Libman-Sacks endocarditis

Libman-Sacks endocarditis Microchapters
Overview
Historical Perspective
Pathophysiology
Epidemiology and Demographics
Risk Factors
Natural History, Complications and Prognosis
Diagnosis
History and Symptoms
Physical Examination
Laboratory Findings
Imaging Findings
Other Diagnostic Studies
Treatment
Differentiating Libman-Sacks Endocarditis from other Diseases

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.
• In 1989, four groups highlighted a probable role of antiphospholipid antibodies in the pathogenesis of valvular heart disease in SLE patients.

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) is only found in Libman-Sacks endocarditis.
• Just like NBTE, Libman-Sacks endocarditis develops due to the endothelial damage and subsequent exposure of the sub-endothelial 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 to be one of the factors in a rodent model.
Hypercoagulability	Trousseau was the first one to note the association between thrombosis and malignancy. Histological evidence of disseminated intravascular coagulation (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 adenocarcinomas of: GIT Ovaries Lungs Acute promyelocytic leukemia

• The vegetations in Libman-Sacks endocarditis are formed from the strands consisting of the following four 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

• Vegetations in Libman-Sacks endocarditis have the following typical features:
  • Small
  • Friable
  • White or tan masses
  • < 1 cm in diameter
  • Irregular
  • Broad based
  • Usually involve the lines along the valve closure on leaflets (which may be normal or previously damaged)
  • Vary from tiny lesions to large, exuberant masses

Allen and Sirota macroscopic classification of NBTE

Type of NBTE	Features
Type 1	Small < 3 mm Univerrucal Firmly attached to the valve
Type 2	Large > 3 mm Univerrucal Adherent to the valve
Type 3	Small 1 - 3 mm Multiverrucal Friable

Libman Sacks Endocarditis. The presence of vegetations predisposes patients to bacterial endocarditis. Source: Brigden et al,1960.

Libman-Sacks endocarditis. Source: Kumar et al, 2010/Courtesy Dr. Fred Schoen, Department of Pathology, Brigham and Women's Hospital

Microscopic Pathology

• Vegetations in Libman-Sacks endocarditis consist of degenerating platelets interwoven with the fibrin strands and form a bland, featureless eosinophilic mass except for a few trapped leukocytes.
• Following three stages have been described in the evolution of vegetations in Libman-Sacks endocarditis:

Stages of evolution of vegetations in Libman-Sacks endocarditis

Stage	Description
Stage 1 (active verrucae)	Consists of fibrin clumps on and within the valvular leaflet tissue (focally necrotic), along with plasma cells and lymphocytes.
Stage 2 (Combined active and healed lesions)	Contains fibrous, vascularized tissue adjacent to necrotic and fibrinous areas.
Stage 3 (Healed lesions)	Consists of dense, fibrous, and vascularized tissue.

Pathology slide of mitral valve vegetation. Lots of necrosis: 10 cm circumference vegetation. Mitral valve tissue shows focal necrosis. No bacterial or fungal organisms were present. Source: Ghulam Murtaza. et al, Department of Internal Medicine, Advocate Christ Medical Center, Oak Lawn, IL, USA

R lung, high power: emboli and large necrotic infarcted tissue. Source: Ghulam Murtaza. et al, Department of Internal Medicine, Advocate Christ Medical Center, Oak Lawn, IL, USA

Low power of the liver: lots of steatosis and congestion, necrosis. Source: Ghulam Murtaza. et al, Department of Internal Medicine, Advocate Christ Medical Center, Oak Lawn, IL, USA

High power pathology slide of the liver showing lots of steatosis, congestion, and necrosis. Source: Ghulam Murtaza. et al, Department of Internal Medicine, Advocate Christ Medical Center, Oak Lawn, IL, USA

Low power pathology slide of the lung showing emboli and necrotic tissue.Source: Ghulam Murtaza. et al, Department of Internal Medicine, Advocate Christ Medical Center, Oak Lawn, IL, USA

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

• Following table shows important risk factors for the development of Libman-Sacks endocarditis:

Risk factors for the development of Libman-Sacks endocarditis

Risk factor	Details
Advanced stage malignancy	Advanced stage malignancies such as: Solid organ malignancy Hematological malignancy
Chronic diseases	Chronic diseases such as: Tuberculosis AIDS Uremia
Connective tissue disorders with hypercoagulable state	SLE patients who are positive for antiphospholipid antibodies.
Trauma	Trauma due to: Indwelling pulmonary catheter Central venous catheter Late effect of radiation therapy Snake bite

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.
• Double-valve Libman-Sacks endocarditis involving both mitral and aortic valves can lead to ventricular fibrillation and cardiac arrest.
• 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

• Diagnosis of Libman-Sacks endocarditis requires a high degree of clinical suspicion especially in patients who don't improve clinically after being treated for infective endocarditis.
• Mckay and Wahler proposed the following triad for the diagnosis of NBTE:

Mckay and Wahler triad for diagnosis of NBTE
1:	Presence of a disease process known to be associated with NBTE
2:	Presence of heart murmur
3:	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.

Common manifestations of patients with Libman-Sacks endocarditis

Manifestation	Description
Heart failure	Heart failure can occur secondary to the valvular dysfunction (most commonly mitral regurgitation), leading to the following signs and symptoms: Dyspnea Orthopnea Paroxysmal nocturnal dyspnea Peripheral edema Lethargy
Cerebrovascular embolism	Cerebrovascular embolism can present as any of the following: Focal weakness Focal numbness Memory loss Vision loss Dysphagia Dysphasia Dysarthria Seizures
Systemic thromboembolism	Systemic thromboembolism can cause any of the following: Pain Peripheral coldness Peripheral numbness Acute abdominal syndromes causing: Abdominal pain Vomiting Left upper quadrant pain (due to splenic infarct from embolization) Flank pain ( due to embolus to the kidney)
Secondary infective endocarditis	Secondary infective endocarditis can present as: Fever Night sweats Weight loss Lethargy Chest pain

Physical Examination

• A patient of Libman-Sacks endocarditis can present with any of the signs and symptoms shown in the following table:

Physical examination findings in a patient of Libman-Sacks endocarditis

Pathology	Physical examination finding
Left ventricular hypertrophy	LVH can present as any of the following: Displacement of apex beat Enlarged and sustained apical impulse S4 S2 (due to aortic root dilatation) ECG findings of LVH include: Increased QRS voltage Increased QRS duration (widened QRS associated with complete or incomplete LBBB) Left axis deviation (horizontal/frankly leftward (≥-30º) QRS axis in the frontal plane leads or normal/vertical axis) Right axis deviation Repolarization abnormalities such as ST depressions and T wave inversions in leads with relatively tall R waves (referred to as LV "strain" pattern or "LVH with associated ST-T wave abnormalities") Prominent positive T waves in the lateral chest leads Left atrial abnormality has the following two important major presentations: Increased duration of P waves (≥120 milliseconds) in the limb leads Biphasic P waves with a prominent negative (terminal) component (≥40 milliseconds in duration and/or ≥1 mV in depth) in V1
Congestive heart failure	Physical examination findings of CHF include: Dyspnea Orthopnea Paroxysmal nocturnal dyspnea Peripheral edema Lethargy Rales on lung examination
Infective endocarditis (IE)	IE can present as: Fever Rigors Night sweats Headache Myalgias Anorexia Malaise Shortness of breath Cough Joint pains Presence of a new or changing heart murmur in 80% to 85% of patients (due to aortic insufficiency, tricuspid regurgitation or mitral regurgitation) Widened pulse pressure (due to aortic insufficiency) Petechiae (10% to 40% of patients) Osler's nodes (7% to 10% of patients) Janeway lesions (6% to 10% of patients) Splinter hemorrhages (5% to 15% of patients) Evidence of embolization Conjunctival hemorrhage Roth's spots in retina Poor oral hygiene Teeth might have periodontitis, plaque or calculus Gingivitis Splenomegaly (15% to 30% patients) Left upper quadrant pain (due to splenic infarct from embolization) Flank pain (due to embolus to the kidney) Stroke and focal neurologic findings (due to septic emboli) Seizures Intracranial hemorrhage Signs of a brain abscess Gangrene of fingers Back pain (due to vertebral osteomyelitis)
Mitral valve disease	High-pitched “blowing” holosystolic murmur of mitral regurgitation (more common) which is best heard at the apex of the heart with the patient in left lateral decubitus position. Mid-diastolic, rumbling murmur of mitral stenosis (with or without an Austin Flint murmur).
Aortic valve disease	Early diastolic murmur of aortic regurgitation Widened pulse pressure due to aortic insufficiency Bobbing of the uvula (new-onset aortic regurgitation)
Tricuspid valve disease	Holosystolic murmur of tricuspid regurgitation

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. 2D transesophageal ultrasound. Image on the left shows a thickened mitral valve with a 1 cm vegetation that can be seen on the anterior mitral leaflet. Image on the right is a four-chamber color flow Doppler view showing biventricular dilatation, severe left ventricular dysfunction. For orientation purposes, left ventricle is the bottom right chamber. Video of both views is attached as a supplementary file. Source: Ghulam Murtaza. et al, Department of Internal Medicine, Advocate Christ Medical Center, Oak Lawn, IL, USA
Chest X-Ray	CXR may show any of the following findings: Cardiomegaly Pulmonary congestion (in case of severe disease) Calcification of the lesions (uncommon)
MRI	According to the ongoing current studies, 4D-flow MRI imaging is considered as a promising useful noninvasive tool compared to the traditional TEE for evaluating the following: Abnormal flow patterns Ventricular dimensions Stroke volume Regional myocardial function MRI of the brain. Images on the top show increased signal on diffusion weighted imaging (DWI) throughout the bilateral frontal, parietal, and occipital lobes. Images on the bottom show a corresponding decreased signal intensity on apparent diffusion coefficient that is consistent with acute abnormal restricted diffusion. These findings suggest new/ongoing acute infarcts.Source: Ghulam Murtaza. et al, Department of Internal Medicine, Advocate Christ Medical Center, Oak Lawn, IL, USA
CT scan (Head)	In patients with cerebrovascular emboli, CT scan of the head without contrast may show extensive multifocal hypoattenuating areas in the involved region as shown in the image below: CT of head without contrast showing extensive multifocal areas of hypoattentuation throughout the bilateral frontal, parietal, occipital, and right > left temporal lobes. No mass effect or midline shift or hemorrhage was seen.Source: Ghulam Murtaza. et al, Department of Internal Medicine, Advocate Christ Medical Center, Oak Lawn, IL, USA

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.
• Treatment of LSE is quite difficult with the main focus being on the correction of the underlying cause.

Common treatment options for Libman-Sacks endocarditis depending on the underlying cause

Treatment option	Details
Steroids and immunosuppressive agents	They are useful in the treatment of underlying disease but they have a controversial role in the pathogenesis of vegetations: Patients treated with steroids have smaller and fewer lesions (mostly on one valve and usually confined to the left side) as compared to the postmortem reports of patients before the advent of steroids. The use of corticosteroids has also lead to the 5 times decline in hypertension and 8 times decline in congestive heart failure rates in the patients of Libman-Sacks endocarditis.
Anticoagulants	In the case of systemic emboli, anticoagulation with warfarin is beneficial. Anticoagulation is advised if there is evidence of one cerebrovascular event. Patients with a potentially curable cancer, coagulopathy should be corrected with heparin (if there is no contraindication).
Other medications	Vasodilators Beta-blockers Diuretics Digoxin
Valve replacement	Valve replacement surgery is done in case of severe valvular disease. Mechanical valves may be more susceptible to thromboemboli as compared to bioprosthetic valves. Mitral valve replacement surgery has an operative mortality of as high as 25% in patients with Libman-Sacks endocarditis.

Differentiating Libman-Sacks Endocarditis from other Diseases

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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