All the patients presenting with possible IBS symptoms should be asked if they have any of the following “red flag” indicators and should be referred to secondary care for further investigation if any are present.

‘Red flag’ symptoms can be connected to cancer and they are considered as alarming signs. Each time the patient reports even only one of the above symptoms, a specialist’s diagnosis is necessary. Special attention must be applied to patients with a positive family history of cancer.

All the patients presenting with possible IBS symptoms should be assessed and clinically examined for the following “red flag” indicators and should be referred to secondary care for further investigation if any are present.

In any of these cases, physical examination and imaging studies such as ultrasound should be performed.

If there is a significant concern that symptoms may suggest ovarian cancer, gynecologist’s consultation and pelvic examination should also be considered.

The final diagnosis of IBS should be considered only if the person has abdominal pain that is either relieved by defecation or associated with altered bowel frequency or stool form. This should be accompanied by at least two of the following four symptoms:

Other features such as lethargy, nausea, backache and bladder symptoms are common in people with IBS and may be used to support the diagnosis.

Additional diagnostic testing in patients who meet the IBS diagnostic criteria the tests for celiac disease may be warranted in patients presenting with diarrhea as their predominant symptom. However, the extensive diagnostic testing is unnecessary for patients without alarm symptoms. In some cases addressing disease-related concerns, discussing reasonable treatment goals and expectations, educating and empowering patients, and addressing somatization issues with patients may provide greater benefit than extensive testing. However, even if the above mentioned diagnostic scheme is performed, many of IBS patients need additional clinical tests to exclude the other infections, inflammatory or neoplastic diseases. Additional tests include:

After all of the above steps are completed, IBS may be recognized. However, to systematize the diagnosis of IBS, the Rome III Diagnostic Criteria were introduced in 2006 and Rome IV criteria in 2016 [3].

There were systematic approaches that attempted to classify the then hazy area of FGIDs as early as 1962, when Chaudhary and Truelove published a retrospective review of IBS patients at Oxford, England. Later on, the “Manning Criteria” for IBS were derived from a paper published in 1978 by Manning and colleagues. This seminal classification started a new era and from then on, scientific work on functional gastrointestinal disorders proceeded with increased enthusiasm.

The “Rome process” is an international effort to create scientific data to help in the diagnosis and treatment of functional gastrointestinal disorders (FGIDs), such as IBS, functional dyspepsia and rumination syndrome. The Rome Diagnostic Criteria are set forth by the Rome Foundation, a non- profit organization, under the professional management of Hilliard Associates based in Raleigh, North Carolina.

The Rome criteria have been evolving from the first set, issued in 1989 through the Rome Classification System for FGIDs (1990), the Rome I Criteria for IBS (1992) and the FGIDs (1994), the Rome II Criteria for IBS (1999) and the FGIDs (1999), the Rome III Criteria (2006) and to the most recent Rome IV criteria (2016). Currently the Rome III Diagnostic Criteria for FGIDs is still the ‘Gold Standard’ for the diagnosis of IBS [4].

Recurrent abdominal pain at least 3 days/month* in the last 3 months associated with two or more of the following:

Diagnostic Criterion fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis.

In pathophysiology research and clinical trials, a pain/discomfort frequency of at least 2 days a week during screening evaluation is recommended for subject eligibility [4].

Patients with IBS are divided into subgroups based on their predominant symptoms:

Around 75 % of patients are alternators, which illustrates the instability of symptoms over time in the same patient [5].

The Rome III diagnostic questionnaire for IBS contains 10 items and answers to questions are on an ordinal scale with individual frequency thresholds for each question. The qualification of patient to an appropriate subgroup is performed on the answers to questions regarding bowel movements habits, frequency and consistency of stools (Table 3.1).

In 2001, Biomarkers Definitions Working Group defined the term “biomarker” as “a characteristic that is measured and evaluated as an indicator of normal biological processes, pathogenetic processes or pharmacologic responses to a therapeutic agent” [6, 7]. Noninvasive biomarkers are particularly desired, as their application would reduce costs and minimize unnecessary diagnostic tests.

There are several obstacles in the search for relevant biological biomarkers in IBS. They include:

Nevertheless, several new markers in IBS have already been proposed.

C-reactive protein (CRP), a member of pentraxin family is an annular (ring-shaped), pentameric protein found in blood plasma, whose levels rise in response to inflammation. It is an acute-phase protein of hepatic origin that increases following interleukin-6 secretion by macrophages and T cells. Its physiological role is to bind to lysophosphatidylcholine expressed on the surface of dead or dying cells (and some types of bacteria) in order to activate the complement system via the C1Q complex [9].

CRP is synthesized by the liver in response to factors released by macrophages and fat cells (adipocytes) [10–12]. Importantly, it is not related to C-peptide (insulin) or protein C (blood coagulation).

CRP is usually used to assess the degree of inflammation and therapeutic success in diseases such as Crohn’s disease and ulcerative colitis. In the study conducted by Hod et al. researchers tried to confirm the hypothesis of elevated high sensitivity CRP (hs-CRP) as a marker of microinflammation in IBS [13]. Hs-CRP levels were higher in IBS patients than HC, but still in the normal laboratory range. This may reflect the low-grade gut inflammation believed to occur in IBS and support its existence. In the study, hs-CRP levels were highest in patients with diarrhea-predominant IBS and in patients with greater disease severity. A cut-off value of 1.08 mg L(-1) demonstrated a sensitivity of 60.2 % and a specificity of 68 % for differentiating IBS from HC. The clinical relevance of CRP values in assessing IBS disease severity or therapy follow-up has not yet been proven.