Benign Pancreatic Hyperenzymemia, Also Known as Gullo's Syndrome.

Benign pancreatic hyperenzymemia, also known as Gullo's syndrome, is a little-known syndrome first described in 1996 in patients studied for an elevation of pancreatic enzymes while otherwise being asymptomatic. We describe the case of a 2-year-old patient who was found to have significant elevation of amylase and lipase levels while he was asymptomatic. Blood tests and imaging tests were performed to determine the etiology, but they gave normal results. The enzyme elevation can even be 10 times the normal value of the enzyme, and only 1 enzyme may elevate, although most often all pancreatic enzymes are elevated. The etiology is not known, although several hypotheses have been suggested. This enzyme elevation is described both in adults and children and also sporadically or with a familial pattern. Knowledge of it can limit the performance of the multiple complementary test, some of which are very invasive in patients who have elevated pancreatic enzymes while they are asymptomatic. It knowledge allows us to confirm a benign prognosis about it and reassure the family about this disease and that in the end it will not require aggressive treatments such as surgery or chemotherapy.

Elevated Lipase in an Infant with Altered Mental Status.

The pancreatic enzymes lipase and amylase serve important functions in digestion/absorption of fats and polysaccharides. Measurement of these enzymes is often used in the emergency department to rule out acute pancreatitis in patients with nonspecific abdominal pain. In acute pancreatitis, serial measurements of plasma lipase and amylase typically follow a predictable temporal pattern of rise-and-fall kinetics: lipase levels rise within 4 to 8 hours, crest at 2× to 50× the upper reference limit at 24 hours, and decline to normal concentrations in 7 to 14 days. In situations in which the duration and magnitude of pancreatic enzyme elevation are more transient, clinicians should consider alternative causes for enzyme elevation. In this case report, incidental discovery of elevated lipase in an African American baby girl who ingested oxycodone resulted in additional laboratory and radiological work-up. Stronger awareness of exogenous influences on gastrointestinal motility may have prevented the need for further testing in this patient.

The endothelial lipase protein is promising urinary biomarker for diagnosis of gastric cancer.

BACKGROUND: Gastric cancer is one of the most common malignant tumors in the world. Finding effective diagnostic biomarkers in urine or serum would represent the most ideal solution to detecting gastric cancer during annual physical examination. This study was to evaluate the potential of endothelial lipase (EL) as a urinary biomarker for diagnosis of gastric cancer. METHODS: The expression levels of EL was measured using Western blotting and immunohistochemical staining experiments on (tissue, serum, and urine) samples of gastric cancer patients versus healthy people. We also checked the EL levels in the urine samples of other cancer types (lung, colon and rectum cancers) and benign lesions (gastritis and gastric leiomyoma) to check if EL was specific to gastric cancer. RESULT: We observed a clear separation between the EL expression levels in the urine samples of 90 gastric cancer patients and of 57 healthy volunteers. It was approximately 9.9 fold average decrease of the EL expression levels in the urine samples of gastric cancer compared to the healthy controls (P <0.0001), achieving a 0.967 AUC value for the ROC (receiver operating characteristic) curve, demonstrating it's highly accurate as a diagnostic marker for gastric cancer. Interestingly, the expression levels of EL in tissue and serum samples were not nearly as discriminative as in urine samples (P = 0.90 and P = 0.79). In immunohistochemical experiments, positive expression of the EL protein was found in 67% (8/12) of gastric adjacent noncancerous and in 58% (7/12) of gastric cancer samples. There was no significant statistical in the expression levels of this protein between the gastric cancer and the matching noncancerous tissues (P =0.67). CONCLUSIONS: The urinary EL as a highly accurate gastric cancer biomarker that is potentially applicable to the general screening with high sensitivity and specificity. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/4527331618757552.

Expression profiles of podocytes exposed to high glucose reveal new insights into early diabetic glomerulopathy.

Podocyte injury has been suggested to have a pivotal role in the pathogenesis of diabetic glomerulopathy. To glean insights into molecular mechanisms underlying diabetic podocyte injury, we generated temporal global gene transcript profiles of podocytes exposed to high glucose for a time interval of 1 or 2 weeks using microarrays. A number of genes were altered at both 1 and 2 weeks of glucose exposure compared with controls grown under normal glucose. These included extracellular matrix modulators, cell cycle regulators, extracellular transduction signals and membrane transport proteins. Novel genes that were altered at both 1 and 2 weeks of high-glucose exposure included neutrophil gelatinase-associated lipocalin (LCN2 or NGAL, decreased by 3.2-fold at 1 week and by 7.2-fold at 2 weeks), endothelial lipase (EL, increased by 3.6-fold at 1 week and 3.9-fold at 2 week) and UDP-glucuronosyltransferase 8 (UGT8, increased by 3.9-fold at 1 week and 5.0-fold at 2 weeks). To further validate these results, we used real-time PCR from independent podocyte cultures, immunohistochemistry in renal biopsies and immunoblotting on urine specimens from diabetic patients. A more detailed time course revealed changes in LCN2 and EL mRNA levels as early as 6 hours and in UGT8 mRNA level at 12 hours post high-glucose exposure. EL immunohistochemistry on human tissues showed markedly increased expression in glomeruli, and immunoblotting readily detected EL in a subset of urine samples from diabetic nephropathy patients. In addition to previously implicated roles of these genes in ischemic or oxidative stress, our results further support their importance in hyperglycemic podocyte stress and possibly diabetic glomerulopathy pathogenesis and diagnosis in humans.

Involvement of lipid peroxidation in spontaneous pancreatitis in WBN/Kob rats.

To cast light on the mechanisms underlying development of spontaneous pancreatitis lesions, tissues from WBN/Kob rats at various ages were histopathologically and immunohistochemically investigated with special reference to the existence of the lipid peroxidation products 4-hydroxy-2-nonenal (HNE), 4-hydroxy-2-hexenal (HHE), and malondialdehyde (MDA). Male 4-20-week-old WBN/Kob rats were killed to allow sampling of pancreatic tissues, which were fixed in cold acetone and 10% neutral-buffered formalin. and then processed for routine histopathology as well as immunohistochemistry for proteins modified by HNE, HHE, and MDA. Although no remarkable histologic changes were noted in younger animals, edema, hemorrhage, inflammatory cell infiltration, fibrosis, vacuolation of acinar cells, and ductular proliferation were observed in exocrine pancreatic tissue from animals at 10-15 weeks of age. In animals aged 20 weeks, the lesions had progressed remarkably and deposits of hemosiderin were apparent with fibrosis. Immunohistochemical examination for lipid peroxidation product-modified proteins showed HNE and MDA to be negative in all pancreatic tissues, but HHE was positive in the areas involving atrophy of acinar cells and fibrosis in the islets. The results of the present study thus provide support for the conclusion that lipid peroxidation during spontaneous pancreatitis in WBN/Kob rats may possibly be involved in the development of diabetes in this model.

[Enzyme preparations in conservative treatment of chronic pancreatitis]. / Fermentnye preparaty pri konservativnom lechenii khronicheskogo pankreatita.

AIM: To study effectiveness of enzyme medicine pancitrate 25,000 in the treatment of chronic pancreatitis (CP). MATERIALS AND METHODS: Pain, stool, creato- and steatorea, other signs of CP were examined before and after pancitrate treatment of 17 patients with chronic pancreatitis aged from 28 to 62 years. RESULTS: Pancitrate 25,000 reduced stomach pains in 16 of 17 patients. Stool returned to normal in 8 of 13 patients. Creato- and steatorea decreased. CONCLUSION: New dosage forms of the enzyme preparations (pancitrate 25,000, in particular) are highly effective both in deficiency of pancreatic external secretion and pain relief in exacerbation of CP.

[The effect of intraperitoneally administered necrolytic enzymes on the course of experimental acute pancreatitis]. / Wplyw dootrzewnowo podawanych enzymów nekrolitycznych na przebieg doswiadczalnego ostrego zapalenia trzustki.

The acute pancreatitis is still serious diagnostic and therapeutic problem. In spite of many experiments there are no satisfactory methods of the treatment of this disease. Usually, it is diagnosed clinically by acute abdominal pain and increased pancreatic enzymes in blood and urine. The main disorder of this disease is the necrosis of the pancreatic gland. The aim of our investigations was the evaluation of effect of necrolytic enzymes on the course of acute experimental pancreatitis. Fibrolan was used. Fibrolan (Parke-Davis) is a preparation, which has necrolytic properties. It consists of two bovine enzymes: fibrinolysin and deoxyribonuclease. The examinations were carried out on 380 Wistar rats. The acute pancreatitis was induced by retrograde injection of 0.1 ml/0.1 kg body weight of 3% sodium taurocholate solution into the pancreatic duct as previously described by other authors. The experimental animals were divided into four groups: K0-control group (healthy animals), KP-animals with acute experimental pancreatitis without medication, S-rats with acute experimental pancreatitis, which were treated with 0.9% NaCl solution, and F-animals with acute experimental pancreatitis treated with Fibrolan. Fibrolan and 0.9% NaCl were injected into the peritoneal cavity three times a day with eight hours intervals from the 24th experimental hour. The serum amylase and lipase activities and the amylase activity in the urine were determined in each animal group in the 24th, 48th, 72nd, 96th, 120th, 144th experimental hour. For histopathological analysis pancreatic tissue samples were taken from the pancreatic gland. The intensification of the histological changes of these tissue samples was judged using a point score as described by Spormann et al. The results were statistically analysed. The animals of the KP group showed significant histological changes of the pancreas during the whole examination time. Point score: 75-100. Microscopically, tissue samples taken from the animals treated with Fibrolan showed less changes from the 72nd examination hour. There were observed regenerative processes and the improvement of the histological state was evident (point score: 0-50). Changes were less in rats treated with 0.9% NaCl solution than in KP group but the regenerative processes were slower than in F group (point score: 50-75). Enzymes levels were significant lower in F group than in others from the 48th experimental hour.

Isolated pancreas rejection in combined kidney pancreas tranplantation.

The clinical success of pancreas transplantation is limited by the difficulty in diagnosing rejection. In simultaneous pancreas kidney (SPK) transplantation, the diagnosis of pancreatic rejection is particularly difficult in the absence of clinical evidence of kidney rejection. Moreover, patients receiving only pancreas grafts will not have a concomitantly grafted kidney to serve as a "sentinel" for rejection. Percutaneous pancreas graft biopsy has been reported in a few small series but has not been adopted for broad clinical use. We describe the evaluation of 69 consecutive episodes of suspected isolated pancreas allograft rejection by percutaneous pancreas allograft biopsy. These rejection episodes occurred in 41 patients with bladder-drained pancreas transplants (25 SPK, 14 pancrease after kidney transplants [PAK], amd two pancreas transplant alone [PTA]). The indications for percutaneous pancreas biopsy were a twofold or greater increase in serum amylase or lipase, or a sustained 40% to 50% drop in urine amylase in the setting of no evidence of renal allograft dysfunction in SPK transplants. Biopsies were performed with color-flow Doppler ultrasound localization using an 18-gauge automated biopsy needle. Pancreatic tissue adequate for histologic evaluation was obtained in 61 of 69 cases (88%). There were two cases of intraabdominal bleeding, one of which required surgical intervention; the other resolved spontaneously. Histologic assessment of the biopsies demonstrated varying degrees of acute cellular rejection in 48 of 61 specimens (79%). Twelve specimens (20%) were free of histologic evidence of rejection, and one specimen (2%) showed acute pancreatitis. At the time of suspected rejection mean serum amylase and lipase values were increased 3.6 and 8.3-fold, respectively, and urine amylase was decreased by a mean of 45%. We conclude that the commonly used markers for pancreas allograft rejection are only about 80% specific for acute rejection. Percutaneous pancreas allograft biopsy is safe and allows the avoidance of unnecessary antirejection therapy with its attendant side effects and cost.

Review of limited systemic absorption of orlistat, a lipase inhibitor, in healthy human volunteers.

Orlistat, a lipase inhibitor, acts locally in the gastrointestinal tract. Systemic absorption is not required for its efficacy, but knowledge of the extent of its systemic absorption is important for its safe use in obese patients, the intended target population. Pharmacokinetic screening was carried out by monitoring plasma concentrations of unchanged orlistat in 25 phase 1 studies (including two mass balance studies) in normal and obese healthy volunteers. The results of these studies indicate an extremely low degree of systemic absorption for orlistat when administered with a hypocaloric, well-balanced diet with 20% to 30% of calories derived from fat (50-80 gm). To further characterize the pharmacokinetics and excretion pathways of orlistat, two mass balance studies using 14C-labeled orlistat were conducted. After oral dosing of radiolabeled orlistat with a fatty meal (28-30 gm fat), almost the entire dose was recovered from fecal samples; little was found in plasma and urine. It is concluded that systemic absorption of orlistat is negligible; at a clinically efficacious dose level, orlistat is unlikely to produce systemic lipase inhibition.

Evaluation of pancreatic lipase activity by simple urine analysis after oral administration of a new iodine-131-labeled triglyceride.

A new iodine-131-labeled triglyceride analogue called "MIPAG" [1,2-dipalmitoyl-3-[(15-p-iodophenyl) pentadecan-1-oyl]rac-glycerol] has been prepared in which 15-(p-iodophenyl)pentadecanoic acid (IPPA) is attached to position-3. MIPAG has been developed for the evaluation of pancreatic exocrine function by simple urine analysis and has been evaluated in rats and humans. After oral administration, IPPA is released from the triglyceride by the action of pancreatic lipases followed by intestinal absorption and the principal IPPA metabolite (p-iodobenzoic acid, IBA) is primarily excreted in the urine. Excretion in the urine and feces was evaluated in rats, as well as the biodistribution in various organs over 21 days. Twenty patients without pancreatic disease (normals) and four patients without pancreatic insufficiency were also investigated. Following oral administration of 30 microCi of MIPAG, urine was collected for two successive 24-h periods. Blood samples were drawn and thin-layer chromatographic (TLC) analysis was performed on the serum lipid extracts. Urine from normals contained 44.9% +/- 7.7% and 61.8% +/- 8.4% of the administered activity after 24 and 48 h, respectively. The patients with pancreatic insufficiency excreted 13.1 +/- 5.6% and 18.9% +/- 6.2%, respectively, which was significantly decreased (P < 0.001) compared with normals. The TLC profiles showed an increasing proportion of IBA with time. Urine analysis after oral administration of MIPAG thus appears to be an attractive new techniques for the evaluation of pancreatic lipase activity by a simple urine analysis.

[High sensitive photometric assay of pancreatic lipase and clinical investigation of urinary lipase in patients with various histopathological types of primary glomerulonephritis].

We measured the activity of urinary lipase by high sensitive photometric method using 1,2-dirinoleoilglycerol as a substrate. Also, we investigated the clinical significance of the activity of urinary lipase in patients with chronic glomerulonephritis (GN) with special reference to the relation between the levels of the enzyme and histopathological changes of the kidney. Urinary activity of N-acetyl-beta-D-glucosaminidase (NAG) and urinary beta 2-microglobulin (BMG) were also measured to compare the difference of renal handling of these 3 substances. We could obtain the following results; 1) Good coefficient of correlation was observed between the activity of urinary lipase and the excretion of urinary BMG. 2) No correlation was observed between the activity of urinary lipase and the amount of urinary NAG in patients with chronic GN. 3) In some of the cases with secondary tubulointerstitial edema and inflammatory infiltration, the values of the activity of urinary lipase were markedly elevated. These results suggested that lipase was removed from the serum mainly by glomerular filtration and reabsorbed almost completely by tubular epithelial cells like the renal handling of BMG. In contrast, NAG secreted through the different renal metabolism in proximal tubule. The activity of urinary lipase might be a diagnostic marker for the secondary acute tubulointerstitial lesions in patients with chronic GN.

Management of chronic pancreatitis with pancreas cyst by endoscopic pancreatic prosthesis.

Cases of chronic pancreatitis accompanied by stenosis or dilation of the pancreatic duct were treated by endoscopic placement of an endoprosthesis and drainage. The purpose of the treatment was the alleviation of pain, restoration of extrapancreatic secretion and retardation of the progression of inflammation. The procedure was performed successfully in 9 of 13 patients, using an endoscopically placed pigtail prosthesis in the pancreatic duct. The successfully treated patients consisted of 9 cases of chronic pancreatitis, 2 cases being pancreas divisum. After disappearance of the symptoms and abnormal endoscopic findings, the drainage tubes were removed after a period of 5-12 months. No serious complications were encountered. Following the procedure, an improvement in appetite and increase of 2-13 kg in body weight was recognized. This method yielded satisfactory results in the treatment of chronic pancreatitis.

Serum and urine alpha--amylase isoenzymes levels after operative cholangiogram. A prospective clinical and biochemical study.

Serum and urine total alpha-amylase isoenzymes values were estimated in two groups of patients, who underwent either elective cholecystectomy and operative cholangiogram (group A-59 patients) or cholecystectomy without operative cholangiogram (group B - 68 patients). Serum and urine total alpha-amylase and pancreatic isoamylase (p-type) values were statistically significantly increased within the first 24 postoperative hours as compared to the preoperative levels only in group A (p less than 0.05). No clinical signs of pancreatitis were observed. Serum lipase alterations did not reach any statistically significant difference in either group. It is concluded that transient hyperamylasaemia after preoperative cholangiogram may be due to a reversible chemical pancreatitis caused by the infused opacifying agent into the common bile duct.

Renal handling of 125I-labelled homologous pancreatic lipase and amylase in the rat.

Experiments were carried out in vivo on rats and in vitro on tubular brush border vesicles in order to study the renal mechanisms of the elimination of pancreatic lipase and amylase from the circulation. Highly purified 125I-labelled homologous lipase, amylase or 125I-labelled di-iodo-tyrosine was injected intravenously in a single dose. The sieving coefficients of lipase and amylase were found to be 0.126 and 0.118 respectively. Less than 1% of the lipase activity but more than 10% of the radioactivity were found in the urine in the course of a 120 min experiment. In experiments with amylase, 16% of the enzyme activity and 19% of the radioactivity were present in the urine. Elimination of both enzymes showed first order kinetics and was of the same magnitude (17-24 min). The elimination curves of the radioactivity consisted of at least two components: a fast component immediately after the injection, which was identical with the decrease of the resp. enzyme activity; and a slow component (half-life 106 min), which in both cases proved to be identical with the half-life of di-iodo-tyrosine. In experiments with amylase, the excretion of protein-free 125I-activity started later than with lipase. The radioactivity of 125I-labelled lipase was taken up faster by brush-border-vesicles than that of 125I-amylase. Liberation of protein-free 125I-activity from both enzymes occurred at the same rate. At the end of the experiments the kidneys had no lipase or amylase activity, but they contained 5.4% (lipase), 3.8% (amylase) of the injected radioactivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Fractional urinary clearance of immunoreactive lipase in chronic pancreatic disease.

Using an immunoenzymatic method, we studied lipase in the serum and urine of 23 controls, 22 chronic pancreatitis patients in symptomatic remission, and in 9 patients with proven pancreatic cancer. Serum and urine lipase and its fractional urinary clearance were compared with those of amylase and immunoreactive trypsin. Lipase immunoreactivity was detectable in the urine of 81.5% of the studied subjects (controls: 82%, chronic pancreatitis: 86%, pancreatic cancer: 66%); its output was higher than the upper limit of controls in 31.8% of chronic pancreatitis and in only 1 of pancreatic cancer, and it was significantly correlated with the urinary output of trypsin (r = 0.487, P less than 0.001), but not with that of amylase. A significant correlation was found between urinary output and serum levels for lipase, but not for trypsin or amylase. Fractional clearance of lipase was of the same magnitude as that of trypsin but only 0.1% that of amylase. 19% of chronic pancreatitis and pancreatic cancer showed a fractional clearance of lipase above the upper limit of controls, compared with 45% for trypsin and 3.2% for amylase. No difference in urinary clearance of the three enzymes was found between chronic pancreatitis and pancreatic cancer. In conclusion, although of no diagnostic relevance in pain-free patients with chronic pancreatic disease, this measurement can provide information on the mechanisms of renal excretion of pancreatic enzymes.

Lipasuria in acute pancreatitis: result of tubular dysfunction?

Lipase, in contrast to amylase, is completely reabsorbed by the proximal tubules after glomerular filtration. Therefore, no lipase is detectable in the unconcentrated urine according to the current opinion. The handling of lipase (detected with an enzyme-immunoassay) by the kidney was investigated in comparison with creatinine, amylase, and beta-2-microglobulin by clearance studies in acute pancreatitis (n = 10), burn injury (n = 4), glomerular proteinuria (n = 8), and controls without evidence of pancreatic or renal diseases (n = 5). In initial stages of acute pancreatitis a measurable clearance of lipase (mean: 49.6 microliters/min, range: 0.5-234) was found in association with corresponding increased clearances of beta-2-microglobulin (mean: 10.5 ml/min, range: 0.02-58.9) and of amylase (mean: 8.9 ml/min, range: 2.4-22.6) in nine of ten patients. This finding is consistent with a defect of tubular function. However, regression analysis failed to show a significant correlation between lipase and beta-2-microglobulin clearance. Repeated measurements during the course of pancreatitis in seven patients showed reversibility of tubular dysfunction. In patients with burn injury a similar elevation of clearances of beta-2-microglobulin and of amylase was found, but tubular dysfunction in this condition was not associated with lipasuria. In glomerular proteinuria a lipase clearance was found in two of five cases with moderate, and in the other three cases with severe impairment of creatinine clearance. beta-2-microglobulin clearance was normal in the former and only slightly elevated in the latter group. In conclusion lipase is measurable in the urine of most patients with acute pancreatitis as a result of a reversible tubular dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)

[Urinary lipase: properties and value of its determination]. / Lipase urinaire: propriétés et intérêt de sa détermination.

Lipase activity was detected by nephelometry in urine specimens from 23 patients. Urinary lipase and plasma activities present different sensitivities to changes in ionic strength and copper ion concentration. Experiments with mixtures of urine specimens with and without lipasic activity showed that there is no lipase inhibitor in urine. Urinary lipase is generally seen in patients presenting signs of renal impairment (increase in uremia and creatinemia) and hematuria. The highest urinary lipase levels in such patients are usually seen when blood lipase is increased. High urinary lipase in the absence of hepatic aliments could, therefore, be indicative of renal disorder.