Abstract
Most developed countries in the world have experienced an epidemiologic transition, in which life expectancy has increased, and chronic diseases have replaced infections as the leading cause of death. 1 In the field of pancreatology, this has translated into increased clinical and research efforts to decrease the burden, morbidity, and mortality associated with benign inflammatory disorders and pancreatic cancer. As a result, there has been a tremendous progress in our understanding of acute pancreatitis and chronic pancreatitis in the last 30 years. In the era of personalized medicine, the goal is now to develop proteomic and metabolomic biomarkers that allow us to utilize targeted therapies for mitigating and potentially curing these disorders. However, low-income countries that lag behind in the epidemiologic transition still have a high burden of infectious diseases (e.g. tuberculosis (TB), malaria, HIV), and the effect of these infectious agents in the pancreas has not been well studied. This editorial will review three studies published in this issue of the United European Gastroenterology Journal, two of which focus on common inflammatory diseases of the pancreas and the third reviews one of the most common infectious diseases that rarely affect the pancreas.2–4
Chronic pancreatitis and diabetes mellitus
Diabetes mellitus is a well-recognized complication of chronic pancreatitis. Longitudinal studies have demonstrated that the cumulative incidence of diabetes mellitus after chronic pancreatitis diagnosis is 40–50% at 10 years and >80% at 25 years.5,6 Traditionally, this has been thought to be a result of progressive parenchymal fibrosis with impaired secretion of insulin and other glucoregulatory islet cell hormones such as glucagon and pancreatic polypeptide. This pathophysiologic paradigm was recently challenged by a study of the North American Pancreatitis Study (NAPS) consortium, which demonstrated an independent effect in the prevalence of diabetes mellitus of both chronic pancreatitis specific characteristics (chronic pancreatitis duration, calcifications, exocrine insufficiency, pancreatic surgery) as well as traditional type 2 diabetes mellitus risk factors (age, overweight/obesity, family history of diabetes mellitus). 7 It has also been recently discovered that patients with chronic pancreatitis-related diabetes mellitus have an indistinguishable genetic risk profile compared with those with type 2 diabetes mellitus. 8 The fact that both conditions share the same genetic basis and demographic risk factors has suggested that chronic pancreatitis-related diabetes mellitus may be a subtype of type 2 diabetes mellitus.
In this issue of the journal, Olesen et al. provide additional data that support the importance of insulin resistance risk factors in chronic pancreatitis-related diabetes mellitus. 2 The authors used data from the Scandinavian Baltic Pancreatic Club (SBPC), a large, cross-sectional, multicenter study of over 1300 chronic pancreatitis patients enrolled between 2016 and 2019 in eight Northern European countries. Subject characteristics were similar to what is currently reported in the literature – mean age 53 years, 67% male, and 59% alcohol etiology. The mean duration of chronic pancreatitis at time of enrollment was five years, with prevalence of diabetes mellitus of 41%, and of exocrine pancreatic insufficiency of 51%. Multivariable logistic regression models were built with a backward selection process to assess for independent factors associated with diabetes mellitus. Similar to previous studies, specific chronic pancreatitis characteristics, including disease duration, presence of calcifications, exocrine insufficiency, and history of pancreatic resection, were independently associated with diabetes mellitus.5,7 Furthermore, the study validated the NAPS2 results in a European cohort, confirming that type 2 diabetes mellitus risk factors such as age, overweight/obesity, and dyslipidemia were independently associated with chronic pancreatitis-related diabetes mellitus. In fact, the strength of the association of obesity (odds ratio (OR) 3.3) and dyslipidemia (OR 4.4) with diabetes mellitus was higher than with any of the other predicting factors in the final model.
We commend the investigators for adding to the growing body of literature in the field of chronic pancreatitis-related diabetes mellitus. Better understanding of modifiable risk factors that affect long-term chronic pancreatitis outcomes is crucial for developing interventions that may alter the natural history of the disease and ultimately prevent chronic pancreatitis complications such as diabetes mellitus. NAPS2 and SBPC have significantly contributed to this goal; however, an important limitation of both studies is their cross-sectional design. Detecting only prevalent cases of diabetes mellitus may over-represent the true burden of pancreatogenic diabetes, by including those with diabetes mellitus diagnosed before chronic pancreatitis – up to one-third in NAPS2 – and who may actually have type 2 diabetes mellitus. In a subgroup analysis of risk factors for diabetes mellitus diagnosis before and after chronic pancreatitis diagnosis in NAPS2, type 2 diabetes mellitus risk factors were only associated with diabetes mellitus diagnosed before chronic pancreatitis and had no evident role afterwards. 7 Large prospective multiethnic cohorts of chronic pancreatitis patients with pre-specified longitudinal data acquisition are needed to determine the true incidence of chronic pancreatitis-related diabetes mellitus, to precisely understand potential risk factors, and to develop diagnostic tests that accurately differentiate diabetes mellitus subtypes in chronic pancreatitis. Such studies are underway in the United States through the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer.9,10 The fact that modifiable risk factors are strongly associated with chronic pancreatitis-related diabetes mellitus opens a door of opportunities for testing specific interventions such as lifestyle modifications, lipid-lowering medications, and metformin in randomized controlled trials that aim to reduce the burden of diabetes mellitus in high-risk chronic pancreatitis patients. Early detection strategies with periodic fasting blood glucose or hemoglobin A1C in high-risk individuals for chronic pancreatitis-related diabetes mellitus also deserves further evaluation.
Evidence-based care of acute pancreatitis
Annually, approximately 2.5 million people worldwide develop acute pancreatitis and 100,000 die from the disease. 11 The clinical course of acute pancreatitis is highly variable, ranging from rapid recovery in most, to local or systemic complications in 20%, and death in 1–3% of patients. Therefore, the two major goals of therapy are to reduce the incidence of local/systemic complications, and to improve overall survival. Despite improved knowledge in the pathogenesis of the disease and increasing numbers of FDA approved drugs for less common conditions, there is still no proven effective disease-specific pharmacologic agent that alters the natural history of acute pancreatitis. 12
The current evidence in the early management of acute pancreatitis is reviewed in this issue of the journal by Garcia-Rayado et al. 3 Early goal-directed fluid resuscitation with lactated Ringer’s solution is the mainstay therapy of acute pancreatitis; however, either too little or too much volume can be harmful. The optimal volume, rate, and duration of intravenous fluid therapy is still unknown. Analgesia is necessary to mitigate disease activity based on modern scoring systems; however, there is no gold standard analgesic, and opioids do not seem to outperform non-opioid analgesics. 13 Gut arousal through oral and nasoenteric feedings is of paramount importance, and parenteral nutrition should be avoided unless enteral nutrition is not feasible. Early onset of oral nutrition with a solid diet is safe and shortens hospital stay in mild acute pancreatitis. Nasoenteric feedings are usually necessary in patients with severe acute pancreatitis or prolonged oral intolerance, but the optimal time of onset, delivery route, and formula type are not well defined with regard to major outcomes. 14
There are still more questions than answers in the personalized care of acute pancreatitis. As a result, there is great variability of how physicians manage acute pancreatitis worldwide – lower fluid volume administration in Europe, less lactated Ringer’s utilization in Latin America, higher opioid analgesic use in North America, and more parenteral nutrition in India. 15 Large-scale multicenter randomized controlled trials are needed to clarify these salient uncertainties in the early management of acute pancreatitis. Such studies need to pay special consideration at the design stage to the study population, timing of randomization/interventions, and clinical outcomes. An ideal design for fluid resuscitation or disease-specific agents should include all acute pancreatitis subjects irrespective of severity prediction, enroll participants within 12–24h of symptom onset and 4–8h of presentation to the emergency department, and measure validated and relevant clinical outcomes. 12 The search for new therapeutic targets and development of novel pharmacologic agents should continue. Once these agents reach phase III in the clinical trial pipeline, using a registry-based trial design with an established multicenter prospective platform such as APPRENTICE would be both feasible and cost-effective. 16
Pancreatic tuberculosis
An estimated 10 million people worldwide develop TB annually, of which 90% occurs in low-income countries of Africa and Asia (southeast and western Pacific regions). 17 The disease is uncommon in high-income countries, with the exception of vulnerable individuals with immunosuppression (e.g. HIV, diabetes), drug abusers, homeless, and immigrants. Tuberculosis can affect almost any organ, but its occurrence in the pancreas is extremely rare and has not been well described.
Using a systematic review methodology, Panic et al. describe in this issue of the journal the clinical features, diagnosis, and treatment of pancreatic TB. 4 Literature search was done in three databases, and case reports or series restricted to the English language were retrieved for further review. A total of 116 studies, published from 1978-2017 and that reported data on 166 patients, were qualitatively synthesized. Subjects with pancreatic TB were predominantly males in their fifth decade of life, mostly from Asia (50%), and presented with abdominal pain (65%), fevers (47%), and a pancreatic mass (80%). Different from pancreatic cancer, pancreatic TB rarely presented with jaundice. Surprisingly, diagnostic laparotomy was the most common approach (55%) for histologic or microbiologic diagnosis, with endoscopic ultrasound (EUS) being under-utilized (28%).
While this work consolidates our current understanding of this rare presentation of a common disease, there are some important limitations that are worth mentioning. The search was not comprehensive enough to capture reports from countries with high TB rates in Africa and South America. Expanding the search to other databases, languages, gray literature, and conference proceedings may have reduced the risk of reporting bias. Furthermore, the use of case reports and case series is prompted to selection bias, and the study may not be representative of the disease in poor-settings where community physicians treat these patients. However, in the absence of higher quality data, this study provides important lessons. Pancreatic TB should be suspected when a pancreatic mass is recognized in cross-sectional imaging among subjects from low-income countries with high incidence of TB, and in subjects from high-income countries with TB risk factors. Tissue acquisition with EUS fine needle aspiration is the gold standard for characterizing solid pancreatic lesions, and endosonographers should be aware of the clinical suspicion for pancreatic TB to guide cytopathologists about the potential need for acid-fast bacillus stains, mycobacterial cultures, and nucleic acid amplification. How the use of EUS and newer fine needle biopsies impacts the need for diagnostic laparotomies in pancreatic TB will need further evaluation.