17: Edema

Edema is defined as an increase in the interstitial fluid volume and is generally not clinically apparent until the interstitial volume has increased by at least 2.5–3 L. It is useful to review some background pathophysiology before discussing the differential diagnosis:

1. Distribution of total body water

   1. 67% intracellular; 33% extracellular

   2. Extracellular water: 25% intravascular; 75% interstitial

2. Regulation of fluid distribution between the intravascular and interstitial spaces

   1. There is a constant exchange of water and solutes at the arteriolar end of the capillaries.

   2. Fluid is returned from the interstitial space to the intravascular space at the venous end of the capillaries and via the lymphatics.

   3. Movement of fluid from the intravascular space to the interstitium occurs through several mechanisms:

      1. Capillary hydrostatic (hydraulic) pressure pushes fluid out of the vessels.

      2. Interstitial oncotic pressure pulls fluid into the interstitium.

      3. Capillary permeability allows fluid to escape into the interstitium.

   4. Movement of fluid from the interstitium to the intravascular space occurs when opposite pressures predominate.

      1. Intravascular (plasma) oncotic pressure from plasma proteins pulls fluid into the vascular space.

      2. Interstitial hydrostatic pressure pushes fluid out of the interstitium.

   5. In skeletal muscle, the capillary hydrostatic pressure and the intravascular oncotic pressure are the most important factors.

   6. There is normally a small gradient favoring filtration out of the vascular space into the interstitium; the excess fluid is removed via the lymphatic system.

3. Edema formation occurs when there is

   1. An increase in capillary hydrostatic pressure (for example, increased plasma volume due to renal sodium retention).

   2. An increase in capillary permeability (for example, burns, angioedema).

   3. An increase in interstitial oncotic pressure (for example, myxedema).

   4. A decrease in plasma oncotic pressure (for example, hypoalbuminemia).

   5. Lymphatic obstruction.

Although it is possible to construct a pathophysiologic framework (Figure 17-1) for the differential diagnosis of edema, it is more useful clinically to use the distribution of the edema as the pivotal point:

1. Bilateral leg edema

   1. Due to a systemic cause (with or without presacral edema, ascites, pleural effusion, pulmonary edema, periorbital edema)

      1. Cardiovascular

         • (1) Systolic or diastolic heart failure (HF)

         • (2) Constrictive pericarditis

         • (3) Pulmonary hypertension

      2. Hepatic (cirrhosis)

      3. Renal

         • (1) Advanced kidney disease of any cause

         • (2) Nephrotic syndrome

      4. Hematologic: anemia

         The most common systemic causes of edema are cardiac, hepatic, and renal diseases.

      5. GI

         • (1) Nutritional deficiency or malabsorption leading to hypoalbuminemia

         • (2) Refeeding edema

      6. Medications

         • (1) Antidepressants: Monoamine oxidase inhibitors

         • (2) Antihypertensives

           • (a) Calcium channel blockers, especially dihydropyridines

           • (b) Direct vasodilators (hydralazine, minoxidil)

           • (c) Beta-blockers

         • (3) Hormones

           • (a) Estrogens/progesterones

           • (b) Testosterone

           • (c) Corticosteroids

         • (4) Nonsteroidal antiinflammatory drugs (NSAIDs)

         • (5) Thiazolidinediones

      7. Endocrine: myxedema

   2. Due to a venous or lymphatic cause

      1. Venous obstruction

         • (1) Bilateral deep venous thrombosis (DVT) (see Chapter 15, Dyspnea, for a full discussion of lower extremity DVT)

         • (2) Bilateral pelvic or retroperitoneal lymphadenopathy or mass

      2. Venous insufficiency

      3. Lymphatic obstruction (lymphedema)

         • (1) Primary (idiopathic, often bilateral)

           • (a) Congenital

           • (b) Lymphedema praecox (onset in puberty) or tarda (onset after age 20)

         • (2) Secondary (more common; generally unilateral—see below)

2. Unilateral limb edema

   1. Venous obstruction

      1. Unilateral DVT

      2. Unilateral lymphadenopathy or mass

   2. Venous insufficiency (more often bilateral)

   3. Lymphedema (secondary)

      1. Neoplasm

      2. Surgery (especially following mastectomy)

      3. Radiation therapy

      4. Miscellaneous (tuberculosis, recurrent lymphangitis, filariasis)

   4. Cellulitis/erysipelas (can also be localized)

   5. Baker cyst (leg only)

3. Localized edema

   1. Burns

   2. Angioedema, hives

   3. Trauma

   4. Cellulitis, erysipelas

Figure 17-2 outlines the diagnostic approach to edema.

Even before examining Mrs. V, you can see that she has significant bilateral leg edema, a pivotal point in her presentation. Although there are some local diseases that can present with bilateral leg edema, the first step in such patients is always to look for systemic causes. While the history and physical are often not sensitive or specific enough to make a diagnosis, they are a good starting point for organizing the differential. So the first question to ask is, “Does Mrs. V have any signs, symptoms, or risk factors pointing to a cardiac, hepatic, or renal cause of her edema?” The results of this exploration will help rank the differential. Mrs. V’s history of a blood transfusion puts her at risk for chronic hepatitis and cirrhosis, and her vague abdominal complaints raise the possibility of ascites, more commonly seen with cirrhosis than HF or kidney disease. She is certainly at risk for both heart and kidney disease because of her history of hypertension and diabetes. While most patients with HF complain of shortness of breath, some describe only fatigue. Medication should be considered as a cause, since pioglitazone frequently causes edema; hypothyroidism does not cause pitting edema, and so is not likely. Finally, although it is uncommon for obstruction to cause bilateral edema, you should think about ovarian cancer causing malignant ascites and venous obstruction if another cause is not found. Table 17-1 lists the differential diagnosis.

Always look for systemic causes of edema in patients with bilateral leg edema.

Leading Hypothesis: Cirrhosis

Textbook Presentation

Patients with cirrhosis can be asymptomatic or have mild symptoms, such as fatigue. Some patients have the classic manifestations of portal hypertension: ascites, edema, variceal bleeding, encephalopathy, or hypersplenism.

Disease Highlights

1. Etiology

   1. More common causes

      1. Alcohol

      2. Chronic hepatitis B or C

      3. Nonalcoholic fatty liver disease (NAFLD)

      4. Hemochromatosis

   2. Less common causes

      1. Drugs and toxins (isoniazid, methotrexate, amiodarone)

      2. Autoimmune hepatitis

      3. Genetic metabolic diseases (Wilson disease, alpha-1-antitrypsin deficiency, glycogen storage diseases, porphyria)

      4. Infections (schistosomiasis, echinococcosis, brucellosis)

      5. Cardiac

      6. Primary or secondary biliary cirrhosis

         The 2 most common causes of cirrhosis in the United States are alcoholic liver disease and chronic hepatitis C.

2. Pathophysiology

   1. Advanced fibrosis, or cirrhosis, causes architectural distortion of the hepatic vasculature, leading to shunting of the blood coming into the liver via the portal vein directly to the hepatic vein outflow system, which causes

      1. Impaired hepatocyte function due to loss of normal sinusoids

      2. Increased intrahepatic resistance, or portal hypertension

      3. Increased risk of hepatocellular carcinoma related to regenerative activity and DNA damage

   2. Consequences of cirrhosis and portal hypertension include

      1. Formation of portosystemic collaterals (ie, varices)

      2. Splanchnic vasodilation

      3. Renal vasoconstriction and hypoperfusion of the kidneys, causing salt and water retention

      4. Increased cardiac output

      5. Decreased production of albumin and clotting factors

      6. Increased capillary hydrostatic pressure

      7. Edema due to a combination of salt and water retention (increasing hydrostatic pressures) and hypoalbuminemia (decreasing intravascular oncotic pressure)

3. Prognosis

   1. Median survival from time of diagnosis of compensated cirrhosis is 10–12 years.

   2. Up to 60% of patients progress to decompensated cirrhosis, defined as worsening portal hypertension and decreased hepatic reserve, at 10 years after diagnosis.

   3. Rates of progression are quite variable and are related to the etiology of the cirrhosis, presence of other liver disease, available treatment (such as for chronic hepatitis B and C), and avoidance of hepatic toxins (such as alcohol).

   4. 5-year mortality approaches 85% after decompensation if transplantation is not performed.

      1. In patients with cirrhosis but no varices and no ascites, the 1-year mortality rate is 1%.

      2. In those with varices but no ascites, the 1-year mortality rate is 3.4%.

      3. In those with varices and ascites, the 1-year mortality rate is 20%; in those with variceal bleeding and ascites, the 1-year mortality is 57%.

   5. The Childs-Pugh-Turcotte classification of cirrhosis severity predicts prognosis (see Chapter 19, GI Bleeding).

Evidence-Based Diagnosis

1. Cirrhosis is a pathologic diagnosis definitively made only by examining the entire liver at autopsy or after liver transplantation.

2. The traditional gold standard is percutaneous liver biopsy, although due to sampling error, the sensitivity has been reported to be as low as 70–80%.

3. The clinical presentation is variable, making clinical diagnosis difficult.

   1. Patients may have physical findings suggestive of chronic liver disease (see below), constitutional symptoms, asymptomatic liver enzyme or radiologic abnormalities, manifestations of portal hypertension (see below), or no symptoms at all. Cirrhosis is sometimes diagnosed at autopsy in patients in whom the disease never manifested.

   2. Physical findings may increase the likelihood that a patient with liver disease has cirrhosis, but rarely rule out cirrhosis (Table 17-2).

   3. Patients who show manifestations of portal hypertension (see below) are assumed to have cirrhosis.

4. Laboratory tests

   1. A low platelet count in a patient with liver disease increases the probability of cirrhosis.

      1. Platelet count < 110 × 10³/mcL: LR+ = 9.8

      2. Platelet count < 160 × 10³/mcL: LR+ = 6.3; LR– = 0.29

   2. Albumin < 3.5 g/dL (LR+ = 4.4) and a prolonged international normalized ratio (INR) (LR+ = 5.0) also increase the likelihood of cirrhosis.

   3. The Bonacini cirrhosis discriminant score combines the alanine aminotransferase:aspartate aminotransferase (ALT:AST) ratio, the platelet count, and the INR into a score from 0–11; scores > 7 increase the likelihood of cirrhosis (LR+ = 9.4).

5. Several noninvasive models and techniques (FibroSURE, FibroScan) have been developed to predict cirrhosis in patients with chronic hepatitis C, although they are not currently used in place of biopsy.

   1. FibroSURE includes the biomarkers alpha-2 macroglobulin, haptoglobin, gamma-glutamyl transpeptidase, apolipoprotein A₁, ALT, and total bilirubin.

      1. Correlates well with liver biopsy

      2. Useful for distinguishing mild fibrosis from cirrhosis, but less accurate in identifying moderate fibrosis.

   2. FibroScan is an imaging method that measures liver stiffness, which correlates with cirrhosis.

      1. For predicting cirrhosis, the sensitivity is 86% and specificity 93% (LR+, 12.2; LR–, 0.15).

      2. Less accurate in identifying moderate fibrosis (sensitivity 64%, specificity 87%; LR+, 4.9; LR–, 0.41)

   3. Test characteristics of ultrasound to diagnose cirrhosis are variable (LR+, 2.5–11.6; LR−, 0.13–0.73).

   4. MRI has sensitivity and specificity as high as 93% and 82%, respectively.

Treatment

Once it has been determined that the patient probably or definitively has cirrhosis, it is important to determine the specific cause of the cirrhosis (see Chapter 26, Jaundice & Abnormal Liver Enzymes) and to determine whether the patient has manifestations of portal hypertension: variceal bleeding, ascites, hepatic encephalopathy, and hypersplenism. The treatment of cirrhosis depends on the underlying cause. Treatments for selected causes of cirrhosis are discussed in Chapter 26, Jaundice & Abnormal Liver Enzymes.

Manifestations of Portal Hypertension

1. Variceal Bleeding

See Chapter 19, GI Bleeding.

2. Ascites

Textbook Presentation

The patient complains of an inability to fasten her pants due to increasing abdominal girth, sometimes accompanied by dyspnea and edema.

Disease Highlights

1. Epidemiology

   1. Over 10 years, ascites develops in 50% of patients with cirrhosis.

   2. 1-year survival rates drop significantly once ascites develops.

2. Pathophysiology: Portal hypertension → arterial vasodilation of the splanchnic circulation → reduction in systemic vascular resistance → underfilling of arterial circulation → sodium and free water retention by the kidneys; also reduced glomerular filtration rate (GFR) → increased capillary permeability and lymph formation in the splanchnic organs.

3. Complications of ascites

   1. Respiratory compromise due to compression of lung volumes

   2. Hepatorenal syndrome (HRS): a syndrome of acute kidney injury associated with cirrhosis and a poor prognosis. The acute kidney injury may be acute (type 1) or subacute (type 2).

      1. Diagnostic criteria

         • (1) Cirrhosis with ascites

         • (2) Serum creatinine > 1.5 mg/dL

         • (3) Serum creatinine stays above 1.5 mg/dL after at least 2 days of diuretic withdrawal and volume expansion with albumin.

         • (4) Absence of shock

         • (5) No current or recent treatment with nephrotoxic drugs

         • (6) Absence of parenchymal kidney disease (< 500 mg/dayof proteinuria, < 50 RBC/hpf, abnormalities on renal ultrasound)

      2. Clinical phases (Table 17-3)

      3. Incidence in patients with cirrhosis and ascites is 18% at 1 year and 39% at 5 years.

      4. The prognosis is poor: 6-month mortality is about 50% for patients with type 2 HRS and 100% for those with type 1.

      5. Precipitants of type 1 HRS include bacterial infections (especially spontaneous bacterial peritonitis), GI bleeding, acute hepatitis, over-diuresis, and large volume paracentesis.

      6. Treatment of HRS

         • (1) Liver transplantation is the definitive treatment for both types of HRS.

         • (2) There are limited data regarding the use of transvenous intrahepatic portosystemic shunts (TIPS) and vasopressin derivatives to treat type 1 HRS.

   3. Spontaneous bacterial peritonitis (SBP)

      1. Prevalence of 10–30% in hospitalized cirrhotic patients, with 1-year recurrence rate of 70% and mortality rate of about 20%; 96% of patients with SBP have a Childs-Pugh-Turcotte grade of B or C

      2. Overgrowth of intestinal bacterial and increased intestinal permeability lead to movement of bacteria into mesenteric lymph nodes; the bacteria can then enter the systemic circulation and colonize the ascitic fluid.

      3. The 3 most common isolates are Escherichia coli, Klebsiella pneumoniae, and pneumococci.

      4. Symptoms include fever (50–75% of patients), abdominal pain (27–72%), chills (16–29%), nausea/vomiting (8–21%), mental status changes (up to 50%), and decreased renal function (33%); about 13% of patients are asymptomatic.

      5. Risk factors for SBP include ascitic fluid total protein level ≤ 1 g/dL, upper GI bleeding, a prior episode of SBP.

      6. Diagnosis of SBP

         • (1) Criteria for performing a diagnostic paracentesis in patients with cirrhosis and ascites:

           • (a) Admission to the hospital for any reason

           • (b) Change in clinical status (fever, abdominal pain, mental status changes, ileus, septic shock)

           • (c) Development of leukocytosis, acidosis, or acute kidney injury

           • (d) Active GI bleeding

         • (2) Always inoculate blood culture tubes with ascitic fluid at the bedside to maximize yield of fluid cultures.

         • (3) Interpretation of ascitic fluid cell counts and cultures (Table 17-4)

           Consider secondary peritonitis if more than 1 organism is cultured from the ascitic fluid.

         • (4) Other ascitic fluid findings that increase the likelihood of SBP include WBC count > 1000 cells/mcL (LR+ = 9.1), pH < 7.35 (LR+ = 9.0), and blood-ascitic fluid pH gradient ≥ 0.1 (LR+ = 11).

      7. Treatment of SBP

         • (1) Empiric treatment should be started prior to return of culture results.

         • (2) IV cefotaxime is the best-studied antibiotic for SBP; oral ofloxacin can be used in outpatients without signs of sepsis or hepatic encephalopathy.

         • (3) IV albumin has been shown to reduce mortality and development of renal impairment, particularly in patients with a total bilirubin > 4 mg/dL, BUN > 30 mg/dL, or creatinine > 1 mg/dL.

         • (4) All patients who recover from SBP should receive secondary prophylaxis with oral norfloxacin, and all patients with acute GI bleeding should receive prophylaxis; other primary prophylaxis is controversial.

         • (5) Since 2-year survival after SBP is only about 30%, liver transplantation should be considered in patients who recover from SBP.

Evidence-Based Diagnosis

1. Physical exam: See Chapter 26, Jaundice & Abnormal Liver Enzymes

2. Peritoneal fluid analysis should be done in all patients with new ascites.

   1. Initial tests should include cell count, albumin, total protein, and culture.

   2. Serum-ascites albumin gradient is used to distinguish ascites due to portal hypertension from ascites due to other causes.

      1. In portal hypertension, ascites occurs due to transudation, without changes in permeability that would allow albumin to leak into the ascitic fluid.

      2. Therefore, the albumin content of ascitic fluid is low relative to serum.

      3. This is in contrast to exudative types of ascites, such as ascites from infection or malignancy, in which albumin can leak into the ascitic fluid.

      4. A serum ascites-albumin gradient (serum albumin-ascitic fluid albumin) of ≥ 1.1 mg/dL has a LR+ of 4.6 for the diagnosis of ascites due to portal hypertension; a serum ascites-albumin gradient of < 1.1 mg/dL has a LR− of 0.06 for the diagnosis of portal hypertension.

Treatment

1. Sodium restriction (sodium intake < 2 g/day) is commonly recommended, but there are no clinical trials showing that it leads to improved outcomes; fluid restriction of 1000–1500 mL/day is recommended if the serum sodium is < 130 mEq/L.

2. Spironolactone is the diuretic of choice to treat the aldosterone driven salt and water retention seen in cirrhosis.

   1. 75% of patients respond

   2. Furosemide or other loop diuretics can be added in patients who do not respond to spironolactone alone; 90% of patients respond to sodium-restricted diets, spironolactone, and loop diuretics.

   3. Hydrochlorothiazide and metolazone are not recommended.

   4. In order to avoid hypovolemia and renal impairment, the rate of weight loss should not exceed 0.5 kg/day in the absence of peripheral edema or 1 kg/day in the presence of edema.

      Aspirin and NSAIDs blunt the natriuretic effect of diuretics and should not be used in patients with ascites.

3. Large volume paracentesis with volume expansion (dextran or albumin) is done in patients unresponsive to diuretics.

4. TIPS

   1. Creates a shunt between the high-pressure portal vein and the low-pressure hepatic vein, leading to improved hemodynamics and a decrease in ascites.

   2. Complications include bleeding, shunt stenosis or thrombosis, right-sided HF, and encephalopathy in 30% of patients.

   3. Used as a bridge to transplant

5. Liver transplantation

6. When should ascites be treated with measures beyond sodium restriction?

   1. Not in grade 1 ascites (detectable only by ultrasound)

   2. Grade 2 (moderate) and grade 3 (severe) ascites are generally treated due to patient discomfort and respiratory compromise.

      1. Grade 2 should be treated with diuretics.

      2. Grade 3 should be treated with paracentesis followed by diuretics.

   3. Refractory ascites (ascites not responsive to maximal tolerated medical therapy) should be treated with repeated paracentesis or TIPS, or both.

3. Hepatic Encephalopathy

Textbook Presentation

The classic presentation of hepatic encephalopathy is a patient with known cirrhosis who has mental status changes or is in a coma.

Disease Highlights

1. A spectrum of reversible neuropsychiatric abnormalities seen in patients with cirrhosis

2. Must exclude other neurologic or metabolic causes prior to diagnosing hepatic encephalopathy

3. Overt hepatic encephalopathy (Table 17-5, grades 1–4) is found in 30–45% of patients with cirrhosis.

4. Minimal hepatic encephalopathy (deficits manifested only on neuropsychological testing) is found in 60% of patients with cirrhosis.

5. Patients with severe hepatic encephalopathy requiring hospitalization have a 1-year survival rate of < 50%.

6. Can be precipitated by a wide variety of insults including

   1. Increased ammonia production due to

      1. Excess dietary protein

      2. Constipation

      3. GI bleeding

      4. Infection

      5. Azotemia

      6. Hypokalemia

      7. Systemic alkalosis

   2. Reduced metabolism of toxins because of hepatic hypoxia due to

      1. Dehydration

      2. Arterial hypotension

      3. Anemia

   3. Increased central nervous depressant effect with use of benzodiazepines or other psychoactive drugs

   4. Reduced metabolism of toxins because diversion of portal blood, due to surgical or intrahepatic shunts

      Always look for the underlying cause of worsening hepatic encephalopathy.

Evidence-Based Diagnosis

1. There is some correlation between the degree of elevation of ammonia (either arterial or venous) and the severity of the encephalopathy, but the ammonia level cannot be used to determine the presence or absence of hepatic encephalopathy.

2. Diagnosis is based on history and exclusion of other causes of encephalopathy in a patient with significant liver dysfunction.

Treatment

1. Identify and treat precipitating causes

2. Patients with an episode of overt hepatic encephalopathy should be treated indefinitely; the approach to minimal hepatic encephalopathy is evolving.

3. Treatment focuses on reduction of intestinal accumulation of ammonia.

4. Lactulose removes both dietary and endogenous sources of ammonia through its cathartic action; it also lowers pH, which reduces the population of urease-producing bacteria, and traps ammonia as ammonium ions in the gut lumen.

   1. Frequently used in clinical practice, although most studies showing an improvement in encephalopathy are of poor quality.

   2. Daily dose should be titrated to result in 2–4 soft stools/day.

   3. Complications include hypovolemia and hypernatremia.

5. Antibiotics reduce the population of urease-producing bacteria.

   1. Rifaximin may be superior to lactulose for overt hepatic encephalopathy and has been shown to improve cognitive status in patients with minimal hepatic encephalopathy.

   2. Neomycin is equivalent to lactulose but has the potential to cause ototoxicity and nephrotoxicity with long-term use.

6. Consideration of liver transplantation is indicated in patients with hepatic encephalopathy.

4. Hypersplenism

Textbook Presentation

Cytopenias are found on routine blood testing in a patient with cirrhosis.

Disease Highlights

1. Splenomegaly is found in 36–92% of patients with cirrhosis; 11–55% have the clinical syndrome of hypersplenism, defined as the presence of leukopenia or thrombocytopenia (or both) with splenomegaly.

2. There is a rough correlation between spleen size and degree of decrease in blood cells.

3. Blood cell abnormalities in liver disease

   1. Thrombocytopenia is due to platelet sequestration in the spleen, impaired bone marrow production, and decreased platelet survival.

   2. Leukopenia is due to sequestration in the spleen and is rare compared with thrombocytopenia (1 series found 64% of cirrhotic patients had thrombocytopenia, but only 5% had leukopenia).

   3. Although not part of the syndrome of hypersplenism, anemia often occurs in patients with cirrhosis and is due to increased destruction in the spleen as well as iron or folate deficiency; there is also reduced erythropoietin production.

Evidence-Based Diagnosis

1. Hypersplenism is a clinical syndrome without a specific set of diagnostic criteria.

2. Hypersplenism is manifested by splenomegaly and a significant reduction in 1 or more cellular elements of the blood, in the presence of normal or hypercellular bone marrow.

Treatment

1. Treatment is usually not necessary.

2. Splenectomy or partial splenic embolization is sometimes done for severe thrombocytopenia with bleeding complications.

3. Granulocyte-macrophage colony-stimulating factor and erythropoietin are rarely used.

4. TIPS does not correct thrombocytopenia.

The physical exam findings of splenomegaly and ascites, along with the laboratory abnormalities of thrombocytopenia, elevated transaminases, and hypoalbuminemia, are all consistent with chronic liver disease. The absence of pulmonary crackles and elevation of the jugular venous pressure makes HF unlikely. However, the findings of proteinuria and hypoalbuminemia are also consistent with nephrotic syndrome.

Alternative Diagnosis: Nephrotic Syndrome

Textbook Presentation

Patients with nephrotic syndrome classically have edema (often periorbital), hypertension, hypoalbuminemia, hyperlipidemia, and at least 3.5 g/24 hour of proteinuria.

Disease Highlights

1. Etiology

   1. Primary glomerular diseases

      1. Etiology uncertain but probably immune mediated

      2. Most common pathologies found in adults are membranous and focal segmental glomerulosclerosis (33% each), with membranous being more common in white patients and focal segmental glomerulosclerosis more common in black patients.

      3. Less common pathologies found in adults are minimal change disease (15%) and membranoproliferative glomerular disease (including IgA nephropathy) (14%).

      4. In patients over age 65 who undergo kidney biopsy (recognizing that many patients with presumed diabetic nephropathy do not have a biopsy), approximately 15% have minimal change disease, 30–40% have membranous, and 10–12% have amyloidosis.

   2. Secondary glomerular disease

      1. Diabetes is the most common cause in the United States.

      2. Systemic lupus erythematosus (SLE) generally causes an inflammatory nephritis, but sometimes causes a noninflammatory, membranous pathology.

      3. Amyloidosis and multiple myeloma should be considered in patients over age 40.

      4. Infections commonly associated with nephrotic syndrome include HIV, hepatitis B, hepatitis C, syphilis, and malaria.

      5. Malignancies, especially lung, breast, prostate, and colon cancer, and Hodgkin lymphoma are associated with nephrotic syndrome.

         • (1) 5–25% of patients with membranous nephropathy have a malignancy, with the association being strongest for patients over 60 years old.

         • (2) The cancer may be diagnosed at the same time as the kidney disease but often is found later.

      6. Many drugs, including NSAIDs, captopril, tamoxifen, lithium, and heroin, can cause nephrotic syndrome.

2. Clinical consequences

   1. Primary sodium retention by the kidney, related to low effective circulating volume, causes edema and hypertension.

   2. Albumin excretion leads to hypoalbuminemia, which also contributes to edema formation.

   3. Alterations in lipoprotein production and catabolism lead to elevations of low-density lipoprotein and sometimes triglycerides.

   4. Immunoglobulin excretion and depression of T cell function causes increased susceptibility to infection.

   5. Thromboembolic complications

      1. Due to increased procoagulatory factors and fibrinogen, altered fibrinolytic system, urinary loss of antithrombin III, and increased platelet activity

      2. Relative risk of DVT is 1.7 with an annual incidence of 1.5%; the annual incidence of renal vein thrombosis is 0.5%.

      3. Relative risk of pulmonary embolism is 1.4 but is 6.8 for patients aged 18–39 years.

      4. Risk factors for venous thromboembolism include serum albumin < 2.0–2.5 mg/dL, protein excretion > 8 g/24 h, being within 6 months of diagnosis

      5. The role of prophylactic anticoagulation is unclear but should be considered in high-risk patients.

      6. Arterial thrombosis is rare.

Evidence-Based Diagnosis

1. Nephrotic syndrome is defined by the presence of urinary protein excretion of at least 3.5 g/24 hours, measured with either a 24-hour specimen or a spot albumin/creatinine ratio > 3000–3500 mcg/mg.

2. Laboratory evaluation should include

   1. CBC

   2. Comprehensive metabolic panel (kidney and liver function, including serum albumin)

   3. Fasting glucose and HgbA_1c

   4. Antinuclear antibody

   5. HIV

   6. Hepatitis B serology (surface antigen, core antibody)

   7. Hepatitis C antibody

   8. Serum and urine protein electrophoresis

3. Renal ultrasound should be done.

4. Renal biopsy is often necessary.

Treatment

1. All patients with nephrotic syndrome should be referred to a nephrologist.

2. Loop diuretics are used to treat the edema; high doses are often needed due to the primary sodium retention by the kidney.

3. Angiotensin-converting enzyme inhibitors reduce proteinuria in both hypertensive and normotensive patients.

   1. The antiproteinuric effect becomes maximal in 28 days.

   2. The effect can be increased by a low-salt diet, diuretic treatment, or both.

4. Corticosteroids and other immunosuppressives are used in selected patients.

Once again, given the pivotal finding of bilateral edema, the first step is to look for systemic causes, focusing first on cardiac, hepatic, and renal causes. Mrs. E’s long-standing history of hypertension raises the possibility of diastolic dysfunction, and the lack of physical exam findings does not rule this out. There are no clinical clues to suggest liver or kidney disease, but these are easy to test for and should always be ruled out. Amlodipine commonly causes edema, but she has taken it for years without symptoms. “Dependent edema,” edema that is worsened by standing and improves or resolves with leg elevation, is consistent with, but not specific for, venous insufficiency. A final consideration would be pulmonary hypertension. Patients with pulmonary hypertension commonly complain of dyspnea in addition to edema, and the tired feeling she experiences with exertion could represent dyspnea. Additionally, sheis overweight, putting her at risk for obstructive sleep apnea and consequent pulmonary hypertension. Table 17-6 lists the differentialdiagnosis.

There is no evidence of kidney disease, liver disease, or diastolic dysfunction. However, the echocardiogram shows the somewhat unexpected finding of pulmonary hypertension (PH). This necessitates revising the original set of diagnostic hypotheses: the leading hypothesis is now PH, and venous insufficiency is the remaining active alternative.

Leading Hypothesis: Pulmonary Hypertension

Textbook Presentation

Patients commonly complain of long-standing dyspnea that progresses over months or years. Syncope, exertional chest pain, and edema occur with more severe PH and impaired right heart function.

Disease Highlights

1. Definition

   1. The normal mean pulmonary artery pressure (PAP) is 12 mm Hg.

   2. The clinical classification was revised in 2008 (Table 17-7).

   3. PH is defined as a mean PAP ≥ 25 mm Hg and a pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg; however, in Group 2 PH related to left heart disease (see Table 17-7), the PCWP is > 15 mm Hg.

2. Epidemiology

   1. The prevalence of Group 1 PAH is 6 cases/million (about 3% of patients with PH); approximately one-half of these are idiopathic (including heritable and drug related), 15–30% are related to connective tissue disease, 10–24% to congenital heart disease, 1–6% to HIV, and 7–10% to portal hypertension.

   2. Left heart disease is the etiology of PH in about 65% of cases; up to 83% of patients with diastolic HF have PH.

   3. Over 50% of patients with advanced chronic obstructive pulmonary disease have PH, as do 32–39% of patients with interstitial lung disease.

   4. Chronic thromboembolic disease is the etiology in 0.5–2% of patients with PH.

Evidence-Based Diagnosis

1. History

   1. In 1 series of patients with PAH, initial symptoms included dyspnea (60%), fatigue (19%), chest pain (7%), syncope (8%), edema (3%).

   2. At the time these patients were given the diagnosis of PAH and were enrolled in the study, 98% had dyspnea, 73% fatigue, 47% chest pain, 36% syncope, 37% edema, and 33% palpitations.

2. Physical exam

   1. Characteristic findings include the following:

      1. An accentuated pulmonary component of S₂

      2. A sustained left lower parasternal movement

      3. Increased jugular a and v waves

      4. A tricuspid regurgitation murmur

      5. Hepatojugular reflux

      6. A pulsatile liver

      7. Elevated jugular venous pressure

      8. Edema

   2. Sustained left lower parasternal movement for detecting severe PH with a mean PAP > 50 mm Hg: sensitivity, 71%; specificity, 80%; LR+, 3.6; LR−, 0.4

   3. A palpable P₂ for detecting severe PH with a mean PAP > 50 mm Hg (studied in patients with mitral stenosis): sensitivity, 96%; specificity, 73%; LR+, 3.6; LR−, 0.05

3. ECG

   1. Expected findings include right axis deviation, right ventricular hypertrophy, and P-pulmonale pattern (right atrial enlargement).

   2. Not sensitive or specific enough to diagnosis PH (sensitivity, 51%; specificity, 86%; LR+, 3.6; LR−, 0.56)

4. Chest film

   1. Expected findings include enlargement of pulmonary arteries and right ventricular enlargement.

   2. Not sensitive or specific enough to diagnose PH (sensitivity, 46%; specificity, 63%; LR+, 1.24; LR–, 0.85)

5. Transthoracic echocardiogram is the best first screening test.

   1. Echocardiogram estimates often correlate fairly well with invasively determined PAPs, but differences of 10–20 mm Hg are common.

   2. Sensitivity ranges from 79% to 100%.

   3. Specificity ranges from 80% to 98%; the specificity may be lower than 50% in patients with mildly elevated PAP on an echocardiogram.

6. Right heart catheterization is the gold standard for diagnosing PH, and most patients with suspected PH need a right heart catheterization to confirm the diagnosis.

Treatment

1. Depends on underlying etiology

2. Correct underlying cause when possible

   1. For obstructive sleep apnea, administer continuous positive airway pressure.

   2. For chronic thromboembolism, begin anticoagulation and consider thromboendarterectomy.

   3. For valvular disease, replace the valve.

   4. For congenital heart disease, repair surgically.

   5. For left ventricular dysfunction, optimize medical regimen.

3. Oxygen therapy for patients with hypoxemia (PO₂ < 55 mm Hg at rest, oxygen saturation < 85% with exercise)

4. Most patients require loop diuretics.

5. Most treatment studies have been performed in patients with PAH.

Alternative Diagnosis: Venous Insufficiency

Textbook Presentation

Venous insufficiency can be asymptomatic or manifested just by small visible, but nonpalpable veins. In more severe cases, the patient has large varicose veins and skin changes ranging from edema to fibrosing panniculitis to ulceration. Symptoms include leg fullness or heaviness, aching leg pain, and nocturnal leg cramps. Symptoms are often worse at the end of the day and in heat, and are sometimes relieved by elevation.

Disease Highlights

1. Anatomy (Figure 17-3)

   1. The superficial saphenous veins join the deep system at the knee (popliteal vein) and the groin (femoral vein).

   2. Perforating veins directly connect the saphenous veins and the deep veins at various points along their parallel courses.

   3. Valves within the veins prevent reflux back toward the feet.

2. Pathophysiology and epidemiology

   1. Chronic venous disease is due to venous hypertension caused by reflux through incompetent valves, venous outflow obstruction, or lack of calf muscle pumping due to obesity or immobility.

      1. Reflux occurs in the superficial system in about 45% of patients, both the superficial and deep systems in about 40%, and in the deep system only in the remainder of patients.

      2. Prolonged standing leads to marked increases in venous pressure in all people; while those with competent valves quickly lower the venous pressure with walking, individuals with incompetent valves have only slight decreases in pressure with walking.

   2. Varicose veins are found in 25–33% of women and 10–20% of men.

   3. Prevalence of skin changes is 3–11%; prevalence of skin ulcers is 0.3–1%.

   4. Risk factors for venous insufficiency include female sex, advancing age, obesity, a history of phlebitis or venous thrombosis, serious leg trauma, pregnancy, prolonged standing, and greater height.

   5. Postthrombotic syndrome (venous insufficiency after a DVT) occurs in 35–69% of patients at 3 years and in 49–100%of patients at 5–10 years; incidence is reduced to 8% if patients are treated with adequate anticoagulation, early mobilization, and long-term use of compression stockings.

3. Classification

   1. Class 1: telangiectasias or reticular veins (nonpalpable subdermal veins up to 4 mm in diameter)

   2. Class 2: varicose veins (palpable, subcutaneous veins > 4 mm in diameter)

   3. Class 3: edema without skin changes

      1. Initially present just at the end of day but can become persistent and massive

      2. Can be unilateral initially

      3. Often begins around medial malleolus

   4. Class 4: skin changes

      1. Pigmentation due to breakdown of extravasated RBCs

      2. Stasis dermatitis: itching, weeping, scaling, erosions, and crusting

      3. Lipodermatosclerosis or fibrosing panniculitis

         • (1) Induration initially at medial ankle, spreading circumferentially round the entire leg, up to mid calf

         • (2) The skin is heavily pigmented and fixed to subcutaneous tissues, with brawny edema above the fibrosis and in the foot below

         • (3) High risk for cellulitis

   5. Classes 5 and 6: healed or nonhealed ulcers

      1. Usually low on the medial ankle or along the path of the long or short saphenous vein

      2. Never above the knee or on the forefoot

      3. Chronic and recurrent, often lasting for months or even years

Evidence-Based Diagnosis

1. Diagnosis is often made based on the appearance of the leg.

2. Venography is the gold standard.

3. Duplex ultrasonography is the best noninvasive test.

   1. Should be done if the diagnosis is in doubt (especially to rule out DVT), in patients with atypical symptoms or presentations, or if surgery is being considered

   2. For diagnosing valvular incompetence, the sensitivity is 84%, specificity is 88%, LR+ = 7, and LR− = 0.18.

   3. For diagnosing severe venous insufficiency, the sensitivity is 77%, specificity is 85%, LR+ = 5.1, and LR− = 0.26.

4. Because many patients have both arterial and venous insufficiency, concurrent arterial disease must be ruled out with the ankle-brachial index.

Treatment

1. Compression stockings are the most important treatment modality.

   1. Have been shown to reduce the risk of postthrombotic syndrome, to accelerate ulcer healing, and to prevent recurrent ulceration

   2. Classified into several grades, based on degree of compression at the ankle

      1. 20–30 mm Hg: for patients with varicose veins, edema, leg fatigue (Classes 2 and 3)

      2. 30–40 mm Hg: for patients with severe varicosities or moderate disease (Classes 4–6)

      3. 40–50 mm Hg: for patients with recurrent ulceration

   3. Knee high stockings are better tolerated than thigh high stockings.

   4. Compliance often poor due to skin irritation, discomfort, and difficulty putting on the stockings.

      Compression stockings should not be used in patients with peripheral arterial disease or with invasive infection at an ulcer site.

   5. Alternative ways to provide compression include elastic wraps and intermittent pneumatic compression pumps.

   6. Ulcers should be covered with a dressing before putting on the compression device.

2. Diuretics are ineffective for the edema unless given with compression therapy.

3. Treatment of venous insufficiency ulcers

   1. Occlusive dressing

   2. Leg elevation and compression

   3. Aspirin, 325 mg daily, might accelerate healing.

   4. Pentoxifylline might accelerate healing.

   5. Topical antibiotics have no role.

   6. Systemic antibiotics indicated only if cellulitis or other invasive infection is present.

4. Interventional therapies

   1. Sclerotherapy for spider veins, venous lakes, varicose veins 1–4 mm in diameter

   2. Endovenous radiofrequency ablation and laser: alternative to vein stripping for great saphenous vein reflux

   3. Iliac vein stenting for venous outflow abnormalities

   4. Vein stripping and ligation

      1. Usually involves removing the saphenous vein with high ligation of the saphenofemoral junction

      2. Shown to result in significant improvement in symptoms in patients with Class 2–6 disease

      3. Surgery plus compression is better than compression alone for preventing ulcer recurrence (12% combined therapy vs. 28% compression alone).

Mrs. K has unilateral limb edema, a key pivotal point limiting the differential. Exploring her history, it is notable that she has chronic lymphedema due to disruption of lymphatic drainage by her previous surgery and radiation therapy. This is an important clinical clue, since patients with lymphatic disruption and lymphedema are at high risk for skin and subcutaneous infections. Pathophysiologically, the edema found in cellulitis is due to a localized increase in capillary permeability due to inflammation; however, patients with underlying limb abnormalities will often present with more diffuse edema. The other primary consideration in any patient with unilateral limb swelling is DVT. Mrs. K has several risk factors for this, including history of cancer, possible venous scarring secondary to radiation, and use of tamoxifen (a drug associated with a relative risk for DVT of about 3). Table 17-8 lists the differential diagnosis.

Always think about DVT in a patient with unilateral limb swelling.

Leading Hypothesis: Cellulitis & Erysipelas

Textbook Presentation

A painful, red, hot, and swollen limb develops acutely in a patient with underlying venous or lymphatic disease.

Disease Highlights

1. Definitions

   1. Cellulitis is an infection of the dermis and subcutaneous tissue.

   2. Erysipelas is a superficial cellulitis with prominent lymphatic involvement.

2. Cellulitis highlights

   1. Risk factors

      1. Edema

      2. Venous insufficiency

      3. Obesity

      4. Diabetes mellitus

      5. History of cellulitis

      6. Injection drug use

      7. Breast cancer treatment

         • (1) Cellulitis of the ipsilateral arm is seen in women in whom lymphedema of the arm develops after mastectomy.

         • (2) Cellulitis of the ipsilateral breast is seen in women in whom localized lymphedema develops after lumpectomy, axillary node dissection, and radiation therapy.

   2. Often an entry site for infection can be identified (leg ulcer, trauma, tinea pedis, eczema, subcutaneous abscess)

   3. Clinical presentation

      1. Presence of systemic symptoms (eg, fever, chills, myalgias) is unusual and suggests concomitant bacteremia or a more serious infection such as necrotizing fasciitis.

      2. Physical findings

         • (1) Nonpalpable, confluent erythema with indistinct margins

         • (2) Generalized swelling

         • (3) Warmth and tenderness of involved skin

         • (4) Tender regional adenopathy sometimes found

         • (5) Lymphangitis and abscess formation sometimes seen

         • (6) In women who have been treated for breast cancer and have arm lymphedema, the humeral area of the ipsilateral extremity is most often involved, with extension to the shoulder and forearm.

         • (7) In breast cellulitis, the infection starts at the lumpectomy site and can extend to the remainder of the breast, the anterior shoulder, back, and ipsilateral upper extremity.

   4. Microbiology

      1. Beta-hemolytic streptococci and Staphylococcus aureus are the most common organisms; S aureus is the more likely cause if there is an abscess or drainage, and streptococci are more likely if there is no abscess or drainage.

         • (1) Community-acquired methicillin-resistant S aureus (CA-MRSA), usually the USA300 genotype, is increasingly common; it is now the most common pathogen cultured from skin and soft tissue infections in urban emergency departments.

         • (2) Risk factors for MRSA

           • (a) Recent antibiotic use or hospitalization

           • (b) Recurrent needle sticks (injection drug use, hemodialysis, insulin use)

           • (c) Homelessness, incarceration

           • (d) Contact sports

           • (e) Patients with a previous CA-MRSA infection or colonization

         • (3) Many patients with CA-MRSA have none of these risk factors

         • (4) Skin abscesses, often with central necrosis, are a very common manifestation of CA-MRSA; patients often think they have been bitten by a spider or other insect.

         • (5) Other manifestations include cellulitis, necrotizing pneumonia, pleural empyema, necrotizing fasciitis, septic thrombophlebitis, myositis, and severe sepsis.

      2. A variety of other organisms may be seen with specific exposures or sites of infection (Table 17-9).

3. Erysipelas highlights

   1. Risk factors for development of erysipelas

      1. Similar to those for cellulitis

      2. Lymphedema and an identified portal of entry (primarily tinea pedis) are the 2 strongest risk factors in 1 study.

         Always treat tinea pedis in a patient with cellulitis, erysipelas, or risk factors for developing those infections.

   2. Clinical presentation

      1. Sudden onset of fever (85% of patients), erythema, edema, and pain

      2. Physical findings

         • (1) Palpable plaque of erythema that extends by 2–10 cm/day

         • (2) Sharply demarcated border

         • (3) Leg is the most common site (90%), then the arm (5%), and then the face (2.5%).

         • (4) Regional adenopathy and lymphangitis sometimes seen

      3. Recurrence rate of 10% at 6 months and 30% at 3 years is usually due to untreated local factors.

      4. Patients should respond to antibiotic therapy in 24–72 hours.

   3. Microbiology

      1. Streptococci are the causative organisms in 90% of cases (group A in about 58–67% of cases caused by streptococci, group B in 3–9%, and group C or G in 14–25%).

      2. S aureus is also found in 10% of cases, although it is unclear whether it is contributing to the infection or just colonizing.

         Consider necrotizing fasciitis in patients with a rapid increase in the size of the infected area, evolution of violaceous bullae, a reddish-purple discoloration of the skin, woody induration of the infected area, disproportionally severe pain or tenderness, severe systemic toxicity.

Evidence-Based Diagnosis

1. Both cellulitis and erysipelas are clinical diagnoses.

2. Blood cultures are positive in 2–5% of patients.

3. Skin biopsy cultures are positive in 5–40% of patients but are rarely necessary.

4. Aspiration of the leading edge of erythema is sometimes done, but the yield is low.

5. Toe web cultures are sometimes helpful in patients with tinea pedis.

6. If there is a skin abscess associated with the cellulitis, it should be drained and the fluid cultured.

7. CT or MRI should be done if necrotizing fasciitis is suspected; MRI is more sensitive, but CT is more specific.

   Cultures are rarely helpful in cellulitis or erysipelas without an associated abscess.

Treatment

1. Cellulitis (2011 Infectious Disease Society of American Guidelines)

   1. Outpatients with purulent cellulitis (associated with purulent drainage or exudate but no drainable abscess): empiric treatment for CA-MRSA with clindamycin, trimethoprim-sulfamethoxazole (TMP-SMX), doxycycline, or linezolid for 5–10 days

   2. Outpatients with nonpurulent cellulitis (no exudate or drainage; no abscess): empiric treatment for beta-hemolytic streptococci with a beta-lactam (cephalexin, amoxicillin, or similar drugs) for 5–10 days

      1. Patients who do not respond should be treated for CA-MRSA.

      2. To treat for both CA-MRSA and beta-hemolytic streptococci, use clindamycin, TMP-SMX (or doxycycline) and a beta-lactam, or linezolid.

   3. 10–20% of MRSA isolates that are sensitive to clindamycin, but resistant to erythromycin, develop inducible clindamycin resistance due to the presence of the erm gene.

   4. Clindamycin sensitive/erythromycin resistant isolates should undergo the “D-Zone Test” to look for inducible resistance (Figure 17-4).

2. Erysipelas

   1. Penicillin G or amoxicillin is effective in > 80% of patients with erysipelas.

   2. Other drugs that have been studied include macrolides and fluoroquinolones.

   3. Should treat for 10–20 days

3. Uncomplicated, slowly progressive infection in a well-appearing patient can be treated with oral antibiotics if

   1. The patient has no GI upset

   2. The limb can be elevated

   3. Serial exams are feasible

4. Patients who appear ill, who have rapidly progressive infection, are immunocompromised, or who might not be able to follow treatment instructions should be admitted for IV antibiotics, generally including either vancomycin, clindamycin, linezolid, or daptomycin.

5. Obtain infectious disease and surgical consultations for patients with rapidly progressive infections, especially if progression occurs while they are receiving appropriate antibiotics and those in whom necrotizing fasciitis is suspected.

Alternative Diagnosis: Upper Extremity DVT (UEDVT)

Textbook Presentation

Patients can be asymptomatic, but generally arm, shoulder, or neck discomfort or fullness as well as arm swelling are the presenting symptoms.

Disease Highlights

1. Classification

   1. Primary UEDVT (20% of cases)

      1. Idiopathic

      2. Effort thrombosis, also known as Paget-Schroetter syndrome

         • (1) Occurs in young men after strenuous exercise, which causes microtrauma to the veins

         • (2) Narrowing of the thoracic outlet at the level of the first rib and clavicle leads to compression of the subclavian vein

   2. Secondary UEDVT (80% of cases) (Table 17-10)

      1. Indwelling central venous catheter–associated UEDVT (up to 70% of cases)

         • (1) UEDVT occurs more often with large catheters than with smaller ones.

         • (2) Risk increases with duration of catheter use, being negligible within 6 days and increasing significantly after 2 weeks.

         • (3) Risk is higher with polyvinyl chloride-coated catheters than with silicone ones.

         • (4) One study found that the risk is about 2.5 times higher with peripherally inserted central catheters than with other central venous catheters.

      2. Malignancy (> 40% of cases): patients with cancer and an indwelling catheter are at especially high risk.

      3. Hypercoagulable states

      4. Other miscellaneous causes (surgery, infection, immobility, concurrent lower extremity DVT)

2. Sites

   1. Subclavian in 18–69% of cases

   2. Axillary in 5–42% of cases

   3. Internal jugular in 8–29% of cases

   4. Brachial in 4–13% of cases

   5. Multiple veins are often involved, but bilateral UEDVT is rare.

3. Clinical features

   1. Pain is present in ~40% of patients.

   2. Edema is present ~80% of patients in some series, but patients with catheter-related UEDVT often do not have edema.

   3. Patients may note numbness, heaviness, paresthesias, pruritus, and coldness.

   4. Dilated cutaneous veins sometimes visible.

4. Complications

   1. Pulmonary embolism has been reported to occur in up to 36% of cases and is more often seen with secondary UEDVT, especially catheter-related; however, more recent studies have found a much lower rate of pulmonary embolism.

      UEDVT can cause pulmonary embolism.

   2. Recurrent thrombosis occurs in up to 10% of patients.

   3. Postthrombotic syndrome is seen in up to 4–34% of patients in different series.

Evidence-Based Diagnosis

1. Venography is the gold standard.

2. Duplex ultrasonography is the most commonly used noninvasive test.

   1. Disadvantages include a blind spot caused by the clavicle, inability to determine compressibility in veins located in the thoracic cavity, and difficulties interpreting the study if there are collateral veins.

   2. Test characteristics come from two small, low quality studies: sensitivity 97%; specificity 94%; LR+, 16.2; LR–, 0.03

3. The test characteristics of D-dimer for the diagnosis of UEDVT are not known.

4. Magnetic resonance and CT venography are sometimes done; sensitivity and specificity are unknown.

5. The American College of Chest Physicians 2012 Guidelines recommend the following diagnostic approach:

   1. Initial evaluation with duplex ultrasound

   2. Follow up testing with a highly sensitive D-dimer or venography (CT, MR, or conventional) in patients with a normal ultrasound and a high clinical suspicion.

   3. No further testing in patients with negative follow up testing

Treatment

1. Anticoagulation with heparin, followed by at least 3 months of warfarin; patients with cancer or chronic indwelling central venous catheters should receive anticoagulation therapy indefinitely.

2. Thrombolysis with or without stent placement is sometimes done, especially in patients who require permanent indwelling catheters.