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Amylase creatinine clearance ratio in alcohol drinkers.
The amylase ceatinine clearance ratio (ACCR) was first described by Levitt et al6 in 1969, and has been proved to be more specific than serum amylase determinations in the diagnosis of pancreatitis.[14] While it has been claimed to rise specifically in pancreatitis, reports of its rise in febrile illnesses, diabetic ketoacidosis and in patients with burns have contradicted this claim of specificity.[5] Nevertheless despite a few false positives, a rise in ACCR remains a good indicator of pancreatic damage. Pancreatitis due to alcohol has been postulated to be due to various factors such as exocrine stimulation with alcohol induced oedema of the ampulla of Vater,[4] stimulation of a protein rich pancreatic juice that has a tendency to spontaneous precipitation of proteins with later calcification of the protein plugs, and relaxation of the resting tone of the sphincter of Oddi with reflux of the acidic duodenal contents into the pancreatic duct.[7] However, none of these postulates satisfactorily explains all the features of pancreatitis. Ingestion of a large quantity of alcohol without the development of clinical pancreatitis is not associated with rise in serum amylase levels. ACCR is a more sensitive test to determine alterations in pancreatic exocrine function, when serum amylase tends to drop after the initial rise in cases of acute pancreatitis. The clearance ratios are considered to be more sensitive an index than the peak levels in measuring organ function. We undertook this study to determine whether ingestion of a moderate quantity of alcohol produced changes in the ACCR.
We collected blood and urine samples from 11 teetotaler doctors and medical students who were asymptomatic to establish the normal range of values for ACCR in our laboratory. The mean value obtained (2.42 ± 1.15%) was similar to that reported in the literature (3.1 ± 1.1%).[14] Nineteen volunteers were included in the study after clinical exclusion of any abdominal disease or diseases which alter ACCR. All our volunteers were free of any form of renal disease. This was confirmed by performing a 24-hour endogenous creatinine clearance test.[11] Three other volunteers were excluded as their clinical histories suggested episodes of abdominal pain probably due to pancreatitis in the past. Of these 19 subjects, 8 were occasional alcohol drinkers (drinking about 150 ml of 40 per cent alcohol on weekends or at parties) and 11 were moderate drinkers (consuming at least 15,0 ml of 40 per cent alcohol 4-5 times a week for at least 5 years). Ethical considerations did not arise as the subjects volunteered for the study. Blood and urine samples were collected before and after the consumption of alcohol. The quantity drunk was 200 ml of 40 per cent alcohol and was measured out by one of us. The duration of the experiment was about 4 hours and food was not taken before the collection of the second sample. The blood and urine samples were coded by one of us (TTG) and analysed separately by another (PNR). The blood and urine samples were immediately refrigerated and analysed the next morning. The code was broken at the end of experiment. All the volunteers were again screened 10 days after the experiment for the basal value of their ACCRs. The biochemical parameters analysed were serum and urinary creatinine and serum and urinary amylase. Serum and urinary amylase levels were determined by, the colorimetric method of Chiamori and Henry with the reducing substances measured by the Folin-Wu method.[3],[10] The amylase creatinine clearance ratio was calculated from the formula, Amylase clearance ACCR = Creatinine clearance x 100 = urinary amylase (units% ) x vol of urine X serum creatinine (me%) x 1000 x 100 serum amylase: (units%) x 1000 urinary creatinine (mg%) x vol. of urine = urinary amylase X serum creatinine x 100 serum amylase urinary creatinine
None of the subjects complained of pain in the abdomen, vomiting or had any symptoms for at least a week after the experiment. [Table 1] shows the values for the endogenous 24-hour creatinine clearance test of the 19 volunteers. [Table 2] shows the values for serum amylase, serum creatinine, urinary amylase and creatinine and the calculated ACCR values before and after alcohol, of the 8 occasional drinkers. [Table 3] shows the values obtained in the 11 regular drinkers before and after alcohol. [Table 4] gives the ACCR values of the occasional and regular drinkers at the time of the experiment and 10 days later. The Wilcoxan Signed Rank Test was used for statistical analysis and the mean ACCR values of each group were compared with the mean ACCR in the normal individuals.[13]
The amylase creatinine clearance ratio is a more sensitive index of pancreatic malfunction, then serum amylase levels.[2], [8], [14] The renal clearance of amylase is 1-3.2 ml/min,[12] and the amylase filtered through the glomerulus is not reabsorbed by the tubular epithelium,[1] though stop flow analysis studies in rats show some reabsorption.[9] The molecular weight of normal serum amylase is 45,000 and it easily passes through the glomerular filter. Ratios of urinary amylase to urinary creatinine have proved to be sensitive for pancreatitis but increases also occur in patients hospitalized for other diseases.[5] Hence it is not as specific as the ACCR. The amylase creatinine clearance ratio obviates variability in renal function and is useful when the patient has more than one cause for a raised serum amylase.[14] The increased amylase clearance found in pancreatitis has been postulated to be due to (i) differential clearance ratios of various isoenzymes of amylase, (ii) partial digestion or alteration of amylase during pancreatitis, causing breakdown to smaller molecules of amylase that retain biologic activity and are easily filtered, and (iii) increased renal permeability.[14] Warshaw and Fuller[14] (1975) have found that the renal clearance ratios of the various isoenzymes of amylase were the same and the urinary amylase molecules in patients of pancreatitis were of the same molecular weight; as the serum amylase from normal individuals, leaving only an increased renal permeability, due to enzymatic action, kinins or other vasoactive substances to explain the rise in ACCR. Our study was conducted as a blind study and we analysed our results only at the end of the experiment. Since we could not ethically offer such large quantities of alcohol to subjects, we had to restrict our study to individuals who were known to us and who would have drunk that quantity of alcohol in any case. The number included in our study is small. Since there was no literature on the quantity of alcohol to be given, we arbitrarily fixed the quantity at 200 ml of 40 per cent alcohol as it was sufficient to produce insobriety without loss of consciousness in most individuals. This study shows that one episode of drinking 200 ml of 40 percent alcohol does cause a normal ACCR (3 33 ± 1.26%) to rise to abnormal levels (7.52 ± 2.99%) in apparently normal individuals who are not regular drinkers (p < 0.001). It also proves that regular heavy drinking of alcohol, increases to an abnormal level, the basal. ACCR (9.36 ± 4.8%) (p < 0.01) and this ratio is lowered after the challenge by alcohol (7.234 ± 4.54%) (p < 0.01). It is not known for how long the ACCR in these occasional drinkers remained elevated. The results at the end of 10 days however demonstrate a return of the ACCR to the basal level in occasional drinkers and a persistent elevation in the case of the regular drinkers. We postulate that drinking moderately large quantities of alcohol (200 ml in our stuly) even occasionally does alter the ACCR. This elevation in ACCR may reflect subclinical damage to the pancreas, and may serve as a warning of more severe future damage. The initial high values, with a fall of ACCR following challenge with alcohol in regular drinkers could be explained as due to the following: (a) permanent parenchymatous damage due to repeated attacks of subclinical pancreatitis, (b) diminished capacity of the pancreatic exocrine system to respond to challenge, probably as a result of continual alcoholic abuse. However, this needs to be further investigated.
We wish to thank- the Dean, K.E.M. Hospital, Bombay, for permission to publish this paper.
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