Gastrinomas are
neuroendocrine tumor
Neuroendocrine tumors (NETs) are neoplasms that arise from cells of the endocrine (hormonal) and nervous systems. They most commonly occur in the intestine, where they are often called carcinoid tumors, but they are also found in the pancreas, lun ...
s (NETs), usually located in the duodenum or pancreas, that secrete
gastrin
Gastrin is a peptide hormone that stimulates secretion of gastric acid (HCl) by the parietal cells of the stomach and aids in gastric motility. It is released by G cells in the pyloric antrum of the stomach, duodenum, and the pancreas.
Gastrin ...
and cause a clinical syndrome known as
Zollinger–Ellison syndrome
Zollinger–Ellison syndrome (Z-E syndrome) is a disease in which tumors cause the stomach to produce too much acid, resulting in peptic ulcers. Symptoms include abdominal pain and diarrhea.
The syndrome is caused by a gastrinoma, a neuroendocrin ...
(ZES).
A large number of gastrinomas develop in the pancreas or duodenum, with near-equal frequency, and approximately 10% arise as primary neoplasms in lymph nodes of the pancreaticoduodenal region (
gastrinoma triangle
Passaro's triangle or Gastrinoma triangle is a presumptive region in the abdomen between three points:
# Superior-porta hepatis (earlier-confluence of the cystic and common bile duct),
# Inferior-junction of the second and third portion of duodenu ...
).
Most gastrinomas are sporadic (75–80%), whereas approximately 20–25% are associated with multiple endocrine neoplasia type 1 (MEN-1).
Over 50% of gastrinomas are malignant and can metastasize to regional lymph nodes and liver. One fourth of gastrinomas are related to
multiple endocrine neoplasia type 1
Multiple endocrine neoplasia type 1 (MEN-1) is one of a group of disorders, the multiple endocrine neoplasias, that affect the endocrine system through development of neoplastic lesions in pituitary, parathyroid gland and pancreas.
It was first d ...
, Zollinger–Ellison syndrome,
peptic ulcer disease
Peptic ulcer disease (PUD) is a break in the inner lining of the stomach, the first part of the small intestine, or sometimes the lower esophagus. An ulcer in the stomach is called a gastric ulcer, while one in the first part of the intestines i ...
.
Signs and symptoms
Gastrinoma in the early stages will have signs and symptoms of
indigestion
Indigestion, also known as dyspepsia or upset stomach, is a condition of impaired digestion. Symptoms may include upper abdominal fullness, heartburn, nausea, belching, or upper abdominal pain. People may also experience feeling full earlier t ...
or similar to
irritable bowel disease (IBD) such as:
*
Hypergastrinemia
Gastrin is a peptide hormone that stimulates secretion of gastric acid (HCl) by the parietal cells of the stomach and aids in gastric motility. It is released by G cells in the pyloric antrum of the stomach, duodenum, and the pancreas.
Gastrin ...
* Refractory or recurrent
peptic ulcers
Peptic ulcer disease (PUD) is a break in the inner lining of the stomach, the first part of the small intestine, or sometimes the lower esophagus. An ulcer in the stomach is called a gastric ulcer, while one in the first part of the intestines i ...
involving
duodenum
The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear, and the terms anterior intestine or proximal intestine m ...
* Chronic
diarrhea
Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin wi ...
* Generalized cancer symptoms
*
Abdominal pain
Abdominal pain, also known as a stomach ache, is a symptom
Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than ...
*
Gastrointestinal bleeding
Gastrointestinal bleeding (GI bleed), also called gastrointestinal hemorrhage (GIB), is all forms of bleeding in the gastrointestinal tract, from the mouth to the rectum. When there is significant blood loss over a short time, symptoms may incl ...
* Obstruction of intestine
* Weight loss
/poor appetite
* Anemia (Due to
vitamin B12 malabsorption, and bleeding)
*
Hematemesis
Hematemesis is the vomiting of blood. It is always an important sign. It can be confused with hemoptysis (coughing up blood) or epistaxis (nosebleed), which are more common. The source is generally the upper gastrointestinal tract, typically abo ...
*
Gastroesophageal reflux disease
Gastroesophageal reflux disease (GERD) or gastro-oesophageal reflux disease (GORD) is one of the upper gastrointestinal chronic diseases where stomach content persistently and regularly flows up into the esophagus, resulting in symptoms and/ ...
* Esophageal complications (
Barrett's esophagus
Barrett's esophagus is a condition in which there is an abnormal (metaplastic) change in the mucosal cells lining the lower portion of the esophagus, from stratified squamous epithelium to simple columnar epithelium with interspersed goblet cells ...
,
esophagitis
Esophagitis, also spelled oesophagitis, is a disease characterized by inflammation of the esophagus. The esophagus is a tube composed of a mucosal lining, and longitudinal and circular smooth muscle fibers. It connects the pharynx to the stomach; s ...
, stricture formation)
* Vomiting
*
Steatorrhea
Steatorrhea (or steatorrhoea) is the presence of excess fat in feces. Stools may be bulky and difficult to flush, have a pale and oily appearance, and can be especially foul-smelling. An oily anal leakage or some level of fecal incontinence may oc ...
Pathophysiology
Gastrin is secreted by the
G cell
In anatomy, the G cell or gastrin cell, is a type of cell in the stomach and duodenum that secretes gastrin. It works in conjunction with gastric chief cells and parietal cells. G cells are found deep within the pyloric glands of the stomach antrum ...
s. G cells are primarily found in the pyloric antrum but can also be found in the duodenum and the pancreas. The primary function of gastrin is to induce the release of
hydrochloric acid
Hydrochloric acid, also known as muriatic acid, is an aqueous solution of hydrogen chloride. It is a colorless solution with a distinctive pungent smell. It is classified as a strong acid
Acid strength is the tendency of an acid, symbol ...
(HCl) from the parietal cells located in the fundus of the stomach. Parietal cells are responsible for hydrochloric (HCl) secretion along with
intrinsic factor
Intrinsic factor (IF), cobalamin binding intrinsic factor, also known as gastric intrinsic factor (GIF), is a glycoprotein produced by the parietal cells (in humans) or chief cells (in rodents) of the stomach. It is necessary for the absorption o ...
that binds to
vitamin B12 and helps with its uptake in the
terminal ileum
The ileum () is the final section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms posterior intestine or distal intestine ma ...
. Other functions of gastrin include stimulating the growth of gastric mucosa and gastric motility and promoting gastric emptying. These mechanisms of the gastrointestinal tract (GIT) are up-regulated by the
vagus nerve
The vagus nerve, also known as the tenth cranial nerve, cranial nerve X, or simply CN X, is a cranial nerve that interfaces with the parasympathetic control of the heart, lungs, and digestive tract. It comprises two nerves—the left and right ...
of the
parasympathetic nervous system
The parasympathetic nervous system (PSNS) is one of the three divisions of the autonomic nervous system, the others being the sympathetic nervous system and the enteric nervous system. The enteric nervous system is sometimes considered part of ...
(PNS), which carries out the majority of its functions by the release of neurotransmitter
Acetylcholine (Ach), and to a lesser extent gastrin releasing peptide (GRP) protein. On the contrary, the functions of GIT are down-regulated by the activation sympathetic nervous system (SNS), which carries out its functions mostly via neurotransmitter
epinephrine
Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands and ...
.
Meal consumption causes distention of the stomach, leading to stimulation of the parasympathetic
vagus nerve
The vagus nerve, also known as the tenth cranial nerve, cranial nerve X, or simply CN X, is a cranial nerve that interfaces with the parasympathetic control of the heart, lungs, and digestive tract. It comprises two nerves—the left and right ...
in the gastric mucosa, which causes the release of GRP protein. In gastrinoma, GRP protein causes larger than normal amounts of gastrin secretion, which leads to hyperplasia of the
parietal cell
Parietal cells (also known as oxyntic cells) are epithelial cells in the stomach that secrete hydrochloric acid (HCl) and intrinsic factor. These cells are located in the gastric glands found in the lining of the fundus and body regions of the ...
s. Hyperplasia of parietal cells causes an abnormal release of HCl into the duodenum, which causes the
ulcer
An ulcer is a discontinuity or break in a bodily membrane that impedes normal function of the affected organ. According to Robbins's pathology, "ulcer is the breach of the continuity of skin, epithelium or mucous membrane caused by sloughing o ...
s of the duodenum. Excessive HCl production also causes hyperperistalsis, a condition marked by excessive rapidity of the passage of food through the stomach and intestine and inhibits the activity of
lipase
Lipase ( ) is a family of enzymes that catalyzes the hydrolysis of fats. Some lipases display broad substrate scope including esters of cholesterol, phospholipids, and of lipid-soluble vitamins and sphingomyelinases; however, these are usually tr ...
, causing severe fatty diarrhea known as steatorrhea. Evenly the long-standing hyper-secretion of gastrin stimulate proliferation of the
enterochromaffin
Enterochromaffin (EC) cells (also known as Kulchitsky cells) are a type of enteroendocrine cell, and neuroendocrine cell. They reside alongside the epithelium lining the lumen of the digestive tract and play a crucial role in gastrointestinal reg ...
like cells (ECL). These cells are found along the side the gastric lumen of the digestive tract.
They play a main role in regulation of gastric secretion and motility when stimulated by nervous system. These cells in return will undergo progressive dysplastic changes starting with hyperplasia to neoplasia throughout the gastrointestinal tract.
Diagnosis
In many cases, gastrinoma is diagnosed based on the patient's history which is typically characterized by recurrent episodes of peptic ulcer disease or by severe reflux esophagitis and/or diarrhea or by acid-related symptoms which fail to respond to standard treatment regimens. To confirm the diagnosis of gastrinoma a series of blood tests must be made. One of those tests is the serum gastrin level, which is the most reliable test for patients with gastrinoma. The normal levels of gastrin are 150 pg/mL ( > 72.15 pmol/L); therefore elevated levels of > 1000 pg/mL (> 480 pmol/L) would establish the diagnosis of gastrinoma.
Another test that can be conducted is the
secretin
Secretin is a hormone that regulates water homeostasis throughout the body and influences the environment of the duodenum by regulating secretions in the stomach, pancreas, and liver. It is a peptide hormone produced in the S cells of the duode ...
stimulated test,
which is useful in patients who have the sign and symptoms of gastrinoma but the gastrin levels are below < 1000 pg/mL. Usually, an Intravenous bolus consisting of secretin 2mcg/kg and is measured in 10 minute intervals up to 30 minutes total. Secretin, which is a hormone released from the duodenal S cells that induce the release of pancreatic
bicarbonate
In inorganic chemistry, bicarbonate (IUPAC-recommended nomenclature: hydrogencarbonate) is an intermediate form in the deprotonation of carbonic acid. It is a polyatomic anion with the chemical formula .
Bicarbonate serves a crucial biochemic ...
(HCO
3) that would neutralize the acidic environment due to high gastrin levels. Therefore, if the patient's level of gastrin remains consistently high indicating gastrin release due to tumor such as gastrinoma.
Other commonly used tests to further confirm the diagnosis are
*
CT scan of the abdominal area
* Somatostatin receptor scintigraphy which is used to identify the location of the tumor
*
PET scan
Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, r ...
* Endoscopic ultrasound if there are no signs of tumor metastases.
Treatment
Surgery is first line treatment in gastrinomas; however it often fails to be curative.
*
Proton-pump inhibitor
Proton-pump inhibitors (PPIs) are a class of medications that cause a profound and prolonged reduction of stomach acid production. They do so by irreversibly inhibiting the stomach's H+/K+ ATPase proton pump.
They are the most potent inhibitors ...
s such as
omeprazole
Omeprazole, sold under the brand names Prilosec and Losec, among others, is a medication used in the treatment of gastroesophageal reflux disease (GERD), peptic ulcer disease, and Zollinger–Ellison syndrome. It is also used to prevent upper g ...
. This group of medications suppress the acid secretion.
*
H2-receptor antagonist similarly decrease acid secretion.
*
Octreotide
Octreotide, sold under the brand name Sandostatin among others, is an octapeptide that mimics natural somatostatin pharmacologically, though it is a more potent inhibitor of growth hormone, glucagon, and insulin than the natural hormone. It was ...
injections directly release somatostatin hormone that inhibits gastrin release.
*
Chemotherapy
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...
.
Prognosis
Patients with gastrinomas that are also known to be part of neuroendocrine neoplasms must have to deal with two factors related to this tumor. First, controlling the high amounts by using medications that inhibit gastrin levels. The second part is stabilizing the tumor progression. Gastrinomas have a rate of 60–90% that will become malignant.
Patients who do not seek medical treatment such anti-ulcer medication have high rate of recurrence and death secondary to ulcer disease. The prognosis of gastrinoma depends on the level of metastases of the tumor. If patients present with hepatic metastases they might have remaining life span of one year with a five-year survival rate of 20–30%. In patients with localized tumor or localized lymph spread the survival rate of five years is 90%. Lastly, surgical resection of local tumor could lead to complete cure without recurrence in 20–25% of patients.
Epidemiology
Gastrinoma is the second most common functional pancreatic neuroendocrine tumor (pNET), with a yearly incidence of approximately 0.5 to 21.5 cases per a million of people worldwide.
Gastrinomas are located predominantly in the duodenum (70%) and pancreas (25%).
Pancreatic gastrinomas are larger than their duodenal counterparts, may occur in any portion of the pancreas, and comprise 25% of these tumors. Gastrinomas are also the most common functional and malignant pancreatic endocrine tumors. They are characterized by gastric hypersecretion that results in peptic ulcers and diarrhea; this condition is known as
Zollinger–Ellison syndrome
Zollinger–Ellison syndrome (Z-E syndrome) is a disease in which tumors cause the stomach to produce too much acid, resulting in peptic ulcers. Symptoms include abdominal pain and diarrhea.
The syndrome is caused by a gastrinoma, a neuroendocrin ...
(ZES).
Research
Recently, research studies have been conducted to seek new medical advances in relation to gastrinoma and Zollinger–Ellison syndrome. The recent studies have shown improved understanding of pathogenesis of pancreatic neuroendocrine tumors, classifications of those tumors, new treatments/preventions to control the gastrin levels in the gastrointestinal tract, and the best and safest surgical approaches. The study concluded that the wide use of proton pump inhibitors itself might further induce
hypergastrinemia
Gastrin is a peptide hormone that stimulates secretion of gastric acid (HCl) by the parietal cells of the stomach and aids in gastric motility. It is released by G cells in the pyloric antrum of the stomach, duodenum, and the pancreas.
Gastrin ...
(increased gastrin levels in circulatory system) by feedback inhibition. The body will try to induce further release when gastrin level is depleted. Some of the new treatments might include medication that is directed towards the liver such as embolization,
chemoembolization
Transcatheter arterial chemoembolization (TACE) is a minimally invasive procedure performed in interventional radiology to restrict a tumor's blood supply. Small embolic particles coated with chemotherapeutic drugs are injected selectively through ...
, and
radioembolization
Selective internal radiation therapy (SIRT), also known as transarterial radioembolization (TARE), radioembolization or intra-arterial microbrachytherapy is a form of radiation therapy used in interventional radiology to treat cancer. It is general ...
in addition to the currently offered treatments such as chemotherapy, somatostatin analogs. Other treatments that are still in phase three of clinical trials include liver transplantation and peptide-radioreceptor therapy.
See also
*
Pancreatic endocrine tumor
Neuroendocrine tumors (NETs) are neoplasms that arise from cells of the endocrine (hormonal) and nervous systems. They most commonly occur in the intestine, where they are often called carcinoid tumors, but they are also found in the pancreas, lung ...
References
External links
Emedicine
{{Endocrine gland neoplasia
Endocrine neoplasia