Chapter 5 Circulatory disorders
Peripheral arterial disease (PAD)
Primary lymphoedema (Milroy’s disease)
INTRODUCTION
Circulatory disorders of the lower limb can be broadly classified as arterial (macrovascular) or capillary (microvascular) disease, which results in ischaemia, or as venous or lymphatic disease, which impairs venous drainage of blood and interstitial fluid. Clinically, the most important of these three groups is arterial disease, because of its potential threat to limb viability and the very significant negative impact on the patient’s quality of life. The most common form of peripheral arterial disease (PAD) is atheromatous arterial disease.
PAD has been regarded as the ‘Cinderella’ of cardiovascular disease, secondary to coronary artery disease and cerebrovascular disease. This view is slowly changing as it is recognised that risk modification in people with PAD is beneficial in reducing the incidence of subsequent cardiovascular disease. As a consequence, effective modification of the risk factors for PAD is now regarded as being cardioprotective and this has highlighted the importance of accurate diagnosis and timely management of PAD.
ARTERIOSCLEROSIS (HARDENING OF THE ARTERIES)
Arteriosclerosis is a term that should be restricted to describing the age-related changes in which the intima and media of the arterial wall become thickened and fibrosed, and there is replacement of the smooth muscle and elastic fibres of the media with collagen. The overall effect of this condition is to increase the rigidity and tortuosity of the vessel and contribute to the age-related increase in blood pressure. In malignant hypertension there is fibrinoid necrosis in the arterioles, and in diabetes mellitus there may be medial calcification (Mönckeberg’s medial sclerosis). This definition of arteriosclerosis is not universally accepted, and the name is sometimes used as a generic term to describe the pathological changes associated with arteriosclerosis and atherosclerosis.
ATHEROSCLEROSIS (MACROVASCULAR DISEASE)
The term atherosclerosis describes thickening of the intima of large and medium-sized arteries, and consequent narrowing of the artery because of lipid and fibrous deposition. Atherosclerosis is a major cause of morbidity and mortality in the western world, due to coronary artery disease, cerebrovascular disease and peripheral vascular disease. It is responsible for about 80% of all deaths in Europe, USA and Japan. This condition causes a progressive narrowing, or occlusion, of the arteries, resulting in ischaemia of the tissues supplied by the diseased vessel. In addition, atheromas serve as sites for thrombus formation, which can result in acute symptoms. The development and rate of progression of the atheroma varies from vessel to vessel (e.g. femoral artery to cerebral artery) and from patient to patient; symptoms usually develop when the arterial obstruction equates to a 50–75% reduction in the diameter of the vessel lumen. Typically, a patient will present with symptoms of ischaemia in one anatomical region (e.g. lower limbs, heart or brain) but as the condition advances symptoms frequently develop in one or both of the other two regions (e.g. patients who present with PAD have a four- to six-fold increased risk of dying from a cardiovascular event).
Epidemiology
In the UK, 5% of men and 2.5% of women over the age of 50 years have intermittent claudication, which is the commonest manifestation of atheromatous PAD, and about 8–12% of these patients will progress to critical limb ischaemia. The prevalence rate of PAD increases with age, and rises to 8% of the population over the age of 70 years. Approximately 50% of all claudicants will be dead within 5 years from the onset of symptoms.
In the USA, 8 to 12 million people are reported to have PAD, with 20–40% presenting with the symptoms of intermittent claudication.
Pathology
In western countries atheromatous plaques begin to appear in the second and third decade of life. The formation of the plaque within the intima of the artery is thought to be the end product of a complex process of repair, initiated in response to an injury to the endothelium. The widely accepted mechanism that explains this process is known as the ‘response to injury hypothesis’.
Atherosclerosis is a complex inflammatory process in which lipids, smooth muscle cells and macrophages accumulate in the intima to form atheromatous plaques. The vascular endothelium plays a pivotal role in maintaining vascular integrity and homeostasis. There are many possible mechanisms by which the endothelium is injured, including mechanical factors (e.g. hypertension and increase in turbulent flow), biochemical abnormalities (e.g. diabetes mellitus, elevated levels of low-density lipoprotein (LDL) and plasma homocysteine), immunological factors (e.g. elevated levels of free radicals), inflammation induced by infection (e.g. Helicobacter pylori) and genetic factors.
The earliest stage of the atheromatous plaque is fatty streaks, which appear microscopically as flat yellow dots or lines on the endothelium. They can be present from childhood onwards, and develop at bifurcations of vessels where turbulent flow may contribute to the damage of the endothelium. The streak develops as circulating monocytes migrate into the intima, taking up oxidised LDL and, because of their histological appearance, these are referred to as foam cells. These cells rupture, releasing their contents and increasing the extracellular pool of lipids. Not all these fatty streaks will evolve into the next stage of development of the atheromatous plaque; many will regress. The next stage of plaque formation is mediated through the release of cytokines, such as platelet-derived growth factor and transforming growth factor-β (TGF-β) by macrophages, monocytes and damaged endothelial cells. These cytokines trigger the accumulation of macrophages, as well as smooth muscle cell migration and proliferation from the media into the intima. Smooth muscle cells produce increased amounts of collagen, which encroaches on the lumen, disrupting laminar flow and reducing blood flow.
The mature fibrolipid plaque is characterised by a core of extracellular lipids, smooth muscle cells and foam cells, which protrude into the lumen of the vessels. The media of vessel beneath the plaque is thinned, and this may contribute to aneurysmal dilatations. The endothelial lining of the plaque is prone to fissure/rupture, resulting in embolus formation and the development of a thrombosis, which may result in acute occlusion of the artery. Thrombosis can arise by two different mechanisms: by superficial endothelial injury, which exposes subendothelial connective tissue, triggering platelet adhesion and resulting in the formation of a thrombus on the surface of the atheromatous plaque; or, in advanced disease, where there is a deep fissure within the plaque, blood from the lumen enters the plaque, resulting in a thrombosis within the plaque, which will distort the vessel and extend into the lumen.
RISK FACTORS
Modifiable factors
Smoking
Cigarette smoking is the single most powerful risk factor for PAD, and it is dose dependent. The relative risk (RR) of developing atherosclerosis if you smoke is up to 10 times higher compared with a matched non-smoker. This risk declines to almost normal after 10 years of abstention. Smoking results in repetitive endothelial injury, and is associated with high levels of carboxyhaemoglobin and low levels of oxygen delivery to tissues. Tissue hypoxia will stimulate the proliferation and migration of arterial smooth muscle cells into the intima, and may diminish the degradation of LDL by smooth muscle cells.
Lipid disorders
Elevated levels of plasma cholesterol (>5.2 mmol/l) positively correlate with an increase in the incidence rate of atherosclerosis. The excess risk is associated with an increase in the concentration of LDL cholesterol (often referred to as the atherogenic particle) and is inversely related to the plasma high-density lipoprotein (HDL) cholesterol concentration. In addition, there is weak positive correlation between increased plasma triglyceride concentration and atherosclerosis. The hypertriglyceridaemia risk factor becomes stronger if LDL cholesterol is raised and HDL cholesterol reduced. Increased concentrations of specific lipoproteins may be primary (i.e. due to hereditary defects in lipoprotein metabolism) or secondary to certain diseases.
Primary hyperlipidaemias
Two genetic disorders which can cause hypercholesterolaemia are:
Diabetes mellitus
Atherosclerosis is much more common in patients with non-insulin-dependent diabetes mellitus (RR 1.5–4.0). This risk is very much related to the background population; for example, European diabetics are much more likely to develop atherosclerosis than are diabetic patients from Japan. The excess risk of amputation of a foot for gangrene is increased 50 times in a diabetic compared with the general population. This increased susceptibility to atherosclerosis is related to: duration of diabetes; increasing age; systolic hypertension; hyperinsulinaemia; hyperlipidaemia, particularly hypertriglyceridaemia; protein urea; and altered vascular reactivity. Other factors are the same as for the general population.
Hypertension
Hypertension is an important risk factor for atherosclerosis, with the risk increasing incrementally with increasing levels of blood pressure. Raised blood pressure (systolic pressures are more predictive than diastolic pressures) is associated with an increased risk (RR 3) of developing atherosclerosis through endothelial shear injury.
Obesity
Obesity is an independent risk factor, particularly if it is central or truncal, but it is frequently seen in association with other risk factors such as diabetes mellitus, sedentary lifestyle and hypertension.
Homocysteine
High levels of this thrombosis-associated amino acid are associated with thromboembolism through the adverse effects on the vascular endothelium. Plasma levels of homocysteine are influenced by a range of genetic and non-genetic factors.
Haemostatic variables
Increased levels of factor VII, factor VIIIC and serum fibrinogen are associated with an increased risk of atherosclerosis. It is not yet known if a reduction in these factors lowers the incidence rate of ischaemic attacks.
Sedentary lifestyle
Lack of regular exercise is associated with an increased risk of atherosclerosis. Exercise has a protective and therapeutic effect, which is related to the increase in HDL cholesterol, development of the collateral circulation and a reduction in blood pressure.
Dietary deficiencies of antioxidant vitamins and polyunsaturated fatty acids
Diets with low levels of vitamin C, vitamin E and other antioxidants may facilitate the production of oxidised LDLs. Diets high in saturated fats are associated with coronary atherosclerosis.
Type A behaviour pattern (TABP)
This classification describes people who tend to exhibit aggression, ambitiousness, restlessness, time urgency and high anxiety. However, it is the individual trait of aggression that is associated with atherosclerosis, and this may relate to an increased level of circulating catecholamines.
Fixed factors
Age and sex
Atherosclerosis in more common in males, but after the menopause the incidence rate increases in women, approaching that of males of the same age.
Family history
Atherosclerosis does show familial patterns, and this could be due to genetic factors, lifestyle choices or a combination of both. It has been estimated that 40% of the risk of developing ischaemic heart disease is determined by genetic factors and the remaining 60% by lifestyle factors.
An alternative explanation to the response to injury/lifestyle hypothesis was put forward by the epidemiologist David Barker in the 1980s, which postulates that the adverse conditions in utero and during infancy increase the risk of cardiovascular disease in later life (Barker hypothesis or fetal origins hypothesis). This hypothesis was built around longitudinal and retrospective case–control studies, where the early health records of newborn babies and young children were matched with the current health status of these babies who are now adults (>50 years old). The results reported that people who are small at birth or during infancy remain biologically different throughout their lives. They have higher blood pressure, a higher incidence rate of type 2 diabetes mellitus, different pattern of lipids, different bone density, altered stress response, less elastic arteries, thicker ventricular walls, and are more likely to age quicker. A number of subsequent studies have added weight to this hypothesis, but it still remains controversial. Perhaps the risk factors for atherosclerosis cannot be explained by one single hypothesis but are embedded in fetomaternal, environmental, inheritance and life-course risk factors.
CLINICAL FEATURES
Patients presenting with PAD will frequently have features of atherosclerosis in vessels supplying other organs (e.g. ischaemic heart disease and cerebrovascular disease). The three cardinal features of symptomatic PAD are intermittent claudication, rest pain and gangrene, each of which reflects an increasing degree of ischaemia. Symptoms usually occur when the arterial obstruction reaches 50–70%. Typically, patients initially present with intermittent claudication, and as the pathology advances this may progress to rest pain, and in a small percentage of patients it may result in peripheral gangrene. In many cases the leg ischaemia does not have time to deteriorate to gangrene because the associated coronary atherosclerosis is responsible for a high and premature mortality rate.
Intermittent claudication
Intermittent claudication typically causes pain in the calf (because the femoropopliteal vessels are the most commonly affected arteries) that is brought on by exercise and relieved by rest. Although the calf is a common site for ischaemic pain, depending on the location of the atheroma pain may also be felt in the buttock, thigh or even on the plantar aspect of the foot. The pain is initially located in one limb, but pathology is usually present in both limbs but to different degrees. The symptoms are described as cramping, tightness or, in the case of the elderly, as a loss of power/movement. All these symptoms will force the patient to stop and rest for a few minutes, during which time there is relief from pain. The symptoms are progressive and start during strenuous exercise, but as the pathology advances pain is eventually felt during mild exercise. Key diagnostic questions must demonstrate that the pain is located in muscle and not in joints. The pain should be exacerbated by an increased level of activity (e.g. walking uphill or into the wind, or climbing stairs) and be relieved by short periods (a few minutes) of rest, but reoccur with exercise. It should be noted that a few patients are able to walk through the claudication; this is probably due to reducing the work rate of muscle.
CASE STUDY 5.1 INTERMITTENT CLAUDICATION
A 50-year-old male patient is referred to you complaining of leg pain on exercise.
QUESTION
What three key questions would you ask to confirm a clinical diagnosis of intermittent claudication?
ANSWERS
Rest pain
Rest pain signifies a more precarious blood supply to the limb than does intermittent claudication, indicating a failure in flow at the microcirculatory level. The pain, which is typically felt at night or when the lower limbs are elevated and warmed, can be excruciating and is described as burning in nature, often located in the forefoot and associated with symptoms of paraesthesia. Patients are wakened from sleep and have to resort to placing their limbs in a dependent position with their feet on cold surfaces to alleviate the pain. In severe cases, patients may not be able to sleep through a complete night because of ischaemic rest pain, and may have to resort to sleeping semi upright with their feet in a dependent position. With progressive ischaemia, rest pain may eventually be continuous despite all attempts to increase blood flow through limb dependency.
Other complaints might include cold feet, which is of a persistent nature and present even in high environmental temperatures. Colour changes may vary, and include: pallor, which is due to diminished blood flow, cyanosis, which is seen when the blood flow is sufficient to prevent blanching; and erythrocyanosis, which is produced by anoxic damage to capillaries and venules, resulting in continued vasodilatation.
Physical signs of PAD will include decreased or absent peripheral pulses below the site of obstruction, premature limb blanching when the limb is elevated from the supine position, the ruddy cyanotic hue that spreads over the lower limbs within 3 minutes when the limb is placed in a dependent position from elevation, and increased capillary filling time (>10 seconds). Congenital absence of peripheral pulses has frequently been reported in the literature (e.g. 10% of people have a congenital absence of the dorsalis pedis), but it is now recognised that this is not as prevalent as the original studies reported. Additional physical signs might include nail changes (e.g. thickening, slow nail plate growth through to loss of the nail plate with scarring), atrophic skin changes (characterised by anhidrosis) and thinning of the skin and loss of subcutaneous tissues.
Critical limb ischaemia is a term used to describe an advanced stage of PAD that is regarded as limb-threatening ischaemia. Five to ten percent of patients develop critical leg ischaemia, with pain in the foot, ulceration or gangrene. Chronic critical limb ischaemia is defined in both diabetic and non-diabetic patients by either of the two following criteria:
The impact of PAD on the patient cannot be simply measured or assessed in terms of distance walked and the severity of pain experienced. Research shows that patients with PAD:
DIAGNOSIS
The diagnosis of PAD in primary care is frequently based on the clinical method, which includes:
Specialist vascular laboratory investigations may include:
CASE STUDY 5.2 PERIPHERAL ARTERIAL DISEASE AND SEVERE VASCULAR DISEASE
Two new patients are referred to you with peripheral arterial disease, and you measure their ankle/brachial pressure index (ABPI) in each patient. In one patient the value is 0.8 and in the other patient it is 0.4.
ANSWER
Both patients have clinical evidence of peripheral arterial disease. In the patient with an ABPI of 0.8 the severity of the disease is mild, and therefore it is very unlikely that any surgical intervention would be considered at this stage. However, the patient should be assessed for risk factors for arterial disease and these should be modified where possible. An ABPI of 0.4 is indicative of very severe vascular disease (critical limb ischaemia) and this patient should be immediately referred to a vascular clinic.
ASSESSMENT OF SKIN BLOOD FLOW
Many podiatrists ask if is it is possible to measure skin blood flow because they wish to know whether or not the skin blood flow (volume not quality) is adequate to support wound healing. There are many different methods and instruments used in the assessment of skin blood flow, these including laser Doppler flowmetry and imaging, capillaroscopy, spectrophotometry, thermography, plethysmography and transcutaneous blood gas monitoring. Measuring skin blood flow is complex and difficult, and cannot be undertaken in routine clinic. Skin blood flow is influenced by many physiological and environmental variables (e.g. temperature, respiration and anxiety), and it is compounded by the fact that skin blood flow exhibits both spatial and temporal variations, all of which make it difficult to establish baseline blood flow norms. Nearly all the instruments are used to measure changes in skin blood flow following a vascular challenge (e.g. iontophoresis of an endothelium-dependent (acetylcholine) or endothelium-independent vasodilator (sodium nitroprusside)). These techniques have made important contributions to our understanding of skin blood flow in both health and disease. The description of each of these techniques is outside the scope of this chapter. However, of note is capillaroscopy, which is a relatively unknown technique in the UK. This allows direct visualisation of the morphology of capillaries located in the eponychium, and, more recently, measurement of capillary blood flow. This technique has contributed to our knowledge of the different morphological changes seen in Raynaud’s disease and Raynaud’s syndrome.
Historically, podiatrists have assessed skin colour, condition and temperature as indicators of the patency of the cutaneous microcirculation. For example, colour and temperature are used as indicators of perfusion and oxygenation:
The technique for assessing skin temperature is to run the back of both hands down both legs simultaneously, noting any significant differences in temperature between the left and right limbs, and the proximal and distal segments. This assessment should be undertaken when the patient has been rested in an environmental temperature of 24°C for 15 minutes. Skin will deteriorate when vascular perfusion and oxygenation is compromised, becoming dry, thin, inelastic, shiny, and hairless, and nail growth will slow or cease. These cutaneous changes take time to develop, and may not always be present at the time of diagnosis of PAD, and are not exclusive to arterial disease.
The classification of PAD can be based on symptoms (e.g. claudication distance, ankle–brachial index, critical limb ischaemia) or on the Fontaine classification. The Fontaine classification consists of four stages:
CLINICAL MANAGEMENT
The effective management of PAD must include a reduction in the risk factors as well as effective management of symptoms. Patients with PAD, even in the absence of ischaemic heart disease and ischaemic stroke, have approximately the same relative risk of death from cardiovascular disease as patients with a history of coronary or cerebrovascular disease. Therefore, the focus of management must be on reducing cardiovascular complications, managing pain and improving quality of life. This can only be effectively achieved through a multidisciplinary approach, which places the patient at the centre, ensuring that he or she is informed, engaged and empowered. Patients with suspected PAD should be referred into secondary care when:
Risk reduction
Smoking
Although there is a paucity of high-quality research evidence (meta-analyses, systematic reviews of randomised controlled trials) concerning smoking-cessation therapy for patients with PAD, there is clear evidence that smoking is associated with a range of vascular disorders, and as a consequence all PAD patients should be actively discouraged from smoking. The selection of the methodology for smoking cessation should be informed by published guidelines, with podiatrists taking a more prominent role in this aspect of management.
Elevated cholesterol
There is good-quality evidence of a benefit of lipid-lowering therapy (e.g. statins) for patients with PAD whose cholesterol levels are >3.5 mmol/l.
Glycaemic control
Research reports that in patients with type 2 diabetes mellitus good glycaemic control reduces the risk of cardiovascular morbidity and mortality (e.g. a 1% reduction in HbA1c is associated with a 14% reduction in risk of myocardial infarction over a 10-year period). Despite the lack of research evidence linking glycaemic control with PAD, good glycaemic control for all patients with diabetes mellitus will reduce the incidence of cardiovascular disease.
Blood pressure control
Hypertension (>140/90 mmHg) is a recognised risk factor for atherosclerosis, and the literature reports a strong association with cardiovascular and cerebrovascular events, and premature mortality. In the context of patients with hypertension and PAD, treatment for hypertension should adhere to the national guidelines, which are applicable to the general population. Concern has been reported about the adverse effect of peripheral vasoconstriction in PAD patients who are prescribed beta blockers.
Obesity
Obesity, which is defined as a body mass index (BMI) >30 kg/m2 is associated with a number of cardiovascular risk factors, such as blood pressure, plasma cholesterol and thrombogenesis. It also limits walking capacity, and therefore could have a negative impact on treatment/rehabilitation.
Drug therapy
Five drugs are licensed for the symptomatic treatment of intermittent claudication: Cilostazol has antiplatelet and vasodilator effects, and is used in patients with short claudication distances. Naftidrofuryl also has a vasodilator effect and is recommended for use in patients who have tried exercise programmes and report a poor quality of life. Oxpentifylline and Inositol nicotinate are vasodilatatory; however, there is no evidence for their efficacy in the treatment of intermittent claudication. Finally, Cinnarizine, which works antagonistically to a number of vasoconstrictors, also lacks evidence of efficacy.
Exercise therapy
Exercise programmes are a relatively inexpensive, low-risk option compared with other more invasive therapies for patients with intermittent claudication. A Cochrane Review investigated the effects of exercise programmes on intermittent claudication, particularly in respect to the reduction of symptoms on walking and an improvement in quality of life. Compared with usual care or placebo, exercise significantly improved maximal walking time and distance, with an overall improvement in walking ability of 50–200%. Improvements were seen for up to 2 years. Due to limited data it was not possible to assess the effect of exercise, compared with placebo or usual care, on mortality, amputation or peak exercise calf blood flow. The authors concluded that exercise programmes were of significant benefit, compared with placebo or usual care, in improving walking time and distance in selected patients with leg pain from intermittent claudication. There still remains considerable debate about what constitutes the optimum exercise regimen, and why there is such a variance in patient compliance.
Alternative therapies
Both Gingkgo biloba and vitamin E are reported to be beneficial in the management of PAD. However, the research evidence is not strong enough to draw any definite conclusions about their effectiveness in the treatment of PAD.
Vascular intervention
Surgical intervention for stable intermittent claudication is rarely required, as the risk to limb viability is low. It is estimated that 6–10% of patients per year will require a surgical intervention. Surgical treatment falls into two groups: angioplasty and stenting, which is most useful in patients with focal disease; and bypass surgery, for those patients with severe disability impacting negatively on their quality of life, who failed to benefit from exercise therapy, risk-factor reduction and medical treatment.
ACUTE ARTERIAL OCCLUSION
This is commonly due to embolism from the heart as a result of mural thrombosis after myocardial infarction or endocarditis. Emboli frequently become lodged in aortic, iliac or popliteal bifurcations, resulting in the limb becoming extremely painful, pale, cold and numb, with an absence of pulses distal to the occlusion, and eventually loss of function. Thrombosis is also a cause of acute occlusion, and this typically occurs in atheromatous arteries. Acute occlusion is a medical emergency that requires pain relief, heparinisation and prompt surgical embolectomy.
VASCULITIS
The term vasculitis describes a group of mixed conditions that are characterised by local inflammation of the wall of the arteries or arterioles, with the inflammation extending to affect veins and capillaries in some cases. The three most frequently seen inflammatory conditions that affect the lower limb vessels are thromboangiitis obliterans, polyarteritis nodosa and vasculitis seen in association with rheumatoid arthritis.
Thromboangiitis obliterans (Buerger’s disease)
Leo Buerger’s original description in 1924 refers to a perivascular inflammation involving distal arteries, veins and nerves, which were frequently agglutinated by fibrous tissue. These segmental lesions, which could develop rapidly, were typically located in distal sections of vessels.
Epidemiology
The typical age at onset is 20–45 years, with males being affected 7–8 times more frequently than females. This higher prevalence rate in males is changing, probably as a consequence of increasing cigarette smoking in young females. Overall, the prevalence rate of the disease is thought to be falling.
Aetiology
Although the exact aetiology remains unknown, Buerger’s disease is now considered to be an accelerated form of atheroma that affects heavy-smoking, young males. There is a slight genetic predisposition associated with HLA A9 and B5.
Clinical features
Patients develop superficial migratory thrombophlebitis, cool dysaesthetic feet, claudication or rest pain, and gangrene. The migratory thrombophlebitis is usually present for at least a year prior to the development of arterial symptoms. Arterial disease is present in both the lower and upper limbs, and the features typically include cold feet/hands, paraesthesia, claudication, severe rest pain, and trophic ulceration and gangrene. Claudication, if present, is typically located to intrinsic foot muscles, and this symptom is often misdiagnosed as metatarsalgia of orthopaedic origin. Proximal limb pulses are usually normal, with distal ones being absent or diminished.
Pathology
The vasculitis affects medium and small arteries and veins. Short segments of the vessel are occluded by thrombus, and there is intense infiltration of the thrombus and the whole thickness of the vessel wall by inflammatory cells, but the wall does not tend to ulcerate. These changes eventually evolve into chronic inflammation and, finally, fibrosis. Different areas of the vessels are affected at different times, with the upper limbs often being the primary site.
Differential diagnosis
The differential diagnosis is from premature atherosclerosis. Features that assist in differentiating thromboangiitis obliterans from premature atherosclerosis include:
Polyarteritis nodosa
Polayarteritis nodosa (PAN) is a necrotising vasculitis affecting medium-sized arteries. This rare disorder affects twice as many males as females and, although it can affect any age group, it has a peak incidence in the fourth and fifth decades of life. It is associated with circulating immune complexes containing the hepatitis B surface antigen, and in populations where hepatitis B is common there is a corresponding high incidence of PAN.
Clinical features
The symptoms and signs of PAN relate to its devastating multisystem inflammatory nature, and vary depending on which organs are predominantly affected. Classical signs include vague systemic illness, muscle pains, mononeuritis multiplex (as a consequence of the involvement of the vas nervorum), abdominal pains, severe hypertension, chest pain, renal impairment, arthritis, claudication, and cutaneous lesions such as palpable purpura, ulceration and gangrene.
Differential diagnosis
This is mainly from other collagen vascular disorders, which can produce indistinguishable lesions. The diagnosis is based on clinical features; angiography shows multiple aneurysms and smooth narrowing of affected vessels. Immunological studies may assist in excluding other collagen vascular diseases:
Rheumatoid vasculitis
Vasculitis is seen in approximately 20% of patients with rheumatoid arthritis who present with nodules and are positive for rheumatoid factor. Vasculitis affects small vessels (terminal arterioles and capillaries), resulting in nail-fold infarcts and small areas of tissue ulceration. In other patients, vasculitis affects small arteries and is responsible for larger areas of cutaneous ulceration and digital gangrene. In some patients the usual signs of vaculitis (skin infarction, neuropathy and scleritis) may be absent, and the key features may be rapid weight loss, fever, malaise and a persistently raised erythrocyte sedimentation rate.
VASOSPASTIC DISORDERS
Raynaud’s phenomenon
In Europe, the broad term Raynaud’s phenomenon is used to describe any form of cold-related vasospasm. This broad classification can then be subdivided into Raynaud’s disease (RD), when the symptoms are consistent with the original description given by Maurice Raynaud in 1862 and where connective tissue disease is absent both clinically and serologically, and Raynaud’s syndrome (RS), where there is an associated disease. This nomenclature allows patients to progress from RP to RS; however, the term Raynaud’s phenomenon is used when there is uncertainty.
Raynaud’s disease is a common condition, occurring in 5–10% of the population, and it is especially common in women aged 20–40 years. The range of disorders associated with Raynaud’s syndrome is wide and includes:
Clinical features
On exposure to cold, typically two or three fingers or toes (in up to 50% of cases) go into a prolonged vasospasm, and turn initially white and feel numb with a progressive loss of fine movement. This is followed by cyanosis, which is due to a slow blood flow and desaturation, and finally the fingers or toes become bright red and painful from a reactive hyperaemia.
Pathology
A number of abnormalities of vascular control have been identified in patients with RD and RS. In RD, increased sympathetic nervous activity is thought to be involved, probably a local vascular hyperreactivity to the sympathetic activity. In addition, calcitonin-gene-related peptide (CGRP), a potent vasodilator, is reduced in patients with RD. The vascular endothelium, a regulator of vascular tone through the production of chemicals such as nitric oxide, endothelin and prostacyclin, has been shown to be involved in the pathogenesis of both RD and RS. Changes in haemostasis, fibrinolysis and haemorrheology have all been reported in patients with RD and RS. Capillaroscopy has demonstrated morphological changes (tortuosity, dilation and drop-out) in nail-fold capillaries in patients with RS.
Treatment
CASE STUDY 5.4 COLD, WHITE TOES
A patient complains intermittently of three cold toes, which appear white in colour from the proximal interphalangeal joints distally.
ACROCYANOSIS
This is a benign condition that presents with persistently cyanosed, cold, clammy and puffy skin, and is seen typically in the hands, feet and, rarely, the face. Peripheral pulses are normal and trophic changes are very rare. It is thought to be due to increased vasomotor tone and a dilatation of the capillaries/venules. Seen mainly in young females it is of minimal clinical significance and improves when the patient moves into a warmer atmosphere.
ERYTHOMELALGIA
This is a rare condition that is characterised by intense paroxysmal hyperaemia, pain and heat. This condition typically affects the hands, feet and face. It is seen in association with a number of disorders, including hypertension, diabetes mellitus, connective tissue disease, spinal cord injury, myeloproliferative disorders and multiple sclerosis.
Treatment is focused on rest, aspirin and treatment of any underlying disorders.
LIVEDO RETICULARIS
This painless condition is characterised by purple rings with central islands of pallor. The typical location is on exposed limbs – backs of the legs and forearms. This condition can be a primary disorder, and is probably due to an increase in vasomotor tone. In other patients it is secondary, and it is seen in association with PAD.
ERYTHEMA ABIGNE
Erythema abigne (also known by many other names, such as fireside tartan and granny’s tartan) presents initially as multiple circular red rings on the sides of legs exposed to direct heat. In advanced cases, the red colour may be replaced by darker brown rings, which are due to the activation of melanocytes. In heavily sedated or demented patients the condition may advance to ulceration due to repeated or continual exposure of the skin to heat.
FROSTBITE
Frostbite is the result of severe cold exposure and the combined effects of wind chilling. The affects are variable and depend upon the extent of the pathology, which might include direct damage to skin, prolonged vasoconstriction and sludging in the microcirculation. The typical picture of mild frost bite is one of pain or numbness, and pale waxy skin that typically blisters within 1–2 days of chilling.
IMMERSION FOOT (TRENCH FOOT)
This condition describes excessive exposure to water. The clinical picture will vary depending on whether the foot is exposed to cold or warm water. Exposure to cold water presents with cold, pulseless, numb, mottled skin, which tends to ulcerate, exposing healthy tissue; exposure to warm water produces painful, tender, macerated tissues that are prone to blistering and bruising.
MICROVASCULAR DISEASE
Microvascular disease occurs in both insulin-dependent and non-insulin-dependent diabetes mellitus, and its development is linked to the duration of diabetes and the degree of glycaemic control. The term microvascular disease refers to the changes seen in the smallest vessels (capillaries and arterioles). Understanding the nature and pathophysiology of microvascular disease will make significant contributions to our knowledge of cutaneous ulceration and its treatment. The vascular endothelium plays key roles in the regulation of blood flow, vascular remodelling, haemostasis and thrombosis, and in inflammation. Microvascular disease damages endothelial cells, impairs their function and thickens the basement membrane. The resultant effect is decreased blood flow and reduced vasodilatatory capacity. This impairs wound healing, and limits the tissue’s ability to respond to traumatic incidents and invasion of microorganisms. In diabetes, microvascular disease is frequently seen in the small vessels of the retina, renal glomeruli and nerve sheaths. Microvascular signs typically develop 10–20 years after the diagnosis of diabetes in young patients, but may present earlier in older patients, possibly due to the period of time for which they have had unrecognised diabetes.
VENOUS DISEASE
Venous disease encompasses thrombosis and thrombophilia (an inherited or acquired state leading to an increased risk of thromoembolic disease).
In 1856, Virchow proposed that thrombosis (homeostasis in the wrong place) would require two of the following three states (referred to as Virchow’s triad):
Although Virchow proposed the three broad headings, developments and research in haematology and vascular medicine have added considerable knowledge and understanding of the biochemical pathways of each mechanism. The clinical presentation of venous thromboembolic disease can vary:
Deep venous thrombosis (DVT)
This is a common and important condition that should be recognised early in its development and have the diagnosis confirmed. Failure to diagnose and instigate effective treatment may result in pulmonary embolism, which could be fatal, or permanently damage and impair the lower-limb venous drainage.
In addition to the risk factors for thrombosis and thrombophilia (see above), the profile of the patient is likely to include: increasing age, obesity, pregnancy, history of previous thrombosis and/or surgery (frequently hip and knee surgery), and use of oral contraceptives.
Clinical diagnosis
The diagnosis is notoriously difficult and there is a proneness to false-positive results when validated against objective tests. Clinical diagnosis (based on signs and symptoms) is reported to be incorrect in up to 70% of cases. Objective tests are based on diagnostic imaging (venography, ultrasound, plethysmography, spiral computerised tomography or magnetic resonance imaging) and haematological assay (usually in patients with a history or family history of DVT) such as for antiphospholipid antibody, homocysteine, factor V Leiden, and protein C and S and antithrombin.
Clinical features
The most common site is the calf, where it is confined to the sinuses of the soleus muscle and the posterior tibial and peroneal veins. The next most common sites are the femoral vein and iliofemoral vein, which produce the most severe manifestations because of their proximal position.
The following are features of DVT:
These symptoms are variable and may be attenuated, depending on the magnitude of the thrombosis, the vessel affected and the state of the collateral circulation. Differential diagnosis should include:
Treatment
The aims of treatment are to prevent propagation of the thrombosis, pulmonary embolism and valvular damage, which could lead to long-term impairment of venous drainage. Treatment will include:
This is the mainstay of treatment as it prevents thrombus extension, new thrombus formation and embolisation of the thrombosis, and reduces the complications of developing pulmonary embolism. Heparin is administered either subcutaneously or intravenously for 6–8 days depending on the extent of the thrombosis. In most patients warfarin therapy will commence at the same time, as it take 2–3 days to decrease the concentration of the vitamin-K-dependent clotting factors. Heparin should be continued until the international normalised ratio (INR) is >2.0 for 2 days consecutively. Following a single episode of venous thromboembolism it is the norm to continue with the oral anticoagulant for 3–6months, but this period will be increased if the patient has a thrombophilic condition. It is important to remember that common drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) can affect the action of warfarin, and therefore patients should have their INR checked when starting and stopping additional medication. Thrombolytic agents are designed to dissolve the thrombus and should only be considered in significant proximal thrombosis where the DVT is considered a significant risk. Haemorrhage is a potential complication of this type of therapy and must be taken into consideration when considering this option.CASE STUDY 5.5 SWELLING IN THE CALF AFTER SURGERY
A 60-year-old woman who has recently undergone surgery presents with pain and swelling in her right calf. The symptoms started insidiously over the past 2 days and seem to be getting worse, as the limb is becoming mildly cyanotic.
ANSWERS
PULMONARY THROMBOEMBOLISM
The most common origin of a pulmonary embolism is from a DVT in the legs (80%) followed by thrombosis in the pelvis (15%). In the UK, 30 000 deaths per year are attributable to pulmonary thromboembolism.
The features of pulmonary thromboembolism depend on the magnitude of the thromboembolism:
SUPERFICIAL THROMBOPHLEBITIS
This is a common, and often recurring, problem seen in primary care that presents with a local area of skin around a superficial vein being, tender, swollen, warm and red. The vein feels indurated and resistant to light finger compression. The onset of the condition is often sudden, and can be triggered by direct trauma to the vein. Superficial thrombophlebitis does not require anticoagulation. Analgesic NSAIDs are usually sufficient, when combined with correct compression therapy (compression is contraindicated in a patient with PAD and an ankle–brachial plexus index of <0.8) and an exercise walking regimen. Antibiotics should only be used when there is evidence of infection.
CHRONIC VENOUS STASIS
This common condition, which affects 1% of the adult population, results from either extensive or repeated venous thrombosis and/or valvular incompetence associated with varicose veins or a failure in the venous pump mechanism(s). There is a familial clustering of the condition, and there is thought to be a genetic element to its development.
Following a DVT there is an increase in venous hypertension in the deep, perforating and superficial veins, which results in damage at the microcirculatory level. The nature of this damage has been extensively debated, and theories have included: tissue hypoxia due to stasis of flow; excessive atrioventricular shunting; and a fibrin cuff acting as a barrier to diffusion. All these theories have been challenged and, while there is agreement that there is a failure at the level of the microcirculation, the exact mechanisms are still to be fully elucidated. Recent interest has been focused on the plugging of the microcirculation by activated white blood cells.
Clinical features
Treatment
The treatment of chronic venous stasis remains unsatisfactory. Treatment is directed at reducing venous hypertension by compression therapy, regular exercise walking regimens and, where possible, limb elevation to aid venous drainage. If chronic venous stasis is due to isolated superficial venous incompetence, surgical ligation, stripping and local sclerosing agents may be a long-term cure.
LYMPHATIC DISEASE
The function of the lymphatic system is to remove macromolecules and excessive fluid from the interstitial spaces and allow transfer of lymphocytes from the lymph nodes to the circulation. Disease of the lymphatic system causes oedema.
LYMPHOEDEMA
Primary lymphoedema (Milroy’s disease)
This is caused by a failure in the development or an absence of lymphatic vessels in embryonic life. It can be seen in isolation or in association with other congenital anomalies (e.g. Turner’s syndrome). The development of the oedema is insidious, and the age at onset will reflect the varying degrees of failure. Lymphograms show varying degrees of hypoplasia, or even aplasia, in the main vessels or, less frequently, there may be gross varicose dilatations and reflux into the skin.
Secondary lymphoedema
Secondary lymphoedema is due to an obstruction of the lymphatic vessels by some known pathological process:
Clinical features
The age of onset varies, and in secondary lymphoedema it depends upon the underlying cause. Primary lymphoedema affects both sexes, although 70–80% of cases are female. In only 10% of cases is oedema present at birth; in 80% of cases it is present before the age of 35 years, and the remaining 10% presents after the age of 35 years. In 80% of primary cases the features develop in one lower limb. The oedema is initially of the pitting type, which is reduced with elevation, but eventually it becomes non-pitting and indurated as a result of fibrosis. The epidermis is classically ‘warty and hyperkeratotic in appearance’ and may predispose to opportunistic infections in 20% of cases.
Diagnosis
Diagnosis is based on the clinical history and presentation, and exclusion of other cause(s) of oedema. A lymphangiogram is a definitive test to confirm lymphatic obstruction.
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