Zollinger-Ellison Syndrome: Causes, Symptoms, Differential Diagnosis

Article by Dr Raghuram Y.S. MD (Ay) and Dr Manasa, B.A.M.S
Zollinger Ellison Syndrome (ZES) is a disease closely related to Peptic ulcers or acid reflux diseases in terms of symptoms and presentation.

It is a disease in which the tumors in the stomach cause the stomach to produce too much acid.  This results in formation of peptic ulcers (painful sores in the stomach due to the reaction of the stomach layers with the acid). ZES presents with abdominal pain and diarrhea.

Causes of ZES
ZE Syndrome is caused by a neuro-endocrine tumor called ‘gastrinoma’. Gastrinoma secretes a hormone called Gastrin. This gastrin causes excessive production of gastric acid.
This in turn leads to growth of gastric mucosa and proliferation of parietal and ECL cells (Enterochromaffin cells which aid production of gastric acids via release of histamine).

Gastrinomas – They may occur as single or multiple small tumors. About ½ – 2/3 of single gastrinomas are malignant in nature. They commonly spread to the liver and to the lymph nodes near the pancreas and small intestine.

About 25% of patients with gastrinomas have multiple tumors as part of a condition called MEN1. MEN1 patients have tumors in their pituitary gland and parathyroid glands along with pancreas tumors.

ZES may occur on its own or as a part of MEN1 (multiple endocrine neoplasia type 1), an autosomal dominant syndrome.

The primary tumor is usually located in the pancreas, duodenum (1st part of small intestine) or abdominal lymph nodes. Other locations where tumors have been found are also described. These locations are called as ectopic locations. They are heart, ovary, gall bladder, liver and kidney.

Signs and Symptoms of ZES: 

  • Abdominal pain
  • Chronic diarrhea, including steatorrhoea (fatty stools)
  • Pain in the oesophagus, especially between and after meals at night
  • Nausea (sensation to vomit)
  • Vomiting
  • Vomiting of blood
  • Loss of appetite
  • Malnourishment

Diagnosis of ZES is suspected in those patients who have severe ulceration of stomach and small intestine which is not responding to the treatment.
Further reading: http://emedicine.medscape.com/article/183555-overview

Pathophysiology

  • Gastrinomas produce gastrin
  • Gastrin acts on the parietal cells of the gastric glands in the stomach.
  • This causes the parietal cells to secrete more hydrogen ions into the stomach lumen (space in the stomach, cavity).
  • Gastrin also acts as a trophic factor for parietal cells causing parietal cell hyperplasia (increase in the amount of organic tissue that results from cell proliferation).
  • Thus there is an increase in the number of acid-secreting cells.
  • Each of these cells produces acid at a higher rate.
  • The increase in acidity contributes to the development of peptic ulcers in the stomach and duodenum (first portion of the small intestine).

Diagnosis of ZES
ZE Syndrome may be suspected when the symptoms of the disease prove resistant to the treatment i.e. when the treatment for peptic ulcers fails even after prolonged administration. It can also be suspected when the symptoms are suggestive of the syndrome or when endoscopy is suggestive of ZES.

The diagnosis is made through several laboratory tests and imaging studies. They are:

  • Secretin stimulation test – This measures the levels of evoked gastrin
  • Fasting gastrin levels – This should be conducted while the patient is fasting and on at least 3 occasions
  • Gastric acid secretion and pH – The normal basal gastric acid secretion is less than 10mEq/hour, in ZE patients; it is usually more than 15 mEq /hour.
  • Increased level of chromogranin A
  • Determination of source of increased gastrin production – with the help of MRI or somatostatin receptor scintigraphy

Differential Diagnosis
Peptic Ulcers
– Thus Peptic ulcers are wounds or sores occurring in stomach or beginning part of the intestine. It commonly occurs in the peptic areas of the body. These ulcers are most commonly caused by the bacteria (and not by the acidic environment). Peptic Ulcer or Peptic Ulcer Disease (PUD) is a break in the inner lining of the stomach, the first part of the small intestine or occasionally the lower oesophagus (food pipe). Ulcer in the stomach is called Gastric Ulcer. Ulcer in the small intestine is called Duodenal ulcer (first part of the small intestine which begins from the lower end of the stomach is called duodenum).

Peptic ulcers present with pain abdomen (epigastric pain), bloating, water-brash, belching, nausea, copious vomiting, loss of appetite, hemetemesis, maelena, etc.

Gastritis is an inflammation or irritation of the stomach lining. Common symptoms are pain or discomfort in the upper abdomen. Pain may be sharp, stabbing or cutting. Other symptoms include belching, nausea, vomiting, bloating, feeling of fullness or burning in the upper part of the belly etc.

Stomach cancer – It occurs when cancerous cells form in the stomach lining. It doesn’t cause symptoms until the later stages, so it’s often not diagnosed until it is more advanced. Advanced stomach cancer is usually associated with nausea, vomiting, frequent heartburn, loss of appetite, sudden weight loss, constant bloating, early satiety, bloody stools, jaundice, excessive fatigue, stomach pain etc.

Gastro-oesophageal reflux disease (GERD) It is a digestive disorder that affects the lower Oesophageal sphincter, the ring of muscle between the oesophagus and stomach. Heartburn also called acid indigestion is the most common symptom of GERD and usually feels like a burning chest pain beginning behind the breastbone and moving upward to the neck and throat. Many people say it feels like food is coming back into the mouth leaving an acid or bitter taste.

Pancreatitis – It is a disease in which the pancreas becomes inflamed. Pancreatic damage happens when the digestive enzymes are activated before they are released into the small intestine and begin attacking the pancreas. It presents with upper abdominal pain that radiates into the back. It gets aggravated by eating, especially fat rich foods. Other symptoms are swollen and tender abdomen, nausea, vomiting, fever, increased heart rate, weight loss, diabetes etc.

Hepatic congestion is a liver dysfunction. It is caused due to venous congestion, usually due to congestive heart failure. There will be a sense of fullness and tenderness in the right hypochondriac region in addition to the heart and lung symptoms. Gastrointestinal catarrh and vomiting of blood may occur. Jaundice, ascites, generalized edema, enlarged liver etc are other complaints. Other names are congestive hepatopathy, nutmeg liver or chronic passive congestion of the liver.

Cholecystitis – is inflammation of gall bladder. It occurs most commonly due to obstruction of the cystic duct by gall-stones arising from the gall bladder (cholelithiasis). It presents with upper abdominal pain. Pain may often radiate to the right shoulder or scapula. Nausea, vomiting and fever are commonly present.

Biliary colic – It describes a type of pain related to the gallbladder that occurs when a gallstone transiently obstructs the cystic duct and the gallbladder contracts. Symptoms will be similar to cholecystitis.

Other conditions – Inferior myocardial infarction, Referred pain (pleurisy, pericarditis), Superior mesenteric artery syndrome etc.

Treatment
Proton pump Inhibitors (PPI) – such as omeprazole and lansaprazole (to slow acid secretion)
Histamine H2-receptor antagonists – such as famotidine and ranitidine (to slow acid secretion)
Once the gastric acid is suppressed, the symptoms normally improve.

History
Before 1955, sporadic reports of unusual cases of peptic ulceration in the presence of pancreatic tumors occurred. R.M. Zollinger and E.H. Ellison were the first to postulate a causal relationship between these findings. They both were surgeons at Ohio State University. In April 1955, The American Surgical Association meeting in Philadelphia heard the first public description of the syndrome. Zollinger and Ellison subsequently published their findings in Annals of Surgery.
Further reading:
http://www.mayoclinic.org/diseases-conditions/zollinger-ellison-syndrome/basics/definition/con-20024097

Zollinger-Ellison Syndrome: Home Remedies:
ZES is primarily related with peptic ulcers and related symptoms. All preventive aspects and home remedies which help in relieving peptic ulcers come handy in dealing the symptoms of ZE syndrome.
Read More: Peptic Ulcers: Home Remedies and Lifestyle Tips

Just Before Finishing –
It is a disease which resembles peptic ulcers. Peptic ulcers or acid producing gastrinomas are the main culprits at the backdrop of ZES. The symptoms of ZES also resemble Peptic Ulcers or Peptic Ulcer Disease (PUD). This article covers the causes, symptoms, pathogenesis and differential diagnosis of ZES.
Click to Consult Dr Raghuram Y.S. MD (Ayu)


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