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Watery diarrhea

CgA, VIP

Glucagonoma

None

Necrolytic migratory erythema

CgA, glucagon, glycentin

Somatostatinoma

None

Mild diabetes, gallstones

CgA, somatostatin

PP-oma

None

None

CgA, PP

Non functioning

None

None

CgA, PP

CgA=Chromogranin A; 5-HIAA= 5-hydroxyindoleacetic acid; PP= Pancreatic polypeptide; VIP= vasointestinal peptide; NKA= neurokinin A; PYY= peptide YY

Table 1. Syndromes, symptoms and secretory products from GEP NETs

CgA=Chromogranin A; 5-HIAA= 5-hydroxyindoleacetic acid; PP= Pancreatic polypeptide; VIP= vasointestinal peptide; NKA= neurokinin A; PYY= peptide YY

Table 1. Syndromes, symptoms and secretory products from GEP NETs

2.1 Granins

The chromogranin family consists of at least three different water soluble acidic glycoproteins (CgA, CgB, and secretogranin II, sometimes called chromogranin C). These proteins are 27 to 100 kDa in size and contain 10% acidic (glutamic or aspartic acid) residues, as well as multiple single and dibasic amino acid residues. All of the granins are found as major components of the soluble core of dense-core secretory granules in NE cells and are secreted from these cells in a physiologically regulated manner. Granins are major constituents of large dense-core secretory vesicles and are co-secreted with peptide hormones and amines. Electron dense or translucent secretory granules are in fact prototypical features of the neuroendocrine cells (1-6).

2.1.1 Chromogranin A (CgA)

Chromogranin A (CgA) has been claimed to be the best general neuroendocrine marker so far available. CgA is a 49 kDa monomeric, hydrophilic, acidic glycoprotein of 460 amino acid and is widely expressed in neuroendocrine cells, where it constitutes one of the most abundant components of secretory granules, and it is secreted from neuroendocrine-derived tumors including functioning and non-functioning GEP NETs, pheochromocytomas, neuroblastomas, medullary thyroid carcinomas and some pituitary tumors. CgA is secreted to the extracellular space, so it's easily detectable in the blood. CgA is co-secreted with the amines and peptides that are present in the neurosecretory granules even if it can be elevated in both functionally active and non-functional NETs. CgA seems to be a "common denominator" peptide in all the components of the diffuse neuroendocrine system (7).

The precise function of CgA remains unknown, but it is thought to be involved in the packaging and processing of neuropeptide precursor and peptide hormones. It may also play a role in the organization of the secretory granule matrix. Moreover CgA has diverse physiological interactions: CgA (or its derivatives) is an inhibitor of catecholamine, insulin, and leptin, having a role in carbohydrate and lipid metabolism; moreover it inhibits parathormone secretion; on the other hand, CgA increases glucagon and amylase release. In addition to its effects on endocrine organs, CgA also regulates reproductive functions and has a role also in the regulation of cardiovascular function: CgA elevations have been reported in essential hypertension (CgA levels correlates with the severity of hypertension) and in chronic heart failure correlating with grade of cardiac dysfunction and mortality. A role of CgA in the regulation of inflammatory response has also been described. In fact increased CgA levels correlate with serum TNF-a receptor levels in a number of inflammatory diseases including rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, chronic obstructive pulmonary disease and chronic heart failure. Patients with sepsis show the highest increase of CgA; CgA positively correlates with inflammatory markers as C-reactive protein and procalcitonin. It remains to be elucidated the pathophysiological relevance of these correlations. Some authors suggest that CgA participates in a negative feedback that limits the activation of endothelial cells (1).

Circulating CgA concentrations are sensitive even if non specific markers of NETs. CgA has been reported to be more sensitive than urinary 5-hydroxyindoleacetic acid (5-HIAA) as well as than pancreatic polypeptide concentrations. The highest values were noted in ileal NETs (200 times the upper normal limit) and IN GEP-NETs associated with MEN1 (150 times the upper normal limit) while gastric type I, pituitary, and parathyroid tumors had lower values (ranging from 2 to 4 times normal). Both functioning and nonfunctioning pancreatic NETs had intermediate values (60-80 times the upper limit of normal) as did Zollinger- Ellison Syndrome (ZES), multiple endocrine neoplasia (MEN)-1, type II and III gastric entero-chromaffin-like (ECL)omas (80-100 times normal). It has also been proposed that CgA is more frequently elevated in well-differentiated tumors compared to poorly differentiated tumors of the midgut, suggesting that the loss of CgA expression in poorly differentiated neuroendocrine carcinomas indicates their incomplete or partial endocrine differentiation. In fact, poorly differentiated NE carcinomas rarely express CgA because of the rarity of large, dense-core granules. The presence of high plasma levels of CgA at diagnosis is an independent prognostic factor that indicates a reduced overall survival.

Effective treatment is often associated with decrease in CgA values. CgA correlates with tumor burden and recurrence. Measurement of CgA may help in the effective diagnosis of NET and has a major utility in predicting disease recurrence, outcome, and efficacy of therapy, so delineating the prognosis (5).

Elevated CgA can occur in normal individuals and in patients with non-NET tumors, although the levels are usually lower than in patients with NET. Less than 1% of CgA tests that are more than 20 times greater than the reference range are false positive. Levels of CgA secretion vary on a day-to-day basis in healthy subjects as well as in individuals with NETs. The mean day-to-day variation of CgA is approximately 25%. Food intake may increase CgA levels, therefore, CgA should be measured in fasting patients to ensure standardization of the results. There are conflicting results on the impact of exercise on CgA. Significant increases in CgA concentration have been reported in healthy subjects, but in patients with heart disease, long-term exercise had no impact on CgA. Finally extreme physical stress also causes CgA elevations. High-serum levels of CgA have also been demonstrated in patients with other malignancies including colon, lung, breast, liver and prostate cancer. Overall CgA has been found to be clinically informative and moderately sensitive in the majority of the studies, and more sensitive than NSE. In prostate cancer elevated CgA seems to indicate a poor prognosis; in small-cell lung carcinoma CgA levels were more frequently elevated and were also higher in cases of more extensive disease; NE differentiation occurs in 34% of primary colorectal cancer (1).

False-positive elevation of CgA may also occur in the following non-neoplastic circumstances: impaired renal function, Parkinson disease, untreated hypertension and pregnancy, steroid treatment or glucocorticoid excess, chronic atrophic gastritis (type A), treatment with proton pump inhibitors (PPI), inflammatory bowel disease, liver disease, hyperthyroidism. In renal failure CgA increases due to a decreased plasma clearance, reaching levels found in neuroendocrine neoplasia. In autoimmune chronic atrophic gastritis, elevated circulating CgA levels are caused by chronic hypergastrinemia and stimulation of ECL cell proliferation. Raised circulating CgA levels in addition to raised gastrin in atrophic gastritis, confounds the diagnosis of gastrinoma in many patients who present with dyspeptic symptoms. But the major cause of elevated CgA levels is the widespread use of PPIs and other acid suppressive medications. All PPI users, even with low dosage (10 mg/d) have elevated fasting CgA levels. The normalization of CgA levels occurs by withdrawal of PPI in 1-2 weeks (1, 10).

There is no universal standard calibration for serum or plasma chromogranin A assays. In addition, different chromogranin A assays, which use different antibodies or antibody combinations, will display different cross-reactivity with the various chromogranin A fragments. Therefore, reference intervals and individual patient results differ significantly between different chromogranin A assays and cannot be directly compared. Several commercially available radioimmunoassays (RIAs) and enzyme-linked immunosorbent assays (ELISAs) have been developed for the measurement of circulating CgA concentrations. Moreover many diagnostic laboratories use in-house assays. The three main different commercial kits are CgA-RIA CT (CIS Bio International, Gif-sur-Yvette Cedex, France), Dako CgA ELISA kit (Dako A/S, Glostrup, Denmark), and CgA EuroDiagnostica (ED) (Malmo", Sweden). All three assays use different standards. In the CIS kit, CgA concentration is expressed in ng/ml and normal range is < 99|g/l, while with the

Dako assay results are expressed in U/l, and normal range is within 19 U/l; with the ED kit CgA levels are expressed in nmol/l and normal range is < 41 nmol/l. Concerning plasma and serum measurement, a strong positive linear relationship has been reported between plasma and serum CgA values, indicating that CgA measurement can be undertaken in both sample types. In conclusion, because CgA concentrations are of considerable clinical relevance, substantial characterization and standardization to ensure uniform reporting are needed (1, 7, 8).

2.1.2 Other granin family peptides

The granin family comprises eight members including CgA and its derivated peptides, CgB, CgC (secretogranin II [SgII]), Sglll, SglV, SgV, SgVI and VGF, but their value as circulating markers for endocrine tumors has not been investigated extensively extensively (1).

Several other CgA-derived peptides, resulting by posttranslational processing have been isolated from extracts of human endocrine tumors. These molecules results in a series of smaller biologically active peptides, such as pancreastatin (corresponding to CgA residues 250-301), catestatin (corresponding to CgA residues 352-372), and vasostatin I and II (corresponding to CgA residues 1-76 and 1-113, respectively). These CgA derived peptides affect secretion of other hormones, play a role in vasoconstriction, and regulate metabolism. Among them, the most clinically interesting is pancreastatin. An endoprotease, the prohormone convertase-1 (PC-1), is involved in the processing of the precursor protein chromogranin A (CGA) to a smaller peptide called pancreastatin (PST), a 49-aminoacid peptide that inhibits insulin secretion, somatostatin release, exocrine pancreatic secretion and gastric acid secretion. PST is found in human stomach- and colon extracts and in a liver metastasis of gastrinoma. Pancreastatin was used before the complete sequence of CgA had been elucidated and before there were any reliable assays that could measure the whole molecule of CgA, as an epitope for antibody production. Pancreastatin antisera were used in immunohistochemistry and RIA to assess the presence of CgA in cells and the concentration of CgA in the circulation. But pancreastatin levels do not equale to CgA concentrations in the circulation. The molecule was found to be significantly increased in patients with NETs metastasized to the liver and concentrations are proportional to the number of hepatic metastases. Monitoring of liver metastases may remain the main advantage of pancreastatin assay (2). It is interesting that pancreastatin is not increased in patients with gastric achlorhydria or hypochlorhydria. Thus, false-positives are less problematic with the pancreastatin assay. It may be a very early biomarker for liver tumor activity, even when CgA is normal (5).

CgB is the second most abundant member of the chromogranin family. Like CgA, it is a strongly acid protein containing approximately 25% acidic amino acid residues. It has 14 dibasic cleavage points but has been less well studied than CgA. Unlike CgA, CgB does not seem to have increased concentrations in patients with renal failure, in patients with atrophic gastritis, or those receiving acid-suppressing therapy. The interest to measure CgB in addition to CgA in patients with GEP NETs is therefore increased. Moreover, in tumors where CgA is not found, CgB may be increased. Such patients include those with MEN 1 and those with tumors in the duodenum or rectum. In addition, CgB is a major granin of the human adrenal medulla and may be a more sensitive marker of pheochromocytomas (2, 5).

Darby And Walsh Human Needs Model
Fig. 1. The granin family and fragments of CgA. The 8 granin proteins include chromogranin A, CgB, CgC (Sgll), Sglll, SglV, 7B2 (SgV), neuroendocrine secretory protein 55 (NESP55 or SgVI), and VGF nerve growth factor-inducible (VGF).

2.2 Pancreatic polypeptide (PP)

Circulating PP is a single chain, 36-aminoacid peptide arising from the PP cells of the pancreas and is expressed in neuroendocrine cells of the gut and the pancreas. The function of PP is to self regulate pancreatic secretion activities (endocrine and exocrine), it also has effects on hepatic glycogen levels and gastrointestinal secretions.

Elevated PP concentration are found in patients with NETs, both pancreatic (20-50%) and gastrointestinal carcinoids (30-50%). Before methods for the measurements of CgA were available, PP was used as a general marker for endocrine tumors, although it is poorly specific. PP is now useful in the diagnosis and monitoring of NETs where no other general marker is raised and in PP-omas. High levels of circulating PP can also be found in diabetes, renal impairment, chronic inflammation, alcoholism and in elder patients. Its secretion is increased after a protein meal, fasting, exercise, and acute hypoglycemia and is decreased by somatostatin and intravenous glucose (2, 11).

2.3 Neuron Specific Enolase (NSE)

NSE is the neuron-specific isomer of the glycolytic enzyme 2-phospho-D-glycerate hydroxylase or enolase. This isomer is present in neurons and neuroendocrine cells and can be used as a biomarker for tumors derived from these cells. As well as CgA, NSE is a marker useful for the diagnosis and the monitoring of patients with neuroendocrine tumors (especially neuroblastoma, small cell lung cancer, less important for GEP NETs); it has other several applications, including the assessment of neuronal damage during stroke. Elevated NSE levels are indicative of poorly differentiated tumors. NSE levels seems not to be related to any secretory activity of the tumor (11, 12).

3. Specific biomarkers

In addition to general markers, there are biomarkers specific for particular GEP-NET associated syndromes. The most typical is carcinoid syndrome and the specific marker is 5-Hydroxyindole Acetic Acid. Other specific markers including insulin, gastrin, vasoactive intestinal peptide, glucagon, bradykinin, substance P, neurotensin, human chorionic gonadotropin, neuropeptide K, and neuropeptide L are each of some value in precisely defining the functionality of individual NETs (see above Table 1).

3.1 5-Hydroxyindole acetic acid (5-HIAA)

5-HIAA is the urinary breakdown of serotonin, which is synthesized and stored in enterochromaffin cells of the gastrointestinal tract (80% of total body serotonin content), in dense granules of platelets and in the serotoninergic neurons of the central nervous system. Serotonin is a ubiquitous tryptophan-derived biogenic amine, involved in homeostasis, vasoconstriction and neurotransmission (7).

Carcinoid syndrome is the typical clinical picture of metastatic ileal carcinoid, occurring in about 18% of patients and is characterized by flushing, diarrhea, abdominal pain; less frequent events are lacrymation, profuse sweating, telangiectasias, cardiac fibrosis, and cutaneous manifestations pellagra-like due to lack of niacin. This syndrome is caused by the massive release of serotonin, which is no longer metabolized in the liver, and other substances, such as tachykinins, prostaglandins, and bradykinins (3) (Table 2).

Clinical features

(%)

Characteristics

Mediators

Flushing

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