Nerve growth factor and diabetic neuropathy

THE LANCET

COMMENTARY

Is site of necrosis in acute pancreatitis a predictor of outcome? For most patients with acute pancreatitis the illness is mild to moderate and resolves spontaneously. However, serious complications will arise in 20–30% of cases, with an overall mortality of about 10%. The ability to correctly predict outcome for patients with acute pancreatitis at an early stage allows for selective intensive monitoring and appropriate early detection and treatment of lifethreatening complications. Clinical opinion has proven to be inaccurate and currently key prognostic features are based on precise biochemical measurements. Multifactor systems and APACHE II scoring are predictive but difficult to use, and C-reactive protein is the most useful laboratory marker. Dynamic contrast-material-enhanced computed tomography (CT) is the non-invasive standard imaging technique of choice for patients with biochemically predicted severe pancreatitis. It can depict the nature of the disease, demonstrate major complications, and guide percutaneous procedures. Two CT-based indices of severity are used to determine outcome: the degree of peripancreatic inflammation and the amount of pancreatic necrosis.1–3 The extent of pancreatic necrosis is classified as <30%, 30 to 50%, and >50% of the gland. Categories A to E represent the spectrum of peripancreatic inflammation, grade A being normal pancreas, whereas patients with two or more fluid collections and/or the presence of gas in or adjacent to the pancreas are classified as grade E.2 The CT severity index combines these scores.2 Kemppainen et al have lately reported that early identification of the exact site of pancreatic tissue necrosis is a new predictor of outcome in severe acute pancreatitis.4 161 patients with acute necrotising pancreatitis underwent dynamic contrast-enhanced CT scanning a mean of 2·9 days after the onset of the disease. The images were retrospectively analysed by one radiologist without prior clinical knowledge of final outcome. Patients were grouped according to the anatomical site (entire, right, mid-part, or left part of pancreas) and the extent of pancreatic tissue necrosis. The relation between these CT indicators and clinical outcome was measured. Only modest correlations were found between the extent of pancreatic necrosis and outcome but clear correlations were seen between the anatomical site of necrosis and outcome. Patients with necrosis of the right part of the pancreas fared significantly worse than did those with leftgland necrosis in extrapancreatic score, incidence of respiratory insufficiency, and infectious complications. Overall clinical outcome was similar for patients with necrosis of the right part of the pancreas and those with an entirely necrotic gland. Site of pancreatic necrosis has not previously been reported to be a reliable prognostic indicator in severe acute pancreatitis although the value of contrast-enhanced dynamic CT scanning is now widely acknowledged. Necrosis of the pancreatic head and body may increase risk of complications because proximal obstruction or destruction of the pancreatic duct is more likely to lead to enzyme leakage than is more distal occlusion. The value of early CT scanning in acute pancreatitis as described by Kemppainen et al4 is, however, controversial, since surgery in the early phase of the disease has never been shown to 1044

reduce mortality. The use of contrast-enhanced CT scans 5–10 days after onset of the disease might be more beneficial because it would allow for simultaneous fineneedle aspiration of necrotic areas in patients with the relevant clinical abnormalities as well as provide other prognostic radiological information.5 Whether the anatomical site of pancreatic necrosis is really a predictor of outcome for patients with severe acute pancreatitis could be quickly made clear because there have been several previous large series with CT scan results readily accessible. Clarification is needed given the prevalence of alcohol-related disease in the Kemppainen study,4 which is atypical of experience in countries such as the UK, where pancreatitis is predominantly gallstone related. It is unfortunate that advances in prediction of severity have not been matched by improvements in therapy.

Jane M Blazeby, Martin J Cooper Department of Surgery, Royal Devon and Exeter Hospital (Wonford), Exeter EX2 5DW, UK 1

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Balthazar EJ, Ranson J, Naidich D, Megibow A, Caccavale R, Cooper M. Acute pancreatitis: prognostic value of CT. Radiology 1985; 156: 767–72. Balthazar EJ, Robinson D, Megibow A, Ranson J. Acute pancreatitis: value of CT in establishing prognosis. Radiology 1990; 174: 331–36. Vesentini S, Bassi C, Talamini G, Cavallini G, Campedelli E, Pederzoli P. Prospective comparison of C-reactive protein level, Ranson score and contrast enhanced computed tomography in the prediction of septic complications of acute pancreatitis. Br J Surg 1993; 80: 755–57. Kemppainen E, Sainio V, Haapiainen R, Kivisaari L, Kivilaakso E, Puolakkainen P. Early localization of necrosis by contrast enhanced computed tomography can predict outcome in severe acute pancreatitis. Br J Surg 1996; 83: 924–29. Lucarotti ME, Virjee J, Alderson D. Patient selection and timing of dynamic computed tomography in acute pancreatitis. Br J Surg 1993; 80: 1393–95.

Nerve growth factor and diabetic neuropathy Nerve growth factor (NGF) is essential for the development and maintenance of small-diameter sensory and autonomic nerve fibres, which bear the tyrosine kinase A receptor and which are dysfunctional in human diabetic sensorimotor diabetic polyneuropathy.1 In experimental models of diabetes, NGF content of nerves was reduced,2 and such decrease caused hypoalgesia3 (whereby a higher heat-pain stimulus is needed to induce pain). Exogenous NGF prevents or reverses some dysfunctions typical of experimental diabetes,4 and NGF excess leads to hyperalgesia3 (lowered heat-pain threshold or a steeperthan-normal stimulus-response curve). Anand and coworkers have provided new data on the possible role of nerve growth factor (NGF) in prevention or treatment of human diabetic polyneuropathy. These investigators studied various small-diameter sensory and autonomic nerve functions (heat-pain, warm and cool thresholds, axon-reflex vasodilation, and gasp reflex) and large-sensory-fibre functions (touch and vibration) at various lower-limb sites in matched diabetic and control patients. They found that length-dependent dysfunction of sensory small-diameter fibres was present before dysfunction of sympathetic fibres and decrease of skin NGF and substance P. Additionally, they found a significant correlation between NGF decrease and dysfunction of axon-reflex vasodilation. They also found that immunostaining of keratinocytes for NGF was

Vol 348 • October 19, 1996

THE LANCET

COMMENTARY decreased in diabetic skin. They propose that a fall in endogenous skin-derived NGF influences the expression of diabetic polyneuropathy, while recognising that metabolic or vascular abnormalities may be the cause of the diabetic polyneuropathy. They suggest further that since loss of nociception and axon-reflex vasodilation contributes to diabetic foot ulceration, early and prolonged NGF treatment at an appropriate dose may be a rational means of prophylaxis for the disorder. Are there sufficient experimental and human data on NGF and diabetic polyneuropathy for phase II and phase III controlled clinical trials to be done? Are such studies needed in the light of recent evidence that control of glycaemia retards or prevents the development of diabetic neuropathy? If the studies are to be done, what categories of diabetic neuropathy should be included, what endpoints and outcomes should be assessed and what is the likelihood of success? The first two questions might be considered together. If diabetic neuropathy and its adverse outcomes could be prevented by near euglycaemia, and it were possible to maintain this level of glycaemic control for all diabetic patients, additional treatment might not be needed. In fact, it is still unclear to what degree diabetic neuropathy is preventable by near euglycaemia. The Diabetes Control and Complications Trial has shown that the likelihood of developing “clinically apparent” diabetic polyneuropathy or nerve-conduction abnormality was significantly lower in the more intensively treated group.6,7 It is unclear what severity of diabetic neuropathy or bad outcomes was prevented by the improved glycaemic control that was obtained. Overall severity of diabetic neuropathy was not assessed. Still unknown is whether there is a threshold level of glycaemic control needed to prevent all diabetic complications. Also unknown is what percentage of patients will be able or willing to strive for this level of glycaemic control. It may be that euglycaemia cannot be achieved, and that medications, such as NGF, if shown to be effective, might prevent or improve small-fibre diabetic neuropathy. The neurobiological and experimental diabetic trial data of NGF seem sufficiently compelling to warrant phase II, and perhaps phase III, trials. Ideally, the patients who should be included for NGF trials should be ones who have, or are likely to develop, small-fibre diabetic neuropathy, who have dysfunction of these classes of fibres, and whose dysfunction is still measurable. Symptoms that might be assessed are pain (burning, lancinating, deep aching, or allodynia), paraesthesia, impotence, sphincter dysfunction, and other sensory and autonomic symptoms. Neurological impairment and nerve-conduction abnormality, especially of the foot and leg, should also be assessed. Perhaps the most important measures for which standard techniques and systems are now available are the measurement of cold-pain and heat-pain detection thresholds.9 One might infer, from the studies by Anand and co-workers, that warm-pain detection threshold and capsaicin-induced axon-reflex vasodilation might also be considered for such testing. Why not use outcomes such as foot ulcers and Charcot joints as endpoints in such studies? Since these complications occur in only a small percentage of diabetic patients and since we still cannot accurately predict who will develop these outcomes, a very large study for a very long time would be needed. Although such a study could

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be considered, it might simply be too expensive. NGF was the prototypic growth factor that led to the discovery of many novel molecules with regulatory influences on cell division, maturation, and survival. It would be exciting if the same molecule could be shown to have a therapeutic effect in prevention or treatment of diabetic polyneuropathy.

Peter J Dyck Department of Neurology, Mayo Clinic, Rochester MN55905, USA 1

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Thomas PK, Tomlinson DR. Diabetic and hypoglycaemic neuropathy. In: Dyck PJ, Thomas PK, Griffin JW, Low PA, Poduslo JF, eds. Peripheral neuropathy, 3rd ed. Philadelphia: W B Saunders Company, 1993: 1219–50. Hellweg R, Wöhrle M, Hartung H-D, Stracke H, Hock C, Federlin K. Diabetes mellitus-associated decrease in nerve growth factor levels is reversed by allogeneic pancreatic islet transplantation. Neurosci Lett 1991; 125: 1–4. Lewin GR, Mendell LM. Nerve growth factor and nociception. Trends Neurosci 1993; 16: 353–59. Apfel SC, Arezzo JC, Brownlee M, Federoff H, Kessler JA. Nerve growth factor administration protects against experimental diabetic sensory neuropathy. Brain Res 1994; 634: 7–12. Anand P, Terenghi G, Warner G, et al. The role of endogenous nerve growth factor in human diabetic neuropathy. Nature Med 1996; 2: 703–07. DCCT Research Group. The effect of intensive diabetes therapy on the development and progression of neuropathy. Ann Intern Med 1995; 122: 561–68. DCCT Research Group. Effect of intensive diabetes treatment on nerve conduction in the diabetes control and complications trial. Ann Neurol 1995; 38: 869–80. Dyck PJ. Quantitative sensory testing: a consensus report from the Peripheral Neuropathy Association. Neurology 1993; 43: 1050–52.

Insulin resistance: circumventing nature’s blocks Discovery of the insulin receptor 25 years ago was followed by an era of expectation. How was the insulin signal passed into cells? Was there a second messenger analogous to cyclic AMP relaying the glucagon signal? No easy solution emerged from early work. The puzzle persisted despite the discovery in 1982 of kinase activity in the intracellular portion of the insulin receptor and hence a means of initiating the intracellular signalling process.1 By the early 1990s increasing evidence pointed not to a single pathway of insulin action but to a network of pathways with multiple points of modulation by other hormones and signalling molecules.2 This network allowed explanation of insulin’s remarkable ability to regulate more processes than any other hormone. In the past 5 years, at least three immediate substrates for the insulin receptor kinase have been confirmed and many of the intermediate signalling molecules have been identified.3,4 Clinical states of insulin resistance involve blocks in the signalling network at one or more sites. Naturally, the more striking syndromes involve blocks at more critical steps. Genetic aberrations producing molecular changes at functional sites on the insulin receptor itself are now well characterised. Some, such as leprechaunism, are severe enough to bring about phenotypic changes before birth.5 Others, such as type A insulin resistance, become evident in childhood or adolescence.6 The Rabson Mendenhall syndrome consists of intrauterine growth retardation, diabetes, nail and tooth dystrophies, precocious puberty, and pineal hypertrophy. A single aminoacid substitution in the insulin-binding site of the receptor has been shown to be causative.7 Because insulin fails to switch on the insulin 1045