Histamine and Key Stool Parameters: Calprotectin, Pancreatic Elastase and More for Comprehensive Gastrointestinal Diagnostics

Discover the latest findings and complementary parameters in gastrointestinal diagnostics. Stay informed and optimise your diagnostic strategies with the latest developments in gastroenterology.        

Eosinophilic protein X is a glycosylated protein that serves as an indicator of activation and degranulation of eosinophilic granulocytes. It correlates with their activation level and provides insights into the type and extent of intestinal immune responses. EPX is involved in the defence against parasites. Due to the highly toxic nature of these proteins, excessive release can cause inflammation of the body’s own tissues, including the mucosa. This possibly leads to increased intestinal permeability.

Elevated stool EPX levels reliably indicate food intolerances which involve mucosal inflammation. Raised levels are also observed in chronic inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis, and can signal protein-induced enteropathy (e.g. gluten intolerance).

Population studies show that around 5% of individuals experience persistent or intermittent chronic diarrhoea. Due to the diffuse symptoms and lack of established diagnostic standards, many diagnoses of irritable bowel syndrome (IBS-D) are not definitive. Notably, up to one-third of IBS-D patients suffer from disturbed bile acid metabolism.

Typical symptoms of bile acid deficiency include steatorrhoea (fatty, bulky stools) and chronic watery diarrhoea. Resulting malabsorption of fat-soluble vitamins may lead to further health issues, including:

• Night blindness (due to vitamin A deficiency)
• Osteoporosis (due to vitamin D deficiency)
• Neurological problems (due to vitamin E deficiency)
• Coagulation disorders (due to vitamin K deficiency)

Distinctions are made between:

Insufficient bile acid production or release into the small intestine results in reduced stool bile acids and increased fat excretion. Fat maldigestion and poor absorption of fat-soluble vitamins (A, D, E, K) are possible.

In approximately 1% of the general population, impaired absorption and associated loss of bile acids are the main cause for chronic diarrhoea.

Chronic diarrhoea is often the main symptom. Stool is typically watery and voluminous. Stool analysis reveals elevated bile acids, but normal fat levels.

This stage also presents with watery diarrhoea – often accompanied by cramping pain. Stool tests show elevated levels of both bile acids and fat.

The most common cause of digestive disorders which result from maldigestion is exocrine pancreatic insufficiency. Quantitative analysis of pancreatic elastase allows for reliable diagnosis or exclusion of this condition.

Deficiency symptoms may include persistent bloating, distended abdomen, feeling of fullness, explosive stools, severe cramping, post-meal discomfort, nausea, intolerance to fatty or oily foods (especially when combined with proteins and alcohol), and unexplained weight loss.

Calprotectin is excreted in stool during intestinal inflammation. Infections of the gastrointestinal tract caused by viruses or bacteria often result in elevated calprotectin levels in stool. Calprotectin is also highly sensitive in detecting:

• Chronic inflammatory bowel disease
• Bleeding or non-bleeding polyps
• Colorectal carcinomas
• Disease progression in Crohn’s disease and ulcerative colitis

Non-steroidal anti-inflammatory drugs (e.g. aspirin, ibuprofen, diclofenac) and COX-2 inhibitors (e.g. celecoxib) can cause enteropathy, which increases calprotectin levels in stool. These medications should ideally be discontinued for 14 days before calprotectin testing to avoid false positives.

Secretory immunoglobulin A is produced in plasma cells which are located in the lamina propria mucosae of the intestinal wall. It serves to neutralise antigens, toxins, and pathogens. Low levels indicate poor stimulation of the intestinal immune system. Elevated levels may be seen in allergic diseases, inflammatory intestinal conditions, autoimmune disorders, and increased susceptibility to infections.

The glycoprotein alpha-1-antitrypsin (A1AT) is mainly synthesised in the liver, but also by intestinal epithelial cells and mucosal immune cells. It belongs to the group of acute-phase proteins. In cases of intestinal inflammation or epithelial damage, A1AT which is localised in the intestinal mucosa leaks into the intestinal lumen and becomes detectable in stool.

Because A1AT is not degraded in the intestine, even low-grade inflammation with increased mucosal permeability may result in elevated stool levels. Thus, it is a marker for leaky gut syndrome and various enteropathies. Non-steroidal anti-inflammatory drugs (e.g. aspirin, ibuprofen, diclofenac) and COX-2 inhibitors (e.g. celecoxib) may also raise A1AT levels due to enteropathies they induce. These medications should ideally be discontinued for 14 days before calprotectin testing to avoid false positives.

Tight junctions between enterocytes form the basis of a functional intestinal barrier. Elevated zonulin levels, which are triggered by dysbiosis or intestinal inflammation, loosen these tight junctions, thereby increasing intestinal permeability.

Zonulin is a sensitive and specific routine diagnostic marker for assessing mucosal barrier function and is associated with leaky gut syndrome and autoimmune conditions such as coeliac disease.

Defensins play a key role in maintaining the mucosal barrier and are considered part of the body's natural antibiotics. They form part of the innate immune system and defend against a broad range of microbial pathogens and toxins which are located on the intestinal mucosa. Defensin deficiency suggests weakened mucosal defence and poor antigen neutralisation. This increases the risk of infections, toxic stress, and food antigen sensitisation.

Non-steroidal anti-inflammatory drugs (e.g. aspirin, ibuprofen, diclofenac) and COX-2 inhibitors (e.g. celecoxib) may also lead to enteropathies with elevated β-defensin levels. A 14-day drug-free interval is recommended before testing to avoid false positives.

Bacterial β-glucuronidases are produced by several bacterial species of the human intestinal microbiota. They can reactivate substances that were previously inactivated via glucuronidation (e.g. hormones, toxins, medications). Some level of β-glucuronidase activity is essential for normal recirculation of compounds such as vitamin D, bilirubin, thyroid hormones, and oestrogens. Increased β-glucuronidase activity may enhance enterohepatic recirculation of toxins, steroid hormones, pharmaceuticals, or carcinogens. Reduced activity can impair intestinal reabsorption.

The bacterial strains that process glucuronides in the human intestine primarily include Bacteroidetes, Firmicutes, Actinobacteria, and Proteobacteria. Members of the Bacteroidetes and Firmicutes strains are dominant in the human intestinal microbiota and constitute the main source of microbial β-glucuronidases. Changes in β-glucuronidase activity may contribute to the development of inflammatory and malignant intestinal diseases. Modulation of this enzymatic activity is possible through dietary interventions or the administration of prebiotics and probiotics.

Carbohydrates are the main substrate for short-chain fatty acid production. Anaerobic intestinal bacteria are crucial for the synthesis of short-chain fatty acids. Commonly occurring faecal bacteria include representatives of the genera Clostridium, Bacteroides, Bifidobacterium, Eubacterium, Escherichia, Lactobacillus, Propionibacterium and Streptococcus. Short-chain fatty acids and their salts result from microbial fermentation of indigestible plant polysaccharides. The most physiologically relevant short-chain fatty acids are acetic acid (acetate), propionic acid (propionate) and butyric acid (butyrate). They are rapidly absorbed and metabolised in various tissues.

In adults with a physiologically stable microbiota and a balanced diet, short-chain fatty acids are produced in a largely consistent ratio and can be detected in the stool. The composition of short-chain fatty acids typically consists of approximately 60% acetic acid, 20-25% propionic acid, and 15-20% butyric acid, which corresponds to a ratio of about 3:1:1. High concentrations of short-chain fatty acids in the faeces – for example, as a result of carbohydrate malabsorption – can lead to sticky stools and increased intestinal motility, which may manifest as diarrhoea and cramps.