ABC) half transporter family, ABCG5 and ABCG8. These genes are expressed in enterocytes and hepatocytes. The proteins heterodimerize to form a functional complex that transports plant sterols such as sitosterol and campesterol, and animal sterols, predominantly cholesterol, across the biliary membrane of hepatocytes into the bile and across the intestinal luminal surface of enterocytes into the gut lumen. In normal individuals, <5% of dietary plant sterols are absorbed by the proximal small intestine. The small amounts of plant sterols that enter the circulation are preferentially excreted into the bile. Thus, levels of plant sterols are kept very low in tissues. In sitosterolemia, the intestinal absorption of sterols is


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InternalMed_Harrison. sterols that enter the circulation are preferentially excreted into the bile. Thus, levels of plant sterols are kept very low in tissues. In sitosterolemia, the intestinal absorption of sterols is increased and biliary and fecal excretion of the sterols is reduced, resulting in increased plasma and tissue levels of both plant sterols and cholesterol. The increase in hepatic sterol levels results in transcriptional suppression of the expression of the LDL receptor, resulting in reduced uptake of LDL and substantially increased LDL-C levels. In addition to the usual clinical picture of hypercholesterolemia (i.e., tendon xanthomas and premature ASCVD), these patients also have anisocytosis and poikilocytosis of erythrocytes and megathrombocytes due to the incorporation of plant sterols into cell membranes. Episodes of hemolysis and splenomegaly are a distinctive clinical feature of this disease compared to other genetic forms of hypercholesterolemia and can be a clue to the diagnosis.


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InternalMed_Harrison. Sitosterolemia should be suspected in a patient with severe hypercholesterolemia without a family history of such or who responds dramatically to dietary therapy and/or ezetimibe but not statins. Sitosterolemia can be diagnosed by a laboratory finding of a substantial increase in the plasma level of sitosterol and/or other plant sterols. It is important to make the diagnosis, because bile acid sequestrants and cholesterol-absorption inhibitors are the most effective agents to reduce LDL-C and plasma plant sterol levels in these patients.


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InternalMed_Harrison. cHoleSteryl eSter StoraGe diSeaSe (ceSd) CESD, also known as lysosomal acid lipase deficiency, is an autosomal recessive disorder characterized by elevated LDL-C, usually in association with low HDLC, together with progressive fatty liver ultimately leading to hepatic fibrosis. Plasma TG levels can also be mild to moderately increased in this disorder. The most severe form of this disorder, Wolman’s disease, presents in infancy and is rapidly fatal. Both Wolman’s disease and CESD are caused by loss-of-function variants in both alleles of the gene encoding lysosomal acid lipase (LAL; gene name LIPA). LAL is responsible for hydrolyzing neutral lipids, particularly TGs and cholesteryl esters, after delivery to the lysosome by cell-surface receptors such as the LDL receptor. It is particularly important in the liver, which clears large amounts of lipoproteins from the circulation. Genetic deficiency of LAL results in accumulation of neutral lipid in the hepatocytes, leading to


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InternalMed_Harrison. particularly important in the liver, which clears large amounts of lipoproteins from the circulation. Genetic deficiency of LAL results in accumulation of neutral lipid in the hepatocytes, leading to hepatosplenomegaly, microvesicular steatosis, and ultimately fibrosis and end-stage liver disease. The etiology of the elevated LDL-C levels is uncertain; one study suggested that VLDL production is increased, but impaired LDL receptor–mediated clearance of LDL is also likely.


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InternalMed_Harrison. CESD should be particularly suspected in nonobese patients with elevated LDL-C, low HDL-C, and evidence of fatty liver in the absence of overt insulin resistance. The diagnosis can be made with a dried blood spot assay of LAL activity and confirmed by DNA genotyping for the most common mutation, followed if necessary by sequencing of the gene to find the second mutation. Liver biopsy is required to assess the degree of inflammation and fibrosis. It is important to make the diagnosis because it has implications for liver monitoring and potentially for therapeutic approaches under development.


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InternalMed_Harrison. familial dySBetalipoproteinemia (fdBl) FDBL (also known as type III hyperlipoproteinemia) is usually a recessive disorder characterized by a mixed hyperlipidemia (elevated cholesterol and TGs) due to the accumulation of remnant lipoprotein particles (chylomicron remnants and VLDL remnants, or IDL). ApoE is present in multiple copies on chylomicron remnants and IDL, and mediates their removal via hepatic lipoprotein receptors (Fig. 421-2). FDBL is due to genetic variants of apoE, most commonly apoE2, that result in an apoE protein with reduced ability to bind lipoprotein receptors. The APOE gene is polymorphic in sequence, resulting in the expression of three common isoforms: apoE3, which is the most common; and apoE2 and apoE4, which both differ from apoE3 by a single amino acid. Although associated with slightly higher LDL-C levels and increased CHD risk, the apoE4 allele is not associated with FDBL. Individuals who carry one or two apoE4 alleles have an increased risk of Alzheimer’s


InternalMed_Harrison

InternalMed_Harrison. associated with slightly higher LDL-C levels and increased CHD risk, the apoE4 allele is not associated with FDBL. Individuals who carry one or two apoE4 alleles have an increased risk of Alzheimer’s disease. ApoE2 has a lower affinity for the LDL receptor; therefore, chylomicron remnants and IDL containing apoE2 are removed from plasma at a slower rate. Individuals who are homozygous for the E2 allele (the E2/E2 genotype) comprise the most common subset of patients with FDBL.


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InternalMed_Harrison. Approximately 0.5% of the general population are apoE2/E2 homo-zygotes, but only a small minority of these individuals actually develop hyperlipidemia characteristic of FDBL. In most cases, an additional, sometimes identifiable, factor precipitates the development of hyperlipoproteinemia. The most common precipitating factors are a high-fat diet, diabetes mellitus, obesity, hypothyroidism, renal disease, HIV infection, estrogen deficiency, alcohol use, or certain drugs. The disease seldom presents in women before menopause. Other mutations in apoE can cause a dominant form of FDBL where the hyperlipidemia is fully manifest in the heterozygous state, but these mutations are very rare.


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InternalMed_Harrison. Patients with FDBL usually present in adulthood with hyperlipidemia, xanthomas, or premature coronary or peripheral vascular disease. In FDBL, in contrast to other disorders of elevated TGs, the plasma levels of cholesterol and TG are often elevated to a similar degree, and the level of HDL-C is usually normal or reduced. Two distinctive types of xanthomas, tuberoeruptive and palmar, are seen in FDBL patients. Tuberoeruptive xanthomas begin as clusters of small papules on the elbows, knees, or buttocks and can grow to the size of small grapes. Palmar xanthomas (alternatively called xanthomata striata palmaris) are orange-yellow discolorations of the creases in the palms and wrists. Both of these xanthoma types are virtually pathognomonic for FDBL. 2443 Subjects with FDBL have premature ASCVD and tend to have more peripheral vascular disease than is typically seen in FH.


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InternalMed_Harrison. The definitive diagnosis of FDBL can be made either by the documentation of very high levels of remnant lipoproteins or by identification of the apoE2/E2 genotype. A variety of methods are used to identify remnant lipoproteins in the plasma, including “β-quantification” by ultracentrifugation (ratio of directly measured VLDL-C to total plasma TG >0.30), lipoprotein electrophoresis (broad β band), or nuclear magnetic resonance lipoprotein profiling. The Friedewald formula for calculation of LDL-C is not valid in FDBL because the VLDL particles are depleted in TG and enriched in cholesterol. The plasma levels of LDL-C are actually low in this disorder due to defective metabolism of VLDL to LDL. DNA-based methods (apoE genotyping) can be performed to confirm homozygosity for apoE2. However, absence of the apoE2/E2 genotype does not strictly rule out the diagnosis of FDBL, because other mutations in apoE can (rarely) cause this condition.


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InternalMed_Harrison. Because FDBL is associated with increased risk of premature ASCVD, it should be treated aggressively. Other metabolic conditions that can worsen the hyperlipidemia (see above) should be managed. Patients with FDBL are typically diet-responsive and can respond favorably to weight reduction and to low-cholesterol, low-fat diets. Alcohol intake should be curtailed. Pharmacologic therapy is often required, and statins are the first line in management. In the event of statin intolerance or insufficient control of hyperlipidemia, cholesterol absorption inhibitors, fibrates, and niacin are also effective in the treatment of FDBL.


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InternalMed_Harrison. Hepatic lipaSe deficiency Hepatic lipase (HL; gene name LIPC) is a member of the same gene family as LPL and hydrolyzes TGs and phospholipids in remnant lipoproteins and HDL. Hydrolysis of lipids in remnant particles by HL contributes to their hepatic uptake via an apoE-mediated process. HL deficiency is a very rare autosomal recessive disorder characterized by elevated plasma levels of cholesterol and TGs (mixed hyperlipidemia) due to the accumulation of lipoprotein remnants, accompanied by elevated plasma level of HDL-C. The diagnosis is confirmed by measuring HL activity in postheparin plasma and/or confirmation of loss-of-function mutations in both alleles of HL/LIPC. Due to the small number of patients with HL deficiency, the association of this genetic defect with ASCVD is not entirely clear, although anecdotally patients with HL deficiency who have premature CVD have been described. As with FDBL, statin therapy is recommended to reduce remnant lipoproteins and cardiovascular


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InternalMed_Harrison. clear, although anecdotally patients with HL deficiency who have premature CVD have been described. As with FDBL, statin therapy is recommended to reduce remnant lipoproteins and cardiovascular risk.


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InternalMed_Harrison. Additional Secondary Causes of Dyslipidemia Many of the secondary causes of dyslipidemia (Table 421-4) have been described above. Additional considerations are discussed here. liver diSorderS (See also Chap. 357) Because the liver is the principal site of formation and clearance of lipoproteins, liver disorders can affect plasma lipid levels in a variety of ways. Hepatitis due to infection, drugs, or alcohol is often associated with increased VLDL synthesis and mild to moderate hypertriglyceridemia. Severe hepatitis and liver failure are associated with dramatic reductions in plasma cholesterol and TGs due to reduced lipoprotein biosynthetic capacity.


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InternalMed_Harrison. Cholestasis is associated with hypercholesterolemia, which can be very severe. A major pathway by which cholesterol is excreted from the body is via secretion into bile, either directly or after conversion to bile acids, and cholestasis blocks this critical excretory pathway. In cholestasis, free cholesterol, coupled with phospholipids, is secreted into the plasma as a constituent of a lamellar particle called LP-X. The particles can deposit in skinfolds, producing lesions resembling those seen in patients with FDBL (xanthomata strata palmaris). Planar and eruptive xanthomas can also be seen in patients with cholestasis.


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InternalMed_Harrison. druGS Many drugs have an impact on lipid metabolism and can result in significant alterations in the lipoprotein profile (Table 421-4). Estrogen administration is associated with increased VLDL and HDL synthesis, resulting in elevated plasma levels of both TGs and HDL-C. This lipoprotein pattern is distinctive because the levels of plasma TG and HDL-C are typically inversely related. Plasma TG levels should be monitored when birth control pills or postmenopausal estrogen Disorders of Lipoprotein Metabolism Renal failure Sepsis Stress Cushing’s syndrome Pregnancy Acromegaly Lipodystrophy Drugs: estrogen, beta blockers, glucocorticoids, bile acid binding resins, retinoic acid Hypothyroidism Hypothyroidism Acromegaly Drugs: growth hor mone, isotretinoin Abbreviations: DM, diabetes mellitus; HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; Lp(a), lipoprotein A; VLDL, very-low-density lipoprotein.


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InternalMed_Harrison. Abbreviations: DM, diabetes mellitus; HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; Lp(a), lipoprotein A; VLDL, very-low-density lipoprotein. therapy is initiated to ensure that the increase in VLDL production does not lead to severe hypertriglyceridemia. Use of low-dose preparations of estrogen or the estrogen patch can minimize the effect of exogenous estrogen on lipids. Plasma concentrations of LDL-C <60 mg/dL are unusual. Although in some cases LDL-C levels in this range may be reflective of malnutrition or serious chronic illness, LDL-C <60 mg/dL in an otherwise healthy individual suggests an inherited condition. The major inherited causes of low LDL-C are reviewed here.


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InternalMed_Harrison. Abetalipoproteinemia The synthesis and secretion of apoB-containing lipoproteins in the enterocytes of the proximal small bowel and in the hepatocytes of the liver involve a complex series of events that coordinate the coupling of various lipids with apoB-48 and apoB100, respectively. Abetalipoproteinemia is a rare autosomal recessive disease caused by loss-of-function mutations in the gene encoding microsomal TG transfer protein (MTP; gene name MTTP), a protein that transfers lipids to nascent chylomicrons and VLDLs in the intestine and liver, respectively. Plasma levels of cholesterol and TG are extremely low in this disorder, and chylomicrons, VLDLs, LDLs, and apoB are undetectable in plasma. The parents of patients with abetalipoproteinemia (obligate heterozygotes) have normal plasma lipid and apoB levels. Abetalipoproteinemia usually presents in early childhood with diarrhea and failure to thrive due to fat malabsorption. The initial neurologic manifestations are loss of deep


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InternalMed_Harrison. lipid and apoB levels. Abetalipoproteinemia usually presents in early childhood with diarrhea and failure to thrive due to fat malabsorption. The initial neurologic manifestations are loss of deep tendon reflexes, followed by decreased distal lower extremity vibratory and proprioceptive sense, dysmetria, ataxia, and the development of a spastic gait, often by the third or fourth decade. Patients with abetalipoproteinemia also develop a progressive pigmented retinopathy presenting with decreased night and color vision, followed by reductions in daytime visual acuity and ultimately progressing to near-blindness. The presence of spinocerebellar degeneration and pigmented retinopathy in this disease has resulted in some patients with abetalipoproteinemia being misdiagnosed as having Friedreich’s ataxia.


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InternalMed_Harrison. Most of the clinical manifestations of abetalipoproteinemia result from defects in the absorption and transport of fat-soluble vitamins.


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InternalMed_Harrison. Vitamin E and retinyl esters are normally transported from enterocytes to the liver by chylomicrons, and vitamin E is dependent on VLDL for transport out of the liver and into the circulation. As a consequence of the inability of these patients to secrete apoB-containing particles, patients with abetalipoproteinemia are markedly deficient in vitamin E and are also mildly to moderately deficient in vitamins A and K. Patients with abetalipoproteinemia should be referred to specialized centers for confirmation of the diagnosis and appropriate therapy. Treatment consists of a low-fat, high-caloric, vitamin-enriched diet accompanied by large supplemental doses of vitamin E. It is imperative that treatment be initiated as soon as possible to prevent development of neurologic sequelae, which can progress even with appropriate therapy. New therapies for this serious disease are needed.


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InternalMed_Harrison. Familial Hypobetalipoproteinemia (FHBL) FHBL generally refers to a condition of low total cholesterol, LDL-C, and apoB due to mutations in apoB. Most of the mutations causing FHBL result in a truncated apoB protein, resulting in impaired assembly and secretion of chylomicrons from enterocytes and VLDL from the liver. Mutations that result in VLDL particles containing a truncated apoB protein are cleared from the circulation at an accelerated rate, which also contributes to patients with this disorder having low levels of LDL-C and apoB. Individuals heterozygous for these mutations usually have LDL-C levels <60–80 mg/dL and also tend to have lower levels of plasma TG. Many FHBL patients have elevated levels of hepatic fat (due to reduced VLDL export) and sometimes have increased levels of liver transaminases, although it appears that these patients infrequently develop associated inflammation and fibrosis.


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InternalMed_Harrison. Mutations in both apoB alleles cause homozygous FHBL, an extremely rare disorder resembling abetalipoproteinemia with nearly undetectable LDL-C and apoB. The neurologic defects in this form of hypobetalipoproteinemia tend to be less severe than is typically seen in abetalipoproteinemia. Homozygous hypobetalipoproteinemia can be distinguished from abetalipoproteinemia by examining the inheritance pattern of the plasma LDL-C level. The levels of LDL-C and apoB are normal in the parents of patients with abetalipoproteinemia and low in those of patients with homozygous hypobetalipoproteinemia.


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InternalMed_Harrison. PCSK9 Deficiency Another inherited cause of low LDL-C results from loss-of-function mutations in PCSK9. PCSK9 is a secreted protein that binds to the extracellular domain of the LDL receptor in the liver and promotes the degradation of the receptor. Heterozygosity for nonsense mutations in PCSK9 that interfere with the synthesis of the protein are associated with increased hepatic LDL receptor activity and reduced plasma levels of LDL-C. Such mutations are particularly frequent in individuals of African descent. Individuals who are heterozygous for a loss-of-function mutation in PCSK9 have an ~30–40% reduction in plasma levels of LDL-C and have a substantial protection from CHD relative to those without a PCSK9 mutation, presumably due to having lower plasma cholesterol levels since birth. This observation led to the development of PCSK9 inhibitors as a new strategy for reducing LDL-C levels and cardiovascular risk. Homozygotes for these nonsense mutations have been reported and have


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InternalMed_Harrison. This observation led to the development of PCSK9 inhibitors as a new strategy for reducing LDL-C levels and cardiovascular risk. Homozygotes for these nonsense mutations have been reported and have extremely low LDL-C levels (<20 mg/dL) but appear otherwise healthy. A sequence variation of somewhat higher frequency (R46L) is found predominantly in individuals of European descent. This mutation impairs, but does not completely destroy, PCSK9 function. As a consequence, the plasma levels of LDL-C in individuals carrying this mutation are more modestly reduced (~15–20%); individuals with these mutations have a 45% reduction in ASCVD risk.


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InternalMed_Harrison. Low levels of HDL-C are very commonly encountered in clinical practice. Low HDL-C is an important independent predictor of increased cardiovascular risk and has been used regularly in standardized risk calculators, including the most recent one from the American Heart Association (AHA)/American College of Cardiology (ACC). However, it remains very uncertain whether low HDL-C is directly causal for the development of ASCVD. HDL metabolism is strongly influenced by TRLs, insulin resistance, and inflammation, among other environmental and medical factors. Thus the HDL-C measurement integrates a number of cardiovascular risk factors, potentially explaining its strong inverse association with ASCVD.