Familial Gullo’s Syndrome: A Clinical Case Report

Mauro Turrin 1 , Lucia Fornasiero 2 

1 Former Department of Internal Medicine, Ospedali Riuniti Padova Sud “Madre Teresa di Calcutta”, Monselice (PD), Italy

2 Former Department of Laboratory Medicine, Ospedali Riuniti Padova Sud “Madre Teresa di Calcutta”, Monselice (PD), Italy

Abstract

This case report describes a male patient born in 1953 presenting an occasional increase in serum amylase and lipase forty years ago. The monitoring of enzymes was accompanied by radiological investigations, which did not reveal pancreatic pathology. In his family, including 10 siblings, half were carriers of this isolated anomaly; multiple cysts in pancreas, kidneys, and liver were present in some family members, in addition to a pancreatic neoplasia in a sister who did not carry the enzymatic abnormality. Our patient developed colon adenocarcinoma at the age of 67.

Here we examine the characteristics of non-pathological chronic pancreatic hyperenzymemia defined as such by the main Italian pioneer Professor Gullo.

Keywords: Hyperamylasemia; Hyperlipasemia; Familial Pancreatic Hyperenzimemia; Gullo’s Syndrome; Magnetic Resonance Cholangiopancreatography Imaging

CMI 2021; 15(1): 15-24

http://dx.doi.org/10.7175/cmi.v15i1.1493

Case Report

Corresponding author

Mauro Turrin

m.turrin@libero.it

Received: 12 January 2021

Accepted: 12 February 2021

Published: 30 March 2021

Introduction

Chronic asymptomatic pancreatic hyperenzymemia (CAPH) is a persistent abnormal increase in the serum concentrations of pancreatic enzymes without pancreatic symptoms and imaging findings of pancreatic diseases. The elevation of serum enzymes is fluctuating, with frequent and temporary findings of levels within the normal range. In 1996, Professor Lucio Gullo for the first time used the expression chronic non pathological hyperamylasemia (CNPH) of pancreatic origin and named it “Gullo’s syndrome” [1,2]. CAPH has been considered a benign condition [3] that can occur sporadically or in familial forms.

Case Description

In a Caucasian subject born in 1953, an increase in amylase and lipase was found during a routine blood test check carried out in 1980. The maximum values achieved were:

• for total amylases 228 U/L (normal values [nv] 10-120 U/ L);
• for pancreatic amylase 151 U/L (nv <53 U/L);
• for lipase 766 U/L (nv <67 U/L).

These findings were never associated with abdominal pains or acute back pain. During the 40-year observation period, the increased values alternated with normal values: no pancreatic disease has been recorded so far. A first ultrasound of the complete abdomen, performed 8 years after the first finding of hyperenzymemia, showed: moderate hepatic steatosis, a small incision at the right kidney, a prostate with adenoma aspect in the central site. The patient was affected by: sleep apnea syndrome, esophageal hiatus hernia, chronic gastritis, diffuse colon diverticulosis, hyperplastic descending colon polyp, arterial hypertension, nasal obstruction, coxarthrosis (arthroplasty), chronic obstructive pulmonary disease, type 2 diabetes mellitus (in diet therapy only), thyroid node, fusiform aneurysm on the right iliac artery, and prostatic hypertrophy. A new diagnosis of renal insufficiency, viral hepatitis, Sjögren syndrome [4], celiac disease, and inflammatory bowel diseas [5] was not made. Alcohol intake was occasional and moderate.

He did not use any drug that could induce hyperamylasemia or hyperlipasemia (Box 1 [6]) or acute pancreatitis (Box 2 [7]).

His family history revealed:

• a mother who died at the age of 63 years after cholecystectomy for multiple cholelithiasis;
• out of 10 siblings, half were carriers of hyperamylasemia (with a maximum value of 1900 U/L) and/or hyperlipasemia (with a maximum value of 1622 U/L), found after the age of 27-44 years;
• a sister, born in 1936, suffering from Hashimoto’s thyroiditis and myelofibrosis, died at 82 years from aplastic anemia;
• a brother, born in 1945, is a carrier of prostate cancer and has pancreatic cysts on abdomen CT scan;
• a 69-year-old brother is a carrier of cystic pancreatic lesions detected by CT scan;
• a brother, born in 1956, is a carrier of isolated hyperenzymemia;
• it should also be noted that out of two sisters without hyperenzymemia, one died at 79 years for cancer of the breast and pancreas, while the other, 81-year-old, carries multiple cysts of pancreas, kidney, and liver.

The genealogic tree is shown in Figure 1, whilst Table I details the clinical features of the family members.

In our subject the presence of macroamylasemia and macrolipasemia was excluded (as well as macro-creatine phosphokinase—macro-CPK). The periodic control of oncological markers (CA19-9) was negative.

The evolution over time of total amylase, pancreatic amylase, and lipase values is shown in Table II and Figures 2 and 3. Additional laboratory tests are shown in Table III.

In 2018, after 38 years from the first finding of hyperenzymemia, the magnetic resonance imaging (MRI) findings of the upper abdomen revealed: liver containing some small cystic formations scattered in both lobes, the greatest being 10 mm large; pancreas within limits; some bilateral renal cystic cortical formation, greater than 17 mm; no areas of pathological enhancement after paramagnetic contrast medium infusion (gadoteridol) of the upper abdomen organs. The magnetic resonance cholangio-pancreatography (MRCP) [2] showed no biliary lithiasis, no dilatation of the intrahepatic biliary tree, hepato-choledochus with a maximum caliber of 7 mm, regular Wirsung duct (Figure 4).

The laboratory tests performed in February 2019 (Table II) demonstrated: total amylase = 151 U/L (nv 10-120 U/L), lipase = 364 U/L (nv 2-67 U/L), γGT = 53 U/L (nv <55 U/L), blood glucose = 107 mg/dL, total cholesterol = 197 mg/dL, triglicerides = 153 mg/dl. The laboratory tests in September 2019 have found: lipase = 219 U/L (nv 13-60 U/L), α faecal calprotectin = 81 μg/g faeces (nv <50 μg/g) [8], CA 19-9 = 80 KU/L (nv <31 KU/L), positive occult blood in the faeces.

In October 2019, colonoscopy showed an ulcer in the right flessure and the biopsy revealed an adenocarcinoma. The patient underwent right hemicolectomy (October 2019) and subsequent 8 cycles of chemotherapy (oxaliplatin + capecitabine). He was negative for the nasopharyngeal swab for COVID-19. Laboratory tests in June 2020, after the last course of chemotherapy, showed: amylase = 65 U/L (nv 10-120 U/L), lipase = 27 U/L (nv 2-67 U/L), CA 19-9 = 9.2 KU/L (nv <35.4 KU/L), CEA = 3.3 μg/L (nv <4.0 μg/L). The contrast-enhanced abdominal CT scan revealed normal pancreas, minute hypodensity of cystic appearance in the liver, bilateral renal cysts, the largest 24 mm on the left.

The most recent laboratory tests, performed in November 2020 (Tables II), detected serum amylase = 141 U/L (nv <100 U/L) and serum lipase = 402 U/L (nv <60 U/L). The contrast-enhanced abdominal CT showed normal pancreas, unchanged liver, and kidney cysts (Figure 5).

Discussion

Our clinical case meets the criteria for the definition of chronic asymptomatic pancreatic hyperenzymemia. In fact, the diagnostic criteria are [9,10]:

• an increase by >10% of the upper normal limits of serum amylase and/or lipase found on >3 occasions, lasting more than 6 months;
• absence of upper abdominal or back pain;
• idiopathic presentation.

We excluded through the MRCP the presence of any associated congenital anomalies (pancreas divisum, annular pancreas, Wirsungocele, cystic lesions at the pancreatic tail, Santorinicele, diffuse dilation of the main pancreatic duct) and intraductal papillary mucinous tumor of the pancreas, as these alterations have been described in some cases [11-14]. We did not perform a MRCP with secretin stimulation, currently considered as the method of choice in the study of CAPH subjects [9,15] for the search for sphincter of Oddi dysfunction or even early (mild) chronic pancreatitis: this investigation would not have added significant data to the always stable clinical picture. Similar considerations apply to the use of endoscopic ultrasonography [16-18].

In the family group in analysis, two brothers with hyperenzymemia had pancreatic cysts, while a third brother had only hepatic and renal cysts. Of two siblings without hyperenzymemia, one had multiple cysts in the pancreas, kidney, and liver, while the second died due to pancreas (and breast) cancer at the age of 79 years. The significance of these associations, as well as the appearance of colon adenocarcinoma in our patient, at the present time is not clear.

The patients must be followed for a period of at least one year before labeling their pancreatic hyperenzymemia as benign, because in 1-2% of cases of pancreatic cancer, asymptomatic pancreatic hyperenzymemia can be an early witnessed laboratory abnormality, especially in elderly age group [19,20].

In adulthood, the prevalence of incidentally found pancreatic cystic lesions is high (between 2.6% and 19.6%) [21-24]. They are heterogeneous and include malignant, benign, and pre-malignant lesions, capable of evolving into invasive carcinoma over time. The differential diagnosis between intraductal papillary mucinous neoplasm, mucinous cystoadenoma and serous cystoadenoma could be made by endoscopic ultrasonography fine needle aspiration or even better with endoscopic ultrasonography through-the-needle microforceps biopsy [25], with the determination of intracystic glucose concentration, having been found to be more sensitive than the concentration of carcinoembryonic antigen [24]; however, this investigation is not carried out in our hospital.

It should be considered that a long-lasting CAPH, defined as benign, should be studied in depth at least with MRCP for the possibility, among others, of finding intraductal papillary mucinous neoplasm in small pancreatic cystic formations [12,14,26].

Also for this reason, the follow-up of hyperenzymemia must be continued for at least two years [27].

In our patient, after the end of chemotherapy for the colon adenocarcinoma, the fluctuations of lipase and amylase remained unchanged.

The ethiology of Gullo’s syndrome remains unknown. It is known that there is a defect in the basolateral surface of the acinar cells that causes the increased secretion of pancreatic enzymes into the blood or the effect of secretin in the pancreatic duct of Wirsung [2].

Regarding the study of cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations and serine peptidase inhibitor, Kazal type 1 (SPINK1) and serine protease 1 (PSSR1) genes, no significant differences compared to the general population have been described in benign familial hyperenzymemia [28-30].

The prevalence of CAPH among subjects who underwent blood tests for multiple pancreatic serum enzymes was 2% in a retrospective cross-sectional observational study in a large sample of the general Italian population [31].

In another Italian case series relating to 125,483 total accesses registered in a University Emergency Department [32], a prevalence of benign pancreatic hyperenzymemia equal to 0.09% cases for every 100,000 accesses was found.

Unlike the very extensive Italian cases, reports in other countries are limited. In literature, few cases are reported in Japan [4,11], Belgium [14], USA [17,33], India [34], Taiwan [35], Brazil [36], Austria [37], Poland [38], Ukraine [39], Australia [40], Spain [41,42], Venezuela [43], Morocco [44], and Germany [45].

The most recent Italian case series was published in December 2019 [46].

Pancreatic hyperenzymemia can appear at almost every age: the ratio of affected men and women is 1.5:1. It is a rare finding in children: only a few sporadic cases have been described in the literature [41,47-49].

The coexistence of hyperenzymemia in siblings is diagnostic for familial form of CAPH, which has an incidence between 4% and 39% in the series described in the literature [3,8,10,12,39,43,50].

Conclusion

In the family group here described, the long follow-up between 31 and 40 years confirms the benignity of the enzymatic anomaly regarding pancreatic diseases. This familial association supports the concept of a genetic basis underlying pancreatic enzyme abnormalities, despite the fact that so far no correlations have been found with the genetic mutations studied.

Consent to publication

The consent to publication was obtained from the patient here described.

Funding

This article has been published without the support of sponsors.

Conflicts of interests

The authors declare they have no competing financial interests concerning the topics of this article.

ORCiD

Mauro Turrin: https://orcid.org/0000-0003-2100-2104

Lucia Fornasiero: https://orcid.org/0000-0003-1138-8613

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