Libman-Sacks endocarditis

Libman-Sacks endocarditis
ICD-10	I39, M32.1
ICD-9	710.0
DiseasesDB	29254
eMedicine	med/1295
MeSH	D008180

Template:Search infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2]

Synonyms and keywords: Nonbacterial thrombotic endocarditis (NBTE), Marantic endocarditis, Verrucous endocarditis

Overview

Libman-Sacks endocarditis (LSE) is a form of nonbacterial thrombotic endocarditis (NBTE) that is considered to be the most common cardiac manifestation seen in patients with systemic lupus erythematosus. LSE is a term used for sterile and verrucous vegetations around the heart valves mostly affecting the mitral and aortic heart valves but other valves may also be involved. Valvular involvement in LSE may lead to valvular regurgitation, aortic insufficiency, thromboembolic cerebrovascular events, and increased risk of infective endocarditis. It is also usually associated with the other autoimmune diseases such as antiphospholipid syndrome (APS) and some malignancies. Secondary APS has a higher rate of cardiac involvement as compared to primary APS, mostly due to the autoimmune causes related to the SLE. LSE can be complicated by embolic cerebrovascular disease, superimposed infective endocarditis, and peripheral arterial embolism. It is also associated with increased mortality, hence, early recognition of LSE and appropriate treatment are of significant importance in preventing any further complications.

Historical Perspective

• In 1888, Zeigler was the first one to describe NBTE, and called it "thromboendocarditis" at that time.
• In 1924, the two American physicians Emanuel Libman, and Benjamin Sacks, working at Mount Sinai Hospital, New York, described the Libman-Sacks endocarditis for the first time, hence, it's named after them. They first presented the complete clinical picture of it with or without skin lesions and described it as unusual non-bacterial endocarditis with verrucous vegetations adherent to the endocardium.
• In 1936, Gross and Friedberg finally coined the term "nonbacterial thrombotic endocarditis" (NBTE) for marantic/verrucous endocarditis.
• In 1983, Graham Hughes described the antiphospholipid antibody syndrome for the first time while working as a rheumatologist at St Thomas Hospital. He named it anticardiolipin syndrome (also known as Hughes syndrome named after him) and described it has the following three characteristics:
  • Venous and/or arterial thrombosis
  • Recurrent pregnancy loss
  • Presence of antiphospholipid antibodies
• In 1985, the association between Libman-Sacks endocarditis and antiphospholipid antibody syndrome was noted for the first time.

Pathophysiology

Pathology

• The pathology of Libman-Sacks endocarditis is the same as nonbacterial thrombotic endocarditis except that focal necrosis (seen in the form of hematoxylin bodies) can be found only in Libman-Sacks endocarditis.
• Just like NBTE, Libman-Sacks endocarditis develops due to the endothelial damage and subsequent exposure of the subendothelial connective tissue to the circulating platelets.
• The factors involved in the pathogenesis can be divided into the ones initiating the Libman-Sacks endocarditis and the subsequent development of vegetations.

Factors responsible for the initiation of Libman-Sacks endocarditis

Initiation factor	Description
Immune complexes	Libman-Sacks endocarditis is especially a prototype
Hypoxia	It was studied by Nakanishi et al in a rodent model
Hypercoagubility	Trousseau was the first one to note the association between thrombosis and malignancy Histological evidence of disseminated intravascular coagulopathy (DIC) is also found in the 50% of patients with NBTE
Carcinomatosis	Following carcinomas are commonly associated with NBTE and Libman-Sacks endocarditis: Mucin producing adenocarcinoma of: GIT Ovaries Lungs Acute promyelocytic leukemia

• The vegetations in Libman-Sacks endocarditis are formed from the strands consisting of following 4 components:
  • Fibrin
  • Neutrophils
  • Lymphocytes
  • Histiocytes
• Most commonly affected valve is the mitral valve with the vegetations involving the ventricular and atrial surface of the valve.
• The lesions of Libman-Sacks endocarditis rarely lead to any significant valvular dysfunction and they only rarely embolize.

Gross pathology

NBTE vegetations are typically small, friable, white or tan masses, < 1 cm in diameter, broad based and irregular, usually along lines of valve closure on leaflets which may be normal or previously damaged Vary from tiny lesions to large and exuberant masses Based on morphology, Allen and Sirota proposed a macroscopic classification of NBTE: Type 1: Small, < 3 mm univerrucal, firmly attached to the valve Type 2: Large, > 3mm univerrucal, adherent to the valve Type 3: Small, 1 - 3mm multiverrucal, friable

Microscopic Pathology

NBTE consists of degenerating platelets interwoven with strands of fibrin and forming a bland, featureless eosinophilic mass except for a few trapped leucocytes Three stages have been described in the evolution of NBTE vegetations: (eMedicine: Libman-Sacks Endocarditis Workup [Accessed 28 February 2018]) Active verrucae: Consist of clumps of fibrin on and within the valvular leaflet tissue which is focally necrotic, with plasma cells and lymphocytes Combined active and healed lesions: Contain vascularized, fibrous tissue adjacent to fibrinous and necrotic areas Healed lesions: Consist of dense, vascularized, fibrous tissue

Epidemiology and Demographics

• Approximately 1 out of 10 SLE patients have vegetations associated with Libman-Sacks endocarditis. Presence of these vegetations is indicative of the association with the following:
  • Lupus duration
  • Disease activity
  • Anticardiolipin antibodies
  • APS manifestations
• There's a variable incidence of positive findings on transthoracic echocardiography.
• Higher incidence of detection of positive findings is shown with transesophageal echocardiography and especially with higher frequency with positive antiphospholipid antibodies.
• Thickening of the leaflets is more common as compared to finding vegetations.
• Positive findings on echocardiography are found in approximately one-third of the patients with antiphospholipid antibody syndrome.
• These positive findings are five to nine times more frequently found in women than men.
• Libman-sacks endocarditis typically occurs in young women, however, children can be rarely involved.
• Nonbacterial thrombotic endocarditis (NBTE) is a rare condition which is most often found during 0.9% to 1.6% of the postmortem studies.

• NBTE affects every age group but most commonly involves patients between the fourth and eighth decades of life with no sex predilection.
• NBTE most commonly affects patients with systemic lupus erythematosus and advanced malignancy.
• According to one autopsy study, patients with underlying malignancy have a higher rate (1.25%) of NBTE as compared to general population (0.2%).
• NBTE is found at higher rates in patients with adenocarcinoma (e.g., lung, colon, ovary, biliary and prostate) (2.7%) as compared to other malignancies (0.47%), with the highest rates observed in patients with mucin-secreting and pancreatic adenocarcinoma (10%).
• Observational studies in patients with systemic lupus erythematosus have reported 6% to 11% prevalence rates with transthoracic echocardiography, with higher rates (43%) observed with more sensitive transesophageal echocardiography.

Risk Factors

• Advanced stage malignancy: solid organ or hematological
• Chronic diseases: tuberculosis, uremia, AIDS
• Connective tissue disorders with hypercoaguable state: SLE patients with APLA positive
• Trauma from indwelling pulmonary catheter or central venous catheter, snake bite, late effect of radiation therapy

Natural History, Complications and Prognosis

Complications

• Systemic emboli may occur in Libman-Sacks endocarditis but not very commonly with the risk being much higher with mitral stenosis and subsequent atrial fibrillation.
• It is difficult to predict the underlying etiology in case of a stroke occurrence in LSE, whether it is due to systemic emboli or the underlying pathology of SLE or APS.
• Valvular disease in LSE can lead to the heart failure.
• There's 1% to 2% chance of congenital heart block (usually complete,or 1st or 2nd degree) in a baby of mother with SLE associated with anti-Ro/SS-A (Sjögren's syndrome antigen A) autoantibodies with a 16% recurrence rate. Fluorinated steroids that do not cross the placenta may be beneficial in preventing the congenital heart block.

Prognosis

• All of the SLE patients have got a shorter life span.
• The occurrence of cardiovascular events is the major cause of mortality in SLE patients as SLE is a risk factor for premature & accelerated coronary atherosclerosis and CAD (coronary artery disease) due to the following associated factors:
  • Hypertension
  • Hyperlipidemia
  • Chronic inflammation
  • Chronic glucocorticoids use

Diagnosis

• Requires a high degree of clinical suspicion in a patient treated for infective endocarditis (IE) and not clinically improving
• Mckay and Wahler proposed a triad for diagnosis of NBTE:
  • Presence of a disease process known to be associated with NBTE
  • Presence of heart murmur and
  • Evidence of multiple systemic emboli

History and symptoms

• Mostly patients with Libman-Sacks endocarditis are asymptomatic.
• There may be the features of valvular disease if valves are severely affected with the mitral valve disease being more common than the aortic valve disease.
• Valvular regurgitation is more frequent than the valvular stenosis.
• Unusually, the tricuspid or pulmonary valves are involved.
• Systemic embolism may also occur with the effects depending upon the destination of the emboli with the brain and kidneys being more likely involved.
• Emboli can also lead to the blockage of peripheral circulation.
• The vegetations in Libman-Sacks endocarditis are mostly sterile but secondary infective endocarditis can also occur.
• There may or may not be the typical SLE features with the characteristic butterfly rash, fever, and arthritis or the APS features, including recurrent miscarriages.
• There are no pathognomonic signs and symptoms that allow for the confident diagnosis of NBTE

Patients can present with:

• Cardiac failure
  • Secondary to valvular dysfunction (most commonly mitral regurgitation), leading to dyspnea, orthopnea, paroxysmal nocturnal dyspnea, peripheral edema, lethargy
• Cerebrovascular embolism
  • Focal weakness or numbness, visual loss, dysphasia, dysarthria, dysphagia, memory loss
• Systemic thromboembolism
  • Pain, coldness and numbness of the peripheries, or acute abdominal syndromes with pain and vomiting
• Secondary infective endocarditis
  • Fever, weight loss, night sweats, lethargy, chest pain

Physical Examination

• A patient of Libman-Sacks endocarditis can present with any of the following signs and symptoms:
  • Left ventricular hypertrophy causing displacement of the apex beat
  • Congestive heart failure physical exam findings
  • Infective endocarditis findings
  • Mitral valve disease findings
  • Aortic valve disease findings

Laboratory findings

Laboratory Investigations in Libman-Sacks Endocarditis	Laboratory test findings
Blood culture	It is important to rule out the coexisting infective endocarditis and other infectious etiologies by taking multiple blood cultures.
SLE investigations (Immunological assays)	Investigations for SLE are positive including: Antinuclear antibodies (SLE screening) Anti-dsDNA antibodies (SLE confirmation and to monitor the progress of disease and lupus nephritis) Anti-Smith antibodies Anti-RNP Antiphospholipid antibodies Anticardiolipin antibodies (associated with an increased risk of cardiac abnormalities) Anti-Ro/SSA Anti-La/SSB False-positive serology in the form of VDRL is also common in SLE
CBC	CBC may show: Neutrophilia Anemia
Studies to rule out DIC	Prothrombin time Partial thromboplastin time Fibrinogen Thrombin time D-dimer Cross-linked fibrin degradation products
Polymerase chain reaction (PCR)	PCR is a rapid and reliable method to detect the culture-negative endocarditis by fastidious organisms.

Imaging findings

Imaging tests in Libman-Sacks Endocarditis	Imagining Findings
Echocardiography	Echocardiography is the key diagnostic test for Libman-Sacks endocarditis (although it doesn't detect all the lesions). Transesophageal echocardiography is superior to transthoracic echocardiography but it is an invasive procedure. As Libman-Sacks endocarditis is commonly complicated by embolic cerebrovascular disease, hence, accurate detection of its vegetations may lead to early therapy and prevention of the associated complications. Although the two-dimensional transesophageal echocardiography (2D-TEE) has a higher diagnostic value for the detection of Libman-Sacks vegetations, but the three-dimensional TEE (3D-TEE) has the following benefits over 2D-TEE: Improved detection Improved characterization & Improved clinical correlations of Libman-Sacks vegetations Provides clinically relevant additive information complementing the 2D-TEE for the characterization, detection, and association with the cerebrovascular disease of Libman-Sacks endocarditis.
Chest X-Ray	CXR may show any of the following findings: Cardiomegaly Pulmonary congestion (in case of severe disease) Calcification of the lesions (uncommon)

Other Diagnostic studies

Cardiac Catheterization

• In case of severe valvular disease, cardiac catheterization may be required with a view to valve replacement.

Treatment

• There is no specific treatment for Libman-Sacks endocarditis.
• Steroids and immunosuppressive agents are useful in the treatment of the underlying disease but there is some controversy about their role in the pathogenesis of vegetations:
  • Compared with reports of postmortems on patients before the advent of steroids, those that have been treated have smaller and fewer lesions, mostly on one valve and usually confined to the left side.
  • Hypertension was 5 times as common and congestive heart failure was 8 times as common as in the days before corticosteroids. The steroids may be directly responsible for hypertension and heart failure. This paper was from 1975 and it is possible that better control of hypertension and heart failure may offset these problems today.
  • Expert opinion seems to conclude that steroids are detrimental to Libman-Sacks endocarditis although some praise them. The situation is far from certain.
• Advice for procedures creating a risk of infective endocarditis can be found in the separate record Prevention of Endocarditis.
• If there are systemic emboli then anticoagulation with warfarin is beneficial but the possible role of aspirin has not been adequately investigated. If there is evidence of 1 cerebrovascular event, anticoagulation is advised.
• In serious valve disease it may be necessary to replace valves. Mechanical valves may be more susceptible to thromboemboli but it is uncertain if bioprosthetic valves are at risk of the disease. The operative mortality of mitral valve replacement in this condition may be as high as 25%.

Treatment is difficult - correction of the underlying cause is of paramount importance In patients with potentially curable cancer, coagulopathy should be corrected and, if there is no contraindication, these patients should be anticoagulated with heparin There are no guidelines for surgical intervention in patients with NBTE - decision is based upon individual case

Differential Diagnosis

Libman-Sacks endocarditis should be differentiated from other diseases presenting with fever, chest pain and anorexia. The differentials include the following:

• Nonbacterial thrombotic endocarditis (Marantic endocarditis)
• Vasculitis
• Temporal arteritis
• Myocardial abscess
• Connective tissue disease
• Fever of unknown origin (FUO)
• Intra-abdominal infections
• Septic pulmonary infarction

Diseases	Diagnostic tests			Physical Examination			Symptoms							Past medical history	Other Findings
	CT scan and MRI	EKG	Chest X-ray	Tachypnea	Tachycardia	Fever	Chest Pain	Hemoptysis	Dyspnea on Exertion	Wheezing	Chest Tenderness	Nasalopharyngeal Ulceration	Carotid Bruit
Pulmonary embolism	On CT angiography: Intra-luminal filling defect On MRI: Narrowing of involved vessel No contrast seen distal to obstruction Polo-mint sign (partial filling defect surrounded by contrast)	S1Q3T3 pattern representing acute right heart strain	Fleischner sign (enlarged pulmonary artery), Hampton hump, Westermark's sign	✔	✔	✔ (Low grade)	✔	✔ (In case of massive PE)	✔	-	-	-	-	Hypercoagulating conditions (Factor V Leiden, thrombophilia, deep vein thrombosis, immobilization, malignancy, pregnancy)	May be associated with metabolic alkalosis and syncope
Infective Endocarditis		Goldberg's criteria may aid in diagnosis of left ventricular dysfunction: (High specificity) SV1 or SV2 + RV5 or RV6 ≥3.5 mV Total QRS amplitude in each of the limb leads ≤0.8 mV R/S ratio <1 in lead V4		✔	✔	✔	-	-	✔	-	-	-	-	Previous myocardial infarction Hypertension (systemic and pulmonary) Cardiac arrythmias Viral infections (myocarditis) Congenital heart defects	Right heart failure associated with: Hepatomegaly Positive hepato-jugular reflex Increased jugular venous pressure Peripheral edema Left heart failure associated with: Pulmonary edema Eventual right heart failure
Non-Bacterial Thrombotic Endocarditis		ST elevation PR depression		✔	✔	✔ (Low grade)	✔ (Relieved by sitting up and leaning forward)	-	✔	-	-	-	-	Infections: Viral (Coxsackie virus, Herpes virus, Mumps virus, HIV) Bacteria (Mycobacterium tuberculosis-common in developing countries) Fungal (Histoplasmosis) Idiopathic in a large number of cases Autoimmune Uremia Malignancy Previous myocardial infarction	May be clinically classified into: Acute (< 6 weeks) Sub-acute (6 weeks - 6 months) Chronic (> 6 months)
Libman Sack Endocarditis		Prolonged PR interval Transient T wave inversions		✔	✔	✔	✔	-	✔	✔	-	-	-	Ill-contact Travelling Smoking Diabetic Recent hospitalization Chronic obstructive pulmonary disease	Requires sputum stain and culture for diagnosis Empiric management usually started before culture results
Vasculitis	On CT scan: (Takayasu arteritis) Vessel wall thickening Luminal narrowing of pulmonary artery Masses or nodules (ANCA-associated granulomatous vasculitis) On MRI: Homogeneous, circumferential vessel wall swelling	Right or left bundle-branch block (Churg-Strauss syndrome) Atrial fibrillation (Churg-Strauss syndrome) Non-specific ST segment and T wave changes	Nodules Cavitation	✔	✔	✔	✔	✔	✔	-	✔	✔	✔	Takayasu arteritis usually found in persons aged 4-60 years with a mean of 30 Giant-cell arteritis usually occurrs in persons aged > 60 years Churg-Strauss syndrome may present with asthma, sinusitis, transient pulmonary infiltrates and neuropathy alongwith cardiac involvement Granulomatous vasculitides may present with nephritis and upper airway (nasopharyngeal) destruction
Fever of unknown origin (FUO)		Multifocal atrial tachycardia (atleast 3 distinct P wave morphologies)		✔	✔	-	-	-	✔	✔	-	-	-	Smoking Alpha-1 antitrypsin deficiency Increased sputum production (chronic bronchitis) Cough	Alpha 1 antitrypsin deficiency may be associated with hepatomegaly

References

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