A factor predictive of post-ERCP pancreatitis?

Conclusions The authors conclude that elevation of the serum amylase levels 2 hours after SOM predicts development of post-SOM pancreatitis exclusively in patients who do not receive a PD stent. An elevated 2-hour serum amylase level that occurs in patients with a PD stent, however, predicts subsequent findings that "may occur because of attenuated pancreatitis."     

Temporary Pancreatic Duct Stenting to Prevent Pancreatitis Induced by Endoscopic Sphincter Dilation

Abstract: To investigate whether prophylactic temporary stenting of the main pancreatic duct would decrease the incidence of pancreatitis after endoscopic sphincter dilation (ESD), we conducted this procedure subsequent to ESD in 13 patients who had common bile duct stones. After ESD and extraction of stones, a stent was placed into the pancreatic duct across the papilla of Vater. The stent was removed endoscopically three days later. Stents were successfully placed in 12 (92.3%) patients. In 11 of the patients, there was no significant elevation of serum amylase values before and after the procedure. The remaining patient, whose stent was identified as occluded, demonstrated elevated serum amylase values. However, there were no other procedure-related complications. Although our report was only limited to 12 cases, our results suggest that temporary pancreatic stenting may help prevent postprocedual pancreatitis. (Dig Endosc 1999; 11:32–36)     

Pancreatitis following bile duct sphincter of Oddi manometry: utility of the aspirating catheter.

The aspirating sphincter of Oddi manometry (SOM) catheter was shown to reduce the frequency of post-procedure pancreatitis from 31% to 4% following a pancreatic duct evaluation. This study was designed to prospectively evaluate the utility of the aspirating manometry catheter in reducing the frequency of pancreatic enzyme elevation and clinical pancreatitis following isolated bile duct manometry. Thirty-eight patients were randomly assigned to undergo bile duct SOM with the standard perfusion (infused group) catheter or the aspirating catheter (aspirated group). Overall, the frequency of both amylase and lipase level elevation at least two times the upper limits of normal was 30% at 2 hours, 25% at 6 hours, and 18% at 18 hours after the procedure and was similar for the aspirated and infused groups. No episodes of clinical pancreatitis occurred in either group. The SOM catheter was perfused with full-strength contrast in 12 consecutive patients undergoing a bile duct evaluation. Only one patient had any contrast material identified in the pancreatic duct. The results of this study support the theory that increased pancreatic duct hydrostatic pressure is the major cause for post-SOM pancreatitis and suggests that SOM evaluation of the bile duct alone appears to be safe.     

Prospective, randomized, controlled trial of prophylactic pancreatic stent placement for endoscopic snare excision of the duodenal ampulla

BACKGROUND: Tumors that arise in the region of the major duodenal papilla account for 5% of GI neoplasms and 36% of resectable pancreaticoduodenal tumors. There is limited published literature that addresses the safety of endoscopic excision of the papilla. Although there is consensus about prophylactic pancreatic-duct stent placement, there is little supporting prospective data. The aim of this randomized, controlled trial was to compare the rates of postsnare ampullectomy pancreatitis in patients who did/did not receive prophylactic pancreatic-duct stent placement. METHODS: Consecutive patients who were to undergo en bloc snare ampullectomy were randomized to placement of pancreatic-duct stent after ampullectomy or to no stent placement. RESULTS: In total, 19 patients were enrolled, and 10 received pancreatic stents. Postprocedure pancreatitis occurred in 3 patients in the 24 hours after endoscopy, all cases occurred in the unstented group, 33% vs. 0% (stented group), p = 0.02. Median peak amylase level was 3692 U/L (range 1819-4700 U/L) and median peak lipase level was 11450 U/L (range 5900-17,000 U/L). All 3 patients were hospitalized for a median of 2 days (range 1-6), and all made a complete recovery. CONCLUSIONS: Our findings suggest that a protective effect is conferred by pancreatic stent placement in reducing postampullectomy pancreatitis. Future large-scale studies are required to confirm this benefit.     

Serum amylase isoenzyme alterations in acute abdominal conditions

To determine the accuracy of the serum amylase in identifying a pancreatic source, amylase isoenzymes were determined prospectively in 65 patients initially evaluated with a complaint of abdominal pain and associated hyperamylasemia. Isoenzyme patterns were demonstrated by an electrophoretic technique, and the results were correlated with clinical diagnoses. Patients were divided into two diagnostic groups. Group I consisted of 42 patients with clinical findings suggesting pancreatitis. P-type isoenzymes were normal or elevated in 31 of these patients (74%), and s-type isoenzymes were normal or elevated in 11 (26%). Group 2 consisted of 23 patients with abdominal pain attributed to causes other than pancreatitis. Four patients (17%) had elevation of p-type isoenzymes, and 19 patients (83%) had predominantly s-type patterns. We conclude that amylase isoenzymes cannot determine unequivocally the cause of hyperamylasemia, but they can enhance the diagnostic specificity of the serum amylase. Elevated serum amylase with a predominant p-type pattern suggests pancreatic disease; elevation of s-type isoenzymes suggests but is not conclusive for, diagnoses other than pancreatitis. Hyperamylasemia with a normal isoenzyme pattern occurred in a few patients in both groups, and it was nondiagnostic.     

Sphincter of Oddi manometry: decreased risk of clinical pancreatitis with use of a modified aspirating catheter.

This study was undertaken to determine whether routine use of a modified triple-lumen five French sphincter of Oddi manometry catheter would reduce the frequency and severity of post-manometry pancreatitis and pancreatic enzyme elevation. Seventy-six patients were alternately assigned to undergo sphincter of Oddi manometry (SOM) with a standard perfusion (infused group) catheter or the newly developed aspiration (aspirated group) catheter. After SOM, there were significantly more patients in the infused group with both amylase and lipase values elevated at least two times the upper limits of normal at 2 (p less than 0.001), 6 (p = 0.01), and 18 hours (p = 0.03) after the procedure. As compared with the standard perfusion system, the aspiration catheter was associated with a decreased frequency of clinical pancreatitis (23.5% vs. 3%, p = 0.01) reduced hospital stay (5 +/- 1.83 days, mean +/- SE, versus 1 day; p = 0.03) and milder pancreatitis. The aspiration manometry catheter should be considered for standard use for SOM, particularly if the pancreatic duct sphincter is being evaluated.     

Pain at 24 hours associated with amylase levels greater than 5 times the upper normal limit as the most reliable indicator of post-ERCP pancreatitis

BACKGROUND: The frequency of post-ERCP/sphincterotomy pancreatitis is between 1.3% and 7.6% in prospective studies. This range likely reflects differences in definitions of pancreatitis and methods of data collection. METHODS: To identify clinical findings and enzymatic values consistent for clinical pancreatitis at 24 hours, the post-ERCP/sphincterotomy course of 1185 procedures was prospectively recorded. Patients were evaluated for pancreatic-type pain, white blood cell count, and serum amylase before and 24 hours after the procedure; pain and amylase levels were also recorded 6 to 8 hours after the procedure. CT was performed in all patients with pain associated with amylase levels greater than 3 times normal. All patients were evaluated clinically at 48 hours. RESULTS: Pancreatic-type pain never occurred in cases with amylase levels lower than 3 times normal; it was significantly (p < 0.001) associated with amylase levels greater than 5 times normal, either 6 to 8 hours or 24 hours after the procedure. Leukocytosis and CT findings consistent with pancreatitis were observed only in patients (41.7% and 29.5%, respectively) with 24-hour amylase levels greater than 5 times normal. None of the 18 patients with pain at 24 hours and serum amylase lower than 5 times normal had symptoms that persisted at 48 hours. Twenty-five (41.7%) of the 60 patients with pain at 24 hours and amylase higher than 5 times normal had 48-hour pain at 48 hours and hyperamylasemia. CONCLUSIONS: Features consistent with clinical pancreatitis were present only among patients with pancreatic-type pain at 24 hours and amylase levels higher than 5 times normal. Additional follow-up is required for these patients.     

Relationship between post-ERCP pancreatitis and the change of serum amylase level after the procedure

AIM： To clarify the relationship between the change of serum amylase level and post-ERCP pancreatitis.
METHODS： Between January 1999 and December 2002, 1291 ERCP-related procedures were performed. Serum amylase concentrations were measured before the procedure and 3, 6, and 24 h afterward. The frequency and severity of post-ERCP pancreatitis and the relationship between these phenomena and the change in amylase level were estimated.
RESULTS： Post-ERCP pancreatitis occurred in 47 patients （3.6%）. Pancreatitis occurred in 1% of patients with normal amylase levels 3 h after ERCP, and in 1%, 5%, 20%, 31% and 39% of patients with amylase levels elevated 1-2 times, 2-3 times, 3-5 times, 5-10 times and over 10 times the upper normal limit at 3 h after ERCP, respectively （level 〈 2 times vs ≥ 2 times, P 〈 0.001）. Of the 143 patients with levels higher than the normal limit at 3 h after ERCP followed by elevation at 6 h, pancreatitis occurred in 26%. In contrast, pancreatitis occurred in 9% of 45 patients with a level higher than two times the normal limit at 3 h after ERCP followed by a decrease at 6 h （26% vs 9%, P 〈 0.05）.
CONCLUSION： Post-ERCP pancreatitis is frequently associated with an increase in serum amylase level greater than twice the normal limit at 3 h after ERCP with an elevation at 6 h. A decrease in amylase level at 6 h after ERCP suggests the unlikelihood of development of post-ERCP pancreatitis.     

Carboxylic ester hydrolase: a serum marker of acute pancreatitis

By use of an enzyme-linked immunosorbent assay we established serum reference values of carboxylic ester hydrolase, a pancreatic secretory lipolytic enzyme, and explored to see if a raised serum level is indicative of acute pancreatitis. Postoperative elevation of carboxylic ester hydrolase was observed in seven out of ten patients who underwent pancreatic surgery. Serum levels of carboxylic ester hydrolase and amylase were determined in 129 patients admitted due to abdominal emergency conditions. Amylase was elevated in 27 patients, and in 20 of these raised carboxylic ester hydrolase levels affirmed the diagnosis acute pancreatitis. In five out of the seven patients with elevated amylase alone no etiologic factor of acute pancreatitis was found. Another 11 patients had raised carboxylic ester hydrolase levels without concomitant elevation of amylase. In all these patients, a likely cause of pancreatic inflammation was identifiable. Hence, a raised carboxylic ester hydrolase level, even in presence of normal amylase, could be indicative of acute pancreatic inflammation.     

The Effect of ERCP on Circulating Pancreatic Enzymes and Pancreatic Protease Inhibitors

The pathogenesis of endoscopic retrograde cholangiopancreatography (ERCP)-induced pancreatitis is poorly understood. To elucidate a role for pancreatic enzymes in ERCP-induced pancreatitis, we measured serum amylase, lipase, trypsin, and elastase in 25 patients undergoing ERCP. Serum alpha 1-antitrypsin and alpha 2-macroglobulin, two major pancreatic protease inhibitors, also were measured. All pancreatic enzymes measured rose significantly after ERCP. Pancreatic duct cannulation was associated with a greater elevation in serum amylase and lipase. Circulating alpha 2-macroglobulin was reduced by 7% (p = 0.04) 6 h after ERCP, whereas circulating alpha 1-antitrypsin increased over the same time period. Papillotomy, stent placement, or underlying disease did not influence changes any further. Three patients developed ERCP-induced pancreatitis. All three patients had circulating alpha 2-macroglobulin levels below 243 mg/dl (p = 0.03). The ERCP-induced alterations in circulating pancreatic enzymes and their inhibitors are similar to changes seen in clinical pancreatitis. Low circulating alpha 2-macroglobulin levels may predispose to ERCP-induced pancreatitis.     

Risk factors for acute pancreatitis after endoscopic papillary balloon dilation

BACKGROUND/AIMS: Although EPBD (endoscopic papillary balloon dilation) may cause acute pancreatitis, risk factors for post-EPBD pancreatitis have not been well described. We retrospectively analyzed risk factors predictive of acute pancreatitis after EPBD. METHODOLOGY: A total of 101 patients underwent EPBD for choledocholithiasis. Post-EPBD acute pancreatitis was investigated. Nineteen potential risk factors, related to clinical characteristics or procedures, were retrospectively analyzed univariately and multivariately. RESULTS: Bile duct clearance was achieved in 96 patients. Serum amylase was elevated after EPBD in 69 patients. Early complications occurred in 11 patients (11%); 5 had minimal (pain persisting for only 12-24 hours) and 6 mild (requiring 1-3 days of treatment) pancreatitis. These 11 patients showed at least a three-fold elevation of serum amylase. Multivariate analysis identified two independent risk factors for pancreatitis (prior history of acute pancreatitis, and bile duct diameter < or = 9 mm). The risk for post-EPBD pancreatitis was not associated with young age, pre-EPBD hyperamylasemia, large or multiple stones, periampullary diverticulum, pancreatic contrast injection, mechanical lithotripsy or residual stones. CONCLUSIONS: Acute pancreatitis, usually mild or minimal, can be anticipated after EPBD for bile duct stones in approximately 10% of patients. In those with previous pancreatitis or a non-dilated bile duct, special care is necessary given the high incidence of pancreatitis.     

Prophylactic effect of somatostatin on post-ERCP pancreatitis: a randomized controlled trial

BACKGROUND: Somatostatin is a potent inhibitor of pancreatic secretion and has been studied for its prophylactic effect on post-ERCP pancreatitis. However, results of previous trials have been inconclusive. METHODS: A prospective double-blind controlled study was performed to evaluate the effectiveness of somatostatin in preventing post-ERCP pancreatitis. Post-ERCP enzyme elevation, abdominal pain and pancreatitis were evaluated and compared between 109 patients randomized to receive somatostatin infusion and 111 patients randomized to receive normal saline infusion (placebo); both started 30 minutes before ERCP and continued for 12 hours. RESULTS: Post-ERCP elevation of serum amylase and lipase levels at 6 and 24 hours after ERCP was less frequent in the group given somatostatin but not statistically significant. There was a tendency toward lower mean serum amylase and lipase levels at 24 hours in patients given somatostatin, although the difference was not statistically significant either. Eight patients given somatostatin (7%) and 18 patients given placebo (16%) had significant abdominal pain after ERCP requiring analgesia (p = 0.04). The frequency of clinical pancreatitis was significantly lower in patients given somatostatin (3%) than in those given placebo (10%) (p = 0.03). CONCLUSIONS: Prophylactic treatment with somatostatin reduced the frequency of post-ERCP pancreatitis.     

Incidence of post-endoscopic retrograde cholangiopancreatography/sphincterotomy pancreatitis depends upon definition criteria

BACKGROUND: The reported incidence of post-endoscopic retrograde-cholangiopancreatography/sphincterotomy pancreatitis ranges between 1.3% and 12.8%. This may likely reflect different definitions of pancreatitis and methods of data collection, rather than differences in patient populations, indications and endoscopic expertise. AIMS: The present study evaluated the incidence of post-endoscopic retrograde-cholangiopancreatography/sphincterotomy pancreatitis using different definition criteria and different data collection methods. PATIENTS: The 24-hour clinical and enzymatic course of 1185 procedures was recorded. METHODS: Pancreatic-like pain and hyperamylasaemia were evaluated either 6 to 8 hours or 24 hours after the procedure; computed tomography scan was performed in those patients with 24-hour pancreatic pain associated with hyperamylasaemia more than three times the upper normal limit. Results. Computed tomography scan findings consistent with pancreatitis were observed in 1.9% of cases, only among those patients with 24-hour pancreatic-like pain and hyperamylasaemia over five times the upper normal limit. The 6-8-hour and 24-hour pancreatic-like pain was associated with serum amylase levels at least three times higher in 11.7% and 6.6% and five times higher or more in 7.4% and 5.1%, respectively; 6-8 and 24-hour hyperamylasaemia higher than five times the upper normal limit, irrespective of pancreatic-like pain, was reported in 8.3% and in 6.9% of cases. No patients with serum amylase values lower than three times the upper normal limit had clinical symptoms. CONCLUSIONS: The incidence of post-procedure pancreatitis ranged from 1.9% to 11.7% depending on the definition criteria adopted.     

A randomized controlled trial of pentoxifylline for the prevention of post-ERCP pancreatitis

BACKGROUND: Pentoxifylline can ameliorate pancreatitis in animal models because of its anti-tumor necrosis factor properties. OBJECTIVE: Our purpose was to study the safety and efficacy of pentoxifylline in the prevention of post-ERCP pancreatitis. DESIGN: Patients due to undergo ERCP for various indications were randomized to receive pentoxifylline 400 mg orally 3 times, beginning the day before ERCP (2 and 10 pm) until the night after the procedure (6 am and 2 and 10 pm) or to receive no preventive medication. Serum amylase values were determined before and 6 and 24 hours after ERCP. Diagnosis and grading of the severity of complications was performed according to consensus criteria. PATIENTS: One hundred fifty-eight patients received pentoxifylline (group A) and 162 had no medication (group B). The groups were similar in distributions of sex, biliary sphincterotomy, pancreatography, pancreatic duct cannulations, stone extraction, stent placement, and presence of periampullary diverticulum. Group A patients were younger (mean age 63 vs 68 years, P<.05) and biliary colic was a more frequent indication (30 vs 12, P<.05). RESULTS: Nine (5.6%) patients in group A and 5 (3%) in group B had pancreatitis (2 and 1 severe, respectively; P=.28). Serum amylase values were similar in baseline and 6- and 24-hour samples. Two (1.2%) patients in group A and 7 (4.3%) in group B had hemorrhage. LIMITATIONS: This was not a double-blind trial. CONCLUSIONS: In this study pentoxifylline did not protect against post-ERCP pancreatitis or hyperamylasemia.     

Stent placement in the pancreatic duct prevents pancreatitis after endoscopic sphincter dilation for removal of bile duct stones

BACKGROUND: Pancreatitis is the most serious complication of endoscopic sphincter dilation. The aim of this study was to determine whether temporary stent placement in the main pancreatic duct decreases the frequency of pancreatitis and level of hyperamylasemia. METHODS: Stents were placed in the pancreatic duct after endoscopic sphincter dilation in 40 consecutive patients with bile duct stones. Stents were removed endoscopically 3 days later. Changes in serum amylase and the frequency of pancreatitis for this group were compared with those in 92 patients who underwent sphincter dilation without pancreatic duct stent placement. RESULTS: Stent placement was successful in 38 of 40 patients. Although the difference in the frequency of pancreatitis was not significantly different between stent and control groups, there was a trend toward a decrease in pancreatitis in the stent group. The level of postprocedure hyperamylasemia was significantly less in the stent group (p < 0.05). There were no procedure-related complications. CONCLUSIONS: Temporary placement of a stent in the pancreatic duct after sphincter dilation for removal of bile duct stones has a beneficial effect in terms of postprocedure hyperamylasemia and appears to reduce the frequency of postprocedure pancreatitis.     

EUS-guided fine-needle aspiration of the pancreas: evaluation of pancreatitis as a complication

BACKGROUND: EUS-guided fine-needle aspiration is rapidly becoming the procedure of choice for the diagnostic evaluation of pancreatic masses. Acute pancreatitis has been reported after EUS-guided fine-needle aspiration of the pancreas. This study evaluated the effect of EUS-guided fine-needle aspiration on the pancreas by serial measurement of amylase and lipase levels and determining the frequency of acute pancreatitis after EUS-guided fine-needle aspiration of pancreatic masses. METHODS: In 100 consecutive patients referred for EUS-guided fine-needle aspiration of a pancreatic mass, amylase and lipase levels were determined immediately before and within 2 hours after the procedure. Additionally, patients were questioned as to the occurrence of symptoms of acute pancreatitis within 48 hours after EUS-guided fine-needle aspiration. RESULTS: For 2 of 100 patients (2%) there was clinical and biochemical evidence of acute pancreatitis after EUS-guided fine-needle aspiration. Both patients had a history of recent pancreatitis. In addition, there was a significant increase in postprocedure lipase levels (p = 0.40) compared with amylase levels in this patient subset. CONCLUSION: The frequency of acute pancreatitis after EUS-guided fine-needle aspiration of the pancreas was 2% in this study. A history of recent pancreatitis appears to be a potential risk factor. Amylase and lipase levels can be elevated after EUS-guided fine-needle aspiration and in most cases have no clinical significance.     

急性胰腺炎患者血淀粉酶变化和CT诊断的比较

目的探讨血淀粉酶的变化规律及其机制。方法本研究对确诊的172例急性胰腺炎(AP)患者随机分为3组,分别在发病≤12 h、12～24 h、48～72 h行CT和血淀粉酶检查。分析不同时间段CT和血淀粉酶检出率。结果 87.5%患者血淀粉酶在6～12 h升高;100%患者血淀粉酶在12 h以上升高。91.3%的患者在12～24 h之间CT检查发现胰腺炎症变化,但与发病大于48 h相比,无显著差异。12 h之内,血淀粉酶升高的阳性率高于CT诊断的阳性率(χ2=22.04,P<0.01)。48～72 h D级、E级检出率明显高于12 h之内和12～24 h之间的检出率。血淀粉酶随着轻症急性胰腺炎分级水平有上升趋势;随着重症急性胰腺炎分级水平有下降趋势。结论血淀粉酶升高的水平与胰腺炎的病情程度无明显相关性,推测其机制可能与胰腺微循环受损程度有关。     

Pancreatic duct stent placement prevents post-ERCP pancreatitis in patients with suspected sphincter of Oddi dysfunction but normal manometry results

BACKGROUND: Placement of a pancreatic duct (PD) stent reduces post-ERCP pancreatitis rates in high-risk patients. Patients with suspected sphincter of Oddi dysfunction (SOD) who are found to have normal manometry results (SOM) are also at high risk for this complication. OBJECTIVE: Our purpose was to determine whether PD stent placement reduces pancreatitis rates in this patient population. DESIGN: Non-randomized, retrospective study. SETTING: Large, tertiary referral center. PATIENTS: From January 1999 to December 2005, patients who underwent ERCP with normal SOM were identified from our ERCP database. Incidence of patient/procedure risk factors for post-ERCP pancreatitis, trainee participation, and prior sphincter therapy were evaluated. INTERVENTIONS: PD stent placement. MAIN OUTCOME MEASUREMENT: Pancreatitis rates. RESULTS: A total of 403 patients were available for analysis: 169 had a PD stent placed (group 1) and 234 did not (group 2). Overall, pancreatitis rates were 2.4% in group 1 and 9.0% in group 2 (P= .006, odds ratio 4.1, 95% CI 1.4-12.0). Other than increased PD opacification in group 1 (P< .001), the incidence of risk factors for pancreatitis, trainee participation, or prior sphincter therapy was similar between the 2 groups. In patients with an intact papilla, stent placement reduced the rate of pancreatitis from 11.5% to 2.7% (P= .012). In patients with prior sphincter therapy, no benefit was seen from stent placement, although there was a trend to decreased pancreatitis rates in stented patients with prior pancreatobiliary sphincterotomy. LIMITATIONS: Nonrandomized, retrospective design. CONCLUSION: Temporary PD stent placement reduces pancreatitis rates in patients with suspected SOD but normal SOM and an intact papilla. Their routine use is recommended when evaluating this difficult, high-risk patient population.     

Clinical evaluation of the pancreatitis-like isoamylase pattern in normal persons.

Amylase isoenzyme analysis of serum and urine has been performed in 4001 normal persons and 500 patients with various disease using electrophoresis on thin layer polyacrylamide gel. Although elevation of amylase activity in amylase-1 and 2 has been reported to be the specific findings in patients with pancreatitis, 1.69% of normal persons had an elevated Amylase-2(named "Dominant Amylase-2") up to the same levels as major isoenzymes (Amylase-1 and 3), along with Amylase-1. Pedigree study confirmed an autosomal dominant mode of inheritance for Dominant Amylase-2. Knowledge of the genetic polymorphism is of importance in clinical assessment of amylase isoenzymes in patients having an elevated Amylase-2 suggestive of pancreatitis. Predominance of the pancreatic components in serum and urine has been revealed to be a specific index of pancreatic involvement. However, the existecne of an inherited trait of pancreatitis-like isoamylase pattern in healthy individuals must be borne in mind. On the basis of the present study, it may be concluded that a rise in the pancreatic type isoenzymes may not necessarily indicate underlying pancreatitis, especially in the absence of elevated amylase and lipase levels.     

A case of acute pancreatitis complicating salmonella enteritis

Summary We report a case of acute pancreatitis complicating Salmonella enteritis. A 43-yr-old woman who was admitted to our department because of Salmonella enteritis developed clinical acute pancreatitis with laboratory and radiographic signs on the fourth hospital day. She was free from symptoms on the eighth hospital day, but her elevated serum amylase and lipase levels persisted for more than 2 mo. In this case, clinical acute pancreatitis was a complication of bacterial enteritis caused by Salmonella enteritidis, and it was characterized by onset a few days after the onset of enteritis and by sustained elevation of serum pancreatic enzyme levels.