Insulin-Pancreas Connections

Majid Ali, M.D.

Beyond Insulin-Pancreas Connections -Not Really.


What Should Acute Pancreatitis Tell Us Americans About Ourselves?

The pancreas gland produces insulin which, in he minds of doctors, nurses, and everyone else, brings up the matter of diabetes. This is regrettable at many levels. Here I raise a different question: What should does acute pancreatitis tell us Americans about ourselves? Following are the causes of acute pancreatitis listed by The New England Journal of Medicine. Please take a few minutes to think about what crucial element is missing in it.

Causes of Acute Pancreatitis

  1. Gallstones                       40%
  2. Alcohol                            30%
  3. Hypertriglyceremia .    2-5 %
  4. Drugs                               Less than 5%
  5.   Autoimmune                Less than 1%
  6. Associated conditions  Diabetes, obesity, smoking      




Acute Pancreatitis

Article: Forsmark CE, Vege SS, Wilcox CM. Acute Pancreatititis. N E. J.Med. 2016;375:1972-1981.

Consider this:
  1. The incidence of acute pancreatitis is increasing in the United States.
  2. It is now one of the most common reasons for hospitalization with a gastrointestinal condition.
  3. On November 17, 2016, The New England Journal published an excellent review article on acute pancreatitis. It is most informative but with one glaring and most regrettable omission. It listed the causes of acute pancreatitis but failed to ven mention the most important cause of the greatest concern for the medical profession as well as the general public at large.



Table 1TABLE 1Causes of Acute Pancreatitis. lists the causes of acute pancreatitis. Gallstones are the most common cause.1,2 Migrating gallstones cause transient obstruction of the pancreatic duct, a mechanism shared by other recognized causes (e.g., endoscopic retrograde cholangiopancreatography [ERCP]), as well as purported causes (i.e., pancreas divisum and sphincter of Oddi dysfunction). A recent trial failed to show that sphincter of Oddi dysfunction contributed to post-cholecystectomy biliary pain,3 and there are no convincing data from controlled trials that either pancreatic sphincter of Oddi dysfunction or pancreas divisum plays a role in acute pancreatitis.4-6

Alcohol is the second most common cause of acute pancreatitis. Prolonged alcohol use (four to five drinks daily over a period of more than 5 years) is required for alcohol-associated pancreatitis7; the overall lifetime risk of pancreatitis among heavy drinkers is 2 to 5%. In most cases, chronic pancreatitis has already developed and the acute clinical presentation represents a flare superimposed on chronic pancreatitis. The risk is higher for men than for women, perhaps reflecting differences in alcohol intake or genetic background.8 The mechanisms by which alcohol causes acute (or chronic) pancreatitis are complex and include both direct toxicity and immunologic mechanisms.9 The type of alcohol ingested does not affect risk, and binge drinking in the absence of long-term, heavy alcohol use does not appear to precipitate acute pancreatitis.10

Drugs appear to cause less than 5% of all cases of acute pancreatitis, although hundreds of drugs have been implicated.11 The drugs most strongly associated with the disorder are azathioprine, 6-mercaptopurine, didanosine, valproic acid, angiotensin-converting–enzyme inhibitors, and mesalamine. Pancreatitis caused by drugs is usually mild. Recent data do not support a role for glucagon-like peptide 1 mimetics in causing pancreatitis.12 It is common for patients to be taking one of the many drugs associated with pancreatitis when they are admitted to the hospital with acute pancreatitis,13 but it is exceedingly difficult to determine whether the drug is responsible.

Mutations and polymorphisms in a number of genes are associated with acute (and chronic) pancreatitis, including mutations in the genes encoding cationic trypsinogen (PRSS1), serine protease inhibitor Kazal type 1 (SPINK1), cystic fibrosis transmembrane conductance regulator (CFTR), chymotrypsin C, calcium-sensing receptor, and claudin-2.14 These mutations may serve as cofactors, interacting with other causes; for example, claudin-2 mutations work synergistically with alcohol.8,14

The cause of acute pancreatitis often cannot be established, and the proportion of persons who are considered to have idiopathic acute pancreatitis increases with age. A number of potential factors might contribute to unexplained pancreatitis, including unidentified genetic polymorphisms, exposure to smoking and other environmental toxins,15 and effects of coexisting diseases that are commonly associated with acute pancreatitis (e.g., obesity and diabetes). Morbid obesity is a risk factor for acute pancreatitis2,16 and for severe acute pancreatitis.17 Type 2 diabetes increases the risk of acute pancreatitis by a factor of 2 or 3.2 Both obesity and diabetes are also risk factors for chronic pancreatitis and pancreatic cancer.18


Acute pancreatitis in the United States accounts for health care costs of $2.5 billion19 and for 275,000 admissions each year. Admissions have increased by at least 20% over the past 10 years. Studies worldwide20-22 have shown a rising but variable incidence of acute pancreatitis, including large increases in incidence in pediatric populations.23 This increased risk of pancreatitis tracks with the worldwide obesity epidemic and increasing rates of gallstones. Approximately 80% of patients admitted with acute pancreatitis have mild, self-limited disease and are discharged within several days. Mortality associated with acute pancreatitis has decreased over time,2 and the overall mortality is now approximately 2%. Death is more likely in certain subgroups of patients, including the elderly, those with more numerous and more severe coexisting conditions (particularly obesity),16,17 those in whom hospital-acquired infections develop,24 and those with severe episodes of acute pancreatitis (characterized by persistent failure of one or more organ systems or infected pancreatic necrosis).


Accurate diagnosis of acute pancreatitis requires at least two of the following three diagnostic features25: abdominal pain consistent with acute pancreatitis, serum lipase or amylase levels that are at least 3 times the upper limit of the normal range, and findings of acute pancreatitis on cross-sectional imaging (computed tomography [CT] or magnetic resonance imaging). Patients with vague abdominal symptoms and a minimally increased serum amylase or lipase level should not receive a diagnosis of acute (or chronic) pancreatitis. Cross-sectional imaging is invaluable in confirming an initial diagnostic impression, in assessing patients for other conditions that might mimic acute pancreatitis, and in evaluating patients with atypical symptoms or small elevations in serum pancreatic enzyme levels.

According to a recent international consensus (see the Supplementary Appendix, available with the full text of this article at, the classifications of moderately severe pancreatitis and severe pancreatitis are defined by the presence of complications that are systemic, local, or both. Systemic complications include failure of an organ system (respiratory, cardiovascular, or renal) and exacerbation of a preexisting disorder (e.g., chronic obstructive pulmonary disease, heart failure, or chronic liver disease). Local complications comprise peripancreatic fluid collections or pseudocysts and pancreatic or peripancreatic necrosis, whether sterile or infected.25 In this classification system, persistent failure of an organ system (i.e., lasting more than 48 hours) is the prime determinant of a poor outcome. The overall mortality is approximately 2%, but it approaches 30% among patients with persistent failure of an organ system. According to another classification system, the presence of both persistent organ failure and infected pancreatic necrosis (“critical” pancreatitis) is associated with the highest mortality (see the Supplementary Appendix).26

By providing standardized definitions and descriptions of severity, as well as radiographic features, these classification systems for acute pancreatitis have value in clinical research. However, they do not provide methods for predicting severity.


Knowing which patient will have severe pancreatitis could allow earlier triage to an intermediate care or intensive care unit and earlier initiation of effective therapy. Prediction of severity has been accomplished through careful observation by an experienced clinician, with symptoms, signs, and the results of routine laboratory and radiographic testing taken into account. This process largely allows the identification of severe pancreatitis as it develops. A host of predictors, including clinical and laboratory markers and various scoring systems, have been developed to improve clinical judgment.

Clinical factors that increase the risk of complications or death among patients with acute pancreatitis include advanced age (≥60 years), numerous and severe coexisting conditions (a score of ≥2 on the Charlson comorbidity index [a weighted sum of diseases according to the codes of the International Classification of Diseases, 10th revision, with higher scores indicating a greater disease burden]), obesity (a body-mass index of >30 [calculated as the weight in kilograms divided by the square of the height in meters]), and long-term, heavy alcohol use.2 A variety of laboratory measures have also been studied, primarily measures of intravascular volume depletion due to third-space losses (i.e., the leakage of fluid from the intravascular spaces and into the interstitial spaces), such as hemoconcentration and azotemia, or markers of inflammation (e.g., elevated levels of C-reactive protein and interleukins 6, 8, and 10). Several of these measures have reasonable predictive value for severe acute pancreatitis. The most useful predictors are elevated blood urea nitrogen and creatinine levels and an elevated hematocrit, particularly if they do not return to the normal range with fluid resuscitation.27,28 The degree of elevation of the serum amylase or lipase level has no prognostic value.

A number of predictive systems use CT findings, but CT evidence of severe acute pancreatitis lags behind clinical findings, and an early CT study can underestimate the severity of the disorder. Several scoring systems have been developed to incorporate clinical, radiographic, and laboratory findings in various combinations: Acute Physiology and Chronic Health Evaluation II (APACHE II), APACHE combined with scoring for obesity (APACHE-O), the Glasgow scoring system, the Harmless Acute Pancreatitis Score (HAPS), PANC 3, the Japanese Severity Score (JSS), Pancreatitis Outcome Prediction (POP), and the Bedside Index for Severity in Acute Pancreatitis (BISAP).29 These scoring systems all have a high false positive rate (i.e., in many patients with high scores, severe pancreatitis does not develop), which is an unavoidable consequence of the fact that in most patients, severe disease does not develop. The scoring systems are complex and cumbersome and not routinely used.

These scoring systems cannot replace ongoing evaluation by an experienced clinician. A few points are worth emphasizing for incorporation into clinical decisions. The presence of the systemic inflammatory response syndrome (SIRS) is usually obvious, although it may not be recognized. SIRS can be diagnosed on the basis of four routine clinical measurements, with findings of two or more of the following values: temperature, below 36°C or above 38°C; pulse, greater than 90 beats per minute; respiratory rate, greater than 20 breaths per minute (or partial pressure of arterial carbon dioxide, <32 mm Hg); and white-cell count, lower than 4000 or higher than 12,000 per cubic millimeter. SIRS that persists for 48 hours or more after the onset of symptoms is indicative of a poor prognosis. Recent guidelines27,28 recommend using demographic and clinical factors at admission (advanced age, high body-mass index, and coexisting conditions), simple laboratory values at admission and during the next 24 to 48 hours (hematocrit, >44%; blood urea nitrogen level, >20 mg per deciliter [7 mmol per liter]; or creatinine level, >1.8 mg per deciliter [159 μmol per liter]), and the presence of SIRS to identify patients who are at greatest risk for severe disease and most likely to benefit from a high-intensity nursing unit. During the first 48 to 72 hours, a rising hematocrit or blood urea nitrogen or creatinine level, persistent SIRS after adequate fluid resuscitation, or the presence of pancreatic or peripancreatic necrosis on cross-sectional imaging constitutes evidence of evolving severe pancreatitis.30

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