Sharon T. Phelan
Thomas E. Nolan
• Empiric therapy for women with pneumonia should be based on the specific patient profiles and the severity of their pneumonia. All patients with possible community-acquired pneumonia should have a chest radiograph to establish the diagnosis and the presence of complications.
• Most patients with hypertension will require two or more antihypertensive medications to achieve optimal blood pressure control less than 140/90 or less than 130/80 mm Hg for patients with diabetes or kidney disease, respectively.
• There is an increased use of cholesterol-lowering drugs, including the “statins,” a class of drugs that lower cholesterol by blocking a liver enzyme necessary to produce cholesterol, and they are very effective in reducing the risk of heart attacks and deaths.
• Type 2 diabetes is frequently not diagnosed until complications appear, and approximately one-third of all people with diabetes may be undiagnosed: individuals at risk should be screened and a comprehensive plan of care initiated for those diagnosed with diabetes.
• The sensitive thyroid-stimulating hormone (TSH) assay is the single best screening test for hyperthyroidism and hypothyroidism: in clinical hypothyroidism, the standard treatment is levothyroxine replacement, which must be tailored to the individual patient.
As health care providers for women, gynecologists are responsible for providing care that extends beyond diseases of the reproductive organs to include much of the general medical care of their patients. Broadening the spectrum of care requires adjustments in practice, with less emphasis placed on the surgical aspects of the specialty. Early diagnosis and treatment of medical illnesses can have a major impact on a woman’s health. Although timely referral is important for complex and advanced diseases, many conditions can be recognized and treated initially by gynecologists.
Respiratory problems are the most common reasons patients seek care from a physician, so gynecologists should be aware of their pathophysiology. Cardiovascular disease has a significant impact on overall morbidity and is the main cause of death in women. Cardiovascular disease is associated with cigarette smoking, hypertension, hypercholesterolemia, and diabetes mellitus. These conditions are responsive to screening, behavior modification, and control to lower risk factors. Thyroid disease is a major cause of morbidity for women. Because of the interaction of hormones and the overall effect on the endocrine system, thyroid disease can be of special significance in women. The gynecologist should provide screening and initial therapy for these conditions and assess the need for referral.
Respiratory Infections
Infections of the respiratory system can range from the common cold to life-threatening illness. Those with risk factors should be counseled about preventive measures. Vaccines against flu and pneumonia should be offered as indicated.
Sinusitis
A problem frequently encountered in women is self-diagnosed “sinus problems.” Many medical problems—headaches, dental pain, postnasal drainage, halitosis, and dyspepsia—may be related to sinus conditions. The sinuses are not an isolated organ, and diseases of the sinuses are often related to conditions that affect other portions of the respiratory system (i.e., the nose, bronchial tree, and lungs). The entire respiratory system can be infected by one particular virus or pathogen (the sinobronchial or sinopulmonary syndrome); however, the most prominent symptoms are usually produced in one anatomic area. Therefore, during the evaluation of symptoms attributable to sinusitis, the presence of other infections should be investigated.
Multiple infectious and chemical agents or reactions to nervous, physical, emotional, or hormonal stimuli may cause an inflammatory response in the respiratory system (1). Systemic diseases such as connective tissue syndromes and malnutrition may contribute to chronic sinusitis. Environmental factors in the workplace and geographic conditions (e.g., cold and damp weather) may aggravate or accelerate the development of sinusitis. Factors contributing to the development of sinus disease include atmospheric pollutants, allergy, tobacco smoke, skeletal deformities, dental conditions, barotrauma from scuba diving or airline travel, and neoplasms.
Most acute infections (lasting less than 4 weeks) begin with a viral agent in the nose or nasopharynx that causes inflammation, blocking the draining ostia (1). The location of the symptoms varies by anatomic site of infection—maxillary sinus over the cheeks, ethmoid sinus across the nose, frontal sinus in the supraorbital area, and sphenoid sinus to the vertex of the head—and typically last 7 to 10 days, clearing with nothing more than a decongestant. Viral agents impede the sweeping motion of ciliary function in the sinus and, in combination with edema from inflammation, may occasionally lead to superinfection with bacteria. The most common bacterial agents infecting sinuses are Streptococcus pneumoniae and Haemophilus influenzae. Gram-negative organisms are usually limited to compromised hosts in intensive care units. Although less than 2% of acute sinusitis cases transition from viral to bacterial infections requiring antibiotics, more than 85% of patients receive antibiotic prescriptions. Chronic sinusitis (lasting more than 12 weeks) develops from either inadequate drainage or compromised local defense mechanisms. The flora usually is polymicrobial, consisting of aerobic and anaerobic organisms.
Sinus ailments frequently occur in middle-age individuals. Acute infection is usually located in the maxillary and frontal sinuses. Classically, infection in the maxillary sinus results from obstruction of the ostia found in the medial wall of the nose. Fever, malaise, a vague headache, and pain in the maxillary teeth are early symptoms. Reports of “fullness” in the face or exploding pressure behind the eyes often are elicited as well as increasing pain with bending over. Pressure and percussion over the malar areas can cause severe pain. Purulent exudates in the middle meatus of the nose or in the nasopharynx often are present. Five clinical findings are most useful in diagnosis: (i) maxillary toothache, (ii) poor response to nasal decongestants, (iii) abnormal transillumination, (iv) colored visible purulent nasal secretions, and (v) a history of colored nasal discharge. When four or more features are present, the likelihood of sinusitis is high, and when none is present, sinusitis is highly unlikely (2). Initial episodes of sinusitis do not require imaging studies; however, when persistent infections occur, studies and referral are indicated. Computed tomography of the sinuses demonstrated that 90% of patients with colds have radiological evidence of sinus disease that usually will resolve in 2 to 3 weeks. Radiographic changes do not reliably identify sinusitis secondary to bacteria. After sinus needle aspiration, about 60% of patients with abnormal radiographic images have positive cultures (3). Unless culture samples are obtained by direct needle drainage, they are contaminated by oropharyngeal flora and are thus of no value. For this reason, therapy usually is empiric.
Systemic decongestants containing pseudoephedrine are useful in shrinking the obstructive ostia and promoting sinus drainage and ventilation. Topical decongestants should be used for no longer than 3 days because prolonged use may lead to rebound vasodilation and worsening of symptoms. Mucolytics like guaifenesin may help thin sinus secretions and promote drainage. Antihistamines should be avoided in acute sinusitis because of their drying effects, which can lead to thickened secretions and poor drainage of the sinuses. Analgesics are recommended for pain relief. Therapies to relieve symptoms include facial hot packs and analgesics. Topical nasal steroids may accelerate the recovery in patients with viral sinusitis and those with a history of chronic rhinitis or recurrent sinusitis who seek treatment of acute rhinosinusitis (4,5). Improvement should be apparent within 48 hours of treatment, but 10 days may be necessary for complete resolution of symptoms. When improvement is not rapid, resistance should be presumed, and other classes of antibiotics should be given (6). In persistent cases, referral to an otolaryngologist for sinus irrigation may be necessary (7).
Broad antibiotic coverage of common aerobes and anaerobes is necessary but should be limited to patients with acute pain, especially unilateral maxillary tooth, facial, or sinus pain, and purulent discharge, particularly if the symptoms initially improved and then worsen. This cluster of symptoms is more suggestive of bacterial rather than viral acute sinusitis. It should be noted that the majority of acute bacterial sinusitis cases resolve in 7 to 10 days without antibiotics, similarly to the viral form. For acute bacterial sinus infections, amoxicillin (500 mg three times a day) or trimethoprim/sulfamethoxazole (1 tablet twice a day) remains the treatment of choice. Amoxicillin is inexpensive, penetrates the sinus tissues well, and can be changed to another antibiotic if symptoms have not improved in 48 to 72 hours. If these give only a minimal or no response after 7 days, consider broader spectrum antibiotics. If beta-lactam resistance is likely, amoxicillin/clavulanic acid (875 mg twice daily) or azithromycin (5-day course once a day) may be used. Other second-line drugs include cefuroxime (250 mg twice daily), ciprofloxacin (500 mg twice daily), clarithromycin (500 mg twice daily), levofloxacin (500 mg once a day), and loracarbef (400 mg twice daily). The usual treatment course is 10 to 14 days, and patients should be informed that relapses might occur if the full course of treatment is not completed.
Chronic sinusitis may result from repeated infections with inadequate drainage. The interval between infections becomes increasingly shorter until there are no remissions. Presenting symptoms are recurrent pain in the malar area or chronic postnasal drip. In the preantibiotic era, chronic sinusitis was the result of repeated acute sinusitis with incomplete resolution, whereas allergy is currently a more common cause. Injury of surface ciliated epithelium results in impaired removal of mucus. A vicious cycle ensues of incomplete resolution of infection, followed by reinfection, and ending with the emergence of opportunistic organisms. Allergies have become an important factor in chronic sinusitis. The swelling and edema of the mucosa in conjunction with hypersecretion of mucus leads to ductal obstruction and infection. Chronic sinusitis is associated with chronic cough and laryngitis with intermittent acute infections. Treatment is directed at the underlying etiology: either allergy control or aggressive management of infections. Resistant cases require computed tomography and endoscopic surgery for polyp removal. Nasoantral window formation is a radical surgery that is occasionally necessary.
No clinical criteria can reliably identify those patients who might benefit from treatment with antibiotics. It is reasonable to treat women with presumed bacterial sinusitis if they have high fever, systemic toxicity, immune deficiency, or possible orbital or intracranial involvement (6). Although very rare, untreated sinus infections may have dire consequences, such as orbital cellulitis, leading to orbital abscess, subperiosteal abscess formation of the facial bones, cavernous sinus thrombosis, and acute meningitis. Brain and dural abscesses are rare; when they occur, it usually is the result of direct spread from a sinus. A patient complaining of abnormal vision such as diplopia, changes in mental status, and periorbital edema should prompt a referral to emergency room for evaluation of intracranial or orbital extension. Computed tomography scanning is the most accurate diagnostic tool. The use of aggressive surgical approaches with broad-spectrum antibiotics is necessary for adequate drainage.
Otitis Media
Otitis media remains primarily a disease of children, but may affect adults, often secondary to a concurrent viral infection of the upper respiratory tract. Diagnosis in most cases reveals fluid behind the tympanic membrane. Treatment is directed to symptoms and involves the use of antihistamines and decongestants, despite few data to support their use. Acute otitis media is usually a bacterial infection; Streptococcus pneumoniae and Hemophilus influenza are the most common pathogens. Symptoms include acute purulent otorrhea, fever, hearing loss, and leukocytosis. Physical examination of the ear reveals a red, bulging, or perforated membrane. Indicated treatment is broad-spectrum antibiotics such as amoxicillin/clavulanic acid, cefuroxime axetil, and trimethoprim-sulfamethoxazole.
Bronchitis
Acute bronchitis is an inflammatory condition of the tracheobronchial tree. Most often it is viral in origin and occurs in winter. Common cold viruses (rhinovirus and coronavirus), adenovirus, influenza virus, and Mycoplasma pneumoniae (a nonviral pathogen) are the most common pathogens involved. Bacterial infections occur less commonly and may be secondary pathogens. Cough, hoarseness, and fever are the usual presenting symptoms. In the initial 3 to 4 days, the symptoms of rhinitis and sore throat are prominent; coughing may last as long as 3 weeks. The prolonged nature of these infections promotes the use of antibiotics to “clear up the infection” (8). Sputum production commonly occurs and may be prolonged in cigarette smokers. Most serious bacterial infections occur in cigarette smokers, who have damage to the lining of the upper respiratory tree and changes in the host flora.
Physical examination discloses a variety of upper airway sounds, usually coarse rhonchi. Rales are usually not present on auscultation, and signs of consolidation and alveolar involvement are absent. During auscultation of the chest, signs of pneumonia such as fine rales, decreased breath sounds, and euphonia (“E to A changes”) should be sought. If the results of the physical examination are uncertain or the patient’s condition appears to be in respiratory distress chest radiography should be performed to detect the presence of parenchymal disease. Paradoxically, as the initial acute syndrome subsides, sputum production may become more purulent. Sputum cultures are of limited value because of the polymicrobial nature of infections. In the absence of complications, treatment is directed to relief of symptoms. The use of antibiotics is reserved for patients in whom chest radiography findings are consistent with pneumonia. Cough is usually the most aggravating symptom and may be treated with antitussive preparations containing either dextromethorphan or codeine. The efficacy of any expectorant is not proved.
Chronic bronchitis is defined as a productive cough from excessive secretions for at least 3 months in a year for 2 consecutive years. Prevalence is estimated to be between 10% and 25% of the adult population who are smokers. Previously the incidence was lower in women than men, but as the prevalence of cigarette smoking in women increased, so too has the incidence of bronchitis in women. Chronic bronchitis is classified as a form of chronic obstructive pulmonary disease (COPD; e.g., “blue bloaters”). Other causes include chronic infections and environmental pathogens found in dust. The cardinal manifestation of disease is an incessant cough, usually in the morning, with expectoration of sputum. Because of frequent exacerbations, the hospitalizations involved and the complexity of medical management, these patients should be referred to an internist.
Pneumonia
Pneumonia is defined as inflammation of the distal lung that includes terminal airways, alveolar spaces, and the interstitium. Pneumonia may have multiple causes, including viral and bacterial infections or aspiration. Aspiration pneumonia is usually the result of depressed awareness commonly associated with the use of drugs and alcohol or anesthesia. Viral pneumonias are caused by multiple infectious agents, including influenza A or B, parainfluenza virus, or respiratory syncytial virus. Most viral syndromes are spread by aerosolization associated with coughing, sneezing, and even conversation. Incubation is short, requiring only 1 to 3 days before the acute onset of fever, chills, headache, fatigue, and myalgias. Symptom intensity is directly related to intensity of the host febrile reaction. Pneumonia develops in only 1% of patients who have a viral syndrome, but mortality rates may reach 30% in immunocompromised individuals and the elderly. An additional risk is the development of secondary bacterial pneumonias after the initial viral insult. These infections are more common in elderly patients and may explain the high fatality in this group (8). Staphylococcal pneumonias, which often arise from a previous viral infection, are extremely lethal regardless of patient age. The best treatment for viral pneumonia is prevention by immunization. Treatment is supportive and consists mostly of administration of antipyretics and fluids.
Bacterial pneumonia is classified as either community acquired or nosocomial, and in many cases the classification determines prognosis and antibiotic therapy. Risk factors that contribute to mortality are chronic cardiopulmonary diseases, alcoholism, diabetes, renal failure, malignancy, and malnutrition. Prognostic features associated with poor outcome include greater than two lobe involvement, respiratory rate greater than 30 breaths per minute on presentation, severe hypoxemia (<60 mm Hg on room air), hypoalbuminemia, and septicemia. Pneumonia is a common cause of adult respiratory distress syndrome (ARDS), with a mortality rate between 50% and 70% (9,10).
Signs and symptoms of pneumonia vary depending on the infecting organism and the patient’s immune status. In typical pneumonias, the usual presentation is a patient with high fever, rigors, productive cough, chills, and pleuritic chest pain. Chest radiography often will show infiltrates (11). The following agents, listed in decreasing order, cause two-thirds of all bacterial pneumonias: Streptococcus pneumoniae, Haemophilus influenza, Klebsiella pneumoniae, gram-negative organisms, and anaerobic bacteria. Atypical pneumonias are more insidious in onset than typical pneumonias. Patients have moderate fever without the characteristic rigors and chills. Additional symptoms include a nonproductive cough, headache, myalgias, and mild leukocytosis. Chest radiography reveals bronchopneumonia with a diffuse interstitial pattern; characteristically, the patient does not appear to be as ill as the x-ray suggests. Common causes of atypical pneumonia include viruses, Mycoplasma pneumoniae, Legionella pneumophila, Chlamydia pneumoniae (also called the TWAR agent), and other rare agents.
A strong index of suspicion is required for diagnosis, especially in elderly and immunocompromised individuals, who have altered response mechanisms. This is true with “typical agents.” Subtle clues in the elderly include changes in mentation, confusion, and exacerbation of other illnesses. The febrile response may be entirely absent, and the results of the physical examination are not predictive of pneumonia. In high-risk groups, an increased respiratory rate of greater than 25 breaths per minute remains the most reliable sign of infection. Mortality in these high-risk groups of patients is strongly correlated with the ability of the host to mount normal defenses to the symptoms of fever, chills, and tachycardia.
All women suspected of having pneumonia should undergo chest radiography to establish the diagnosis and to detect alternate diagnoses such as congestive heart failure and tumors. The chest radiograph can detect complications like pleural effusions and multilobar disease. Laboratory studies helpful in identifying community-acquired pneumonia are sputum Gram stain, sputum culture, and two sets of blood culture. An “adequate sputum” sample (defined as more than 25 neutrophils with less than 10 epithelial cells per low-powered field on microscopic examination) may be difficult to obtain. Respiratory therapists are an excellent resource for inducing sputum. Hospitalized patients undergo assessment of blood–gas exchange by either oximetry or arterial blood–gas analysis. Diagnosis of Legionella pneumoniae requires a different laboratory technique: measuring urinary antigen levels. Mycoplasma pneumoniae should be suspected when cold agglutinin findings are positive in the presence of the appropriate clinical symptoms.
The American Thoracic Society updated their original guidelines in 2001 (10). These clinical recommendations use an evidence-based approach for the diagnosis and management of community-acquired pneumonia. Therapy should be directed at the responsible or most likely pathogen, but in many cases of pneumonia, the exact cause cannot be determined, and empiric therapy should be initiated. The American Thoracic Society recommends empiric therapy based on four groups of specific patient profiles, the presence of modifying factors, and pneumonia severity (Table 9.1).
Table 9.1 Modifying Factors that Increase the Risk of Infection with Specific Pathogens
|
Penicillin-resistant and-drug resistant pneumococci |
|
Age >65 years |
|
Beta-lactam therapy within the past 3 months |
|
Alcoholism |
|
Immune-suppressive illness (including therapy with corticosteroids) |
|
Multiple medical comorbidities |
|
Exposure to a child in a day-care center |
|
Enteric gram-negatives |
|
Residence in a nursing home |
|
Underlying cardiopulmonary disease |
|
Multiple medical comorbidities |
|
Recent antibiotic therapy |
|
Pseudomonas aeruginosa |
|
Structural lung disease (bronchiectasis) |
|
Corticosteroid therapy (>10 mg of prednisone per day) |
|
Broad-spectrum antibiotic therapy for >7 days in the past month |
|
Malnutrition |
|
Adapted from American Thoracic Society. Guidelines for the management of adults with community-acquired pneumonia. Am J Respir Crit Care Med 2001;163:1730–1754. |
• Group I. Outpatients with no cardiopulmonary disease (congestive heart failure or COPD) and no modifying factors. These patients are in the lowest-risk group and are usually infected by pathogens such as Chlamydia pneumoniae, Mycoplasma pneumoniae, or Streptococcus pneumoniae. Patients should be treated with an advanced generation macrolide such as azithromycin, clarithromycin, or doxycycline.
• Group II. Outpatients with cardiopulmonary disease or modifying factors. Patients in this group usually have some comorbidities and are older than 50 years of age. Aerobic gram-negative bacilli, mixed infections with atypical pathogens, and drug-resistant S. pneumoniae (DRSP) should be considered in this patient population. Drug recommendations include monotherapy with an antipneumococcal fluoroquinolone, such as gatifloxacin or levofloxacin; a combination of a macrolide (or doxycycline) with a beta-lactam such as cefpodoxime, cefuroxime, or amoxicillin-clavulanate; or parenteral ceftriaxonefollowed by cefpodoxime.
• Group III. Inpatients who are not in the intensive care unit and have cardiopulmonary or modifying factors. Drugs for these patients include intravenous fluoroquinolone monotherapy or a combination of an intravenous beta-lactam agent plus either intravenous or oral administration of an advanced macrolide or doxycycline. For the small group of inpatients who do not have cardiopulmonary diseases or modifying factors, intravenous azithromycin alone can be used. Alternatives include doxycycline plus a beta-lactam agent (if macrolide allergy or intolerance is present) or monotherapy with an antipneumococcal fluoroquinolone.
• Group IV. Inpatients in the intensive care unit. These patients usually have the most severe pneumonia, and all antibiotics are given intravenously. Immediate consultation with an internist, hospitalist, or infectious disease specialist is recommended.
Oxygen therapy and hydration should be initiated in addition to antibiotic therapy. Most patients will have an adequate clinical response within 3 days of treatment. Oral antibiotics may be given when patients meet the following criteria: ability to eat and drink, improvement in cough and dyspnea, afebrile (<100°F) on two occasions 8 hours apart, and a decreasing white blood cell count. If other clinical features are favorable, patients may be switched to oral antibiotics even if febrile. They may be discharged on the same day that oral antibiotics are started if other medical and social factors are favorable.
Vaccination
The pneumococcal vaccine should be given to people at high risk for pneumonia, which includes adults 65 years or older and people with special health problems, such as heart or lung disease, alcoholism, kidney failure, diabetes, HIV infection, or certain types of cancer. Repeat vaccination is recommended 5 years after the first dose is given. The vaccine is active against 23 types of pneumococcal strains, and most individuals develop protection within 2 to 3 weeks of inoculations.
The influenza vaccine should be given every fall to high-risk groups: individuals 50 years of age or older; anyone with serious long-term health problems such as heart disease, lung disease, kidney disease, diabetes, and weak immune systems as with HIV and AIDS; individuals on long-term steroids or receiving cancer treatment; women who are pregnant during the flu season (November through April); and anyone coming in close contact with people at risk of serious influenza like physicians, nurses, and family members. Vaccination is best given from October to mid-November. Antiviral agents should not be used as a substitute for vaccination but may be a useful adjunct. The four agents approved for use in the United States are amantadine, rimantadine, zanamivir, and oseltamivir.These drugs should be given within 2 days of the onset of symptoms to shorten the duration of uncomplicated illness caused by influenza (11–13).
Cardiovascular Disease
The risk factors for coronary artery disease are presented in Table 9.2. Central to treating cardiovascular disease is the control of contributing diseases and risk factors through lifestyle modifications (Table 9.3). Aerobic exercise protects against cardiovascular disease (14). Additional aspects of prevention of myocardial disease, renal disease, and stroke include control of hypertension, identification and control of diabetes and obesity, and control of dietary fats, especially cholesterol, in susceptible individuals (Fig. 9.1). The presence or absence of target organ damage shown in Table 9.4also determines the risk of coronary artery disease in hypertensive patients.
Table 9.2 Major Risk Factors for Coronary Artery Disease
|
Age >55 for men and >65 for women |
|
Family history of cardiovascular disease (men <55 y; women <65 y) |
|
Physical inactivity |
|
Diabetes mellitus |
|
Cigarette smoking |
|
Dyslipidemia |
|
Obesity (body mass index ≥30) |
|
Hypertension |
|
Microalbuminuria or estimated glomerular filtration rate <60 mL/min |
|
Adapted from Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII). JAMA2003;289:2560–2572. |
Table 9.3 Lifestyle Adjustments to Manage Hypertension
|
Weight reduction to maintain a body mass index of 18.5–24.9 |
|
Limit alcohol use to 2 drinks per day for men (24 oz beer, 10 oz of wine, 3 oz of 80-proof whiskey) and no more than 1 drink per day in women and lighter-weight persons |
|
Regular aerobic exercise (at least 30 minutes per day of brisk walking most days of the week) |
|
Decrease salt intake to less than 2.4 g of sodium or 6 g of sodium chloride per day |
|
Consume a diet rich in fruits, vegetables, and low-fat dairy products with a reduced content of saturated and total fat |
|
Adapted from Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII). JAMA2003;289:2560–2572. |
Hypertension
The relationship between hypertension and cardiovascular events such as stroke, coronary artery disease, congestive heart disease, and renal disease is well known. More than 50 million people in the United States have hypertension. It is found in 15% of the population between the ages of 18 and 74 years; the incidence increases with age and varies with race. The contribution of hypertension to overall cardiovascular morbidity and mortality in women was thought to be less important than that in men, but this may reflect the relative absence of research in women (15). After age 50, women have a higher incidence of hypertension than men; this may be a confounding variable related to the overall mortality of men at an earlier age (16). More than 60% of those individuals older than age 60 years can be classified as hypertensive (17). Recognition and treatment of hypertension may decrease the development of renal and cardiac disease.
Figure 9.1 Disease and risk factors contributing to cardiovascular disease.
Table 9.4 Target Organ Damage
|
Stroke or transient ischemic attacks |
|
Hypertensive retinopathy |
|
Heart disease |
|
Angina or prior myocardial infarction Congestive heart failure Prior coronary revascularization Left ventricular hypertrophy Chronic kidney disease |
|
Peripheral arterial disease |
|
Adapted from Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII). JAMA2003;289:2560–2572. |
Epidemiology
The incidence of hypertension is twice as high in African Americans than in whites. Geographic variations exist: the southeastern United States has a higher prevalence of hypertension and stroke, regardless of race (16). One multi-institutional study confirmed an increased incidence of hypertension in African Americans, and that the incidence is increased in individuals with lower levels of education (17). Preventive measures can be most effective in those at highest risk, such as in African American women and individuals from the lowest socioeconomic level (17). The influence of genetic predisposition is poorly understood. Studies of women are limited to those that determine side effects of medication and the impact of certain medications on long-term lipid status (13).
Table 9.5 Laboratory Tests and Procedures Recommended in the Evaluation of Uncomplicated Hypertensiona
|
Urinalysis |
|
Complete blood count |
|
Potassium |
|
Creatinine or estimated glomerular filtration rate |
|
Calcium |
|
Fasting glucose |
|
Lipid profile that includes HDL, LDL, and triglycerides after a 9- to 12-hour fast |
|
12-lead electrocardiogram |
|
HDL, high-density lipoprotein; LDL, low-density lipoprotein. aIf any of the above are abnormal, consultation or referral to an internist is indicated. Adapted from Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII). JAMA2003;289:2560–2572. |
Table 9.6 Blood Pressure (BP) Classification (Adults 18 Years and Older)
|
Category |
Systolic BP (mm Hg) |
Diastolic BP (mm Hg) |
|
Normal |
<120 |
and <80 |
|
Prehypertension |
120–139 |
or 80–89 |
|
Stage 1 hypertension |
140–159 |
or 90–99 |
|
Stage 2 hypertension |
>160 |
or >100 |
|
Modified from Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII). JAMA2003;289:2560–2572. |
||
Classically, hypertension is defined as blood pressure levels higher than 140/90 when measured on two separate occasions. Medication may be indicated only for individuals at high risk. Individuals at low risk, such as white women with no other risk factors, may benefit from lifestyle modification alone. Life insurance risk tables indicate that when blood pressure is controlled to lower than 140/90, normal survival occurs over a 10- to 20-year follow-up, regardless of gender. Current recommendations are based on sustained blood pressures higher than 140/90 (18).
More than 95% of individuals with hypertension have primary or essential hypertension (cause unknown), whereas fewer than 5% have secondary hypertension resulting from another disorder.Key factors to be determined in the history and physical examination include presence of prior elevated readings, previous use of antihypertensive agents, a family history of cardiovascular death before age 55, and excessive intake of alcohol or sodium. Lifestyle modification is considered important in the therapy of hypertension; thus, a detailed history of diet and physical activity should be obtained (14). Baseline laboratory evaluations to rule out reversible causes of hypertension (secondary hypertension) are listed in Table 9.5. Diagnosis and management are based on the classification of blood pressure readings, as presented in Table 9.6.
The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) released their seventh report in 2003. The purpose was to provide an evidence-based approach to the prevention and management of hypertension. Following are key points of this report:
• Systolic blood pressure in those older than 50 years is a more important cardiovascular risk factor than diastolic blood pressure.
• Beginning at 115/75 mm Hg, the risk of cardiovascular disease doubles for each increment of 20/10 mm Hg.
• Individuals who are normotensive at 55 years of age will have a 90% lifetime risk of developing hypertension.
• Patients with prehypertension (systolic blood pressure 120–139 mm Hg or diastolic blood pressure 80–89 mm Hg) require health-promoting lifestyle modifications to prevent the progressive rise in blood pressure and cardiovascular disease.
• For uncomplicated hypertension, thiazide diuretic should be used in most cases for medical treatment, either alone or combined with drugs from other classes.
• Other antihypertensive drug classes (angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, beta-blockers, calcium channel blockers) should be used in the presence of specific high-risk conditions(Table 9.7).
• Two or more antihypertensive medications are required to achieve optimal blood pressure levels (<140/90 mm Hg or <130/80 mm Hg, respectively) for patients with diabetes or chronic kidney disease.
• For patients whose blood pressure is more than 20 mm Hg above the systolic blood pressure goal or more than 10 mm Hg above the diastolic blood pressure goal, initiation of therapy using two agents, one of which will be a thiazide diuretic, should be considered.
Table 9.7 Drug Choices for Hypertension with Compelling Indications
Regardless of therapy or care, hypertension will be controlled only if patients are motivated to maintain their treatment plan. If blood pressure control is not easily achieved, if the systolic blood pressure is higher than 180 mm Hg, or if the diastolic reading is higher than 110 mm Hg, referral to an internist is recommended. Referral is indicated if secondary hypertension is suspected or evidence of end-organ damage (renal insufficiency or congestive heart failure) is present.
Measurement of Blood Pressure
An essential variable in evaluation of hypertension is how measurements are obtained and the need to standardize measurements (19). “White coat” or office hypertension (i.e., elevated just by seeing a physician) may occur in up to 30% of patients. For patients who have repeated normal measures outside of the office, it is reasonable to use ambulatory or home monitoring devices. Given the variation of accuracy and patient interpretation, it is advisable for the patient to bring their blood pressure unit into the office to calibrate it against the office-based measurements. In most patients, office readings are sufficient to adequately diagnose and monitor hypertension and eliminate problems of reliability with commercial devices and patient interpretation skills.
Blood pressure protocols for measurement should be standardized. The patient should be allowed to rest for 5 minutes in a seated position and the right arm used for measurements (for unknown reasons, the right arm has higher readings). The cuff should be applied 2 cm above the bend of the elbow and the arm positioned parallel to the floor. The cuff should be inflated to 30 mm Hg above the disappearance of the brachial pulse, or 220 mm Hg. The cuff should be deflated slowly at a rate no more than 2 mm Hg per second.
The cuff size is important, and most cuffs are marked with “normal limits” for the relative size they can accommodate. The most common clinical problem encountered is small cuffs used with obese patients, resulting in “cuff hypertension.” Phase IV Korotkoff sounds are described as the point when pulsations are muffled, whereas phase V is complete disappearance. Most experts in hypertension advocate the use of phase V Korotkoff sounds, but phase IV sounds may be used in special circumstances, with the reason documented.
Figure 9.2 Algorithm for the drug choices for hypertensive patients unresponsive to lifestyle changes. Goal blood pressure (BP) is <140/90 mm Hg, or <130/80 mm Hg for those with diabetes or chronic kidney disease, respectively. ACE, angiotensin-converting enzyme; ARB, angiotensin-receptor blocker; CCB, calcium channel blocker. (Modified from Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII). JAMA2003;289:2560–2572, with permission.)
The use of automated devices may help eliminate discrepancies in measurements. Regardless of the method or device used, two measurements should be obtained with less than a 10 mm Hg disparity to be judged adequate. When repeated measures are performed, there should be a 2-minute rest period between readings. Blood pressure has a diurnal pattern, so determinations preferably should be done at the same time. Ambulatory monitoring is not cost-effective in all patients, but may be used to evaluate resistance to therapy, to assess “white coat” hypertension, and to determine whether syncopal episodes are related to hypotension or episodic hypertension (20).
Therapy
Nonpharmacologic interventions or lifestyle modifications should be attempted before initiation of medication unless the systolic blood pressure exceeds 139 mm Hg or the diastolic blood pressure exceeds 89 mm Hg. Drug therapy should be initiated for systolic blood pressure greater than 130 mm Hg or diastolic blood pressure greater than 80 mm Hg in those with diabetes or chronic renal failure. An important element in lifestyle modifications is to modify all contributors to cardiovascular disease. In obese patients, weight loss, especially in individuals with truncal and abdominal obesity, can play a significant role in the prevention of atherosclerosis (14,21). A loss of just 10 pounds was reported to lower blood pressure (22). Inquiries into dietary practices should be made to eliminate excess salt in the diet, specifically certain food groups that are high in sodium, such as canned goods, snack food, pork products, and soy sauce (23). Cholesterol and fat intake in the diet should be limited. Dietary interventions that use calcium, magnesium, and potassium supplementation did not make a clinically significant reduction in pressure (24). An exercise program, weight loss, and moderating alcohol intake (to no more than two alcoholic beverages per day) contribute to overall cardiovascular health. Aerobic exercise alone may prevent hypertension in 20% to 50% of normotensive individuals (14).
The goal of therapy is for the patient to lower blood pressure into the “normal range”: a systolic reading less than or equal to 120 mm Hg and a diastolic reading less than or equal to 80 mm Hg. If lifestyle modifications are not sufficient to control blood pressure, then pharmacologic intervention is indicated (Fig. 9.2).
Diuretics
The most commonly used medication for initial blood pressure reduction is a thiazide diuretic. The mechanism of action is to reduce plasma and extracellular fluid volume. This lowering of volume is thought to decrease peripheral resistance. Cardiac output initially decreases and then normalizes (25). The important long-term effect is a slight decrease in extracellular fluid volume. The maximum therapeutic dose of thiazides should be lowered to 25 mg, rather than the commonly used 50 mg. The benefit of higher doses is eliminated by the corresponding increase in side effects. Potassium-sparing diuretics (spironolactone, triamterene, or amiloride) are available in fixed doses and should be prescribed to prevent the development of hypokalemia. Potassium supplementation is less effective than the use of potassium-sparing agents. Thiazide diuretics are best used in patients with creatinine levels less than 2.5 g/L. Loop diuretics (furosemide) work better than thiazide diuretics at lower glomerular filtration rates and higher serum creatinine levels. Control of hypertension with concurrent renal insufficiency is difficult and is probably best handled by an internist or nephrologist. Thiazides and loop diuretics should not be used concurrently because profound diuresis may occur and lead to renal impairment. Concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs) limits the effectiveness of this class of drugs. Other side effects that further limit the usefulness of thiazide diuretics include hyperuricemia, which may contribute to acute gout attacks, glucose intolerance, and hyperlipidemias (26). The metabolic side effects of these drugs limit their popularity.
Adrenergic Inhibitors
Beta-blockers were used extensively for years as antihypertensive agents. The mechanism of action is decreasing cardiac output and plasma renin activity, with some increase in total peripheral resistance. As a class, they are an excellent source of first-line therapy, especially for migraine sufferers. The original formulation, propranolol, is highly lipid soluble and contributed to bothersome side effects such as depression, sleep disturbances (nightmares in the elderly), and constipation in higher doses. Propranolol has a relative lack of beta selectivity, which promotes other undesirable phenomena. Formulations such as atenolol are water soluble, are beta1 selective, and have fewer side effects than propranolol. At higher doses, beta2 effects emerge. There is no evidence to support speculation that beta1 selective agents may be safe for use in individuals who have asthma. An advantage of water-soluble agents is a longer half-life. Reduced dosing schedules improve compliance. Side effects of beta-blockers include an increase in triglyceride levels and a decrease in high-density lipoprotein (HDL) cholesterol and blunting of adrenergic release in response to hypoglycemia. NSAIDs may decrease the effectiveness of beta-blockers. Contraindications to beta-blockers are asthma, sick sinus syndrome, or bradyarrhythmia. Beta-blockers are often used for the treatment of angina and after myocardial infarctions. However, if these drugs are acutely withdrawn, a rebound phenomenon of ischemia may occur, leading to acute myocardial infarction. Despite these potential problems, beta-blockers continue to be useful in counteracting reflex tachycardia, which often occurs with the use of smooth muscle relaxing drugs.
Use of alpha1-adrenergic drugs became popular in men because of their minimal effects on potency and unique relationship to lipids. They may contribute to stress urinary incontinence in women because of altered urethral tone. As single agents, they decrease total cholesterol and low-density lipoprotein (LDL) cholesterol while increasing HDL cholesterol, in contrast to the metabolic effects of beta-blocking agents. Their mode of action is to promote vascular relaxation by blocking postganglionic norepinephrine vasoconstriction in the peripheral vascular smooth muscle. Prazosin and doxazosin are two preparations available in this class. A serious side effect of these drugs, which is commonly described in the elderly patients, is called the “first-dose effect.” In susceptible individuals, severe orthostasis was reported when therapy was initiated but subsided after several days. When alpha1-adrenergic drugs are used in combination with diuretics, hypotension may be further exacerbated. Therapy should begin with small doses taken at bedtime followed by incremental increases. Other side effects that may limit the usefulness of these agents in some patients include tachycardia, weakness, dizziness, and mild fluid retention.
Angiotensin-Converting Enzyme Inhibitors
The angiotensin-converting enzyme (ACE) inhibitors are first-line drugs in the treatment of hypertension. Their rapid rise in popularity results from the introduction of new formulations, which allow dosing once or twice a day with a good therapeutic response. There are relatively few side effects; chronic cough is the most worrisome and is a common reason of discontinuing the use of this group of drugs. Other side effects are occasional first-dose hypotension and blood dyscrasias. Occasionally, patients will suffer from rashes, loss of taste, fatigue, or headaches. Other agents should be considered for patients at risk for pregnancy (a strict contraindication). ACE inhibitors can be used in combination with other agents, including diuretics, calcium channel antagonists, and beta-blocking agents. In contrast to beta-blocking agents, these medications can be used in patients with asthma, depression, and peripheral vascular disease. For unknown reasons, they are less effective in African Americans unless a diuretic is used concomitantly. Use with diuretics increases the effectiveness of both drugs, but hypovolemia may result. If renal failure is present, hyperkalemia may result from potassium supplementation and altered tubular metabolism. Any NSAID, including aspirin, may decrease the antihypertensive effectiveness. Use of NSAIDs, volume depletion, and renal artery stenosis may precipitate acute renal failure when administration of an ACE inhibitor is initiated. Creatinine levels should be measured at the start of therapy and 1 week after initiation of any ACE inhibitor. An increase of up to 35% of the baseline creatinine value is acceptable, and treatment should be continued unless hyperkalemia develops.
Angiotensin-Receptor Blockers
The angiotensin-receptor blockers such as losartan and valsartan interfere with the binding of angiotensin II to AT1 receptors. As with ACE inhibitors, they are effective in lowering blood pressure without causing the side effect of coughing. Angiotensin-receptor blockers have favorable effects on the progression of kidney disease in individuals who have diabetes, and on those without diabetes and congestive heart failure.
Calcium-Channel Blockers
Calcium-channel blockers represent a major therapeutic breakthrough for patients with coronary artery disease. They are effective in patients with hypertension and peripheral vascular disease.The mechanism of action is to block calcium movement across smooth muscle, therefore promoting vessel wall relaxation. Calcium channel blockers are useful in treating concurrent hypertension and ischemic heart disease as an alternative to beta-blockers, if needed. Additionally, these drugs are particularly effective in the elderly and African Americans. Side effects noted include headache, dizziness, constipation, gastroesophageal reflux, and peripheral edema. The addition of long-acting calcium-channel blockers made these preparations more amenable for use in hypertension. A relative contraindication for use of these drugs is the presence of congestive heart failure or conduction disturbances.
Direct Vasodilators
Hydralazine is a potent vasodilator used for years in obstetrics for severe hypertension associated with preeclampsia and eclampsia. The mechanism of action is direct relaxation of vascular smooth muscle, primarily arterial. Major side effects include headaches, tachycardia, and fluid (sodium) retention that may result in paradoxical hypertension. Several combinations are used to counter the side effects and enhance antihypertensive effects. Diuretics may be added to reverse fluid retention caused by excess sodium. When used in combination with beta-blockers, tachycardia and headaches may be controlled without compromising the objective of lowering blood pressure. Drug-induced lupus was widely stated as a potential side effect but is rare with normal therapeutic doses of 25 to 50 mg three times daily. Minoxidil is another extremely potent drug in this class but is of limited use to the gynecologist because of its side effects in women (beard growth). Because of minoxidil’s potency, only experienced practitioners should use it.
Central-Acting Agents
Central-acting agents (methyldopa and clonidine) have long been used in obstetrics. The mechanism of action is to inhibit the sympathetics in the central nervous system, resulting in peripheral vascular relaxation. Side effects, including taste disorders, dry mouth, drowsiness, and the need for frequent dosing (except for the transdermal form of clonidine), limited the popularity of this group of drugs. Sudden withdrawal of clonidine may precipitate a hypertensive crisis and induce angina. Clonidine withdrawal syndrome is more likely to occur with concomitant use of beta-blockers. Compliance is always a major issue, and side-effect profiles contribute significantly to patient nonadherence. With the introduction of new classes of drugs with improved efficacy and reduced side effects, use of medications in this class is expected to decline.
Monitoring Therapy
Blood pressure readings should be monitored frequently by a nurse, the patient, or in the office at 1- to 2-week intervals. If the patient has other diseases (i.e., cardiovascular, renal), therapy should be initiated earlier and directed to the target organ. If lifestyle modification alone is successful, close monitoring is necessary at 3- to 6-month intervals. When lifestyle modification is unsuccessful, a blood pressure medication should be started to decrease target organ disease.
When beginning therapy, concurrent medical conditions treatable with a common agent should be sought. Gender is not an important consideration in choosing an antihypertensive agent. Concurrent diseases and race are important for patients who:
• Have migraine headaches, for which beta-blockers or calcium channel agonists may be the best choice
• Are African American and are likely to respond better to a combination of diuretics and calcium channel blockers
• Have diabetes, chronic kidney disease, and heart failure, for which ACE inhibitors should be used
• Have had myocardial infarctions and should receive beta-blockers because they reduce the risk for sudden death and recurrent myocardial infarctions.
A summary of the compelling indications for individual drug classes is listed in Table 9.7.
Once antihypertensive medications are initiated, monitoring should be instituted at approximately monthly intervals to determine blood pressures and to assess side effects. Patients with stage II hypertension or with complicated comorbid illnesses may need more frequent monitoring. The serum creatinine and potassium levels should be monitored 1 to 2 times per year. When blood pressure goals are reached, patients may be seen in the office at 3- to 6-month intervals. Patients capable of home blood pressure monitoring should be encouraged to measure blood pressure at the same time twice weekly (20). If intolerable side effects develop, a different class of medications should be used and the patient’s progress monitored. Patients whose blood pressure is difficult to control with two agents should be considered for referral. Causes of resistance to therapy include diseases missed during the initial evaluation, unrecognized early end-stage disease, and poor compliance. Patients with evidence of target organ disease should be considered for referral to the appropriate specialist for more intensive diagnostic workup and therapy.
Cholesterol
The dietary influence of cholesterol on atherosclerosis and its relationship to hypertension and cardiovascular events (myocardial infarction and stroke) is widely debated in the scientific and lay communities. The controversy centers on the effect of dietary cholesterol in assessing risk and prevention of cardiovascular disease (26,27). Many assume that all cholesterol and fat in the diet have negative health consequences (28). Cholesterol metabolism is complex, and some of our knowledge is extrapolated from animal models. The role of cholesterol testing (who, when, and at what age) is hotly debated among health care professionals, and the test itself is fraught with multiple variables that affect results. Understanding the metabolism of cholesterol will help identify and treat patients at risk of complications from hypercholesterolemia.
Terms and Definitions
Cholesterol is usually found in an esterized form with various proteins and glycerides that characterize the stage of metabolism. The following components are important lipid particles in cholesterol metabolism:
Chylomicrons
This large lipoprotein particle consists of dietary triglycerides and cholesterol. Chylomicrons are secreted in the intestinal lumen, absorbed in the lymph, and passed into general circulation. In adipose tissue and skeletal muscle, they adhere to binding sites on the capillary wall and are metabolized for energy production.
Lipoprotein Particle
Lipoprotein particles are separated into five classes based on physical characteristics. The various cholesterol metabolites are separated by density. As lipoprotein particles are metabolized and lipids are removed for energy production, they become more dense. Attached apoproteins are modified as cholesterol moves from the so-called exogenous pathway (dietary) to the endogenous pathway (postabsorption and metabolization by the liver).
Following are the subdivisions of the lipoprotein classes (Fig. 9.3).
Figure 9.3 Metabolic pathways of lipid metabolism. Apo, apoprotein; LP, lipoprotein; FFA, free fatty acid; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein; HDL, high-density lipoprotein; LCAT, lecithin cholesterol acyltransferase.
Prehepatic Metabolites
Chylomicrons and remnants are composed of major lipids and apoproteins of the A, B-48, C and E classes. These are large particles made up of dietary cholesterol molecules that are absorbed with triglycerides.
Posthepatic Metabolites
Very low-density lipoproteins (VLDL) are transient remnants found after initial liver metabolism and compose only 10% to 15% of cholesterol particles. They consist of endogenously synthesized triglycerides.
Intermediate density lipoproteins (IDL) consist of cholesterol esters, which are posthepatic remnants derived from dietary sources. Metabolites of IDL are transient lipoproteins measured only in certain pathologic conditions.
Low-density lipoprotein (LDL) is mainly composed of the cholesterol ester and is associated with B-100 apoprotein. LDL cholesterol is approximately 60% to 70% of total cholesterol. Elevated levels of LDL cholesterol are associated with increased myocardial infarction in women older than 65 years of age. There is a structural class called LDL (a′) that is associated with myocardial infarction.
High-density lipoprotein (HDL) is composed of cholesterol esters with apoproteins A-I and A-II. These particles are 20% to 30% of total cholesterol and are the most dense.
Metabolism
Cholesterol metabolism is divided into two pathways: (i) the exogenous pathway derived from dietary sources, and (ii) the endogenous pathway or the lipid transport pathway. Individuals vary in their ability to metabolize cholesterol, with patients classified as normals, hyporesponders, and hyperresponders (29). Hyporesponders may be given cholesterol-loaded diets with no effect on serum cholesterol measurements. Hyperresponders, in contrast, have high serum cholesterol levels, regardless of dietary intake. Explanations for these differences are well described in animal models, but not in humans.
When a meal is eaten, cholesterol is transported as dietary fat. The average daily American diet contains approximately 100 g of triglyceride and approximately 1 g of cholesterol. Triglycerides are found in the core lipoprotein particles and are removed through the capillary endothelium and the chylomicron. Theories suggest that hypo- and hyperresponses to dietary cholesterol may occur secondary to the liver’s ability to recognize and metabolize apoprotein E. In the animal model, populations with large numbers of liver receptors for apoprotein E easily metabolize cholesterol and are labeled hyporesponders. Individuals with a reduced number of apoprotein E receptors are unable to metabolize cholesterol as readily, which increases the number of lipid particles. These individuals are considered hyperresponders. Despite dietary cholesterol modification, these individuals continue to have high serum cholesterol levels.
After metabolic degradation of dietary chylomicrons, apoprotein substitution occurs and liver metabolism of cholesterol esters begins. Lipid transport is now in the endogenous pathway.Carbohydrates are synthesized to fatty acids and esterified with glycerol to form triglycerides. These newly formed triglycerides are not of dietary origin and are placed in the core of VLDL. These particles are relatively large and carry five to ten times more triglyceride than cholesterol esters with apoprotein B-100. Hypertriglyceridemia is an independent risk factor for cardiovascular disease. The relationship between hypertriglyceridemia and cardiovascular disease is well known but poorly defined.
VLDL particles are transported to tissue capillaries, where they are broken down to usable fuels, monoglycerides, and fatty acids. After metabolic enzymatic degradation in the peripheral tissues, IDL remains and is either catabolized in the liver by binding to LDL receptors or modified in the peripheral tissues. As noted previously, they are associated with apoprotein E receptors, the liver recognition receptors. The LDL cholesterol, or the so-called high-risk cholesterol, is found in high circulating levels.
Despite the negative connotation of LDL in cardiovascular disease, it is a very important cellular metabolite and precursor for adrenocortical cells, lymphocytes, and renal cells. The liver uses LDL for synthesis of bile acids and free cholesterol, which is secreted into the bile. In the normal human, 70% to 80% of LDL is removed from the plasma each day and secreted in the bile by utilization of the LDL receptor pathway.
The final metabolic pathway is the transformation of HDL cholesterol in extrahepatic tissue. HDL cholesterol carries the plasma enzyme lecithin cholesterol acyltransferase (LCAT). LCAT allows HDL cholesterol to resynthesize lipids to VLDL cholesterol and recycle the lipid cascade. HDL cholesterol acts as a “scavenger” and therefore reverses the deposit of cholesterol into tissues. There is good evidence that HDL cholesterol is responsible for the reversal of atherosclerotic changes in vessels, hence the term “good cholesterol” (27).
Hyperlipoproteinemia
When cholesterol is measured, various fractions are reported. Plasma cholesterol or total cholesterol consists of cholesterol and unesterified cholesterol fractions. If triglycerides are analyzed in conjunction with cholesterol, then assumptions can be made concerning which metabolic pathway may be abnormal. Elevation of both total cholesterol and triglycerides signifies a problem with chylomicrons and VLDL synthesis. If the triglyceride-to-cholesterol ratio is greater than 5:1, the predominant fractions are chylomicrons and VLDL. A triglycerides-to-cholesterol ratio less than 5:1 signifies a problem in the VLDL and LDL fractions.
Table 9.8 Initial Classification Based on the Total Cholesterol, LDL, HDL, and Triglyceride Levels
|
Initial Classification |
|
|
Total cholesterol |
|
|
<200 mg/dL |
Desirable blood cholesterol |
|
200–239 mg/dL |
Borderline high blood cholesterol |
|
≥240 mg/dL |
High blood cholesterol |
|
LDL cholesterol |
|
|
<100 mg/dL |
Optimal cholesterol |
|
100–129 mg/dL |
Near or above optimal |
|
130–159 mg/dL |
Borderline high |
|
160–189 mg/dL |
High |
|
≥190 mg/dL |
Very high |
|
HDL cholesterol |
|
|
<40 mg/dL |
Low HDL cholesterol |
|
≥60 mg/dL |
High HDL cholesterol |
|
Triglycerides |
|
|
<150 mg/dL |
Normal |
|
150–199 mg/dL |
Borderline high |
|
200–499 mg/dL |
High |
|
>500 mg/dL |
Very high |
|
LDL, low-density lipoprotein; HDL, high density lipoprotein. |
|
|
Adapted from Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on the Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486–2497. |
|
Hyperlipoproteinemias are defined by establishing a “normal population” and then setting various limits at the 10th and 90th percentiles. Standards for women set the 80th percentile for cholesterol at 240 mg/dL and the 50th percentile at 200 mg/dL (Table 9.8). A diet low in animal fat and high in vegetable and fiber consumption helps control the level of cholesterol (27–29). Plasma elevations of chylomicrons, LDL, VLDL, various remnants of IDL, and VLDL are classified by the elevated fraction.
Evaluation
There are multiple causes of variation in cholesterol measurements (30,31). Major sources of variation within individuals include diet, obesity, smoking, ethanol intake, and the effects of exercise.Other clinical conditions that affect cholesterol measurements include hypothyroidism, diabetes, acute or recent myocardial infarction, and recent weight changes. Measurements can be altered by fasting, position of the patient while the sample is drawn, the use and duration of venous occlusion, various anticoagulants, and the storage and shipping conditions.
Factors Affecting Test Results
Intrapersonal variation is well described. If multiple samples are taken within a given day, weekly and monthly variations can be as high as 6%. At least two specimens should be taken 1 month apart and should be collected in the same dietary state in order for a lipid value to be considered accurate.
• Age and gender contribute to variations in total cholesterol measurements. Before age 50, women have lower lipid values than men, after which age the level in women is higher than in men. This finding may be modified by exogenous oral conjugated estrogens.
• Seasonal variation also occurs, with lipid samples in December or January being found to be approximately 2.5% higher than those measured in June or July.
• The effect of diet and obesity is well established. Weight reduction in an obese individual affects the triglyceride level, which may decrease as much as 40%. Total cholesterol and LDL decrease less than 10% with diet; however, HDL increases approximately 10%. Weight gain negates any benefit from prior weight loss. Accuracy of lipid measurements depends on the stability of the patient’s weight.
• Alcohol and cigarette smoking are well-known modifiers of cholesterol. Moderate sustained alcohol intake increases HDL and decreases LDL; there is a complementary increase in triglycerides. Alcohol has a protective effect when taken in moderation (defined as approximately 2 alcoholic drinks [2 ounces of absolute alcohol] per day), but this effect is negated in higher quantities. The increase in HDL is in the HDL3 fraction, which is important in the scavenger mechanism of removing LDL. Smoking has the opposite effect, increasing LDL and triglyceride levels and decreasing HDL. HDL3 decreases with cigarette smoking. The critical number of cigarettes smoked is 15 to 20 per day, regardless of gender, and a variation in the number smoked will affect results. Caffeine has a mixed effect on lipoprotein measurements and should be avoided for 12 hours before blood collection.
• Exercise is an important variable in the overall risk management of heart disease. Moderate levels of exercise are as important in overall cardiovascular health as control of hypertension and cessation of cigarette smoking. Strenuous exercise lowers the concentrations of triglycerides and LDL and increases HDL in the serum. Because of these acute blood changes, vigorous exercise should be avoided within 12 hours of drawing the blood for testing.
• Certain disease states and medications affect cholesterol measurements. Use of diuretics and propranolol increases triglycerides and decreases HDL. Diuretics may increase total cholesterol levels. Diabetes, especially in the presence of poor control, may be associated with very high levels of triglycerides and LDL and decreased levels of HDL. This may explain why these individuals are prone to cardiovascular diseases. Patients with diabetes under tight control have improved lipoprotein profiles.
• Pregnancy is associated with decreased total cholesterol in the first trimester and continuous increases of all fractions over the second and third trimesters (32). The LDL and triglyceride concentrations are the lipoproteins most affected by pregnancy.
• Patients with hypothyroidism have increased levels of total cholesterol and LDL.
Testing
Because of the diurnal variation of blood triglycerides, blood samples should be collected in the morning after a 12-hour fast. Excessive quantities of water should not be consumed before blood is drawn. After 2 minutes of venous occlusion, serum cholesterol levels can increase 2% to 5%. Therefore, the sample used for cholesterol testing should be collected first if multiple blood samples are required. One of the most important aspects of overall standardization of lipoprotein measurements is the laboratory used. It may be worthwhile to consult a clinical pathologist to determine if the laboratory complies with Centers for Disease Control and Prevention (CDC) standards for cholesterol and lipoprotein measurements.
Management
When hyperlipidemia is confirmed on at least two separate occasions, secondary causes should be diagnosed or excluded by taking a detailed medical and drug history, measuring serum creatinine and fasting glucose levels, and testing thyroid and liver function. Causes of secondary dyslipidemia include diabetes, hypothyroidism, obstructive liver disease, chronic renal failure, and use of medications such as progestins, anabolic steroids, and corticosteroids. Therapeutic lifestyle changes should be initiated in all patients to reduce their risk of coronary heart disease:
1. Reduced intakes of saturated fats (<7% of total calories) and cholesterol (<200 mg per day)
2. Therapeutic options for enhancing LDL lowering, such as plant stanols/sterols (2 g per day) and increased viscous (soluble) fiber (10–25 g per day)
3. Weight reduction
4. Increased physical activity
Figure 9.4 is a suggested algorithm for cholesterol control based on LDL levels. Cholesterol fat-lowering diet books abound in most bookstores and allow the patient to choose a diet she will best follow. The role of exercise and cigarette cessation should be stressed to all patients. Patients with a family history of cardiovascular disease (history of premature coronary artery problems and strokes) should be tested and started on conservative programs in their 20s. After 3 to 6 months, if the LDL remains above 160 mg/dL with zero to one risk factor or above 130 mg/dL with two or more risk factors, then medical therapy should be initiated. Any woman with coronary heart disease or equivalents such as diabetes or other forms of atherosclerotic disease (peripheral arterial disease, abdominal aortic aneurysm, and symptomatic carotid artery disease) should initiate lifestyle changes if her LDL is 100 mg/dL or more and drug therapy if her LDL is 130 mg/dL or more. Anyone with an LDL 190 mg/dL or higher should be considered for drug therapy (33).
Figure 9.4 Treatment decisions based on the LDL cholesterol. LDL, low-density lipoprotein; HDL, high-density lipoprotein. *Coronary heart disease (CHD) risk equivalents: Diabetes or other forms of atherosclerotic disease like peripheral arterial disease, abdominal aortic aneurysm, and symptomatic carotid artery disease. (Adapted from The Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program [NCEP] Expert Panel on the Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486–2497.)
The bile acid-binding resins cholestyramine and colestipol were the mainstay of therapy. Their usefulness is limited by side effects such as constipation, bloating, nausea, and heartburn, and by their tendency to interfere with the absorption of other drugs. Nicotinic acid (500 mg three times daily) decreases triglycerides, LDL, and lipoprotein (a′) and increases HDL more than any other drug. Flushing, pruritus, gastrointestinal distress, and, rarely, hepatotoxicity are a few of the adverse effects of nicotinic acid. Starting at a low dose and pretreating with aspirin 325 mg or ibuprofen 200 mg can minimize the facial flushing. Fibric acid derivatives like clofibrate and gemfibrozilare used to lower triglycerides and increase HDL but may increase LDL in some patients. The HMG-CoA (3-hydroxy-3methyl-glutaryl-coenzyme A) reductase inhibitors (statins) include atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin. These medicines inhibit HMG-CoA reductase, the enzyme that catalyzes the rate-limiting step in cholesterol synthesis. Several clinical trials showed that pravastatin, simvastatin, and lovastatin have a beneficial effect in cardiovascular disease. Statins are better tolerated than other lipid-lowering drugs, but reported side effects include severe myalgias, muscle weakness with increases in creatine phosphokinase, and, rarely, rhabdomyolysis, leading to renal failure.
Diabetes Mellitus
Diabetes mellitus (DM) is a chronic disorder of altered carbohydrate, protein, and fat metabolism resulting from a deficiency in the secretion or function of insulin. The disease is defined by the presence of either fasting hyperglycemia or elevated plasma glucose levels based on an oral glucose tolerance testing (OGTT). The major complications of DM are primarily vascular and metabolic. The prevalence of DM is higher in women and certain ethnic groups, although a background rate in the general population is 6.29%, which has increased threefold in 15 years (34). Risk factors for DM are:
1. Age greater than 45 years
2. Adiposity or obesity
3. A family history of diabetes
4. Race/ethnicity
5. Hypertension (blood pressure 140/90 mm Hg or greater)
6. HDL cholesterol less than or equal to 35 mg/dL and/or a triglyceride level greater than or equal to 250 mg/dL
7. History of gestational diabetes or delivery of a baby weighing more than 9 pounds
Major complications of DM include blindness, renal disease, gangrene of an extremity, heart disease, and stroke. Diabetes is one of the four major risk factors for cardiovascular disease.
Classification
In January 1999, the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus published a report revising the system that was in use since 1979 (35,36). The goal of the revision was to provide guidelines for nomenclature and testing that might reduce diagnostic confusion and improve patient well-being (Table 9.9). The terms insulin dependent diabetes mellitus (IDDM) and noninsulin dependent diabetes mellitus (NIDDM) were replaced by the terms type 1 and type 2 diabetes mellitus.
Table 9.9 Classification of Diabetes Mellitus
|
1. Type 1 diabetes A. Idiopathic B. Immune mediated 2. Type 2 diabetes 3. Other types of diabetes: A. Impaired glucose tolerance (IGT) B. Endocrinopathies (Cushing's, acromegaly, pheochromocytoma, hyperaldosteronism) C. Drug- or chemical-induced D. Diseases of the exocrine pancreas (pancreatitis, neoplasia) E. Infections F. Genetic defects of beta-cell function and insulin action G. Gestational diabetes mellitus |
|
Adapted from The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care2000;23:S4–S42. |
Type 1 Diabetes Mellitus
With type 1 diabetes, the major metabolic disturbance is the absence of insulin from the destruction of beta cells in the pancreas. Insulin is necessary for glucose metabolism and cellular respiration. When insulin is absent, ketosis results. The cause of type 1 diabetes is unknown; data suggest an autoimmune association from either a viral infection or toxic components in the environment. Studies in the past decade showed a correlation between many autoimmune diseases and the human leukocyte antigens (HLA).
Insulin-sensitive tissues (muscle, liver, and fat) fail to metabolize glucose efficiently in the absence of insulin. In uncontrolled type 1 diabetes, an excess of counter-regulatory hormones (cortisol, catecholamines, and glucagon) contributes to further metabolic dysfunction. In the absence of adequate amounts of insulin, increasing breakdown products of muscle (amino acid proteolysis), fat (fatty acid lipolysis), and glycogen (glucose glycogenolysis) are recognized. There is an increase in glucose production from noncarbohydrate precursors as a result of gluconeogenesis and ketogenesis in the liver. Without prompt treatment, severe metabolic decompensation (i.e., diabetic ketoacidosis) will occur and may lead to death.
Type 2 Diabetes Mellitus
Type 2 diabetes mellitus is a heterogeneous form of diabetes that commonly occurs in older age groups (>40 years) and more frequently has a familial tendency than type 1 diabetes. This form of diabetes mellitus accounts for approximately 90% to 95% of those with diabetes. The presence of risk factors strongly influences the development of type 2 diabetes in susceptible populations.
Risk factors for type 2 diabetes include ethnicity, obesity, family history of DM, sedentary lifestyle, impaired glucose tolerance, upper-body adiposity, and a history of gestational diabetes and hyperinsulinemia.
In contrast to an absence of insulin that occurs with type 1 diabetes, in type 2 diabetes the altered metabolism of insulin results in insulin resistance. This condition is characterized by impaired glucose uptake in target tissues. A compensatory increase in insulin secretion results, causing higher-than-normal circulating insulin levels (36). Obesity is present in 85% of affected patients. The cause of type 2 diabetes is unknown, but defects in both the secretion and action of insulin are suspected.
Many patients diagnosed with type 2 diabetes at an early age eventually exhaust endogenous pancreatic insulin and require injected insulin. When under severe stress, such as infection or surgery, they may develop diabetic ketoacidosis or a hyperglycemic hyperosmolar nonketotic state.
Diagnosis
Three methods are available to diagnose diabetes mellitus in nonpregnant women:
1. A single fasting blood glucose greater than or equal to 126 mg/dL on two separate occasions
2. A random blood glucose equal to or above 200 mg/dL in an individual with classic signs and symptoms of diabetes (polydipsia, polyuria, polyphagia, and weight loss)
3. A 2-hour OGTT greater than or equal to 200 mg/dL (fasting sample, 60-, and 120-minute samples) after a 75-g load of glucose. A 2-hour OGTT should not be performed if the first two criteria are present.
Diagnostic criterion for impaired glucose intolerance (IGT) is a fasting glucose greater than or equal to 100 mg/dL but less than 126 mg/dL (36).
A 2-hour OGTT should be performed under the following conditions:
1. A 10-hour fast should precede morning testing.
2. The patient should sit throughout the procedure.
3. No smoking is permitted during the test interval.
4. Caffeinated beverages should not be consumed.
5. More than 150 g of carbohydrates should be ingested for 3 days before the test.
6. No drugs should be taken before the test.
7. The patient should not be bedridden or under stress.
Patients who should be considered for diabetes testing are:
• All individuals 45 years of age or older (repeat at 3-year intervals)
• Persons with classic signs and symptoms of diabetes (i.e., polyuria, polydipsia, polyphagia, and weight loss)
• Ethnic groups at high risk (Pacific Islanders, Native Americans, African Americans, Hispanic Americans, and Asian Americans)
• Obesity (body mass index >27 kg/m2)
• History of a first-degree relative with diabetes
• Women with gestational diabetes or who have delivered a baby weighing more than 9 pounds
• Individuals with hypertension (blood pressure >140/90 mm Hg)
• An HDL cholesterol level less than or equal to 35 mg/dL or triglyceride level greater than or equal to 250 mg/dL
• Presence of impaired glucose tolerance on previous testing
Assessment of Glycemic Control
The only acceptable method for assessment of glycemic control is determination of blood glucose by direct enzyme analysis, not by measurement of urine values, which do not correlate.Glucometers with memory storage made home glucose monitoring more reliable. Physician treatment guidelines are in Table 9.10 and patient guidelines in Table 9.11. In a 10 multicenters' study, the diabetes control and complication trial (DCCT), performed under the auspices of the National Institutes of Health, showed a marked reduction (40%–50%) in complications of neuropathy, retinopathy, and nephropathy when patients with type 1 diabetes received intensive therapy (accomplished by a team approach) as compared with those who received standard therapy.
Table 9.10 Physician Guidelines in the Therapy of Diabetes Mellitus
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• Establish diagnosis and classify type of diabetes mellitus (DM). • The oral glucose tolerance test (OGTT) is not recommended for routine clinical use because of its higher cost, time requirement, and limited reproducibility. • Initiate diabetes education classes to learn blood glucose monitoring and diabetes medications; to learn signs, symptoms, and complications; and to learn how to manage sick days. • Place patient on ADA diet with appropriate caloric, sodium, and lipid restrictions. • Establish cardiac risk factors, kidney function (serum creatinine, urine for microalbuminuria). • If neuropathy is present, refer to a neurologist. • Establish extent of fundoscopic lesion (refer to ophthalmologist as needed). • Check feet and toenails at least once a year and refer to a foot specialist. • Use finger-stick blood glucose for daily diabetic control. • Follow chronic glycemic control by HgA1c every 2 to 3 months in the office. • Initial general health evaluation should consist of a complete history and physical examination and the following laboratory tests: CBC with differential, chemistry profile, lipid profile, urinalysis, thyroid function tests, urine for microalbuminuria, and ECG (baseline at age 40 or older, repeat yearly). • Oral hypoglycemic agents like the sulfonylureas may be considered if fasting blood glucose does not decline or increase and if the patient has diabetes for fewer than 10 years, does not have severe hepatic or renal disease, and is not pregnant or allergic to sulfa drugs. • While on oral hypoglycemic agents, check the HgA1C every 3 months and at least two times a year if stable. • If the HgA1C is <7% or the postprandial glucose is <200 mg/dL, omit the oral hypoglycemic agents, place on diet alone, and follow every 3 months. • If the fasting serum glucose is >200 mg/dL consistently or the HgA1C is more than 10%, consider starting insulin and referring the patient to an internist. • Administer the flu vaccine every fall and the pneumococcal vaccine every 6 years. |
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ADA, American Diabetic Association; HgA1c, hemoglobin A1C; CBC, complete blood count; ECG, electrocardiogram. |
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Adapted from The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care2000;23:S4–S42. |
Table 9.11 Patient Guidelines for Treatment of Type 2 Diabetes
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• Initiate an ADA reducing diet (50% CHO, 30% fat, 20% protein, high fiber) with three meals a day. • Maintain ideal body weight or to reduce weight by 5% to 15% in 3 months if obese. • Modify risk factors (smoking, exercise, fat intake). • Check fasting blood glucose by finger stick daily for 2 months. If FBS declines, no other therapy is needed. If FBG does not decline or increases, use of an oral hypoglycemic agent may be considered. |
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ADA, American Diabetic Association; CHO, carbohydrate; FBS, fasting blood glucose. |
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Adapted from The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care2000;23:S4–S42. |
Treatment
Type 2 diabetes is treated by a combination of lifestyle adjustments and medications.
Lifestyle
Diet is the most important component of DM management and usually the hardest way to achieve control. Three major strategies are used: weight loss, low-fat diet (≤30% of calories from fat), and physical exercise. Obese patients should reduce their weight to ideal body weight. Metabolic advantages of weight reduction are improved lipid profile and improved glucose control secondary to increased insulin sensitivity and decreased insulin resistance. The greater the weight loss, the greater the improvement in lipid disorders. Physical exercise promotes weight loss and improves insulin sensitivity and dyslipidemia in those people who are in high-risk groups for cardiovascular and microvascular diseases (37).
Oral Hypoglycemic Agents
Oral hypoglycemic agents are recommended for many type 2 diabetic patients. The first oral hypoglycemic agents introduced were first- and second-generation sulfonylureas. Other classes of drugs that have different effects in patients with type 2 diabetes —such as biguanides, thiazolidinediones, alpha-glucosidase inhibitors, and insulin secretagogues—were introduced. The mode of action of sulfonylureas is based on two different mechanisms: (i) enhanced insulin secretion from the pancreas, and (ii) an extrapancreatic effect that is poorly understood. Endogenous insulin secretion (as measured by C-peptide) is necessary for oral hypoglycemic agents to work. If the fasting blood glucose on an adequate diabetic diet is greater than 250 mg/dL, there is little effect. Frequent evaluation to monitor control (every 3 to 4months) is important. If glucose levels cannot be controlled with oral hypoglycemic agents (i.e., sulfonylureas) or other medicines (i.e., metformin, a biguanide), insulin therapy should be initiated and referral should be considered because of the increased rate of complications.
Thyroid Diseases
Thyroid disorders are more common in women and some families, although the exact rate of inheritance is unknown (38,39). In geriatric populations, the incidence may be as high as 5% (40). The laboratory diagnosis of thyroid disease can be difficult because of altered hormonal states such as pregnancy and exogenous hormones. Thyroid hormones act in target tissues by binding to nuclear receptors, which induce change in gene expression. Extrathyroidal conversion of thyroxine (T4) to triiodothyronine (T3) takes place in target tissue. T3 binds the nuclear receptor with higher affinity than T4, which makes T3 more biologically active. Pituitary thyroid stimulating hormone (TSH) and hypothalamic thyrotropin-releasing hormone (TRH) regulate hormone production and thyroid growth by normal feedback physiology. Thyroid-stimulating immunoglobulins (TSI), once known as a long-acting thyroid stimulator (LATS), bind to the TSH receptor, which results in hyperthyroid Graves disease.
More than 99% of circulating T4 and T3 concentrations are bound by plasma proteins, predominately to thyroxine-binding globulin (TBG), and the remaining 1% of thyroid hormones are free.Free levels of thyroid hormones remain constant despite physiologic or pharmacologic alterations. Regardless of total serum protein levels, active thyroid hormone remains stable. In healthy women, transitions from puberty to menopause do not alter free thyroid hormone concentrations. Excess endogenous or exogenous sources of estrogen increase TBG plasma concentration by decreasing hepatic clearance. Androgens (especially testosterone) and corticosteroids have the opposite effect by increasing hepatic TBG clearance.
Thyroid function tests may be misleading in women receiving exogenous sources of estrogen because of altered binding characteristics. In euthyroid individuals, elevations of thyroid hormone concentrations arise from three mechanisms: (i) increased protein binding because of altered albumin and estrogen states, (ii) decreased peripheral conversion of T4 to T3, or (iii) congenital tissue resistance to thyroid hormones, which is rare. Postmenopausal hormonal therapy and pregnancy alter laboratory findings and complicate interpretation of thyroid function studies. Most laboratories compensate by reporting a free T4 level that mathematically corrects for physiologic alterations. If questions arise, a clinical pathologist should be consulted.
Hypothyroidism
Overt hypothyroidism occurs in 2% of women, and at least an additional 5% develop subclinical hypothyroidism. This is another disease that disproportionally impacts women five- to eightfold more commonly than men. This is especially true in the elderly, in whom many of the signs and symptoms are subtle. The principal cause of hypothyroidism is autoimmune thyroiditis (Hashimoto’s thyroiditis). A familial predisposition is observed in many cases, but the specific genetic or environmental trigger is unknown. The incidence of autoimmune thyroiditis increases with age, affecting up to 15% of women older than 65 years. Many have subclinical hypothyroidism, which is defined as an elevated serum TSH concentration with a normal serum free T4 level. It is uncertain whether treatment will improve quality of life in otherwise healthy patients who have subclinical hypothyroidism (41,42). Chronic autoimmune thyroiditis (Hashimoto's) is the more common cause of hypothyroidism in countries without iodine deficiency. In this process one has both cellular and antibody-mediated destruction of the thyroid, which can result in either a goiter or atrophic thyroid. Autoimmune thyroiditis may be associated with other endocrine (e.g., type 1 diabetes, primary ovarian failure, adrenal insufficiency, and hypoparathyroidism) and nonendocrine (e.g., vitiligo and pernicious anemia) disorders (43). When autoimmune diseases are present, there should be a high degree of suspicion for concurrent thyroid disorders. With postpartum thyroiditis there will be a hyperthyroid phase followed by a hypothyroid phase that can last for months. Iatrogenic causes of hypothyroidism occur after surgical removal or radioactive iodine therapy for hyperthyroidism (Graves) or thyroid cancer. Radiation was used to treat acne and other dermatologic disorders 45 years ago; patients undergoing such treatment have an increased risk of thyroid cancer and require close monitoring. Although worldwide iodine deficiency goiter is the most common form of hypothyroidism, this is uncommon in North America given the iodine supplementation in salt as well as other dietary sources. Hypothyroidism rarely occurs secondary to pituitary or hypothalamic diseases from TSH or TRH deficiency, but this must be considered if symptoms occur after neurosurgical procedures.
Clinical Features
Manifestations of hypothyroidism include a broad range of signs and symptoms: fatigue, lethargy, cold intolerance, nightmares, dry skin, hair loss, constipation, periorbital carotene deposition (causing a yellow discoloration), carpal tunnel syndrome, weight gain (usually less than 5–10 kg), depression, irritability, hyperlipidemia, and impaired memory. Menstrual dysfunction is common, either as menorrhagia or amenorrhea. Infertility may arise from anovulation, but exogenous thyroid hormone is not useful for anovulatory euthyroid women. The finding of hyperlipidemia may be the first indication of hypothyroidism, especially the presence of high triglycerides. Empirical use of thyroid extract should be discouraged.
Hypothyroidism is not a cause of premenstrual syndrome (PMS), but worsening PMS may be a subtle manifestation of hypothyroidism (44). Hypothyroidism may cause precocious or delayed puberty. Hyperprolactinemia and galactorrhea are unusual manifestations of hypothyroidism; however, assessment of thyroid function should be considered. To distinguish primary hypothyroidism from a prolactin-secreting pituitary adenoma, TSH levels should be assessed in women who have amenorrhea, galactorrhea, and hyperprolactinemia.
Diagnosis
Recommendations for screening for thyroid disorders in women range from every 5 years starting at age 35 in women (American Thyroid Association), to age 50 (American College of Physicians), to periodically in older women (American Academy of Family Physicians and American Association of Clinical Endocrinologist), to evidence is insufficient to recommend for or against screening (United States Preventive Services Task Force) (45–49).
Suspected hypothyroidism should always be confirmed with laboratory studies. Primary hypothyroidism is characterized by the combination of an elevated serum TSH with a low serum free T4level. Autoimmune thyroiditis can be confirmed by the presence of serum antithyroid peroxidase (formerly referred to as antimicrosomal) antibodies. An elevated TSH with a normal free T4 level implies subclinical hypothyroidism. Central hypothyroidism, although rare, is distinguished by a low or low-normal serum free T4 level with either a low or inappropriate normal serum TSH concentration.
Therapy
Synthetic L-thyroxine (T4) is the treatment of choice for hypothyroidism and is available as generic levothyroxine. There is debate about the value of replacing thyroxine in the subclinical hypothyroidism patient. Such replacement did not result in improved survival, decreased cardiovascular morbidity, or improve quality of life (44). The mode of action is by conversion of T4 to T3 in peripheral tissues. Levothyroxine should be taken on an empty stomach. Absorption may be poor when taken in combination with aluminum hydroxide (common in antacids), cholestyramine, ferrous sulfate, or fatty meals. The usual T4 requirement is weight related (approximately 1.6 μg/kg) but decreases for the elderly. Normal daily dosage is 0.1 to 0.15 mg but should be adjusted to maintain TSH levels within the normal range. TSH levels should be checked in 6 weeks and when dosages or brands are changed.
In the early 1980s, many clinicians thought that increasing the serum T4 to mildly elevated levels would enhance conversion of T4 to T3. Subsequent data proved that even a mild increase of T4 was associated with cortical bone loss and atrial fibrillation, particularly in older women (44). A low initial T4 dose (0.025 mg per day) should be initiated in the elderly or patients with known or suspected coronary artery disease. Rapid replacement may worsen angina and in some cases induce myocardial infarction.
Hyperthyroidism
Hyperthyroidism affects 2% of women during their lifetime, most often during their childbearing years and impacts women fivefold more commonly than men. Graves disease represents the most common disorder; it is associated with orbital inflammation, causing the classic exophthalmus associated with the disease and a characteristic dermopathy, pretibial myxedema. It is an autoimmune disorder caused by TSH reception antibodies that stimulate gland growth and hormone synthesis. The etiology of Graves disease in genetically susceptible women is unknown. Autonomously functioning benign thyroid neoplasias are less common causes of hyperthyroidism and are associated with toxic adenomas and toxic multinodular goiter. Transient thyrotoxicosis may be the result of unregulated glandular release of thyroid hormone in postpartum (painless, silent, or lymphocytic) thyroiditis and subacute (painful) thyroiditis. Other rare causes of thyroid overactivity include human chorionic gonadotropin–secreting choriocarcinoma, TSH-secreting pituitary adenoma, and struma ovarii. Factitious ingestion or iatrogenic overprescribing should be considered in patients with eating disorders.
Clinical Features
Symptoms of thyrotoxicosis include fatigue, diarrhea, heat intolerance, palpitations, dyspnea, nervousness, and weight loss. In young patients there may be paradoxical weight gain from an increased appetite.Thyrotoxicosis may cause vomiting in pregnant women, which may be confused with hyperemesis gravidarum (50). Tachycardia, lid lag, tremor, proximal muscle weakness, and warm moist skin are classic physical findings. The most dramatic physical changes are ophthalmologic and include lid retraction, periorbital edema, and proptosis. These eye findings occur in less than one-third of women. In elderly adults, symptoms are often more subtle, with presentations of unexplained weight loss, atrial fibrillation, or new onset angina pectoris. Menstrual abnormalities span from regular menses to light flow to anovulatory menses and associated infertility. Goiter is common in younger women with Graves disease, but may be absent in older women. Toxic nodular goiter is associated with nonhomogeneous glandular enlargement, whereas in subacute thyroiditis the gland is tender, hard, and enlarged.
Diagnosis
Most thyrotoxic patients have elevated total and free T4 and T3 concentrations (measured by radioimmune assay). In thyrotoxicosis, serum TSH concentrations are virtually undetectable, even with very sensitive assays (sensitivity measured to 0.1 units). Sensitive serum TSH measurements may aid in the diagnosis of hyperthyroidism. Radioiodine uptake scans are useful in the differential diagnosis of established hyperthyroidism. Scans with homogeneous uptake of radioactive iodine are suggestive of Graves disease, whereas heterogeneous tracer uptake is suggestive of a diagnosis of toxic nodular goiter. Thyroiditis and medication-induced thyrotoxicosis have diminished glandular radioisotope concentration.
Therapy
Antithyroid medications, either propylthiouracil (PTU 50–300 mg every 6–8 hours) or methimazole (10–30 mg per day) are used for initial therapy. After metabolic control is achieved, definitive therapy is obtained by thyroid ablation with radioiodine, which results in permanent hypothyroidism. Both antithyroid drugs block thyroid hormone biosynthesis and may have additional immunosuppressive effects on the gland. The primary difference in oral medications is that PTU partially inhibits extrathyroidal T4-to-T3 conversion, whereas methimazole does not. Methimazole has a longer half-life and permits single daily dosing, which may encourage compliance. Euthyroidism is typically restored in 3 to 10 weeks, and treatment with oral antithyroid agents is continued for 6 to 24 months, unless total ablation with radioiodine or surgical resection is performed. Surgery is less popular because it is invasive and may result in inadvertent parathyroid removal, which commits the patient to lifelong calcium therapy.
The relapse rate with oral antithyroid medications is 50% over a lifetime. Lifelong follow-up is important when medical therapy is used solely because of the high relapse rate. Both medications have infrequent (5%) minor side effects, which include fever, rash, or arthralgias. Major toxicity (e.g., hepatitis, vasculitis, and agranulocytosis) occurs in less than 1%. Agranulocytosis cannot be predicted by periodic complete blood counts; therefore, patients who have a sore throat or fever should stop taking the medication and call their physician immediately.
Therapy with iodine-131 provides a permanent cure of hyperthyroidism in 90% of patients. The principal drawback to radioactive iodine therapy is the high rate of postablative hypothyroidism, which occurs in at least 50% of patients immediately after therapy, with additional cases developing at a rate of 2% to 3% per year. Based on the assumption that hypothyroidism will develop, these patients should be given lifetime thyroid replacement therapy. Beta-adrenergic blocking agents such as propranolol or atenolol are useful adjunctive therapy for control of sympathomimetic symptoms such as tachycardia (51). An additional benefit of beta-blockers is the blocking of peripheral conversion of T4 to T3. In rare cases of thyroid storm, PTU, beta-blockers, glucocorticoids, and high-dose iodine preparations (intravenous sodium iodide) should be administered immediately, and referral to an intensive care unit is advisable.
Thyroid Nodules and Cancer
Thyroid nodules are common and found on physical examination in up to 5% of patients. Nodules may be demonstrated on ultrasound in approximately 50% of 60-year-olds. The vast majority of nodules when discovered are asymptomatic and benign; however, malignancy and hyperthyroidism must be excluded (52). Ultrasound-guided fine-needle aspiration is recommended in the presence of the following factors: history of radiation to the head, neck, or upper chest; family history of thyroid cancer; ultrasound findings suggestive of malignancy; or a nodule larger than 1.5 cm in diameter (53).
Thyroid function tests should be performed before fine-needle aspiration and, if results are abnormal, the underlying disease should be treated. Because most nodules are “cold” on scanning, it is more cost-effective to proceed with tissue sampling rather than scanning. Needle biopsy provides a diagnosis in 95% of cases; in the 5% of patients in whom the diagnosis cannot be established, excisional biopsy is necessary. Only 20% of excisional biopsies of an “indeterminate aspiration” are found to be malignant (54). Lesions that are confirmed malignant on biopsy should be treated with extirpative surgery, and benign nodules should be palpated every 6 to 12 months. Thyroxine suppressive therapy for benign nodules is not recommended (53).
Papillary thyroid carcinoma is the most common malignancy, found in 75% of thyroid cancers. For unclear reasons the incidence of papillary cancer increased by almost threefold in the past 30 years, from 2.7 to 7.7 per 100,000 people (55). This may represent the more ready diagnosis of smaller cancers. The majority of cancers are found incidentally during routine examinations. Risk factors include a history of radiation exposure during childhood and family history. Signs include rapid growth of neck mass, new onset hoarseness, or vocal cord paralysis. In the setting of rapid growth, fixed nodule, new onset hoarseness, or the presence of lymphadenopathy, it is important to be sure a fine-needle aspiration is done. Thyroidectomy is the primary treatment with radioactive iodine and TSH suppression with thyroxine. Patients younger than 50 years of age with a primary tumor of less than 4 cm at presentation, even with associated cervical lymph node metastasis, are usually cured. In the elderly, anaplastic tumors have a poor prognosis and progress rapidly despite therapy.
Follicular thyroid cancer is the second most common thyroid cancer, comprising up to 10% of cases. These tend to occur in an older population with peak ages of 40 to 60. It has a threefold greater prevalence in women than men. This form of cancer tends to have vascular invasion, frequently with distant metastases. The prognosis tends to be less favorable with this form of cancer than with papillary cancers, although women do have a better prognosis than men.
Irritable Bowel Syndrome
Irritable bowel syndrome (IBS) is a common problem, affecting about 10% to 15% of the population, with women being twice as likely to have the diagnosis (56). Given that its primary symptom is typically crampy chronic abdominal pain, IBS is often in the differential diagnosis for patients with chronic pelvic pain. Stress and certain foods will often trigger the pain, and defecation often will provide some relief from the pain. Other gastrointestinal symptoms include diarrhea and constipation, gastroesophageal reflux disease, nausea, bloating, and flatulence. What makes this a more difficult diagnosis is the spectrum of additional symptoms, including dysmenorrhea, dyspareunia, fibromyalgia complaints, urinary symptoms of frequency and urgency, and even sexual dysfunction.
This spectrum of symptoms renders diagnosis difficult and led to a consensus group that created the Rome criteria in 1992, revised in 2005 (57). The resulting Rome III criteria are: recurrent abdominal pain or discomfort for at least 3 days per month for 3 months associated with two or more of the following:
• Improvement with defecation
• Onset associated with a change in frequency of stool
• Onset associated with a change in the appearance of the stool
IBS should be a diagnosis of exclusion with consideration initially given to other causes for the dominant symptom. If that is diarrhea, considerations of lactose intolerance, infectious etiology, malabsorption, or celiac disease should be entertained. Symptoms that result in weight loss, rectal bleeding, anemia, or that are noctural or progressive could indicate something other than IBS unless proven otherwise.
A basic workup might include complete blood count and chemistries. Evaluation of diarrhea, if that is the dominant symptom, should potentially include stool cultures if infectious etiology is suspected or 24-hour stool collection (if osmotic) of secretory diarrhea is suspected. Flexible sigmoidoscopy is not done routinely unless needed to rule out inflammatory conditions or malignancy in families with Lynch syndrome. Initiate dietary reviews for lactose intolerance or gluten sensitivity.
Management
General management of IBS can be extremely difficult. Often, the first step is to reassure the patient that this is a functional disease and is not related to cancer or malignancy, assuming those were eliminated by history and examination. Many individuals have some underlying concerns that diagnostic testing needs to be performed or that something is being missed. Constant reassurance is an important aspect of management. The patient needs to be an active participant in her care and understand the chronic nature of the disease. A symptom diary for several weeks may show a link between various foods and stressors that may be modifiable. Some individuals are able to link various stressors in their lives to symptoms while others will not have identifiable causes. Common triggers include stress, anxiety, medication (antibiotics, antacids), menstrual cycles, abusive relationships, certain foods (lactose, sorbitol), and travel. Patients should be counseled about dietary interventions, including increasing dietary fiber, decreasing total fat intake, and avoiding foods that trigger symptoms. Stool softeners are recommended for individuals with hard stools, and bulk aiding agents may be helpful for those individuals with constipation. The overuse of laxatives is to be discouraged. Good bowel habits should be discussed. Patients with poor habits should set aside a quiet time every day to attempt defecation. Many individuals get into a habit of ignoring stooling symptoms, leading to further problems with lower gastrointestinal disease.
Antidiarrheal agents, specifically loperamide or diphenoxylate, are often useful in patients with mild disease. The goal is to reduce the number of bowel movements and help to relieve rectal urgency. Anticholinergics including hyoscyamine and dicyclomine hydrochloride often are helpful. Powder opium, an antidiarrheal, combined with an antispasmodic (belladonna alkaloid), is another option for refractory disease. Antispasmodic agents have anticholinergic agents as the primary ingredient, and compliance may be a problem because side effects include dry mouth, visual disturbances, and constipation. These agents can precipitate toxic megacolon, which may result in severe colitis. Toxic megacolon is a medical and potential surgical emergency, in some cases requiring colectomy. Even though these patients may be extremely difficult to treat, judicious use of symptom-based pharmacologic approaches, reassurance, and patient insight may be helpful. The quality of life for some individuals with IBS is extremely compromised, requiring intense counseling. It may be difficult to treat them in a busy primary care practice. Those with a concurrent psychiatric disease, such as depression, will often benefit from psychiatric consultation and pharmacologic treatment of the underlying disease in the overall management.
Individuals with chronic, debilitating irritable bowel syndrome should be referred to a gastroenterologist. Any suspicion of organic disease with systemic changes, including weight loss and bloody diarrhea, should be considered for referral.
Studies suggest a relationship between IBS symptoms and an imbalance of central nervous system neurotransmitters related to stress in the environment (58,59). Serotonins (5-hydroxytryptamine or 5-HT) are important in the development of gut disorders. Only 5% of total body serotonin is found in the central nervous system, while 95% is found in the gastrointestinal tract. Other neurotransmitters associated with gastrointestinal disorders include calcitonin, neurotensin, substance P, nitric oxide, vasoactive intestinal peptide, and acetylcholine. These neurotransmitters function at the level of the bowel and the central nervous system.
Several compounds were studied that interact with serotonin receptors in the bowel (5 HT-3 and 5 HT-4). The 5-HT-3 antagonist, alosetron, was introduced to treat patients with diarrhea. Patients with other symptoms, including alternating diarrhea and constipation, and individuals with primary constipation received the drug, resulting in severe constipation in approximately one-third of patients. There were reports of ischemic colitis with the use of this drug. Although the drug was withdrawn for a time period, the U.S. Food and Drug Administration allowed its reintroduction. Tegaserod is a 5-HT-4 receptor (serotonin receptor) agonist that is approved for short-term use in patients with constipation. It has gastrointestinal stimulatory effects facilitated by intercolonergic transmission as its primary mode of action. There are many 5-HT drugs under development that will be introduced over the next 2 to 5 years.
Gastroesophageal Reflux Disease
The term gastroesophageal reflex disease (GERD) is a commonly used label for many forms of indigestion and heartburn. The American College of Gastroenterology defines it as symptoms or mucosal damage produced by the abnormal reflux of gastric contents into the esophagus (60). The term “abnormal” is key because some reflux is physiologic, usually occurring postprandial and typically being asymptomatic. Given the variation in definition, its prevalence is hard to determine, but it is clear that GERD is more common in the Western world.
Symptoms of GERD include heartburn (burning sensation in the retrosternal area) commonly postprandial, regurgitation gastric contents into mouth, dysphagia from esophageal inflammation, and chest pain that can be confused as angina. Dysphagia that is progressive is concerning for Barrett’s metaplasia or adenocarcinoma and merits an endoscopic evaluation (61).
Treatment of GERD is multifaceted with lifestyle modification and use of antacids and over-the-counter H2 receptor antagonists or proton pump inhibitors (PPI). Lifestyle modifications include smoking cessation, avoidance of eating late in the evening, avoidance of being supine after eating, weight loss, avoidance of tight clothing, and restriction of alcohol use. Dietary modifications are helpful but should not be draconian, which will ensure noncompliance. Key foods to try to minimize are fatty foods, chocolate, peppermint, and excessive alcohol. The patient can monitor her own symptoms for the foods that are most problematic for her.
Medications that reduce acid secretions are best and include H2 blockers or proton pump inhibitors. They do not prevent the reflux but decrease the damage done by the acid when refluxed. Medication needs to be titrated to the severity of the symptoms. H2 blockers commonly work well for acute pain but in placebo-controlled studies in chronic cases without resolution of heartburn after the common 6-week course, it was found that patients on PPI do better. Maintenance therapy is recommended for patients who have rapid recurrence of symptoms (in less than 2–3 months) after they stop their medication. Otherwise patients can be managed with episodic treatments. The linkage of Helicobacter pylori infections and GERD is poorly understood but seems to be mediated through increased gastric acid secretion. Treatment can initially worsen GERD and may not improve it (62). Benefits and risks should be discussed with the patient prior to testing and treating for H. pylori. The management of GERD during pregnancy is similar to the treatment in the nonpregnant patient.
Carpal Tunnel Syndrome
Carpal tunnel syndrome (CTS) is the cluster of symptoms brought on by compression in the carpal tunnel of the median nerve. These are paresthesia, pain, and weakness. The symptoms are commonly worse at night and may wake the patient from sleep. It is thought women may be more likely to present with complaints of CTS because of their small wrists, repetitive motion injury at work (typing, holding telephone, and reading), and pregnancy with increased edema. The pain and paresthesia can be located in the wrist or hand or can be in the forearm. The weakness may cause a patient to have difficulty opening jars, lifting a plate, turning a doorknob, or holding a glass.
A detailed history is very diagnostic but the use of a couple simple tests can help to confirm it (63). The most common one is the Phalen maneuver, in which the patient flexes her palms at the wrist as close to 90 degrees as possible. Then with the dorsal portion of the hands touching and the arms parallel to the floor, the patient presses the flexed hands against each other for approximately 1 minute. This should reproduce her symptoms along the median nerve. The Tinel test involves percussion over the top of the carpal tunnel where the median nerve travels. A positive test is when the percussion reproduces the pain and paresthesia. Additional testing such as nerve conduction studies should be reserved for patients who do not respond to conservative management or have significant muscle weakness.
Treatment involves lifestyle modification to decrease repetitive motion injuries or prolonged marked flexion at the wrist. A carpal tunnel brace can be very helpful in maintaining adequate extension at the wrist, thereby “opening” the tunnel and reducing compression on the medial nerve. Only if these strategies do not work is a surgical intervention indicated.
Mitral Valve Prolapse Syndrome, Dysautonomia, and Postural Orthostatic Tachycardia Syndrome
The terms mitral valve prolapse syndrome (MVPS), dysautonomia, and postural orthostatic tachycardia syndrome (POTS) all refer to a syndrome in which the patient has problems with palpitations, hypotension, syncope, dyspnea, panic/anxiety disorder, numbness, hyperflexible joints, pectus excavatum, and gastric emptying disorders. Initially patients (typically fivefold times more likely to be women) who presented with these symptoms were thought to be somatizing their anxiety disorder. It is now accepted that it is a syndrome that appears to involve the autonomic nervous system (64). This often will present first in early adolescence with gradual worsening of the symptoms. The patients are very slender in build and lose weight to a low body mass index over a number of months as the syndrome evolves. This weight loss is the probable cause of the secondary amenorrhea that prompts these women to seek gynecologic care. The symptoms are not clearly explained by the degree of mitral valve prolapse, so many feel MVPS is a marker for individuals at risk for this complex of symptoms. Increased sympathetic activity is the common pathway for most of the proposed mechanisms for POTS or MVPS. There appears to be a genetic component, with over 10% of patients reporting the diagnosis in family members with orthostatic intolerance (65,66).
A tilt table test is often key to the diagnosis. Treatment focuses on the symptoms and maintaining intravascular volume by encouraging oral intake of water and salts (67). Physical fitness with aerobic exercises to increase muscle mass and reduce dependent pooling of blood; avoidance of smoking, caffeine, and alcohol; and limiting simple carbohydrates will minimize symptoms over time. Additional medications, including adrenoreceptor agonists, acetylcholinesterase inhibitor, mineralocorticoid agonist, beta-blockers, and selective serotonin reuptake inhibitors, may be necessary. Because this is a multifaceted disease, it may be best to refer the patient during the acute phase to a physician who is experienced with this syndrome.
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