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PAN can involve virtually any organ system with the exception of the lungs. The disease demonstrates a predilection for certain organs, particularly the skin, peripheral nerves, gastrointestinal tract, and kidneys. A nearly universal complaint among patients is some type of pain, caused by myalgias, arthritis, peripheral nerve infarction, testicular ischemia, or mesenteric vasculitis.
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Constitutional Symptoms
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Fevers are a common feature of PAN. The characteristics of the fever vary substantially among patients, ranging from periods of low-grade temperature elevation to spiking febrile episodes accompanied by chills (patterns of low-grade fever are more common than are hectic fevers). Tachycardia with or without fever may be another feature of PAN. Malaise, weight loss, and myalgias are also common.
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Vasculitis of medium-size arteries may produce several types of skin lesions. These cutaneous findings include livedo racemosa (Plate 48), nodules, papules, ulcerations, and digital ischemia leading to gangrene. All of these findings or combinations of them may occur in the same patient. The livedo racemosa (often termed “livedo reticularis”), which may have a diffuse distribution over the extremities and buttocks, does not blanch with the application of pressure to the skin. Nodules, papules, and ulcers tend to occur on the lower extremities, particularly near the malleoli, in the fleshy parts of the calf, and over the dorsal surfaces of the feet. Nodules frequently evolve into ulcerations that have scalloped borders (Figure 35–1) and heal with scarring.
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Although the principal skin manifestations relate to disease caused by arteritis in medium-sized muscular arteries and arterioles, crops of purpura (caused by the involvement of smaller blood vessels) occur in a minority of patients. Digital ischemia, often accompanied by splinter hemorrhages, sometimes leads to tissue loss.
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Arthralgias of large joints (knees, ankles, elbows, wrists) occur in up to 50% of patients; however, true synovitis is seen in substantially fewer patients.
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Mononeuritis multiplex, the infarction of named nerves by inflammation in the vasa nervorum, occurs in approximately 60% of patients with PAN. The most commonly involved nerves are the sural, peroneal, radial, and ulnar. Vasculitic neuropathy tends to involve the longest (ie, distal) nerves first and usually begins asymmetrically. Thus, the first motor symptoms of vasculitic neuropathy may be a foot or wrist drop (resulting from infarctions of the peroneal and radial nerves, respectively). In advanced stages, the neuropathy may mimic a confluent, symmetric polyneuropathy. Careful history taking, however, may unmask its initial asymmetry. Both sensory and motor findings are characteristic of vasculitic neuropathy because with the exception of the sural nerve (a pure sensory nerve), peripheral nerves typically have mixed sensory and motor fibers bundled within the same nerve.
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Gastrointestinal Tract
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The gastrointestinal manifestations of PAN occur in approximately half of all patients and are among the most challenging symptoms to diagnose correctly because of their nonspecific nature. Postprandial abdominal pain (“intestinal angina”) is common. Involvement of the mesenteric arteries in PAN may lead to the disastrous complications of mesenteric infarction or aneurysmal rupture, each of which is associated with a high mortality rate. Angiography of the mesenteric vessels reveals multiple microaneurysms (Figure 35–2A). These range in size from lesions that are barely visible to the naked eye to several centimeters in diameter. Sometimes PAN is detected at cholecystectomy or appendectomy in the absence of other disease manifestations. In such cases, surgical removal of the involved organ may be curative.
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Intraparenchymal Renal Inflammation
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This major feature of PAN is found in 40% of patients. The inflammatory process targets the renal and interlobar arteries (the medium-sized, muscular arteries within the kidney) and occasionally also involves the smaller arcuate and interlobular arteries. Angiography may reveal microaneurysms within the kidney or large, wedge-shaped renal infarctions (Figure 35–2B). Renal artery involvement or involvement of intra-renal arterioles in PAN may lead to renin-mediated hypertension. Red blood cell casts on urinalysis imply glomerulonephritis and thus usually implicate another disease (eg, microscopic polyangiitis). However, both proteinuria and hematuria may be observed in PAN.
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Tachycardia may reflect either direct cardiac involvement or a general inflammatory state. Congestive heart failure and myocardial infarction sometimes occur. Specific heart lesions are rarely diagnosed while the patient is alive; however, autopsy series indicate that cardiac involvement is present in a majority of patients with PAN. Patchy necrosis of the myocardium caused by subclinical arteriolar involvement is a common finding at autopsy.
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Central nervous system involvement occurs in a small percentage of patients with PAN. The usual presentations are encephalopathy and strokes. Renin-mediated hypertension may contribute to both of these neurologic complications. Other unusual presentations of PAN include involvement of the eyes (scleritis), pancreas, testicles, ureters, breasts, and ovaries.
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Although the laboratory features of PAN are often strikingly abnormal and help characterize the disease process as inflammatory, they do not distinguish PAN from a host of other inflammatory diseases. Anemia, thrombocytosis, and elevation of acute phase reactants are typical (Table 35–1). The erythrocyte sedimentation rate and C-reactive protein are often useful in longitudinal evaluations of disease activity but are imperfect for this purpose.
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One of the diagnostic challenges in PAN is the fact that the disorder is not associated with any of the autoantibodies found in other immune-mediated conditions. Assays for antinuclear antibodies and rheumatoid factor are generally negative in patients with PAN, albeit low titers of these antibodies are detected in a minority of patients. Patients with HBV-associated PAN are generally hypocomplementemic, regardless of whether they have demonstrable cryoglobulins. When associated with HBV, PAN usually develops within weeks to months of the acute viral infection.
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When tested by immunofluorescence, the sera of some patients with PAN are positive for antineutrophil cytoplasmic antibodies (ANCAs). However, specific enzyme immunoassays for antibodies to proteinase-3 or myeloperoxidase (the two antigens known to be associated with systemic vasculitis) are negative. Thus, PAN is not considered to be a form of ANCA-associated vasculitis.
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The diagnosis of PAN requires either a tissue biopsy or an angiogram that demonstrates microaneurysms.
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In the skin, medium-sized arteries lie within the deep dermis and in the subdermal adipose tissue. Thus, the diagnosis of PAN can be made by obtaining biopsy specimens of the skin that capture lobules of subcutaneous fat. Biopsies of nodules, papules, and the edges of ulcers have higher yields than biopsies of livedo racemosa.
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PAN is a panarteritis characterized by transmural necrosis and a homogeneous, eosinophilic appearance of the blood vessel wall (fibrinoid necrosis). The cellular infiltrate is pleomorphic, with both polymorphonuclear cells and lymphocytes present in varying degrees at different stages. Degranulation of neutrophils within and around the arterial wall leads to leukocytoclasis. During later stages, complete occlusion may occur secondary to endothelial proliferation and thrombosis. Throughout involved tissues, the coexistence of acute and healed lesions is typical.
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Nerve Conduction Studies
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Nerve conduction studies are useful in detecting the typical axonal pattern of nerve injury and identifying involved nerves for biopsy. Because muscle tissue is highly vascular and may harbor involved vessels even in the absence of symptoms or signs of muscle involvement, biopsies of adjacent muscle should be performed simultaneously (eg, the gastrocnemius, if the sural nerve is biopsied). Blind biopsies of asymptomatic organs such as the testicle, however, are rarely diagnostic.
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The vascular wall inflammation in PAN may be strikingly segmental, affecting only part of the circumference of a given artery. Segmental necrosis, in turn, leads to aneurysm formation. Lesions known as microaneurysms can occur throughout the mesenteric and renal vasculature. Even in patients without gastrointestinal symptoms, mesenteric angiography may demonstrate telltale microaneurysms.
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Conventional, catheter-based angiography generally has a higher resolution than computed tomography or magnetic resonance angiograms and remains the gold-standard approach to the detection of microaneurysms. The interpretation of angiograms requires experience. Alternating areas of vascular narrowing and dilatation can be caused by a variety of non-vasculitic processes, including (most commonly) vasospasm. The finding of true microaneurysms, however, is diagnostic of PAN in the proper setting.