Fibromuscular Dysplasia

Fibromuscular dysplasia (FMD) is a nonatherosclerotic, noninflammatory, medium-sized angiopathy due to fibroplasia of the vessel wall. The condition leads to complications related to arterial stenosis, aneurysm, or dissection. The clinical presentation can differ depending on which arteries are affected, but may include secondary hypertension from renal artery stenosis (RAS), neurologic deficits from cerebrovascular involvement, claudication due to limb involvement, and intestinal angina from mesenteric artery disease. The diagnosis is confirmed with imaging, such as computed tomography with angiography. Treatment includes lifestyle modifications, antihypertensive therapy for RAS patients, and potential revascularization.

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Overview

Definition

Fibromuscular dysplasia (FMD) is a noninflammatory, nonatherosclerotic angiopathy characterized by stenosis, aneurysm, dissection, and tortuosity of medium-sized arteries.

Fibromuscular dysplasia primarily affects the renal (most common), carotid, visceral, external iliac, and vertebral arteries.

Epidemiology

  • Common, and often found incidentally
  • Women > men
  • Affects all ages, but primarily young to middle-aged adults
  • Caucasians are more commonly affected.
  • Frequent cause of renal artery stenosis (RAS) in young patients

Pathophysiology

The cause of this disease is unknown.

  • Possibly due to a combination of genetics, hormones, and an underlying connective tissue defect → arterial wall weakness → arterial dilation and injury → compensatory fibroplasia (development of fibrous tissue) in the vessel wall
  • This can result in:
    • Stenosis
    • Artery dissection
    • Aneurysm formation
  • Disease manifestations result from:
    • Disruption in blood flow through affected vessels
    • Aneurysm rupture
    • Intravascular thrombi and embolization
  • In RAS: FMD results in arterial stenosis → ↓ renal perfusion → ↑ renin production through activation of the renin-angiotensin-aldosterone system (RAAS) → secondary hypertension
Fibromuscular dysplasia

Diagram showing fibroplasia of the tunic media, which can result in narrowing of the arterial lumen: Aneurysms may form as well, with thinning of the vessel wall.

Image by Lecturio.

Classification

  • Multifocal FMD 
    • Most common type
    • “String of beads” appearance on angiography
    • Primarily corresponds to medial fibroplasia
      • Due to alternating collagen-containing fibromuscular webs and aneurysmal dilation
      • Internal elastic lamina may be absent in the dilated areas. 
    • May also be due to perimedial fibroplasia
      • Outer zone of the media is replaced with collagen, resulting in irregular thickening.
      • Aneurysm formation is less common.
  • Focal FMD 
    • Tubular or circumferential stenosis on angiography
    • Primarily corresponds to intimal fibroplasia (caused by circumferential collagen deposition in the intima)
    • Rare manifestations:
      • Medial hyperplasia (smooth muscle hyperplasia)
      • Periarterial hyperplasia (fibrous adventitia expansion)
Multifocal and focal fibromuscular dysplasia

Representations of multifocal FMD and focal FMD

Image by Lecturio.

Clinical Presentation

The clinical presentation depends on the affected vessels and the degree of blood flow disruption. Most patients are asymptomatic. 

  • Cerebrovascular arteries (most common presentation in women):
    • Headache
    • Pulsatile tinnitus
    • Neck pain
    • Cervical bruit
    • Transient ischemic attack (TIA) or stroke
    • Amaurosis fugax (vision loss due to a lack of blood flow to the eye)
    • Horner’s syndrome (ptosis, miosis, and anhidrosis)
  • Renal arteries (most common presentation in men):
    • Hypertension
    • Abdominal bruit
    • Flank pain
  • Mesenteric arteries:
    • Intestinal angina
    • Weight loss
    • Epigastric bruit
  • Limb arteries:
    • Claudication 
    • Cyanotic toes 
    • Asymmetric pulses
    • Weakness
    • Paresthesias
    • Femoral bruit

Diagnosis

When to suspect FMD

  • Young, hypertensive patients (especially women < 60 years of age) with:
    • Severe, resistant, or sudden worsening of hypertension
    • Onset of hypertension < 35 years of age
    • Significant rise in creatinine with the initiation of:
      • Angiotensin-converting enzyme (ACE) inhibitors
      • Angiotensin receptor blockers (ARBs) 
    • Abdominal bruit
  • Patients < 60 years of age without risk factors for atherosclerosis and:  
    • Carotid bruit
    • TIA or stroke
    • Aortic aneurysm
  • Significant headache or tinnitus with no explanation
  • Peripheral or coronary arterial dissection or aneurysms
  • Subarachnoid hemorrhage
  • Renal infarction

Diagnosis

Imaging is used to confirm the diagnosis.

  • Noninvasive testing (preferred):
    • Computed tomography with angiography (CTA) 
      • Method of choice
      • Less sensitive for small branch involvement
      • Will show the characteristic “string of beads” or smooth, concentric, focal stenosis
    • Magnetic resonance imaging with angiography (MRA)
      • Used when CTA is contraindicated
      • More useful in detecting aneurysms and dissections
      • Vessel resolution tends to be inconsistent.
    • Duplex ultrasonography
      • Generally not used for diagnosis
      • May report changes in velocity, turbulent flow, and tortuosity that could signal FMD
  • Invasive testing:
    • Digital subtraction angiography (DSA)
      • Reference standard
      • Catheter-based procedure
      • Dye is injected and imaged with serial radiographs.
      • Used when there is a high suspicion of FMD and revascularization is planned

Management

Management of renal FMD

  • Lifestyle modifications
    • Diet
    • Exercise
    • Smoking cessation
    • Has not shown much benefit as an isolated therapy
  • Antihypertensive therapy
    • Multifocal FMD can be controlled with medication therapy.
    • 1st line: 
      • ACE inhibitors
      • ARBs
      • Goal is to block the RAAS.
      • Use may be limited by a decrease in glomerular filtration rate (GFR) or hyperkalemia.
    • 2nd line: 
      • Thiazide diuretics
      • Dihydropyridine calcium channel blockers
      • Beta-blockers 
  • Revascularization
    • Indications:
      • Recent-onset hypertension in younger patients with low risk of atherosclerotic disease (particularly with focal FMD)
      • Resistant hypertension despite appropriate 3-drug therapy
      • Progressive renal insufficiency thought to be from RAS
      • Children with hypertension
    • Hypertension can be cured in focal FMD, but not in multifocal FMD.
      • May be due to the younger age of patients and shorter duration of hypertension at onset
    • Goal is to prevent renal atrophy and chronic kidney disease (of particular concern in focal FMD).
    • Options:
      • Percutaneous transluminal angioplasty (preferred)
      • Aortorenal bypass surgery (usually reserved for complex cases)
  • Followup and serial monitoring
    • Blood pressure
    • Serum creatinine 
    • Renal ultrasound

Management of non-renal FMD

  • Most patients are asymptomatic and do not require intervention.
  • Lifestyle and risk factor modifications 
    • Goal is to reduce the risk of atherosclerosis, which could accelerate arterial stenosis.
    • Diet, exercise, and smoking cessation
    • Diabetes, hyperlipidemia, and hypertension management
  • Aspirin for stroke prophylaxis in patients with cerebrovascular FMD
  • Revascularization:
    • TIA or stroke
    • Claudication
    • Mesenteric ischemia

Differential Diagnosis

  • Atherosclerotic disease: narrowing of arteries due to patchy intimal plaques. Risk factors include diabetes, hyperlipidemia, hypertension, and smoking. Patients tend to be older. The clinical presentation depends on the vessels involved, but can include heart disease, stroke, RAS, and peripheral artery disease. Diagnosis is based on clinical history, duplex ultrasound, or angiography. The characteristic appearance of FMD on angiography will not be seen. Treatment includes risk factor modification, antiplatelet agents, and revascularization.
  • Vasculitis: a vascular inflammatory disease, often resulting in ischemia, necrosis, and organ damage. Any vessel can be involved. Etiologies include autoimmune disorders, drugs, and infections. Unlike FMD, patients present with fever, arthralgias, arthritis, and potential end-organ damage. Diagnosis involves inflammatory markers, autoimmune serology, infectious workup, and biopsy, which will differentiate this condition from FMD. Management depends on the underlying cause.
  • Primary hypertension: idiopathic elevation in blood pressure, and most commonly associated with increasing age (unlike RAS, which is due to FMD). Most patients are asymptomatic, but severe elevations can cause headache and dizziness. Diagnosis is based on history and 3 separate blood pressure readings. Treatment includes lifestyle modifications and antihypertensive therapy. Patients who do not respond to treatment should be evaluated for secondary hypertension, such as RAS.

References

  1. Olin, J.W. (2020). Clinical manifestations and diagnosis of fibromuscular dysplasia. In Forman, J.P. (Ed.), Uptodate. Retrieved December 1, 2020, from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-fibromuscular-dysplasia
  2. Olin, J.W. (2020). Treatment of fibromuscular dysplasia of the renal arteries. In Forman, J.P. (Ed.), Uptodate. Retrieved December 1, 2020, from https://www.uptodate.com/contents/treatment-of-fibromuscular-dysplasia-of-the-renal-arteries
  3. Wilson, J.A., and Hughes, R.L. (2018). Fibromuscular dysplasia. In Lutsep, H.L. (Ed.), Medscape. Retrieved December 1, 2020, from https://emedicine.medscape.com/article/1161248-overview
  4. Teo, K.K. (2019). Fibromuscular dysplasia. [online] MSD Manual Professional Version. Retrieved December 1, 2020, from https://www.msdmanuals.com/professional/cardiovascular-disorders/peripheral-arterial-disorders/fibromuscular-dysplasia
  5. Kasper, D.L., Fauci, A.S., Hauser, S.L., Longo, D.L., Lameson, J.L., and Loscalzo, J. Harrison’s Principles of Internal Medicine. New York, NY: McGraw-Hill Education; 2018.

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