Thromboangiitis Obliterans (Buerger's Disease)

Jeffrey W. Olin, D.O.

N Engl J Med 2000; 343:864-869September 21, 2000

Thromboangiitis obliterans (Buerger's disease) is a nonatherosclerotic segmental inflammatory disease that most commonly affects the small and medium-sized arteries, veins, and nerves of the arms and legs.1 Von Winiwarter first described a patient with thromboangiitis obliterans in 1879.2Twenty-nine years later, Leo Buerger provided a detailed and accurate description of the pathological findings in 11 amputated limbs.3 Thromboangiitis obliterans differs from other forms of vasculitis in some important ways. Pathologically, there is a highly cellular and inflammatory thrombus with relative sparing of the blood-vessel wall. The acute-phase reactants (as assessed by the Westergren sedimentation rate and serum C-reactive protein level) are usually normal. Results of serologic tests for the immunologic markers (circulating immune complexes, complement levels, and cryoglobulins) and the commonly measured autoantibodies (antinuclear antibody and rheumatoid factor) are normal or negative, yet an immune reaction has been demonstrated in the arterial intima. 4 Although Buerger's disease has a worldwide distribution, it is more prevalent in the Middle East and Far East than in North America and western Europe, 5,6 in part because of differences in diagnostic criteria. At the Mayo Clinic, the proportion of patients with the diagnosis of Buerger's disease has steadily declined, from 104 per 100,000 patients in 1947 to 12.6 per 100,000 in 1986.6,7 The prevalence of the disease among all patients with peripheral arterial disease varies from as low as 0.5 to 5.6 percent in western Europe to as high as 45 to 63 percent in India, 16 to 66 percent in Korea and Japan, and 80 percent in Israel among Jews of Ashkenazi ancestry. 8-10

CAUSE AND PATHOGENESIS

The cause of Buerger's disease is unknown. However, use of or exposure to tobacco is central to the initiation and progression of the disease. 11 There is an extremely strong association between the heavy use of tobacco and thromboangiitis obliterans.12,13 Thromboangiitis obliterans is more common in countries with heavy use of tobacco. There is an extremely high prevalence of thromboangiitis obliterans in India among people of low socioeconomic class who smoke bidis (homemade cigarettes with raw tobacco). 14 There have been occasional cases of thromboangiitis obliterans in users of smokeless tobacco or snuff.15,16 Although a few investigators believe that Buerger's disease can occur in nonsmokers,17 most view current or past smoking as a requirement for the diagnosis.7,11,18-21

Using an antigen-sensitive thymidine-incorporation assay, Adar and colleagues22 found an increased cellular sensitivity to types I and III collagen (normal constituents of human arteries) in patients with thromboangiitis obliterans, as compared with patients with arteriosclerosis obliterans or normal men. In a study by Eichhorn et al.,23 7 patients with active thromboangiitis obliterans had mean serum antiendothelial-cell antibody titers of 1857 arbitrary units, as compared with values of 126 in 30 normal subjects (P<0.001) and 461 in 21 patients in remission (P<0.01). Although measuring antiendothelial-cell antibody titers appears to be a promising method of following disease activity in patients with Buerger's disease, additional studies are required to delineate further the sensitivity and specificity of this test. There is impaired endothelium-dependent vasorelaxation in the peripheral vasculature of patients with Buerger's disease.24 Forearm blood flow was measured by plethysmography in the nondiseased limb after the infusion of acetylcholine (an endothelium-dependent vasodilator) and sodium nitroprusside (an endothelium-independent vasodilator). The increase in forearm blood flow in response to intraarterial acetylcholine was lower in patients with thromboangiitis obliterans than in normal subjects (14.1 vs. 22.9 ml per minute per deciliter of tissue volume, P<0.01), and endothelium-dependent vasodilatation is impaired even in the nondiseased limbs of patients with thromboangiitis obliterans. There was no significant difference between patients and normal subjects in the increase in forearm blood flow in response to sodium nitroprusside (13.1 and 16.3 ml per minute per deciliter, respectively), indicating that nonendothelial mechanisms of vasodilatation are intact.

PATHOLOGICAL FINDINGS
In thromboangiitis obliterans, inflammatory thrombi affect both the arteries and the veins. The histopathological findings vary according to the duration of the disease. The findings are most likely to be diagnostic in the acute phase of the disease, most commonly when a segment of a vessel with superficial thrombophlebitis undergoes biopsy. In the subacute (intermediate) phase of the disease, the findings may be suggestive, but in the chronic or end-stage phase of the disease, all that remains is organized thrombus and fibrosis of the blood vessels.25-30 The hallmark of the acute-phase lesion is an occlusive, highly cellular, inflammatory thrombus, with less inflammation in the walls of the blood vessels. Polymorphonuclear leukocytes, microabscesses, and multinucleated giant cells may be present (Figure 1
FIGURE 1

Typical Acute Histologic Lesion of Buerger's Disease in a

Vein with Intense Thromboangiitis, Showing a Microabscess in the Thrombus and Two Multinucleated Giant Cells (Arrows) (Hematoxylin and Eosin, 400). ).

In the intermediate phase, there is progressive organization of the thrombus in the arteries and veins. In all three stages, the normal structure of the vessel wall, including the internal elastic lamina, generally remains intact. This feature distinguishes thromboangiitis obliterans from arteriosclerosis and from other types of systemic vasculitis, in which there is usually striking disruption of the internal elastic lamina and the media. 13 Although Buerger's disease most commonly affects the small and medium-sized arteries and veins in the arms, hands, legs, and feet, it has been reported in many other vascular beds. There are case reports of involvement of the cerebral arteries, coronary arteries, renal arteries, mesenteric arteries, aorta, pulmonary arteries, and iliac arteries.31-35 Multiple-organ involvement in thromboangiitis obliterans has also been observed.36,37 When thromboangiitis obliterans occurs in unusual locations, the diagnosis should be made only when histopathological examination identifies the acute-phase lesion.

CLINICAL FEATURES
Buerger's disease typically occurs in young male smokers, with the onset of symptoms before the age of 40 to 45 years. Several published series have shown an increasing prevalence of the disease in women, ranging from 11 percent to 23 percent.7,11,18 However, the prevalence among women in Japan and other Asian countries remains low, despite increased smoking by Asian women.19,38 Buerger's disease usually begins with ischemia of the distal small arteries and veins. As the disease progresses, it may involve more proximal arteries. Involvement of the large arteries is unusual and rarely occurs in the absence of small-vessel occlusive disease.39 Patients may present with claudication of the feet, legs, hands, or arms. Foot or arch claudication may be mistaken for an orthopedic problem. As the disease progresses, typical calf claudication and eventually ischemic pain at rest and ischemic ulcerations on the toes, feet, or fingers may develop (Figure 2
Acute Buerger's Disease.).
FIGURE 2

Ischemic Ulcers on the Distal Portion of the Left Great Toe and Second Toe in a Patient with

At the Cleveland Clinic Foundation, 112 patients with Buerger's disease were evaluated and treated between 1970 and 1987. 11 Their demographic characteristics and presenting clinical symptoms and signs are shown inTable 1

TABLE 1

Demographic Characteristics and Presenting Symptoms and Signs of 112 Patients with Thromboangiitis Obliterans, 1970 through 1987. . Seventy-six percent of the patients

had ischemic ulcerations at the time of presentation. 11 In Shionoya's series, all patients with Buerger's disease had more than one involved limb.19 Two limbs were affected in 16 percent of patients, three limbs in 41 percent, and all four limbs in 43 percent. Because of the likelihood of involvement of more than one limb, it is advisable to obtain an arteriogram of both arms, both legs, or all four limbs in patients who present with clinical involvement of only one limb. It is not uncommon to see arteriographic abnormalities consistent with Buerger's disease in limbs that are not yet clinically involved. In patients with leg ulceration in whom Buerger's disease is a possibility, the Allen test should be performed to assess the circulation in the hands and fingers40,41 (Figure 3 The Allen Test.). An abnormal result on the Allen test in a young smoker with leg ulcerations is highly suggestive of thromboangiitis obliterans, since it demonstrates small-vessel involvement in both the arms and the legs. An abnormal result can also be present in other types of small-vessel occlusive disease of the hands, such as scleroderma, the CREST syndrome (calcinosis cutis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia), repetitive trauma (vibratory-tool use or hypothenar hammer syndrome), emboli, hypercoagulable states, and vasculitis. The distal nature of thromboangiitis obliterans and the involvement of the legs and arms help to differentiate it from atherosclerosis. Superficial thrombophlebitis occurs in approximately 40 percent of patients with thromboangiitis obliterans (Figure 2).11 The thrombophlebitis may be migratory and may parallel disease activity.12 Raynaud's phenomenon is present in approximately 40 percent of patients. Laboratory and Arteriographic Findings
FIGURE 3

There are no specific laboratory tests to aid in the diagnosis of thromboangiitis obliterans. A complete serologic profile should be obtained, including a complete blood count with differential count; liver-function tests; renal-function tests; urinalysis; measurement of blood sugar while the patient is fasting, acute-phase reactants (Westergren sedimentation rate and C-reactive protein), antinuclear antibody, rheumatoid factor, complement, and serologic markers for the CREST syndrome and scleroderma (anticentromere antibody and Scl-70); and screening for hypercoagulability, including tests for antiphospholipid antibodies.

A proximal source of emboli may be ruled out by echocardiography (transthoracic, transesophageal, or both) and arteriography. The angiographic features of Buerger's disease are involvement of the small and medium-sized vessels, such as the palmar, plantar, tibial, peroneal, radial, and ulnar arteries and the digital arteries of the fingers and toes; segmental occlusive lesions (diseased arteries interspersed with normal-appearing arteries); more severe disease distally, and normal proximal arteries with no evidence of atherosclerosis; collateralization around areas of occlusion (corkscrew collaterals) (Figure 4FIGURE 4
Angiogram of the Hand Showing Multiple Occlusions

of the Digital Arteries, with Collateralization (Corkscrew Collaterals) around the Areas of Occlusion (Arrows).); and no apparent source of emboli.42-45The disease is usually

confined to the distal circulation and is almost always infrapopliteal in the legs and distal to the brachial artery in the arms. Arteriographic findings may be suggestive but are not pathognomonic. The arteriographic findings in Buerger's disease may be identical to those in scleroderma, the CREST syndrome, systemic lupus erythematosus, rheumatoid vasculitis, mixed connective-tissue disease, and the antiphospholipid-antibody syndrome. The presence of diabetes mellitus rules out the diagnosis of thromboangiitis obliterans. Diagnostic Criteria Several different criteria have been proposed for the diagnosis of thromboangiitis obliterans. Papa et al.46 have proposed various clinical, angiographic, histopathological, and exclusionary criteria and have devised a scoring system. Mills and Porter47 have proposed major and minor diagnostic criteria. The clinical criteria of Shionoya20,48 are a history of smoking, onset before the age of 50 years, infrapopliteal arterial occlusions, either arm involvement or phlebitis migrans, and the absence of risk factors for atherosclerosis other than smoking. Our criteria are an age of less than 45 years and current (or recent) history of tobacco use; the presence of distal-extremity ischemia (indicated by claudication, pain at rest, ischemic ulcers, or gangrene) documented by noninvasive vascular testing; exclusion of autoimmune diseases, hypercoagulable states, and diabetes mellitus by laboratory tests; exclusion of a proximal source of emboli by echocardiography and arteriography; and consistent arteriographic findings in the clinically involved and noninvolved limbs.11,13 A biopsy is rarely needed unless the patient presents with unusual characteristics, such as large-artery involvement or an age of more than 45 years.

TREATMENT

The only proven strategy to prevent progression of the disease and avoid amputation is the complete discontinuation of cigarette smoking or other use of tobacco in any form.11,49-51 Even smoking one or two cigarettes a day, using smokeless tobacco (chewing tobacco or snuff), or using nicotine replacement may keep the disease active.15,16 Among 120 patients with Buerger's disease, 43 percent had discontinued cigarette smoking after an average of 7.6 years of follow-up.52 If there was no gangrene when the patient discontinued smoking, amputation did not occur. Overall, 94 percent of those who quit smoking avoided amputation, whereas 43 percent of those who continued smoking required one or more amputations. One patient had 18 different operations, resulting in bilateral amputations above the knees and above the elbows. 37 There is a misconception that it is extremely difficult to get patients with thromboangiitis obliterans to discontinue smoking. In fact, it may be easier to persuade patients with Buerger's disease to stop smoking than patients with atherosclerosis.11,52 Physicians must educate and counsel their patients repeatedly about the importance of discontinuing the use of all tobacco products. Patients can be reassured that if they are able to discontinue tobacco use, the disease will remit and amputation can be avoided. The correlation between smoking and disease activity is so strong that if the patient claims to have stopped using tobacco and the disease is still active, measurements of urinary nicotine and cotinine (a metabolic byproduct of nicotine) should be performed. These tests will help determine whether the patient is still smoking, using nicotine-replacement products, or being exposed to large amounts of environmental tobacco smoke.53,54 Patients may continue to have claudication or Raynaud's phenomenon even after the complete discontinuation of tobacco use, however. Except for discontinuation of tobacco use, no forms of therapy are definitive. Fiessinger and Schafer55 conducted a prospective, randomized, double-blind trial comparing the effects of a six-hour daily infusion of iloprost (a prostaglandin analogue) with those of aspirin. Iloprost was superior to aspirin at 28 days, with total relief of pain at rest and complete healing of all trophic changes. At six months, 88 percent of the patients receiving iloprost had had a response to therapy, as compared with 21 percent of the aspirin group. Only 6 percent of the iloprost group required amputation, as compared with 18 percent of the aspirin group. Iloprost helps patients with critical limb ischemia get through the period when they first discontinue cigarette smoking. Oral iloprost is not nearly as effective as the intravenous form.56 Iloprost is available in many European countries, but not in the United States.

There is little information on the use of intra-arterial thrombolytic therapy 57,58 in the treatment of Buerger's disease. Hussein and el Dorri 57 used selective lowdose intraarterial streptokinase (a 10,000-unit bolus followed by 5000 units per hour) in 11 patients with long-standing Buerger's disease who had gangrene or pregangrenous lesions of the toes or feet. They reported an overall success rate (defined as avoidance or alteration in the level of amputation) of 58 percent. Further study will be required to determine the role of thrombolytic therapy. Surgical revascularization is usually not possible for patients with Buerger's disease, because of the diffuse segmental involvement and distal nature of the disease. Often no distal target vessel is available for bypass surgery. However, if the patient has severe ischemia and there is a distal target vessel, bypass surgery with the use of an autologous vein should be considered. 59-61 Sasajima and colleagues61 reported a five-year rate of primary patency of 49 percent and a rate of secondary patency of 62 percent in 61 patients after infrainguinal bypass. The patency rates were 67 percent in those who discontinued smoking and 35 percent in those who continued to smoke. 61 Another surgical approach is omental transfer.62,63 Singh and Ramteke62 reported on 50 patients with thromboangiitis obliterans who underwent omental transfer for pain at rest, nonhealing ischemic ulcers, or both. All patients had an improvement in skin temperature, and 36 patients had decreased pain at rest. The ulcers healed in 32 of 36 patients. Surgical therapy for thromboangiitis obliterans is uncommon in the United States, both because a reasonable target vessel for bypass is usually not found and because most patients do very well if they are able to discontinue smoking. The role of sympathectomy in preventing amputation or treating pain remains unclear.11,38Occasionally, sympathectomy may help the healing of superficial ischemic ulcerations. We recently treated a patient with a spinal cord stimulator, resulting in complete healing of all arm ulcerations when all other conservative measures had failed.64 Isner and colleagues65 reported the use of intramuscularly administered vascular endothelial growth factor gene therapy in seven limbs of six patients with Buerger's disease. Ischemic ulcers healed in three of five limbs in four patients, and the other two patients had relief of pain at rest.

SOURCE INFORMATION
From the Heart and Vascular Institute of New Jersey, Morristown. Address reprint requests to Dr. Olin at the Heart and Vascular Institute of New Jersey, 111 Madison Ave., Morristown, NJ 07960, or at olinjw1@aol.com.