How fast did you progress to severe CP?

Hi Candice - I had an EUS 10 years ago which showed 3 minor criteria for CP. Lipase slightly elevated (less than twice the normal). I decided to move on with my life and not think about it. For the last ten years I have felt relatively well with isolated episodes of indigestion and very nimor pain on the left side of the abdomen that last seconds. I had a CT last week which revealed no abnormalities in the pacreas. I am due for an EUS later this month just for reassurance. 

What do you make of it? I really thought I would be in a really bad shape 10 years after the "minimal change chronic pancreatitis" diagnosis. However, I think the word indetermine was included in the report. 

I have never been to ER for pain. I never had an acute attack. Just this persistent elevated lipase with discomfort. Amylase was 125 recently (ref 25-140) not sure if that means anything. 95% of my meals are well tolerated without pain. Again, a decade later. 

My best hope is that I was misdiagnosed or that it is moving very slowly. 

Thank you Dianne. I am optimistic. I have to be. I have to young daughters that I need to support and a wonderful supportive wife. I don't want to let them down. Please feel well for me. If you allow me, please get a copy of The Book of Joy. It is a life changing book. 

Bless you always,

H. 

This is what Dr. Forsmark wrote about patient like you and myself (the "indetermine" group)..

Reaching a correct diagnosis is straightforward in most patients with long-standing chronic pancreatitis. These patients have easily identifiable abnormalities of the pancreas. These abnormalities may be of the stucture or the function of the gland. Abnormalities of pancreatic structure might include pancreatic ductal dilation, pancreatic parenchymal atrophy, or pancreatic calcifications. Abnormalities of pancreatic function could include exocrine or endocrine insufficiency. This type of patient usually has a long history of clinical illness, often with multiple clinic visits or hospitalizations for abdominal pain or complications of chronic pancreatitis. Although the management of this type of patient may be quite challenging, the diagnosis is not. Widely available diagnostic tests such as computed tomography (CT) or magnetic resonance imaging (MRI with magnetic resonance cholangiopancreatography [MRCP]) will document the presence of chronic pancreatitis.[1]

It is also well recognized by clinicians that the diagnosis of chronic pancreatitis is not so straightforward in all patients. One prototypical patient might be a young or middle-aged person with a chronic abdominal pain syndrome in whom CT and MRI/MRCP results are normal. Perhaps modest increases in amylase or lipase levels have been documented occasionally. An evaluation for other causes of abdominal pain has been unrevealing. Patients like this (and with multiple variations on this theme) may be labeled as having chronic pancreatitis. Having that label attached carries significant implications, including on the patient's emotional and financial well-being. These types of patients, who do not have easily identifiable abnormalities of pancreatic function or structure, might be said to have early chronic pancreatitis (also called minimal change chronic pancreatitis) and comprise a diverse group that may pose a substantial diagnostic dilemma.[2,3] What diagnostic approach allows us to be as accurate as possible in this group of patients?

The concept of early diagnosis is a very challenging one in chronic pancreatitis. The development of easily identifiable chronic pancreatitis may take many years. Pancreatic calcification may not develop for years or even decades of disease. Diabetes or steatorrhea may only develop after 10 or 20 years of disease. In some patients, they never develop. There is an evolving paradigm that provides some framework for this concept. The paradigm suggests that most chronic pancreatitis begins with clinical or subclinical episodes of acute pancreatitis, with the development of cellular necrosis or apoptosis. This injury may heal without sequelae, but with each additional episode the likelihood increases that the inflammatory milieu within the pancreas will shift towards chronic inflammation, the activation of pancreatic stellate cells, and the development of fibrosis (ie, chronic pancreatitis). This paradigm places acute pancreatitis on one end of a spectrum and chronic pancreatitis on the other end of the same spectrum. The transition from one to the other may not occur, and if it does occur the transition may be subtle and difficult to precisely identify. Early might mean making a diagnosis before obvious advanced structural and functional abnormalities have developed in the diseased pancreas. Early also might mean making a diagnosis before symptoms become chronic or long-standing. This latter definition of early could be potentially the most useful, perhaps allowing clinicians to identify patients on the road to chronic pancreatitis in whom some intervention might slow or even prevent the development of advanced chronic pancreatitis.

Any diagnostic approach is hampered further by the fact that chronic pancreatic inflammation and fibrosis may develop in the apparent absence of clinical chronic pancreatitis. As an example, autopsy studies of chronic alcoholics have found substantial pancreatic fibrosis in at least half, whereas only about 10% of all chronic alcoholics had developed the clinical illness of chronic pancreatitis.[4] Presumably, many social drinkers may have similar changes. Similarly, pancreatic inflammation and fibrosis occur commonly with advancing age in the absence of any symptoms of chronic pancreatitis.[5] The distinction between normal and abnormal may therefore be difficult to identify. It is probably useful to think about an indeterminate zone between normal and abnormal. Patients may reach this transition or indeterminate zone and never progress to clinical chronic pancreatitis, or may pass through this zone to symptomatic chronic pancreatitis. It has been suggested we envision a pancreatopathy, somewhere between normal and chronic pancreatitis.[6]

Almost by definition, making a diagnosis early would imply that advanced structural and functional abnormalities have not developed. In other words, these are patients in whom a CT scan (or an MRI) shows either normal results or at least inconclusive results. In such patients who are suspected of having chronic pancreatitis, a number of possible diagnostic tests might be considered. In the past, the choice was fairly straightforward. This was the situation when endoscopic retrograde cholangiopancreatography (ERCP) was performed. ERCP was believed to give the most detailed and accurate diagnostic information, and in fact often was considered the gold standard test for diagnosis. ERCP is a tarnished gold standard in this regard, in that the test is subject to rather substantial interobserver and intraobserver variation in interpretation, chronic pancreatitis can exist with a normal ERCP, and other diseases can mimic the changes seen by ERCP in patients with chronic pancreatitis.[3] In the few centers that had direct pancreatic function testing, this was used in lieu of ERCP to make an early diagnosis. Direct pancreatic function testing is superior to ERCP for early diagnosis,[7] but the lack of availability meant that most clinicians and most patients did not have access to it. Pancreatic function testing can have many definitions, but here I use it to describe a particular type of testing that uses a hormonal secretagogue to maximally stimulate pancreatic secretion (of bicarbonate-rich fluid of ductal origin or enzyme-rich fluid of acinar origin) followed by the collection and analysis of this fluid. The test measures the maximum stimulated secretory output of the gland, and detects a decrease in this output long before there is secretory failure (ie, exocrine insufficiency). This historically has been done by placing an oroduodenal tube into the duodenum for collection of fluid, a procedure that may be difficult for patients to tolerate. The test is not standardized and each center has developed its own procedures and normal ranges, further hampering making the test more widely available.

In addition to ERCP and these direct pancreatic function tests, a number of new and newly modified tests are now becoming available to clinicians. These include tests that give much more detailed information on pancreatic structure such as multidetector CT, endoscopic ultrasonography (including elastography and digital image analysis), and MRI with MRCP using gadolinium enhancement and secretin stimulation. Of these, endoscopic ultrasound (EUS) has certainly become very widely used in patients with suspected chronic pancreatitis. Currently, EUS relies on 9 sonographic criteria.[6] Although still undergoing study, it has become clear that a normal EUS (0–2 criteria) essentially rules out the diagnosis of chronic pancreatitis. Similarly, it also is clear that a very abnormal EUS (5–9 criteria) effectively rules in chronic pancreatitis. The interpretation of 3 to 4 criteria is indeterminate. In addition to these diagnostic tests, there has been ongoing effort to make direct pancreatic function testing more accessible. These have included collecting pancreatic juice directly from the pancreatic duct at the time of ERCP (intraductal secretin test) and also using standard endoscopes in place of the traditional oroduodenal tube to collect pancreatic secretions. The intraductal secretin test is inaccurate and has not been able to be widely adopted. Pancreatic function testing using an endoscope instead of an oroduodenal tube to collect pancreatic secretions may have advantages that might allow it more widespread use. First among these is patient acceptance (because the patients are sedated). It appears that modest levels of sedation, using a narcotic and a benzodiazepine, do not have major effects on stimulated pancreatic secretion. In addition, the pancreatic secretions that are collected can be analyzed by any central laboratory in any hospital.

Endoscopic-based pancreatic function tests have undergone several iterations and have several variations.[8,9,10] Similar to traditional pancreatic function tests, either secretin or cholecystokinin (or both) can be administered to stimulate pancreatic secretion. If secretin is given, a bicarbonate-rich ductal fluid is produced, and the bicarbonate concentration in sequential samples can be measured. If cholecystokinin is given, an enzyme-rich fluid is obtained, and levels of enzyme activity (usually lipase) can be measured. After administering either of these secretagogues, it may take up to 60 minutes for peak output to occur. Hence, these tests usually require that pancreatic secretions are collected and analyzed over 30 to 60 minutes. This means keeping an endoscopy room occupied and a patient sedated for up to 60 minutes, which may be cost-prohibitive. Nonetheless, if a patient with a chronic pain syndrome can have the diagnosis of chronic pancreatitis either ruled out or firmly established, this may save substantial resources in the long run.

The study by Parsi et al[11] in this issue of the journal used a cholecystokinin-based pancreatic function test as part of the diagnostic algorithm for patients referred for a chronic abdominal pain syndrome in whom cross-sectional imaging (CT and MRI/MRCP) showed either normal or inconclusive results.[11]These were patients referred to a tertiary university center with particular interest in pancreatitis. Patients were referred for ERCP and in addition to undergoing ERCP they also underwent an endoscopic-based pancreatic function test. The results of both tests were compared against a composite gold standard. Similar to most studies in this area, the choice of a gold standard is difficult and often involves a bit of circular reasoning. In this particular study, chronic pancreatitis was diagnosed during up to 7 years of follow-up evaluation and was defined by the development of advanced (Cambridge class II or IV) pancreatic ductal abnormalities on ERCP or MRCP during follow-up evaluation, histologic confirmation, exocrine insufficiency (steatorrhea responsive to pancreatic enzyme supplementation), or, lastly, an abnormal pancreatic function test with abdominal pain responsive to pancreatic enzyme therapy. This last one is a bit loose, but only 2 patients were ultimately diagnosed using this particular criterion. In an attempt to minimize bias, ERCP interpretations were performed in a blinded fashion by a panel of experts.

The study included 35 patients with an average age of 46 years (range, 24–77 y), of whom slightly more than half were women. With follow-up periods of 1 to 7 years (median, 7 y), 24 patients were judged to have developed chronic pancreatitis using this composite gold standard. In about half of these, the disease was ascribed to alcohol. In these 24 patients, the index ERCP (performed at the time of the referral) was abnormal in 17 (including 12 who were Cambridge III or IV).

The results of ERCP and endoscopic pancreatic function test were in agreement in 60% of the patients. Of the remaining patients, ERCP was correct in half of the patients and pancreatic function test was correct in half of the patients. In the entire group, the sensitivity of ERCP was 71% and the specificity was 91%. For the endoscopic pancreatic function test, the corresponding values were 96% and 37%, respectively. The high sensitivity of the pancreatic function test means that a normal test rules out chronic pancreatitis with a high degree of certainty.

Ultimately, any clinician will need to decide what she or he is really interested in. All tests are imperfect. A test with high sensitivity would be chosen if the cost of missing the disease was great. In addition, a highly sensitive test is most helpful when it is negative, allowing one to rule out a disease (high negative predictive value). A highly specific test is chosen to confirm or rule in a disease. Highly specific tests are most helpful when they are positive (high positive predictive value). In this particular study, ERCP is the highly specific test and pancreatic function testing is the highly sensitive test. In addition to these considerations, any choice of diagnostic test must take into account cost, risk (level of invasiveness), and availability. Obviously, if we could eliminate the need for an invasive and costly test (eg, ERCP) by using a less expensive, costly, and risky pancreatic function test first, then we would have performed a useful service. It is just this way that pancreatic function tests should be used, early enough in the diagnostic process that risky or costly tests might be avoided. All clinicians have seen complications from ERCP and these tend to occur most in patients who need the test least (eg, a young person with a chronic abdominal pain syndrome and a negative CT or MRCP).

In the current environment, a number of highly sophisticated imaging tests are also on the horizon or in clinical use. For instance, MRI technology may now asses not only pancreatic parenchymal and ductal structure but also parenchymal enhancement with gadolinium and even pancreatic function by quantifying fluid output from the pancreas after injection of the secretagogue secretin. EUS may assess tissue characteristics via elastography or analyze images by computer. CT technology using multidetectors continues to improve image quality. Within even this environment, however, a need remains for pancreatic function testing. Conventional direct pancreatic function testing, although accurate, will continue to be available at very few centers. Endoscopic-based pancreatic function testing is something that interested clinicians could consider adding to the armamentarium of diagnostic tools for these challenging patients. A diagnostic protocol using either EUS or direct pancreatic function testing initially, followed by the other in equivocal cases, would seem to satisfy the need for an accurate and low-risk approach to diagnosis.