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InternalMed_Harrison. The majority of patients with low HDL-C have some combination of genetic predisposition and secondary factors. Variants in dozens of genes have been shown to influence HDL-C levels. Even more important quantitatively, obesity and insulin resistance have strong suppressive effects on HDL-C, and low HDL-C in these conditions is widely observed. Furthermore, the vast majority of patients with elevated TGs have reduced levels of HDL-C. Most patients with low HDL-C who have been studied in detail have accelerated catabolism of HDL and its associated apoA-I as the physiologic basis for the low HDL C. Importantly, although HDL-C remains an important biomarker for assessing cardiovascular risk, it is not currently a direct target of intervention for raising the level in order to reduce cardiovascular risk. Certain therapeutic approaches in clinical development, such as inhibitors of CETP (see below), have the potential to change this paradigm.


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InternalMed_Harrison. Mutations in genes encoding proteins that play critical roles in HDL synthesis and catabolism can result in reductions in plasma levels of HDL-C. Unlike the genetic forms of hypercholesterolemia, which are invariably associated with premature coronary atherosclerosis, genetic forms of hypoalphalipoproteinemia (low HDL-C) are often not associated with clearly increased risk of ASCVD.


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InternalMed_Harrison. Gene Deletions in the APOA5-A1-C3-A4 Locus and Coding Mutations in APOA1 Complete genetic deficiency of apoA-I due to a complete deletion of the APOA1 gene results in the virtual absence of circulating HDL and appears to increase the risk of premature ASCVD. The genes encoding APOA5, APOA1, APOC3, and APOA4 are clustered together on chromosome 11. Some patients with no apoA-I have genomic deletions that include other genes in the cluster. ApoA-I is required for LCAT activity. In the absence of LCAT, free cholesterol levels increase in both plasma (not HDL) and in tissues. The free cholesterol can form deposits in the cornea and in the skin, resulting in corneal 2445 opacities and planar xanthomas. Premature CHD is associated with apoA-I deficiency.


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InternalMed_Harrison. Missense and nonsense mutations in the apoA-I gene are present in some patients with low plasma levels of HDL-C (usually 15–30 mg/ dL), but are a rare cause of low plasma HDL-C levels. Most individuals with low plasma HDL-C levels due to missense mutations in apoA-I do not appear to have premature CHD. Patients who are heterozygous for an Arg173Cys substitution in apoA-I (so-called apoA-IMilano) have very low plasma levels of HDL-C due to impaired LCAT activation and accelerated clearance of the HDL particles containing the abnormal apoA-I. Despite having very low plasma levels of HDL-C, these individuals do not have an increased risk of premature CHD. A few selected missense mutations in apoA-I and apoA-II promote the formation of amyloid fibrils, which can cause systemic amyloidosis.


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InternalMed_Harrison. Tangier Disease (ABCA1 Deficiency) Tangier disease is a rare autosomal co-dominant form of extremely low plasma HDL-C levels that is caused by mutations in the gene encoding ABCA1, a cellular transporter that facilitates efflux of unesterified cholesterol and phospholipids from cells to apoA-I (Fig. 421-3). ABCA1 in the liver and intestine rapidly lipidates the apoA-I secreted from the basolateral membranes of these tissues. In the absence of ABCA1, the nascent, poorly lipidated apoA-I is immediately cleared from the circulation. Thus, patients with Tangier disease have extremely low circulating plasma levels of HDL-C (<5 mg/dL) and apoA-I (<5 mg/dL). Cholesterol accumulates in the reticuloendothelial system of these patients, resulting in hepatosplenomegaly and pathognomonic enlarged, grayish yellow or orange tonsils. An intermittent peripheral neuropathy (mononeuritis multiplex) or a sphingomyelia-like neurologic disorder can also be seen in this disorder. Tangier disease is


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InternalMed_Harrison. grayish yellow or orange tonsils. An intermittent peripheral neuropathy (mononeuritis multiplex) or a sphingomyelia-like neurologic disorder can also be seen in this disorder. Tangier disease is probably associated with some increased risk of premature atherosclerotic disease, although the association is not as robust as might be anticipated, given the very low levels of HDL-C and apoA-I in these patients. Patients with Tangier disease also have low plasma levels of LDL-C, which may attenuate the atherosclerotic risk. Obligate heterozygotes for ABCA1 mutations have moderately reduced plasma HDL-C levels (15–30 mg/dL), and their risk of premature CHD remains uncertain.


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InternalMed_Harrison. Familial LCAT Deficiency This rare autosomal recessive disorder is caused by mutations in LCAT, an enzyme synthesized in the liver and secreted into the plasma, where it circulates associated with lipoproteins (Fig. 421-3). As reviewed above, the enzyme is activated by apoA-I and mediates the esterification of cholesterol to form cholesteryl esters. Consequently, in familial LCAT deficiency, the proportion of free cholesterol in circulating lipoproteins is greatly increased (from ~25% to >70% of total plasma cholesterol). Deficiency in this enzyme interferes with the maturation of HDL particles and results in rapid catabolism of circulating apoA-I.


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InternalMed_Harrison. Two genetic forms of familial LCAT deficiency have been described in humans: complete deficiency (also called classic LCAT deficiency) and partial deficiency (also called fish-eye disease). Progressive corneal opacification due to the deposition of free cholesterol in the cornea, very low plasma levels of HDL-C (usually <10 mg/dL), and variable hypertriglyceridemia are characteristic of both disorders. In partial LCAT deficiency, there are no other known clinical sequelae. In contrast, patients with complete LCAT deficiency have hemolytic anemia and progressive renal insufficiency that eventually leads to end-stage renal disease. Remarkably, despite the extremely low plasma levels of HDL-C and apoA-I, premature ASCVD is not a consistent feature of either LCAT deficiency or fish eye disease. The diagnosis can be confirmed in a specialized laboratory by assaying plasma LCAT activity or by sequencing the LCAT gene.


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InternalMed_Harrison. Primary Hypoalphalipoproteinemia The condition of low plasma levels of HDL-C (the “alpha lipoprotein”) is referred to as hypoalphalipoproteinemia. Primary hypoalphalipoproteinemia is defined as a plasma HDL-C level below the tenth percentile in the setting of relatively normal cholesterol and TG levels, no apparent secondary causes of low plasma HDL-C, and no clinical signs of LCAT deficiency or Tangier


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InternalMed_Harrison. Disorders of Lipoprotein Metabolism 2446 disease. This syndrome is often referred to as isolated low HDL. A family history of low HDL-C facilitates the diagnosis of an inherited condition, which may follow an autosomal dominant pattern. The metabolic etiology of this disease appears to be primarily accelerated catabolism of HDL and its apolipoproteins. Some of these patients may have ABCA1 mutations and therefore technically have heterozygous Tangier disease. Several kindreds with primary hypoalphalipoproteinemia and an increased incidence of premature CHD have been described, although it is not clear if the low HDL-C level is the cause of the accelerated atherosclerosis in these families. Association of hypoalphalipoproteinemia with premature CHD may depend on the specific nature of the gene defect or the underlying metabolic defect that either directly or indirectly causes the low plasma HDL-C level.


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InternalMed_Harrison. INHERITED CAUSES OF VERY HIGH LEVELS OF HDL-C CETP Deficiency Loss-of-function mutations in both alleles of the gene encoding CETP cause substantially elevated HDL-C levels (usually >150 mg/dL). As noted above, CETP transfers cholesteryl esters from HDL to apoB-containing lipoproteins (Fig. 421-3). Absence of this transfer activity results in an increase in the cholesteryl ester content of HDL and a reduction in plasma levels of LDL-C. The large, cholesterol-rich HDL particles circulating in these patients are cleared at a reduced rate. CETP deficiency was first diagnosed in Japanese persons and is rare outside of Japan. The relationship of CETP deficiency to ASCVD remains unresolved. Heterozygotes for CETP deficiency have only modestly elevated HDL-C levels. Based on the phenotype of high HDL-C in CETP deficiency, pharmacologic inhibition of CETP is under development as a new therapeutic approach to both raise HDL-C levels and lower LDL-C levels, but whether it will reduce risk of


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InternalMed_Harrison. HDL-C in CETP deficiency, pharmacologic inhibition of CETP is under development as a new therapeutic approach to both raise HDL-C levels and lower LDL-C levels, but whether it will reduce risk of ASCVD remains to be determined.


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InternalMed_Harrison. SCREENING, DIAGNOSIS, AND MANAGEMENT OF DISORDERS OF LIPOPROTEIN METABOLISM


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InternalMed_Harrison. Plasma lipid and lipoprotein levels should be measured in all adults, preferably after a 12-h overnight fast. In most clinical laboratories, the total cholesterol and TGs in the plasma are measured enzymatically, and then the cholesterol in the supernatant is measured after precipitation of apoB-containing lipoproteins to determine the HDL-C. The LDL-C is then estimated using the following equation: (The VLDL cholesterol content is estimated by dividing the plasma TG by 5, reflecting the ratio of TG to cholesterol in VLDL particles.) This formula (the Friedewald formula) is reasonably accurate if test results are obtained on fasting plasma and if the TG level does not exceed ~200 mg/dL; by convention it cannot be used if the TG level is >400 mg/dL. LDL-C can be directly measured by a number of methods. Further evaluation and treatment are based primarily on the clinical assessment of absolute cardiovascular risk using risk calculators such as the AHA/ACC risk calculator based on a


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InternalMed_Harrison. of methods. Further evaluation and treatment are based primarily on the clinical assessment of absolute cardiovascular risk using risk calculators such as the AHA/ACC risk calculator based on a large amount of observational data.


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InternalMed_Harrison. A critical first step in managing a lipoprotein disorder is to attempt to determine the class or classes of lipoproteins that are increased or decreased in the patient. Once the hyperlipidemia is accurately classified, efforts should be directed to rule out any possible secondary causes of the hyperlipidemia (Table 421-4). Although many patients with hyperlipidemia have a primary (i.e., genetic) cause of their lipid disorder, secondary factors frequently contribute to the hyperlipidemia. A careful social, medical, and family history should be obtained. A fasting glucose should be obtained in the initial workup of all subjects with an elevated TG level. Nephrotic syndrome and chronic renal insufficiency should be excluded by obtaining urine protein and serum creatinine. Liver function tests should be performed to rule out hepatitis and cholestasis. Hypothyroidism should be ruled out by measuring serum thyroid-stimulating hormone.


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InternalMed_Harrison. Once secondary causes have been ruled out, attempts should be made to diagnose the primary lipid disorder because the underlying genetic defect can provide important prognostic information regarding the risk of developing CHD, the response to drug therapy, and the management of other family members. Obtaining the correct diagnosis often requires a detailed family medical history, lipid analyses in family members, and sometimes specialized testing.


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InternalMed_Harrison. Severe Hypertriglyceridemia If the fasting plasma TG level is >1000 mg/dL, the patient has chylomicronemia. If the cholesterol-to-TG ratio is >10, familial chylomicronemia syndrome must be considered, and LPL activity measured in postheparin plasma can help with making that diagnosis. Most adults with chylomicronemia also have elevated VLDL levels. These individuals usually do not have a Mendelian disorder but instead are genetically predisposed and have secondary factors (diet, obesity, glucose intolerance, alcohol ingestion, estrogen therapy) that contribute to the hyperlipidemia. Such patients are a risk of acute pancreatitis and should be treated to reduce their TG levels and thus their risk of pancreatitis.


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InternalMed_Harrison. Severe Hypercholesterolemia If the levels of LDL-C are very high (greater than a ninety-fifth percentile for age and sex), it is likely that the patient has a genetic cause of hypercholesterolemia. At present, there is no compelling reason to perform molecular studies to further refine the molecular diagnosis because the clinical management is not affected. Recessive forms of severe hypercholesterolemia are rare, but if a patient with severe hypercholesterolemia has parents with normal cholesterol levels, ARH, sitosterolemia, and CESD should be considered. Patients with more moderate hypercholesterolemia that does not segregate in families as a monogenic trait are likely to have polygenic hypercholesterolemia.


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InternalMed_Harrison. Combined Hyperlipidemia The most common errors in the diagnosis of lipid disorders involve patients with combined hyperlipidemia. Elevations in the plasma levels of both cholesterol and TGs are seen in patients with increased plasma levels of VLDL and LDL or of remnant lipoproteins. A β-quantification to determine the VLDL cholesterol/TG ratio in plasma (see discussion of FDBL) or a direct measurement of the plasma LDL-C should be performed at least once prior to initiation of lipid-lowering therapy to determine if the hyperlipidemia is due to the accumulation of remnants or to an increase in both LDL and VLDL. Measurement of plasma apoB levels can help identify patients with FCHL who may require more aggressive treatment. APPROACH TO THE PATIENT: The major goals in the clinical management of lipoprotein disorders are: (1) prevention of acute pancreatitis in patients with severe hypertriglyceridemia; and (2) prevention of CVD and related cardiovascular events.


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InternalMed_Harrison. Although the observational relationship between severe hypertriglyceridemia, particularly chylomicronemia, and acute pancreatitis is well-established, there has never been a clinical trial designed or powered to prove that intervention to reduce TGs reduces the risk of pancreatitis. Nevertheless, it is generally considered appropriate medical practice to intervene in patients with TGs >500 mg/dL in order to reduce the risk of pancreatitis. It remains controversial whether individuals with severe hypertriglyceridemia are at increased risk for ASCVD.


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InternalMed_Harrison. Lifestyle Modifying the lifestyle of the patient with severe hypertriglyceridemia often is associated with a significant reduction in plasma TG level. Patients who drink alcohol should be encouraged to decrease or preferably eliminate their intake. Patients with severe hypertriglyceridemia often benefit from a formal dietary consultation with a dietician intimately familiar with counseling patients on the dietary management of high TGs. Dietary fat intake should be restricted to reduce the formation of chylomicrons in the intestine. The excessive intake of simple carbohydrates should be discouraged because insulin drives TG production in the liver. Aerobic exercise and even increase in regular physical activity can have a positive effect in reducing TG levels and should be strongly encouraged. For patients who are overweight, weight loss can help to reduce TG levels. In extreme cases, bariatric surgery has been shown to not only produce effective weight loss but also substantially


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InternalMed_Harrison. For patients who are overweight, weight loss can help to reduce TG levels. In extreme cases, bariatric surgery has been shown to not only produce effective weight loss but also substantially reduce plasma TG levels.


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InternalMed_Harrison. Pharmacologic Therapy for Severe Hypertriglyceridemia Despite the above interventions, however, many patients with severe hypertriglyceridemia require pharmacologic therapy (Table 421-5). Patients who persist in having fasting TG >500 mg/dL despite active lifestyle management are candidates for pharmacologic therapy. There are three classes of drugs that are used for management of these patients: fibrates, omega-3 fatty acids (fish oils), and niacin. In addition, statins can reduce plasma TG levels and also reduce ASCVD risk.


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InternalMed_Harrison. fiBrateS Fibric acid derivatives, or fibrates, are agonists of PPARα, a nuclear receptor involved in the regulation of lipid metabolism. Fibrates stimulate LPL activity (enhancing TG hydrolysis), reduce apoC-III synthesis (enhancing lipoprotein remnant clearance), promote β-oxidation of fatty acids, and may reduce VLDL TG production. Fibrates are a first-line therapy for severe hypertriglyceridemia (>500 mg/dL). This class of therapeutic agents sometimes lowers but more often raises the plasma level of LDL-C in individuals with severe hypertriglyceridemia. Fibrates are generally well tolerated, but are associated with an increase in the incidence of gallstones. Fibrates can cause myopathy, especially when combined with other lipid-lowering therapy (statins, niacin), and can raise creatinine. Fibrates should be used with caution in patients with CKD. Importantly, fibrates can potentiate the effect of warfarin and certain oral hypoglycemic agents, so the anticoagulation status and


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InternalMed_Harrison. Fibrates should be used with caution in patients with CKD. Importantly, fibrates can potentiate the effect of warfarin and certain oral hypoglycemic agents, so the anticoagulation status and plasma glucose levels should be closely monitored in patients on these agents.


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InternalMed_Harrison. omeGa 3 fatty acidS (fiSH oilS) Omega-3 fatty acids, or omega-3 polyunsaturated fatty acids (n-3 PUFAs), commonly known as fish oils, are present in high concentration in fish and in flaxseed. The most widely used n-3 PUFAs for the treatment of hyperlipidemias are the two active molecules in fish oil: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). n-3 PUFAs have been concentrated into tablets and in doses of 3–4 g/d are effective at lowering fasting TG levels. Fish oils are a reasonable consideration for first-line therapy in patients with severe hypertriglyceridemia (>500 mg/ dL) to prevent pancreatitis. Fish oils can cause an increase in plasma LDL-C levels in some patients. In general, fish oils are well tolerated, with the major side effect being dyspepsia. They appear to be safe, at least at doses up to 3–4 g, but can be associated with a prolongation in the bleeding time.


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InternalMed_Harrison. nicotinic acid Nicotinic acid, or niacin, is a B-complex vitamin that has been used as a lipid-modifying agent for more than five decades. Niacin suppresses lipolysis in the adipocyte through its effect on the niacin receptor GPR109A and has other effects on hepatic lipid metabolism that are poorly understood. Niacin reduces plasma TG and LDL-C levels and also raises the plasma concentration of HDL-C. Because it has a number of side effects and can be difficult to use, it is at best a third-line agent for the management of severe hypertriglyceridemia. Niacin therapy is generally started at lower doses and gradually titrated up to higher doses. The most frequent side effect of niacin is cutaneous flushing, which is mediated by activating GPR109A in the skin. Niacin can cause dyspepsia and can exacerbate esophageal reflux and peptic ulcer disease. Mild elevations in transaminases occur in up to 15% of patients treated with any form of niacin. Niacin can raise plasma levels of uric acid


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InternalMed_Harrison. can exacerbate esophageal reflux and peptic ulcer disease. Mild elevations in transaminases occur in up to 15% of patients treated with any form of niacin. Niacin can raise plasma levels of uric acid and precipitate gouty attacks in susceptible patients. Acanthosis nigricans, a dark-colored coarse skin lesion, and maculopathy are infrequent side effects of niacin.


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InternalMed_Harrison. In contrast to hypertriglyceridemia and pancreatitis, there are abundant and compelling data that intervention to reduce LDL-C substantially reduces the risk of CVD, including myocardial infarction and stroke, as well as total mortality. Thus, it is imperative that patients with hypercholesterolemia be assessed for cardiovascular risk and for the need for intervention. It is also worth noting that patients at high risk for CVD who have plasma LDL-C levels in the “normal” or average range also benefit from intervention to reduce LDL-C levels.


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InternalMed_Harrison. Lifestyle The first approach to a patient with hypercholesterolemia and high cardiovascular risk is to make any necessary lifestyle changes. In obese patients, efforts should be made to reduce body weight to the ideal level. Patients should receive dietary counseling to reduce the content of saturated fats, trans fats, and cholesterol in the diet. Regular aerobic exercise has relatively little impact on reducing plasma LDL-C levels, although it has cardiovascular benefits independent of LDL lowering. Pharmacologic Therapy for Hypercholesterolemia The decision to use LDL-lowering drug therapy (Table 421-5)—with a statin being first-line therapy—depends on the level of LDL-C as well as the level of cardiovascular risk. In general, patients with a Mendelian disorder of elevated LDL-C such as FH must be treated to reduce the very high lifetime risk of CVD, and treatment should be initiated as early as possible in adulthood or, in some cases, during childhood.


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InternalMed_Harrison. Otherwise, the decision to initiate LDL-lowering drug therapy is generally determined by the level of cardiovascular risk. In patients with established CVD, statin therapy is well supported by clinical trial data and should be used regardless of the LDL-C level. For patients >40 years old without clinical CVD, the AHA/ACC risk calculator (http://my.americanheart .org/professional/StatementsGuidelines/PreventionGuidelines/ Prevention-Guidelines_UCM_457698_SubHomePage.jsp) can be used to determine the 10-year absolute risk for CVD, and current guidelines suggest that a 10-year risk >7.5% merits consideration of statin therapy regardless of plasma LDL-C level. For younger patients, the assessment of lifetime risk of CVD may help inform the decision to start a statin.


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InternalMed_Harrison. HmG-coa reductaSe inHiBitorS (StatinS) Statins inhibit HMG-CoA reductase, a key enzyme in cholesterol biosynthesis. By inhibiting cholesterol biosynthesis, statins lead to increased hepatic LDL receptor activity and accelerated clearance of circulating LDL, resulting in a dose-dependent reduction in plasma levels of LDL-C. The magnitude of LDL lowering associated with statin treatment varies widely among individuals, but once a patient is on a statin, the doubling of the statin dose produces an ~6% further reduction in the level of plasma LDL-C. The statins currently available differ in their LDL-C–reducing potency (Table 421-5). Currently, there is no convincing evidence that any of the different statins confer an advantage that is independent of the effect on LDL-C. Statins also reduce plasma TGs in a dose-dependent fashion, which is roughly proportional to their LDL-C–lowering effects (if the TGs are <400 mg/dL). Statins have a modest HDL-raising effect (5–10%) that is not


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InternalMed_Harrison. reduce plasma TGs in a dose-dependent fashion, which is roughly proportional to their LDL-C–lowering effects (if the TGs are <400 mg/dL). Statins have a modest HDL-raising effect (5–10%) that is not generally dose-dependent.


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InternalMed_Harrison. Statins are well tolerated and can be taken in tablet form once a day. Potential side effects include dyspepsia, headaches, fatigue, and muscle or joint pains. Severe myopathy and even rhabdomyolysis occur rarely with statin treatment. The risk of statin-associated myopathy is increased by the presence of older age, frailty, renal insufficiency, and coadministration of drugs that interfere with the metabolism of statins, such as erythromycin and related antibiotics, antifungal agents, immunosuppressive drugs, and fibric acid deriva- Disorders of Lipoprotein Metabolism Abbreviations: GI, gastrointestinal; HDL-C, high-density lipoprotein cholesterol; HoFH, homozygous familial hypercholesterolemia; LDL, low-density lipoprotein; LDL-C, LDL-cholesterol; LPL, lipoprotein lipase; TG, triglyceride; VLDL, very-low-density lipoprotein.


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InternalMed_Harrison. tives (particularly gemfibrozil). Severe myopathy can usually be less frequent monitoring of transaminases in patients taking statins. avoided by careful patient selection, avoidance of interacting drugs, The statin-associated elevation in liver enzymes resolves upon dis-and instructing the patient to contact the physician immediately in continuation of the medication. the event of unexplained muscle pain. In the event of muscle symp-Statins appear to be remarkably safe. Meta-analyses of large toms, the plasma creatine kinase (CK) level should be obtained to randomized controlled clinical trials with statins do not suggest an differentiate myopathy from myalgia. Serum CK levels need not be increase in any major noncardiac diseases except type 2 diabetes. A monitored on a routine basis in patients taking statins, because an small excess percentage of those taking statins will develop diabetes elevated CK in the absence of symptoms does not predict the devel-but the benefits associated


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InternalMed_Harrison. patients taking statins, because an small excess percentage of those taking statins will develop diabetes elevated CK in the absence of symptoms does not predict the devel-but the benefits associated with the reduction in cardiovascular opment of myopathy and does not necessarily suggest the need for events outweigh the increase in incidence of diabetes. Statins are the discontinuing the drug. drug class of choice for LDL-C reduction and are by far the most


InternalMed_Harrison

InternalMed_Harrison. Another consequence of statin therapy can be elevation in widely used class of lipid-lowering drugs. liver transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]). They should be checked before starting cHoleSterol aBSorption inHiBitorS Cholesterol within the lumen therapy, at 2–3 months, and then annually. Substantial (greater than of the small intestine is derived from the diet (about one-third) three times the upper limit of normal) elevation in transaminases is and the bile (about two-thirds) and is actively absorbed by the relatively rare, and mild-to-moderate (one to three times normal) enterocyte through a process that involves the protein NPC1L1. elevation in transaminases in the absence of symptoms need not Ezetimibe (Table 421-5) is a cholesterol absorption inhibitor that mandate discontinuing the medication. Severe clinical hepatitis binds directly to and inhibits NPC1L1 and blocks the intestinal associated with statins is exceedingly rare, and


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InternalMed_Harrison. inhibitor that mandate discontinuing the medication. Severe clinical hepatitis binds directly to and inhibits NPC1L1 and blocks the intestinal associated with statins is exceedingly rare, and the trend is toward absorption of cholesterol. Ezetimibe (10 mg) inhibits cholesterol absorption by almost 60%, resulting in a reduction in delivery of dietary sterols in the liver and an increase in hepatic LDL receptor expression. The mean reduction in plasma LDL-C on ezetimibe (10 mg) is 18%, and the effect is additive when used in combination with a statin. Effects on TG and HDL-C levels are negligible. When used in combination with a statin, monitoring of liver transaminases is recommended. The only roles for ezetimibe in monotherapy are in patients who do not tolerate statins and in sitosterolemia.


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InternalMed_Harrison. Bile acid SeQueStrantS (reSinS) Bile acid sequestrants bind bile acids in the intestine and promote their excretion rather than reabsorption in the ileum. To maintain the bile acid pool size, the liver diverts cholesterol to bile acid synthesis. The decreased hepatic intracellular cholesterol content results in upregulation of the LDL receptor and enhanced LDL clearance from the plasma. Bile acid sequestrants, including cholestyramine, colestipol, and colesevelam (Table 421-5), primarily reduce plasma LDL-C levels but can cause an increase in plasma TGs. Therefore, patients with hypertriglyceridemia generally should not be treated with bile acid–binding resins. Cholestyramine and colestipol are insoluble resins that must be suspended in liquids. Colesevelam is available as tablets but generally requires up to six to seven tablets per day for effective LDL-C lowering. Most side effects of resins are limited to the gastrointestinal tract and include bloating and constipation. Because


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InternalMed_Harrison. requires up to six to seven tablets per day for effective LDL-C lowering. Most side effects of resins are limited to the gastrointestinal tract and include bloating and constipation. Because bile acid sequestrants are not systemically absorbed, they are very safe and the cholesterol-lowering drug of choice in children and in women of childbearing age who are lactating, pregnant, or could become pregnant. They are effective in combination with statins and in combination with ezetimibe and are particularly useful with one or both of these drugs for patients with severe hypercholesterolemia or those with statin intolerance.


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InternalMed_Harrison. Specialized druGS for HomozyGouS fH Two “orphan” drugs are approved specifically for the management of homozygous FH. They include a small-molecule inhibitor of MTP, called lomitapide, and an antisense oligonucleotide against apoB, called mipomersen. These drugs reduce VLDL production and LDL-C levels in homozygous FH patients. Due to their mechanism of action, each drug causes an increase in hepatic fat, the long-term consequences of which are unknown. In addition, lomitapide is associated with gastrointestinal-related side effects, and mipomersen is associated with skin reactions and flu-like symptoms.


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InternalMed_Harrison. ldl apHereSiS Patients who remain severely hypercholesterolemic despite optimally tolerated drug therapy are candidates for LDL apheresis. In this process, the patient’s plasma is passed over a column that selectively removes the LDL, and the LDL-depleted plasma is returned to the patient. Patients on maximally tolerated combination drug therapy who have CHD and a plasma LDL-C level >200 mg/dL or no CHD and a plasma LDL-C level >300 mg/ dL are candidates for every-other-week LDL apheresis and should The metabolic Syndrome Robert H. Eckel


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InternalMed_Harrison. The metabolic Syndrome Robert H. Eckel The metabolic syndrome (syndrome X, insulin resistance syndrome) consists of a constellation of metabolic abnormalities that confer increased risk of cardiovascular disease (CVD) and diabetes mellitus. Evolution of the criteria for the metabolic syndrome since the original definition by the World Health Organization in 1998 reflects growing clinical evidence and analysis by a variety of consensus conferences and professional organizations. The major features of the metabolic syndrome include central obesity, hypertriglyceridemia, low levels of high-density lipoprotein (HDL) cholesterol, hyperglycemia, and 2449 hypertension (Table 422-1).


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InternalMed_Harrison. The most challenging feature of the metabolic syndrome to define is waist circumference. Intraabdominal circumference (visceral adipose tissue) is considered most strongly related to insulin resistance and risk of diabetes and CVD, and for any given waist circumference the distribution of adipose tissue between SC and visceral depots varies substantially. Thus, within and between populations, there is a lesser vs. greater risk at the same waist circumference. These differences in populations are reflected in the range of waist circumferences considered to confer risk in different geographic locations (Table 422-1).


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InternalMed_Harrison. The prevalence of the metabolic syndrome varies around the world, in part reflecting the age and ethnicity of the populations studied and the diagnostic criteria applied. In general, the prevalence of the metabolic syndrome increases with age. The highest recorded prevalence worldwide is among Native Americans, with nearly 60% of women ages 45–49 and 45% of men ages 45–49 meeting the criteria of the National Cholesterol Education Program and Adult Treatment Panel III (NCEP:ATPIII). In the United States, the metabolic syndrome is less common among African-American men and more common among Mexican-American women. Based on data from the National Health and Nutrition Examination Survey (NHANES) 2003–2006, the age-adjusted prevalence of the metabolic syndrome in U.S. adults without diabetes is 28% for men and 30% for women. In France, studies of a cohort of 30to 60-year-olds have shown a <10% prevalence for each sex, although 17.5% of people 60–64 years of age are affected. Greater global


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InternalMed_Harrison. 28% for men and 30% for women. In France, studies of a cohort of 30to 60-year-olds have shown a <10% prevalence for each sex, although 17.5% of people 60–64 years of age are affected. Greater global industrialization is associated with rising rates of obesity, which are expected to increase the prevalence of the metabolic syndrome dramatically, especially as the population ages. Moreover, the rising prevalence and severity of obesity among children is reflected in features of the metabolic syndrome in a younger population.


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InternalMed_Harrison. The frequency distribution of the five components of the syndrome for the U.S. population (NHANES III) is summarized in Fig. 422-1. Increases in waist circumference predominate among women, whereas increases in fasting plasma triglyceride levels (i.e., to >150 mg/dL), reductions in HDL cholesterol levels, and hyperglycemia are more likely in men. RISK FACTORS Overweight/Obesity Although the metabolic syndrome was first described in the early twentieth century, the worldwide overweight/ obesity epidemic has recently been the force driving its increasing recognition. Central adiposity is a key feature of the syndrome, and the syndrome’s prevalence reflects the strong relationship between waist circumference and increasing adiposity. However, despite the importance of obesity, patients who are of normal weight may also be insulin resistant and may have the metabolic syndrome.


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InternalMed_Harrison. Sedentary Lifestyle Physical inactivity is a predictor of CVD events and the related risk of death. Many components of the metabolic syndrome are associated with a sedentary lifestyle, including increased adipose tissue (predominantly central), reduced HDL cholesterol, and increased triglycerides, blood pressure, and glucose in genetically susceptible persons. Compared with individuals who watch television or videos or use the computer <1 h daily, those who do so for >4 h daily have a twofold increased risk of the metabolic syndrome. Aging The metabolic syndrome affects nearly 50% of the U.S. population older than age 50, and at >60 years of age women are more often affected than men. The age dependency of the syndrome’s prevalence is seen in most populations around the world.


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InternalMed_Harrison. Diabetes Mellitus Diabetes mellitus is included in both the NCEP and the harmonizing definitions of the metabolic syndrome. It is estimated that the great majority (~75%) of patients with type 2 diabetes or impaired glucose tolerance have the metabolic syndrome. The presence of the metabolic syndrome in these populations relates to a The Metabolic Syndrome NCEP:ATPIII 2001 Harmonizing Definitionb Low HDLc cholesterol: <40 mg/dL and <50 mg/dL for men and women, respectively, or specific medication Hypertension: blood pressure ≥130 mmHg systolic or


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InternalMed_Harrison. Hypertension: blood pressure ≥130 mmHg systolic or HDL cholesterol level <40 mg/dL and <50 mg/dL for men and women, respectively, or • Fasting plasma glucose level ≥100 mg/dL (alternative indication: drug treatment of aNational Cholesterol Education Program and Adult Treatment Panel III. bIn this analysis, the following thresholds for waist circumference were used: white men, ≥94 cm; African-American men, ≥94 cm; Mexican-American men, ≥90 cm; white women, ≥80 cm; African-American women, ≥80 cm; Mexican-American women, ≥80 cm. For participants whose designation was “other race—including multiracial,” thresholds that were once based on Europid cutoffs (≥94 cm for men and ≥80 cm for women) and on South Asian cutoffs (≥90 cm for men and ≥80 cm for women) were used. For participants who were considered “other Hispanic,” the International Diabetes Federation thresholds for ethnic South and Central Americans were used. cHigh-density lipoprotein.


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InternalMed_Harrison. higher prevalence of CVD than in patients who have type 2 diabetes or impaired glucose tolerance but do not have this syndrome. Cardiovascular Disease Individuals with the metabolic syndrome are twice as likely to die of cardiovascular disease as those who do not, and their risk of an acute myocardial infarction or stroke is threefold higher. The approximate prevalence of the metabolic syndrome among patients with coronary heart disease (CHD) is 50%, with a prevalence of ~35% among patients with premature coronary artery disease (before or at age 45) and a particularly high prevalence among women. With appropriate cardiac rehabilitation and changes in lifestyle (e.g., nutrition, physical activity, weight reduction, and—in some cases—pharmacologic therapy), the prevalence of the syndrome can be reduced.


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InternalMed_Harrison. Lipodystrophy Lipodystrophic disorders in general are associated with the metabolic syndrome. Both genetic lipodystrophy (e.g., Berardinelli-Seip congenital lipodystrophy, Dunnigan familial partial lipodystrophy) and acquired lipodystrophy (e.g., HIV-related lipodystrophy in % of subjects FIGURE 422-1 Prevalence of the metabolic syndrome components, from NHANES 2003–2006. NHANES, National Health and Nutrition Examination Survey; TG, triglyceride; HDL-C, high-density lipoprotein cholesterol; BP, blood pressure. The prevalence of elevated glucose includes individuals with known diabetes mellitus. (Created from data in ES Ford et al: J Diabetes 2:1753, 2010.) patients receiving antiretroviral therapy) may give rise to severe insulin resistance and many of the components of the metabolic syndrome.


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InternalMed_Harrison. ETIOLOGY Insulin Resistance The most accepted and unifying hypothesis to describe the pathophysiology of the metabolic syndrome is insulin resistance, which is caused by an incompletely understood defect in insulin action (Chap. 417). The onset of insulin resistance is heralded by postprandial hyperinsulinemia, which is followed by fasting hyperinsulinemia and ultimately by hyperglycemia.


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InternalMed_Harrison. An early major contributor to the development of insulin resistance is an overabundance of circulating fatty acids (Fig. 422-2). Plasma albumin-bound free fatty acids are derived predominantly from adipose-tissue triglyceride stores released by intracellular lipolytic enzymes. Fatty acids are also derived from the lipolysis of triglyceride-rich lipoproteins in tissues by lipoprotein lipase. Insulin mediates both antilipolysis and the stimulation of lipoprotein lipase in adipose tissue. Of note, the inhibition of lipolysis in adipose tissue is the most sensitive pathway of insulin action. Thus, when insulin resistance develops, increased lipolysis produces more fatty acids, which further decrease the antilipolytic effect of insulin. Excessive fatty acids enhance substrate availability and create insulin resistance by modifying downstream signaling. Fatty acids impair insulin-mediated glucose uptake and accumulate as triglycerides in both skeletal and cardiac muscle, whereas increased


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InternalMed_Harrison. create insulin resistance by modifying downstream signaling. Fatty acids impair insulin-mediated glucose uptake and accumulate as triglycerides in both skeletal and cardiac muscle, whereas increased glucose production and triglyceride accumulation take place in the liver.


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InternalMed_Harrison. Leptin resistance has also been raised as a possible pathophysiologic mechanism to explain the metabolic syndrome. Physiologically, leptin reduces appetite, promotes energy expenditure, and enhances insulin sensitivity. In addition, leptin may regulate cardiac and vascular function through a nitric oxide–dependent mechanism. However, when obesity develops, hyperleptinemia ensues, with evidence of leptin resistance in the brain and other tissues resulting in inflammation, insulin resistance, hyperlipidemia, and a plethora of cardiovascular disorders, such as hypertension, atherosclerosis, CHD, and heart failure.


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InternalMed_Harrison. The oxidative stress hypothesis provides a unifying theory for aging and the predisposition to the metabolic syndrome. In studies of insulin-resistant individuals with obesity or type 2 diabetes, the offspring of patients with type 2 diabetes, and the elderly, a defect in mitochondrial oxidative phosphorylation that leads to the accumulation of triglycerides and related lipid molecules in muscle has been identified.


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InternalMed_Harrison. Recently, the gut microbiome has emerged as an important contributor to the development of obesity and related metabolic disorders, including the metabolic syndrome. Although the mechanism remains uncertain, interaction among genetic predisposition, diet, and the compensate for defects in insulin action, insulin secretion and/or clear-intestinal flora is important. ance must be modified so that euglycemia is sustained. Ultimately, this Increased Waist Circumference Waist circumference is an important compensatory mechanism fails, usually because of defects in insulin component of the most recent and frequently applied diagnostic secretion, resulting in progression from impaired fasting glucose and/ criteria for the metabolic syndrome. However, measuring waist cir-or impaired glucose tolerance to diabetes mellitus. cumference does not reliably distinguish increases in SC adipose tissue


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InternalMed_Harrison. Hypertension The relationship between insulin resistancefrom those in visceral fat; this distinction requires CT or MRI. With and hypertension is well established. Paradoxically, under increases in visceral adipose tissue, adipose tissue–derived free fatty normal physiologic conditions, insulin is a vasodilator withacids are directed to the liver. In contrast, increases in abdominal SC secondary effects on sodium reabsorption in the kidney. However, infat release lipolysis products into the systemic circulation and avert the setting of insulin resistance, the vasodilatory effect of insulin is lostmore direct effects on hepatic metabolism. Relative increases in vis- but the renal effect on sodium reabsorption is preserved. Sodium reabceral versus SC adipose tissue with increasing waist circumference sorption is increased in whites with the metabolic syndrome but not inin Asians and Asian Indians may explain the greater prevalence of


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InternalMed_Harrison. Africans or Asians. Insulin also increases the activity of the sympathe syndrome in those populations than in African-American men, thetic nervous system, an effect that may be preserved in the setting ofin whom SC fat predominates. It is also possible that visceral fat is a insulin resistance. Insulin resistance is characterized by pathway-marker for—but not the source of—excess postprandial free fatty acids specific impairment in phosphatidylinositol-3-kinase signaling. In thein obesity.


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InternalMed_Harrison. endothelium, this impairment may cause an imbalance between the Dyslipidemia (See also Chap. 421) In general, free fatty acid flux to production of nitric oxide and the secretion of endothelin 1, with a the liver is associated with increased production of ApoB-containing, consequent decrease in blood flow. Although these mechanisms are triglyceride-rich, very low-density lipoproteins (VLDLs). The effect provocative, evaluation of insulin action by measurement of fasting of insulin on this process is complex, but hypertriglyceridemia is an insulin levels or by homeostasis model assessment shows that insulin 2452 resistance contributes only partially to the increased prevalence of hypertension in the metabolic syndrome. Another possible mechanism underlying hypertension in the metabolic syndrome is the vasoactive role of perivascular adipose tissue. Reactive oxygen species released by NADPH oxidase impair endothelial function and result in local vasoconstriction. Other paracrine effects


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InternalMed_Harrison. is the vasoactive role of perivascular adipose tissue. Reactive oxygen species released by NADPH oxidase impair endothelial function and result in local vasoconstriction. Other paracrine effects could be mediated by leptin or other proinflammatory cytokines released from adipose tissue, such as tumor necrosis factor α. Hyperuricemia is another consequence of insulin resistance and is commonly observed in the metabolic syndrome. There is growing evidence not only that uric acid is associated with hypertension but also that reduction of uric acid normalizes blood pressure in hyperuricemic adolescents with hypertension. The mechanism appears to be related to an adverse effect of uric acid on nitric acid synthase in the macula densa of the kidney and stimulation of the renin-angiotensin aldosterone system.


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InternalMed_Harrison. Proinflammatory Cytokines The increases in proinflammatory cytokines—including interleukins 1, 6, and 18; resistin; tumor necrosis factor α; and the systemic biomarker C-reactive protein—reflect overproduction by the expanded adipose tissue mass (Fig. 422-2). Adipose tissue–derived macrophages may be the primary source of proinflammatory cytokines locally and in the systemic circulation. It remains unclear, however, how much of the insulin resistance is caused by the paracrine effects of these cytokines and how much by the endocrine effects.


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InternalMed_Harrison. Adiponectin Adiponectin is an anti-inflammatory cytokine produced exclusively by adipocytes. Adiponectin enhances insulin sensitivity and inhibits many steps in the inflammatory process. In the liver, adiponectin inhibits the expression of gluconeogenic enzymes and the rate of glucose production. In muscle, adiponectin increases glucose transport and enhances fatty acid oxidation, partially through the activation of AMP kinase. Adiponectin levels are reduced in the metabolic syndrome. The relative contributions of adiponectin deficiency and overabundance of the proinflammatory cytokines are unclear.


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InternalMed_Harrison. CLINICAL FEATURES Symptoms and Signs The metabolic syndrome typically is not associated with symptoms. On physical examination, waist circumference may be expanded and blood pressure elevated. The presence of either or both of these signs should prompt the clinician to search for other biochemical abnormalities that may be associated with the metabolic syndrome. Less frequently, lipoatrophy or acanthosis nigricans is found on examination. Because these physical findings characteristically are associated with severe insulin resistance, other components of the metabolic syndrome should be expected.


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InternalMed_Harrison. Associated Diseases • cardiovaScular diSeaSe The relative risk for new-onset CVD in patients with the metabolic syndrome who do not have diabetes averages 1.5–3 fold. However, an 8-year follow-up of middle-aged participants in the Framingham Offspring Study documented that the population-attributable CVD risk in the metabolic syndrome was 34% among men and only 16% among women. In the same study, both the metabolic syndrome and diabetes predicted ischemic stroke, with greater risk among patients with the metabolic syndrome than among those with diabetes alone (19% vs. 7%) and a particularly large difference among women (27% vs. 5%). Patients with the metabolic syndrome are also at increased risk for peripheral vascular disease.


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InternalMed_Harrison. TyPe 2 diabeTes Overall, the risk for type 2 diabetes among patients with the metabolic syndrome is increased threeto fivefold. In the Framingham Offspring Study’s 8-year follow-up of middle-aged participants, the population-attributable risk for developing type 2 diabetes was 62% among men and 47% among women. Other Associated Conditions In addition to the features specifically associated with the metabolic syndrome, other metabolic alterations accompany insulin resistance. Those alterations include increases in ApoB and ApoCIII, uric acid, prothrombotic factors (fibrinogen, plasminogen activator inhibitor 1), serum viscosity, asymmetric dimethylarginine, homocysteine, white blood cell count, proinflammatory cytokines, C-reactive protein, microalbuminuria, nonalcoholic fatty liver disease and/or nonalcoholic steatohepatitis, polycystic ovary syndrome, and obstructive sleep apnea.


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InternalMed_Harrison. nonalcoHolic fatty liver diSeaSe (See alSo cHap. 367e) Fatty liver is a relatively common condition, affecting 25–45% of the U.S. population. However, in nonalcoholic steatohepatitis, triglyceride accumulation and inflammation coexist. Nonalcoholic steatohepatitis is now present in 3–12% of the population of the United States and other Western countries. Of patients with the metabolic syndrome, ~25–60% have nonalcoholic fatty liver disease and up to 35% have nonalcoholic steatohepatitis. As the prevalence of overweight/obesity and the metabolic syndrome increases, nonalcoholic steatohepatitis may become one of the more common causes of end-stage liver disease and hepatocellular carcinoma.


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InternalMed_Harrison. Hyperuricemia (see also cHaP. 431e) Hyperuricemia reflects defects in insulin action on the renal tubular reabsorption of uric acid and may contribute to hypertension through its effect on the endothelium. An increase in asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, also relates to endothelial dysfunction. In addition, microalbuminuria may be caused by altered endothelial pathophysiology in the insulin-resistant state. polycyStic ovary Syndrome (see also cHaP. 412) Polycystic ovary syndrome is highly associated with insulin resistance (50–80%) and the metabolic syndrome, with a prevalence of the syndrome between 40% and 50%. Women with polycystic ovary syndrome are two to four times more likely to have the metabolic syndrome than are women without polycystic ovary syndrome.


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InternalMed_Harrison. oBStructive Sleep apnea (See alSo cHap. 38) Obstructive sleep apnea is commonly associated with obesity, hypertension, increased circulating cytokines, impaired glucose tolerance, and insulin resistance. With these associations, it is not surprising that individuals with obstructive sleep apnea frequently have the metabolic syndrome. Moreover, when biomarkers of insulin resistance are compared between patients with obstructive sleep apnea and weight-matched controls, insulin resistance is found to be more severe in those with apnea. Continuous positive airway pressure treatment improves insulin sensitivity in patients with obstructive sleep apnea.


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InternalMed_Harrison. The diagnosis of the metabolic syndrome relies on fulfillment of the criteria listed in Table 422-1, as assessed using tools at the bedside and in the laboratory. The medical history should include evaluation of symptoms for obstructive sleep apnea in all patients and polycystic ovary syndrome in premenopausal women. Family history will help determine risk for CVD and diabetes mellitus. Blood pressure and waist circumference measurements provide information necessary for the diagnosis.


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InternalMed_Harrison. Laboratory Tests Measurement of fasting lipids and glucose is needed in determining whether the metabolic syndrome is present. The measurement of additional biomarkers associated with insulin resistance can be individualized. Such tests might include those for ApoB, high-sensitivity C-reactive protein, fibrinogen, uric acid, urinary microalbumin, and liver function. A sleep study should be performed if symptoms of obstructive sleep apnea are present. If polycystic ovary syndrome is suspected on the basis of clinical features and anovulation, testosterone, luteinizing hormone, and follicle-stimulating hormone should be measured. LIFESTYLE (SEE ALSO CHAP. 416)


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InternalMed_Harrison. LIFESTYLE (SEE ALSO CHAP. 416) Obesity is the driving force behind the metabolic syndrome. Thus, weight reduction is the primary approach to the disorder. With weight reduction, improvement in insulin sensitivity is often accompanied by favorable modifications in many components of the metabolic syndrome. In general, recommendations for weight loss include a combination of caloric restriction, increased physical activity, and behavior modification. Caloric restriction is the most important component, whereas increases in physical activity are important for maintenance of weight loss. Some but not all evidence suggests that the addition of exercise to caloric restriction may promote greater weight loss from the visceral depot. The tendency for weight regain after successful weight reduction underscores the need for long-lasting behavioral changes.


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InternalMed_Harrison. Diet Before prescribing a weight-loss diet, it is important to emphasize that it has taken the patient a long time to develop an expanded fat mass; thus, the correction need not occur quickly. Given that ~3500 kcal = 1 lb of fat, ~500-kcal restriction daily equates to weight reduction of 1 lb per week. Diets restricted in carbohydrate typically provide a rapid initial weight loss. However, after 1 year, the amount of weight reduction is minimally reduced or no different from that with caloric restriction alone. Thus, adherence to the diet is more important than which diet is chosen. Moreover, there is concern about low-carbohydrate diets enriched in saturated fat, particularly for patients at risk for CVD. Therefore, a high-quality dietary pattern—i.e., a diet enriched in fruits, vegetables, whole grains, lean poultry, and fish—should be encouraged to maximize overall health benefit.


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InternalMed_Harrison. Physical Activity Before a physical activity recommendation is provided to patients with the metabolic syndrome, it is important to ensure that the increased activity does not incur risk. Some high-risk patients should undergo formal cardiovascular evaluation before initiating an exercise program. For an inactive participant, gradual increases in physical activity should be encouraged to enhance adherence and avoid injury. Although increases in physical activity can lead to modest weight reduction, 60–90 min of daily activity is required to achieve this goal. Even if an overweight or obese adult is unable to undertake this level of activity, a significant health benefit will follow from at least 30 min of moderate-intensity activity daily. The caloric value of 30 min of a variety of activities can be found at www.heart.org/HEARTORG/GettingHealthy/WeightManagement/ LosingWeight/Losing-Weight_UCM_307904_Article.jsp. Of note, a variety of routine activities, such as gardening, walking,


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InternalMed_Harrison. can be found at www.heart.org/HEARTORG/GettingHealthy/WeightManagement/ LosingWeight/Losing-Weight_UCM_307904_Article.jsp. Of note, a variety of routine activities, such as gardening, walking, and housecleaning, require moderate caloric expenditure. Thus, physical activity need not be defined solely in terms of formal exercise such as jogging, swimming, or tennis.


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InternalMed_Harrison. Behavior Modification Behavioral treatment typically includes recommendations for dietary restriction and more physical activity, resulting in weight loss that benefits metabolic health. The subsequent challenge is the duration of the program because weight regain so often follows successful weight reduction. Long-term outcomes may be enhanced by a variety of methods, such as the Internet, social media, and telephone follow-up to maintain contact between providers and patients.


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InternalMed_Harrison. Obesity (See also Chap. 416) In some patients with the metabolic syndrome, treatment options need to extend beyond lifestyle intervention. Weight-loss drugs come in two major classes: appetite suppressants and absorption inhibitors. Appetite suppressants approved by the U.S. Food and Drug Administration include phentermine (for short-term use [3 months] only) as well as the more recent additions phentermine/topiramate and lorcaserin, which are approved without restrictions on the duration of therapy. In clinical trials, the phentermine/topiramate combination has resulted in ~10% weight loss in 50% of patients. Side effects include palpitations, headache, paresthesias, constipation, and insomnia. Lorcaserin results in less weight loss—typically ~5% beyond placebo—but can cause headache and nasopharyngitis. Orlistat inhibits fat absorption by ~30% and is moderately effective compared with placebo (~5% more weight loss). Orlistat has been shown to reduce the incidence of type 2 diabetes,


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InternalMed_Harrison. nasopharyngitis. Orlistat inhibits fat absorption by ~30% and is moderately effective compared with placebo (~5% more weight loss). Orlistat has been shown to reduce the incidence of type 2 diabetes, an effect that was especially evident among patients with impaired glucose tolerance at baseline. This drug is often difficult of take because of oily leakage per rectum.


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InternalMed_Harrison. Metabolic or bariatric surgery is an option for patients with the 2453 metabolic syndrome who have a body mass index >40 kg/m2, or >35 kg/m2 with comorbidities. An evolving application for metabolic surgery includes patients with a body mass index as low as 30 kg/m2 and type 2 diabetes. Gastric bypass or vertical sleeve gastrectomy results in dramatic weight reduction and improvement in the features of the metabolic syndrome. A survival benefit with gastric bypass has also been realized. LDL CHOLESTEROL (SEE ALSO CHAP. 421)


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InternalMed_Harrison. LDL CHOLESTEROL (SEE ALSO CHAP. 421) The rationale for the NCEP:ATPIII’s development of criteria for the metabolic syndrome was to go beyond LDL cholesterol in identifying and reducing the risk of CVD. The working assumption by the panel was that LDL cholesterol goals had already been achieved and that increasing evidence supports a linear reduction in CVD events as a result of progressive lowering of LDL cholesterol with statins. For patients with the metabolic syndrome and diabetes, a statin should be prescribed. For those patients with diabetes and known CVD, the current evidence supports a maximum of penultimate dose of a potent statin (e.g., atorvastatin or rosuvastatin). For those patients with the metabolic syndrome but without diabetes, a score that predicts a 10-year CVD risk exceeding 7.5% should also take a statin. With a 10-year risk of <7.5%, use of statin therapy is not evidence based.


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InternalMed_Harrison. Diets restricted in saturated fats (<7% of calories) and trans-fats (as few as possible) should be applied aggressively. Although less evidence exists, dietary cholesterol should also be restricted. If LDL cholesterol remains elevated, pharmacologic intervention is needed. Treatment with statins, which lower LDL cholesterol by 15–60%, is evidence based and is the first-choice medication intervention. Of note, for each doubling of the statin dose, LDL cholesterol is further lowered by only ~6%. Hepatotoxicity (more than a threefold increase in hepatic aminotransferases) is rare, and myopathy is seen in ~10% of patients. The cholesterol absorption inhibitor ezetimibe is well tolerated and should be the second- choice medication intervention. Ezetimibe typically reduces LDL cholesterol by 15–20%. The bile acid sequestrants cholestyramine, colestipol, and colesevalam may be more effective than ezetimibe but, because they can increase triglyceride levels, must be used with caution in


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InternalMed_Harrison. by 15–20%. The bile acid sequestrants cholestyramine, colestipol, and colesevalam may be more effective than ezetimibe but, because they can increase triglyceride levels, must be used with caution in patients with the metabolic syndrome. In general, bile sequestrants should not be administered when fasting triglyceride levels are >250 mg/dL. Side effects include gastrointestinal symptoms (palatability, bloating, belching, constipation, anal irritation). Nicotinic acid has modest LDL cholesterol–lowering capabilities (<20%). Fibrates are best employed to lower LDL cholesterol when both LDL cholesterol and triglycerides are elevated. Fenofibrate may be more effective than gemfibrozil in this setting.


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InternalMed_Harrison. TRIGLYCERIDES (SEE ALSO CHAP. 421) The NCEP:ATPIII has focused on non-HDL cholesterol rather than on triglycerides. However, a fasting triglyceride value of <150 mg/ dL is recommended. In general, the response of fasting triglycerides relates to the amount of weight reduction achieved: a weight reduction of >10% is necessary to lower fasting triglyceride levels.


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InternalMed_Harrison. A fibrate (gemfibrozil or fenofibrate) is the drug of choice to lower fasting triglyceride levels, which are typically reduced by 30–45%. Concomitant administration with drugs metabolized by the 3A4 cytochrome P450 system (including some statins) increases the risk of myopathy. In these cases, fenofibrate may be preferable to gemfibrozil. In the Veterans Affairs HDL Intervention Trial, gemfibrozil was administered to men with known CHD and levels of HDL cholesterol <40 mg/dL. A coronary disease event and mortality rate benefit was experienced predominantly among men with hyperinsulinemia and/or diabetes, many of whom were identified retrospectively as having the metabolic syndrome. Of note, the degree of triglyceride lowering in this trial did not predict benefit. Although levels of LDL cholesterol did not change, a decrease in LDL particle number correlated with benefit. Several additional clinical trials have not shown The Metabolic Syndrome


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InternalMed_Harrison. Endocrinology and Metabolism Health and Disease F. Richard Bringhurst, Marie B. Demay, Stephen M. Krane, Henry M. Kronenberg BONE STRUCTURE AND METABOLISM 423 SEC Tion 4 2454 clear evidence that fibrates reduce CVD risk; however, post hoc analyses of several studies demonstrated that patients with baseline triglyceride levels >200 mg/dL and HDL cholesterol levels <35 mg/ dL did benefit. Other drugs that lower triglyceride levels include statins, nicotinic acid, and—in high doses—omega-3 fatty acids. For this purpose, an intermediate or high dose of the “more potent” statins (atorvastatin, rosuvastatin) is needed. The effect of nicotinic acid on fasting triglycerides is dose related and ~20–35%, an effect that is less pronounced than that of fibrates. In patients with the metabolic syndrome and diabetes, nicotinic acid may increase fasting glucose levels. Omega-3 fatty acid preparations that include high doses of docosahexaenoic acid plus eicosapentaenoic acid (~1.5–4.5 g/d) or


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InternalMed_Harrison. syndrome and diabetes, nicotinic acid may increase fasting glucose levels. Omega-3 fatty acid preparations that include high doses of docosahexaenoic acid plus eicosapentaenoic acid (~1.5–4.5 g/d) or eicosapentaenoic acid alone lower fasting triglyceride levels by ~30–40%. No drug interactions with fibrates or statins occur, and the main side effect of their use is eructation with a fishy taste. This taste can be partially blocked by ingestion of the nutraceutical after freezing. Clinical trials of nicotinic acid or high-dose omega-3 fatty acids in patients with the metabolic syndrome have not been reported.


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InternalMed_Harrison. HDL CHOLESTEROL (SEE ALSO CHAP. 421) Very few lipid-modifying compounds increase HDL cholesterol levels. Statins, fibrates, and bile acid sequestrants have modest effects (5–10%), whereas ezetimibe and omega-3 fatty acids have no effect. Nicotinic acid is the only currently available drug with predictable HDL cholesterol-raising properties. The response is dose related, and nicotinic acid can increase HDL cholesterol by ~30% above baseline. After several trials of nicotinic acid versus placebo in statin-treated patients, there is still no evidence that raising HDL with nicotinic acid beneficially affects CVD events in patients with or without the metabolic syndrome. BLOOD PRESSURE (SEE ALSO CHAP. 298) The direct relationship between blood pressure and all-cause mortality rate has been well established in studies comparing patients


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InternalMed_Harrison. BLOOD PRESSURE (SEE ALSO CHAP. 298) The direct relationship between blood pressure and all-cause mortality rate has been well established in studies comparing patients Bone is a dynamic tissue that is remodeled constantly throughout life. The arrangement of compact and cancellous bone provides strength and density suitable for both mobility and protection. In addition, bone provides a reservoir for calcium, magnesium, phosphorus, sodium, and other ions necessary for homeostatic functions. Bone also hosts and regulates hematopoiesis by providing niches for hematopoietic cell proliferation and differentiation. The skeleton is highly vascular and receives about 10% of the cardiac output. Remodeling of bone is accomplished by two distinct cell types: osteoblasts produce bone matrix, and osteoclasts resorb the matrix.


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InternalMed_Harrison. The extracellular components of bone consist of a solid mineral phase in close association with an organic matrix, of which 90–95% is type I collagen (Chap. 427). The noncollagenous portion of the organic matrix is heterogeneous and contains serum proteins such as albumin as well as many locally produced proteins, whose functions are incompletely understood. Those proteins include cell attachment/ with hypertension (>140/90 mmHg), patients with pre-hypertension (>120/80 mmHg but <140/90 mmHg), and individuals with normal blood pressure (<120/80 mmHg). In patients who have the metabolic syndrome without diabetes, the best choice for the initial antihypertensive medication is an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker, as these two classes of drugs appear to reduce the incidence of new-onset type 2 diabetes. In all patients with hypertension, a sodium-restricted dietary pattern enriched in fruits and vegetables, whole grains, and low-fat dairy


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InternalMed_Harrison. appear to reduce the incidence of new-onset type 2 diabetes. In all patients with hypertension, a sodium-restricted dietary pattern enriched in fruits and vegetables, whole grains, and low-fat dairy products should be advocated. Home monitoring of blood pressure may assist in maintaining good blood-pressure control.


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InternalMed_Harrison. IMPAIRED FASTING GLUCOSE (SEE ALSO CHAP. 417) In patients with the metabolic syndrome and type 2 diabetes, aggressive glycemic control may favorably modify fasting levels of triglycerides and/or HDL cholesterol. In patients with impaired fasting glucose who do not have diabetes, a lifestyle intervention that includes weight reduction, dietary fat restriction, and increased physical activity has been shown to reduce the incidence of type 2 diabetes. Metformin also reduces the incidence of diabetes, although the effect is less pronounced than that of lifestyle intervention. INSULIN RESISTANCE (SEE ALSO CHAP. 418)


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InternalMed_Harrison. INSULIN RESISTANCE (SEE ALSO CHAP. 418) Several drug classes (biguanides, thiazolidinediones [TZDs]) increase insulin sensitivity. Because insulin resistance is the primary pathophysiologic mechanism for the metabolic syndrome, representative drugs in these classes reduce its prevalence. Both metformin and TZDs enhance insulin action in the liver and suppress endogenous glucose production. TZDs, but not metformin, also improve insulin-mediated glucose uptake in muscle and adipose tissue. Benefits of both drugs have been seen in patients with nonalcoholic fatty liver disease and polycystic ovary syndrome, and the drugs have been shown to reduce markers of inflammation. signaling proteins such as thrombospondin, osteopontin, and fibronectin; calcium-binding proteins such as matrix gla protein and osteocalcin; and proteoglycans such as biglycan and decorin. Some of the proteins organize collagen fibrils; others influence mineralization and binding of the mineral phase to the matrix.


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InternalMed_Harrison. The mineral phase is made up of calcium and phosphate and is best characterized as a poorly crystalline hydroxyapatite. The mineral phase of bone is deposited initially in intimate relation to the collagen fibrils and is found in specific locations in the “holes” between the collagen fibrils. This architectural arrangement of mineral and matrix results in a two-phase material well suited to withstand mechanical stresses. The organization of collagen influences the amount and type of mineral phase formed in bone. Although the primary structures of type I collagen in skin and bone tissues are similar, there are differences in posttranslational modifications and distribution of intermolecular cross-links. The holes in the packing structure of the collagen are larger in mineralized collagen of bone and dentin than in unmineralized collagens such as those in tendon. Single amino acid substitutions in the helical portion of either the α1 (COL1A1) or α2 (COL1A2) chains of type I collagen


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InternalMed_Harrison. of bone and dentin than in unmineralized collagens such as those in tendon. Single amino acid substitutions in the helical portion of either the α1 (COL1A1) or α2 (COL1A2) chains of type I collagen disrupt the organization of bone in osteogenesis imperfecta. The severe skeletal fragility associated with this group of disorders highlights the importance of the fibrillar matrix in the structure of bone (Chap. 427).


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InternalMed_Harrison. Osteoblasts synthesize and secrete the organic matrix and regulate its mineralization. They are derived from cells of mesenchymal origin (Fig. 423-1A). Active osteoblasts are found on the surface of newly BMPs PTH, Vit D, IGFs, 2455 BMPs, Wnts Mesenchymal osteoblast progenitor Osteoblast precursor Collagen (I) Alkaline phosphatase Osteocalcin, osteopontin Bone sialoprotein c-src+ ˜3 integrin+ PYK2 kinase+ Cathepsin K+ TRAF+ Carbonic anhydrase II+ Runx 2 Hematopoietic osteoclast progenitor M-CSF Osteoclast precursor Active osteoblast Mononuclear osteoclast Quiescent osteoclast Active osteoclast PU-1+ c-fos+ NK°B+ TRAF+ CommitmentRANK Ligand DifferentiationM-CSF RANK Ligand IL-1,IL-6 FusionRANK Ligand IL-1 A B


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InternalMed_Harrison. FIGURE 423-1 Pathways regulating development of (A) osteoblasts and (B) osteoclasts. Hormones, cytokines, and growth factors that control cell proliferation and differentiation are shown above the arrows. Transcription factors and other markers specific for various stages of development are depicted below the arrows. BMPs, bone morphogenic proteins; IGFs, insulin-like growth factors; IL-1, interleukin 1; IL-6, interleukin 6; M-CSF, macrophage colony-stimulating factor; NFκB, nuclear factor κB; PTH, parathyroid hormone; PU-1, a monocyteand B lymphocyte–specific ets family transcription factor; RANK ligand, receptor activator of NFκB ligand; Runx2, Runt-related transcription factor 2; TRAF, tumor necrosis factor receptor–associated factors; Vit D, vitamin D; wnts, wingless-type mouse mammary tumor virus integration site.


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InternalMed_Harrison. (Modified from T Suda et al: Endocr Rev 20:345, 1999, with permission.) forming bone. As an osteoblast secretes matrix, which then is mineralized, the cell becomes an osteocyte, still connected with its blood supply through a series of canaliculi. Osteocytes account for the vast majority of the cells in bone. They are thought to be the mechanosensors in bone that communicate signals to surface osteoblasts and their progenitors through the canalicular network and thereby serve as master regulators of bone formation and resorption. Remarkably, osteocytes also secrete fibroblast growth factor 23 (FGF23), a major regulator of phosphate metabolism (see below). Mineralization of the matrix, both in trabecular bone and in osteones of compact cortical bone (Haversian systems), begins soon after the matrix is secreted (primary mineralization) but is not completed for several weeks or even longer (secondary mineralization). Although this mineralization takes advantage of the high concentrations


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InternalMed_Harrison. matrix is secreted (primary mineralization) but is not completed for several weeks or even longer (secondary mineralization). Although this mineralization takes advantage of the high concentrations of calcium and phosphate, already near saturation in serum, mineralization is a carefully regulated process that is dependent on the activity of osteoblast-derived alkaline phosphatase, which probably works by hydrolyzing inhibitors of mineralization.


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InternalMed_Harrison. Genetic studies in humans and mice have identified several key genes that control osteoblast development. Runx2 is a transcription factor expressed specifically in chondrocyte (cartilage cells) and osteoblast progenitors as well as in hypertrophic chondrocytes and mature osteoblasts. Runx2 regulates the expression of several important osteoblast proteins, including osterix (another transcription factor needed for osteoblast maturation), osteopontin, bone sialoprotein, type I collagen, osteocalcin, and receptor-activator of NFκB (RANK) ligand. Runx2 expression is regulated in part by bone morphogenic proteins (BMPs). Runx2-deficient mice are devoid of osteoblasts, whereas mice with a deletion of only one allele (Runx2 +/−) exhibit a delay in formation of the clavicles and some cranial bones. The latter abnormalities are similar to those in the human disorder cleidocranial dysplasia, which is also caused by heterozygous inactivating mutations in Runx2.


InternalMed_Harrison

InternalMed_Harrison. The paracrine signaling molecule, Indian hedgehog (Ihh), also plays a critical role in osteoblast development, as evidenced by Ihh-deficient mice that lack osteoblasts in the type of bone formed on a cartilage mold (endochondral ossification). Signals originating from members of the wnt (wingless-type mouse mammary tumor virus integration site) family of paracrine factors are also important for osteoblast proliferation and differentiation. Numerous other growth-regulatory factors affect osteoblast function, including the three closely related transforming growth factor βs, fibroblast growth factors (FGFs) 2 and 18, platelet-derived growth factor, and insulin-like growth factors (IGFs) I and II. Hormones such as parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D (1,25[OH]2D) activate receptors expressed by osteoblasts to assure mineral homeostasis and influence a variety of bone cell functions.


InternalMed_Harrison

InternalMed_Harrison. Resorption of bone is carried out mainly by osteoclasts, multinucleated cells that are formed by fusion of cells derived from the common precursor of macrophages and osteoclasts. Thus, these cells derive from the hematopoietic lineage, quite different from the mesenchymal cells that become osteoblasts. Multiple factors that regulate osteoclast development have been identified (Fig. 423-1B). Factors produced by osteoblasts or marrow stromal cells allow osteoblasts to control osteoclast development and activity. Macrophage colony-stimulating factor (M-CSF) plays a critical role during several steps in the pathway and ultimately leads to fusion of osteoclast progenitor cells to form multinucleated, active osteoclasts. RANK ligand, a member of the tumor necrosis factor (TNF) family, is expressed on the surface of osteoblast progenitors and stromal fibroblasts. In a process involving cell-cell interactions, RANK ligand binds to the RANK receptor on osteoclast progenitors, stimulating


InternalMed_Harrison

InternalMed_Harrison. on the surface of osteoblast progenitors and stromal fibroblasts. In a process involving cell-cell interactions, RANK ligand binds to the RANK receptor on osteoclast progenitors, stimulating osteoclast differentiation and activation. Alternatively, a soluble decoy receptor, referred to as osteoprotegerin, can bind RANK ligand and inhibit osteoclast ~3 weeks ~3 months Osteoid Osteocyte Osteoclast Active osteoclast precursors Bone remodeling unit Osteoblast Lining cells Activation Resorption Bone formation Mineralization Cement line Reversal Resting bone surface FIGURE 423-2 Schematic representation of bone remodeling. The cycle of bone remodeling 2456 differentiation. Several growth factors and Osteoclast cytokines (including interleukins 1, 6, precursor Osteoblast and 11; TNF; and interferon γ) modulate osteoclast differentiation and function. Most hormones that influence osteoclast function do not target these cells directly but instead act on cells of the osteoblast lineage to


InternalMed_Harrison

InternalMed_Harrison. γ) modulate osteoclast differentiation and function. Most hormones that influence osteoclast function do not target these cells directly but instead act on cells of the osteoblast lineage to increase production of M-CSF and RANK. Both PTH and 1,25(OH)2D increase osteoclast number and activity by this indirect mechanism. Calcitonin, in contrast, binds to its receptor on the basal surface of osteoclasts and directly inhibits osteoclast function. Estradiol has is carried out by the basic multicellular unit (BMU), which consists of a group of osteoclasts and multiple cellular targets in bone, includ-osteoblasts. In cortical bone, the BMUs tunnel through the tissue, whereas in cancellous bone, ing osteoclasts, immune cells, and osteo-they move across the trabecular surface. The process of bone remodeling is initiated by contracblasts; actions on all these cells serve to tion of the lining cells and the recruitment of osteoclast precursors. These precursors fuse to form decrease osteoclast


InternalMed_Harrison

InternalMed_Harrison. remodeling is initiated by contracblasts; actions on all these cells serve to tion of the lining cells and the recruitment of osteoclast precursors. These precursors fuse to form decrease osteoclast number and decrease multinucleated, active osteoclasts that mediate bone resorption. Osteoclasts adhere to bone and bone resorption. subsequently remove it by acidification and proteolytic digestion. As the BMU advances, osteo


InternalMed_Harrison

InternalMed_Harrison. Osteoclast-mediated resorption of clasts leave the resorption site and osteoblasts move in to cover the excavated area and begin bone takes place in scalloped spaces the process of new bone formation by secreting osteoid, which eventually is mineralized into new (Howship’s lacunae) where the osteoclasts bone. After osteoid mineralization, osteoblasts flatten and form a layer of lining cells over new are attached through a specific αvβ3 inte-bone. grin to components of the bone matrix such as osteopontin. The osteoclast forms a tight seal to the underlying matrix and secretes protons, chloride, and The response of bone to fractures, infection, and interruption of proteinases into a confined space that has been likened to an extracel-blood supply and to expanding lesions is relatively limited. Dead bone lular lysosome. The active osteoclast surface forms a ruffled border must be resorbed, and new bone must be formed, a process carried that contains a specialized proton pump ATPase that


InternalMed_Harrison

InternalMed_Harrison. Dead bone lular lysosome. The active osteoclast surface forms a ruffled border must be resorbed, and new bone must be formed, a process carried that contains a specialized proton pump ATPase that secretes acid and out in association with growth of new blood vessels into the involved solubilizes the mineral phase. Carbonic anhydrase (type II isoenzyme) area. In injuries that disrupt the organization of the tissue such as a within the osteoclast generates the needed protons. The bone matrix fracture in which apposition of fragments is poor or when motion is resorbed in the acid environment adjacent to the ruffled border by exists at the fracture site, progenitor stromal cells recapitulate the proteases, such as cathepsin K, that act at low pH. endochondral bone formation of early development and form carti-


InternalMed_Harrison

InternalMed_Harrison. In the embryo and the growing child, bone develops mostly by lage that is replaced by bone and, variably, fibrous tissue. When there remodeling and replacing previously calcified cartilage (endochon-is good apposition with fixation and little motion at the fracture site, dral bone formation) or, in a few bones, is formed without a cartilage repair occurs predominantly by formation of new bone without other matrix (intramembranous bone formation). During endochondral mediating tissue. bone formation, chondrocytes proliferate, secrete and mineralize a Remodeling of bone occurs along lines of force generated by matrix, enlarge (hypertrophy), and then die, enlarging bone and pro-mechanical stress. The signals from these mechanical stresses are viding the matrix and factors that stimulate endochondral bone for-sensed by osteocytes, which transmit signals to osteoclasts and osteomation. This program is regulated by both local factors, such as IGF-I blasts or their precursors. One such


InternalMed_Harrison

InternalMed_Harrison. endochondral bone for-sensed by osteocytes, which transmit signals to osteoclasts and osteomation. This program is regulated by both local factors, such as IGF-I blasts or their precursors. One such signal made by osteocytes is and -II, Ihh, PTH-related peptide (PTHrP), and FGFs, and by systemic sclerostin, an inhibitor of wnt signaling. Mechanical forces suppress hormones, such as growth hormone, glucocorticoids, and estrogen. sclerostin production and thus increase bone formation by osteo-


InternalMed_Harrison

InternalMed_Harrison. New bone, whether formed in infants or in adults during repair, blasts. Expanding lesions in bone such as tumors induce resorption has a relatively high ratio of cells to matrix and is characterized by at the surface in contact with the tumor by producing ligands such as coarse fiber bundles of collagen that are interlaced and randomly PTHrP that stimulate osteoclast differentiation and function. Even in dispersed (woven bone). In adults, the more mature bone is orga-a disorder as architecturally disruptive as Paget’s disease, remodeling is nized with fiber bundles regularly arranged in parallel or concentric dictated by mechanical forces. Thus, bone plasticity reflects the inter-sheets (lamellar bone). In long bones, deposition of lamellar bone in action of cells with each other and with the environment. a concentric arrangement around blood vessels forms the Haversian Measurement of the products of osteoblast and osteoclast activsystems. Growth in length of bones is dependent on


InternalMed_Harrison

InternalMed_Harrison. the environment. a concentric arrangement around blood vessels forms the Haversian Measurement of the products of osteoblast and osteoclast activsystems. Growth in length of bones is dependent on proliferation of ity can assist in the diagnosis and management of bone diseases.


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InternalMed_Harrison. cartilage cells and the endochondral sequence at the growth plate. Osteoblast activity can be assessed by measuring serum bone-specific Growth in width and thickness is accomplished by formation of alkaline phosphatase. Similarly, osteocalcin, a protein secreted from bone at the periosteal surface and by resorption at the endosteal osteoblasts, is made virtually only by osteoblasts. Osteoclast activity surface, with the rate of formation exceeding that of resorption. In can be assessed by measurement of products of collagen degradation. adults, after the growth plates of cartilage close, growth in length and Collagen molecules are covalently linked to each other in the extracelendochondral bone formation cease except for some activity in the lular matrix through the formation of hydroxypyridinium cross-links cartilage cells beneath the articular surface. Even in adults, however, (Chap. 427). After digestion by osteoclasts, these cross-linked peptides remodeling of bone (within


InternalMed_Harrison

InternalMed_Harrison. cross-links cartilage cells beneath the articular surface. Even in adults, however, (Chap. 427). After digestion by osteoclasts, these cross-linked peptides remodeling of bone (within Haversian systems as well as along the can be measured both in urine and in blood. surfaces of trabecular bone) continues throughout life. In adults, ~4% of the surface of trabecular bone (such as iliac crest) is involved in active resorption, whereas 10–15% of trabecular surfaces are covered with osteoid, unmineralized new bone formed by osteoblasts. Over 99% of the 1–2 kg of calcium present normally in the adult Radioisotope studies indicate that as much as 18% of the total skeletal human body resides in the skeleton, where it provides mechanical stacalcium is deposited and removed each year. Thus, bone is an active bility and serves as a reservoir sometimes needed to maintain extracelmetabolizing tissue that requires an intact blood supply. The cycle of lular fluid (ECF) calcium concentration (Fig.


InternalMed_Harrison

InternalMed_Harrison. is an active bility and serves as a reservoir sometimes needed to maintain extracelmetabolizing tissue that requires an intact blood supply. The cycle of lular fluid (ECF) calcium concentration (Fig. 423-3). Skeletal calcium bone resorption and formation is a highly orchestrated process carried accretion first becomes significant during the third trimester of fetalout by the basic multicellular unit, which is composed of a group of life, accelerates throughout childhood and adolescence, reaches a peak osteoclasts and osteoblasts (Fig. 423-2). in early adulthood, and gradually declines thereafter at rates that rarely 0.4–1.5 g 0.25–0.5 g 0.25–0.5 g 0.1–0.2 g 0.25–0.5 g 7.9–9.7 g 0.3–1 g 0.15–.3 g


InternalMed_Harrison

InternalMed_Harrison. FIGURE 423-3 Calcium homeostasis. Schematic illustration of calcium content of extracellular fluid (ECF) and bone as well as of diet and feces; magnitude of calcium flux per day as calculated by various methods is shown at sites of transport in intestine, kidney, and bone. Ranges of values shown are approximate and were chosen to illustrate certain points discussed in the text. In conditions of calcium balance, rates of calcium release from and uptake into bone are equal. exceed 1–2% per year. These slow changes in total skeletal calcium content contrast with relatively high daily rates of closely matched fluxes of calcium into and out of bone (~250–500 mg each), a process mediated by coupled osteoblastic and osteoclastic activity. Another 0.5–1% of skeletal calcium is freely exchangeable (e.g., in chemical equilibrium) with that in the ECF.


InternalMed_Harrison

InternalMed_Harrison. The concentration of ionized calcium in the ECF must be maintained within a narrow range because of the critical role calcium plays in a wide array of cellular functions, especially those involved in neuromuscular activity, secretion, and signal transduction. Intracellular cytosolic free calcium levels are ~100 nmol/L and are 10,000-fold lower than ionized calcium concentrations in the blood and ECF (1.1–1.3 mmol/L). Cytosolic calcium does not play the structural role played by extracellular calcium; instead, it serves a signaling function. The steep chemical gradient of calcium from outside to inside the cell promotes rapid calcium influx through various membrane calcium channels that can be activated by hormones, metabolites, or neurotransmitters, swiftly changing cellular function. In blood, total calcium concentration is normally 2.2–2.6 mM (8.5–10.5 mg/dL), of which ~50% is ionized. The remainder is bound ionically to negatively charged proteins (predominantly albumin and


InternalMed_Harrison

InternalMed_Harrison. In blood, total calcium concentration is normally 2.2–2.6 mM (8.5–10.5 mg/dL), of which ~50% is ionized. The remainder is bound ionically to negatively charged proteins (predominantly albumin and immunoglobulins) or loosely complexed with phosphate, citrate, sulfate, or other anions. Alterations in serum protein concentrations directly affect the total blood calcium concentration even if the ionized calcium concentration remains normal. An algorithm to correct for protein changes adjusts the total serum calcium (in mg/dL) upward by 0.8 times the deficit in serum albumin (g/dL) or by 0.5 times the deficit in serum immunoglobulin (in g/dL). Such corrections provide only rough approximations of actual free calcium concentrations, however, and may be misleading, particularly during acute illness. Acidosis also alters ionized calcium by reducing its association with proteins. The best practice is to measure blood ionized calcium directly by a method that employs calcium-selective


InternalMed_Harrison

InternalMed_Harrison. illness. Acidosis also alters ionized calcium by reducing its association with proteins. The best practice is to measure blood ionized calcium directly by a method that employs calcium-selective electrodes in acute settings during which calcium abnormalities might occur.


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InternalMed_Harrison. Control of the ionized calcium concentration in the ECF ordinarily is accomplished by adjusting the rates of calcium movement across intestinal and renal epithelia. These adjustments are mediated mainly via changes in blood levels of the hormones, PTH and 1,25(OH)2D. Blood ionized calcium directly suppresses PTH secretion by activating calcium-sensing receptors (CaSRs) in parathyroid cells. Also, ionized 2457 calcium indirectly affects PTH secretion by lowering 1,25(OH)2D production. This active vitamin D metabolite inhibits PTH production by an incompletely understood mechanism of negative feedback (Chap. 424).


InternalMed_Harrison

InternalMed_Harrison. Normal dietary calcium intake in the United States varies widely, ranging from 10–37 mmol/d (400–1500 mg/d). An Institute of Medicine report recommends a daily allowance of 25–30 mmol (1000–1200 mg) for most adults. Intestinal absorption of ingested calcium involves both active (transcellular) and passive (paracellular) mechanisms. Passive calcium absorption is nonsaturable and approximates 5% of daily calcium intake, whereas active absorption involves apical calcium entry via specific ion channels (TRPV5 and TRPV6), whose expression is controlled principally by 1,25(OH)2D, and normally ranges from 20 to 70%. Active calcium transport occurs mainly in the proximal small bowel (duodenum and proximal jejunum), although some active calcium absorption occurs in most segments of the small intestine. Optimal rates of calcium absorption require gastric acid. This is especially true for weakly dissociable calcium supplements such as calcium carbonate. In fact, large boluses of calcium


InternalMed_Harrison

InternalMed_Harrison. intestine. Optimal rates of calcium absorption require gastric acid. This is especially true for weakly dissociable calcium supplements such as calcium carbonate. In fact, large boluses of calcium carbonate are poorly absorbed because of their neutralizing effect on gastric acid. In achlorhydric subjects and for those taking drugs that inhibit gastric acid secretion, supplements should be taken with meals to optimize their absorption. Use of calcium citrate may be preferable in these circumstances. Calcium absorption may also be blunted in disease states such as pancreatic or biliary insufficiency, in which ingested calcium remains bound to unabsorbed fatty acids or other food constituents. At high levels of calcium intake, synthesis of 1,25(OH)2D is reduced; this decreases the rate of active intestinal calcium absorption. The opposite occurs with dietary calcium restriction. Some calcium, ~2.5–5 mmol/d (100–200 mg/d), is excreted as an obligate component of intestinal secretions and


InternalMed_Harrison

InternalMed_Harrison. intestinal calcium absorption. The opposite occurs with dietary calcium restriction. Some calcium, ~2.5–5 mmol/d (100–200 mg/d), is excreted as an obligate component of intestinal secretions and is not regulated by calciotropic hormones.


InternalMed_Harrison

InternalMed_Harrison. The feedback-controlled hormonal regulation of intestinal absorptive efficiency results in a relatively constant daily net calcium absorption of ~5–7.5 mmol/d (200–400 mg/d) despite large changes in daily dietary calcium intake. This daily load of absorbed calcium is excreted by the kidneys in a manner that is also tightly regulated by the concentration of ionized calcium in the blood. Approximately 8–10 g/d of calcium is filtered by the glomeruli, of which only 2–3% appears in the urine. Most filtered calcium (65%) is reabsorbed in the proximal tubules via a passive, paracellular route that is coupled to concomitant NaCl reabsorption and not specifically regulated. The cortical thick ascending limb of Henle’s loop (cTAL) reabsorbs roughly another 20% of filtered calcium, also via a paracellular mechanism. Calcium reabsorption in the cTAL requires a tight-junctional protein called paracellin-1 and is inhibited by increased blood concentrations of calcium or magnesium, acting via the


InternalMed_Harrison

InternalMed_Harrison. mechanism. Calcium reabsorption in the cTAL requires a tight-junctional protein called paracellin-1 and is inhibited by increased blood concentrations of calcium or magnesium, acting via the CaSR, which is highly expressed on basolateral membranes in this nephron segment. Operation of the renal CaSR provides a mechanism, independent of those engaged directly by PTH or 1,25(OH)2D, by which serum ionized calcium can control renal calcium reabsorption. Finally, ~10% of filtered calcium is reabsorbed in the distal convoluted tubules (DCTs) by a transcellular mechanism. Calcium enters the luminal surface of the cell through specific apical calcium channels (TRPV5), whose number is regulated. It then moves across the cell in association with a specific calcium-binding protein (calbindin-D28k) that buffers cytosolic calcium concentrations from the large mass of transported calcium. Ca2+-ATPases and Na+/Ca2+ exchangers actively extrude calcium across the basolateral surface and thereby


InternalMed_Harrison

InternalMed_Harrison. that buffers cytosolic calcium concentrations from the large mass of transported calcium. Ca2+-ATPases and Na+/Ca2+ exchangers actively extrude calcium across the basolateral surface and thereby maintain the transcellular calcium gradient. All these processes are stimulated directly or indirectly by PTH. The DCT is also the site of action of thiazide diuretics, which lower urinary calcium excretion by inducing sodium depletion and thereby augmenting proximal calcium reabsorption. Conversely, dietary sodium loads, or increased distal sodium delivery caused by loop diuretics or saline infusion, induce calciuresis.


InternalMed_Harrison

InternalMed_Harrison. The homeostatic mechanisms that normally maintain a constant serum ionized calcium concentration may fail at extremes of calcium intake or when the hormonal systems or organs involved are compromised. Thus, even with maximal activity of the vitamin D–dependent 2458 intestinal active transport system, sustained calcium intakes <5 mmol/d (<200 mg/d) cannot provide enough net calcium absorption to replace obligate losses via the intestine, the kidney, sweat, and other secretions. In this case, increased blood levels of PTH and 1,25(OH)2D activate osteoclastic bone resorption to obtain needed calcium from bone, which leads to progressive bone loss and negative calcium balance. Increased PTH and 1,25(OH)2D also enhance renal calcium reabsorption, and 1,25(OH)2D enhances calcium absorption in the gut. At very high calcium intakes (>100 mmol/d [>4 g/d]), passive intestinal absorption continues to deliver calcium into the ECF despite maximally downregulated intestinal active transport and


InternalMed_Harrison

InternalMed_Harrison. the gut. At very high calcium intakes (>100 mmol/d [>4 g/d]), passive intestinal absorption continues to deliver calcium into the ECF despite maximally downregulated intestinal active transport and renal tubular calcium reabsorption. This can cause severe hypercalciuria, nephrocalcinosis, progressive renal failure, and hypercalcemia (e.g., “milk-alkali syndrome”). Deficiency or excess of PTH or vitamin D, intestinal disease, and renal failure represent other commonly encountered challenges to normal calcium homeostasis (Chap. 424).