Zollinger-Ellison Syndrome

Sample for Zollinger-Ellison Syndrome

1. Gastrin is unstable in the serum, even on refrigeration.
2. A fasting sample is preferred.
3. Separate the serum immediately and freeze it.
4. It can be stored at – 70 °C for a longer period of time.

History of Zollinger-Ellison Syndrome

1. Zollinger and Ellison first noticed pancreatic islet cell lesions with hypersecretion of gastric acid.
2. They noticed severe peptic ulceration.
3. Ulcers are present in 90% to 95% of patients.
4. The ratio of duodenal to gastric ulcer is 6:1.

Definition of Zollinger-Ellison syndrome

1. Zollinger-Ellison syndrome is due to gastrin-secreting tumors called Gastrinomas, which may be duodenal or pancreatic endocrine tumors.
2. Zollinger-Ellison syndrome:
   1. Gastrin-producing islet cell tumors cause gastric-acid hypersecretion with the formation of peptic ulcers and diarrhea.
   2. Gastrin level is >600 pg/mL suggesting Gastrinoma.
3. Non-beta cells of the pancreatic tumor produce a large amount of gastrin, and patients suffer from ulcers.
   1. Gastrin level is highly increased.
   2. Gastrin leads to increased production of acid, and there is a high level of HCL which leads to multiple ulcers in the stomach and small bowel.
4. Gastrinoma may arise in the pancreas, peripancreatic region, or wall of the duodenum.

Pathophysiology of Zollinger-Ellison Syndrome

1. Gastrin is a potent hormone for the secretion of gastrin from gastric G cells, Proximal duodenal G cells, and pancreatic delta cells.
   1. This is under the control of vagal stimulation.
2. Gastrin has three molecular forms:
   1. Big gastrin consists of 34 amino acids, G ^-34.
   2. Little gastrin consists of 17 amino acids, G -17.
   3. Minigastrin consists of 14 amino acids, G -14.
3. Pentagastrin is a synthetic derivative used for gastric function testing to see the production of HCL.
4. Differential diagnosis of Gastrinoma can be made by giving stimulating agents like:
   1. Secretin infusion.
   2. Calcium infusion.
   3. Standard meal.

Gastrin production:

1. Endocrine cells (G cells) of the antral mucosa of the stomach.
2. The lesser amount of the G cells of proximal duodenum.
3. A small amount from delta cells in the pancreas.

4. Gastrin, after absorption into the blood, goes to the liver and stimulates the parietal cell of the stomach to produce  HCL.
   1. Gastrin is a very strong gastric acid secretion stimulant.
   2. It is more potent than histamine.
   3. Gastrin’s main role is to increase the secretion of HCL.

Inhibitory factors for gastrin secretion are:

1. High gastric acidity.
2. The gastric inhibitory polypeptide is produced by the K cells of the intestinal mucosa (middle and distal duodenum and proximal jejunum in response to foods like fats, glucose, and amino acids.
3.  The vasoactive intestinal polypeptide is produced by the H cells of the intestinal mucosa.                                                
4. Gastrin is a weaker stimulant of pepsinogen + intrinsic factor.

Gastrin is secreted in response to:

1. Antral distension.
2. Meals.
3. Partially digested food (Proteins).
4. Free amino acids also stimulate gastrin.
5. Carbohydrates and Fats have little effect on gastrin secretion.
6. Other gastrin-release stimulants are:
   1. Alcohol.
   2. Caffeine.
   3. Insulin-induced hypoglycemia.
   4. Calcium ingestion or I/V infusion.

5. Vagal stimulation by:
   1. Smell.
   2. Tasting.
   3. Swallowing.
   4. Chewing.
6. Increased fasting gastrin level is associated with increasing age over 60 years.
7. Secretion of gastrin depends upon the pH of gastric acid (HCl):
   1. pH  5 to 7: Gastrin secretion is maximum.
   2. pH  2.5: Gastrin secretion is reduced by 80%.
   3. pH  1.0:  Maximum suppression of Gastrin production.

Grossly Gastrinoma is:

1. Gastrinomas arise in the pancreas and or the wall of the duodenum.
2. More than 50% of tumors are invasive and have already metastasized.
3. Around 25% of the patient with gastrinoma have multiple tumors as a part of a condition called multiple endocrine neoplasia type 1 (MEN 1).
   1. MEN 1 has tumors in the pituitary gland and parathyroid gland in addition to the tumor of the pancreas.

Clinical Presentation of Zollinger-Ellison Syndrome

1. Zollinger-Ellison syndrome is divided into two types:
   1. Type 1 is called G-cell hyperplasia without the presence of Gastrinoma.
   2. Type II is due to the gastrinoma of the pancreas or duodenum.
2. Patients with Zollinger–Ellison syndrome may experience abdominal pain and chronic diarrhea, including steatorrhea (fatty stools).
   1. Zollinger syndrome is suspected when:
      1. Clinical history.
      2. Radiological evidence of ulceration.
      3. Excessive acid secretion.
3. These patients have severe ulceration of the stomach and small bowel, especially if they fail to respond to treatment.
   1. The ulcers are present in 90 to 95%.
   2. The ratio of duodenal to stomach ulcers is 6:1.
4. Other signs and symptoms are:
   1. Esophageal chest pain.
   2. Pain in the esophagus, especially between and after meals at night.
   3. Nausea.
   4. Wheezing.
   5. Hematemesis (digested blood).
   6. Malnourishment.
   7. Loss of weight due to loss of appetite.
5. There is chronic diarrhea with variable severity and accompanied by hypokalemia.
   1. >50% of the patients have diarrhea, and in 30% are the presenting symptoms.

Normal Gastrin level

Source 1 

• To convert into Si units x 1.0 = ng/L

Source 2

• 0 to 180 pg/mL
• Levels are higher in old people.

Other sources

• Fasting level-up to 100 ng/L.
• Older people over 60 years = 100 to 800 ng/L.
• Adult = 0 to 180 ng/L.
• Child = 0 to 125 ng/L.
• The level fluctuates during the day:
  • Highest during the daytime.
    • Highest after the meal.
  • The lowest level is from 3.00 to 7.00 am.

Diagnosis of Gastrinoma 

1. Raised level of Gastrin (Hypergastrinemia).
2. Fasting gastrin level is markedly raised from 2 to 2000 times normal.
3. A gastrin level of 1000 ng/L is diagnostic.
   1. The fasting gastrin level is raised in >95% of the cases.
   2. Mostly it is >1000 pg/mL (1000 ng/L), and these values are diagnostic of gastrinoma.

Gastrin level in gastrinoma

Diagnosis of Zollinger-Ellison syndrome:

Management of Zollinger-Ellison Syndrome

1. Surgical removal of the tumor.
2. Medical management: Proton pump inhibitors to reduce acid secretion.
3. Totally resected tumors have a good prognosis, and the syndrome may disappear.
4. Patients with liver metastasis have a poor prognosis.

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