Skeletal muscle: A new piece in the pancreatitis puzzle

The pancreas is a much more complex organ than meets the eye. Cross-sectional imaging is well positioned to heighten our understanding of diseases of the pancreas and their sequelae.¹ It is increasingly used for not only a qualitative assessment of visually discernible areas of pathology in the pancreas but also an objective quantification and in-depth characterisation of pancreas composition.^2,3 Furthermore, a growing body of evidence indicates the involvement of extra-pancreatic organs and tissues in the pathogenesis of diseases of the exocrine pancreas and their sequelae.¹ Computed tomography scans contain information about the radiodensity of a specific tissue type, which is referred to as radiation attenuation. This parameter is particularly useful in the quantitative evaluation of skeletal muscle composition. The first study that used this approach in diseases of the exocrine pancreas was published in 2015 and involved 230 patients with pancreatic cancer.⁴ The authors from Kyoto University (Japan) showed that low muscle radiation attenuation (signifying increased fat content in skeletal muscle) on preoperative abdominal images is an independent risk factor for mortality after curative resection of pancreatic cancer. In the current issue of the Journal, Sternby and 19 co-authors report a computed tomography study of 454 patients with acute pancreatitis from several European countries.⁵ They found that muscle radiation attenuation in the lowest tertile is significantly associated with a severe course of acute pancreatitis, in both unadjusted and adjusted analyses.

Several methodological nuances should be kept in mind when interpreting this study. Low muscle radiation attenuation could be a reflection of not only increased fat content but also increased water content in muscle tissue (i.e. muscle oedema). The latter is far more likely in patients during the course of acute pancreatitis than in outpatients during follow-up. Unfortunately, important data on fluid balance, use of diuretics, enteral nutrition, comorbidities and time since onset of pancreatitis were not collected.⁶ The results might also have been affected by retroperitoneal fat stranding and peripancreatic necrosis as patients with these imaging findings were not excluded or analysed separately. The studied parameters were not normalised for anthropometrics, which would have been important as skeletal muscle size is often affected by them. Only data on area (at the level of the third lumbar vertebra) were analysed whereas data on volume would have been more informative.⁷ The use of chemical-shift magnetic resonance imaging would have been required though to avoid excessive exposure to ionising radiation. Given the above caveats, studying skeletal muscle in the early stage of acute pancreatitis with the use of computed tomography is pretty much a dead end.

To date, skeletal muscle in the context of diseases of the exocrine pancreas has been considered mainly from the perspective of the association between loss of muscle mass or strength (sarcopenia) and in-hospital outcomes. What has been overlooked is that skeletal muscle plays a key role in maintaining glucose homeostasis as it accounts for up to 80% of glucose disposal in the postprandial state and skeletal muscle fatty acid oxidation covers about 90% of the energy requirements in the rested state.⁸ Diabetes of the exocrine pancreas has emerged as the second most common type of new-onset diabetes in adults.^1,9 Its most common sub-type, post-pancreatitis diabetes mellitus (PPDM), leads to a 13% higher risk of all-cause mortality compared with type 2 diabetes.¹⁰ Moreover, the efficacy of metformin and insulin, common antidiabetic medications, is significantly different between PPDM and type 2 diabetes.^11,12 Given that any type of diabetes is characterised to some degree by unresponsiveness of myocytes to insulin stimulation (and the resulting impaired glucose uptake into muscle cells), gaining insights into skeletal muscle phenotypes during the follow-up of people with abnormal glucose metabolism after an attack of pancreatitis represents an opportunity to advance our understanding of the pathogenesis of PPDM. One possible mechanism linking skeletal muscle and PPDM is skeletal muscle fat deposition. It is theorised that oxidative stress (frequently observed during an attack of pancreatitis¹³) leads to impaired skeletal muscle mitochondrial function and impaired fatty acid disposal via oxidation, which subsequently results in increased skeletal muscle fat deposition. Fat deposition may cause impaired insulin signaling directly (via inhibitory effects of diacylglycerol and ceramide) or indirectly (via secretion of pro-inflammatory adipokines).^14,15 Purposely designed studies are now warranted to substantiate skeletal muscle as a so far missing piece of the metabolic puzzle that must be put together with a view to preventing the progression of pancreatitis and its sequelae, epitomized by the ‘holistic prevention of pancreatitis’ framework.¹