Chapter 9 Metabolic disorders
Metabolic disorders have a considerable importance with regard to public health and may result in significant disease to the foot. They include diabetes, obesity and metabolic bone disorders.
The manifestations of diabetes result from a persistently raised blood glucose level as a consequence of reduced production and/or impaired effectiveness of insulin.
Diabetes mellitus can be divided into two main groups: type 1 diabetes mellitus and type 2 diabetes mellitus. In addition, there is a small group with secondary diabetes.
Type 1 diabetes indicates that there is an almost complete lack of effective insulin, and in the absence of insulin treatment these patients will usually progress to diabetic ketoacidosis. Most of these patients are children and young people under 30 years of age, although it is important to note that type 1 diabetes can present in middle age and in the elderly.
Type 1 diabetes results from damage to the pancreatic beta cells, and genetic, immunological and, probably, environmental (e.g. viral) factors are involved, which lead eventually to total destruction of the beta cell. Type 1 diabetes is a polygenic disease, indicating that many different genes contribute to its expression. The important genetic risk factor for the development of type 1 diabetes is the major histocompatibility complex (MHC) antigens/human leucocyte antigens (HLA). Ninety per cent of people with diabetes in the UK have either HLA-DR3 or HLA-DR4, or both. This leads to the beta cell demonstrating improper antigens to T cells, and eventually results in the production of antibodies that attack the beta cell. Lymphocytes infiltrate the islets of Langerhans, and antibodies against islet cells are present in the sera of 80% of type 1 diabetic patients. There may be certain trigger events, such as viral infections, which precipitate this series of reactions. An increased prevalence of newly diagnosed type 1 diabetes has been found in children aged 4–6 and 11–14 years. These age groups coincide with entry to primary and secondary school.
In type 2 diabetes there is a relative, but not an absolute, lack of insulin. Peripheral tissue becomes insulin-resistant; that is, less sensitive to the effects of insulin. There is also a strong inheritable genetic association in type 2 diabetes: having relatives (especially first-degree relatives) with type 2 diabetes increases the risk of developing type 2 diabetes very considerably. In 25% of cases a first-degree relative has type 2 diabetes, and virtually all identical twins of patients with type 2 diabetes develop the disease, even if brought up in different environments.
Type 2 diabetes is the most common type of diabetes. Patients are usually older than 40 years at diagnosis but may be younger, and are often obese. Although considered a disease of adults, type 2 diabetes is increasingly diagnosed in children in association with rising obesity rates. Patients with type 2 diabetes may have relatively few symptoms and do not usually develop ketoacidosis. These patients have normal or increased levels of insulin but this is associated with relative ineffectiveness of insulin at the cellular level. Type 2 patients may, nevertheless, receive insulin therapy and, indeed, up to 25% of patients do so simply to control their blood glucose. They do not need insulin for survival; however, in certain stressful reactions, such as infection and coronary thrombosis, patients with type 2 diabetes patients may also require insulin therapy.
Secondary diabetes occurs when there is direct damage, removal or impairment of action of the mass of beta cells. This type of diabetes is uncommon but causes of a beta-cell deficit include:
Gestational diabetes is impaired glucose tolerance that occurs in pregnancy.
Diabetes is diagnosed on finding a random blood glucose level of more than 11.1 mmol/l and symptoms of hyperglycaemia. The standard oral glucose tolerance test is rarely required to establish the diagnosis, although the accepted values of capillary blood glucose of a 75 g glucose load to diagnose diabetes is ≥7.0 mmol/l fasting and ≥11.1 mmol/l at 2 hours.
The classic symptoms are thirst, polyuria and weight loss, combined with pruritus vulvae or balanitis. The intensity of symptoms varies greatly; they tend to be more severe or more acute in type 1 than type 2 diabetes. The lack of insulin leads initially to hyperglycaemia, and when the glucose concentration in the blood reaches a level of 10 mmol/l the glucose exceeds the tubular reabsorptive capacity and glycosuria results.
In states of severe insulin deficiency, glucose has to be obtained by metabolising amino acids from the breakdown of proteins in a process called gluconeogenesis. Increased breakdown of fat also occurs with the formation of ketone bodies, including acetone, which leads to severe metabolic acidosis, so-called ketoacidotic coma.
The duration of symptoms in type 1 diabetes is usually a few weeks. This can lead to wasting and physical weakness and eventually to vomiting and dehydration. Insulin is needed urgently and, if not given, ketoacidosis will develop, presenting as drowsiness, dehydration and overbreathing (together with acetone in the breath). These are the clinical features of ketoacidosis, which requires urgent admission to hospital and insulin therapy. Occasionally, patients with type 1 diabetes may have a late onset and a slow but persistent progression of the disease.
The presentation of type 2 diabetes is generally less acute. Patients sometimes complain of only one of the classic symptoms. Symptoms develop over variable periods, frequently over several weeks or months. An increasing number of patients are found to have diabetes at routine screening examinations of either urine or blood. Some older patients with type 2 diabetes present for the first time because of diabetic complications. Foot sepsis or ulceration presenting as an emergency almost always indicates a diagnosis of diabetes.
Type 1 diabetes results from the complete absence of insulin, and this can be treated effectively by the replacement of that insulin. Human insulin, commonly prepared by genetic manipulation of yeast, is now widely used. There are also insulin analogues that contain a slightly different structure to that of human insulin.
Types of insulin can be divided into very rapid-acting analogues, fast-acting, intermediate-acting and long-acting human insulin and extended long-acting analogues. Pre-mixed insulins containing a fixed ratio of rapid- or fast-acting insulin to intermediate-acting insulin are also available. Many insulins are now available in cartridges to fit the several available pen injection devices. To achieve glycaemic targets people with type 1 diabetes need multiple daily injections (3 or 4 per day) or to have a continuous subcutaneous insulin infusion (CSII) via an insulin pump; the latter should be considered as part of an intensive diabetes management programme.
Regular amounts of carbohydrate at fixed times are important in insulin treatment to reduce the swings of blood glucose and, in particular, to avoid hypoglycaemia. Thus, the importance of snacks mid-morning, mid-afternoon and before bedtime should be emphasised. During infection or illness the blood glucose tends to increase. Insulin needs to be increased at these times, particularly when patients stop eating or are vomiting, because hepatic production of glucose in itself often leads to significant hyperglycaemia.
Stress-related ‘resistance’ to insulin and the consequent increase in the hepatic release of glucose explains why the insulin requirements in the sick patient will be the same or even greater than normal, even if the patient is not eating. An adequate fluid and calorie intake with appropriate insulin must be maintained, all monitored by regular blood glucose measurements.
Diet is the cornerstone of treatment, and elimination of simple rapidly absorbed sugars is the minimum necessary requirement. Furthermore, for overweight patients, energy supply must be restricted in order to reduce to ideal weight; 50% of the calorie intake should be from carbohydrates and not more than 35% from fats.
Treatment of type 2 diabetes consists of lowering the insulin requirements, together with the use of agents such as sulfonylureas that can increase beta-cell production of insulin, biguanides to modify glucose output, and acarbose to reduce the rates of glucose absorption. Recently introduced are the thioglitazones, pioglitazone and rosiglitazone, which can improve sensitivity to insulin, and in particular increase peripheral glucose utilisation. These drugs should not be used in patients with heart failure, as there is an increased risk of fracture in females. New therapies for type 2 diabetes have recently become available that are based on incretins, which are intestinal hormones that increase insulin from the pancreas and inhibit glucagon release. They are released after the contact of food with the gut. The main incretin of therapeutic use is glucagon-like peptide-1 (GLP-1), which improves beta-cell responsiveness to glucose, inhibits gastric emptying and has a central nervous system effect, resulting in reduced food intake. Endogenous incretin peptides are short-lived due to their degradation by the enzyme dipeptidyl-peptidase-IV (DPP-IV). The recruitment of the incretin–DPP-IV pathways into diabetes management has led to the development of GLP-1 analogues that are resistant to the actions of DPP-IV and DPP-IV inhibitors, which protect the natural incretin hormones from deactivation. Exenatide (Byetta) is the first GLP-1 analogue available in the UK, and it is licensed for use in addition to oral antihyperglycaemic agents. Sitagliptin and vildaglipti are oral DPP-IV inhibitors that can be used to treat type 2 diabetes, either as monotherapy or added to other therapies such as sulfonylurea, metformin or glitazones (DeFronzo et al 2005).
When drug and dietary therapy fails, insulin must be prescribed.
In the diabetic patient, a fall in glucose to symptomatic levels represents a temporary mismatch of insulin level to intestinal glucose uptake – a meal may have been missed or delayed, a dose of insulin mismeasured, or unusual exertion undertaken. Symptoms vary from patient to patient, but remain fairly consistent within the individual.
Patients may experience symptoms of hypoglycaemia when the blood glucose is <3 mmol/l, although some who have lost their warning symptoms may pass below this threshold. Others who have suffered previously poor control may be aware of hypoglycaemia at slightly higher levels. With increasing age and duration of diabetes, especially in those who keep their diabetes tightly controlled, there is an increasing tendency towards loss or warning hypoglycaemia.
Symptoms fall into two groups: sympathetic symptoms from activation of the sympathetic nervous system in response to hypoglycaemia; and neuroglycopaenic symptoms, which result from a reduction of glucose supply to the brain.
Early warning sympathetic symptoms are shaking, trembling, sweating and pins and needles in the tongue and lips.
Mild neuroglycopaenic symptoms are double vision, difficulty in concentrating and slurring of speech. Moderate symptoms are confusion, change in behaviour and truculence, and late symptoms are epileptic fits, especially in children, hemiplegia in the elderly and unconsciousness.
Treatment can be as simple as persuading the diabetic patient to take sugar in some form. If the patient is conscious then oral glucose as a drink, tablet or gel can be used. The following items contain 10 g of carbohydrate: Lucozade 60 ml, Ribena 15 ml, Coke (not diet) 80 ml. To prevent relapse of hypoglycaemia, this should be followed by more slowly absorbed carbohydrate such as biscuits or sandwiches. The unconscious patient should be placed in the recovery position with the airway maintained and should be treated with intravenous glucose, usually 20–50 ml of 50% glucose. If the response is not immediate a further dose should be given after 5 minutes, followed by an infusion of 10% glucose.
If intravenous access cannot be obtained, intramuscular glucagon (1 mg) can be given. When oral hypoglycaemics are the cause of hypoglycaemia, the patient should be admitted to hospital, as these agents can continue to cause hypoglycaemia for up to 48 hours.
Diabetic patients may develop a variety of complications, which include microvascular disease (retinopathy and nephropathy), nervous system abnormalities and macrovascular disease (coronary, peripheral vascular and cerebral vascular disease). It is now known that sustained optimal diabetic control in young insulin-dependent diabetic patients delays the onset and retards the progress of diabetic complications.
Retinopathy, nephropathy and neuropathy are reduced by 35–70%, as demonstrated in the Diabetic Control and Complications Trial (DCCT) (Diabetic Control and Complications Trial Research Group 1993) in the USA, which compared the effects of tight control with conventional control in 1441 patients. However, hypoglycaemia was three times more common in the tight-control group compared with conventional treatments. In type 2 diabetes, the UK Prospective Diabetes Study (UKPD) demonstrated significant reductions in microvascular and neuropathic complications with intensive therapy. (UK Prospective Diabetes Study (UKPDS) Group 1998).
With regard to macrovascular disease there is no definite evidence that controlling diabetes can alter the course of the disease. In the DCCT there was a trend toward a lower risk of cardiovascular disease events with intensive control (risk reduction 41%, 95% CI 10–68%) but the number of events was small. The UKPDS observed a 16% reduction in cardiovascular complications (combined fatal or non-fatal myocardial infarction and sudden death) in the intensive glycaemic control group, although this difference was not statistically significant (p = 0.052) and there was no suggestion of benefit on other cardiovascular disease outcomes such as stroke in type 2 diabetes.
The microvascular and neurological complications of type 1 diabetes are rarely seen before 5–7 years’ disease duration, and occur most commonly after 10–20 years. However, in patients with type 2 diabetes 20% have evidence of complications at diagnosis.
Diabetes is the most common cause of blindness under the age of 65 years in the UK. Ten per cent of diabetic patients who have had retinopathy for 40 years or more become blind, while many more have impaired vision. Eye complications include:
There is increased capillary permeability. Dilatation of retinal veins is the earliest recognisable sign. First, microaneurysms appear; these look like red dots and then develop over the retina and may involve the macula. Haemorrhages, which are large and more irregular in shape than microaneurysms, then occur. Large haemorrhages may extend into the vitreous humour. Hard exudates are yellow-white discrete particles of lipid that can occur in rings around leaking capillaries. They can cause blindness when they develop on the macula and are more common in type 2 diabetes.
Proliferative retinopathy reflects capillary non-perfusion. There is new vessel formation, often near the disc, with venous irregularity, cluster haemorrhages and cotton-wool spots. Haemorrhages into the vitreous cause sudden blindness, and are followed by fibrosis, leading to retinal detachment. New vessels are treated with laser photocoagulation.
Diabetic nephropathy is now the leading cause of end-stage renal failure. While type 1 diabetes is responsible for the majority of cases in those under 50 years of age, there are now more patients with type 2 diabetes in end-stage renal failure, especially in the non-white populations. The development of proteinuria, which is indicative of nephropathy, is a serious prognostic factor, anticipating not only a decline in renal function but also an increase in cardiovascular disease.
The clinical hallmark of diabetic nephropathy is persistent proteinuria, which is defined as a 24-hour urinary excretion of ≥500 mg of protein on at least three occasions over at least 6 months. An earlier stage, microalbuminuria or incipient nephropathy, is associated with lower levels of albumin excretion. Eighty per cent of these patients progress to overt proteinuria. Regular measurement of blood pressure in these patients is crucial, and effectively tracks progression of renal damage. Renal support treatment is now well established for diabetic patients, comprising dialysis – usually chronic ambulatory peritoneal dialysis (CAPD) and haemodialysis and renal transplantation.
Peripheral nerves are prone to several different types of damage in diabetes and there are thus highly distinctive syndromes. These include:
A classification of diabetic neuropathies is summarised in Box 9.1.
This is a very common condition affecting 11–50% of diabetic patients, depending on the criteria used or the population selected. Neuropathy is always diffuse and symmetrical (stocking distribution), probably starting with involvement of the smallest fibres (pain, temperature, autonomic) and sometimes, but not always, progressing to involve all types of nerve fibre.
Small, non-medullated nerve fibres are the first to be affected and this gives rise to some of the characteristic features of diabetic neuropathy. This small-fibre degeneration leads to loss of pain- and temperature-sensing modalities, with associated autonomic features, and in these early stages other sensory modalities can remain intact, notably light touch sensation. Early neuropathy is frequently not detected in the clinic because temperature and pain sensation are difficult to assess. Sympathetic failure causes loss of sweating and denervation of peripheral vessels, leading to vascular rigidity and calcification, with a very high peripheral blood flow, chiefly from opening of arteriovenous anastomoses. These blood flow changes can occur quite early in the course of diabetes but need sophisticated techniques for their detection.
Small-fibre neuropathies sometimes progress as a selective entity in some patients, leading to symptomatic autonomic neuropathy (causing diarrhoea, gastroparesis, orthostatic hypotension, impotence, neurogenic bladder, gustatory sweating and other problems), often associated with Charcot joints (Winkler et al 2000). These patients sometimes develop iritis as well, and there is some evidence that immune mechanisms may be involved. On the other hand, in some patients neuropathy progresses to involve all types of nerve fibre, and in the worst cases the feet and lower legs become anaesthetic. Major motor involvement is surprisingly uncommon, even in the severest cases.
The evolution of sensory and autonomic diabetic neuropathy is extremely slow and very variable, occurring over many years, with the increasing age of the patient and duration of diabetes. It never remits. Study is further complicated by the differential rate of progression of the different types of fibre, and there are only a few observations over periods of 5–10 years.
Painful neuropathies in diabetes have highly characteristic features, which include constant ‘burning’, paraesthesia and shooting pains, together with exquisite contact discomfort caused by clothes and bedclothes. The pains are continuous day and night and cause severe insomnia. They are accompanied by profound weight loss. They occur either in a symmetrical sensory stocking distribution affecting both feet, or they may be confined to a single or adjacent group of nerve roots affecting the feet and/or legs, or to one or both thighs, often but not always accompanied by wasting and sometimes debilitating weakness, causing falls. The latter syndrome is known as proximal motor neuropathy or diabetic amyotrophy and is due to either radiculopathy or femoral neuropathy. All these conditions normally recover in 6–18 months.
Neurological examination of the feet in cases of symmetrical painful neuropathy can be confusing, because abnormalities range from severe sensory neuropathy with major deficits in all modalities (the ‘painless painful foot’) to an almost complete lack of neurological abnormalities. This makes assessment and diagnosis of this condition very complex.
Median nerve compression in the carpal tunnel syndrome (usually bilateral) may occur in up to 10% of patients. Diagnosis may be difficult in diabetic patients with severe polyneuropathy involving the hands. Electromyographic studies are necessary to measure conduction in the median nerves. Treatment is by surgical decompression. Ulnar nerve compression is less frequent, but again should be investigated by means of conduction studies. Patients should be advised not to lean on their elbows.
Autonomic function declines with age in the same way that peripheral nerve conduction progressively slows through life. Deterioration of neurological function is accelerated in diabetes, although this decline is not uniform. In some patients it is scarcely different from normal, while in others it is accelerated to the point of severe symptomatic autonomic neuropathy, which is associated with an increased mortality. Symptomatic autonomic neuropathy is surprisingly uncommon compared to the extremely common finding of abnormal autonomic function tests, which can be demonstrated in any diabetic population (Edmonds 2004).
Numerous symptoms can be ascribed to diabetic autonomic neuropathy. Dysfunction may be present in the cardiovascular system, causing postural hypotension, and in the gastrointestinal system, causing severe uncontrollable diarrhoea. In the genitourinary system, difficulty with micturition and impotence are important symptoms. A classic symptom of autonomic neuropathy is gustatory sweating (i.e. sweating in the upper third of the body provoked by eating cheese or spicy food).
The presence of autonomic neuropathy may be confirmed by abnormalities in standard autonomic function tests.
Loss of heart-rate variability during deep breathing is the most reliable and simplest test of autonomic neuropathy. It is best assessed using a cardiotachograph during deep respirations (6 breaths/min), taking average readings over six breaths; it can be performed using an ordinary electrocardiograph during a single deep breath (5 seconds in, 5 seconds out). The heart-rate difference (maximum rate during inspiration minus minimum rate during expiration) in those aged under 55 years is always >10. The increase in heart rate on standing up should be >12 at 15 seconds and there should normally be an overshoot as well. The Valsalva manoeuvre can be included in the tests; a mercury sphygmomanometer is used, the patient blowing hard through the empty barrel of a 20-ml syringe to maintain the mercury column at 40 mm for 10 seconds. Maximum heart rate during blowing, followed by minimum heart rate after cessation are recorded. There should be a bradycardia after cessation of blowing. The ratio of maximum to minimum heart rate is normally >1.21 and is clearly abnormal when <1.10.
Major arterial disease that affects the coronary circulation and cerebral arteries and causes peripheral vascular disease of the feet and legs may represent the most serious of the problems. The prevalence is higher in a diabetic than in a non-diabetic population but it is much greater in those patients who develop proteinuria from diabetic nephropathy. Three-quarters of diabetic patients diagnosed over 60 years of age die from cardiovascular disease, chiefly from myocardial infarction. The proportion is even higher among those with nephropathy. Other risk factors are well known, namely smoking, hypertension, hyperlipidaemia and obesity.
The clinical features of major arterial disease are very similar to those in non-diabetic patients but the following differences should be noted:
The foot in diabetes can be affected by neuropathies and circulatory changes with or without additional problems from trauma and infection, causing potentially serious foot problems (Edmonds & Foster 2005). The clinical abnormalities affecting the lower limb are thus diverse, ranging from permanent abnormalities and symptoms in the feet to the crippling but reversible disorders due to mononeuropathy (proximal motor neuropathy), causing a painful wasting disease of the thigh. A summary of potential disorders affecting the leg is shown in Table 9.1.
Table 9.1 Leg abnormalities in diabetes
| Neuropathy | Ischaemia | |
|---|---|---|
| Symptoms | None | None |
| Paraesthesiae | Claudication | |
| Pain | Rest pain | |
| Oedema | ||
| Painful wasted thigh | ||
| Foot drop | ||
| Structural damage | Ulcer | Ulcer |
| Sepsis | Sepsis | |
| Abscess | Gangrene | |
| Osteomyelitis | ||
| Digital gangrene | ||
| Charcot joints |
The feet are the target of peripheral neuropathy, leading chiefly to sensory deficit and autonomic dysfunction. Ischaemia results from atherosclerosis of the leg vessels which, in the diabetic, is often bilateral, multisegmental and distal, involving arteries below the knee. Infection is rarely a sole factor but often complicates neuropathy and ischaemia. Nevertheless, it is responsible for considerable tissue necrosis in the diabetic foot.
For practical purposes the diabetic foot can be divided into two entities: the neuropathic foot, in which neuropathy predominates and there is a good circulation, and the neuroischaemic foot, where there is both neuropathy and the absence of foot pulses. The purely ischaemic foot, with no concomitant neuropathy, is rarely seen in diabetic patients, and its management is the same as for the neuroischaemic foot.
The neuropathic foot results in a warm, numb, dry and usually painless foot in which the pulses are palpable. It leads to three complications: the neuropathic ulcer, which is found mainly on the sole of the foot; the neuropathic (Charcot) foot; and, rarely, neuropathic oedema. In contrast, the neuroischaemic foot is cool and the pulses are absent. It is complicated by rest pain, ulceration on the margins of the foot from localised pressure necrosis and gangrene.
Neuropathic ulcers result from noxious stimuli, unperceived by the patient because of loss of pain sensation, causing mechanical, thermal and chemical injuries. This characteristically occurs at sites of high mechanical pressure on the plantar surface of the foot. The presence of neuropathy (even in its earliest stage, with relatively mild sensory defects) may itself disturb the posture of the foot and so predispose to local increases in pressure, which are also commonly caused by deformities such as claw or hammer toes, pes cavus, Charcot joints and previous ray amputations. The high vertical and shear forces under the plantar surface of the metatarsal heads and toes lead to the formation of callosities of which the patient is often unaware. Repetitive mechanical forces lead to inflammatory autolysis and subkeratotic haematomas, which eventually break through to the skin surface, forming an ulcer. Direct mechanical injuries to the plantar surface result from treading on nails and other sharp objects. However, the most frequent cause of ulceration brought about by mechanical factors is the neglected callosity.
Ulcers can become infected by staphylococci, streptococci, coliforms and anaerobic bacteria. If untreated, cellulitis can develop, with tracking of infection to involve underlying tendons, bones and joints. Staphylococci and streptococci act synergistically when they are present together: streptococci produce hyaluronidase, which facilitates spread of necrotising toxins from the staphylococci.
In the deep tissues of the foot, aerobic organisms act synergistically with microaerophilic or anaerobic organisms, leading to necrotising infection, the production of subcutaneous gas and, finally, gangrene.
Excess callous tissue should be reduced with a scalpel by the podiatrist to expose the floor of the ulcer and allow efficient drainage of the lesion. The broken skin increases the great risk of infection to the patient because there is a clear portal of entry for invading bacteria to enter the foot. In addition, in the presence of neuropathy and ischaemia, the inflammatory response is impaired. The patient lacks protective pain sensation, which would otherwise automatically force him or her to detect the problem and rest the foot.
Bacterial growth in ulcers impedes the wound-healing rate. Quantitative microbiology has shown that wound healing slows with increased bacterial load. There is a complex host–bacteria relationship. Many wounds are colonised with a stable bacterial population. If the bacterial burden increases there will be bacterial imbalance, which may show itself as increased exudate before frank infection develops. The crucial problem is when to intervene with antibiotics.
It is important to look for early signs of infection, and the next step is to take a bacteriological swab from the floor of the ulcer and, according to the organisms isolated, prescribe the appropriate oral antibiotics until the ulcer has healed (e.g. amoxicillin 500 mg t.d.s. for streptococcal infections; flucloxacillin 500 mg q.d.s. for staphylococcal sepsis; metronidazole 400 mg t.d.s. for anaerobic infections; and ciprofloxacin 500 mg b.d. for Gram-negative infections). If the ulcer is superficial and there is no cellulitis, treatment can take place on an outpatient basis.
Redistribution of weight-bearing forces on vulnerable parts of the foot should be attempted using special footwear, such as moulded insoles with energy-absorbing properties (e.g. plastozote and microcellular rubber). Special shoes may be needed to accommodate the shape of the foot. In cases of severe deformity it is necessary to construct shoes individually for the patient. However, in most patients, extra-depth ‘stock’ shoes will usually suffice (Chantelau & Leisch 1994).
In the case of large indolent ulcers, total contact plaster casts may be used that conform to all the contours of the foot, thereby reducing shear forces on the plantar surface (Mueller et al 1989). Various casts are available and their use is governed by local experience and expertise. Techniques include:
Great care must be taken, especially with the fitting of plasters, to prevent chafing and subsequent ulcer formation elsewhere on the foot or ankle. Alternatively, a removable cast walker may be used.
If cellulitis or skin discoloration is present, the limb is threatened and urgent hospital admission should be arranged. After samples for blood cultures have been taken, intravenous antibiotics are administered to treat possible infection with staphylococci, streptococci, Gram-negative bacteria and anaerobes (flucloxacillin 500 mg i.v. 6-hourly; amoxicillin 500 mg i.v. 8-hourly; ceftazidine 1 g i.v. 8-hourly; and metronidazole 500 m.g. i.v. 8-hourly). This antibiotic regimen may need revision after the results of bacterial cultures are available. If the toe complicated by ulceration becomes necrotic, then the patient should undergo digital or ray amputation (which includes the metatarsal head). Such wounds usually heal extremely well in the neuropathic foot (see Ch. 10).
The precipitating event for a neuropathic joint is usually a minor traumatic episode, such as tripping, which results in a swollen, erythematous, hot and sometimes painful foot. Initially, radiographs are likely to be normal, but subsequently serial radiographs show evidence of bony fracture, osteolysis, fragmentation, new bone formation, subluxation and joint disorganisation.
This destructive process often takes place over only a few months and can lead to considerable deformity of the foot. The metatarsal–tarsal joints are most commonly involved (Sanders & Frykberg 2008).
Early diagnosis is essential. The initial presentation of unilateral warmth and swelling in a neuropathic foot is extremely suggestive of a developing Charcot joint. Bone scans are more sensitive indicators of new bone formation than is radiography and should be used to confirm the diagnosis.
This comprises immobilisation of the injured part, which can be achieved by non-weight bearing, using crutches or a total contact plaster cast. The immobilisation is continued until the oedema and local warmth have resolved. The foot should then be gradually mobilised using a moulded insole in a special shoe. Recently, bisphosphonates have been used to inhibit osteoclastic activity, leading to a reduction in foot temperature and resolution of symptoms.
The neuroischaemic foot results from atherosclerosis of the vessels of the leg with neuropathy predisposing it to minor trauma. In diabetic patients atherosclerosis is multisegmental, bilateral and distal, often involving the popliteal, the tibial and the peroneal arteries.
The clinical features of ischaemia are intermittent claudication, rest pain, ulceration and gangrene. However, the most frequent symptom is ulceration. The ulcers present as areas of necrosis often surrounded by a rim of erythema. In contrast to ulceration in the neuropathic foot, callous tissue is usually absent. Furthermore, ulceration in the ischaemic foot is often painful, although this varies from patient to patient according to the coexistence of a peripheral neuropathy. In the ischaemic foot the most frequent sites of ulceration are the tips of the toes, the medial surface of the head of the first metatarsal, the lateral surface of the fifth metatarsal head and the heel.
Medical management is indicated if the ulcer is small and shallow and is of recent onset (i.e. within the previous month). Ischaemic ulcers may be painful and it may be necessary to prescribe opiates. It is the role of the podiatrist to remove necrotic tissue from the ulcers and, in the case of subungual ulcers, to cut back the nail to allow drainage of the ulcer. Ulcer swabs are taken as with the neuropathic foot, and the ulcers are cleaned with normal saline and dressed with a sterile non-adherent dressing. It is important to eradicate infection with prompt and specific antibiotic therapy after consultation with a microbiologist. However, severe sepsis in the ischaemic foot is an indication for emergency admission: first, to control sepsis by intravenous antibiotics and surgical debridement; and, secondly, to assess the possibility of revascularisation by either angioplasty or reconstruction. Footwear should be supplied to accommodate the foot, and in most cases an extra-depth ready-made shoe to protect the borders of the foot is adequate, unless there is severe deformity, when bespoke shoes will be needed. If any lesion, however small and trivial, in the pulseless foot has not responded to conservative treatment within 4 weeks, the patient should be considered for arteriography and revascularisations.
One of the most important advances in the last 20 years has been the development of new techniques of revascularisation of the diabetic foot. Patients with relatively localised disease (e.g. stenosis or short (<10 cm) occlusions) often do well with angioplasty, particularly in the iliac, superficial femoral and popliteal arteries. However, diabetic patients often have lesions in the calf arteries, but recent advances in catheter techniques and imaging have made it possible to perform angioplasty. Such endovascular procedures have been shown to be feasible and successful in the tibial and peroneal arteries of the diabetic patient (Faglia et al 2005). More recently, subintimal angioplasty has been used to recanalise long arterial occlusions in the tibial arteries (Lazaris et al 2004). Given the same lesion, a diabetic patient will do as well as a non-diabetic patient following femoral popliteal angioplasty, assuming equality of other factors such as inflow and outflow.
Angioplasty must be applied when tissue loss is not extensive and when arterial stenoses and occlusions are still suitable for this procedure. Angioplasty has become an important part of the management of the ischaemic foot that has become infected. Diabetes is not a contraindication to arterial bypass in the leg, and distal bypass to either the tibial or peroneal vessels is often necessary to restore pulsatile blood flow to the diabetic foot, which is vital in cases of severe sepsis and necrosis.
There is a different approach to dry digital necrosis or gangrene in the ischaemic foot compared with the neuropathic foot. If it is possible to improve the circulation by arterial reconstruction then digital amputation can be performed in the ischaemic foot. However, if it is not feasible to improve the circulation, amputation of a necrotic toe should not be performed as the stump is unlikely to heal. Recently, the use of a vacuum assisted closure (VAC) pump has improved healing in postoperative wounds in the ischaemic foot, allowing digital amputation in the ischaemic foot even though it may not have been revascularised. Successful autoamputation, in which the necrotic digit drops off to reveal a healed stump, can occur as long as infection is controlled and there is regular debridement by the podiatrist along the demarcation line.
Excess of body fat can be measured only indirectly, and the commonest assessment is weight in relation to height and age. The body mass index (BMI) is commonly used and equals weight (in kg) over height (in metres); the normal range is up to 25. Genetic, environmental and socio-economic factors are important in the aetiology of obesity. Rarely, endocrine diseases such as hypothyroidism and Cushing’s syndrome may be a direct cause of obesity.
Obesity in the human species is a disorder of intake. Excess energy intake or decreased energy expenditure are the major determinants of obesity in genetically susceptible individuals. In animal studies, a defect in thermogenesis has been identified in brown fat cells which limits the ability of these animals to burn off calories, although these findings have not been confirmed in humans. Obese subjects have disturbed regulation of appetite and energy expenditure. They often have a reduced perception of their calorie intake.
Major long-term health hazards of obesity are type 2 diabetes and the effects on the cardiovascular system, including hypertension and coronary artery disease. Osteoarthritis is a very common condition in obese individuals. Excess weight imposes a severe burden on individuals with respiratory disease, and in simple obesity one of the most frequent complaints is breathlessness on mild exertion. Back ache is also common and is induced by ligamentous strain. Obesity protects against osteoporosis.
An increase in body fat is associated with an increased morbidity and mortality, and associated risk factors such as hyperlipidaemia, hyperglycaemia, hypertension, hyperuricaemia and lack of exercise play a major role.
Specific disorders associated with obesity, such as myxoedema and Cushing’s syndrome, should be searched for and treated. The cornerstone of treatment is to reduce the calorie intake to below energy expenditure, with a supervised diet and exercise and behaviour modification.
Crash diets may induce severe metabolic disturbances and even cardiac arrest, but their effects are not permanent. The aim of treatment is to achieve a healthy and enjoyable pattern of eating with the patient in control of his or her weight reduction. Rapport also is important to improve compliance, and initially weight-reduction targets should be modest.
Medical treatments to decrease appetite have a limited role. Currently available are sibutramine, a serotonin and non-adrenergic reuptake inhibitor and appetite suppressant, and orlistat, an intestinal lipase inhibitor.
There are more radical approaches, such as bariatric surgery, which can be divided into malabsorptive surgery to shorten the length of the gut by gastric bypass, and restrictive surgery to induce early satiety (e.g. gastric stapling, gastric balloon). Wiring of the jaws, prolonged behavioural courses and surgical removal of excess adipose tissue have also been used. However, these approaches are not without dangers.
A brief account of bone metabolism is given here, and the clinical features of hyper- and hypocalcaemia are described, followed by short accounts of osteomalacia and rickets, hyperparathyroidism, renal osteodystrophy and Paget’s disease.
The connective tissue matrix of bone, the osteoid, consists of collagen fibres in a polysaccharide ground substance. The osteoid is made rigid by the deposition of mineral, mainly of crystalline bone salts of calcium phosphate and carbonate. The mineralisation of osteoid is dependent partly on the chemical concentration at the tissue surface of calcium, phosphate and hydrogen ions, and of the enzyme alkaline phosphatase, and partly on the activity of osteoclasts and osteoblasts. Parathormone (PTH) and calcitonin strongly affect the osteoclasts and osteoblasts, and vitamin D acts especially on the chemical environment.
PTH is synthesised in the parathyroid glands and is the main factor in calcium homeostasis. Its secretion increases when calcium levels fall, stimulating calcium release from bone and calcium reabsorption by the kidney. Calcitonin is secreted by parafollicular cells (C-cells) of the thyroid gland. When infused at high levels, it diminishes plasma calcium by reducing the rate of osteoclastic resorption of bone and increasing urinary excretion. Vitamin D, in its active form, influences calcium and phosphate flux in bone, kidney and intestine. Over 90% of the parent hormone is synthesised in the skin, and the level of the critical highly active form 1,25(OH)2D3 is directly influenced by the concentration of calcium ion and PTH.
The commonest causes of hypercalcaemia are malignancy and hyperparathyroidism. Any tendency to hypercalcaemia can be aggravated by dehydration, impaired renal function, or circumstances stimulating bone demineralisation, such as immobilisation or fracture.
Hypercalcaemia interferes with reabsorption of water by the renal tubules, producing polyuria and causing thirst, eventually producing renal stones. There is decreased neuromuscular excitability, which may lead to general muscle weakness. Decreased excitability also affects smooth muscle, causing constipation. Anorexia and vomiting are also common. Patients with hypercalcaemia may feel generally ill and depressed, and may be diagnosed as having some psychological disorder. Calcium deposits may occur at the junction of the cornea and sclera. The deposits have a granular gritty appearance and are associated with increased vascularity. If bone is affected by the primary disease there may be pain and weakness, perhaps with fractures. Severe hypercalcaemia produces confusion, coma, anuria and death, sometimes through cardiac arrest.
If possible, a specific diagnosis of the cause of hypercalcaemia should be made, but other general measures are useful as temporary expedients or to achieve symptomatic relief. Rehydration is essential and diuresis may be further encouraged by the combination of generous intravenous fluid infusion with normal saline and loop diuretics such as furosemide. Steroids (hydrocortisone 400 mg/day i.v. intravenously infusion or prednisolone 40–60 mg/day orally) can be effective, especially in malignancy.
Calcium is an ion of considerable importance in numerous cell systems, but the acute clinical effects of hypocalcaemia are mainly those of increased neuromuscular excitability, while the long-term effects are mainly ectodermal.
In hypocalcaemia and tetany, there may be peripheral paraesthesia, muscle cramps, epileptic fits, laryngeal spasm in children, occasionally acute hypertension, or psychosis, and the important physical signs, Chvostek’s and Trousseau’s.
Chvostek’s sign is elicited by tapping over the facial nerve as it emerges from the parotid gland beneath the zygoma. A hemifacial twitch constitutes a positive response. Trousseau’s sign is elicited by the application of a cuff to the arm and raising the pressure to above the patient’s systolic blood pressure for 3 minutes, by which time the hands should have adopted the classic ‘main d’accoucher’ position (wrist and metacarpophalangeal joints flexed and fingers extended).
The signs of long-standing hypocalcaemia may also include: a dry, scaly skin; loss of eyelashes, thin eyebrows, patchy alopecia and scanty axillary and pubic hair; brittleness of nails; (in children) hypoplasia or aplasia of teeth; cataracts; calcification in the basal ganglia; rarely, papilloedema; susceptibility to moniliasis, probably due to immune deficiency; and cardiomegaly, with a prolonged QT interval on the electrocardiogram.
In emergencies, a slow intravenous injection of 10–20 ml of 10% calcium gluconate solution (diluted in 100–200 ml of 0.9% saline) should be instituted until symptoms are relieved or total plasma calcium reaches 1.9 mmol/l.
In the long term, dietary calcium can be supplemented and a vitamin D preparation administered carefully. To avoid overdose, levels of calcium and phosphate should be monitored frequently at first and then at intervals not exceeding 6 months, even when the situation is apparently stable. 1-α-hydroxylated derivatives of vitamin D are preferred for their shorter half-life. Usual daily maintenance doses are 1 µg for 1-α-(OH)D3 (alfacalcidol) and 1,25(OH)2D3 (calcitriol).
By definition, osteoporosis is the state of less bone being present than is normal for the patient’s age and sex. It is associated with loss of structural integrity of the internal architecture of bone. Osteoporosis becomes clinically important only after fracture, but treatment of the disorder after the onset of fractures is less than satisfactory, with prevention being a more effective approach.
Although osteoporosis does occur commonly in the foot and ankle after injury, often to a severe degree, the two forms encountered most often are the senile and the related postmenopausal osteoporosis. Osteoporosis is related to an inequality between the rates of osteoblastic accretion of new bone and osteoclastic removal of old bone. Although the spine and proximal femur are the sites of the most significant fractures in osteoporosis, the foot and ankle are frequent sites for fractures in an osteoporotic patient. Toe and metatarsal fractures are very common. However, a bone with osteoporosis is not deficient in its response to fracture repair, and usually a very active osteoblastic response leads to adequate fracture callus.
A patient with osteoporosis may present for the first time with an injury to the foot without a prior diagnosis of osteoporosis having been reached. Usually, osteoporosis is a diagnosis of exclusion, and osteomalacia, renal pathology and hyperparathyroidism should be excluded by screening for serum calcium, phosphorus and alkaline phosphatase, although the last of these may be slightly increased following fracture (especially of long bones).
The aim of therapy is to reduce the rate of bone loss by adequate calcium intake, female hormone-replacement therapy (which prevents menopausal bone loss), regular physical exercise and a diet with a daily intake of 1–1.5 g/day calcium (one pint of milk contains approximately 750 mg of calcium). In severe cases, drug therapy may be used, including bisphosphonates, raloxifene and parathyroid hormone.
Osteomalacia and rickets are conditions in which there is defective mineralisation of the matrix of bone. In rickets, the defect is present in infancy and childhood. Osteomalacia is the adult counterpart of rickets. In children, rickets is rarely seen until the patient is over 1 year old, when he or she presents with abnormal patterns of bone modelling, epiphyseal growth and dentition. Rickets is rarely seen in children today because of the addition of vitamin D to milk.
There are many causes of osteomalacia (and rickets), some of which are very rare. They may be divided into three main groups: nutritional, malabsorptive and renal. Nutritional causes follow from lack of vitamin D, either due to deficient synthesis in the skin or low dietary intake. Malabsorption of vitamin D occurs in coeliac disease, gastric surgery, bowel resection and biliary cirrhosis. With regard to the kidney, osteomalacia and rickets can follow from renal glomerular failure as well as renal tubular failure. The effects of renal glomerular failure on the skeleton are complex and are termed ‘renal osteodystrophy’, with excessive bone resorption, defective bone mineralisation and, in some cases, osteoporosis (see below). Many renal tubular disorders also lead to osteomalacia.
In the adult, osteomalacia may produce bone and muscle tenderness, often due to subclinical fractures. In the leg, the presenting symptom may be aching pain adjacent to an affected portion of the tibia. An increased blood flow is indicated by the increased warmth in the anterior leg. Deformity results from weight bearing and the gastrocneminus pulling forces on the tibia when the disease is in its lytic and weakened phase. Patients who have developed bowing of the femurs and tibias can then develop degenerative arthritis of both the ankle and knee joints due to the abnormal wear on the articular surfaces secondary to the bone deformity.
Rickets is not seen until after the patient is 1 year old, when swelling of the ankles and wrists may be an early physical finding. The earliest clinical symptoms are tiredness and muscular weakness. There is bone pain and pain on movement. Dentition is delayed and the teeth may be deformed and quickly become carious. Swelling and tenderness of the distal ends of the radius and ulna are common, as is the rickety rosary (costochondral swellings). Frontal and parietal bossing of the skull occurs and occipitoparietal flattening may result from the softness of the skull (craniotabes). If the child can stand or walk, bowing of the legs may result from weight bearing and kyphoscoliosis may appear. Radiographs show widening and decreased density of the line of calcification next to the metaphysis, with irregularity and concavity of the metaphysis itself. In severe cases, there may be rarefaction with deformities in the shaft of the bone.
Rickets and osteomalacia can always be cured by administering vitamin D or one of its potent derivatives – alfacalcidol or calcitriol. Patients will need a long-term maintenance dosage of one of these derivatives. Surgical correction of deformity is occasionally required.
The majority of patients are asymptomatic, but hyperparathyroidism may present as a form of osteoporosis with a fracture. Very occasionally, the giant-cell tumour seen in association with severe hyperparathyroidism may present as a mass in the tibia. The radiological abnormalities are due to bone resorption by osteoclasts and subperiosteal resorption of the cortices of phalanges in the feet, as well as the hands, is the early bony abnormality.
The skeletal disorders found in chronic renal failure are collectively called renal osteodystrophy and may occur singly or in various combinations. The condition may develop early in the course of chronic renal disease and may persist after renal transplantation. The main bone changes that occur are osteomalacia, caused by the deficiency of active metabolites of vitamin D, and secondary hypoparathyroidism, which is associated with increased retention of phosphate by the kidneys. Retention of phosphate, with resulting hypocalcaemia, stimulates the parathyroid glands to secrete parathormone, which leads to mobilisation of calcium from bone by osteoclastic resorption. Bony pathology includes hyperparathyroidism with osteitis fibrosa, osteomalacia, and decreased availability of vitamin D, calcium and phosphates, osteoporosis, osteonecrosis, osteosclerosis and periosteal new bone formation (a radiographic finding) and extraskeletal calcification.
A further abnormality seen in the steroid-treated renal patient is a vascular necrosis of the talus, often in association with a renal transplant.
Management of renal osteodystrophy is according to the mechanisms involved in the pathogenesis of the disease. Treatment with phosphate-binding agents or a low-phosphate diet decreases phosphate retention and prevents progressive secondary hyperparathyroidism and soft-tissue calcification. Vitamin D therapy is indicated in hypoparathyroidism and in osteomalacia due to vitamin D deficiency. Parathyroidectomy is indicated in patients with severe forms of secondary hyperparathyroidism.
Paget’s disease is a focal disorder of bone remodelling characterised by excessive osteoclastic resorption. Patients with Paget’s disease are usually aged over 40 years but the prevalence essentially doubles with every decade over the age of 50 years.
The majority of patients are asymptomatic. In patients with symptoms the most notable feature is bone pain, which is probably a result of combined increased vascularity and new bone formation, which stretches the periosteum. Degenerative joint disease leads to distortion of the articular surface. The abnormal bone texture allows long bones to bend, and fractures commonly develop on the convex margin. Neurological symptoms may result from involvement of the spine, leading to paraplegia. Neuropathies of the cranial and peripheral nerves may occur secondary to entrapment.
The earliest radiological abnormality in a long bone is resorption of a previously normal cortex. Microscopically, osteoclasts are noted within resorption cavities and this is associated with increased osteoblastic activity with the formation of new osteotrabeculae adjacent to the site of bone resorption.
Serum alkaline phosphatase is a marker for bone formation and provides a simple method of evaluating a patient over the course of time. Indeed, the detection of Paget’s disease may be due to the elevated alkaline phosphatase levels obtained during screening examinations. The urinary excretion of hydroxyproline indicates collagen breakdown, and this level is markedly raised in many patients with Paget’s disease, often in association with the degree of elevation of the alkaline phosphatase activity.
The biochemical changes are similar in rickets and osteomalacia. The plasma calcium is usually a little low and occasionally considerably reduced. The plasma phosphate level is low but the alkaline phosphatase is frequently increased.
The treatment of Paget’s disease is by drugs that inhibit bone resorption. This is reflected by an early fall in urinary hydroxyproline and then serum alkaline phosphatase. Bisphosphonates act directly on osteoclasts to inhibit resorption of bone. Calcitonin appears to be equally effective but must be administered by injection and is not now generally used.
Metabolic disorders are complex, some producing unique challenges for the podiatrist in formulating patient management plans. Metabolic diseases, in particular those affecting bone, will provide problems for podiatric management.
Diabetes mellitus is the commonest metabolic disorder seen by podiatrists. The management of podiatric complications of diabetes is discussed in Chapter 10 and elsewhere in this chapter.
The podiatrist must be familiar with metabolic disorders for two major reasons. First, signs and symptoms presenting in the feet and lower limbs enable the practitioner to make the primary diagnosis of a metabolic disorder. The second reason is that established metabolic disease will have implications for patient risk categorisation and provision of podiatric care.
Many metabolic disorders involve bone; the podiatric implications of metabolic bone disease will be discussed. Osteoporosis may be idiopathic or secondary to other conditions such as renal disease or steroid therapy. Localised osteoporosis occurs after limb immobilisation. Podiatric complications associated with osteoporosis include fractures, including ‘minimal trauma’ stress fractures (march fracture). Following fractures of the femur the gait may be altered, with consequent effects on the feet.
Abnormal neurological signs and symptoms are often detected in the feet following nerve root irritation and damage associated with vertebral-body osteoporosis. In rare cases, damaged vertebrae may compress the spinal cord.
Fractures affecting the upper limb (e.g. a Colles’ fracture associated with a fall onto an outstretched hand) are associated with osteoporosis. The immediate and possibly longer term restriction of mobility at the wrist will compromise a patient’s ability to care for his or her feet.
It must be remembered that if osteoporosis is secondary to another disorder or pathology the underlying cause can itself have adverse effects on the feet. Abnormal mechanical forces applied to osteoporotic bone increase the likelihood of fractures. This can occur in a limb affected by poliomyelitis, when the bones may be osteoporotic from disuse but may also be subjected to abnormal stresses. Osteoporosis is a secondary complication in people receiving steroid therapy; the other iatrogenic effects from the drug can compromise tissue viability in the feet. Rheumatoid arthritis is complicated by localised osteoporosis where, again, the primary disease has profound effects on the feet and lower limb (see Ch. 8).
In the adult the podiatric effects of osteomalacia are relatively non-specific, but include bone pain and tenderness that can restrict mobility. Hypotonia of muscles and proximal muscle weakness can produce a waddling gait. Fractures and pseudofractures (Looser’s zones) may be seen on radiographs. There may be signs and symptoms of hypocalcaemia, which may cause peripheral paraesthesia and even tetany.
In children the condition is known as rickets; the resultant bone softening leads to skeletal deformity. Rickets results in impaired growth at the epiphyses leading to skeletal abnormalities such as bowing of the tibia, fibula and femur, with concomitant alterations in gait. Gait can also be adversely affected because of kyphosis and lordosis of the spine, associated hypotonia of muscles, and muscle weakness may compound the problem. Pathological fractures can also occur.
The feet may be affected by Paget’s disease of the bone. This localised disorder of bone remodelling leads to abnormal organisation of woven and lamellar bone. The effects of Paget’s disease on the foot and lower limb include pain, particularly affecting the pelvis, lumbar spine and femur. ‘Sabre tibia’, describes the appearance of the tibia when it becomes bowed in the sagittal plane; this will alter biomechanical stresses within the leg and alter the direction of mechanical stress to the foot and ankle. Stress fractures can occur, particularly in weight-bearing bones such as the metatarsals and fibula. Osteoarthroses eventually occur at joints where mechanical forces have altered congruity. Neurological effects may be detected in the foot, secondary to nerve compression at a local or at spinal-cord level. Osteosarcoma, a rare complication of Paget’s disease, occurs in 0.2% of patients, and often involves the pelvis or femur. The disease can alter the bone structure of the skull and cause enlargement. Auditory nerve compression may ensue and cause deafness; this will have implications for effective communication between the podiatrist and the patient. The overlying skin of affected bone often feels warm because of increased vascularity of the diseased bone. The increased vascularity can eventually cause high output cardiac failure.
Bone metabolism is complex and involves organs such as the liver and kidney. Damage to these organs (e.g. oedema and impaired tissue viability) has implications for podiatric management. Signs and symptoms of hypercalcaemia may be seen during periods of immobilisation; these include drowsiness, muscle weakness and hyporeflexia viability.
Thus an understanding of metabolic disorders is necessary for podiatrists so that they may identify the symptoms of these diseases and formulate care plans in established cases.
Chantelau E, Leisch A. Footwear, uses and abuses. In: Boulton AJM, Connor H, Cavanagh PR, editors. The foot in diabetes. Chichester: Wiley; 1994:99-108.
Diabetes Control and Complications Trial Research Group. Effect of intensive treatment of diabetes on the development and progression of long term complications in insulin dependent diabetes mellitus. New England Journal of Medicine. 1993;329:977-986.
DeFronzo RA, Ratner RE, Han J, et al. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005;28(5):1092-1100.
Edmonds ME. Autonomic neuropathy. In De Fronzo RA, Ferrannini E, Keen H, Zimmer P, editors: International textbook of diabetes, 3rd edn, Chichester.: Wiley, 2004.
Edmonds ME, Foster AVM. Managing the diabetic foot, 2nd edn. Oxford: Blackwell Science; 2005.
Faglia E, Dalla Paola L, Clerici G, et al. Peripheral angioplasty as the first-choice revascularization procedure in diabetic patients with critical limb ischemia: prospective study of 993 consecutive patients hospitalized and followed between 1999 and 2003. European Journal of Vascular and Endovascular Surgery. 2005;29(6):620-627.
Lazaris AM, Tsiamis AC, Fishwick G, et al. Clinical outcome of primary infrainguinal subintimal angioplasty in diabetic patients with critical lower limb ischemia. Journal of Endovascuar Therapeutics. 2004;11(4):447-453.
Mueller MJ, Diamond JE, Sinacore DR. Total contact casting in treatment of diabetic plantar ulcers. Diabetes Care. 1989;12:384-388.
Sanders LJ, Frykberg RG. The Charcot foot. In: Bowker JH, Pfeffer MA, editors. Levin & O’Neal’s The diabetic foot. 7th edn. St Louis, MI: Mosby; 2008:257-284.
UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-853.
Winkler AS, Ejskjaer N, Edmonds M, Watkins PJ. Dissociated sensory loss in diabetic autonomic neuropathy. Diabetic Medicine. 2000;17:457-462.
Bowker JH, Pfeifer MA, editors. Levin & O’Neal’s The diabetic foot, 7th edn, St. Louis, MI: Mosby Year Book, 2008.
Edmonds M, Foster AVM, Sanders L. A practical manual of diabetic foot care, 2nd edn. Oxford: Blackwell; 2007.
The International Working Group on the Diabetic Foot. International Consensus on the Diabetic Foot. Available at http://www.iwgdf.org, 2007.
Turner HE, Wass JAH. Oxford handbook of endocrinology and diabetes, 2nd edn. Oxford: Oxford University Press; 2009.
2009 Standards of medical care in diabetes. Diabetes Care. 2009;32(Suppl 1):S13-S61.
Boulton AJM, Cavanagh PR, Rayman G, editors. The foot in diabetes, 4th edn, Chichester: Wiley, 2006.
Watkins PJ, Amiel SA, Howell SL, Turner E. Diabetes and its management, 6th edn. Oxford: Blackwell; 2003.