Zollinger Ellison syndrome is not a very common disorder, characterised with the presence of one or more than one tumors called gastrinomas present in either pancreas or duodenum or in both. The gastrinomas release a hormone called gastrin which causes the parietal cells of the stomach to produce much more acid causing peptic ulcers in the duodenum. Other than the commonly present areas such as pancreas, duodenum or abdominal lymph nodes the gastrinomas can also present at other distant sites. Some gastrinomas behave like cancerous tumors and starts spreading to remaining areas of the body.
Normally in Zollinger Ellison syndrome there is a combination of gastric acid hyper secretion, peptic ulceration and tumor of the non beta cells of islets of pancreas. Usually the parietal cells in the stomach release correct amount of gastrin, the released gastrin now goes along the blood stream to stimulate other cells in the stomach to produce gastric acid that aids break down of food. But these gastrinomas (tumors) release huge amounts of gastrin than normal, subsequently causing sores in the duodenum called peptic ulcers.
The causes of Zollinger Ellison syndrome may be Sporadic or MEN1(multiple endocrine neoplasia type 1). But scientists are not quite sure about the causes of most of the gastrinomas that appear sporadic. MEN1 is the root cause in 25% of gastrinoma cases.
CAUSES
The causes of Zollinger Ellison syndrome are the gastrinomas (tumors) of the pancreas. This tumor causes the parietal cells of the stomach to perform to its maximum activity, which results in ulceration of the stomach. Causes of Zollinger Ellison syndrome may be sporadic or MEN1.
PATHOPHYSIOLOGY
Excess amount of gastrin that released causes parietal cells of the stomach to produce more H+ions into the lumen of the stomach. On the other hand for parietal cells gastrin mimics as trophic factor, resulting in parietal cell hyperplasia. Hence there is an increase in number of acid secreting cells, with higher acid output rate. Thus the raise in acidity leads to the formation of peptic ulcers.
Gastrin on its own also stimulates acid secretion, which results in raised basal acid secretion. The huge amount of acid produced contributes to diarrhoea malabsorption and mucosal ulceration. However malabsorption in Zollinger Ellison syndrome may be resulted from several other factors, it may be due to bile salts precipitation or inactivation of pancreatic enzymes or damage of mucosal lining directly by acid. Zollinger Ellison syndrome is Sporadic in 75%of cases,and in remaining 25% of cases it is linked with MEN1.
PRESENTATION
Epigastric pain and diarrhoea are seen in patients suffering from Zollinger Ellison syndrome.
Presence of gastrointestinal bleeding makes the patient look pale.
Presence of epigastric tenderness is very common.
In 75% of Sporadic cases specially in men epigastric pain due to peptic ulceration can occur.
In 73% of MEN1 cases specially in women diarrhoea is the major feature that can occur.
In 55% we can see both of them
In 17% of cases vomiting, nausea and weight loss can be evident.
44% can suffer from the gastro oesophageal reflux pain.
In 25% of cases gastro intestinal bleeding is the major presenting symptom.
Perforation and bleeding complications are seen in most of the children with the disease.
SYMPTOMS
Abdominal pain
Loss of weight
Nausea
Black feaces
Diarrhoea
Vomiting
DIAGNOSIS
Clinical precipitation of Zollinger Ellison syndrome arises when the symptoms listed above remains resistant after treatment.
Patients suffering from severe ulceration of stomach, without symptoms, can also be diagnosed.
Initially it is, most probably, considered as peptic ulcer.
Diagnosis can also be performed when there is a combination of peptic ulcer with diarrhoea.
Duodenal ulcers and gastric ulcers are caused by H.pylori infection in almost all cases. In Zollinger Ellison syndrome H.pylori infection is not associated because high acid levels itself can cause ulceration. However it is evident that high levels of acid itself can kill the organisms. So there is absolutely no chance of H.pylori growth in Zollinger Ellison syndrome.
The typical feature to diagnose a Zollinger Ellison syndrome is the presence of duodenal ulcer which is larger than the normal when an endoscopy is performed.
Diagnosis should be performed when the ulcers are larger than 2 cm in diameter and also when there are multiple ulcers.
Imaging studies and laboratory tests are the common procedures used for the diagnosis of Zollinger Ellison syndrome.
PROVOCATION TESTS
SECRETIN STIMULATION TESTS
The food present in the stomach normally stimulates secretin, which leads to the release of fluid containing bicarbonate ions from pancreas this helps in neutralising the gastric acid. This further leads to the inhibition of both secretin release and secretion of anstral gastrin. Even though there is more amount of gastrin release from gastrinomas.
Secretin should be administered intravenously, and blood samples are collected for every 5 minutes until 20 minutes.
When the concentration of serum gastrin increases more than 200 pg/ml after 15 minutes of the dose administration then the test is positive.
For this test 94% of sensitivity and 100% of specificity should be reported.
CALCIUM STIMULATION TEST
Gastrin that is stored in the gastrinomas can be released by calcium.
10% calcium gluconate is administered intravenously and levels of gastrin checked for every 30 minutes until 3 hours.
If the gastrin level increases more than 395 pg/ml from the base line then the test is positive.
For this test 100% of specificity should be reported but sensitivity is poor at 62%.
IMAGING
There are number of potential imaging techniques
To detect metastases and to locate primary tumour CT scan may be used. Approximately half of the primary tumours are detected, but small ones of 1cm diameter or less than that are often missed out.
CT scan is very good when compared to MRI and ultrasound scans.
SRS when combined with Endoscopic ultrasonography (EUS) is the investigation of choice because it is the most sensitive technique to detect primary and metastatic lesions.
THERAPY
Control of hyperacidity is the main target of medical management. Surgery is done only to remove gastrinomas. However a surgery in case of emergency is performed in bleeding and perforating complications.
Surgical removal of the tumours is the only possible way of obtaining complete cure or treated with chemotherapy (doxorubicin, 5-flourouracil, streptozotocin). Octreotide is used to relieve symptoms.
Pharmacological agents such as proton pump inhibitors such as (omeprazole, pantaprazole) and H2 receptor blockers (cimitidine, ranitidine) are used to decrease acid secretion.
However still surgery is required to remove gastrinomas but total gastrectomy is not recommended.
To relieve abdominal pain and diarrhoea subcutaneous octreotide is used.
An intravenous proton pump inhibitor is used to control gastrin secretion in case of acute condition.
Oral PPIs can be used to control acid secretion but higher dose is required.
Surgery is recommended for tumours larger than 2.5 cm. Chemotherapy, interferon and octreotide are useful in case of metaststic disease. But most of the studies have shown that the response to these pharmacological agents are low.
Risk of liver metastasis can be decreased for sporadic patients by surgical resection of the tumour.
Risk of metastasis can be reduced in MEN1 patients by surgery but cure is very rarely achieved.
Chemotherapy is useful if the tumours are wide spread and cannot be removed by surgery.
It is often challenging to find and remove all the gastrinomas.
