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Technical Briefs |
1
Laboratorio di Analisi Chimico-cliniche and
2
Dipartimento di Medicina Interna e Terapia Medica, Sezione di Medicina Interna e Nefrologia, Università degli Studi di Pavia, Instituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, I-27100 Pavia, Italy, and
3
Laboratorio di Analisi Chimico-cliniche, Ospedale di Circolo, Varese, Italy;
a address for correspondence: Laboratorio di Analisi Chimico-cliniche, Instituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, I-27100 Pavia, Italy
Measurements of the activity of both lipase
(triacylglycerolacylhydrolase, EC 3.1.1.3) and 
-amylase (EC 3.2.1.1)
in serum are commonly used as aids in the diagnosis and follow-up of
acute and recurrent pancreatitis (1); 19% of pancreatitic
patients present with normal serum amylase (2), thus leaving
lipase as the main hematochemical marker of this disease in a
substantial number of patients.
Lipase and amylase are increased also in conditions other than pancreatitis, such as several nonmalignant hepatobiliary and gastrointestinal diseases, sepsis, renal failure, pulmonary failure, and subdural bleeding (1)(2)(3)(4).
In 1987, Stein et al. (5) reported on a non-Hodgkin's lymphoma patient with major lipase activity (up to seven times the upper reference value), with no parallel increase in amylase; in this case, the authors demonstrated a specific immunoglobulin G with high affinity for lipase as the cause of increased serum lipase activity.
More recently, Donnelly et al. (6) have reported a chronic increase in serum lipase, again with no associated hyperamylasemia or clinical evidence of pancreatitis, which the authors suggested to be tumor-derived; furthermore, Muñoz-Perez et al. (7), after observing chronic increased serum lipase in another patient with massive abdominal metastases from a suspected pancreatic adenocarcinoma, suggested that the biochemical profile characterized by increased lipase and normal amylase could be an early finding of a malignant neoplasm.
We report on four cases in which serum lipase increase first anticipated an otherwise undetectable tumor relapse or progression.
Serum lipase activity was measured with a commercially available kinetic colorimetric co-lipase method (Lipase KC, Bayer Italia S.p.A., Divisione Diagnostici). Briefly, in the assay, pancreatic lipase catalyzes the hydrolysis of the 1,2-diglyceride sulfate to produce fatty acids and 2-monoglyceride. The latter, in the presence of specific auxiliary enzyme, release glycerol, which is then converted, by glycerokinase, into glycerol-3-phosphate and hydrogen peroxide. Finally, in the presence of peroxidase, the H2O2 delivered oxidizes the chromogen system to a violet dye. The mean value of the absorbance (A550) changes per minute is calculated. The reference interval for serum was 8–57 U/L at 37 °C (8).
case 1
A 61-year-old man was diagnosed in December 1992 with malignant
rectosigmoid adenocarcinoma after mild anemia was observed. Early
infiltration of the vesical dome was found at subsequent anterior
resection; the whole mass was ablated, and the patient was started on
postoperative irradiation and adjuvant chemotherapy. After treatment,
the patient remained free of evidence of disease till May 1994, when
abdominal computed tomography showed liver metastases. His CA 19.9 was
109 IU/L (normal reference values, 
37 IU/L). Advanced systemic
chemotherapy, started in June 1994, controlled the growth of
metastases. In November 1995, abdominal ultrasonography (US) showed
stable liver findings and no pancreatic or extrahepatic biliary
involvement. Hematochemical tests confirmed the previous findings of
hepatocellular injury (150 U/L aspartate aminotransferase and 164 U/L
alanine aminotransferase), high lipase (170 U/L; normal reference
values, 8–57 U/L), normal amylase, and CA 19.9 of 37 IU/L.
The treatment was then discontinued on the patient's request, mainly because the disease was stable. In January 1996, abdominal US showed marked disease progression in the liver, with many new secondary lesions. Lipase remained high (197 U/L), amylase was normal, and CA 19.9 had increased again (215 IU/L). The patient then received second-line chemotherapy, and he is still alive.
case 2
A barium enema on a 52-year-old woman in April 1994, identified lesions in the colon at the hepatic flexure. Biopsy during colonscopy permitted the histologic diagnosis of colon adenocarcinoma. After resection and with distant metastases excluded, the patient was staged as C2 according to Dukes' classification, modified by Astler and Coller (9); she then received six cycles of adjuvant combination chemotherapy. Before surgery, CA 19.9 was increased (324.67 IU/L).
After adjuvant treatment, instrumental and hematochemical findings, including CA 19.9 titration, were normal. However, high lipase (120 U/L) was first found in May 1995, whereas amylase and tumor markers remained normal.
Three months later, CA 19.9 was markedly increased (94 IU/L). Subsequent liver US showed a liver metastasis. Lipase titers remained high, whereas amylase was unchanged. Laparatomy was then performed to resect the metastasis and to position a small intrahepatic catheter; incidentally, no objective signs of pancreatitis were found during the surgical procedure. Subsequently, the patient started on locoregional chemotherapy but died 9 months later of cancer-related liver failure.
case 3
Hepatocellular carcinoma was suspected at liver US performed in
January 1995, in a 64-year-old woman with previous hepatitis B and C,
and carcinoma was confirmed at subsequent US-guided needle biopsy. The
patient was inoperable because of multifocal cancer and poor liver
function (29 g/L albumin and 870 mg/L cholesterol; prothrombin time was
42% of control), and she therefore was started on a course of
combination chemotherapy. At that time, both amylase and lipase were
within the reference intervals (215 and 44 U/L, respectively), whereas
CA 19.9 and 1-fetoprotein (1-FP)
were high (150 and 92 U/L, respectively). Instrumental tests after
chemotherapy cycle 3 showed complete response, with no more signs of
disease appearing at computed tomography. CA 19.9 was markedly lower
(37 IU/L), and 1-FP concentration was normal (7 U/L).
Subsequent US performed 4 weeks after computed tomography confirmed
disease remission. Three months later, US showed no sign of disease
progression, but lipase was high (242 U/L), even with no other
biohumoral changes; particularly, CA 19.9 and 1-FP
titers were much the same as in the former tests (44 U/L and 11 U/L,
respectively), whereas amylase remained in the normal range (220 U/L).
US performed 1.5 months later because of severe jaundice and abdominal
pain showed marked disease progression in the liver. Lipase was again
high (351 U/L), amylase was unchanged, and tumor markers were positive
again (CA 19.9 was 157 U/L and 1-FP was 397 U/L).
The patient died of liver failure three weeks later. No signs of pancreatitis were evidenced at autopsy.
case 4
A 64-year-old chronic alcoholic and hepatitis C virus-positive
hepatopathic man was referred to the Otorhinolaryngology Department of
our Hospital in February, 1995, because of mainly inspiratory laryngeal
dyspnea. A subglottic laryngeal cancer (T2) with
bilateral lymph nodes (N3) but no distant (M0)
metastases was diagnosed. Preoperative tests showed high lipase (318
U/L) and no hyperamylasemia (180 U/L amylase). Other hematochemical
tests showed only increased 
GT (87 U/L) and alkaline phosphatase
(344 U/L). Subsequent abdominal US showed no neoplastic evolution and
no gross focal lesions in the pancreatico-bilio-choledochal region,
which was, however, partly masked by abdominal gas. In March 1995, the
patient underwent total laryngectomy with bilateral functional emptying
and then was started on adjuvant irradiation, including the anterior
mediastinum. Major signs of hepatocellular necrosis were found at 3
months of follow-up (136 U/L aspartate aminotransferase and 124 U/L
alanine aminotransferase), together with worsening GT (112 U/L) and
alkaline phosphatase (416 U/L). Once again, no hyperamylasemia was
found, but lipase was high (412 U/L); tumor marker assessment showed
high CA 19.9 only (69 IU/L). Subsequent abdominal US depicted a focal
liver lesion, ~2 cm in diameter, which needle biopsy proved to be a
well-differentiated hepatocellular carcinoma with cholangiocellular
differentiation areas. The patient then underwent US-guided
percutaneous alcoholization; no signs of disease progression in the
liver or recurrence in the head and neck have been observed since then.
Serum lipase activity increased in all our patients without a parallel increase in serum amylase titers; the combination of accurate clinical, biochemical, and instrumental study of these patients allowed us to exclude the possibility of a normoamylasemic pancreatic injury, and the presence of appropriate concentrations of bile salts and colipase in the reagent favors a full and specific action of lipase assay, at the same time inhibiting serum esterase (8). Furthermore, not one of the above patients had fat emboli or received large heparin doses, conditions that could have interfered with lipase titration.
An increase in lipase activity preceded the progression or relapse of a previously known colorectal or hepatic cancer in three cases; in the extant patient, increased lipase titers, observed during the staging of a laryngeal cancer and not decreasing after the surgical removal of the primary head and neck tumor, preceded the development of a subsequent second neoplasm, a primary hepatocellular carcinoma.
Furthermore, an increase in lipase activity preceded, by an average of
2.6 months (4, 1.5, 3, and 2 months, respectively), the increase of
specific tumor markers, such as CA 19.9 and 1-FP.
Several possible mechanisms may explain this unexpected increase in lipase activity, such as the presence of an unusual lipase isoenzyme, a decrease in the clearance of lipase or rate of its inactivation in the circulation, the persistence of lipase in blood after complexation of lipase with a plasma protein (5), or the direct production of lipase from the neoplastic mass, as suggested by Donnelly et al. (6) in a patient with a retroperitoneal malignancy, and by Lopez-Soriano et al. (10).
Several authors claim that the nonspecificity of lipase assays for
pancreatitis is due to the pancreas being sensitive to other abdominal
disease; as a matter of fact, the possibility that tumors may produce
humoral factors influencing pancreatic metabolism and/or lipolytic
activity is supported by a recent study suggesting that tumor necrosis
factor- is involved in activating the lipid metabolic changes that
develop in rats after transplantation of a fast-growing tumor
(11).
Although we did not investigate which of the above mechanisms was
involved in our patients, we consider intriguing the hypothesis of a
tumor marker-like role for lipase; indeed, in our experience, lipase
acted as an extremely precocious signal of malignancy in all patients,
anticipating the increase of more common tumor markers, such as CA 19.9
and 1-FP.
However, only prospective studies on an adequate number of patients could definitely assess the real role of lipase from this point of view.
References
treatment interferes with changes in lipid metabolism in a tumour cachexia model. Clin Sci 1994;87:349-355.
[Medline]
[Order article via Infotrieve]
The following articles in journals at HighWire Press have cited this article:
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  Y. E. Taes, H. Louagie, J.-P. Yvergneaux, M. L. De Buyzere, H. De Puydt, J. R. Delanghe, and J. A. Lott Prolonged Hyperlipasemia Attributable to a Novel Type of Macrolipase Clin. Chem., December 1, 2000; 46(12): 2008 - 2013. [Abstract] [Full Text] [PDF]
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