Lower extremity arterial disease (LEAD) is one of the manifestations of systemic atherosclerosis. It is associated with a high risk of cardiovascular morbidity and mortality, functional impairment, and decreased quality of life. An early diagnosis of LEAD allows a more rapid initiation of lifestyle changes and specific treatment, with a better prognosis. LEAD has the same morbidity and mortality as coronary artery disease . It has similar risk factors to coronary and cerebrovascular diseases, with which it is associated in most cases .
LEAD increases the general cardiovascular risk, patients with this disease having a fivefold to sixfold higher risk of morbidity or mortality than from other atherosclerotic causes, such as coronary artery disease or stroke.
The initial evaluation of patients should focus on screening for specific risk factors, in order to diagnose the disease at an early stage, including asymptomatic patients and those with atypical symptoms.
LEAD often goes undiagnosed by physicians and can be ignored by patients, who mistake the symptoms for something else. Patients with LEAD may present with pain, cramping or tiredness in the legs or hip muscles during physical effort (such as walking or climbing stairs). Typically, the pain disappears with rest.
The most used classifications of LEAD are Fontaine (in Europe) and Rutherford (in the USA).
The Fontaine classification describes four stages of LEAD:
Stage I – Asymptomatic
Stage I includes patients who are asymptomatic for most of the time, but in whom a careful history may reveal non-specific, subtle symptoms, such as paresthesia. Physical examination may reveal cold extremities, reduced peripheral pulse or murmurs in the peripheral arteries.
Stage II – Intermittent claudication. Patients usually have a constant distance at which the pain appears:
Stage IIa – Intermittent claudication after more than 200 m of walking.
Stage IIb – Intermittent claudication after less than 200 m of walking.
Stage III – Rest pain. Rest pain appears especially during the night when the legs are raised up on to the bed, which diminishes the gravitational effect present by day; also, during the night, the lack of sensory stimuli allows patients to focus on their legs.
Stage IV – Ischaemic ulcers or gangrene (which may be dry or humid) .
The Rutherford classification describes seven stages of peripheral artery disease:
Stage 0 – Asymptomatic.
Stage 1 – Mild claudication.
Stage 2 – Moderate claudication – the distance that delineates mild, moderate and severe claudication is not specified in the Rutherford classification, as it is in the Fontaine classification.
Stage 3 – Severe claudication.
Stage 4 – Rest pain.
Stage 5 – Ischaemic ulceration not exceeding ulcers of the digits of the foot.
Stage 6 – Severe ischaemic ulcers or frank gangrene.
Both the Fontaine and Rutherford classifications have the same stages of peripheral artery disease. The first stage of both classifications includes asymptomatic patients. In the next stage, respectively, stage II Fontaine and stages 1 to 3 Rutherford, which describe patients with claudication, there are differences between the two classifications. The Fontaine classification specifies exactly the distance at which the pain occurs – 200 m, respectively, stage IIa – a distance longer than 200 m, with no pain before, and stage IIb – a distance shorter than 200 m. Therefore, the pain can be objectively appreciated by the physician. On the other hand, the Rutherford classification describes the claudication as mild, moderate and severe, with no precise limit between the stages. The next stage (stage III Fontaine and stage 4 Rutherford) includes patients with rest pain, without differences between the two classifications. The differences appear again in the last stage. The last stage of the Fontaine classification (stage IV) includes both ischaemic ulcers and gangrene, dry or humid, meaning that ischaemic ulcers are considered as severe as gangrene, according to this classification. The last two stages of the Rutherford classification differentiate minor tissue loss (stage 5) from major tissue loss (stage 6).
The Fontaine classification is solely based on clinical symptoms, without other diagnostic tests. Usually, it is used for clinical research and it is not routinely used in patient care .
The Rutherford classification is more detailed and describes acute and chronic limb ischaemia separately. It also associates clinical symptoms with objective findings - ankle-brachial index (ABI), pulse volume recordings and vascular Doppler ultrasound.
The Rutherford classification for chronic limb ischaemia:
Stage 0: Clinical description – asymptomatic (no haemodynamically significant occlusive disease).
Objective criteria – normal treadmill or reactive hyperaemia test.
Stage 1: Clinical description – mild claudication.
Objective criteria – completes treadmill exercise; ankle pressure (AP) after exercise >50 mmHg but at least 20 mmHg lower than resting value.
Stage 2: Clinical description – moderate claudication.
Objective criteria – between categories 1 and 3.
Stage 3: Clinical description – severe claudication.
Objective criteria – cannot complete treadmill exercise and AP after exercise <50 mmHg.
Stage 4: Clinical description – ischaemic rest pain.
Objective criteria – at rest AP <40 mmHg, flat or barely pulsatile ankle or metatarsal pulse volume recording (PVR); toe pressure (TP) <30 mmHg.
Stage 5: Clinical criteria – minor tissue loss, non-healing ulcer, focal gangrene with diffuse pedal ischaemia.
Objective criteria – at rest AP <60 mmHg, ankle or metatarsal PVR flat or barely pulsatile; TP <40 mmHg.
Stage 6: Clinical description – major tissue loss, extending above transmetatarsal (TM) level, functional foot no longer salvageable.
Objective criteria – same as category 5.
It is also important to evaluate the onset of the symptoms and the character of the pain. The treadmill exercise test is used to identify LEAD with normal ABI at rest, but with diminished ABI after exercise. Patients who cannot perform the treadmill test can be examined by plantar flexion or thigh blood pressure cuff compression [2,3].
The Rutherford classification for acute limb ischaemia:
I. Viable: not immediately threatened, no sensory loss, no muscle weakness, arterial and venous Doppler audible.
a. marginally – salvageable if promptly treated, minimal sensory loss (toes) or none, no muscle weakness, arterial Doppler signal inaudible, venous Doppler signal audible.
b. immediately: salvageable with immediate revascularisation, more than toes sensory loss, rest pain; mild, moderate muscle weakness; arterial Doppler signal inaudible, venous Doppler signal audible.
III. Irreversible: major tissue loss or permanent nerve damage inevitable; profound, anaesthetic sensory loss; profound muscle weakness, paralysis; arterial and venous Doppler signal inaudible .
The Rutherford classification is used for clinical research and for clinical management, because it includes objective findings and it is more accurate .
As mentioned before, in the early stages the disease may be asymptomatic. The asymptomatic patients are a critical mass, because this is the clinical stage associated with the best prognosis, if the diagnosis is made correctly. If therapy is initiated in asymptomatic patients with LEAD, it may prevent evolution to the next stages of the disease. In asymptomatic patients, the focus should be on controlling the risk factors, for example ceasing smoking, controlling the blood glucose level in diabetic patients, and initiating a lipid-lowering therapy, with the aim of controlling systemic atherosclerosis, including lower limb atherosclerosis.
Approximately 40% of patients with LEAD are asymptomatic, defined as the absence of leg symptoms in the presence of an ABI <0.90 or pulse abolition . Asymptomatic patients may be either those with peripheral neuropathy, such as patients with diabetes mellitus, or those who cannot walk enough to experience pain (heart failure, osteoarthritis, other diseases of the muscular or osteoarticular system). The risk of mortality is equal in both asymptomatic and symptomatic patients.
When claudication occurs, patients usually seek a medical consultation, because claudication is associated with an important limitation in walking ability . There are patients who may be asymptomatic for a long period of time, until advanced stages of the disease, with ischemic rest pain. In the last stage, arterial ulcers appear, that are painful and usually complicated with inflammation or infection. When the ulcer is painless, we should suspect a peripheral neuropathy, especially in diabetic patients.
Another category of patients is those with atypical symptoms (for example, leg muscle symptoms that are present at rest and with exercise), who represent 50% of patients with LEAD . Only approximately 10% of patients complain of typical symptoms, such as intermittent claudication . Usually, claudication remains stable (about 70-80% of cases), but in about 10-20% of patients it worsens, and in 1-2% of patients it progresses to acute limb ischaemia.
Differences related to gender
The presence of asymptomatic LEAD or with atypical leg symptoms has been observed in both men and women, but there are gender differences in the prevalence of specific symptoms. According to several studies, women present asymptomatic LEAD more often than men; they also present atypical symptoms more frequently, which appear at rest. Female patients not only tend to be more asymptomatic than men, but also their symptoms may be masked or misinterpreted as osteoporosis, arthritis, or spinal stenosis, conditions that are more frequent in women . Women with LEAD have greater functional impairment than women without LEAD and, furthermore, have greater functional impairment than men with LEAD . Some possible reasons, which could explain why functional impairment is more severe in women than in men, may be reduced calf muscle haemoglobin oxygen saturation, and the lesser strength of the legs in women . A study in which LEAD participants were followed for four years demonstrated that women have greater mobility loss and functional decline than men . Also, women have a higher incidence of disability in walking the same pre-set distance, for instance, fewer blocks in a city walk before they need to stop walking, as well as an overall reduced walking speed. Because women are more often asymptomatic or may present with unusual signs, the disease is harder to diagnose, which leads to later intervention, in an advanced stage, and to a higher risk of critical limb ischemia. Real-life data show that, although women have a greater functional decline, they are less likely to receive revascularisation.
LEAD is associated with several conditions particularly found in women, such as hypothyroidism, osteoporosis, and oral contraceptive use, which leads to an increased incidence of LEAD. Postmenopausal women with osteoporosis have a higher risk of vascular disease, including LEAD, than postmenopausal women with normal bone mineral density, so that a patient known to have arthritis should be screened for cardiovascular disease in order to prevent acute myocardial infarction, stroke, and acute limb ischaemia. Some studies have observed an association between hypothyroidism and LEAD, so there is a need to screen for LEAD in women with hypothyroidism . The use of oral contraceptives is well known to be associated with a high risk of arterial and venous thrombosis, but these drugs also increase the risk of LEAD. A study compared current oral contraceptive users with non-users and noticed that current oral contraceptive users have an increased risk of LEAD . First-generation oral contraceptive drugs were associated with a high risk of LEAD, while second- and third-generation oral contraceptives have been shown to have an almost threefold increased risk compared to non-users . The risk of oral contraceptives is even higher in association with the traditional risk factors for LEAD – smoking, dyslipidaemia, diabetes mellitus, and arterial hypertension .
There is no known difference in the sensitivity and accuracy of the diagnosis in women and men; however, because of the lack of symptoms and also because the association of LEAD with coronary and carotid artery disease is less frequent in women, they are less likely to be screened for LEAD. That is the reason why they are more likely to be undiagnosed and undertreated.
Patients with chronic kidney disease (CKD) are more likely to develop LEAD, because they have additional risk factors such as hypoalbuminaemia, albuminuria  and calcified arteries. The risk of LEAD increases with the decrease in glomerular filtration rate (GFR). Albuminuria is associated with endothelial dysfunction, which is a risk factor for systemic atherosclerosis, including LEAD, and with medial arterial calcification, which increases the stiffness of the arterial walls and leads to the rise of ABI value, that is a “false normal” value [10-12]. Hyperparathyroidism and vitamin D deficiency are other factors that increase the stiffness of the arteries, leading to “false normal” ABI values in patients with CKD. Chronically dialysed patients with uraemia present chronic inflammation, hypoalbuminaemia and an increased risk of LEAD. For patients with CKD who have normal ABI (0.9-1.4) or even higher (>1.4), more tests should be performed, such as vascular Doppler ultrasound, toe-brachial index measurement, treadmill test, and segmental pressure recordings, in order to diagnose a possible peripheral artery disease, especially if the suspicion is high . The most efficient is Doppler ultrasound, an accurate method of diagnosis, with no potential risks , in contrast to diagnostic angiography, which has the risk of contrast-induced nephropathy, especially in subjects with GFR <30 mL/min/1.73 m2, and should be avoided as much as possible in patients with CKD.
In summary, lower extremity artery disease is a highly prevalent disease, with morbidity and mortality similar to coronary artery disease, but is less investigated and consequently less treated. The heterogeneity of signs and symptoms has led to the development of several classifications of the disease. All physicians should be familiar with these classification systems and have a clear understanding of them, in order to diagnose LEAD correctly and to provide the necessary primary care. Asymptomatic patients or those with atypical symptoms are a continuous challenge for the physician with regard to the diagnosis and optimal treatment. There is a need for a multidisciplinary team for accurate management of the disease.