Background: Acute pancreatitis is a painful, potentially life-threatening condition of the pancreas with a typically abrupt and unexpected onset, an unpredictable course, which is severe 20%-30% of the time and has no specific treatment apart from supportive care and management of its complications as they occur. While acute pancreatitis causes 3,510 deaths and 274,000 hospitalizations in the United States, accounting for 0.1%-0.6% of the diagnosis codes in the general population, it comprises 2%-3% of the diagnosis codes in the Department of Veterans Affairs (VA) system, showing a higher prevalence of acute pancreatitis among Veterans. Alcoholism is the most common etiology of acute pancreatitis (AP) among Veterans. Binge drinking is a risk factor for severe disease, lung injury, shock, multisystem organ failure, and mortality. Proximal limb amputee Soldiers hospitalized from 1944 to 1945 and separated for disability had a 3.8-fold relative risk of developing acute pancreatitis compared with distal amputees and an increased risk of dying from it between 1946 and April 1977. This suggests that Veterans are more prone to develop acute pancreatitis; and alcoholism, which is the commonest cause of pancreatitis in Veterans, also increases the risk of severe disease. Veterans with severe disabilities are affected even more often, and have a higher mortality from severe acute pancreatitis. In this study based on strong data, we will identify and propose simple, yet novel and reliable ways to predict and treat acute pancreatitis.Hypothesis: Our central hypothesis is that alcohol increases the systemic bioavailability of unsaturated fatty acids generated from visceral fat lipolysis, which along with the resulting hypocalcemia and hypoalbuminemia, worsen cell injury and cause multisystem organ failure (MSOF), thus converting AP to severe AP (SAP). This is based on the following observations: (1) Fat necrosis seen on CT scans is an established part of criteria for SAP in humans. (2) Human pancreatic fat necrosis has high amounts of unsaturated fatty acids and is their source. (3) Patients with SAP have high unsaturated fatty acids in the circulation. (4) We find alcohol increases free fatty acids in the circulation of rodents, which as a consequence die early with lung injury, saponification of calcium by the fatty acids, losing albumin into the peritoneal cavity, developing a low serum albumin, calcium and shock. (5) We note Veterans with alcoholic AP who needed intensive care unit (ICU) care and longer hospitalization had lower serum calcium and albumin earlier in the disease. (6) In vitro albumin and calcium prevent and abort deleterious signaling by unsaturated fatty acids. We propose to test a novel yet simple [Serum free fatty acid/Serum calcium x albumin)] ratio as a reliable predictor and therapeutic target in the management of alcoholic AP. Our approach also brings into question the commonly used 'calcium correction in hypoalbuminemia' http://www.mdcalc.com/calcium-correction-forhypoalbuminemia/, which leaves a low serum calcium and albumin uncorrected, worsening AP.Objective: (1) Study [Serum free fatty acid/(Serum calcium x albumin)] as a predictor and therapeutic target in alcoholic SAP. (2) Study unique pathophysiology in alcoholic SAP-related lung injury and immune paralysis. Study Design: Aim 1: Clinical studies in Veterans: Compare the [Serum free fatty acid/(Serum calcium x albumin)] ratio to conventional predictors of SAP. Study acute alcoholic cardiomyopathy in in alcoholic SAP-related lung injury and circulating dead inflammatory cells in immune paralysis. Aim 2: Basic: Determine how alcohol alone or with unsaturated fatty acids worsens organ failure in SAP. Here, the impact of our hypothesis and competing ones will be studied on the end points of SAP: (1) Alcohol alone may worsen AP independent of unsaturated fatty acids. (2) Alcohol forms fatty acid ethyl esters from fatty acids, which worsen pancreatitis. (3) Serum calcium and albumin are SAP markers but do not influence its severity. We will also test if correcting the calcium and albumin deficit therapeutically based on the 'ratio' improves outcomes in rats with SAP. We will then integrate the clinical and basic findings into recommendations for alcoholic AP in Step 3. Here, we will propose novel mechanisms, better predictors, and therapeutic interventions for alcoholic SAP. Relevance: Our proposal is focused on acute pancreatitis, which is a Fiscal Year 2015 Peer Reviewed Medical Research Program Topic Area. As noted in the Background section, this is highly relevant to our Veterans. The proposed hypotheses will be put to rigorous testing and compared to alternate predictors and hypothesis in both clinical and basic studies. If our hypothesis is true, it would change the paradigm of managing serum calcium and albumin, and acute lung injury during SAP. This would provide a better, novel yet simple predictor and management for SAP, and potentially AP in general. This would benefit our Veterans who are commonly afflicted by it.
|Effective start/end date||9/30/16 → 9/29/19|
- Congressionally Directed Medical Research Programs: $1,760,804.00