Severe Alcoholic Pancreatitis-Associated Acute Lung Injury in Veterans: Risks, Mechanisms, Prediction, and Therapeutic Relevance

Background: Acute pancreatitis is a painful, potentially life-threatening condition of the pancreas with a typically abrupt and unexpected onset. Twenty to thirty percent of the time it can be severe, such as causing difficulty in breathing, failing kidneys, sometimes causing death. There is no reliable way to predict who is going to have a severe attack, and there is no specific treatment for acute pancreatitis. Approximately 274,000 Americans are hospitalized for pancreatitis every year, and it causes 3,510 deaths, costing the system $3.7 billion.

Whereas acute pancreatitis accounts for less than 0.6% of the diagnosis in the general hospitals, it comprises up to 3% of these in the Department of Veterans Affairs (VA) system. This suggests that acute pancreatitis is more common among Veterans. Veterans who had amputations of their proximal limbs due to Service-related trauma, when followed for 30 years had a 3.8-fold increased risk of developing acute pancreatitis compared to distal amputees. These Veterans also had a higher chance of dying from acute pancreatitis. Alcohol is the commonest cause of pancreatitis in Veterans and binge drinking makes pancreatitis severe.

Unsaturated fatty acids are normally stored in an inactive form in fat cells. In pancreatitis, these cells are damaged, releasing the fatty acids. In the free form, these fatty acids are toxic. We have recently discovered that alcohol increases the serum levels of free fatty acids, and these result in severe injury to the lungs, heart, and kidneys, causing early death. We have also learnt that there are two natural agents that reduce the toxicity of unsaturated fatty acids. These are albumin and calcium. During pancreatitis, however, we lose albumin due to leaky blood vessels and the calcium forms soaps with the fatty acids. This results in a reduction in the amount of albumin and calcium available to neutralize the fatty acids.

Current State of Treatment: In conventional medicine, we find a commonly used 'correction' http://www.mdcalc.com/calcium-correction-for-hypoalbuminemia/, which leaves a low calcium and albumin uncorrected. Doing so may actually worsen pancreatitis. We propose replacing these as below.

The Proposal: In this proposal, we propose to test a novel yet simple [Serum free fatty acid/(Serum calcium x albumin)] 'ratio' as a reliable early predictor and therapeutic target in the management of alcoholic acute pancreatitis. This will allow calculating the calcium, albumin deficit and replacement.

The Research: Our proposal has both clinical and basic experimental arms. The clinical arm will study the ability of our 'ratio' in predicting the severity of pancreatitis within the first day or two in Veterans with alcoholic pancreatitis. We will do so by comparing the ratio to other predictors, which are available (however, these are incorrect about 1/3 times). The ratio will also be compared to an early echocardiogram done in Veterans and the number of dead inflammatory cells in their blood. These respectively will help determine if collective lung-heart damage causes breathing problems, and also whether death of inflammatory cells increases the risk of infections that occur later in severe pancreatitis. In the basic arm, we will verify that it is indeed alcohol increasing the blood levels of unsaturated fatty acids, which worsens pancreatitis. We will do so by studying alcohol alone and comparing fatty acids toxicity in the presence of alcohol and also to their metabolites known as 'fatty acid ethyl esters.' The reasoning behind the echocardiogram data in humans will be confirmed in animal experiments by studying what happens with alcohol, fatty acids, the combination or their metabolites. We will also study the effect of replacing albumin and calcium in rodents that have pancreatitis and study if this is beneficial. In doing so, we will also learn if the calcium, albumin deficit calculated by the ratio is an accurate target to calculate the amount to replaced.

The Benefits: These studies will help develop predictors and treatment strategies for acute pancreatitis, which commonly afflicts our Veterans. By combining the clinical and basic arms, we will have a deeper understanding of the observations we make in Veterans with alcoholic pancreatitis. These will hopefully undo common misconceptions (such as the one regarding 'correction' of calcium, albumin mentioned above) and make the management of alcoholic acute pancreatitis more relevant and safe for our Veterans.