lucio gullo - iperenzimemia pancreatica benigna o sindrome di gullo

Lucio Gullo - Iperenzimemia pancreatica benigna o sindrome di Gullo

http://www.leadershipmedica.com/sommari/2006/numero_02/medicina/Articolo_1/articolo_ing.htm[09-Jan-15 7:11:28 AM]

Tab. 1 Iperenzimemie pancreatiche

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Benign pancreatic hyperenzymemiaor Gullo's syndrome

Lucio Gullo

Curriculum Bibliografia

AbstractBenign pancreatic hyperenzymemia is a new syndrome recently described byme and characterized by an abnormal increase in serum pancreatic enzymes inthe absence of pancreatic disease. Hyperenzymemia can be sporadic orfamilial, it involves all the pancreatic enzymes and is persistent, although thevalues fluctuate considerably even temporarily returning to normal levels.Recognition of this syndrome is very important as it helps to reassure subjectswith this anomaly, usually very concerned, that the syndrome is benign andthat no pancreatic diseases are present; it also helps to avoid the need to carryout numerous examinations and sometimes also hospitalization and treatments

that are completelyuseless.

IntroductionIn 1986 I first saw a 46-year-old man, in excellent health, who had had abnormally high serumpancreatic enzymes for several months. He had been admitted to my department for suspectedpancreatic disease but all the biohumoral and imaging techniques carried out, includingwirsungography, were normal. I thought that the hyperenzymemia could be the expression of apancreatic disease (chronic pancreatitis? tumor?) that was still not evident but which would haveemerged in the days or months that followed. Instead, no pancreatic disease ever becameapparent, the patient continued to enjoy good health in the years that followed and still does,hisserum pancreatic enzymes are frequently high and imaging techniques show anabsolutely normal pancreas. Since then, I have seen numerous other subjects, children andadults, with the same enzymatic anomaly, and with a normal pancreas (1, 2). In this article, Iwill describe the main characteristics of this new syndrome.

Phatological pancreatichyperenzymemiaThere are many forms of pancreatic hyperenzymemia and they may be pathological and non-pathological; the most frequent forms are pathological and, in particular, are caused by diseasesof the pancreas (Table 1).In general, an increase in the normal serum values of pancreatic enzymes is due to the presenceof acute pancreatitis, but even chronic pancreatitis, especially during the painful attacks or whencomplicated by pseudocysts, tumors and pancreatic trauma can also cause hyperenzymemia.Pancreatic hyperenzymemia can also sometimes be encountered in other diseases, mainly cysticfibrosis, celiac disease, intestinal infarct or perforation, renal insufficiency, kidney transplant,hepatitis and cirrhosis of the liver, chronic intestinal inflammatory diseases, and acute pancreaticischemia after surgery involving the heart or the aorta, especially the thoracic aorta (3). Theseforms of hyperenzymemia are usually easy to recognize and their identification can be ofconsiderable diagnostic help. In addition to these forms, there is also a vast group of non-pathological pancreatic hyperenzymemias (Table 1).

Nonpathological pancreatichyperenzymemias

HyperamylasemiaThis form of hyperenzymemia has beenwell-known for many years. An increase in

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just the serum values of amylase can befound in healthy subjects in variousconditions, in the absence of pancreaticdiseases (4-7). This group includeshyperamylasemia due to the presence ofmacroamylase, salivary hyperamylasemiaand mixed, salivary and pancreatic,hyperamylasemia. Macroamylase is amacrocomplex consisting of normal serumamylase bound to an abnormal serumprotein; this macrocomplex accumulates inthe circulation as it is too large to befiltered by the renal glomerulus and causes hyperamylasemia. Salivary hyperamylasemia is due toan increase in the serum of the amylase produced by the salivary glands, while the mixed formis caused by an increase ofboth the salivary and pancreatic enzyme in the circulation. A simple criterion for distinguishingmacroamylasemia from the other two forms of hyperamylasemia is the dosage of amylasuria,which is normal when hyperamylasemia is due to macroamylase and increased in the othertwo forms. Two studies published in 1997 (8) and 2002 (9) described cases of familialhyperamylasemia. Each study described just one subject with hyperamylasemia, reporting thatthe enzymatic defect was also present in some of the patient's relatives. Both patients, however,suffered from recurrent abdominal pain, which casts some doubt on the complete absence ofany disease of the pancreas.

Benign pancreatic hyperenzymemia or Gullo's syndrome

This is a new form of pancreatic hyperenzymemia which I described for the first time,characterized by an abnormal increase in the serum of all pancreatic enzymes.There is a sporadic form (1) and a familial form (2). In the first study dedicated to this anomaly(1), I described the sporadic form in 18 subjects, seen between January 1987 andJune 1991 (10 males and 8 females, mean age 47 years, range 25-66). The interval between theinitial detection of hyperenzymemia and the start of the study varied from 4 months to 10 years,with a mean value of 12.6 months. These were all normal subjects, in excellent health andwithoutany disease. At the time of the study they underwent various examinations, includingultrasound, CT and/or wirsungography. After the initial observation they were clinically followeduntil December 1995. The pancreatic hyperenzymemia had been discovered during routine testswhich had also by chance included amylase. Figure 1 shows the individual serum values ofamylase, isoamylase, lipase and trypsin detected at the time of the study. As can be seen, theenzymes were abnormally high in all subjects. The increase above the upper limit of the normalrange varied from 1.4 to 4.1 times for amylase, from 1.8 to 6.0 times for pancreatic isoamylase,from 1.5 to 7.7 times for lipase and from 1.6 to 13.9 times for trypsin. During the subsequentfollow-up which lasted for around five years,the enzymes remained high, albeit with considerablyfluctuating values and sometimes returning to within the normal range, as shown in figures 2and 3 which report the serum enzyme levels of two cases followed for nine years. Neither of the18 subjects studied has presented any signs or symptoms of pancreatic disease in the years thatfollowed the study. In a subsequent study (2). I described the familial form of this benignpancreatic hyperenzymemia, a form that involves more than one member of the same family. Inthis study, I reported seven families in which two or more members, making a total of 19subjects (11 males and 8 females; mean age, 32.7 years; range 3- 84), had this enzymaticdefect. None of these 19 subjects had signs or symptoms of pancreatic disease; routine bloodtests and abdominal ultrasound scans were normal in all of them.

Figura 1



Figura 2

Figura3

Figure 3 shows the serum values of amylase, isoamylase and lipase in the 19 subjects at thetime of the study. It can be seen that the enzymes were higher than normal, with increasesranging from 1.3 to 5.2 times the upper normal limit for amylase, from 1.4 to 8.6 times for



pancreatic isoamylase and from 1.6 to 18.0 times for lipase. The determination of the serumpancreatic enzymes was repeated over the following months and years and the results weresimilar, with fluctuations and transient normalizations. The members of the seven familiesaffected by hyperenzymemia were a mother, her two sisters and two daughters; a mother andher two children; a father and two children; three fathers and their respective three children, andone brother and sister. Overall, there were five children under the age of 10 years.

Figura 4

Figure 4 shows the family tree of the seven families; the carriers of the enzymatic alterationare indicated with a star.

Figura 5

In a subsequent study (10) we found that in subjects with this form of hyperenzymemia the



administration of secretin, a hormone that stimulates pancreatic secretion, leads to a markedincrease of serum pancreatic enzymes, especially lipase. This suggests that the abnormalsecretion of circulating enzymes occurs not only in basal conditions but also after hormonalstimulation. The underlying mechanism of this abnormal passage of enzymes from thepancreatic cell into the blood is unknown. The fact that the defect has been detected in morethan one member of the same family indicates the possibility of a genetic basis. In a studywhich has been recently published (11) we evaluated whether mutations of the cystic fibrosisgene (CFTR,cystic fibrosis transmembrane regulator) may play a role in the etiology of this form ofhyperenzymemia. The results showed that only seven of the 70 subjects studied had mutationsof this gene; this frequency is similar to that is found in the general population and the resultdoes not therefore support a role of CFTR gene mutations in the etiology of this form ofpancreatichyperenzymemia. In another paper, currently in press (12), we decided to study whetherpancreatic hyperenzymemia remains constant or whether it varies over a number of days. Wetherefore measured serum pancreatic enzymes for five consecutive days in a vast group ofsubjects affected by this new syndrome. We found that in most cases the hyperenzymemia isnot constant, and the values can vary from one day to the next, at times even returning towithin the normal range. Figure 5 shows the values for one of these cases. The reason forthese frequent variations is unknown.

Studies by other authors on benign pancreatic hyperenzymemiaVery few studies have been published on this topic. In a letter to the editor which appearedafter my first article on the syndrome (1), some authors (13) claimed that the hyperenzymemiacould be caused by pancreatic steatosis, secondary to a condition of hypercholesterolemia and/orhypertriglyceridemia present in some of the subjects affected by the enzymatic abnormality.The diagnosis of pancreatic steatosis had been made with ultrasound. Apart from the fact thatpancreatic steatosis has never been described in humans, a study of the pancreas which weperformed in a group of subjects with hyperenzymemia and increased cholesterol and/ortriglycerides using magnetic resonance, which clearly reveals the presence of any pancreatic fattyinfiltration, unmistakably showed that the pancreas was normal and free of any fatty infiltration(12). In another letter to the editor following my first study (1), a group of Spanish authors (14)reported five cases of sporadic pancreatic hyperenzymemia similar to those which I haddescribed and confirmed my results. Finally, I recall a study that was published in 1991 (15)reporting three cases of hyperamylasemia and hyperlipasemia without apparent causes. Theauthors concluded that, although subclinical pancreatic damage could not be excluded, thefindingstill had an indeterminate clinical significance. One of the three subjects had in fact formerly hadacute pancreatitis and another was a heavy drinker, making it difficult to claim the absence ofpossible causes of the hyperenzymemia, at least in these two cases.

Association of benign pancreatic hyperenzymemia and nonpathological serumincreases of other compoundsBenign serum increases of other compounds have been known for many years to exist. The firstof these to be reported was the increase in unconjugated bilirubin or Gilbert's syndrome (16),clinically characterized by mild and intermittent jaundice. Another benign increase was firstreported in 1980 by Rowland et al (17) who described the possibility of nonpathological serumincreases of creatine phosphokinase (CK), which was confirmed more recently in other studies(18, 19). In some of the subjects with benign pancreatic hyperenzymemia I have found anassociation with Gilbert's syndrome or with an increase in creatine phosphokinase. In others, Ihave found an association with a nonconstant and nonpathological increase in transaminases(20). Whether these associations are casual or have a common genesis is not clear.

Final ConsiderationsThe following considerations should be bornein mind for correct recognition ofbenign pancreatichyperenzymemia:1.This form of hyperenzymemia appears in healthy subjects, it persists over time withconsiderable fluctuations, often returning to within the normal range and there is no clinical ormorphological evidence of pancreatic disease; it may be sporadic or familial.2. At least a year must pass after the first finding of hyperenzymemia before it can beconsidered with sufficient certainty to be this new syndrome. It is important to remember that,although a very rare occurrence (1-2%), isolated pancreatic hyperenzymemia, especially insubjects over the age



of 50-60, can be the first clinical sign of a tumor of the pancreas which does not become evidentfor several months.3. In almost all cases (~95%) the serum levels of all the pancreatic enzymes are abnormallyhigh; sometimes (~5% of cases) there is only an increase in amylase or, even more rarely, inonly lipase.4. The correct diagnosis of this form of hyperenzymemia is very important as it reassures thecarriers of this enzymatic abnormality, usually very concerned, that they do not have a diseaseof the pancreas and it avoids often numerous tests, and sometimes hospitalisation andtreatment,that are of no use whatsoever.

Lucio Gullo Director of the Istituto di Medicina Interna,

Universit di Bologna, Ospedale S. OrsolaBologna, Italy

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