Constipation

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

Constipation is defined as straining, hard stool, sensation of incomplete evacuation, sensation of obstruction, necessity of manual maneuvers, less than 3 bowel movements per week, lack of loose stool, and lack of irritable bowel syndrome (IBS). Constipation is classified according to etiology into seven subtypes including gastrointestinal, neurologic, metabolic, endocrine, psychiatric, drug-induced, and idiopathic The defecation process consist of three important stages, include filling of the rectum, sensation of rectum fullness, and relaxation of pelvic floor muscles in a coordinated fashion. Primary constipation is caused by anorectal and colonic problems, while secondary constipation is caused by organic and metabolic diseases or medications. Diseases that disturb the nervous system may lead to constipation, such as diabetes mellitus, autonomic neuropathy, Chagas’ disease, and Hirschsprung’s disease. Chronic use of the laxative may lead to melanosis coli, which is identified by hyperpigmentation and brownish discoloration of colonic mucosa. The primary histopathological finding in melanosis coli is brown granular pigment in lamina propria. Diagnostic study of choice for constipation is ROME III criteria. Rome III criteria includes symptom onset for more than 6 months and two or more number of specific symptoms. Specific constipation symptoms include straining, hard stool, sensation of incomplete evacuation, sensation of obstruction, necessity of manual maneuvers, less than 3 bowel movements per week, lack of loose stool, and lack of irritable bowel syndrome (IBS). Chronic constipation treatment includes both behavioral and pharmacological interventions. Behavioral management mostly consists of life style and dietary modification, while pharmacological interventions are mostly based on laxatives. Increasing physical activity is postulated to improve constipation and colonic transit time in patients with constipation. The most important behavioral treatment for constipation is biofeedback, consisting of teaching the patients how to use their abdominal and pelvic muscles during defecation. Probiotics are live microorganism spores that are given orally to improve the gastrointestinal tract function. Recently, using probiotics in food industry is growing. Bifidobacterium and Lactobacillus are most evaluated organisms as probiotics.

The Egyptian Ebers papyrus, from 16th century BC is the first book that presented a basic description for constipation. Ebers papyrus defined constipation as intoxication of body with hazardous agents from feces in bowels. In early 1900s, all-bran products were first introduced to prevent and treat auto-intoxicated patients due to constipation. In 1970s and 1980s, Denis Burkitt, an English surgeon, claimed the hypothesis about dietary fibers followed by the definition of “The Commonest Western disease”.

Constipation is classified according to etiology into seven subtypes include gastrointestinal, neurologic, metabolic, endocrine, psychiatric, drug-induced, and idiopathic.

About 1.5 liter fluid enters the colon from small intestine every day. Colon only excrete out 200-400 mL stool. The defecation process consist of three important stages, include filling of the rectum, sensation of rectum fullness, and relaxation of pelvic floor muscles in a coordinated fashion. Primary constipation is caused by anorectal and colonic problems, while secondary constipation is caused by organic and metabolic diseases or medications. Diseases that disturb the nervous system may lead to constipation, such as diabetes mellitus, autonomic neuropathy, Chagas’ disease, and Hirschsprung’s disease. Chronic use of the laxative may lead to melanosis coli, which is identified by hyperpigmentation and brownish discoloration of colonic mucosa. The primary histopathological finding in melanosis coli is brown granular pigment in lamina propria.

Constipation in adults may be due to side effects of medications, such as antispasmodics, anticholinergics, analgesics; or may be associated with systemic disorders, such as diabetes mellitus and hypothyroidism. Idiopathic constipation should be considered once the secondary causes are ruled out and it may be associated with normal or slow colonic transit, dysfunction in defecation, or both. Constipation in childhood often resolves with age after proper guidance regarding diet, toilet training, and toileting behaviors.

Diseases that cause constipation should differentiate from each others, such as malignancy, diabetic autonomic neuropathy, irritable bowel syndrome, rectocele, fissure, anismus, systemic sclerosis, hypothyroidism, Parkinson’s disease, multiple sclerosis, hypomagnesemia, hypocalcemia, and depression.

The incidence of constipation is approximately 16,666 per 100,000 individuals in general population (one in every six). The prevalence of constipation is approximately 2,000 to 28,000 per 100,000 individuals in general population. It is estimated that 4-56 million people are suffering from constipation in United States. The prevalence of constipation is approximately 1,900 to 27,200 (with an average of 14,800) per 100,000 individuals in North America. The general decline in 10-year survival rate of people with functional constipation is about 12%, comparing to normal population. The incidence of constipation increases with age. The non-White to White ratio of involving in constipation is from 1.13 to 2.89 (Mean 1.68, Median 1.41). Females are more commonly affected by constipation than males. The female to male ratio is approximately 2.2 to 1. Developing countries with lower income show higher prevalence of constipation rather than developed countries with higher income. Educational years in the population show an inverse relationship with prevalence of constipation.

The most potent risk factor in the development of constipation is inappropriate diet. Common risk factors include female gender, > 65 years of age, pregnancy, and Iron supplements.

According to the USPSTF, screening for constipation is not recommended in general population. In palliative care patients, screening for constipation by specific questionnaire about subjective and objective findings is recommended.

The symptoms of constipation can develop in the different decades of life, and starts with symptoms such as bloating, mucus passage, and abdominal pain. Then the symptoms increase in severity by hardening of stool which is contributes to straining and inability to pass the stool, may be need for manual evacuation. Common complications of chronic constipation include hemorrhoid, anal fissure, fecal impaction, and rectal prolapse. The colonic transit time (CTT) more than 100 hours is associated with a particularly poor prognosis among patients with constipation.

Diagnostic study of choice for constipation is ROME III criteria. Rome III criteria includes symptom onset for more than 6 months and two or more number of specific symptoms. Specific symptoms of constipation include straining, hard stool, sensation of incomplete evacuation, sensation of obstruction, necessity of manual maneuvers, less than 3 bowel movements per week, lack of loose stool, and lack of irritable bowel syndrome (IBS).

A positive history of straining, hard stools, sensation of incomplete evacuation, sensation of anorectal obstruction, use of manual maneuvers, and less than 3 defecations weekly is suggestive of constipation. The most common symptoms of constipation include infrequent bowel movements, abdominal bloating, necessity to strain, and anal pain. Less common symptoms of constipation include abdominal fullness, visible abdominal distention, incomplete evacuation, abdominal pain, rectal bleeding, and mass protrusion. Bristol Stool Form Scale and Patient Assessment Constipation-Quality of Life (PAC-QOL) are two questionnaire based on patients symptoms, help to diagnose constipation and quality of life in constipated patients.

Physical examination of patients with constipation is usually remarkable for anal fissure or palpable lumpy mass in abdomen (particularly in left quadrant). The presence of thrombosed external hemorrhoids, skin tags, rectal prolapse, anal fissure, anal warts, excoriation or evidence of pruritus ani due to fecal soiling on physical examination are suggestive of constipation. Patients with chronic constipation usually appear to be discomfort while sitting due to anal pain.

There are no diagnostic laboratory findings necessary for diagnosing constipation in young people without alarm signs. Laboratory test for exclusion of underlying diseases are complete blood count, blood urea nitrogen (BUN)/creatinine, serum phosphate levels, blood glucose levels, liver function tests (LFTs), fecal occult blood test, thyroid function tests, serum calcium levels, and serum magnesium levels. In case of high suspicion, other laboratory tests may be needed such as serum protein electrophoresis, urine porphyrins, serum parathyroid hormone, and serum cortisol levels.

An abdominal X-ray may be helpful in the diagnosis of constipation. Findings on an X-ray suggestive of constipation is interpreted according to three scoring system, including Barr, Blethyn, and Leech systems. Barr scoring system is the first scoring method used to interpret abdominal X-ray suggestive of constipation. The total score of more than 10 was postulated as diagnosis of constipation. The revised scoring system of Blethyn (a simplified version of Barr scoring system) is based on the amount of remained feces in large bowel. The Blethyn scoring system consists of 4 grades of fecal retention in bowels. The most studies and organized scoring system for diagnosis of constipation is Leech method. The score of more than 8 is considered as constipation.

There are no CT scan findings associated with constipation.

Different MRI modalities may be helpful in the diagnosis of constipation underlying diseases. Four types of MRI which are used for diagnosing constipation are conventional pelvic MRI, dynamic MRI (MR defecography), endoanal MRI, and fluoroscopic MRI. Pelvic MRI mostly reveals the general structure and anatomy of pelvic organs. Findings on MR defecography suggestive of constipation include various types of rectal prolapse (mucosal or full-thickness), disorders of pelvic floor muscles movements, very acute anorectal angle, and Increased perineal descent degree during rectal evacuation. The major findings on endoanal MRI are thinning of sphincter muscles, disruption of sphincter muscles, and changes in the anorectal angle. MRI fluoroscopy is a real time modality that evaluates the pelvic floor and viscera during defecation, valsalva maneuver, and evacuation process.

Endoanal ultrasound may be helpful for diagnosing underlying diseases causing constipation, particularly sphincter pathologies. Findings on an ultrasound suggestive of sphincter disorders are decline in thickness, depth, and size of the sphincter muscle. Endoanal ultrasound findings are scored through Starck scoring system, based on thickness, depth, and size of the sphincter muscles. The sphincter abnormality is classified as small (score of 1-4), moderate (score of 5-7), or large (score of 8-16).

Barium enema may be helpful in diagnosing underlying diseases of constipation. Findings on a barium enema suggestive of constipation are redundant sigmoid colon, megacolon, megarectum, extrinsic compression, and intraluminal masses. Defecography may be helpful in diagnosing underlying diseases causing constipation. Findings on a defecography suggestive of constipation are poor activation of levator ani muscle, prolonged retention or inability to expel the barium, absence of a stripping wave in the rectum, mucosal intussusceptions, or rectocele. The transit time of the colon can be measured by means of various methods, include radiopaque marker ingestion, radioisotope and scintigraphy study, and wireless motility capsule.

Endoscopic evaluation of patients with constipation include flexible sigmoidoscopy and colonoscopy. Flexible sigmoidoscopy is the direct visualization of the rectum and sigmoid colon. However, colonoscopy is study of the whole colon lumen. Every patient with alarm signs have to be evaluated using colonoscopy. In younger patients, flexible sigmoidoscopy would be sufficient for further investigation of alarm signs. Colonic manometry is 24-hour measurement of pressure within the large bowel, using specific probes and portable recorders. Anorectal manometry is studying the pressure activity of anorectum during rest and defecation, along with rectal sensation, rectoanal reflexes, and anal sphincter function. Balloon expulsion test is a simple bedside test to evaluate the ability of patient to evacuate the artificial stool. Rectal biostat test consists of a very compliant plastic balloon, which is inserted into the rectum, concurrently connected to computer device to measure the pressure.

Chronic constipation treatment includes both behavioral and pharmacological interventions. Behavioral management mostly consists of life style and dietary modification, while pharmacological interventions are mostly based on laxatives. Increasing physical activity is postulated to improve constipation and colonic transit time in patients with constipation. The most important behavioral treatment for constipation is biofeedback, consisting of teaching the patients how to use their abdominal and pelvic muscles during defecation. Probiotics are live microorganisms that are eaten to improve the gastrointestinal tract function. Recently, use of probiotics in food industry is growing. Bifidobacterium and Lactobacillus are most studied organisms as probiotics.

Surgery is not the first-line treatment option for patients with constipation. Surgery is usually reserved for patients with either rectopexy, total colectomy, and subtotal colectomy with ileorectal anastomosis. 

Constipation is usually easier to prevent than to treat. The relief of constipation with osmotic agents, i.e., lactulose, polyethylene glycol (PEG), or magnesium salts, should also be immediately followed by prevention using increased fiber (fruits, vegetables, and grains) and a nightly decreasing dose of osmotic laxative. Effective measures for the primary prevention of constipation include fiber supplementation, appropriate fluid intake, toilet habits, and exercise.

Effective measures for the secondary prevention of constipation include appropriate dietary modification and addition of fiber, suitable laxative and stool softener therapies, and avoiding harmful food products while constipated.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

The Egyptian Ebers papyrus, from 16th century BC is the first book that presented a basic description for constipation. Ebers papyrus defined constipation as intoxication of body with hazardous agents from feces in bowels. In early 1900s, all-bran products were first introduced to prevent and treat auto-intoxicated patients due to constipation. In 1970s and 1980s, Denis Burkitt, an English surgeon, claimed the hypothesis about dietary fibers followed by the definition of “The Commonest Western disease”.

• The Egyptian Ebers papyrus, from 16th century BC, is the first book that presented a basic description for constipation. Ebers papyrus defined constipation as intoxication of body with hazardous agents from feces in bowels.^[1]
• In 18th century, the personal physician of Louis XV in France, presented a similar definition as Ebers papyrus. He mentioned the constipation as blood pollution with released toxins from remained wastes in the intestines.^[2]
• In the beginning of 19th century, physicians believed that constipation was a disease of civilization and urban population was mostly involved with constipation.^[3]
• In 1850s, an American health manual revealed that “daily emptying the bowels is of the utmost importance in being healthy“. Daily bowel movement was also suggested to prevent derangement and disturbance in body.^[4]
• In 1906, Charles Bouchard, a French physician proposed the “auto-intoxication theory“, constipated person is continuously trying to commit suicide by auto-intoxication with toxins which are produced by feces remaining in his intestine.^[5]
• In 1923, William Walsh, an American physician, mentioned that not all the symptoms and severity of constipation are related to poisons released from feces remaining in bowels.^[6]
• In 1924, Arbuthnot Lane, a British physician, pointed out the relation between colon cancer and constipation. Lane presented that “the whiter your bread, the sooner you’re dead”.^[7]
• In 1928, Charles Campbell, an American physician, postulated that wastes remaining in colon are decomposing and may make the body full of poisons.^[8]
• In 1928, Victor Paucher, a French internist, suggested that stasis of feces in bowels make poisons secreted into blood and creates “Sewer-like blood”.^[9]

								1900
																						All-bran products were first introduced for the prevention and treatment of auto-intoxication due to constipation
														Early 1900s
																						Yeasts introduced in the yogurt were also postulated to prevent the constipation and following auto-intoxication
																						Arbuthnot Lane, a British physician, introduced Phenolphthalein as a strong laxative for children
														1913
																						Arbuthnot Lane also revealed that maintaining the normal human “drainage scheme” is the primary treatment for constipation
														1981								Denis Burkitt an English surgeon, claimed the hypothesis about dietary fibers followed by the definition of “The Commonest Western disease”
								2000

• In early 1900s, all-bran products were first introduced for the prevention and treatment of auto-Intoxication due to constipation.^[3]
• In early 1900s, yeasts were also postulated to prevent the constipation and the auto-intoxication that follows, when introduced in the yogurt.^[3]
• In 1913, Phenolphthalein was introduced as a strong laxative for children. Phenolphthalein quickly became the best laxative.^[7]
• From 1900 to 1920, Arbuthnot Lane, a British physician, revealed that maintaining the normal human “drainage scheme” is the primary treatment for constipation.^[7]
• In 1970s and 1980s, Denis Burkitt an English surgeon, claimed the hypothesis about dietary fibers followed by the definition of “The Commonest Western disease”.^[10]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

Constipation may be classified according to etiology into seven subtypes include gastrointestinal, neurologic, metabolic, endocrine, psychiatric, drug-induced, and idiopathic.

Constipation may be classified according to etiology into five subtypes:^[1][2]

• Gastrointestinal
• Neurologic
• Metabolic
• Endocrine
• Psychiatric

Constipation classification

Etiology

Neurologic

Metabolic

Endocrine

Gastrointestinal

Psychiatric

Drugs

Idiopathic

Obstruction

Aganglionosis

Idiopathic megacolon

Hirschprung disease

Chagas disease

•Multiple sclerosis • Parkinson’s disease • Spinal cord injury

•Hypercalcemia •Hypomagnesemia • Porphyria • Hypokalemia

• Hypothyroidism • Diabetes mellitus •Panhypopituitarism

• Depression • Eating disorder

• Analgesics • Anticholinergics • Cation-containing agents • Neuron targeting agents

• Normal colonic transit • Slow colonic transit • Dyssynergic defecation

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

About 1.5 liter fluid enters the colon from small intestine every day. Colon only excrete out 200-400 mL stool. The defecation process consist of three important stages, include filling of the rectum, sensation of rectum fullness, and relaxation of pelvic floor muscles in a coordinated fashion. Primary constipation is caused by anorectal and colonic problems, while secondary constipation is caused by organic and metabolic diseases or medications. Diseases that disturb the nervous system may lead to constipation, such as diabetes mellitus, autonomic neuropathy, Chagas’ disease, and Hirschsprung’s disease. Chronic use of the laxative may lead to melanosis coli, which is identified by hyperpigmentation and brownish discoloration of colonic mucosa. The primary histopathological finding in melanosis coli is brown granular pigment in lamina propria.

• Water absorption
  • About 1.5 liter fluid enters the colon from small intestine every day. Colon excrete out only 200-400 mL stool.
  • Colon absorb water and transit the stool into rectum to store and expel. The amount of water that is absorbed in rectum depends on the state of hydration.^[1]
  • Both sodium and chloride are the key elements in reabsorbing water from colon. The more time stool remains in the colon, the drier it becomes.^[2]
• Motility
  • There are two mechanism of gross motility in colon including:^[1]
    • Repetitive non-propulsive contractions: The primary type of contraction responsible for mixing and absorption of contents.
    • High-amplitude propagated contractions (HAPCs): Large coordinated contraction responsible for pushing the stool forward. Increases in the morning and after drinking and/or eating.
  • Normal colonic transit time is about 20-72 hours.^[3]
  • HAPCs are usually decreased in constipation and maybe the main pathophysiology of constipation.^[4]
  • On molecular basis, the primary movements of the gut (peristalsis) are regulated through serotonin (5-hydroxytriptamine [5HT]). 5HT is released from enterochromaffin cells when the bowel wall undergo traction (e.g., due to food or bolus). There are seven subtypes of the 5HT receptors, among which 5HT₄ and 5HT₃ are the most important for peristalsis. 5HT₄ drives 5HT effect on the gut and 5HT₃ is responsible for the bowel sensation.^[5]

• The defecation process consist of three important stages including:^[6]
  1. Filling of the rectum
  2. Sensation of rectum fullness
  3. Relaxation of pelvic floor muscles in a coordinated fashion
• Anal sphincters and puborectalis muscle are anatomical contributors of normal fecal consistency.
• Resting anal sphincter tone is due to both involuntary internal (70%) and voluntary external (30%) anal sphincters tone.
• Rectoanal inhibitory reflex (RAIR) consist of relaxing the internal anal sphincter in response to rectal distention due to flatus or stool. RAIR is completely regulated by the gut and is not controlled by peripheral or central nervous system. Presence of RAIR rules out Hirschsprung’s disease as a differential diagnosis.^[2]
• When stool enters in rectum, the internal sphincter is relaxed by reflex. If the defecation is inconvenient, the puborectalis muscle is contracted and external sphincter is closed. In case defecation is desired, the puborectalis muscle is voluntarily relaxed and external sphincter is opened. Therefore, defecation may be assisted with valsalva maneuver.^[7]

• Primary constipation is caused by anorectal and colonic problems, while secondary constipation is caused by organic and metabolic diseases or medications.

• Primary constipation is considered when the secondary causes of constipation are ruled out. Without any certain causes or alarm signs, empiric therapy with dietary fibers and laxatives is administered. If the laxative treatment is successful, there will be no need to additional work up.
• Colonic transit test is needed if further work up is necessary for constipation. The procedure consist of ingestion of marker-contained capsule and taking an abdominal X-ray after 120 h (5 days).^[8]
• After locating and counting the markers, if more than 20% of markers remains within the colon, it is defined as slow transit disease.
  • Normal-transit constipation
    • The most common form of constipation referred to clinicians is normal transit constipation, which is also known as functional constipation.^[9]
    • Majority of the patients experience normal transit time and stool frequency. Numerous patients meet the criteria for irritable bowel syndrome with constipation (IBS-C) or psychological disorders.^[10]
    • Rome III criteria for functional constipation is presence of two or more than two of the followings for ≥ 3 months and onset ≥ 6 months before the diagnosis:^[11]
      • < 3 defecation per week
      • Straining during defecation
      • Lumpy or hard stool
      • Sensation if incomplete emptying of rectum
      • Sensation of in anorectal obstruction
      • Manual evacuation need for defecation
    • Most of the patients are cured with dietary fibers, osmotic laxatives, or enterokinetics.
  • Slow-transit constipation
    • Slow-transit constipation is consisted of significant decreased number of defecations, less than once a week and the majority of times involve young women.^[12]
    • The more severe form, called “colonic inertia”, is the condition in which eating and prokinetics does not lead to increase in motor activity and HAPCs.^[13]
    • The slow-transit constipation is due to decreased number of interstitial cells of Cajal (ICC) and alteration of myenteric plexus neurons which secretes substance P.^[14][15]
    • Hypoganglionosis, inflammatory neuropathy, and leiomyopathy are other causes of slow-transit constipation.
  • Defecation disorder
    • Straining and spending long times in toilet are the main findings in patients with defecation disorder.
    • Patients with defecation disorder often have problems with both liquid and firm stools. Therefore, laxatives are not effective mostly.
    • Anorectal manometery and balloon expulsion test are the gold-standard tests for diagnosing functional defecation disorder.^[16]
    • The majority of the functional defecation disorders are due to dyssynergia. Dyssynergia is an acquired condition due to disorganized toilet habits, chronic pain during defecation, obstetrics and back injuries.^[17]
    • The primary defect in dyssynergia is lack of coordination among abdominal, rectoanal, and pelvic floor muscles contractions during defecation process.^[17]

• Most of medications can lead to constipation as a side effect. Therefore, a comprehensive history of medications is needed in every patients with constipation.^{[18][19][20][21][22]}

Group	Drug	Alternatives
Antihypertensives	Clonidine	Beta-blockers Angiotensin-converting enzyme inhibitors Angiotensin II receptor antagonists
	Calcium channel blockers
	Ganglionic blockers
Antidepressants	Tricyclic antidepressants	Selective 5HT reuptake inhibitors 5HT norepinephrine reuptake inhibitors
Cation-containing drugs	Oral iron supplementation	Intravenous supplementation of iron Addition of a laxative
Aluminum-containing drugs	Sucralfate	Proton pump inhibitors
	Antacids
Analgesics	Opiates	Different class of analgesic drugs Using an opiate in combination with a peripherally active opiate receptor antagonist, such as naloxone or methylnaltrexone
	Cannabinoids
Anti-Parkinson		Regular use of laxatives
Antiepileptic
Antipsychotic
Antihistamines		Replaced with other groups
Antispasmodics
Vinca alkaloids

• Diseases that disturb the nervous system may lead to constipation, such as diabetes mellitus, autonomic neuropathy, Chagas’ disease, and Hirschsprung’s disease.
• Both hyperglycemia and hypoglycemia may lead to bowel movement disturbance and constipation.^[23]

• Genetic studies have shown the role of genetics in childhood constipation by various mechanisms.
• Genes involved in the pathogenesis of childhood constipation and related diseases are as following:^[24]

Group	Gene	OMIM/Chromosome	Syndrome	Other manifestations
Autonomic nervous system	GFAP	203450/17q21	Alexander disease	Seizures Neurodegeneration Spasticity
	LMNB1	169500/5q23	Cavitating leukodystrophy – autonomic failure	Cerebellar and pyramidal failure Orthostatic hypotension Bowel and bladder control problems
	PHOX2B	209880/4p12	Congenital central hypoventilation syndrome	Hypoventilation Ocular abnormalities Hirschsprung disease
	HSN2	201300/12p13	Hereditary sensory and autonomic neuropathy type II and III	Autonomic dysfunction Defective lacrimation Incoordination
	IKBKAP	223900/9q31
	MECP2	300005/Xq28	MECP2 duplication	MR Hypotonia Seizures Autonomic dysfunctioning Spasticity
	SCN9A	167400/2q24	Paroxysmal extreme pain disorder	Rectal pain Sphincter hypertrophy
	TCF4	610954/18q21	Pitt-Hopkins syndrome	MR Overbreathing Clubbing fingers Unusual face Hirschsprung disease
	NRXN1	610954/2p16.3
Innervation	ATRX	301040/Xq13	Alpha-thalassemia mental retardation syndrome	MR Alpha-thalassemia Short stature Microcephaly Unusual face Hirschsprung disease
	RET	162300/10q11	MEN2B	Multiple endocrine adenomatosis Dysmorphic features Hirschsprung disease Gastrointestinal ganglioneuromatosis
	ZEB2	235730/2q22	Mowat-Wilson syndrome	MR Microcephaly Unusual face Short stature Hirschsprung disease
	HPSE2	236730/10q24	Ochoa syndrome	Unusual facial expression Hydroureters Hydronephrosis
Muscular	COL4A5	308940/Xq22	Alport syndrome with diffuse leiomyomatosis	Hematuria Leiomyomatosis Cataracts Deafness
	COL4A6
	PTRF-CAVIN	613327/17q21	Congenital generalized lipodystrophy, type 4	Lipodystrophy Insulin resistance Pyloric stenosis Cardiac arrhythmia
	DES	601419/2q35	Desmin-related myopathy	Skeletal muscle weakness Cardiac problems
	SCN4A	170500/17q23	Hyperkalemic periodic paralysis (HYPP)	Episodic flaccid generalized muscle weakness
	ZNF9	160900/3q21	Myotonic dystrophy	Myotonia Muscular dystrophy Cataract Hypogonadism Frontal balding
	DMPK	602668/19q13
	SMN1	253300/5q12	Spinal muscular atrophy	Acute spinal muscular atrophy Severe hypotonia
	AXPC1	609033/1q31	Posterior column ataxia with retinitis pigmentosa	Posterior column ataxia Retinitis pigmentosa Esophageal achalasia
	CBP	180849/16p13	Rubinstein-Taybi syndrome	MR Broad thumbs Broad halluces Unusual face Growth retardation
	EP300	180849/22q13
	HUWE1	300706/Xp11	Turner mental retardation syndrome	MR Macrocephaly Contractures Holoprosencephaly
	UPF3B	300676/Xq25	X-linked syndromic mental retardation -14	MR Hypotonia Slender body build Long face
Electrolyte disturbance	SLC12A3	263800/16q13	Gitelman syndrome	Hypokalemic metabolic alkalosis Salt wasting
	SLC6A8	300036/Xq28	Creatinine transporter defect	MR Hypotonia Seizures Behavioral problems
	CASR	239200/3q21	Hyperparathyroidism – neonatal familial	Hypotonia Respiratory distress Irritability Polyuria
	AVPR2	304800/Xq28	Nephrogenic diabetes insipidus	Vomiting Anorexia Failure to thrive Fever
	SPINK5	256500/5q32	Netherton syndrome	Ichthyosis Eczema Brittle hair Alopecia
Malformation	HLXB9	176450/7q36	Currarino syndrome	Anal atresia Sacral anomalies Presacral mass
	MED12	305450/Xq13	FG syndrome	MR Macrocephaly Anal malformation Pyloric stenosis Hypotonia
	FLNA	305450/Xq28
	SIX3	157170/2p21	Holoprosencephaly	MR Microcephaly Cleft lip Cleft palate Hypotelorism Sacral agenesis Holoprosencephaly
	VANGL1	600145/1p13	Sacral defect with anterior meningocele	Caudal dysgenesis

Associated conditions with constipation are included:

• Diabetes mellitus
• Hypothyroidism
• Systemic sclerosis
• Parkinson’s disease
• Depression
• Eating disorders
• Colon cancer
• External compression from malignant lesion
• Strictures: diverticular or postischemic
• Rectocele (if large)
• Postsurgical abnormalities
• Megacolon
• Anal fissure
• Hypercalcemia
• Hypokalemia
• Hypomagnesemia
• Uremia
• Heavy metal poisoning
• Myopathies
• Parkinson’s disease
• Spinal cord injury or tumor
• Cerebrovascular disease
• Depression
• Degenerative joint disease
• Autonomic neuropathy
• Cognitive impairment
• Immobility
• Cardiac disease

• On gross pathology, there is no finding related to constipation.

• On microscopic histopathological analysis, there is no finding related to constipation.
• Chronic use of the laxative may lead to melanosis coli, which is identified by hyperpigmentation and brownish discoloration of colonic mucosa.
• The primary histopathological finding in melanosis coli is brown granular pigment in lamina propria.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mugilan Poongkunran M.B.B.S [2], Eiman Ghaffarpasand, M.D. [3]

Constipation in adults may be due to side effects of medications, such as antispasmodics, anticholinergics, analgesics; or may be associated with systemic disorders, such as diabetes mellitus and hypothyroidism. Idiopathic constipation should be considered once the secondary causes are ruled out and it may be associated with normal or slow colonic transit, dysfunction in defecation, or both. Constipation in childhood often resolves with age after proper guidance regarding diet, toilet training, and toileting behaviors.

Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated. These conditions include the followings:^[1]

• Atropine poisoning
• Hypokalemia
• Lead poisoning
• Opium poisoning
• Severe dehydration
• Spinal cord injury
• Superior mesenteric artery occlusion
• Volvulus

Common causes of constipation include:^{[2][3][4][5][6]}

• Hardening of the feces
  • Improper mastication
  • Insufficient intake of dietary fiber
  • Dehydration
  • Medications (aluminium, calcium, diuretic, iron)
• Paralysis or slowed transit
  • Hypothyroidism
  • Hypokalemia
  • Injured anal sphincter (patulous anus)
  • Medications (loperamide, codeine, morphine and certain tricyclic antidepressants)
  • Severe illness due to other causes
  • Acute intermittent porphyria
  • Lead poisoning
• Dyschezia (usually the result of suppressing defecation)
• Constriction, where part of the intestine or rectum is narrowed or blocked
  • Stenosis
  • Diverticulosis
  • Pelvic masses
  • Retained foreign body or a bezoar
• Psychosomatic constipation
  • Functional constipation
  • Irritable bowel syndrome
• Smoking cessation
• Abdominal surgery
• Childbirth

Less common causes of constipation include:^{[7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]}

• Acute intermittent porphyria
• Adjustable gastric band
• Anal atresia
• Anal carcinoma
• Autism
• Autonomic neuropathy
• Bortezomib
• Cap polyposis
• Chronic inflammatory demyelinating polyneuropathy
• Chronic intestinal pseudo-obstruction
• Dermatitis herpetiformis
• Desvanlafaxine
• Diverticular stricture,
• Eosinophilic colitis
• Fluorouracil
• Fructose malabsorption
• Glucagonoma
• Hereditary coproporphyria
• Histone deacetylase inhibitors
• Iliac artery aneurysm
• Intestinal pseduoobstruction
• Janumet (sitagliptin and metformin)
• Jacobsen syndrome
• Lambert-Eaton myasthenic syndrome
• Milnacipran hydrochloride
• Multiple endocrine neoplasia (MEN 2b)
• Occult spinal dysraphism sequence
• Ogilvie’s syndrome
• Painful defecation
• Pseudohypoparathyroidism
• Sirolimus
• Thalidomide
• Vincristine
• Williams-Beuren syndrome

Cardiovascular	Iliac artery aneurysm, Superior mesenteric artery occlusion.
Chemical / poisoning	Atropine poisoning, Lead poisoning, Opium poisoning.
Dermatologic	Dermatitis herpetiformis.
Drug Side Effect	5-HT3 antagonist, 5-hydroxytryptophan, Acamprosate, Acebutolol, Acetaminophen, Aldesleukin, Alendronate, Alfentanil, Alfuzosin, Alosetron, Alprazolam, Aluminium hydroxide, Amiodarone, Amitriptyline, Amlodipine, Amobarbital, Anagrelide, Anastrozole, Aprepitant, Aripiprazole, Atorvastatin, Atovaquone, Atropine, Auranofin, Axitinib, Azacitidine Barium sulfate, Basiliximab, Benzatropine, Benzonatate, Bepridil, Beta blockers, Bezafibrate, Bicalutamide, Bile acid sequestrant, Bortezomib, Bromocriptine, Buspirone, Busulfan, Butabarbital, Butorphanol, Calcitriol, Calcium carbonate, Capecitabine, Caspofungin acetate, Carbamazepine, Carbidopa, Carboplatin, Carfilzomib, Carteolol, Cerivastatin, Cetuximab, Chlordiazepoxide, Chloropyramine, Chlorpromazine, Chlorpropamide, Cholestyramine, Cidofovir, Cimetidine, Cisapride, Citalopram, Cladribine, Clobazam, Clofarabine, Clomipramine, Clonazepam, Clonidine, Clorazepate, Clozapine, Codeine, Colesevelam, Colestipol, Colofac, Crizotinib, Cyclizine, Cyclobenzaprine, Cytarabine liposome Daptomycin, Darbepoetin alfa, Darifenacin, Darunavir, Desipramine, Desvenlafaxine, Dextroamphetamine, Dextropropoxyphene, Diacetyldihydromorphine, Diazepam, Dicyclomine, Diethylcathinone, Diflunisal, Dihydroetorphine, Diltiazem, Dimenhydrinate, Diphenhydramine, Disopyramide, Diuretic, Dolasetron, Dolasetron, Doripenem, Dosulepin hydrochloride, Doxepin, Droperidol, Duloxetine, Efavirenz, Enfuvirtide, Enzalutamide, Epoetin alfa, Eribulin, Esomeprazole, Estazolam, Estradiol, Ethcathinone, Ethosuximide, Ethylmorphine, Etodolac, Etoposide, Everolimus, Famotidine, Felbamate, Felodipine, Fenofibrate, Fenoprofen, Fentanyl, Ferrous sulfate, Fesoterodine, Fludarabine phosphate, Fluorouracil, Fluoxetine, Fluphenazine, Flurazepam, Flurbiprofen, Fluvoxamine, Fulvestrant, Furosemide, Gabapentin, Ganciclovir, Gatifloxacin, Gemcitabine, Gemfibrozil, Glipizide, Glycopyrrolate, Granisetron, Guanethidine, Guanfacine, H2 antagonist, Haloperidol, Hexamethonium, Histone deacetylase inhibitors, Hydralazine, Hydrocodone, Hydrocodone bitartrate and Homatropine methylbromide, Hydroxyurea, Hydroxyzine, Hyoscyamine, Hydrochlorothiazide, Ibandronate, Imatinib, Imipramine, Indomethacin, Insulin lispro, Interferon beta-1b, Ipratropium, Irinotecan hydrochloride, Iron supplements, Isocarboxazid, Isradipine, Itraconazole, Ivermectin, Kaolin, Ketorolac tromethamine, Lacidipine, Lamivudine, Lamotrigine, Lansoprazole, Lanthanum, Leflunomide, Lenalidomide, Letrozole, Leuprolide, Levalbuterol, Levetiracetam, Levodopa, Levomethadyl, Levorphanol, Linezolid, Lofepramine, Lomotil, Lorcaserin, Loperamide, Loprazolam, Lorazepam, Lovastatin, Lovaza, Loxapine, Magaldrate, Mebendazole, Meclizine, Meclofenamate, Mefenamic acid, Meperidine, Meropenem, Mesalamine, Mesna, Mesoridazine, Metformin, Methadone, Methsuximide, Methyprylon, Metoprolol, Mifepristone, Milnacipran hydrochloride, Misoprostol, Modafinil, Morphine, Motofen, Nabumetone, Naproxen sodium, Nateglinide, Nefazodone, Netupitant and palonosetron, Nicardipine, Nifedipine, Nilotinib, Nilutamide, Nimodipine, Nisoldipine, Nizatidine, Nortriptyline, Olanzapine, Omeprazole, Ondansetron, Oxaliplatin, Oxazepam, Oxcarbazepine, Oxybutynin, Oxycodone, Palonosetron, Pamidronate, Pancrelipase, Paroxetine, Peginterferon alfa-2b, Pemetrexed, Pentamidine Isethionate, Pergolide, Perphenazine, Pethidine, Phenelzine, Phentermine, Phenytoin, Pholcodine, Pimozide, Piperacillin sodium, Piroxicam, Posaconazole, Pramipexole, Prazepam, Prazosin, Prednisolone, Pregabalin, Procarbazine, Prochlorperazine, Procyclidine, Progesterone, Promethazine, Propafenone, Propantheline, Propoxyphene, Propranolol, Protriptyline, Quetiapine, Rabeprazole, Ranitidine, Ranolazine, Rasagiline, Rasburicase, Reboxetine, Repaglinide, Ribavirin, Rilmenidine, Risperidone, Rivastigmine, Ropinirole, Rosuvastatin, Sacrosidase, Saquinavir, Scopolamine, Scopolamine, Secobarbital, Selegiline, Sertraline, Sevelamer, Sibutramine, Siltuximab, Simethicone, Simvastatin, Sirolimus, Sitaxsentan, Sorafenib, Sotalol, Sucralfate, Sufentanil, Sulindac, Sunitinib, Suxamethonium chloride, Tacrolimus, Tamoxifen, Tapentadol, Tegaserod, Temazepam, Temozolomide, Terazosin, Teriparatide, Tetraferric tricitrate decahydrate, Thalidomide, Thioridazine hydrochloride, Thiothixene, Tianeptine, Tiludronate, Tinidazole, Tiotropium, Tolterodine, Tolmetin, Topiramate, Topotecan, Trametinib dimethyl sulfoxide, Tranylcypromine, Tretinoin, Triazolam, Triclofos, Trifluoperazine, Trihexyphenidyl, Trimethadione, Trimipramine, Tropisetron, Trospium, Valganciclovir hydrochloride, Valproic acid, Venlafaxine, Verapamil, Vicodin, Vigabatrin, Viloxazine, Vinblastine, Vincristine, Vincristine sulfate liposome, Vindesine, Vinorelbine, Vorinostat, Zaleplon, Zidovudine, Zileuton, Ziprasidone, Zoledronic acid, Zolpidem, Zonisamide, Zotepine.
Ear Nose Throat	No underlying causes
Endocrine	Conn’s syndrome, Diabetes mellitus, Glucagonoma, Hashimoto’s thyroiditis, Hyperparathyroidism, Hypothyroidism, Multiple endocrine neoplasia, Multiple endocrine neoplasia type 1, Multiple endocrine neoplasia type 2, Myxedema, Panhypopituitarism, Parathyroid adenoma, Pheochromocytoma, Primary parathyroid hyperplasia, Pseudohypoparathyroidism.
Environmental	Cow’s milk intolerance
Gastroenterologic	Anal atresia, Anal carcinoma, Ascites, bowel adhesion, Bowel obstruction, cap polyposis, Celiac disease, Chronic amebiasis, Colectomy, Colonic stricture, Colorectal cancer, Congenital malformation, Corrosive enemas, Crohn’s disease, Diverticular stricture, Diverticulitis, Enterocele, Eosinophilic colitis, Extrinsic compression, Gastroptosis, Hernia, Hirschsprung’s disease, Ileus, Imperforate anus, Inflammatory bowel disease, Intraabdominal/pelvic tumors, Intussusception, Irritable bowel syndrome, Ischemic colitis, Megacolon, Megarectum, Ogilvie’s syndrome, Painful defecation, Paralytic ileus, Pelvic masses, Pelvic tumors, Perianal abscess, Proctitis, Rectal cancer, Rectal prolapse, Rectal ulcer, Rectocele, Ulcerative colitis, Visceral myopathies, Volvulus, Wandering spleen.
Genetic	Batten disease, Berdon syndrome, Cerebral palsy, Cornelia de Lange syndrome, Cystic fibrosis, Down syndrome, Gastroschisis, Hereditary coproporphyria, Hereditary internal anal sphincter myopathy, Megacolon, Megarectum, Prune belly syndrome.
Hematologic	Acute intermittent porphyria, Amyloidosis, Hereditary coproporphyria, Iron deficiency anemia.
Iatrogenic	Adjustable gastric band, Colectomy, painful defecation, Peritoneal dialysis, Postoperative complications, Postoperative ileus, Toilet training issues, Upper gastrointestinal series.
Infectious Disease	Blastocystosis, Botulism, Chagas disease, Chronic amebiasis, Hookworm, Lassa fever, Lymphogranuloma venereum, Syphilis, Tuberculosis, Typhoid fever, Opisthorchis infection, Polio.
Musculoskeletal / Ortho	Ankylosing spondylitis, Guillain-Barre syndrome, Lambert-Eaton myasthenic syndrome, Muscular dystrophy, Osteitis fibrosa cystica, Paraplegia, Spinal cord injury, Spinal cord tumor.
Neurologic	Amyotrophic lateral sclerosis, Autonomic neuropathy, Cerebral palsy, Chagas disease, Chronic inflammatory demyelinating polyneuropathy, Diabetes mellitus, Guillain-Barre syndrome, Hirschsprung’s disease, Intestinal neuronal dysplasia, Lambert-Eaton myasthenic syndrome, Meningocele, Multiple sclerosis, Muscular dystrophy, Neurofibromatosis, Occult spinal dysraphism sequence, Paraplegia, Parkinson’s disease, Progressive supranuclear palsy, Pseduoobstruction, Scleroderma, Spina bifida, Spinal cord injury, Spinal cord lesions, Static encephalopathy, Tabes dorsalis, Tethered spinal cord syndrome.
Nutritional / Metabolic	Cow’s milk intolerance, Food intolerance, Hypercalcemia, Hypervitaminosis D, Hypokalemia, Iron deficiency anemia, Ketogenic diet, Lack of fiber, Low residue diet, Milk-alkali syndrome, Severe dehydration, Starvation.
Obstetric/Gynecologic	Childbirth, Complication of pregnancy, Extremely low birth weight, Ovarian cancer, Rectovaginal or bowel endometriosis, Uterine fibroid.
Oncologic	Colorectal cancer, Intraabdominal/pelvic tumors, Multiple endocrine neoplasia (MEN 2b), Neuroblastoma, Ovarian cancer, Parathyroid adenoma, Rectal carcinoma, Renal cell carcinoma, Sacrococcygeal teratoma, Spinal cord tumor, Stomach cancer, Uterine fibroid.
Opthalmologic	No underlying causes
Overdose / Toxicity	Acamprosate, Amiodarone, Atropine, Carboplatin, Fentanyl, Phenytoin, Hypervitaminosis D, Haloperidol.
Psychiatric	Anorexia nervosa, Autism, Bipolar disorder, Eating disorder, Emotional stress, Major depression, Obsessive compulsive disorder, Pseudocyesis, Psychosis.
Pulmonary	Cystic fibrosis.
Renal / Electrolyte	Hypercalcemia, Hypokalemia, Renal cell carcinoma, Severe dehydration, Uremia.
Rheum / Immune / Allergy	Amyotrophic lateral sclerosis, Ankylosing spondylitis, Chronic inflammatory demyelinating polyneuropathy, Cow’s milk intolerance, Food intolerance, Guillain-Barre syndrome, Lambert-Eaton myasthenic syndrome, Rett syndrome, Scleroderma.
Sexual	Tabes dorsalis.
Trauma	Spinal cord injury.
Urologic	Urogenital neoplasm.
Miscellaneous	Dietary pattern change, Dieting, Extended bed rest, Functional constipation, Idiopathic, Normal aging, Smoking cessation, SSRI discontinuation syndrome, Travel constipation.

Template:WikiDoc Sources

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

Diseases that cause constipation should differentiate from each others, such as malignancy, diabetic autonomic neuropathy, irritable bowel syndrome, rectocele, fissure, anismus, systemic sclerosis, hypothyroidism, Parkinson’s disease, multiple sclerosis, hypomagnesemia, hypocalcemia, and depression.

• Diseases that cause constipation should differentiate from each others, such as malignancy, diabetic autonomic neuropathy, irritable bowel syndrome, rectocele, fissure, anismus, systemic sclerosis, hypothyroidism, Parkinson’s disease, multiple sclerosis, hypomagnesemia, hypocalcemia, and depression.

•Weight loss>10 lb •FHx of CRC •Acute onset in elderly •Hematochezia •Iron deficiency anemia •Positive OB

•Analgesic •Anticholinergic ••Antihistamines ••Antispasmodics ••Antidepressants ••Antipsychotics •Cation-containing agent ••Iron supplements ••Aluminum (antacids, sucralfate) ••Barium •Neuron targeting agents ••Opiates ••Antihypertensive ••Ganglionic blocker ••Calcium channel blockers ••5-HT3 antagonist

Alarm signs

Drugs

Constipation

Abdominal pain

YES

NO

Irritable bowel syndrome Malignancy Diabetic autonomic neuropathy

Hypothyroidism Hypomagnesemia Hypocalcemia Systemic sclerosis Multiple sclerosis Parkinson’s disease Depression Fissure Anismus Rectocele

Weight loss

Anal pain

YES

NO

YES

NO

Irritable bowel syndrome Diabetic autonomic neuropathy

Fissure Anismus Rectocele

Hypothyroidism Hypomagnesemia Hypocalcemia Systemic sclerosis Multiple sclerosis Parkinson disease Depression

Polyuria Polydipsia Polyphagia

Mass protrusion

Dry skin

YES

NO

YES

NO

YES

NO

Fissure Anismus

Hypothyroidism Systemic sclerosis

Hypomagnesemia Hypocalcemia Multiple sclerosis Parkinson’s disease Depression

Rectal bleeding

Dysphagia

Neurologic symptoms (tremor, abnormal gait)

YES

NO

YES

NO

YES

NO

Multiple sclerosis Parkinson disease

Hypomagnesemia Hypocalcemia Depression

Basal ganglia atrophy in MRI

Electrolyte disturbance

YES

NO

YES

YES

NO

Malignancy

Diabetic autonomic neuropathy

Irritable bowel syndrome

Rectocele

Fissure

Anismus

Systemic sclerosis

Hypothyroidism

Parkinson’s disease

Multiple sclerosis

Hypomagnesemia

Hypocalcemia

Depression

To review the differential diagnosis of Constipation and Abdominal pain, click here.

To review the differential diagnosis of Constipation and Anal pain, click here.

To review the differential diagnosis of Constipation and Rectal bleeding, click here.

To review the differential diagnosis of Constipation and Weight loss, click here.

To review the differential diagnosis of Constipation and Tremor, click here.

Diseases		History and Symptoms								Physical Examination				Laboratory Findings			Other Findings	Diagnostic study of choice
														Electrolyts [Ca, K, Mg]	Biochemical tests
		GI symptoms				Extra GI symptoms				Abnormal gait	Anal protruding mass	DRE	Deep tendon reflex		FBS	TSH
		Dysphagia	Abdominal pain	Anal pain	Rectal bleeding	Weight loss	Polyphagia, Polyuria, Polydipsia	Dry skin	Tremor
Gastrointestinal diseases	Malignancy	–	–	+/-	+	++	–	–	–	–	–	Empty rectum	Normal	Normal	Normal	Normal	Acute change in bowel habits Rectal bleeding Anemia	Rectosigmoidoscopy with biopsy
	Irritable bowel syndrome (IBS)	–	+	+/-	–	–	–	–	–	–	–	Normal	Normal	Normal	Normal	Normal	Frequent change in bowel habit Abdominal pain alleviating with bowel movement	Rolling out other pathophysiologies
	Rectocele	–	–	–	–	–	–	–	–	–	+	Bulging rectum	Normal	Normal	Normal	Normal	Obstruction Absence of defecation and faltus	Anoscopy
	Anal fissure	–	–	+++	+	–	–	–	–	–	–	Increased sphincter tone	Normal	Normal	Normal	Normal	Rectal bleeding after defecation Painful DRE	DRE
	Anismus	–	–	+	–	–	–	–	–	–	–	Increased sphincter tone	Normal	Normal	Normal	Normal	Absence of defecation and flatus	DRE
	Diverticulosis	–	+	–	+	–	–	–	–	–	–	Normal	Normal	Normal	Normal	Normal	Chronic constipation Bowel obstruction	Colonoscopy
Neurogenic diseases	Diabetic autonomic neuropathy	–	–	–	–	+	++	+/-	–	+/-	–	Normal	↓	Normal	↑↑	Normal	Distal neuropathy Gastroparesis Nausea and vomiting	FBS and HbA1C
	Anorexia nervosa	–	–	–	–	++	–	+/-	–	–	–	Normal	Normal	↓ Electrolytes	↓	Normal	↓↓↓ BMI Amenorrhea Depressed mood	Clinical characteristics
	Parkinson’s disease	+/-	–	–	–	–	–	–	++	+	–	Normal	↑↑	Normal	Normal	Normal	Muscle stiffness Drooling	Brain MRI
	Multiple sclerosis	+	–	–	–	–	–	–	+	+	–	Normal	↓↑	Normal	Normal	Normal	Blurred vision Erectile dysfunction	Brain MRI CSF biochemical profile
	Depression	–	–	–	–	+	–	–	–	–	–	Normal	Normal	Normal	Normal	Normal	Hopelessness Weakness and fatigue Depressed mood	Psychological examination
	Hirschsprung disease	–	+	–	+	+	–	–	–	–	–	Blood tinged glove	Normal	Normal	Normal	Normal	Abdominal distention Growth retardation Vomiting	Barium enema
	Cerebral palsy	+	–	–	–	+	–	–	+	+	–	Normal	↑	Normal	Normal	Normal	Spastic extremities paralysis Paresthesia	Brain MRI Physical examination
	Chagas disease	+	–	–	–	+	–	–	–	–	–	Normal	↓	Normal	Normal	Normal	Cardiomyopathy Megaesophagus or megacolon	Peripheral blood smear
Endocrine diseases	Hypothyroidism	–	–	–	–	–	–	+	–	–	–	Normal	↓↓	Normal	Normal	↑↑	Weakness and fatigue Dysmenorrhea	Thyroid function tests (TFT)
	Cystic fibrosis	–	+	–	–	+	–	–	–	–	–	Normal	Normal	Normal	Normal	Normal	Recurrent pneumonia Absent vas deferens	Sweat Cl test
	Lead poisoning	–	+++	–	–	–	–	–	+	–	–	Normal	Normal	Normal	Normal	Normal	Sideroblastic anemia Dysesthesia Amnesia	Plasma lead level
	Pheochromocytoma	–	–	–	–	–	–	–	+	–	–	Normal	Normal	Normal	Normal	Normal	Hypertension crisis Severe headache Blurred vision	Urine vanillyl mandelic acid (VMA) level
	Panhypopituitarism	–	–	–	–	–	–	–	–	–	–	Normal	↓	Normal	Normal	Normal	Hypothyroidism Amenorrhea Growth retardation	Hormone levels Brain MRI
Electrolyte disturbances	Hypomagnesemia	–	+	–	–	–	–	–	+	–	–	Normal	↓	↓↓ Mg	Normal	Normal	Nystagmus Seizure	Plasma Mg level
	Hypocalcemia/Hypercalcemia	–	+	–	–	–	–	–	–	–	–	Normal	↓	↓Ca/↑Ca	Normal	Normal	Muscle weakness Dysesthesia	Plasma Ca level
	Hypokalemia	–	+	–	–	–	–	–	–	+/-	–	Normal	↓	↓K	Normal	Normal	Metabolic alkalosis Paralysis Seizure	Plasma K level
Systemic diseases	Pregnancy	–	–	–	–	–	–	–	–	–	–	Normal	Normal	Normal	Normal	Normal	Lower extremities edema Dyspnea Nausea and vomiting	Plasma βhCG Ultrasonography
	Systemic sclerosis	+	–	–	–	–	–	+	–	–	–	Normal	Normal	Normal	Normal	Normal	Raynaud phenomenon Fingertip ulcer	Clinical characteristics Anti-centromere and anti-Scl-70 antibodies

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