Major criteria
Minor criteria
Major criteria A
Cysts
Hyperechoic foci with shadowing (parenchymal calcifications)
Stranding
Main pancreatic duct calculi
Hyperechoic foci without shadowing
Lobularity without honeycombing
Major criteria B
Irregular main pancreatic duct contour
Lobularity with honeycombing
Dilated main pancreatic duct
Hyperechoic main pancreatic duct margin
Dilated side branches
Consistent with chronic pancreatitis
1 major A feature (+) ≥3 minor features
1 major A feature (+) major B feature
2 major A features
Suggestive of chronic pancreatitis
1 major A feature (+) <3 minor features
1 major B feature (+) ≥3 minor features
≥5 minor features (any)
Indeterminate for chronic pancreatitis
3 to 4 minor features, no major features
1 major B feature alone or with <3 minor features
Normal
≤2 minor features (except for cysts, dilated main pancreatic duct, hyperechoic foci without shadowing, and dilated side branches, with no major features)
However, even perfectly sensitive tests for chronic pancreatitis may not be diagnostic of exocrine insufficiency. Steatorrhea does not occur until the pancreas has lost 90 % of its exocrine reserve [6]. There may be significant discordance between EUS findings of chronic pancreatitis and exocrine insufficiency as measured by secretin pancreatic function testing [7, 8], implying that parenchymal changes and exocrine insufficiency may occur concurrently or that there is a significant reserve capacity for absorption that is still adequate in early parenchymal disease. Instead of inferring pancreatic function from structural diagnosis via pancreatic imaging, direct and indirect tests of pancreatic function may be preferred for definitive diagnosis of pancreatic exocrine insufficiency.
Traditional secretin test of pancreatic function is performed by placing a double-lumen “Dreiling” tube under fluoroscopy so that distal port is in the duodenum and the proximal port in the stomach. After aspiration of gastric contents, duodenal secretions are stimulated by secretin or CCK and collected for bicarbonate and enzymatic content for upward of 1 h in serial increments. This test is both uncomfortable for the patient and also laborious for the lab and therefore rarely performed. Endoscopic pancreatic function testing (EPFT) maintains the same principles of Dreiling tube testing but has the advantage of improving patient tolerance and operator convenience by performing the test under sedation during EUS or routine upper endoscopy [9, 10]. However, specimen collection time remains up to 1 h. Indirect tests of pancreatic function avoid intestinal intubation and the hassle and expense of traditional function testing.
Fecal fat is not specific to pancreatic exocrine insufficiency but instead a measure of global malabsorption. Quantitative fecal fat analysis is performed after amassing a 72-h stool collection, while the patient maintains intake of 100 g of fat/day and subsequent titration to yield fecal fat per 24 h. The upper limit of normal for fat excretion in stool is considered 7 g/day on a 100 g of fat/day diet. But an otherwise healthy patient with induced diarrhea can have as much as 14 g fat in the stool per day [11]. In general, very high fecal fats (>30 gm/day) are associated with pancreatic insufficiency, whereas milder steatorrhea (10–30 gm/day) are more suggestive of mucosal disease.
Stool may also be stained and examined under microscopy in a qualitative test as a screen for fat malabsorption (Sudan stain). Acidification of the stool mixture allows for staining of both split fats (fatty acids) and neutral fats (triglycerides). The test can be performed without acidification which results in preferential staining of triglycerides. Increased staining for neutral fats implies a disorder of digestion such as pancreatic exocrine insufficiency, while increased staining for split fats implies malabsorption at the brush border.
Fecal chymotrypsin and elastase testing have the advantage of convenient testing on random stool collections but are hampered by being insensitive to mild-to-moderate pancreatic exocrine insufficiency, though they are very sensitive for severe disease causing steatorrhea. Fecal chymotrypsin activity assays are also affected by exogenous pancreatic enzyme supplementation which must be stopped beforehand. In addition, fecal elastase ELISA assays are more sensitive than fecal chymotrypsin, and the antibody test is specific for human elastase while being not affected by pancreatic enzyme supplementations. However, fecal elastase testing is also insensitive for mild-to-moderate pancreatic insufficiency. Both tests may produce false-positive results if the submitted stool sample is unformed and dilute (i.e., dilution from diarrhea) [12, 13].
The 13C-mixed triglyceride breath test measures 13CO2 after 13C-marked triglyceride is cleaved by lipase, absorbed by the gut, and metabolized by the liver. Exhaled breath samples are collected every 30 min for 6 h after ingestion of the marked meal. The sensitivity of the test for diagnosis of fat maldigestion is higher than 90 % but suffers from its unavailability in routine clinical practice [14].
The bentiromide, or N-benzoyl-tyrosyl para-aminobenzoic acid (NBT-PABA), test is sensitive for severe pancreatic insufficiency and malabsorption but, as with other indirect tests of pancreatic dysfunction, not sensitive to mild or moderate pancreatic impairment. Additionally, the test is hampered by being nonspecific for pancreatic exocrine dysfunction as any limitation in enterocyte absorption, liver conjugation, or renal secretion may result in false-positive results [12, 15]. In addition, the substrate necessary to perform the test is currently not available in the United States, though it is available in Europe.
Another indirect test operating on the same principles as the bentiromide test is the fluorescein dilaurate assay. It too relies on hydrolysis of the fluorescein dilaurate by specific pancreatic arylesterases to yield fluorescein, which is then absorbed and collected in the urine. This is then compared to urine fluorescein measured after free fluorescein ingestion on another day and reported as a ratio [16].
9.4 Pancreatic Exocrine Insufficiency in Diabetes
On average, 51 % of patients with type 1 diabetes mellitus and 35 % of patients with type 2 diabetes mellitus demonstrate pancreatic exocrine insufficiency (PEI) on fecal elastase testing where PEI is defined as fecal elastase less than 200 μg/g [17]. In a study of 1,000 patients with diabetes, including 697 with type 2 diabetes, 28.5 % of patients with type 1 and 19.9 % of patients with type 2 diabetes had severe PEI as defined by fecal elastase less than 100 μg/g [18]. In patients with type 2 diabetes, levels of fecal elastase may be lower in those with poor glycemic control [19]. However, there is a wide range of prevalence of PEI in these studies, with one cross-sectional study yielding only 6 % in type 1 diabetes, 10 % in patients with type 2 diabetes using insulin, and no patients with PEI and type 2 diabetes who did not require insulin [20]. The wide range of prevalence in existing studies may be due to publication bias, sampling bias (predominantly Caucasian patients sampled), reliance on a single diagnostic test of PEI (fecal elastase), as well as lack of age-matched controls of patients with other chronic conditions.
Given wide-ranging estimates, it is difficult to determine the true prevalence of PEI in patients with diabetes, especially as it translates to steatorrhea and maldigestion. Fecal elastase may be insensitive to mild and moderate pancreatic insufficiency, as well falsely positive in dilute specimens (i.e., diarrhea), and its relevance for clinical maldigestion and clinical steatorrhea remains poorly delineated in diabetic patients. Even so, there is a subset of patients with PEI as measured by fecal elastase who have clinical symptoms. In one study of patients with diabetes and abnormal fecal elastase testing, 60 % were found to have steatorrhea by quantitative fecal fat analysis, with 27 % of these patients having clinical steatorrhea [21]. Pancreatic enzyme replacement for patients with pancreatic insufficiency due to diabetes is unstudied.
Changes in gross and histological pancreatic morphology frequently accompany diabetes mellitus and may be a plausible link between diabetes and chronic pancreatitis. Pancreatic atrophy is often seen in autopsy studies of diabetes patients as well as with ultrasonography, computed tomography, and magnetic resonance imaging (MRI) [22–24]. Morphological changes of the pancreas in diabetes may be partially explained by the lack of trophic effect of insulin on acinar tissue. Residual exocrine function correlates well with residual beta-cell function in type 1 diabetes mellitus [25]. Yet, because not every patient with type 1 diabetes has pancreatic exocrine insufficiency, trophic action of insulin must not be the only factor. Indeed, as much of the close regulation of pancreatic exocrine function is carried out by neurohormonal mediators, diabetic neuropathy may also play a role in exocrine insufficiency in diabetics [26].
9.5 Diabetes in the Setting of Pancreatic Disease
Though the true prevalence of PEI arising from diabetes is not definitively known, PEI leading to diabetes mellitus, termed type 3c diabetes (T3cDM) [27], appears to be less common and accounts for 5–10 % of diabetic populations [28]. A T3cDM diagnosis is made in the absence of type 1 diabetes autoimmune markers and in the setting of imaging and laboratory evidence of PEI [29]. Management of T3cDM has not been well studied, given large trials have excluded this subset of patients. The conventional belief is that patients with T3cDM encounter frequent episodes of hypoglycemia due to a lack of counter-regulator hormones such as somatostatin and glucagon. In a cohort of patients with T3cDM as a result of total pancreatectomy, no patients reported a severe hypoglycemic event, and HbA1c values were not statistically different from the entire diabetic population [30]. Without dedicated clinical trials, treatment for type 3c diabetes is not standardized and commonly reflects methods used for type 2 diabetes. Given its antineoplastic and antidiabetic properties, metformin may be beneficial in this subset of patients.
9.6 Diabetes and Pancreatic Adenocarcinoma
Diabetes has been associated with an increased risk of cancer. In a Swedish population study, 24 cancer types were found to have an increased incidence among those with type 2 diabetes. Pancreatic cancer had the highest standardized incidence ratio of 2.98 (observed/expected cancer cases) compared to other cancer sites [31].
The three cell types found in the normal pancreas include acinar, ductal, and islet cells. Acinar cells comprise a majority of the organ volume (80 %), but greater than 85 % of malignant lesions arise from the ductal structures resulting in adenocarcinoma. With the increasing utilization of cross-sectional imaging, identification of premalignant lesions such as intraductal papillary mucinous neoplasm, mucinous cystic neoplasm, and solid-pseudopapillary tumors may be detected and intervened before the advent of carcinoma. This scenario remains the exception as most pancreatic cancer arises in the absence of a known premalignant lesion.
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