Lucio Gullo - Iperenzimemia pancreatica benigna o sindrome di Gullo

Lucio Gullo - Iperenzimemia pancreatica benigna o sindrome di Gullo
:: Medicina
SOMMARIO
Benign pancreatic hyperenzymemia

or Gullo's syndrome
Lucio Gullo
Curriculum
Bibliografia
Abstract
Benign pancreatic hyperenzymemia is a new syndrome recently described by
me and characterized by an abnormal increase in serum pancreatic enzymes in
the absence of pancreatic disease. Hyperenzymemia can be sporadic or
familial, it involves all the pancreatic enzymes and is persistent, although the
values fluctuate considerably even temporarily returning to normal levels.
Recognition of this syndrome is very important as it helps to reassure subjects
with this anomaly, usually very concerned, that the syndrome is benign and
that no pancreatic diseases are present; it also helps to avoid the need to carry
out numerous examinations and sometimes also hospitalization and treatments
that are completely
useless.
Introduction
In 1986 I first saw a 46-year-old man, in excellent health, who had had abnormally high serum
pancreatic enzymes for several months. He had been admitted to my department for suspected
pancreatic disease but all the biohumoral and imaging techniques carried out, including
wirsungography, were normal. I thought that the hyperenzymemia could be the expression of a
pancreatic disease (chronic pancreatitis? tumor?) that was still not evident but which would have
emerged in the days or months that followed. Instead, no pancreatic disease ever became
apparent, the patient continued to enjoy good health in the years that followed and still does,
his
serum pancreatic enzymes are frequently high and imaging techniques show an
absolutely normal pancreas. Since then, I have seen numerous other subjects, children and
adults, with the same enzymatic anomaly, and with a normal pancreas (1, 2). In this article, I
will describe the main characteristics of this new syndrome.
Phatological pancreatichyperenzymemia
There are many forms of pancreatic hyperenzymemia and they may be pathological and nonpathological; the most frequent forms are pathological and, in particular, are caused by diseases
of the pancreas (Table 1 ).
In general, an increase in the normal serum values of pancreatic enzymes is due to the presence
of acute pancreatitis, but even chronic pancreatitis, especially during the painful attacks or when
complicated by pseudocysts, tumors and pancreatic trauma can also cause hyperenzymemia.
Pancreatic hyperenzymemia can also sometimes be encountered in other diseases, mainly cystic
fibrosis, celiac disease, intestinal infarct or perforation, renal insufficiency, kidney transplant,
hepatitis and cirrhosis of the liver, chronic intestinal inflammatory diseases, and acute pancreatic
ischemia after surgery involving the heart or the aorta, especially the thoracic aorta (3). These
forms of hyperenzymemia are usually easy to recognize and their identification can be of
considerable diagnostic help. In addition to these forms, there is also a vast group of nonpathological pancreatic hyperenzymemias (Table 1 ).
Nonpathological
hyperenzymemias
pancreatic Tab. 1
Iperenzimemie pancreatiche
Hyperamylasemia
This form of hyperenzymemia has been
well-known for many years. An increase in
http://www.leadershipmedica.com/sommari/2006/numero_02/medicina/Articolo_1/articolo_ing.htm[09-Jan-15 7:11:28 AM]
:: Primo Piano
just the serum values of amylase can be

found in healthy subjects in various
conditions, in the absence of pancreatic
diseases (4-7). This group includes
hyperamylasemia due to the presence of
macroamylase, salivary hyperamylasemia
and mixed, salivary and pancreatic,
hyperamylasemia. Macroamylase is a
macrocomplex consisting of normal serum
amylase bound to an abnormal serum
protein; this macrocomplex accumulates in
the circulation as it is too large to be
filtered by the renal glomerulus and causes hyperamylasemia. Salivary hyperamylasemia is due to
an increase in the serum of the amylase produced by the salivary glands, while the mixed form
is caused by an increase of
both the salivary and pancreatic enzyme in the circulation. A simple criterion for distinguishing
macroamylasemia 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 other
two forms. Two studies published in 1997 (8) and 2002 (9) described cases of familial
hyperamylasemia. Each study described just one subject with hyperamylasemia, reporting that
the 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 of
any 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 and
June 1991 (10 males and 8 females, mean age 47 years, range 25-66). The interval between the
initial 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 and
without
any disease. At the time of the study they underwent various examinations, including
ultrasound, CT and/or wirsungography. After the initial observation they were clinically followed
until December 1995. The pancreatic hyperenzymemia had been discovered during routine tests
which had also by chance included amylase. Figure 1 shows the individual serum values of
amylase, isoamylase, lipase and trypsin detected at the time of the study. As can be seen, the
enzymes were abnormally high in all subjects. The increase above the upper limit of the normal
range 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 subsequent
follow-up which lasted for around five years,the enzymes remained high, albeit with considerably
fluctuating values and sometimes returning to within the normal range, as shown in figures 2
and 3 which report the serum enzyme levels of two cases followed for nine years. Neither of the
18 subjects studied has presented any signs or symptoms of pancreatic disease in the years that
followed the study. In a subsequent study (2). I described the familial form of this benign
pancreatic hyperenzymemia, a form that involves more than one member of the same family. In
this study, I reported seven families in which two or more members, making a total of 19
subjects (11 males and 8 females; mean age, 32.7 years; range 3- 84), had this enzymatic
defect. None of these 19 subjects had signs or symptoms of pancreatic disease; routine blood
tests 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 the
time of the study. It can be seen that the enzymes were higher than normal, with increases
ranging 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 serum
pancreatic enzymes was repeated over the following months and years and the results were
similar, with fluctuations and transient normalizations. The members of the seven families
affected by hyperenzymemia were a mother, her two sisters and two daughters; a mother and
her two children; a father and two children; three fathers and their respective three children, and
one 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 alteration
are 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 marked

increase of serum pancreatic enzymes, especially lipase. This suggests that the abnormal
secretion of circulating enzymes occurs not only in basal conditions but also after hormonal
stimulation. The underlying mechanism of this abnormal passage of enzymes from the
pancreatic cell into the blood is unknown. The fact that the defect has been detected in more
than one member of the same family indicates the possibility of a genetic basis. In a study
which has been recently published (11) we evaluated whether mutations of the cystic fibrosis
gene (CFTR,
cystic fibrosis transmembrane regulator) may play a role in the etiology of this form of
hyperenzymemia. The results showed that only seven of the 70 subjects studied had mutations
of this gene; this frequency is similar to that is found in the general population and the result
does not therefore support a role of CFTR gene mutations in the etiology of this form of
pancreatic
hyperenzymemia. In another paper, currently in press (12), we decided to study whether
pancreatic hyperenzymemia remains constant or whether it varies over a number of days. We
therefore measured serum pancreatic enzymes for five consecutive days in a vast group of
subjects affected by this new syndrome. We found that in most cases the hyperenzymemia is
not constant, and the values can vary from one day to the next, at times even returning to
within the normal range. Figure 5 shows the values for one of these cases. The reason for
these frequent variations is unknown.
Studies by other authors on benign pancreatic hyperenzymemia
Very few studies have been published on this topic. In a letter to the editor which appeared
after my first article on the syndrome (1), some authors (13) claimed that the hyperenzymemia
could be caused by pancreatic steatosis, secondary to a condition of hypercholesterolemia and/or
hypertriglyceridemia 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 that
pancreatic steatosis has never been described in humans, a study of the pancreas which we
performed in a group of subjects with hyperenzymemia and increased cholesterol and/or
triglycerides using magnetic resonance, which clearly reveals the presence of any pancreatic fatty
infiltration, 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 had
described 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. The
authors concluded that, although subclinical pancreatic damage could not be excluded, the
finding
still had an indeterminate clinical significance. One of the three subjects had in fact formerly had
acute pancreatitis and another was a heavy drinker, making it difficult to claim the absence of
possible causes of the hyperenzymemia, at least in these two cases.
Association of benign pancreatic hyperenzymemia and nonpathological serum
increases of other compounds
Benign serum increases of other compounds have been known for many years to exist. The first
of 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 first
reported in 1980 by Rowland et al (17) who described the possibility of nonpathological serum
increases 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 an
association with Gilbert's syndrome or with an increase in creatine phosphokinase. In others, I
have 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 Considerations
The following considerations should be bornein mind for correct recognition ofbenign pancreatic
hyperenzymemia:
1.This form of hyperenzymemia appears in healthy subjects, it persists over time with
considerable fluctuations, often returning to within the normal range and there is no clinical or
morphological 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 be
considered 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 in
subjects over the age
of 50-60, can be the first clinical sign of a tumor of the pancreas which does not become evident
for several months.
3. In almost all cases (~95%) the serum levels of all the pancreatic enzymes are abnormally
high; sometimes (~5% of cases) there is only an increase in amylase or, even more rarely, in
only lipase.
4. The correct diagnosis of this form of hyperenzymemia is very important as it reassures the
carriers of this enzymatic abnormality, usually very concerned, that they do not have a disease
of the pancreas and it avoids often numerous tests, and sometimes hospitalisation and
treatment,
that are of no use whatsoever.
Lucio Gullo
Director of the Istituto di Medicina Interna,
Universit di Bologna, Ospedale S. Orsola
Bologna, Italy
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Benign pancreatic hyperenzymemia

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