What is the most likely diagnosis?A 52-year-old healthy male presents to your office complaining of a 2-year history of intermittent leg heaviness and swelling in both legs that has become more bothersome over the past 3 months. He works as a mailman and states that this heaviness is increasingly impairing his ability to carry the mail. He tells you “The swelling in my legs is often worse in the evening, especially when I have been walking my mail route.” He finds that by the end of the day he has swelling up to his mid calf and that the top of his socks leave dents in his skin. He complains of brown spots and dryness and itching on his feet and ankles. He denies unusual shortness of breath, fatigue, sleep disturbance, but states that he has been using over-the-counter ibuprofen for several months for knee pain. On examination, his body mass index (BMI) is 23 kg/m2, blood pressure is 130/85 mm Hg, pulse is 72 beats/min, and respiratory rate is 16 breaths/min. The heart, lung, abdominal examination is normal. His legs show mid-calf symmetrical pitting swelling bilaterally, bulging and varicose veins on his calves, brown millimeter-size macules on the feet and ankles. The posterior tibial and dorsalis pedis pulses are regular and strong.
What is the most likely diagnosis?
What further evaluation should be considered?
What is the next step in therapy?
Summary: A 52-year-old man presents with a classic signs and symptoms of venous insufficiency. It is bilateral, chronic, and dependant and without significant constitutional, cardiac, or pulmonary symptoms. Physical findings show varicosities and stasis dermatitis. The edema often interferes with and is aggravated by his work and possibly worsened with the recent use of ibuprofen.
• Most likely diagnosis: Venous insufficiency aggravated by use of nonsteroidal anti-inflammatory drugs (NSAIDs).
• Further evaluation necessary: Ensure that there are no other comorbid conditions: sleep studies and echocardiography if sleep apnea and pulmonary hypertension is considered; echocardiogram, chest radiograph (CXR), electrocardiogram (ECG), brain natriuretic peptide (BNP) if congestive heart failure (CHF) or other cardiac cause considered; electrolytes, serum creatinine, and urinalysis if renal causes considered; and albumin if low-protein states are considered. Ankle brachial index (ABI) testing should be considered if potential treatments could aggravate peripheral arterial disease (PAD).
• Beneficial treatment: Leg elevation, support stockings, low sodium diet, and avoidance of aggravating medications. Consider oral horse chestnut seed extract for edema. Surgical options should be considered if comorbid PAD or venous stasis ulcers are present.
1. Become familiar with the presenting signs and symptoms of common causes of lower extremity swelling.
2. Understand the clinical evaluation used to diagnose and identify low-risk lower extremity swelling from swelling indicative of severe comorbid conditions or those causes with significant risk.
3. Become familiar with the management of common causes of lower extremity swelling.
4. Define different types of lower extremity swelling and levels of lower extremity edema.
In older people, chronic venous insufficiency is the most common cause of bilateral lower extremity swelling, affecting up to 2% of the general population with increasing prevalence with age. Although, venous insufficiency can often be diagnosed clinically without extensive testing, for persons older than 45 years, there is increasing chance of pulmonary hypertension (most commonly secondary to obstructive sleep apnea) and congestive heart failure as the etiology of the lower extremity swelling. There are many medications also associated with fluid retention and should always be considered in the differential as a potential cause of or contributor to lower extremity swelling.
VENOUS EDEMA: An excess of low viscosity, protein poor interstitial fluid resulting in pitting in affected area of body.
LYMPHEDEMA: An excess of protein rich interstitial fluid within the skin and subcutaneous tissue. Primary forms are rare and often genetically related. Secondary lymphedema is more common and often related to previous malignancies, surgery, radiation, and infections.
LIPIDEMA: A form of fat maldistribution that can appear to be leg swelling with foot sparing. This is not a true form of edema.
MYXEDEMA: A dermal edema secondary to an increased deposition of connective tissue components (mucopolysaccharides) seen in various forms of thyroid disease.
Edema is defined as a palpable swelling. The most common cause of leg edema in North American patients older than 50 years is due to venous insufficiency. Venous insufficiency affects up to 30% of the population. Congestive heart failure (CHF) affects around 1%. The mostly likely cause of leg edema in women younger than 50 is idiopathic edema. Most patients should be assumed to have one of these causes unless a history and physical may indicate a secondary cause. The two exceptions to this rule is in pulmonary hypertension and early congestive heart failure. These can present with lower extremity edema before they can become clinically obvious in other ways.
History
The key elements of the history include duration of edema (acute [≤72 hours] versus chronic), presence of pain, current medications being taken, overnight improvement, signs/symptoms of sleep apnea (snoring, easy falling asleep during day), and history of chronic medical conditions, including heart, liver, and kidney or past history of pelvic/abdominal malignancies or radiation therapy. Family history of clotting disorders, varicosities, and lymphedema are also important to document.
The key elements of the physical examination include signs of sleep apnea such as a BMI >30 kg/m2 and a thick neck circumference >17 in (42 cm). Unilateral limb swelling is commonly seen with venous insufficiency, lymphedema, and deep vein thrombosis (DVT). Bilateral limb swelling is commonly seen with idiopathic, medicine related, or with systemic diseases. Generalized edema is seen in advanced systemic diseases such as congestive heart failure, renal failure, and liver failure. Tenderness of swelling can be seen with deep vein thrombosis and lipidema. Pitting is seen with venous edema, DVT, CHF, and early lymphedema. Myxedema and chronic lymphedema do not pit. Varicosities are seen with venous insufficiency. In lymphedema, a Kaposi-Stemmer sign (inability to pinch fold of skin on dorsum of foot at base of 2nd toe) is seen. Skin changes that can be seen include brown hemosiderin spots, dry dermatitis and skin ulceration (venous insufficiency), warm tender moist skin (complex regional pain syndrome/reflex sympathetic dystrophy), brawny induration, and warty texture with papillomatosis (lymphedema). Signs of systemic disease include jaundice, ascites and spider hemangioma (liver disease, cirrhosis), jugular venous distention, and lung crackles/rales (CHF).
The majority of patients older than 50 years who present with leg swelling have venous insufficiency. Always consider pulmonary hypertension (sleep apnea or other causes) in your differential of probable venous insufficiency. If the etiology is unclear, a complete blood count, basic metabolic profile, urinalysis, thyroid stimulating hormone, and albumin can rule out common systemic diseases associated with leg swelling. Urine protein and albumin <2 g/dL can be seen in nephrotic syndrome. If the patient is found to have nephrotic syndrome, serum lipid profile should also be obtained.
If the clinical history and examination indicate a cardiac etiology, obtaining an electrocardiogram, echocardiogram, brain natriuretic peptide (BNP), and chest x-ray is appropriate. A normal BNP is good at ruling out CHF with a sensitivity of 90%.
In young women with idiopathic edema who desire testing confirmation, or if the etiology is unclear, a morning to evening weight gain of >0.7 kg is consistent with this diagnosis. A water load test: drink 20 cc/kg (max 1500 cc) in the morning and collect all urine 1 hour before consumption until 4 hours after, and repeat this. In the first trial, the patient is standing for the 4-hour time frame. In the second trial, the patient remains recumbent. In idiopathic edema <55% of water consumed is urinated standing and >65% urinated in recumbent position. Idiopathic edema is often associated with obesity and with depression. Patients can complain of hand and face swelling in addition to leg swelling. On history, many will be using diuretics to self treat.
If DVT is suspected (acute edema), a D-dimer level should be ordered. Because of its high sensitivity and low specificity, a normal D-dimer essentially rules out DVT but a positive D-dimer is not diagnostic of DVT. If D-dimer is positive, a venous Doppler of the lower extremities should be ordered.
An echocardiogram should be considered in patients >45 years old to rule out pulmonary hypertension or in any patient when sleep apnea is suspected. A sleep study will be useful if this diagnosis is considered.
If liver disease is suspected, liver function tests, albumin, and coagulation studies should be evaluated. If a malignancy is suspected, an abdominal and pelvic examination and CT scan should be considered. Tumors commonly associated with edema include prostate cancer, ovarian cancer, and lymphoma.
Lifestyle modifications necessary to manage idiopathic edema include intermittent laying down, avoidance of heat, low-sodium diet, decreased fluid intake, and weight loss. Patients with this disorder often have a secondary hyperaldosteronism due to this condition. Therefore, if needed, spironolactone in the early evening is considered the medication of choice. If not successful, a thiazide diuretic can be added. Avoid loop diuretics due to higher risk of electrolyte and renal side effects. Compression stockings are less successful with this condition. Diuretic abuse is common in this condition, and can lead to a mild hypovolemia that can stimulate reninangiotensin-aldosterone secretion, which can lead to edema rebound when the diuretic is stopped. Diuretic-induced rebound edema can be minimized by weaning off over 3 to 4 weeks. Patients need to be reassured that the initial worsening of edema is common with the withdrawal.
For venous insufficiency, nonpharmacologic mainstays are compression leg stockings and leg elevation. Often higher compressions of 30-40 mm Hg at the ankle are needed to control the swelling. If arterial insufficiency is a consideration, venous and arterial Dopplers should be done prior to application of the stockings. Higher compression stockings can be difficult for some patients to put on, so instruct the patient to put them on in the morning before the leg swelling progresses. Advising the patient to roll the stockings off in the evening so that they can be rolled back on in the morning is also helpful. Stocking applicators can also be prescribed.
Horse chestnut seed extract can inhibit elastin and hyaluronidase which in a 300-mg twice-a-day dosing has been shown to modestly decrease symptoms associated with venous insufficiency. Loop diuretics in low doses can be used short term for patients severely affected. Surgical interventions are available for those with severe disease who are unresponsive to less-invasive measures.
Patients with lymphedema should be educated regarding the chronic nature of the condition. Reasonable expectations for treatment must be set and understood, as this can be difficult to manage. Treatments include exercise, elevation, intermittent pneumatic compression devices, manual lymph drainage massage, and surgical procedures. Diuretics are not helpful. Patients often have tinea pedis and should be aggressively treated to prevent cellulitis. For patients with recurrent cellulitis, prophylactic antibiotics may be considered.
Acute DVT is treated with low-molecular-weight heparin (LMWH). Warfarin therapy can be started simultaneously with a target international normalized ratio (INR) of 2.0 to 3.0. Heparin should be continued for at least 5 days and when INR is therapeutic it can be discontinued. The duration of warfarin therapy varies based on cause and recurrence rate of the DVT. If anticoagulation therapy is contraindicated, then inferior vena cava filter may be indicated to prevent life-threatening pulmonary embolism.
60.1 A 60-year-old woman presents for follow-up of lymphedema that developed following a mastectomy and lymph node dissection for breast cancer. She finds the swelling to be quite uncomfortable and it limits the use of her arm. Which of the following treatment options would be recommended?
A. Intermittent pneumatic compression
B. Oral warfarin
C. Oral furosemide
D. Oral hydrochlorothiazide
E. Horse chestnut seed extract
60.2 Which patient would have the most benefit from a laboratory or diagnostic testing evaluation for systemic disease as a cause of lower extremity swelling?
A. A 35-year-old woman with cyclic bilateral ankle swelling without significant pain. She is taking over-the-counter (OTC) ibuprofen for her menstrual cramps. On examination, she has +1 pitting at the ankles.
B. A 44-year-old man with 3-year history of left greater than right, pain-free, moderate swelling in his calves. He has normal BMI, no daytime somnolence and no constitutional symptoms. He is not taking any OTC or prescription medications. On examination, he has mild varicosities and hemosiderin skin deposits on both legs with nontender +1 pitting edema. Calf circumferences measure 17 cm on the left and 15.5 cm on the right.
C. A 50-year-old man with mild bilateral +2 lower extremity edema that has slowly been worsening over the last year. He has a history of hypertension and is taking hydrochlorothiazide, benazepril, and amlodipine. On review of systems, he complains of daily fatigue, and some increasing constipation.
D. A 25-year-old woman on oral contraceptives with bilateral +1 lower extremity pitting swelling over a 2-year period. On examination, she has a body mass index of 26 kg/m2, no varicosities, no skin changes, and an otherwise negative review of symptoms. She does admit to using OTC weight-loss aids regularly.
60.3 A 65-year-old man with a history of prostate cancer and radiation therapy 3 years ago presents with chronic bilateral leg swelling. He denies dyspnea, chest pain, orthopnea, wheezing. He denies daytime somnolence or snoring. On examination, there is non-pitting up to his calf with a “squaring” appearance of the foot. You are unable to pinch skin on dorsum of foot at second toe. What is the most likely diagnosis?
A. Deep vein thrombosis
B. Secondary lymphedema
C. Myxedema
D. Venous stasis
E. Hypoalbuminemia secondary to prostate cancer
60.1 A. In lymphedema, diuretics unfortunately have little impact. Management options include support, pneumatic compression, manual lymph drainage, and surgery. In venous insufficiency, horse chestnut seed extract can be used to decrease signs and symptoms. Loop diuretics can be used short term to decrease edema burden.
60.2 C. Patients older than 45 with lower extremity edema and systemic signs such as fatigue, somnolence, and constipation could benefit from an evaluation for systemic disease as a cause for lower extremity swelling. A CBC, BMP, UA, TSH, and albumin would be reasonable in this patient. Sleep studies and an echocardiogram would also be useful due to the increased risk for pulmonary hypertension as a cause of edema in patients older than 45 years of age. Liver functions tests would be useful in patients who present with ascites. NSAIDs (5% edema rate), calcium channel blockers (50% edema rate), and oral contraceptives are medications that are associated with edema. The most common cause of unilateral edema without pain with onset >72 hours is venous insufficiency. Patients who cross their legs predominantly on one side can have greater disparity in leg swelling and varicosities.
60.3 B. The most common cause of lymphedema is secondary to malignancy (prostate, ovarian, lymphoma), surgery, and radiation therapy. The positive Kaposi-Stemmer is seen in lymphedema. Chronic bilateral lower extremity swelling is unlikely to represent a DVT. Myxedema is associated with thyroid disorders. Hypoalbuminemia is seen in advance malignancies, nephrotic syndrome, protein-losing enteropathies, and liver disease.
Idiopathic edema and venous insufficiency are the most common causes of lower extremity swelling in patients without systemic disease and often can be diagnosed with history alone.
Pulmonary hypertension secondary to sleep apnea should be considered in patients presenting with leg swelling who are older than 45, have a neck circumference >17 in (42 cm), have daytime somnolence, and a history of snoring.
If there is an unclear etiology of the lower extremity swelling, rule out lipidema and lymphedema.
It is reasonable to rule out most systemic causes in patients older than 45 with a few simple laboratory tests.
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