William Jeffcoate

Diabetic foot ulcers

Ulceration of the foot in diabetes is common and disabling and frequently leads to amputation of the leg. Mortality is high and healed ulcers often recur. The pathogenesis of foot ulceration is complex, clinical presentation variable, and management requires early expert assessment. Interventions should be directed at infection, peripheral ischaemia, and abnormal pressure loading caused by peripheral neuropathy and limited joint mobility. Despite treatment, ulcers readily become chronic wounds. Diabetic foot ulcers have been neglected in health-care research and planning, and clinical practice is based more on opinion than scientific fact. Furthermore, the pathological processes are poorly understood and poorly taught and communication between the many specialties involved is disjointed and insensitive to the needs of patients.

Multiorgan failure is an adaptive, endocrine-mediated, metabolic response to overwhelming systemic inflammation

Sepsis and other critical illnesses produce a biphasic inflammatory, immune, hormonal, and metabolic response. The acute phase is marked by an abrupt rise in the secretion of so-called stress hormones with an associated increase in mitochondrial and metabolic activity. The combination of severe inflammation and secondary changes in endocrine profile diminish energy production, metabolic rate, and normal cellular processes, leading to multiple organ dysfunction. This perceived failure of organs might instead be a potentially protective mechanism, because reduced cellular metabolism could increase the chances of survival of cells, and thus organs, in the face of an overwhelming insult. We propose that, first, multiple organ failure induced by critical illness is primarily a functional, rather than structural, abnormality. Indeed, it may not be failure as such, but a potentially protective, reactive mechanism. Second, the decline in organ function is triggered by a decrease in mitochondrial activity and oxidative phosphorylation, leading to reduced cellular metabolism. Third, this effect on mitochondria might be the consequence of acute-phase changes in hormones and inflammatory mediators.

The Charcot Foot in Diabetes

The diabetic Charcot foot syndrome is a serious and potentially limb-threatening lower-extremity complication of diabetes. First described in 1883, this enigmatic condition continues to challenge even the most experienced practitioners. Now considered an inflammatory syndrome, the diabetic Charcot foot is characterized by varying degrees of bone and joint disorganization secondary to underlying neuropathy, trauma, and perturbations of bone metabolism. An international task force of experts was convened by the American Diabetes Association and the American Podiatric Medical Association in January 2011 to summarize available evidence on the pathophysiology, natural history, presentations, and treatment recommendations for this entity.

The role of proinflammatory cytokines in the cause of neuropathic osteoarthropathy (acute Charcot foot) in diabetes

The pathogenesis of the acute Charcot foot of diabetes remains unclear. All patients with this condition have evidence of peripheral neuropathy, with loss of protective sensation and abnormal foot biomechanics. However, the acute Charcot foot is also characterised by a pronounced inflammatory reaction and the pathogenic significance of this inflammation has received little attention. We suggest that an initial insult--which may or may not be detected--is sufficient to trigger an inflammatory cascade through increased expression of proinflammatory cytokines, including TNFalpha and interleukin 1beta. This cascade then leads to increased expression of the nuclear transcription factor, NF-kappaB, which results in increased osteoclastogenesis. Osteoclasts cause progressive bone lysis, leading to further fracture, which in turn potentiates the inflammatory process. The potential role of proinflammatory cytokines suggests the possibility of new treatments for this sometimes devastating complication of diabetes.

A systematic review of the effectiveness of interventions to enhance the healing of chronic ulcers of the foot in diabetes

The outcome of management of diabetic foot ulcers is poor and there is uncertainty concerning optimal approaches to management. We have undertaken a systematic review to identify interventions for which there is evidence of effectiveness. A search was made for reports of the effectiveness of interventions assessed in terms of healing, ulcer area or amputation in controlled clinical studies published prior to December 2006. Methodological quality of selected studies was independently assessed by two reviewers using Scottish Intercollegiate Guidelines Network (SIGN) criteria. Selected studies fell into the following categories: sharp debridement and larvae; antiseptics and dressings; chronic wound resection; hyperbaric oxygen (HBO); reduction of tissue oedema; skin grafts; electrical and magnetic stimulation and ultrasound. Heterogeneity of studies prevented pooled analysis of results. Of the 2251 papers identified, 60 were selected for grading following full text review. Some evidence was found to support hydrogels as desloughing agents and to suggest that a systemic (HBO) therapy may be effective. Topical negative pressure (TNP) may promote healing of post‐operative wounds, and resection of neuropathic plantar ulcers may be beneficial. More information was needed to confirm the effectiveness and cost‐effectiveness of these and other interventions. No data were found to justify the use of any other topically applied product or dressing, including those with antiseptic properties. Further evidence to substantiate the effect of interventions designed to enhance the healing of chronic ulcers is urgently needed. Until such evidence is available from robust trials, there is limited justification for the use of more expensive treatments and dressings. Copyright

Eighty-six cases of Addison's disease

OBJECTIVES Since there have been no recent reviews of Addisons disease, we have undertaken a retrospective case‐notes review of all identifiable cases in Nottingham to define the prevalence, incidence and causes of Addisons disease. We have also reviewed the criteria for interpretation of the short Synacthen test in diagnosis.

Diabetic foot osteomyelitis: a progress report on diagnosis and a systematic review of treatment†

The International Working Group on the Diabetic Foot appointed an expert panel to provide evidence‐based guidance on the management of osteomyelitis in the diabetic foot. Initially, the panel formulated a consensus scheme for the diagnosis of diabetic foot osteomyelitis (DFO) for research purposes, and undertook a systematic review of the evidence relating to treatment. The consensus diagnostic scheme was based on expert opinion; the systematic review was based on a search for reports of the effectiveness of treatment for DFO published prior to December 2006.

Controversies in Diagnosing and Managing Osteomyelitis of the Foot in Diabetes

The optimal approach to diagnosing and managing osteomyelitis of the foot in diabetes is unclear. Diagnosis is based on clinical signs, supplemented by a variety of imaging tests. Bone biopsy is the accepted criterion standard for diagnosis but is not used by many. Management traditionally involves surgical removal of infected bone, combined with antibiotic therapy. However, recent studies have shown that antibiotics alone may apparently eliminate bone infection in many cases. There is also evidence that early amputation of infected digits is frequently noncurative. Agreement on criteria for diagnosing osteomyelitis is required, and randomized trials are urgently needed, to determine the relative benefits of various surgical interventions and the optimal deployment of antibiotics. We review the microbiology of osteomyelitis of the foot in diabetes, the benefits and limitations of various diagnostic procedures, and the evidence for the effectiveness of both surgical and nonsurgical approaches to management.

Amputation as a marker of the quality of foot care in diabetes

Strategic targets for the management of foot ulcers focus on reducing the incidence of amputation. While data on the incidence of amputation can be obtained relatively easily, the figures require very careful interpretation. Variation in the definition of amputation, population selection and the choice of numerator and denominator make comparisons difficult. Major and minor amputation have to be distinguished as they are undertaken for different reasons and are associated with different costs and functional implications. Many factors influence the decision of whether or not to remove a limb. In addition to disease severity, co-morbidities, and social and individual patient factors, many aspects of the structure of care services affect this decision, including access to primary care, quality of primary care, delays in referral, availability and quality of specialist resources, and prevailing medical opinion. It follows that a high incidence of amputation can reflect a higher disease prevalence, late referral, limited resources, or a particularly interventionist approach by a specialist team. Conversely, a low incidence of amputation can indicate a lower disease prevalence or severity, good management of diabetes in primary and secondary care, or a particularly conservative approach by an expert team. An inappropriately conservative approach could conceivably enhance suffering by condemning a person to months of incapacity before they die with an unhealed ulcer. The reported annual incidence of major amputation in industrialised countries ranges from 0.06 to 3.83 per 103 people at risk. Some centres have documented that the incidence is falling, but this is often from a baseline value that was unusually high. Other centres have reported that the incidence has not changed. The ultimate target is to achieve not only a decrease in incidence, but also a low overall incidence. This must be accompanied by improvements in morbidity, mortality, and patient function and mood.

Factors contributing to the presentation of diabetic foot ulcers

We have undertaken a prospective study of the presentation of all 669 ulcers seen in a specialist multidisciplinary foot clinic between 1 January 1993 and 1 August 1996, with particular reference to the factors which precipitated ulceration as well as to any delays in referral. Nearly two‐thirds (61.3 %) of all lesions were first detected by the patient or a relative, and the remainder by a healthcare professional. The median (range) time which elapsed between ulcer onset and first professional review was 4 (0–247) days, and the median time between first review and first referral to the specialist clinic was 15 (0–608) days. Significant delays were judged to have occurred in 39 instances. The most common precipitant of ulceration was rubbing from footwear, which was responsible for 138 (20.6 %). Fifty‐eight (8.7 %) were the result of immobilization from other illness, and a further 24 were the consequence of surgery. Overall, professional factors contributed to the development or deterioration of 106 lesions (15.8 % total). These results should form the basis of strategies designed to minimize the onset of ulceration in those known to be at risk: educational strategies need to be directed at professionals as much as at patients.