Zollinger-Ellison syndrome

Generality

Zollinger-Ellison syndrome is a rare disease characterized by the presence of gastrinomas in the pancreas or duodenum.

Figure: Illustration of a pancreas and a duodenum during Zollinger-Ellison syndrome. From the pharmacy-and-drugs.com website

Gastrinomas are tumors, almost always malignant, that secrete important amounts of gastrin. The presence in the blood of high levels of the gastrin hormone strongly stimulates the acid secretion of the stomach, giving rise to continuous peptic ulcers, severe abdominal pain, diarrhea, etc.

Diagnosis requires numerous tests, as different diseases can determine the same symptoms as Zollinger-Ellison syndrome.

The best therapeutic solution is represented by surgery; however, this is feasible only under certain conditions. Possible alternatives are different, but almost always limited to improving symptoms.

What is Zollinger-Ellison syndrome?

For Zollinger-Ellison syndrome we mean the set of signs and symptoms related to the presence of multiple peptic ulcers, due to gastric hyperacidity resulting from gastrin secretion by one or more pancreatic and / or duodenal tumors, called gastrinomas .

Zollinger-Ellison syndrome is otherwise known as ZES, an acronym for the English Zollinger-Ellison Syndrome .

Pancreas and duodenum

The pancreas is an exocrine and endocrine gland which, among its various functions, also produces enzymes necessary for digestion.

The duodenum, on the other hand, is the first tract of the small intestine (or small intestine ) and represents a fundamental collection point for digestive enzymes, which must intervene on the ingested food.

WHAT IS A GASTRINOMA AND FROM WHERE IT ORIGINES?

Gastrinoma is an almost always malignant neoplasm, which originates from the so-called gastrin- secreting G cells, located in some areas of the stomach, duodenum and pancreas.

Gastrin is a peptide hormone which, once secreted, promotes the production of essential substances for the digestive process, such as hydrochloric acid and digestive enzymes.

EFFECTS OF GASTRINOMES

Gastrinomas induce gastrin hypersecretion → large amounts of this hormone make the stomach environment strongly acid → significant gastric acidity causes peptic ulcers (erosions of the mucous membrane of the stomach and / or duodenum).

Peptic ulcers associated with Zollinger-Ellison syndrome primarily affect the duodenum and jejunum, which represent respectively the initial and intermediate tract of the small intestine.

Other effects of gastrinomas:

• Increased levels of ACTH ( adrenocorticotropic hormone )
• Increase in VIP levels ( vasoactive intestinal peptide )
• Increased glucagon levels

WHERE CAN GASTRINOMAS BE FORMED?

Gastrinomas arising during Zollinger-Ellison syndrome are located mainly in the duodenum (60-65%) and pancreas (30%). However, they could also form in the lymph nodes adjacent to the above mentioned sites, in the stomach, in the liver, in the bile ducts, in the ovaries, in the heart and in the lungs.

Figure: endoscopic image of a peptic ulcer caused by an excess of gastrin. From the site en.wikipedia.org

If gastric localization is explained by the presence of gastrin-secreting G cells in the stomach, the reasons leading to the development of gastrinomas in other minor sites remain unknown.

Epidemiology

The SEZ is very rare: its annual incidence, in fact, is equal to 0.5-2 cases per million people.

It mainly affects individuals between the ages of 30 and 50 and prefers the male sex.

Causes

Like all malignant tumors, gastrinomas are also the result of genetic DNA mutations. Specifically, the causes of these mutations are still unknown.

ASSOCIATION WITH MEN1

About 25% of patients affected by Zollinger-Ellison syndrome suffer from another disease, called type 1 multiple endocrine neoplasia ( MEN1 ). The latter causes the appearance of tumors, called neuroendocrine tumors, at the level of the pituitary and parathyroid endocrine glands.

Symptoms and Complications

To learn more: Symptoms Zollinger-Ellison syndrome

The characteristic symptoms of Zollinger-Ellison syndrome are abdominal pain and diarrhea .

With them, they can also appear very often:

• Nausea and blood vomiting (or hematemesis )
• Acid reflux and persistent heartburn
• Sense of pain and malaise in the highest part of the stomach
• Sense of weakness
• Weight loss due to a loss of appetite
• Malnutrition
• Anemia

WHEN TO REFER TO THE DOCTOR?

It is a good idea to consult your doctor if you have persistent abdominal or overdose pain, accompanied by recurrent episodes of diarrhea, vomiting and nausea.

It is important not to neglect these disorders, since a disease such as Zollinger-Ellison syndrome, if diagnosed late, is hardly treatable with success.

COMPLICATIONS

The repetition of peptic ulcers, due to the continuous presence of acid secretions in the stomach, can cause gastrointestinal bleeding and perforation .

Furthermore, since gastrinomas are malignant tumors, there is a risk that they may disseminate metastases, especially in the liver.

NB: metastases are cancer cells that have moved from their original location and moved elsewhere, contaminating the lymph nodes and / or other organs of the body.

Diagnosis

To be diagnosed, Zollinger-Ellison syndrome requires an elaborate examination and procedure process:

• Physical examination, during which the doctor evaluates the symptomatology complained by the patient and any clinical signs.
• Analysis of the patient's clinical and family history . Knowing whether the suffering individual has, or has had, close relatives (parents or siblings) affected by MEN1 may be important information, given the not uncommon association between the two diseases.
• Blood tests . They are used to measure gastrin levels in the blood (gastrinemia). If gastrin is elevated it could be Zollinger-Ellison syndrome, but also other morbid conditions, such as gastric atrophy, kidney failure, pheochromocytoma or pernicious anemia. This is why it is necessary to thoroughly investigate the reasons for a high gastrinemia.
• Secretin stimulation test . The intravenous injection of secretin (a peptide hormone also secreted by the body to reduce the too high acidity of the stomach) causes, in individuals with ZES, a very particular reaction, which consists substantially in a sudden increase (NB: no more of 30 minutes) of gastrin blood levels.
• Upper gastrointestinal endoscopy . It consists in introducing, in the patient's digestive system, an instrument equipped with light and a camera, capable of showing the internal aspect of the stomach and duodenum. Thin and flexible, this instrument, which is called an endoscope, also offers the possibility of taking a sample of cells for a biopsy.

  During the examination, the patient is conscious but sedated.

• CT (computerized axial tomography), NMR (nuclear magnetic resonance), ultrasound and scintigraphy for somatostatin receptors (SRS). They are used to identify the exact location of gastrinomas and their appearance (single, multiple etc).
• Endoscopic ultrasound . It consists in inserting, in the digestive tract, an ultrasound probe, in order to examine the stomach and the duodenum and, possibly, also take a tissue sample for a bioptic examination.
• Chromogranin A measurement. Chromogranin A is a marker of neuroendocrine tumors, such as those caused by MEN1.

Blood gastrin levels (unit of measurement is the picogram / milliliter, or pg / mL)

• Normal person: no more than 200 pg / mL
• Person with ZES: at least 1, 000 pg / mL

Treatment

In the case of Zollinger-Ellison syndrome, surgical removal of gastrinomas is the best therapeutic solution. However, the conditions do not always exist to be able to put this kind of intervention into practice.

The alternative solution is to treat the disease as a peptic ulcer, then administering proton pump inhibitors ( IPPs ) and H2-antagonists ( anti-H2 ) to the patient. The administration of these drugs acts only on the symptoms, alleviating them, but it does not regress the tumors and does not protect the patient from the possible dissemination of metastases.

Liver metastases can be removed with a surgical operation only if the malignant cells, which have reached the liver, are concentrated in a circumscribed area and are not found in depth.

HOW AND WHEN TO OPERATE?

Gastrinomas are surgically removable, through a laparoscopic or laparotomy operation, provided they are single and well localized. If, on the other hand, gastrinomas are multiple and scattered in multiple sites, or if they are associated with MEN1, surgery is an impractical solution.

Alternatively, but only in certain situations, you can try to solve the problem with one of the following treatments:

• Surgical removal limited to the largest gastrinoma .
• Embolization . The doctor interrupts the blood supply to the area where the tumors reside, thus causing the death of cancer cells.
• Destruction of tumor cells by radiofrequency ablation .
• Chemotherapy and / or radiotherapy .

IPP AND ANTI-H2 BASED THERAPY

Proton pump inhibitors (IPPs) and H2-antagonists (anti-H2) reduce acid production in the stomach, alleviating symptoms caused by massive gastrin production.

These drugs are effective, but only if taken in large doses and for prolonged periods.

Long-term treatment with IPP and anti-H2 may cause serious side effects in people over the age of 50 such as: hip, wrist and / or vertebrae fractures.

IN THE CASE OF METASTASIS IN THE LIVER

If the liver metastases were concentrated only in a single area of ​​the liver and isolated from the rest of the organ, it is possible to remove them surgically.

In the absence of such conditions, the only feasible remedy is liver transplantation, a delicate operation and not without possible complications.

OTHER TREATMENTS

If peptic ulcers perforate the stomach, a specific intervention is planned.

If they cause serious blood loss, an immediate blood transfusion is needed to remedy anemia.

Prognosis

If the diagnosis is timely, there is a greater chance of intervening with a surgical operation (as the tumor may still appear in single form) and cure the patient definitively.

In cases where the gastrinoma is not removed in time, is located in a location that is difficult to access, or is associated with MEN1, surgical intervention becomes a very remote hypothesis, so the patient is forced to live with the symptoms typical of Zollinger-Ellison syndrome (peptic ulcers, diarrhea, etc.).