Disease-a-Month 61 (2015) 308–318
Contents lists available at ScienceDirect
Disease-a-Month journal homepage: www.elsevier.com/locate/disamonth
Clinical pearls in general internal medicine John B. Bundrick, MD, Scott C. Litin, MD
Case 1 A 73-year-old woman presents with 3 months of progressive fatigue and mild dyspnea on exertion. She has also noticed symptoms of restless legs in the evening, which is new for her. Her examination is normal apart from mild pallor. Her hemoglobin, which was normal a year ago, is now 8.8 g/dL. Her MCV is 78 fL. The serum ferritin is 22 mcg/L. Antibody to tissue transglutaminase (tTG) IgA is negative. She underwent an esophagogastroduodenoscopy (EGD) 2 years ago for the evaluation of dysphagia and heartburn, and it was negative apart from a large hiatal hernia and a Schatzki’s ring. The ring was dilated and she was started on omeprazole 20 mg once daily at that time, with complete resolution of both symptoms. Screening colonoscopy 2 years ago was normal (with good views of the colon). She is on no other medications. She currently denies any early satiety, dysphagia, heartburn, reflux, abdominal discomfort, nausea, weight loss, melena, or hematochezia. Her bowel movements are normal. What would be the next best step in elucidating the cause of her iron deficiency anemia? A. B. C. D. E.
Helicobacter pylori stool antigen, repeat EGD, repeat colonoscopy, capsule endoscopy, CT enterography.
Discussion The occurrence of iron deficiency anemia in the context of a large hiatal hernia, with no “red flag” gastrointestinal (GI) symptoms and adequate recent colon screening, is highly suggestive of Cameron’s lesions as the underlying cause. These are linear erosions that develop at the waist of a large hiatal hernia as it crosses the diaphragm, primarily related to mechanical factors. They are commonly missed on initial endoscopy, unless careful attention is paid to this area. Most patients will be lacking any significant GI symptoms and will present primarily with manifestations of the iron deficiency anemia. http://dx.doi.org/10.1016/j.disamonth.2015.04.002 0011-5029/& 2015 Mosby, Inc. All rights reserved.
J.B. Bundrick, S.C. Litin / Disease-a-Month 61 (2015) 308–318
309
This patient presented with occult GI bleeding without any features or history of overt bleeding (and with relatively recent upper and lower endoscopies to exclude sinister disease). In this setting, the other leading consideration would be vascular ectasias, either in the small bowel or the gastroduodenum (which can also be frequently missed on initial EGD). If a careful repeat EGD were negative for Cameron’s lesions (and vascular ectasias), then capsule endoscopy could potentially be considered. However, recent ASGE guidelines recommend repeating the EGD prior to any small bowel evaluation when an upper GI source is highly suspected (as in this case). CT enterography would be very low yield in the absence of any overt bleeding or obstructive symptoms. There is nothing to suggest peptic ulcer disease or gastritis at this point, and testing for H pylori would thus be of no utility (and would require holding her omeprazole). Since her screening colonoscopy was recently done and was adequate, the likelihood of missed colon cancer would also be very low. Management of Cameron’s lesions is individualized to the patient. Although the provocative factors are primarily mechanical, most experts advise proton pump inhibitors (PPI). Robust iron replacement over the long term is sufficient in many patients to prevent recurrent anemia, with thrice daily oral dosing (in combination with vitamin C, to overcome the poor absorption related to the PPI). Periodic administration of parenteral iron may be needed if the oral iron is not tolerated or is inadequate. In rare cases, surgery may need to be considered.
Clinical pearl In patients with large hiatal hernias, Cameron’s lesions are a commonly missed cause of occult GI bleeding.
References 1. Cameron AJ, Higgins JA. Linear gastric erosion. A lesion associated with large diaphragmatic hernia and chronic blood loss anemia. Gastroenterology. 1986;91(2):338–342. 2. Fisher L, Lee Krinsky M, et al. The role of endoscopy in the management of obscure GI bleeding. Gastrointest Endosc. 2010;72(3):471–479.
Case 2 A 33-year-old woman presents for evaluation of “fluid retention and puffiness in my legs”. This has been present since her early teenage years and has worsened gradually to a mild degree since onset. It is modestly increased when she is on her feet all day and when the weather is warm. It fluctuates only minimally in association with her weight. She has never had any episodes of cellulitis or ulceration. Her sister and her mother both have a similar condition in their legs. Her medical history and review of systems are otherwise unremarkable, and her only medication is an oral contraceptive (for purposes of birth control). On examination, her height is 166 cm, and her weight is 75 kg (BMI ¼ 27). She has generalized, symmetric enlargement of both lower extremities, with a trace of pitting edema.
The skin and subcutaneous tissues of the legs are soft, pliable, and hypersensitive to pressure. The feet are spared, and the skin appears normal.
310
J.B. Bundrick, S.C. Litin / Disease-a-Month 61 (2015) 308–318
Question Which of the following would be the most appropriate next step in management of this patient? A. B. C. D. E.
Lymphoscintigraphy, graduated compression stockings, check serum fasting glucose, change oral contraceptive to progestin-only formulation, reassurance.
Discussion This is a classic example of lipedema, a harmless condition that occurs almost exclusively in women and involves a symmetric distribution of fat in the lower extremities. Generalized obesity need not necessarily be present, and the condition itself is not associated with the metabolic syndrome (nor other detrimental effects of central obesity). Other female family members often have a similar condition. On examination, the feet and ankles are almost always spared, and this is a distinguishing characteristic of lipedema. Frequently, the subcutaneous adipose in the legs is sensitive to pressure, a phenomenon referred to as “adiposa dolorosa.” For this reason, graduated compression stockings are often not a feasible option (but neither are they generally required, as the edema tends to be modest, and there are no long-term complications of the disorder). There is no known direct association with the use of oral estrogens.
Clinical pearl Lipedema can be diagnosed clinically on the basis of distinctive characteristics, and further unnecessary testing thus avoided.
References 1. Fonder MA, Loveless JW, Lazarus GS. Lipedema, a frequently unrecognized problem. J Am Acad Dermatol. 2007;57:S1–S3. 2. Rudkin GH, Miller TA. Lipedema: a clinical entity distinct from lymphedema. Plastic Reconstr Surg. 1994;94:841–847.
Case 3 A 70-year-old man has had recurrent episodes of painless gross hematuria for the past 6 months. These last for approximately 3 days at a time and occur on average about twice monthly, and they are a major nuisance to him. He has mild obstructive bladder symptoms (which are not bothersome to him) and no urgency. He has never smoked. He feels generally well. No prior history of nephrolithiasis and no back pain. No aspirin or any other medications. Examination is pertinent for 2þ BPH with no nodules. BP is 110/70. CT urogram is normal. Cystoscopy shows mildly obstructive BPH and is otherwise normal. Cytology of the urine is normal. Urinalysis shows 4100 RBC/HPF. Urine gram stain and culture are negative. PSA is 2.6 ng/mL.
J.B. Bundrick, S.C. Litin / Disease-a-Month 61 (2015) 308–318
311
Question Which of the following would be the most appropriate next step? A. B. C. D. E.
Start finasteride 5 mg per day, start tamsulosin 0.4 mg per day, start bicalutamide 50 mg per day, transrectal needle biopsy of the prostate, transurethral microwave therapy (TUMT) of the prostate.
Discussion BPH is a common cause of gross hematuria in elderly men, and is by far the most likely etiology when the initial evaluation (CT urogram and cystoscopy) has excluded other causes (such as stones, renal cell cancer, and bladder cancer). The mechanism is related to increased vascularity of the enlarged prostate gland. Recurrent episodes such as those experienced by this patient, while not reflective of a serious underlying condition, can nonetheless be quite troublesome to the patient. Several studies have now demonstrated that finasteride is highly effective in decreasing recurrent hematuria in this setting, with a success rate of over 80% and a mean onset of action of only 12 days. Pre- and post-treatment biopsies have demonstrated substantial reduction in levels of VEGF and vascularity of the prostate after only 14 days of therapy. Effectiveness is maintained even in patients who remain on long-term warfarin or aspirin. Tamsulosin and TUMT are not needed for his mild obstructive symptoms, and there is no evidence that these would have any effect on his bleeding. Bicalutamide may help with the hematuria but would be excessive in the absence of prostate cancer. Prostate cancer is unlikely, and the needle biopsy would likely aggravate his bleeding.
Clinical pearl Finasteride is a useful treatment for decreasing recurrent gross hematuria secondary to BPH.
References 1. Kearney MC, Bingham JB, et al. Clinical predictors in the use of finasteride for control of gross hematuria due to benign prostatic hyperplasia. J Urol. 2002;167(6):2489–2491. 2. Carrasquillo RJ, Nealy SW, et al. 5-Alpha-reductase inhibitors in diseases of the prostate. Curr Opin Endocrinol Diabetes Obes. 2014;21(6):488–492.
Case 4 A 67-year-old man returns to your office for follow-up of his hypertension and chronic kidney disease (CKD). He has been feeling well with no complaints and has no history of cardiovascular disease or diabetes. He checks his blood pressure (BP) regularly at home, and it has averaged 132/76. His current medications include lisinopril 20 mg and amlodipine 5 mg each morning, in addition to atorvastatin 40 mg each evening. He takes aspirin 81 mg per day. He has a history of a rash to hydrochlorothiazide. His blood pressure (BP) is 136/80 with pulse 88, regular rhythm. His examination is normal, with no peripheral edema.
312
J.B. Bundrick, S.C. Litin / Disease-a-Month 61 (2015) 308–318
Laboratory testing demonstrates a serum creatinine of 1.5 mg/dL with an eGFR of 50 mL/min. His urine test for microalbumin shows 45 mg albumin/g of creatinine (normal o 30 mg/g). His 10-year estimated ASCVD risk prior to starting atorvastatin was 12%. Which of the following would be most likely to significantly reduce his CV risk? A. B. C. D. E.
Change lisinopril to ramipril, add low-dose beta blocker, adjust medications to attain BP of o 130/80, move one of his antihypertensive doses to bedtime, vitamin D 1000 units per day.
Discussion The normal circadian rhythm of BP is that of a nocturnal drop in the range of 10–20%, which is known as the “dipping” pattern. It has been well established that non-dippers have a cardiovascular morbidity and mortality that is considerably higher than that of dippers. In addition, the incidence of cardiovascular events (acute coronary syndrome and stroke) is known to peak in the morning hours. This observation has led to the concept of “chronotherapy” in treatment of hypertension, which attempts to restore the normal dipping pattern by moving at least part of the antihypertensive regimen to bedtime dosing. Several trials in a variety of hypertensive populations have demonstrated a beneficial effect of this approach. A representative study included 661 patients with mild CKD (about half of them with stage 3A CKD, the remainder with creatinine clearance above 60 mL/min but with positive microalbuminuria) who were on a stable once daily antihypertensive regimen, dosed in the morning at baseline. As with most populations of CKD patients, about two-third of them were non-dippers. They were randomized (in an open-label design, with blinded endpoint adjudication) to either move at least one of their medications to bedtime or keep them all in the morning. After 5 years of follow-up, the annual absolute risk of major cardiovascular (CV) events (CV death, MI, and stroke) was reduced by almost 1% in the bedtime dosing group (annual event rate of 1.45% for morning dosing vs. 0.51% with bedtime dosing). Ambulatory BP monitoring demonstrated significant decreases in sleep time BP, with restoration of the normal dipping pattern in one-third of those in the bedtime dosing group. Similar results were also obtained in a trial of over 400 hypertensive patients with diabetes, leading the American Diabetes Association to give a level A recommendation for this strategy in their 2014 guidelines. As we await further evidence, it seems reasonable to consider this strategy for most hypertensive patients. Possible exceptions may include those patients at greater risk for falls in the night, or for whom compliance would be impacted by moving some medications to evening. There is no evidence suggesting superiority of ramipril over lisinopril in this population, nor for any reduction in CV events from adding a beta blocker. While low vitamin D levels have been associated with a slight increase in CV risk, meta-analyses of interventions to supplement those with low levels have shown no benefit. The currently recommended target for BP in CKD is o 140/90. There is evidence of potential benefit from further BP reduction in those with proteinuric CKD, and several guidelines do advise a lower target of o 130/80 in that subgroup. However, the levels of proteinuria for which this seems beneficial are in the range of 500– 1000 mg per day—well above the level indicated by his modest degree of microalbuminuria.
Clinical pearl In hypertensive patients with mild CKD or diabetes (and perhaps others), moving at least one of their antihypertensive daily doses to bedtime reduces CV morbidity and mortality.
J.B. Bundrick, S.C. Litin / Disease-a-Month 61 (2015) 308–318
313
References 1. Hermida RC, Ayala DE, et al. Bedtime dosing of antihypertensive medications reduces cardiovascular risk in CKD. J Am Soc Nephrol. 2011;22(12): 2313–2321. 2. Judd E, Calhoun DA. Management of hypertension in CKD: beyond the guidelines. Adv Chronic Kidney Dis. 2015;22(2):116–122.
Case 5 A 53-year-old woman has had 5 months of nonproductive cough, which has been quite bothersome to her and has resulted in occasional episodes of urinary stress incontinence. She is otherwise healthy, and her only medication is levothyroxine for hypothyroidism. She has never smoked. She has no history of allergies and denies any nasal symptoms. She also denies any heartburn or regurgitation. Trials of sedating antihistamine and oral decongestant as well as twice-daily proton pump inhibitor (PPI) have been ineffective. Her physical examination (including lungs and ENT) and chest x-ray are both normal, as is spirometry (before and after bronchodilator).
Question Which of the following tests would be most likely to help provide direction on further management of her cough? A. B. C. D. E.
Allergy skin testing, exhaled nitric oxide, eosinophil count on peripheral blood, high-resolution CT scan of chest, sinus x-rays.
Discussion Chronic cough, defined as that which lasts beyond 8 weeks, is often a source of significant distress. After excluding smoking, ACE inhibitors, and chronic bronchitis, the three categories of upper airway cough syndrome (UACS), gastroesophageal reflux disease (GERD), and asthma account for up to 90% of cases. Many patients with chronic cough will have more than one of these conditions, and most management algorithms advise a sequential strategy of either testing or empiric therapy focused upon these three main causes. UACS refers to those etiologies of nasal or sinus origin: rhinitis, postnasal drip, and rhinosinusitis. Most algorithms recommend a trial of first-generation antihistamines and oral decongestants, or in older patients a combination of intranasal topical therapies including an antihistamine, ipratropium, and a steroid. If the cough is related to UACS, clinical improvement should be evident within 2–4 weeks. Cough related to GERD may often occur in the absence of typical GERD symptoms. A trial of twice-daily PPI for 2–3 months is generally recommended, although several recent randomized trials and a 2011 Cochrane review indicate no evidence of benefit of PPI over placebo in chronic cough. This lack of response to acid suppression is potentially related to the effects of nonacidic reflux, and esophageal impedance and pH testing may help clarify the mechanism of cough in patients for whom UACS and eosinophilic airway disease (vide infra) have been excluded.
314
J.B. Bundrick, S.C. Litin / Disease-a-Month 61 (2015) 308–318
Eosinophilic airway disease accounts for a significant proportion of those with chronic cough. This is usually in the form of asthma, although up to 10% of cases of chronic cough may be related to the more recently described entity of nonasthmatic eosinophilic bronchitis (NAEB). Cough variant asthma is the term used for those with that symptom as the primary manifestation of their disease, and many will not have evidence of bronchodilator response on spirometry (although almost all of them will have a positive methacholine challenge test). NAEB lacks the pathognomonic bronchial hyperresponsiveness of asthma, but may be detected by sputum eosinophilia or elevated levels of exhaled nitric oxide (ENO), a marker of eosinophilic airway inflammation. An elevated ENO level (438 ppb) predicts a favorable response to inhaled corticosteroid, regardless of underlying etiology (asthma or NAEB), and a low ENO level indicates a greatly reduced chance of response to steroid. While the precise role of ENO testing in evaluation of chronic cough remains to be defined, it is a much less expensive alternative (or perhaps initial adjunct, at this point) to methacholine challenge and may offer better prediction for steroid responsiveness. Skin testing, peripheral blood eosinophil count, and CT chest would have no diagnostic utility in this case. Some experts recommend CT sinus after failing initial steps in the algorithm (though it would be of very low yield in this particular patient), but sinus x-rays are considered too insensitive.
Clinical pearl Exhaled nitric oxide may have a role in identifying patients with chronic cough who are likely to respond to inhaled corticosteroids.
References 1. Iyer VN, Lim KG. Chronic cough: an update. Mayo Clin Proc. 2013;88(10):1115–1126. 2. Chang AB, Lasserson TJ, et al. Gastro-oesophageal reflux treatment for prolonged nonspecific cough in children and adults. Cochrane Database Syst Rev. 2011;(1):CD004823.
Case 6 A 65-year-old woman with dilated cardiomyopathy underwent cardiac catheterization 2 years ago, which demonstrated normal coronary arteries and an LVEF of 35%. She had presented at that time with Class III symptoms of heart failure. She was diuresed and has since done well on a regimen of carvedilol, lisinopril, and spironolactone. An echocardiogram 6 months ago showed an improved LVEF of 40%. She can walk up a couple of flights of stairs without stopping but does get moderate dyspnea with that level of activity, perhaps more noticeable over the past couple of months. However, she has also had more trouble with DJD in her knee over the past few months and has curtailed her activity for that reason. She wonders if she is simply noticing the effects of deconditioning or if her heart failure has worsened. She denies any orthopnea or paroxysmal nocturnal dyspnea. On examination, she appears generally well and is breathing comfortably at rest. BP is 120/70 and pulse 68 with regular rhythm.
Which of the following would be most reassuring for predicting that her left ventricular (LV) filling pressure is not significantly elevated? A. Normal JVP, B. absence of an S3,
J.B. Bundrick, S.C. Litin / Disease-a-Month 61 (2015) 308–318
315
C. absence of rales, D. negative abdominojugular reflux, E. absence of peripheral edema.
Discussion Several studies have examined the diagnostic utility of certain physical examination findings for predicting elevated LV filling pressure in patients with systolic dysfunction. These have generally involved patients undergoing cardiac catheterization for non-acute reasons (e.g., transplant evaluation) who were examined immediately beforehand by two or more cardiologists. The criterion standard in these studies has been an elevated LV end-diastolic pressure (LVEDP) or pulmonary capillary wedge pressure (defined as 4 15 or 4 18 mm Hg, depending upon the study). In these patients, an elevated JVP is helpful for ruling in high filling pressures, with a likelihood ratio positive (LR þ) of 8 but is less useful for ruling it out when absent (LR in the 0.5 range). The abdominojugular reflux maneuver is more sensitive, with an LR in the 0.25– 0.30 range. The optimal technique for performing this maneuver was perfected by Ewy (1988) during bedside examination of patients undergoing right heart catheterization. It involves applying 20 mm Hg of pressure with one hand over the upper mid-abdomen for 10 s while watching for a rise in the level of the JVP, and a sudden drop of at least 3 cm in JVP upon release. The presence of an S3 in patients with known systolic dysfunction increases the chances of elevated filling pressure (LRþ ¼ 5.7), but it is very insensitive. Peripheral edema is also insensitive in this setting. Unlike the acute setting, rales have a remarkably low sensitivity in chronic CHF, occurring in less than a third of those with documented elevation of LV filling pressures. This is thought to relate to compensatory mechanisms of the pulmonary lymphatics and capillaries, which absorb the excess fluid over time.
Clinical pearl In patients with chronic CHF with reduced EF, the abdominojugular reflux maneuver is the most sensitive bedside test for the detection of elevated filling pressures, and rales have remarkably low sensitivity.
References 1. Butman SM, Ewy GA, et al. Bedside cardiovascular examination in patients with severe chronic heart failure: importance of rest or inducible jugular venous distension. J Am Coll Cardiol. 1993;22(4):968–974. 2. Ewy GA. The abdominojugular test: technique and hemodynamic correlates. Ann Intern Med. 1988;109(6):456–460.
Case 7 A 44-year-old woman with no prior history of psychiatric illness presents with marked irritability and “edginess,” periods of tearfulness, depressed mood, anhedonia, fatigue, a sensation of “bloating,” and increased appetite (with a craving for carbohydrates in particular). These symptoms begin consistently about 5 days prior to the onset of her menses and resolve within 2 days after the start of her menses. Her menstrual periods are regular, she is otherwise
316
J.B. Bundrick, S.C. Litin / Disease-a-Month 61 (2015) 308–318
healthy, and is on no medications. She is concerned because these symptoms are beginning to put a mild strain on her relationships with her family and close friends. Which of the following would be the most appropriate therapy for attempting to alleviate her condition? A. B. C. D. E.
Mirtazapine given for 2 weeks prior to onset of menses, oral contraceptive (OCP) with low-dose estrogen and drospirenone, fluoxetine given for 2 weeks prior to onset of menses, continuous bupropion, Depot medroxyprogesterone.
Discussion This patient has a symptom complex, which would be diagnostic for premenstrual dysphoric disorder (PMDD). The chief differential diagnostic consideration would be a mere exacerbation of another disorder (major depression, panic disorder, dysthymic disorder, and personality disorder), but in her case there is no history to suggest these, and her symptoms resolve completely after onset of menses. The selective serotonin reuptake inhibitors (SSRI) have been shown to be effective in managing this condition. Fluoxetine, paroxetine, escitalopram, citalopram, and sertraline have all been studied, and provide substantial improvement in over 60% of cases, often apparent within a few days. The serotonin–norepinephrine reuptake inhibitor (SNRI) venlafaxine has been found to be similarly effective. Other “second-line” antidepressant agents of lower tolerability have also been studied, and in general those with increased serotonergic activity (e.g., clomipramine) are more effective than those whose primary action is noradrenergic (e.g., desipramine and maprotiline) or dopaminergic (e.g., bupropion). Interestingly, multiple studies have reported that intermittent use of citalopram during the 2 weeks preceding the onset of menses (luteal phase dosing) is equally effective to use it continuously. Due to benefits with regard to overall burden of adverse effects and cost, it is reasonable to start with luteal phase dosing and then move to continuous use in those who fail to respond after three cycles. Progesterone and other progestogens are no more effective than placebo (and in theory might even be expected to worsen the symptoms). Mirtazapine has not been studied. An OCP with low-dose estrogen and drospirenone (and a shortened pill-free interval) is also effective, but generally considered second-line therapy in women who fail SSRI (unless, of course, it is used for contraception or another primary indication).
Clinical pearl Symptoms of premenstrual dysphoric disorder are often helped by use of an SSRI agent. It is reasonable to start with intermittent administration 2 weeks prior to onset of menses.
References 1. Steiner M, Li T. Luteal phase and symptom-onset dosing of SSRIs/SNRIs in the treatment of premenstrual dysphoria: clinical evidence and rationale. CNS Drugs. 2013;27(8):583–589. 2. Marjoribanks J, Brown J, et al. “Selective serotonin reuptake inhibitors for premenstrual syndrome.” Cochrane Database Syst Rev. 2013;6:CD001396.
J.B. Bundrick, S.C. Litin / Disease-a-Month 61 (2015) 308–318
317
Case 8 A 57-year-old man presents for follow-up of hypertension, which is not yet controlled on a regimen of lisinopril 40 mg with chlorthalidone 25 mg each morning and amlodipine 10 mg each evening. He is adherent to his regimen and is following appropriate lifestyle measures. His BMI is 26, and he does not have any symptoms of obstructive sleep apnea (OSA). He has no history of cardiovascular disease or symptoms thereof. His blood pressure (BP) today in the office is 152/82 with a regular pulse of 62 beats per minute. His home readings have averaged 146/78. Physical examination is normal, apart from 2 mm of pitting edema at the mid-tibial levels bilaterally. There is no abdominal bruit. Laboratory testing reveals serum sodium of 137 meq/L; potassium 4.0 meq/L; and creatinine of 1.6 mg/dL, with an eGFR by MDRD of 49 mL/min/1.73 m2.
Doppler of the renal arteries shows no evidence of stenosis. His plasma aldosterone concentration (PAC) is 12 ng/dL, with plasma renin activity (PRA) of 1.0 ng/mL/h, for a PAC/PRA ratio of 12. Urinalysis is bland, and microalbumin is 65 mg/g creatinine.
Question What would be the next best step in management for this patient? A. B. C. D. E.
Add spironolactone 25 mg per day, add aliskiren 75 mg per day, switch diuretic to torsemide 10 mg per day, catheter-based renal sympathetic denervation, add losartan 50 mg per day.
Discussion This man has resistant hypertension, as he is on adequate doses of three medications (including a diuretic) and is not at goal BP ( o140/90). After non-adherence and white coat hypertension have been excluded, common secondary causes include OSA, renal artery stenosis, and primary aldosteronism (PA). In this patient, these etiologies would be unlikely based on the clinical and laboratory findings. PA occurs in 7–20% of those with resistant hypertension and is screened for by means of the PAC and PRA. Recommendations for when to proceed with confirmatory testing vary somewhat, but generally PA is unlikely unless the PAC is 4 15 ng/dL with a PAC/PRA ratio 430. Even though this patient is on an ACE inhibitor (which can raise PRA and thus “falsely” lower the ratio in patients with PA), he is far enough below the cutoff that confirmatory testing for PA would not be indicated at this time. Even in patients with resistant hypertension who do not have PA, aldosterone antagonists appear to be beneficial. The mechanism of this effect is not entirely clear but may relate in part to elevated mineralocorticoid receptor sensitivity. This benefit has been demonstrated in several randomized, double-blind, placebo-controlled trials, with average BP reductions in the range of 10–14 mm Hg systolic and 4–6 mm Hg diastolic in the two largest studies. The vast majority of study participants were on an ACE inhibitor or an ARB at baseline, but those with eGFR of o 40 mL/min/1.73 m2 were excluded. The mean baseline PAC and PAC/PRA ratios were normal
318
J.B. Bundrick, S.C. Litin / Disease-a-Month 61 (2015) 308–318
(9.4 ng/dL and 15, respectively), and significant BP reduction was noted in all subgroups apart from those with a PAC/PRA ratio of o 7. Doses of spironolactone were 25–50 mg once daily. Spironolactone should only be used with caution in those with eGFR o 45 mL/min/1.73 m2 or baseline serum potassium of 44.5 meq/L and should be avoided altogether in those with eGFR o 30 mL/min/1.73 m2. Serum potassium must be carefully monitored (e.g., including an early check within 1 week of initiation or dose change, at 4 weeks, then every few months if stable). The addition of direct renin inhibitors (aliskiren) and angiotensin receptor blockers to a regimen containing an ACE inhibitor has been shown to lack benefit and result in worsening renal function. Thiazide diuretics tend to lose efficacy as eGFR falls below 30 mL/min/1.73 m2, and in that situation a switch to torsemide would be reasonable; however, this patient is well above that threshold. While catheter-based sympathetic denervation showed some promise in an initial unblinded trial, a sham-controlled study in 2014 showed no benefit compared to medical therapy. Clinical pearl In many patients with resistant hypertension, the addition of low-dose aldosterone antagonist is effective in improving blood pressure control (even in the absence of primary aldosteronism). References 1. Vongpatanasin W. Resistant hypertension: a review of diagnosis and management. J Am Med Assoc. 2014;311(21):2216–2224. 2. Oxlund CS, Henriksen JE, et al. “Low dose spironolactone reduces blood pressure in patients with resistant hypertension and type 2 diabetes mellitus: a double blind randomized clinical trial. J Hypertens. 2013;31(10):2094–2102. 3. Vaclavik J, Sedlak R, et al. Addition of spironolactone in patients with resistant arterial hypertension (ASPIRANT): a randomized, double-blind, placebo-controlled trial. Hypertension. 2011;57(6):1069–1075. Answers: 1-B; 2-E; 3-A; 4-D; 5-B; 6-D; 7-C; and 8-A
Contents lists available at ScienceDirect
Disease-a-Month journal homepage: www.elsevier.com/locate/disamonth
Clinical pearls in general internal medicine John B. Bundrick, MD, Scott C. Litin, MD
Case 1 A 73-year-old woman presents with 3 months of progressive fatigue and mild dyspnea on exertion. She has also noticed symptoms of restless legs in the evening, which is new for her. Her examination is normal apart from mild pallor. Her hemoglobin, which was normal a year ago, is now 8.8 g/dL. Her MCV is 78 fL. The serum ferritin is 22 mcg/L. Antibody to tissue transglutaminase (tTG) IgA is negative. She underwent an esophagogastroduodenoscopy (EGD) 2 years ago for the evaluation of dysphagia and heartburn, and it was negative apart from a large hiatal hernia and a Schatzki’s ring. The ring was dilated and she was started on omeprazole 20 mg once daily at that time, with complete resolution of both symptoms. Screening colonoscopy 2 years ago was normal (with good views of the colon). She is on no other medications. She currently denies any early satiety, dysphagia, heartburn, reflux, abdominal discomfort, nausea, weight loss, melena, or hematochezia. Her bowel movements are normal. What would be the next best step in elucidating the cause of her iron deficiency anemia? A. B. C. D. E.
Helicobacter pylori stool antigen, repeat EGD, repeat colonoscopy, capsule endoscopy, CT enterography.
Discussion The occurrence of iron deficiency anemia in the context of a large hiatal hernia, with no “red flag” gastrointestinal (GI) symptoms and adequate recent colon screening, is highly suggestive of Cameron’s lesions as the underlying cause. These are linear erosions that develop at the waist of a large hiatal hernia as it crosses the diaphragm, primarily related to mechanical factors. They are commonly missed on initial endoscopy, unless careful attention is paid to this area. Most patients will be lacking any significant GI symptoms and will present primarily with manifestations of the iron deficiency anemia. http://dx.doi.org/10.1016/j.disamonth.2015.04.002 0011-5029/& 2015 Mosby, Inc. All rights reserved.
J.B. Bundrick, S.C. Litin / Disease-a-Month 61 (2015) 308–318
309
This patient presented with occult GI bleeding without any features or history of overt bleeding (and with relatively recent upper and lower endoscopies to exclude sinister disease). In this setting, the other leading consideration would be vascular ectasias, either in the small bowel or the gastroduodenum (which can also be frequently missed on initial EGD). If a careful repeat EGD were negative for Cameron’s lesions (and vascular ectasias), then capsule endoscopy could potentially be considered. However, recent ASGE guidelines recommend repeating the EGD prior to any small bowel evaluation when an upper GI source is highly suspected (as in this case). CT enterography would be very low yield in the absence of any overt bleeding or obstructive symptoms. There is nothing to suggest peptic ulcer disease or gastritis at this point, and testing for H pylori would thus be of no utility (and would require holding her omeprazole). Since her screening colonoscopy was recently done and was adequate, the likelihood of missed colon cancer would also be very low. Management of Cameron’s lesions is individualized to the patient. Although the provocative factors are primarily mechanical, most experts advise proton pump inhibitors (PPI). Robust iron replacement over the long term is sufficient in many patients to prevent recurrent anemia, with thrice daily oral dosing (in combination with vitamin C, to overcome the poor absorption related to the PPI). Periodic administration of parenteral iron may be needed if the oral iron is not tolerated or is inadequate. In rare cases, surgery may need to be considered.
Clinical pearl In patients with large hiatal hernias, Cameron’s lesions are a commonly missed cause of occult GI bleeding.
References 1. Cameron AJ, Higgins JA. Linear gastric erosion. A lesion associated with large diaphragmatic hernia and chronic blood loss anemia. Gastroenterology. 1986;91(2):338–342. 2. Fisher L, Lee Krinsky M, et al. The role of endoscopy in the management of obscure GI bleeding. Gastrointest Endosc. 2010;72(3):471–479.
Case 2 A 33-year-old woman presents for evaluation of “fluid retention and puffiness in my legs”. This has been present since her early teenage years and has worsened gradually to a mild degree since onset. It is modestly increased when she is on her feet all day and when the weather is warm. It fluctuates only minimally in association with her weight. She has never had any episodes of cellulitis or ulceration. Her sister and her mother both have a similar condition in their legs. Her medical history and review of systems are otherwise unremarkable, and her only medication is an oral contraceptive (for purposes of birth control). On examination, her height is 166 cm, and her weight is 75 kg (BMI ¼ 27). She has generalized, symmetric enlargement of both lower extremities, with a trace of pitting edema.
The skin and subcutaneous tissues of the legs are soft, pliable, and hypersensitive to pressure. The feet are spared, and the skin appears normal.
310
J.B. Bundrick, S.C. Litin / Disease-a-Month 61 (2015) 308–318
Question Which of the following would be the most appropriate next step in management of this patient? A. B. C. D. E.
Lymphoscintigraphy, graduated compression stockings, check serum fasting glucose, change oral contraceptive to progestin-only formulation, reassurance.
Discussion This is a classic example of lipedema, a harmless condition that occurs almost exclusively in women and involves a symmetric distribution of fat in the lower extremities. Generalized obesity need not necessarily be present, and the condition itself is not associated with the metabolic syndrome (nor other detrimental effects of central obesity). Other female family members often have a similar condition. On examination, the feet and ankles are almost always spared, and this is a distinguishing characteristic of lipedema. Frequently, the subcutaneous adipose in the legs is sensitive to pressure, a phenomenon referred to as “adiposa dolorosa.” For this reason, graduated compression stockings are often not a feasible option (but neither are they generally required, as the edema tends to be modest, and there are no long-term complications of the disorder). There is no known direct association with the use of oral estrogens.
Clinical pearl Lipedema can be diagnosed clinically on the basis of distinctive characteristics, and further unnecessary testing thus avoided.
References 1. Fonder MA, Loveless JW, Lazarus GS. Lipedema, a frequently unrecognized problem. J Am Acad Dermatol. 2007;57:S1–S3. 2. Rudkin GH, Miller TA. Lipedema: a clinical entity distinct from lymphedema. Plastic Reconstr Surg. 1994;94:841–847.
Case 3 A 70-year-old man has had recurrent episodes of painless gross hematuria for the past 6 months. These last for approximately 3 days at a time and occur on average about twice monthly, and they are a major nuisance to him. He has mild obstructive bladder symptoms (which are not bothersome to him) and no urgency. He has never smoked. He feels generally well. No prior history of nephrolithiasis and no back pain. No aspirin or any other medications. Examination is pertinent for 2þ BPH with no nodules. BP is 110/70. CT urogram is normal. Cystoscopy shows mildly obstructive BPH and is otherwise normal. Cytology of the urine is normal. Urinalysis shows 4100 RBC/HPF. Urine gram stain and culture are negative. PSA is 2.6 ng/mL.
J.B. Bundrick, S.C. Litin / Disease-a-Month 61 (2015) 308–318
311
Question Which of the following would be the most appropriate next step? A. B. C. D. E.
Start finasteride 5 mg per day, start tamsulosin 0.4 mg per day, start bicalutamide 50 mg per day, transrectal needle biopsy of the prostate, transurethral microwave therapy (TUMT) of the prostate.
Discussion BPH is a common cause of gross hematuria in elderly men, and is by far the most likely etiology when the initial evaluation (CT urogram and cystoscopy) has excluded other causes (such as stones, renal cell cancer, and bladder cancer). The mechanism is related to increased vascularity of the enlarged prostate gland. Recurrent episodes such as those experienced by this patient, while not reflective of a serious underlying condition, can nonetheless be quite troublesome to the patient. Several studies have now demonstrated that finasteride is highly effective in decreasing recurrent hematuria in this setting, with a success rate of over 80% and a mean onset of action of only 12 days. Pre- and post-treatment biopsies have demonstrated substantial reduction in levels of VEGF and vascularity of the prostate after only 14 days of therapy. Effectiveness is maintained even in patients who remain on long-term warfarin or aspirin. Tamsulosin and TUMT are not needed for his mild obstructive symptoms, and there is no evidence that these would have any effect on his bleeding. Bicalutamide may help with the hematuria but would be excessive in the absence of prostate cancer. Prostate cancer is unlikely, and the needle biopsy would likely aggravate his bleeding.
Clinical pearl Finasteride is a useful treatment for decreasing recurrent gross hematuria secondary to BPH.
References 1. Kearney MC, Bingham JB, et al. Clinical predictors in the use of finasteride for control of gross hematuria due to benign prostatic hyperplasia. J Urol. 2002;167(6):2489–2491. 2. Carrasquillo RJ, Nealy SW, et al. 5-Alpha-reductase inhibitors in diseases of the prostate. Curr Opin Endocrinol Diabetes Obes. 2014;21(6):488–492.
Case 4 A 67-year-old man returns to your office for follow-up of his hypertension and chronic kidney disease (CKD). He has been feeling well with no complaints and has no history of cardiovascular disease or diabetes. He checks his blood pressure (BP) regularly at home, and it has averaged 132/76. His current medications include lisinopril 20 mg and amlodipine 5 mg each morning, in addition to atorvastatin 40 mg each evening. He takes aspirin 81 mg per day. He has a history of a rash to hydrochlorothiazide. His blood pressure (BP) is 136/80 with pulse 88, regular rhythm. His examination is normal, with no peripheral edema.
312
J.B. Bundrick, S.C. Litin / Disease-a-Month 61 (2015) 308–318
Laboratory testing demonstrates a serum creatinine of 1.5 mg/dL with an eGFR of 50 mL/min. His urine test for microalbumin shows 45 mg albumin/g of creatinine (normal o 30 mg/g). His 10-year estimated ASCVD risk prior to starting atorvastatin was 12%. Which of the following would be most likely to significantly reduce his CV risk? A. B. C. D. E.
Change lisinopril to ramipril, add low-dose beta blocker, adjust medications to attain BP of o 130/80, move one of his antihypertensive doses to bedtime, vitamin D 1000 units per day.
Discussion The normal circadian rhythm of BP is that of a nocturnal drop in the range of 10–20%, which is known as the “dipping” pattern. It has been well established that non-dippers have a cardiovascular morbidity and mortality that is considerably higher than that of dippers. In addition, the incidence of cardiovascular events (acute coronary syndrome and stroke) is known to peak in the morning hours. This observation has led to the concept of “chronotherapy” in treatment of hypertension, which attempts to restore the normal dipping pattern by moving at least part of the antihypertensive regimen to bedtime dosing. Several trials in a variety of hypertensive populations have demonstrated a beneficial effect of this approach. A representative study included 661 patients with mild CKD (about half of them with stage 3A CKD, the remainder with creatinine clearance above 60 mL/min but with positive microalbuminuria) who were on a stable once daily antihypertensive regimen, dosed in the morning at baseline. As with most populations of CKD patients, about two-third of them were non-dippers. They were randomized (in an open-label design, with blinded endpoint adjudication) to either move at least one of their medications to bedtime or keep them all in the morning. After 5 years of follow-up, the annual absolute risk of major cardiovascular (CV) events (CV death, MI, and stroke) was reduced by almost 1% in the bedtime dosing group (annual event rate of 1.45% for morning dosing vs. 0.51% with bedtime dosing). Ambulatory BP monitoring demonstrated significant decreases in sleep time BP, with restoration of the normal dipping pattern in one-third of those in the bedtime dosing group. Similar results were also obtained in a trial of over 400 hypertensive patients with diabetes, leading the American Diabetes Association to give a level A recommendation for this strategy in their 2014 guidelines. As we await further evidence, it seems reasonable to consider this strategy for most hypertensive patients. Possible exceptions may include those patients at greater risk for falls in the night, or for whom compliance would be impacted by moving some medications to evening. There is no evidence suggesting superiority of ramipril over lisinopril in this population, nor for any reduction in CV events from adding a beta blocker. While low vitamin D levels have been associated with a slight increase in CV risk, meta-analyses of interventions to supplement those with low levels have shown no benefit. The currently recommended target for BP in CKD is o 140/90. There is evidence of potential benefit from further BP reduction in those with proteinuric CKD, and several guidelines do advise a lower target of o 130/80 in that subgroup. However, the levels of proteinuria for which this seems beneficial are in the range of 500– 1000 mg per day—well above the level indicated by his modest degree of microalbuminuria.
Clinical pearl In hypertensive patients with mild CKD or diabetes (and perhaps others), moving at least one of their antihypertensive daily doses to bedtime reduces CV morbidity and mortality.
J.B. Bundrick, S.C. Litin / Disease-a-Month 61 (2015) 308–318
313
References 1. Hermida RC, Ayala DE, et al. Bedtime dosing of antihypertensive medications reduces cardiovascular risk in CKD. J Am Soc Nephrol. 2011;22(12): 2313–2321. 2. Judd E, Calhoun DA. Management of hypertension in CKD: beyond the guidelines. Adv Chronic Kidney Dis. 2015;22(2):116–122.
Case 5 A 53-year-old woman has had 5 months of nonproductive cough, which has been quite bothersome to her and has resulted in occasional episodes of urinary stress incontinence. She is otherwise healthy, and her only medication is levothyroxine for hypothyroidism. She has never smoked. She has no history of allergies and denies any nasal symptoms. She also denies any heartburn or regurgitation. Trials of sedating antihistamine and oral decongestant as well as twice-daily proton pump inhibitor (PPI) have been ineffective. Her physical examination (including lungs and ENT) and chest x-ray are both normal, as is spirometry (before and after bronchodilator).
Question Which of the following tests would be most likely to help provide direction on further management of her cough? A. B. C. D. E.
Allergy skin testing, exhaled nitric oxide, eosinophil count on peripheral blood, high-resolution CT scan of chest, sinus x-rays.
Discussion Chronic cough, defined as that which lasts beyond 8 weeks, is often a source of significant distress. After excluding smoking, ACE inhibitors, and chronic bronchitis, the three categories of upper airway cough syndrome (UACS), gastroesophageal reflux disease (GERD), and asthma account for up to 90% of cases. Many patients with chronic cough will have more than one of these conditions, and most management algorithms advise a sequential strategy of either testing or empiric therapy focused upon these three main causes. UACS refers to those etiologies of nasal or sinus origin: rhinitis, postnasal drip, and rhinosinusitis. Most algorithms recommend a trial of first-generation antihistamines and oral decongestants, or in older patients a combination of intranasal topical therapies including an antihistamine, ipratropium, and a steroid. If the cough is related to UACS, clinical improvement should be evident within 2–4 weeks. Cough related to GERD may often occur in the absence of typical GERD symptoms. A trial of twice-daily PPI for 2–3 months is generally recommended, although several recent randomized trials and a 2011 Cochrane review indicate no evidence of benefit of PPI over placebo in chronic cough. This lack of response to acid suppression is potentially related to the effects of nonacidic reflux, and esophageal impedance and pH testing may help clarify the mechanism of cough in patients for whom UACS and eosinophilic airway disease (vide infra) have been excluded.
314
J.B. Bundrick, S.C. Litin / Disease-a-Month 61 (2015) 308–318
Eosinophilic airway disease accounts for a significant proportion of those with chronic cough. This is usually in the form of asthma, although up to 10% of cases of chronic cough may be related to the more recently described entity of nonasthmatic eosinophilic bronchitis (NAEB). Cough variant asthma is the term used for those with that symptom as the primary manifestation of their disease, and many will not have evidence of bronchodilator response on spirometry (although almost all of them will have a positive methacholine challenge test). NAEB lacks the pathognomonic bronchial hyperresponsiveness of asthma, but may be detected by sputum eosinophilia or elevated levels of exhaled nitric oxide (ENO), a marker of eosinophilic airway inflammation. An elevated ENO level (438 ppb) predicts a favorable response to inhaled corticosteroid, regardless of underlying etiology (asthma or NAEB), and a low ENO level indicates a greatly reduced chance of response to steroid. While the precise role of ENO testing in evaluation of chronic cough remains to be defined, it is a much less expensive alternative (or perhaps initial adjunct, at this point) to methacholine challenge and may offer better prediction for steroid responsiveness. Skin testing, peripheral blood eosinophil count, and CT chest would have no diagnostic utility in this case. Some experts recommend CT sinus after failing initial steps in the algorithm (though it would be of very low yield in this particular patient), but sinus x-rays are considered too insensitive.
Clinical pearl Exhaled nitric oxide may have a role in identifying patients with chronic cough who are likely to respond to inhaled corticosteroids.
References 1. Iyer VN, Lim KG. Chronic cough: an update. Mayo Clin Proc. 2013;88(10):1115–1126. 2. Chang AB, Lasserson TJ, et al. Gastro-oesophageal reflux treatment for prolonged nonspecific cough in children and adults. Cochrane Database Syst Rev. 2011;(1):CD004823.
Case 6 A 65-year-old woman with dilated cardiomyopathy underwent cardiac catheterization 2 years ago, which demonstrated normal coronary arteries and an LVEF of 35%. She had presented at that time with Class III symptoms of heart failure. She was diuresed and has since done well on a regimen of carvedilol, lisinopril, and spironolactone. An echocardiogram 6 months ago showed an improved LVEF of 40%. She can walk up a couple of flights of stairs without stopping but does get moderate dyspnea with that level of activity, perhaps more noticeable over the past couple of months. However, she has also had more trouble with DJD in her knee over the past few months and has curtailed her activity for that reason. She wonders if she is simply noticing the effects of deconditioning or if her heart failure has worsened. She denies any orthopnea or paroxysmal nocturnal dyspnea. On examination, she appears generally well and is breathing comfortably at rest. BP is 120/70 and pulse 68 with regular rhythm.
Which of the following would be most reassuring for predicting that her left ventricular (LV) filling pressure is not significantly elevated? A. Normal JVP, B. absence of an S3,
J.B. Bundrick, S.C. Litin / Disease-a-Month 61 (2015) 308–318
315
C. absence of rales, D. negative abdominojugular reflux, E. absence of peripheral edema.
Discussion Several studies have examined the diagnostic utility of certain physical examination findings for predicting elevated LV filling pressure in patients with systolic dysfunction. These have generally involved patients undergoing cardiac catheterization for non-acute reasons (e.g., transplant evaluation) who were examined immediately beforehand by two or more cardiologists. The criterion standard in these studies has been an elevated LV end-diastolic pressure (LVEDP) or pulmonary capillary wedge pressure (defined as 4 15 or 4 18 mm Hg, depending upon the study). In these patients, an elevated JVP is helpful for ruling in high filling pressures, with a likelihood ratio positive (LR þ) of 8 but is less useful for ruling it out when absent (LR in the 0.5 range). The abdominojugular reflux maneuver is more sensitive, with an LR in the 0.25– 0.30 range. The optimal technique for performing this maneuver was perfected by Ewy (1988) during bedside examination of patients undergoing right heart catheterization. It involves applying 20 mm Hg of pressure with one hand over the upper mid-abdomen for 10 s while watching for a rise in the level of the JVP, and a sudden drop of at least 3 cm in JVP upon release. The presence of an S3 in patients with known systolic dysfunction increases the chances of elevated filling pressure (LRþ ¼ 5.7), but it is very insensitive. Peripheral edema is also insensitive in this setting. Unlike the acute setting, rales have a remarkably low sensitivity in chronic CHF, occurring in less than a third of those with documented elevation of LV filling pressures. This is thought to relate to compensatory mechanisms of the pulmonary lymphatics and capillaries, which absorb the excess fluid over time.
Clinical pearl In patients with chronic CHF with reduced EF, the abdominojugular reflux maneuver is the most sensitive bedside test for the detection of elevated filling pressures, and rales have remarkably low sensitivity.
References 1. Butman SM, Ewy GA, et al. Bedside cardiovascular examination in patients with severe chronic heart failure: importance of rest or inducible jugular venous distension. J Am Coll Cardiol. 1993;22(4):968–974. 2. Ewy GA. The abdominojugular test: technique and hemodynamic correlates. Ann Intern Med. 1988;109(6):456–460.
Case 7 A 44-year-old woman with no prior history of psychiatric illness presents with marked irritability and “edginess,” periods of tearfulness, depressed mood, anhedonia, fatigue, a sensation of “bloating,” and increased appetite (with a craving for carbohydrates in particular). These symptoms begin consistently about 5 days prior to the onset of her menses and resolve within 2 days after the start of her menses. Her menstrual periods are regular, she is otherwise
316
J.B. Bundrick, S.C. Litin / Disease-a-Month 61 (2015) 308–318
healthy, and is on no medications. She is concerned because these symptoms are beginning to put a mild strain on her relationships with her family and close friends. Which of the following would be the most appropriate therapy for attempting to alleviate her condition? A. B. C. D. E.
Mirtazapine given for 2 weeks prior to onset of menses, oral contraceptive (OCP) with low-dose estrogen and drospirenone, fluoxetine given for 2 weeks prior to onset of menses, continuous bupropion, Depot medroxyprogesterone.
Discussion This patient has a symptom complex, which would be diagnostic for premenstrual dysphoric disorder (PMDD). The chief differential diagnostic consideration would be a mere exacerbation of another disorder (major depression, panic disorder, dysthymic disorder, and personality disorder), but in her case there is no history to suggest these, and her symptoms resolve completely after onset of menses. The selective serotonin reuptake inhibitors (SSRI) have been shown to be effective in managing this condition. Fluoxetine, paroxetine, escitalopram, citalopram, and sertraline have all been studied, and provide substantial improvement in over 60% of cases, often apparent within a few days. The serotonin–norepinephrine reuptake inhibitor (SNRI) venlafaxine has been found to be similarly effective. Other “second-line” antidepressant agents of lower tolerability have also been studied, and in general those with increased serotonergic activity (e.g., clomipramine) are more effective than those whose primary action is noradrenergic (e.g., desipramine and maprotiline) or dopaminergic (e.g., bupropion). Interestingly, multiple studies have reported that intermittent use of citalopram during the 2 weeks preceding the onset of menses (luteal phase dosing) is equally effective to use it continuously. Due to benefits with regard to overall burden of adverse effects and cost, it is reasonable to start with luteal phase dosing and then move to continuous use in those who fail to respond after three cycles. Progesterone and other progestogens are no more effective than placebo (and in theory might even be expected to worsen the symptoms). Mirtazapine has not been studied. An OCP with low-dose estrogen and drospirenone (and a shortened pill-free interval) is also effective, but generally considered second-line therapy in women who fail SSRI (unless, of course, it is used for contraception or another primary indication).
Clinical pearl Symptoms of premenstrual dysphoric disorder are often helped by use of an SSRI agent. It is reasonable to start with intermittent administration 2 weeks prior to onset of menses.
References 1. Steiner M, Li T. Luteal phase and symptom-onset dosing of SSRIs/SNRIs in the treatment of premenstrual dysphoria: clinical evidence and rationale. CNS Drugs. 2013;27(8):583–589. 2. Marjoribanks J, Brown J, et al. “Selective serotonin reuptake inhibitors for premenstrual syndrome.” Cochrane Database Syst Rev. 2013;6:CD001396.
J.B. Bundrick, S.C. Litin / Disease-a-Month 61 (2015) 308–318
317
Case 8 A 57-year-old man presents for follow-up of hypertension, which is not yet controlled on a regimen of lisinopril 40 mg with chlorthalidone 25 mg each morning and amlodipine 10 mg each evening. He is adherent to his regimen and is following appropriate lifestyle measures. His BMI is 26, and he does not have any symptoms of obstructive sleep apnea (OSA). He has no history of cardiovascular disease or symptoms thereof. His blood pressure (BP) today in the office is 152/82 with a regular pulse of 62 beats per minute. His home readings have averaged 146/78. Physical examination is normal, apart from 2 mm of pitting edema at the mid-tibial levels bilaterally. There is no abdominal bruit. Laboratory testing reveals serum sodium of 137 meq/L; potassium 4.0 meq/L; and creatinine of 1.6 mg/dL, with an eGFR by MDRD of 49 mL/min/1.73 m2.
Doppler of the renal arteries shows no evidence of stenosis. His plasma aldosterone concentration (PAC) is 12 ng/dL, with plasma renin activity (PRA) of 1.0 ng/mL/h, for a PAC/PRA ratio of 12. Urinalysis is bland, and microalbumin is 65 mg/g creatinine.
Question What would be the next best step in management for this patient? A. B. C. D. E.
Add spironolactone 25 mg per day, add aliskiren 75 mg per day, switch diuretic to torsemide 10 mg per day, catheter-based renal sympathetic denervation, add losartan 50 mg per day.
Discussion This man has resistant hypertension, as he is on adequate doses of three medications (including a diuretic) and is not at goal BP ( o140/90). After non-adherence and white coat hypertension have been excluded, common secondary causes include OSA, renal artery stenosis, and primary aldosteronism (PA). In this patient, these etiologies would be unlikely based on the clinical and laboratory findings. PA occurs in 7–20% of those with resistant hypertension and is screened for by means of the PAC and PRA. Recommendations for when to proceed with confirmatory testing vary somewhat, but generally PA is unlikely unless the PAC is 4 15 ng/dL with a PAC/PRA ratio 430. Even though this patient is on an ACE inhibitor (which can raise PRA and thus “falsely” lower the ratio in patients with PA), he is far enough below the cutoff that confirmatory testing for PA would not be indicated at this time. Even in patients with resistant hypertension who do not have PA, aldosterone antagonists appear to be beneficial. The mechanism of this effect is not entirely clear but may relate in part to elevated mineralocorticoid receptor sensitivity. This benefit has been demonstrated in several randomized, double-blind, placebo-controlled trials, with average BP reductions in the range of 10–14 mm Hg systolic and 4–6 mm Hg diastolic in the two largest studies. The vast majority of study participants were on an ACE inhibitor or an ARB at baseline, but those with eGFR of o 40 mL/min/1.73 m2 were excluded. The mean baseline PAC and PAC/PRA ratios were normal
318
J.B. Bundrick, S.C. Litin / Disease-a-Month 61 (2015) 308–318
(9.4 ng/dL and 15, respectively), and significant BP reduction was noted in all subgroups apart from those with a PAC/PRA ratio of o 7. Doses of spironolactone were 25–50 mg once daily. Spironolactone should only be used with caution in those with eGFR o 45 mL/min/1.73 m2 or baseline serum potassium of 44.5 meq/L and should be avoided altogether in those with eGFR o 30 mL/min/1.73 m2. Serum potassium must be carefully monitored (e.g., including an early check within 1 week of initiation or dose change, at 4 weeks, then every few months if stable). The addition of direct renin inhibitors (aliskiren) and angiotensin receptor blockers to a regimen containing an ACE inhibitor has been shown to lack benefit and result in worsening renal function. Thiazide diuretics tend to lose efficacy as eGFR falls below 30 mL/min/1.73 m2, and in that situation a switch to torsemide would be reasonable; however, this patient is well above that threshold. While catheter-based sympathetic denervation showed some promise in an initial unblinded trial, a sham-controlled study in 2014 showed no benefit compared to medical therapy. Clinical pearl In many patients with resistant hypertension, the addition of low-dose aldosterone antagonist is effective in improving blood pressure control (even in the absence of primary aldosteronism). References 1. Vongpatanasin W. Resistant hypertension: a review of diagnosis and management. J Am Med Assoc. 2014;311(21):2216–2224. 2. Oxlund CS, Henriksen JE, et al. “Low dose spironolactone reduces blood pressure in patients with resistant hypertension and type 2 diabetes mellitus: a double blind randomized clinical trial. J Hypertens. 2013;31(10):2094–2102. 3. Vaclavik J, Sedlak R, et al. Addition of spironolactone in patients with resistant arterial hypertension (ASPIRANT): a randomized, double-blind, placebo-controlled trial. Hypertension. 2011;57(6):1069–1075. Answers: 1-B; 2-E; 3-A; 4-D; 5-B; 6-D; 7-C; and 8-A
