What is the ideal biological marker in diagnosis of diabetic neuropathies?

As diabetes mellitus rapidly increases worldwide, diabetic neuropathy is the most common long-term debilitating complication of diabetes, and is the main initiating factor for foot ulceration and amputation without trauma. Foot ulceration and amputation is much more common in neuropathic patients, with the annual incidence rising from <1% in those without neuropathy to more than 7% in those with established neuropathic deficits. As the reversible change in nerve-loss repair only occurs in small peripheral nerve fibers, earlier detection, accurate diagnosis and early treatment of diabetic neuropathy are important strategies to induce reversible change in small nerve fibers. Small peripheral nerve fibers, which constitute 70–90% of peripheral nerve fibers, regulate several main functions, such as tissue blood flow, temperature, pain perception and sweat production. Many clinical trial data show that small fiber damage might precede large fiber damage in diabetic neuropathy. Damage to small nerve fibers causes the characteristic symptoms of painful diabetic neuropathy, which are typically distal symmetrical and associated with nocturnal exacerbation. The symptoms are very variable in each patient, and are described in various terms such as, prickling, aching, numbness and burning pain with intermittent sharp stabbing electric shock-like pains. Recently, Tesfaye et al. proposed that “If nerve conduction is normal, a validated measure (with class 1 evidence) of small fiber neuropathy may be used” to define and quantify the severity of diabetic neuropathies. Nerve conduction study is based on relative ease of quantification, reproducibility, and reasonable sensitivity and specificity, which are regarded as gold standard methods to assess all types of fiber damage. However, it cannot accurately evaluate small nerve fibers, which are the earliest to be damaged and show repair even in advanced diabetic neuropathy. THIS was supported by recent data from many studies that reported minimal worsening and improvements in nerve conduction velocity results with little relationship to other methods of small fiber function in diabetic neuropathy patients. Other diagnostic methods of neurological symptoms and deficits questionnaires, and neurological examinations have been shown to have less reproducibility and low to moderate sensitivity. However, quantitative sensory tests have an advantage of evaluating both small and large nerve fiber function, but they require specific equipment and show low reproducibility. Furthermore, quantitative sensory tests require the cooperation and alertness of the patients. Table 1 shows classifications and characteristics for the diagnosis of diabetic neuropathies by the invasiveness, interpretation, advantages and disadvantages. As seen in Table 1, ideal biological markers for diabetic neuropathies should be easy to use, reliable, sensitive and non-invasive to enable repeated assessment as often or as long as necessary to define diagnosis and progression or response to therapeutic intervention. However, to date, we have not had the aforementioned gold standard and single novel complete biomarker for diagnosis, progression and treatment of diabetic neuropathies. Many researchers have tried to find the ideal biomarker for diabetic neuropathies. When we evaluate the efficacy of a new treatment modality, an improvement and aggravation of diabetic neuropathic symptoms and signs has to appear and be monitored during the intervention period. Although current methods have a good ability to diagnose diabetic neuropathies, their usefulness to define a therapeutic response and observe clinical outcome parameters might have significant limitations. These are major reasons why many clinical trials examining the therapeutic effects in human diabetic neuropathies have failed to reach predetermined primary end-points, such as neuropathic deficit symptoms, electrophysiological results and clinical outcome improvements. Nerve fiber morphology in sural and peroneal nerve biopsies, and recently developed skin punch biopsies, which observe and monitor intra-epidermal nerve fiber density, can be accurately used as quantifying tools for nerve fiber damage and repair, but both are invasive procedures and require a pathology laboratory. In diabetic patients, there are many problems associated with invasive procedures, such as small wound healing complications, and non-reiterative and painful methods. Ding et al. measured microvascular dysfunction with quantitative and qualitative retinal photographic grading and computer-based evaluation methods in patients with diabetic neuropathies. They also carried out quantitative sensory testing, such as 10-g monofilament and hand-held neurothesiometer for vibration perception threshold measurement. They reported that individuals with a suboptimal arteriolar caliber and larger arteriolar branching coefficient, as well as diabetic retinopathy and focal arteriolar narrowing, were more likely to have diabetic neuropathy than those without these signs. Diabetic patients with two or more signs were six times more likely to have *Corresponding author. Tae Sun Park Tel.: +82-63-250-1794 Fax: +82-63-254-1609 E-mail address: [email protected] Received 13 December 2012; accepted 20 December 2012