Sandbox MWH

Irritable Bowel Syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Muhammad Waleed Haider, M.D.[2]

Synonyms and Keywords: Spastic colon, functional bowel disorder, IBS

Historical Perspective

Irritable Bowel syndrome (IBS) was first mentioned in the Rocky Mountain Medical Journal in 1950. IBS was described as a psychosomatic disorder, not explained by any biochemical or structural abnormalities. Apley and Nash conducted a famous study on 1000 children in Bristol, United Kingdom and were the first to describe recurrent abdominal pain (RAP) as the predominant feature of IBS. In 1978, the first diagnostic criteria i.e. the Manning criteria was described. It did not specify any required duration for the symptoms of IBS. The subsequent criteria saw a reduction in the required duration of symptoms to facilitate early diagnosis and treatment. In Rome in 1995, an international group of gastroenterologist defined the diagnostic criteria for IBS and this was published in 1999 under the title of the Rome II criteria. This criteria underwent modification and was described as the Rome III criteria. Since June 2016, the criteria being followed is the Rome IV criteria.

Discovery

• In 1950, the concept of irritable bowel syndrome (IBS) was mentioned for the first time without the recognition of any particular etiology, in the Rocky Mountain Medical Journal.
• IBS was described as a psychosomatic disorder, not explained by any biochemical or structural abnormalities.
• In 1958, Apley and Nash conducted a study on 1000 children in Bristol, United Kingdom and were the first to describe Recurrent abdominal pain (RAP), as the predominant feature of IBS.
• Recurrent abdominal pain was defined as pain in the abdomen occurring over a duration of at least 3 months, with the severity enough to cause significant impairment of function.
  

Classificatiion

Irritable bowel syndrome (IBS) may be classified according to Rome IV criteria into 4 sub-types based on predominant type of bowel habits:

• IBS with predominant constipation
• IBS with predominant diarrhea
• IBS with mixed bowel habits:
  • Alternating patterns of stool passage which is not in conjuncture with the normal bowel movements.
• IBS unclassified:
  • Patients who meet the diagnostic criteria for IBS but whose bowel habits do not fit into any of the above subtypes.

• Post infectious IBS (PI-IBS):
  • Post-infectious IBS is an additional sub-type that is acute in onset and occurs subsequent to an infectious illness of the gastrointestinal tract. Post-infectious IBS is characterized by two or more of the following:
    • Vomiting
    • Fever
    • Positive stool culture
    • Diarrhea

Subtype	Hard or Lumpy Stools	Soft (Mushy) or Watery Stools
IBS with Constipation	≥ 25 percent	≤ 25 percent
IBS with Diarrhea	≤ 25 percent	≥ 25 percent
Mixed IBS	≥ 25 percent	≥ 25 percent
Unsubtyped IBS	Insufficient abnormality of stool consistency to meet criteria for IBS with constipation, diarrhea or mixed sub types

Pathophysiology

Pathogenesis

IBS occurs as a result of an interplay between four main factors:

CNS dysregulation and psychosocial factors

Intrinsic gastrointestinal factors: • Motor abnormalities • Visceral hypersensitivity • Immune activation and mucosal inflammation • Altered gut microbiota • Abnormal serotonin pathways

Irritable Bowel Syndrome

Genetic factors: • Twin concordance • Familial aggregation • Single nucleotide polymorphisms(SNPs) • TNF polymorphism

Environmental factors: •Diet •Infections

Diet

• Fermentable oligosaccharides, monosaccharides, disaccharides, and polyols (FODMAPs) are present in stone fruits, artificial sweeteners, lactose-containing foods, and legumes. Changes in diet such as increased amounts (FODMAPs) can alter gut microflora.
• Fermentation and osmotic effects of FODMAPs produce abdominal discomfort and diarrhea in IBS.
• FODMAPs yield carbon dioxide, methane, and hydrogen that are responsible for bloating.
• Osmotically active carbohydrate by products lead to diarrhea by enhancing intestinal contractions and precipitating fluid secretion.

Infection

• Infectious gastroenetritis triggers micro inflammation and up to one third of irritable bowel syndorme cases follow acute gastroenteritis.
• Micro inflammation of the gut causes activation of the lymphocytes, mast cells and pro inflammatory cytokines that stimulate the enteric nervous system and lead to abnormal visceral and motor responses within the gastrointestinal tract.

Intrinsic gastrointestinal factors[edit | edit source]

• Motor abnormalities:
  • IBS is referred to as ‘spastic colon’ due to changes in colonic motor function.
  • Manometry recordings from the transverse, descending and sigmoid colon have shown that IBS leads to altered colonic and small intestinal tumor function, such as increased frequency and irregularity of luminal contractions.
  • Motor changes lead to symptoms of diarrhea and constipation.
    • Diarrhea-prone IBS patients have increased responses to ingestion, CRH (corticotropin releasing hormone), CCK (cholecystokinin), which increase the peak amplitude of high-amplitude propagating contractions (HAPCs) and lead to abdominal discomfort with accelerated transit through the colon.
    • Constipation-prone IBS patients show fewer high-amplitude propagating contraction (HAPCs) as compared to diarrhea prone IBS patients, delayed transit through the colon and decreased motility.

Visceral hypersensitivity:

• IBS is associated with a decreased threshold for perception of visceral stimuli (i.e. visceral hypersensitivity)
• Rectal distension produces painful and non-painful sensations at lower volumes in IBS patients as compared to healthy controls, suggesting the presence of afferent pathway disturbances in visceral innervation.
• Visceral hypersensitivity contributes to IBS by involving the following:
  • Spinal hyperexcitability
    • Secondary to activation of neurotransmitters such as:
    • NDMA receptor
    • Nitric oxide
  • Activation of specific gastrointestinal mediators that lead to afferent nerve fiber sensitization:
    • Kinins
    • Serotonin
  • Central (brainstem and sortical) modulation with increased activation of anterior cingulate cortex, thalamus and insula.
    • These structures are involved in processing of pain.
    • Cortical and brainstem modulation translate into long term hypersensitivity due to neuroplasticity.
    • Semi permanent changes(seen on functional MRI and PET scan) in the neural response to visceral stimulation contribute to visceral hypersensitivity.
  • Recruitment of peripheral silent nocireceptors cause increased end organ sensitivity due to
    • Hormonal activation ( increased serotonin affects gastrointestinal and visceral pain perception)
    • Immune activation(recruitment of inflammatory mediators)

Spinal hyperexcitability

Activation of • N-methyl D aspartate (NMDA) receptor • nitric oxide

Central (brainstem and cortical) modulation

Increased activation of: • Anterior cingulate cortex • Thalamus • insula

Visceral Hypersensitivty

Activation of specific gastrointestinal mediators

Kinins and serotonin activation lead to afferent nerve fiber sensitization

Recruitment of peripheral silent nociceptors

Increased end organ sensitivity due to hormonal or immune activation

Immune activation and mucosal inflammation

Mast cells

IMMUNE ACTIVATION AND MUCOSAL INFLAMMATION

Lymphocytes

Proinflammatory cytokines

• IBS in patients with history of inflammatory bowel disease, celiac disease or microscopic colitis points towards the fact that immune activation and local gastrointestinal mucosal inflammation play an important role in its pathogenesis.
• IBS patients have high mucosal counts of lymphocytes (T cells, B cells), mast cells and immune mediators such as prostanoids, proteases, cytokines and histamines.

Lymphocytes:

• Activation of humoral immunity in IBS is specific for the gastrointestinal tract. Increased number of lymphocytes have been found in the small intestine and colon of IBS patients.
• IBS patients with diarrhea have enhanced mucosal humoral activity, associated with activation and proliferation of B cells and immunoglobin production, identified by microarray profiling.
• IBS patients with severe disease have an increase in lymphocyte infiltration in the myentric plexus.

Mast cells:

• IBS leads to an increased number of mast cells in IBS patients in the jejunum, terminal ileum and colon.
• Higher numbers of activated mast cells are found in proximity to colonic nerve fibres in the mucosa of the gastrointestinal tract of IBS patients

Proinflammatory cytokines:

• Cytokines are protein mediators of the immune response. Increased levels of cytokines have been found in IBS patients.
• Higher amounts of TNF are produced by the peripheral blood mononuclear cells of IBS patients.
• Other cytokines such as interleukin 6, interleukin 10, and TNF alpha are raised in IBS patients.
• Increased concentration of cytokines is directly proportional to the severity and frequency of pain.
• The TNF antagonist infliximab counteracts pain in IBS patients, proving TNF involvement in mechanical hypersensitivity of the colonic afferent nerve endings.

Associated conditions

Several medical comorbidities appear with greater frequency in IBS patients.

Headache, Fibromyalgia, and Depression

IBS patients may be identified with comorbidities such as headache, fibromyalgia and depression.

Inflammatory Bowel Disease

• IBS and IBD are interrelated diseases, as patients with IBD experience IBS-like symptoms when their IBD is in remission.
• IBS is believed to be a type of low-grade IBD as serum markers associated with inflammation have also been found in patients with IBS.
• IBS patients are 16.3 times more likely to develop IBD.

Abdominal Surgery

• IBS patients are 87% more likely to undergo abdominal and pelvic surgery, and three times more likely to undergo gallbladder surgery.
• IBS patients were twice as likely to undergo hysterectomy.

Endometriosis[edit | edit source]

There is a statistically significant link between migraine headaches, IBS, and endometriosis.

Gross Pathology

• On gross pathology, the GI tract appears normal in IBS.

Microscopic Pathology

Microscopic changes that may be found in IBS patients are as follows:

Location	Layer of Intestine involved	Mast Cells	T Lymphocytes	Enterochromaffin Cells
Rectum	Mucosa	+++/-	+/-	+/-
Terminal Ileum	Mucosa	-	++	-
Cecum	Mucosa	++	-	-
Colon	Muscularis Externa	+/-	-	-
Jejunum	Myenteric Plexus	++	-	-

Risk Factors

Common risk factors in the development of IBS may be categorized as psychological, epidemiological, genetic, and infections.

Common risk factors

Common risk factors in the development of IBS include:

Psychological risk factors:

• Stress
• Anxiety

Psychiatric risk factors:

• Depression

• Panic disorders

• History of physical or sexual abuse or adverse early life events

Past medical history

• History of gastrointestinal disorders such as IBD
• History of acute GI infections such as traveler's diarrhea i.e post infectious state
  • Salmonella infection
  • Giardiasis
• History of antibiotic use
• Immune causes:
  • History of IBD
  • Celiac disease
  • Microscopic colitis

Less common risk factors

• Less common risk factors in the development of IBS include:
  • Age: Second decade of life
  • Gender: Women (possibly due to changes in menstrual cycle)
  • Past history of abuse
  • Family history of IBS (genetics)
  • Hormonal changes
    • Alteration of sex hormones
    • Alteration of serotonin levels
  • History of migraine headaches
  • History of pain disorders such as fibromyalgia
  • Food sensitivities: Fatty food, wheat, carbonated drinks, sorbitol and alcohol
• Abdominal obesity

Epidemiology and Demographics

Incidence

• The incidence of IBS is approximately 200 per 100,000 individuals worldwide.

Prevalence

• The prevalence of IBS is approximately 11,200 per 100,000 individuals worldwide.
• The prevalence of IBS varies with geographical and demographic distribution.
• The prevalence of IBS in USA and Europe is ranges from a low of 10,000 per 100,000 individuals to a high of 20,000 per 100,000 individuals.

Age

• IBS commonly affects individuals younger than 35 years of age.
• The incidence of IBS decreases with age.
• The prevalence of IBS is 25% lower in individuals over 50 years of age.

Race

• There is no racial predilection to IBS.

Gender

• Females are more commonly affected by IBS than males. The female to male ratio is approximately 1:2. This is due to social and biological factors.

Social factors:

• Females are predominantly affected by IBS as the likelihood of diagnosis of IBS is 2-3 times more in women as compared to men. This is because health care seeking behavior for symptoms is 4-5 times higher in women as compared to men.

Biological factors:

• The fluctuation of sex hormones in women during the menstrual cycle causes exacerbation of IBS symptoms.
• Women have a lower threshold for pain and are at greater risk for development of functional and chronic pain disorders such as IBS and fibromyalgia.
• Pediatric population:
• Worldwide, the prevalence of IBS is higher in girls.
• The prevalence of IBS in Asia is higher in girls as compared to boys.

Children

• In the Western pediatric population, IBS is the commonest cause of functional recurrent abdominal pain (RAP) as it accounts for more than 50% of all cases.

Developed and developing countries

• In USA and Australia, 1 in every 10 people fulfill the Rome IV criteria  for IBS.
• In Asia, Africa and South America, IBS is becoming increasingly prevalent as a disease of urbanization and industrialization. This is due to increased access to health care, higher stress levels and differing dietary choices.

Differentiating Irritable Bowel Syndrome from other Diseases

Diseases with similar symptoms

• Celiac disease
• Crohn's disease
• Zollinger-Ellison Syndrome
• VIPoma
• Diverticulitis
• Endometriosis
• Gallstones
• Gastroesophageal reflux disease (GERD)
• Inflammatory bowel disease
• Lactose Intolerance
• Thyroid disease--Hyperthyroidism / Hypothyroidism
• Chronic Pancreatitis
• Small Intestinal Bacterial Overgrowth
• Intermittent Small Bowel Obstruction

Differential Diagnosis of Irritable bowel syndrome on the basis of abdominal pain and diarrhea

Diarrhea with abdominal pain/cramping may be caused by infectious causes, celiac disease, parasites, food allergies and lactose intolerance. See the list of causes of diarrhea for other conditions which can cause diarrhea. Celiac disease in particular is most often misdiagnosed as IBS. The differential diagnosis of irritable bowel syndrome based on abdominal pain and diarrhea is as follows:

Cause	Osmotic Gap	History	Physical Examination	Gold Standard	Treatment
		Abdominal pain followed by diarrhea	Abdominal tenderness when palpated in severe disease Blood seen on rectal exam Fever Tachycardia Hypotension	Colonoscopy with Biopsy	Topical mucosamine and corticosteroids are preferred Mesalamine and sulfasalazine are used for remission