C. difficile  toxins have a  cytopathic  effect in cell culture, and neutralization of any effect observed with specific antisera is the practical  gold standard  for studies investigating new CDI diagnostic techniques. [ 20 ]  Toxigenic culture, in which organisms are cultured on selective media and tested for toxin production, remains the gold standard and is the most sensitive and specific test, although it is slow and labor-intensive. [ 49 ]


Assessment of the A and B toxins by enzyme-linked immunosorbent assay ( ELISA ) for toxin A or B (or both) has a  sensitivity  of 63–99% and a  specificity  of 93–100%, depending on detection assays. [ 47 ]


Previously, experts recommended sending as many as three stool samples to rule out disease if initial tests are negative, but evidence suggests repeated testing during the same episode of diarrhea is of limited value and should be discouraged. [ 50 ]   C. difficile  toxin should clear from the stool of somebody previously infected if treatment is effective. Many hospitals only test for the prevalent toxin A. Strains that express only the B toxin are now present in many hospitals, however, so testing for both toxins should occur. [ 51 ] [ 52 ]  Not testing for both may contribute to a delay in obtaining laboratory results, which is often the cause of prolonged illness and poor outcomes. [ citation needed ]


Stool  leukocyte  measurements and stool  lactoferrin  levels also have been proposed as diagnostic tests, but may have limited diagnostic accuracy. [ 53 ]


Testing of stool samples by  real-time polymerase chain reaction  is able to detect  C. difficile  about 93% of the time and when positive is incorrectly positive about 3% of the time. [ 54 ]  This is more accurate than cytotoxigenic culture or cell cytotoxicity assay. [ 54 ]  Another benefit is that the result can be achieved within three hours. [ 54 ]  Drawbacks include a higher cost and the fact that the test only looks for the gene for the toxin and not the toxin itself. [ 54 ]  The latter means that if the test is used without confirmation, overdiagnosis may occur. [ 54 ]  Repeat testing may be misleading, and testing specimens more than once every seven days in people without new symptoms is highly unlikely to yield useful information. [ 55 ]  The screening specificity is relatively low because of the high number of false positive cases from asymptomatic infection. [ 47 ]


Self containment by housing people in private rooms is important to prevent the spread of  C. difficile . [ 56 ]  Contact precautions are an important part of preventing the spread of  C. difficile. C. difficile does not often occur in people who are not taking antibiotics so limiting use of antibiotics decreases the risk. [ 57 ]


The most effective method for preventing CDI is proper  antibiotic  prescribing. In the hospital setting, where CDI is most common, most people who develop CDI are exposed to antibiotics. Although proper antibiotic prescribing is highly recommended, about 50% is considered inappropriate. This is consistent whether in the hospital, clinic, community, or academic setting. A decrease in CDI by limiting antibiotics or by limiting unnecessary prescriptions in general, both in an outbreak and non-outbreak setting has been demonstrated to be most strongly associated with reduced CDI. Further, reactions to medication may be severe: CDI infections were the most common contributor to adverse drug events seen in U.S. hospitals in 2011. [ 58 ]  In some regions of the UK, reduced used of  fluoroquinolone  antibiotics seems to lead to reduced rates of CDI. [ 59 ]


Some evidence indicates  probiotics  may be useful to prevent infection and recurrence. [ 60 ] [ 61 ]  Treatment with  Saccharomyces boulardii  in those who are not immunocompromised with  C. difficile  also may be useful. [ 62 ] [ 63 ]  Initially, in 2010, the  Infectious Diseases Society of America  recommended against their use due to the risk of complications. [ 60 ] [ 62 ]  Subsequent reviews, however, did not find an increase in adverse effects with treatment, [ 61 ]  and overall treatment appears safe and moderately effective in preventing C. difficile-associated diarrhea. [ 64 ]


One study in particular found that there does appear to be a "protective effect" of probiotics, specifically reducing the risk of antibiotic-associated diarrhea (AAD) by 51% in 3,631 outpatients, but it is important to note that the types of infections in the subjects were not specified. [ 65 ]


Rigorous infection protocols are required to minimize this risk of transmission. [ 66 ]  Infection control measures, such as wearing gloves and noncritical medical devices used for a single person with CDI, are effective at prevention. [ 67 ]  This works by limiting the spread of  C. difficile  in the hospital setting. In addition, washing with soap and water will wash away the spores from contaminated hands, but alcohol-based hand rubs are ineffective. [ 68 ]  These precautions should remain in place among those in hospital for at least 2 days after the diarrhea has stopped. [ 69 ]


Bleach wipes containing 0.55%  sodium hypochlorite  have been shown to kill the spores and prevent transmission. [ 70 ]  Installing lidded toilets and closing the lid prior to flushing also reduces the risk of contamination. [ 71 ]


Those who have CDIs should be in rooms with other people with CDIs or by themselves when in hospital. [ 67 ]


Common hospital  disinfectants  are ineffective against  C. difficile  spores, and may promote spore formation, but various  oxidants    (e.g 1% sodium  hypochlorite  solution) rapidly destroy spores. [ 72 ]   Hydrogen peroxide vapor  (HPV) systems used to sterilize a room after treatment is completed have been shown to reduce infection rates and to reduce risk of infection to others. The incidence of CDI was reduced by 53% [ 73 ]  or 42% [ 74 ]  through use of HPV. Ultraviolet cleaning devices, and housekeeping staff especially dedicated to disinfecting the rooms of people with  C. difficile  after discharge may be effective. [ 75 ]


Carrying  C. difficile  without symptoms is common. Treatment in those without symptoms is controversial. In general, mild cases do not require specific treatment. [ 3 ] [ 20 ]   Oral rehydration therapy  is useful in treating dehydration associated with the diarrhea. [ citation needed ]


Several different antibiotics are used for  C. difficile , with the available agents being more or less equally effective. [ 76 ]


Vancomycin  or  fidaxomicin  by mouth are the typically recommended for mild, moderate, and severe infections. [ 77 ]  They are also the first-line treatment for pregnant women, especially since metronidazole may cause birth defects. [ 78 ]  Typical vancomycin 125 mg is taken four times a day by mouth for 10 days. [ 78 ] [ 48 ]  Fidaxomicin is taken at 200 mg twice daily for 10 days. [ 48 ]  It may also be given rectally if the person develops an  ileus . [ 77 ]


Fidaxomicin is tolerated as well as vancomycin, [ 79 ]  and may have a lower risk of recurrence. [ 76 ]  Fidaxomicin has been found to be as effective as vancomycin in those with mild to moderate disease, and it may be better than vancomycin in those with severe disease. [ 3 ] [ 80 ]  Fidaxomicin may be used in those who have recurrent infections and have not responded to other antibiotics. [ 80 ]   Metronidazole  (500 mg 3 times daily for 10 days [ 48 ] ) by mouth is recommended as an alternative treatment only for  C. difficile  infections when the affected person is  allergic  to first-line treatments, is unable to tolerate them, or has financial difficulties preventing them from accessing them. [ 77 ] [ 81 ]  In fulminant disease vancomycin by mouth and intravenous metronidazole are commonly used together. [ 77 ]


Medications used to slow or stop  diarrhea , such as  loperamide , may only be used after initiating the treatment. [ 48 ]


Cholestyramine , an  ion-exchange resin , is effective in binding both toxin A and B, slowing bowel motility, and helping prevent dehydration. [ 82 ]  Cholestyramine is recommended with vancomycin. A last-resort treatment in those who are immunosuppressed is  intravenous immunoglobulin . [ 82 ]  Monoclonal antibodies against  C. difficile  toxin A  and  C. difficile  toxin B  are approved to prevent recurrence of  C. difficile  infection including  bezlotoxumab . [ 83 ]


Evidence to support the use of probiotics in the treatment of active disease is insufficient. [ 62 ] [ 84 ] [ 85 ] [ 86 ]  Researchers have recently begun taking a mechanical approach to fecal-derived products. It is known that certain microbes with 7α-dehydroxylase activity can metabolize primary to secondary bile acids, which inhibit C. difficile. Thus, incorporating such microbes into therapeutic products such as probiotics may be protective, although more pre-clinical investigations are needed. [ 87 ]


Fecal microbiota transplant , also known as a stool transplant, is roughly 85% to 90% effective in those for whom antibiotics have not worked. [ 88 ] [ 89 ] [ 90 ]  It involves infusion of the microbiota acquired from the feces of a healthy donor to reverse the bacterial imbalance responsible for the recurring nature of the infection. [ 91 ]  The procedure replenishes the normal colonic microbiota that had been wiped out by antibiotics, and re-establishes resistance to colonization by  Clostridioides difficile . [ 92 ]  Side effects, at least initially, are few. [ 90 ]


Fecal microbiota, live  (Rebyota) was approved for medical use in the United States in November 2022. [ 93 ]


Fecal microbiota spores, live  (Vowst) was approved for medical use in the United States in April 2023. [ 94 ] [ 95 ]  It is the first fecal microbiota product that is taken  by mouth . [ 94 ]  A 2023 review article discusses the beneficial effects of fecal microbiota transplantation in recurrent  Clostridioides difficile  infection  [ 96 ]


In those with severe  C. difficile  colitis,  colectomy  may improve the outcomes. [ 97 ]  Specific criteria may be used to determine who will benefit most from surgery. [ 98 ]


Recurrent CDI occurs in 20 to 30% of the patients, with increasing rates of recurrence with each subsequent episode. [ 99 ]  In clinical settings, it is virtually impossible to distinguish a recurrence that develops as a relapse of CDI with the same strain of  C. difficile  versus reinfection that is the result of a new strain. [ citation needed ]  However, in laboratory settings paired isolates can be differentiated using  Whole-Genome Sequencing  or  Multilocus Variable-Number Tandem-Repeat Analysis . [ 100 ]


Several treatment options exist for recurrent  C. difficile  infection. For the first episode of recurrent  C. difficile  infection, the 2017 IDSA guidelines recommend oral vancomycin at a dose of 125 mg four times daily for 10 days if metronidazole was used for the initial episode. If oral vancomycin was used for the initial episode, then a prolonged oral vancomycin pulse dose of 125 mg four times daily for 10–14 days followed by a taper (twice daily for one week, then every two to three days for 2–8 weeks) or fidaxomicin 200 mg twice daily for 10 days. For a second recurrent episode, the IDSA recommends options including the aforementioned oral vancomycin pulse dose followed by the prolonged taper; oral vancomycin 125 mg four times daily for 10 days followed by  rifaximin  400 mg three times daily for 20 days; fidaxomicin 200 mg twice daily for 10 days, or a fecal microbiota transplant. [ 81 ]


For patients with C. diff infections that fail to be resolved with traditional antibiotic regimens, fecal microbiome transplants boasts an average cure rate of >90%. [ 101 ]  In a review of 317 patients, it was shown to lead to resolution in 92% of the persistent and recurrent disease cases. [ 102 ]  It is clear that restoration of gut flora is paramount in the struggle against recurrent CDI. With effective antibiotic therapy, C. difficile can be reduced and natural colonization resistance can develop over time as the natural microbial community recovers. Reinfection or recurrence may occur before this process is complete. Fecal microbiota transplant may expedite this recovery by directly replacing the missing microbial community members. [ 103 ]  However, human-derived fecal matter is difficult to standardize and has multiple potential risks, including the transfer of infectious material and long-term consequences of inoculating the gut with a foreign fecal material. As a result, further research is necessary to study the long term effective outcomes of FMT. [ citation needed ]


After a first treatment with metronidazole or vancomycin,  C. difficile  recurs in about 20% of people. This increases to 40% and 60% with subsequent recurrences. [ 104 ]


C. difficile  diarrhea is estimated to occur in eight of 100,000 people each year. [ 105 ]  Among those who are admitted to hospital, it occurs in between four and eight people per 1,000. [ 105 ]  In 2011, it resulted in about half a million infections and 29,000 deaths in the United States. [ 4 ]


Due in part to the emergence of a  fluoroquinolone -resistant strain,  C. difficile -related deaths increased 400% between 2000 and 2007 in the United States. [ 106 ]  According to the CDC, " C. difficile  has become the most common microbial cause of healthcare-associated infections in U.S. hospitals and costs up to $4.8 billion each year in excess health care costs for acute care facilities alone." [ 107 ]


Ivan C. Hall and Elizabeth O'Toole first named the bacterium  Bacillus difficilis  in 1935, choosing its specific epithet because it was resistant to early attempts at isolation and grew very slowly in culture. [ 104 ] [ 108 ]   André Romain Prévot  subsequently transferred it to  Clostridium ,  binomen  Clostridium difficile . [ 109 ] [ 110 ]  Its combination was later changed to  Clostridioides difficile  after being transferred to the new genus  Clostridioides . [ 111 ]


Pseudomembranous colitis first was described as a complication of  C. difficile  infection in 1978, [ 112 ]  when a toxin was isolated from people with pseudomembranous colitis and  Koch's postulates  were met.


The genus name is from the  Greek   klōstēr  ( κλωστήρ ), "spindle", [ 131 ]  and the specific name is from  Latin   difficile , neuter singular form of  difficilis  "difficult, obstinate", [ 132 ]   chosen  in reference to  fastidiousness  upon culturing.


Regarding the pronunciation of the current and former genus assignments,  Clostridioides  is  / k l ɒ ˌ s t r ɪ d i ˈ ɔɪ d i s /  and  Clostridium  is  / k l ɒ ˈ s t r ɪ d i əm / . Both genera still have species assigned to them, but this species is now classified in the former. Via the norms of  binomial nomenclature , it is understood that the former binomial name of this species is now an alias. [ citation needed ]


Regarding the specific name,  / d ɪ ˈ f ɪ s ɪ l i / [ 133 ]  is the traditional norm, reflecting how medical English usually pronounces naturalized New Latin words (which in turn largely reflects  traditional English pronunciation of Latin ), although a restored pronunciation of  / d ɪ ˈ f ɪ k ɪ l eɪ /  is also sometimes used (the  classical Latin  pronunciation is reconstructed as  [kloːsˈtrɪdɪ.ũː   dɪfˈfɪkɪlɛ] ). The specific name is also commonly pronounced  / ˌ d iː f i ˈ s iː l / , as though it were French, which from a  prescriptive  viewpoint is a "mispronunciation" [ 133 ]  but from a  linguistically descriptive  viewpoint cannot be described as erroneous because it is so widely used among health care professionals; it can be described as "the non-preferred variant" from the viewpoint of sticking most regularly to New Latin in  binomial nomenclature , which is also a valid viewpoint, although New Latin specific names contain such a wide array of extra-Latin roots (including surnames and jocular references) that extra-Latin pronunciation is involved anyway (as seen, for example, with  Ba humbugi ,  Spongiforma squarepantsii , and hundreds of others). [ citation needed ]


Colitis  is swelling or  inflammation  of the large intestine ( colon ). [ 1 ]  Colitis may be  acute  and self-limited or  long-term . It broadly fits into the category of  digestive diseases .


In a medical context, the label  colitis  (without qualification) is used if:


The  signs  and  symptoms  of colitis are quite variable and dependent on the cause of the given colitis and factors that modify its course and severity. [ 2 ]


Common symptoms of colitis may include: mild to severe  abdominal pains  and  tenderness  (depending on the stage of the disease), persistent  hemorrhagic   diarrhea  with pus either present or absent in the  stools ,  fecal incontinence ,  flatulence ,  fatigue ,  loss of appetite  and unexplained  weight loss . [ 3 ]


More severe symptoms may include:  shortness of breath , a fast or  irregular heartbeat  and  fever . [ 3 ]


Other less common or rare  non-specific symptoms  that may accompany colitis include:  arthritis ,  mouth ulcers , painful, red and swollen skin and irritated,  bloodshot eyes . [ 3 ]


Signs seen on  colonoscopy  include: colonic mucosal  erythema  (redness of the colon's inner surface),  ulcerations  and  hemorrhage . [ 4 ]


Symptoms suggestive of colitis are worked-up by obtaining the  medical history , a physical examination and laboratory tests ( CBC ,  electrolytes , stool culture and sensitivity, stool ova and parasites et cetera).  Additional tests may include medical imaging (e.g. abdominal  computed tomography ,  abdominal X-rays ) and an examination with a camera inserted into the rectum ( sigmoidoscopy ,  colonoscopy ). [ 5 ]


An important investigation in the assessment of colitis is biopsy for  histopathology . A very small piece of tissue (usually about 2mm) is removed from the bowel mucosa during endoscopy and examined under the microscope by a histopathologist. A biopsy report generally does not state the diagnosis, but should state any presence of chronic colitis, give an indication of disease activity, as well as state the presence of any epithelial damage (erosions and ulcerations). [ 6 ]


Histopathology findings generally associated with chronic colitis include: [ 6 ]


Other findings include basal plasmacytosis and mucin depletion. [ 6 ]
Histopathology findings generally associated with active colitis include: [ 6 ]


There are many types of colitis. They are usually classified by the cause.


Types of colitis include:


A subtype of infectious colitis is  Clostridioides difficile  colitis , [ 8 ]  which is informally abbreviated as "C-diff colitis". It classically forms  pseudomembranes  and is often referred to as pseudomembranous colitis, which is its (nonspecific)  histomorphologic  description.


Enterohemorrhagic  colitis may be caused by  Shiga toxin  in  Shigella dysenteriae  or  Shigatoxigenic group  of  Escherichia coli  (STEC), which includes  serotype   O157:H7  and other enterohemorrhagic  E. coli . [ 9 ]


Parasitic  infections, like those caused by  Entamoeba histolytica , can also cause colitis.


Indeterminate colitis  is the classification for colitis that has features of both  Crohn's disease  and  ulcerative colitis . [ 10 ]   Indeterminate colitis' behaviour is usually closer to ulcerative colitis than Crohn's disease. [ 11 ]


Treatment for this condition can include medications such as steroids and dietary changes.  In some instances, hospitalization and surgery may be required. [ 12 ]


Moreover, several studies recently have found significant relationship between colitis and  dairy allergy  (including: cow milk, cow milk UHT and casein), [ 13 ] [ 14 ] [ 15 ]  suggesting some patients may benefit from an  elimination diet .


The use of oral  probiotic  supplements to modify the composition and behavior of the microbiome has been considered as a possible therapy for both induction and maintenance of remission in people with Crohn's disease and ulcerative colitis. A Cochrane review in 2020 did not find clear evidence of improved remission likelihood, nor lower adverse events, in people with Crohn's disease, following probiotic treatment. [ 16 ]


For ulcerative colitis, there is low-certainty evidence that probiotic supplements may increase the probability of clinical remission. [ 17 ]  People receiving probiotics were 73% more likely to experience disease remission and over 2x as likely to report improvement in symptoms compared to those receiving a placebo, with no clear difference in minor or serious adverse effects. [ 17 ]  Although there was no clear evidence of greater remission when probiotic supplements were compared with  5‐aminosalicylic acid  treatment as a  monotherapy , the likelihood of remission was 22% higher if probiotics were used in combination with 5-aminosalicylic acid therapy. [ 17 ]  Whereas in people who are already in remission, it is unclear whether probiotics help to prevent future relapse, either as a monotherapy or  combination therapy . [ 18 ]


One study reported successfully treating experimental colitis in mice with  mesenchymal stem cells . [ 19 ]


Additional research was conducted by Huang  et al.  that analyzed specific genes and biological markers that are associated with the risk of colon cancer development in patients with colitis. The results showed a correlation between certain biomarkers and the development of disease. [ 20 ]


Colitis is common in parts of the world where  helminthic  colonisation is rare, and uncommon in those areas where most people carry worms.  Infections  with helminths may alter the autoimmune response that causes the disease. Early trials of  Trichuris suis  ova (TSO) showed promising results when used in people with IBD [ 21 ] [ 22 ] [ 23 ] [ 24 ]  but later trials failed at Phase 2, and most were eventually discontinued. [ 25 ]  However, the phase 2 trials had used a different formulation of TSO from the one that had been used in the earlier studies that had shown positive outcomes. [ 26 ]


Colorectal cancer  ( CRC ), also known as  bowel cancer ,  colon cancer , or  rectal cancer , is the development of  cancer  from the  colon  or  rectum  (parts of the  large intestine ). [ 5 ]  Signs and symptoms may include  blood in the stool , a change in  bowel movements , weight loss, abdominal pain and fatigue. [ 9 ]  Most colorectal cancers are due to lifestyle factors and genetic disorders. [ 2 ] [ 3 ]  Risk factors include diet,  obesity , smoking, and lack of  physical activity . [ 2 ]  Dietary factors that increase the risk include  red meat ,  processed meat , and  alcohol . [ 2 ] [ 4 ]  Another risk factor is  inflammatory bowel disease , which includes  Crohn's disease  and  ulcerative colitis . [ 2 ]  Some of the inherited genetic disorders that can cause colorectal cancer include  familial adenomatous polyposis  and  hereditary non-polyposis colon cancer ; however, these represent less than 5% of cases. [ 2 ] [ 3 ]  It typically starts as a  benign tumor , often in the form of a  polyp , which over time becomes  cancerous . [ 2 ]


Colorectal cancer may be diagnosed by  obtaining a sample  of the colon during a  sigmoidoscopy  or  colonoscopy . [ 1 ]  This is then followed by  medical imaging  to determine whether the disease has spread. [ 5 ]   Screening  is effective for preventing and decreasing deaths from colorectal cancer. [ 10 ]  Screening, by one of a number of methods, is recommended starting from the age of 45 to 75. It was recommended starting at age 50 but it was changed to 45 due to increasing numbers of colon cancers. [ 10 ] [ 11 ]  During colonoscopy, small polyps may be removed if found. [ 2 ]  If a large polyp or tumor is found, a  biopsy  may be performed to check if it is cancerous.  Aspirin  and other  non-steroidal anti-inflammatory drugs  decrease the risk of pain during polyp excision. [ 2 ] [ 12 ]  Their general use is not recommended for this purpose, however, due to side effects. [ 13 ]


Treatments used for colorectal cancer may include some combination of surgery,  radiation therapy ,  chemotherapy , and  targeted therapy . [ 5 ]  Cancers that are confined within the wall of the colon may be curable with surgery, while  cancer that has spread widely  is usually not curable, with management being directed towards improving  quality of life  and symptoms. [ 5 ]  The  five-year survival rate  in the United States was around 65% in 2014. [ 6 ]  The individual likelihood of survival depends on how advanced the cancer is, whether or not all the cancer can be removed with surgery, and the person's overall health. [ 1 ]  Globally, colorectal cancer is the third most common type of cancer, making up about 10% of all cases. [ 14 ]  In 2018, there were 1.09 million new cases and 551,000 deaths from the disease. [ 8 ]  It is more common in  developed countries , where more than 65% of cases are found. [ 2 ]  It is less common in women than men. [ 2 ]


The signs and symptoms of colorectal cancer depend on the location of the  tumor  in the  bowel , and whether it has spread elsewhere in the body ( metastasis ). The classic warning signs include: worsening  constipation , blood in the  stool , decrease in stool caliber (thickness), loss of appetite, loss of weight, and  nausea  or  vomiting  in someone over 50 years old. [ 15 ]  Around 50% of people who have colorectal cancer do not report any symptoms. [ 16 ]


Rectal bleeding  or  anemia  are high-risk symptoms in people over the age of 50. [ 17 ]  Weight loss and changes in a person's bowel habit are typically only concerning if they are associated with rectal bleeding. [ 17 ] [ 18 ]


75–95% of colorectal cancer cases occur in people with little or no genetic risk. [ 19 ] [ 20 ]  Risk factors include older age, male sex, [ 20 ]  high intake of fat,  sugar ,  alcohol ,  red meat ,  processed meats ,  obesity ,  smoking , and a lack of  physical exercise . [ 19 ] [ 21 ]  The Rectal Cancer Survival Calculator developed by the  MD Anderson Cancer Center  additionally considers race to be a risk factor; however, there are equity issues concerning whether this might lead to inequity in clinical decision making. [ 22 ] [ 23 ]  Approximately 10% of cases are linked to insufficient activity. [ 24 ]  The risk from alcohol appears to increase at greater than one drink per day. [ 25 ]  Drinking five glasses of water a day is linked to a decrease in the risk of colorectal cancer and  adenomatous  polyps. [ 26 ]   Streptococcus gallolyticus  is associated with colorectal cancer. [ 27 ]  Some strains of  Streptococcus bovis/Streptococcus equinus  complex are consumed by millions of people daily and thus may be safe. [ 28 ]  25 to 80% of people with  Streptococcus bovis/gallolyticus  bacteremia have concomitant colorectal tumors. [ 29 ]  Seroprevalence of  Streptococcus bovis/gallolyticus  is considered as a candidate practical marker for the early prediction of an underlying bowel lesion at high risk population. [ 29 ]  It has been suggested that the presence of antibodies to  Streptococcus bovis/gallolyticus  antigens or the antigens themselves in the bloodstream may act as markers for the carcinogenesis in the colon. [ 29 ]


Pathogenic  Escherichia coli  may increase the risk of colorectal cancer by producing the  genotoxic   metabolite ,  colibactin . [ 30 ]


People with  inflammatory bowel disease  ( ulcerative colitis  and  Crohn's disease ) are at increased risk of colon cancer. [ 31 ] [ 32 ]  The risk increases the longer a person has the disease, and the worse the severity of inflammation. [ 33 ]  In these high risk groups, both prevention with  aspirin  and regular  colonoscopies  are recommended. [ 34 ]   Endoscopic  surveillance in this high-risk population may reduce the development of colorectal cancer through early diagnosis and may also reduce the chances of dying from colon cancer. [ 34 ]  People with inflammatory bowel disease account for less than 2% of colon cancer cases yearly. [ 33 ]  In those with Crohn's disease, 2% get colorectal cancer after 10 years, 8% after 20 years, and 18% after 30 years. [ 33 ]  In people who have ulcerative colitis, approximately 16% develop either a  cancer precursor  or cancer of the colon over 30 years. [ 33 ]


Those with a family history in two or more  first-degree relatives  (such as a parent or sibling) have a two to threefold greater risk of disease, and this group accounts for about 20% of all cases. A number of genetic syndromes are also associated with higher rates of colorectal cancer. The most common of these is  hereditary nonpolyposis colorectal cancer  (HNPCC, or Lynch syndrome) which is present in about 3% of people with colorectal cancer. [ 20 ]  Other syndromes that are strongly associated with colorectal cancer include  Gardner syndrome  and  familial adenomatous polyposis  (FAP). [ 35 ]  For people with these syndromes, cancer almost always occurs and makes up 1% of the cancer cases. [ 36 ]  A total  proctocolectomy  may be recommended for people with FAP as a preventive measure due to the high risk of malignancy. Colectomy, removal of the colon, may not suffice as a preventive measure because of the high risk of rectal cancer if the rectum remains. [ 37 ]  The most common polyposis syndrome affecting the colon is  serrated polyposis syndrome , [ 38 ]  which is associated with a 25-40% risk of CRC. [ 39 ]


Mutations in the pair of genes ( POLE  and  POLD1 ) have been associated with familial colon cancer. [ 40 ]


Most deaths due to colon cancer are associated with metastatic disease. A gene that appears to contribute to the potential for metastatic disease, metastasis associated in colon cancer 1 ( MACC1 ), has been isolated. [ 41 ]  It is a  transcriptional  factor that influences the expression of  hepatocyte growth factor . This gene is associated with the proliferation, invasion, and scattering of colon cancer cells in  cell culture , and tumor growth and metastasis in mice. MACC1 may be a potential target for cancer intervention, but this possibility needs to be confirmed with clinical studies. [ 42 ]


Epigenetic  factors, such as abnormal  DNA methylation  of  tumor suppressor  promoters, play a role in the development of colorectal cancer. [ 43 ]


Ashkenazi Jews  have a 6% higher risk rate of getting  adenomas  and then colon cancer due to mutations in the  APC gene  being more common. [ 44 ]


Colorectal cancer is a disease originating from the  epithelial cells  lining the colon or rectum of the  gastrointestinal tract , most frequently as a result of genetic mutations in the  Wnt signaling pathway  that increases signaling activity. [ 45 ]  The Wnt signaling pathway normally plays an important role for normal function of these cells including maintaining this lining. Mutations can be  inherited  or  acquired , and most probably occur in the  intestinal crypt   stem cell . [ 46 ] [ 47 ] [ 48 ]  The most commonly mutated gene in all colorectal cancer is the  APC  gene, which produces the APC protein. [ 45 ]  The APC protein prevents the accumulation of  β-catenin  protein. Without APC,  β-catenin  accumulates to high levels and translocates (moves) into the  nucleus , binds to DNA, and activates the  transcription  of proto- oncogenes . These genes are normally important for stem cell renewal and differentiation, but when inappropriately expressed at high levels, they can cause cancer. [ 45 ]  While APC is mutated in most colon cancers, some cancers have increased β-catenin because of mutations in β-catenin (CTNNB1) that block its own breakdown, or have mutations in other genes with function similar to APC such as  AXIN1 ,  AXIN2 ,  TCF7L2 , or  NKD1 . [ 49 ]


Beyond the defects in the  Wnt signaling pathway , other mutations must occur for the cell to become cancerous. The  p53  protein, produced by the  TP53  gene, normally monitors  cell division  and induces their  programmed death  if they have Wnt pathway defects. Eventually, a  cell line  acquires a mutation in the  TP53  gene and transforms the tissue from a  benign epithelial tumor  into an invasive  epithelial cell cancer . Sometimes the gene encoding p53 is not mutated, but another protective protein named  BAX  is mutated instead. [ 49 ]


Other proteins responsible for programmed cell death that are commonly deactivated in colorectal cancers are  TGF-β  and DCC ( Deleted in Colorectal Cancer ). TGF-β has a deactivating mutation in at least half of colorectal cancers. Sometimes TGF-β is not deactivated, but a downstream protein named  SMAD  is deactivated. [ 49 ]  DCC commonly has a deleted segment of a chromosome in colorectal cancer. [ 50 ]


Approximately 70% of all  human genes  are expressed in colorectal cancer, with just over 1% of having increased expression in colorectal cancer compared to other forms of cancer. [ 51 ]  Some genes are  oncogenes : they are overexpressed in colorectal cancer. For example, genes encoding the proteins  KRAS ,  RAF , and  PI3K , which normally stimulate the  cell to divide  in response to growth factors, can acquire mutations that result in over-activation of cell proliferation. The chronological order of mutations is sometimes important. If a previous APC mutation occurred, a primary KRAS mutation often progresses to cancer rather than a self-limiting  hyperplastic  or borderline lesion. [ 52 ]   PTEN , a tumor suppressor, normally inhibits PI3K, but can sometimes become mutated and deactivated. [ 49 ]


Comprehensive,  genome -scale analysis has revealed that colorectal carcinomas can be categorized into hypermutated and non-hypermutated tumor types. [ 53 ]  In addition to the oncogenic and inactivating mutations described for the genes above, non-hypermutated samples also contain mutated  CTNNB1 ,  FAM123B ,  SOX9 ,  ATM , and  ARID1A . Progressing through a distinct set of genetic events, hypermutated tumors display mutated forms of  ACVR2A ,  TGFBR2 ,  MSH3 ,  MSH6 , SLC9A9,  TCF7L2 , and  BRAF . The common theme among these genes, across both tumor types, is their involvement in Wnt and TGF-β signaling pathways, which results in increased activity of  MYC , a central player in colorectal cancer. [ 53 ]


Mismatch repair  (MMR) deficient tumours are characterized by a relatively high number of poly-nucleotide  tandem repeats . [ 54 ]  This is caused by a deficiency in MMR proteins – which are typically caused by  epigenetic  silencing and or inherited mutations ( e.g. ,  Lynch syndrome ). [ 55 ]  15 to 18 percent of colorectal cancer tumours have MMR deficiencies, with 3 percent developing due to Lynch syndrome. [ 56 ]  The role of the mismatch repair system is to protect the integrity of the genetic material within cells ( i.e. , error detecting and correcting). [ 55 ]  Consequently, a deficiency in MMR proteins may lead to an inability to detect and repair genetic damage, allowing for further cancer-causing mutations to occur and colorectal cancer to progress. [ 55 ]


The polyp to cancer progression sequence is the classical model of colorectal cancer  pathogenesis . [ 57 ]  In this  adenoma-carcinoma sequence , [ 58 ]  normal epithelial cells progress to  dysplastic  cells such as  adenomas , and then to carcinoma, by a process of progressive genetic mutation. [ 59 ]  Central to the polyp to CRC sequence are gene mutations, epigenetic alterations, and local inflammatory changes. [ 57 ]  The polyp to CRC sequence can be used as an underlying framework to illustrate how specific molecular changes lead to various cancer subtypes. [ 57 ]


The term "field cancerization" was first used in 1953 to describe an area or "field" of epithelium that has been preconditioned (by what were largely unknown processes at the time) to predispose it towards development of cancer. [ 60 ]  Since then, the terms "field cancerization", "field carcinogenesis", "field defect", and " field effect " have been used to describe pre-malignant or pre-neoplastic tissue in which new cancers are likely to arise. [ 61 ]


Field defects are important in progression to colon cancer. [ 62 ] [ 63 ]


However, as pointed out by Rubin, "The vast majority of studies in cancer research has been done on well-defined tumors  in vivo , or on discrete neoplastic foci  in vitro . Yet there is evidence that more than 80% of the somatic mutations found in mutator phenotype human colorectal tumors occur before the onset of terminal clonal expansion." [ 64 ] [ 65 ]  Similarly, Vogelstein et al. [ 66 ]  pointed out that more than half of somatic mutations identified in tumors occurred in a pre-neoplastic phase (in a field defect), during growth of apparently normal cells. Likewise, epigenetic alterations present in tumors may have occurred in pre-neoplastic field defects. [ 67 ]


An expanded view of field effect has been termed "etiologic field effect", which encompasses not only molecular and pathologic changes in pre-neoplastic cells but also influences of exogenous environmental factors and molecular changes in the local  microenvironment  on neoplastic evolution from tumor initiation to death. [ 68 ]


Epigenetic  alterations are much more frequent in colon cancer than genetic (mutational) alterations. As described by Vogelstein et al., [ 66 ]  an average cancer of the colon has only 1 or 2 oncogene mutations and 1 to 5 tumor suppressor mutations (together designated "driver mutations"), with about 60 further "passenger" mutations. The oncogenes and tumor suppressor genes are well studied and are described above under  Pathogenesis . [ 69 ] [ 70 ]


In addition to epigenetic alteration of expression of miRNAs, other common types of epigenetic alterations in cancers that change gene expression levels include direct hypermethylation or hypomethylation of CpG islands of protein-encoding genes and alterations in histones and chromosomal architecture that influence gene expression. [ 71 ]  As an example, 147 hypermethylations and 27 hypomethylations of protein coding genes were frequently associated with colorectal cancers. Of the hypermethylated genes, 10 were hypermethylated in 100% of colon cancers, and many others were hypermethylated in more than 50% of colon cancers. [ 72 ]  In addition, 11 hypermethylations and 96 hypomethylations of miRNAs were also associated with colorectal cancers. [ 72 ]  Abnormal (aberrant)  methylation  occurs as a normal consequence of normal aging and the risk of colorectal cancer increases as a person gets older. [ 73 ]  The source and trigger of this age-related methylation is unknown. [ 73 ] [ 74 ]  Approximately half of the genes that show age-related methylation changes are the same genes that have been identified to be involved in the development of colorectal cancer. [ 73 ]  These findings may suggest a reason for age being associated with the increased risk of developing colorectal cancer. [ 73 ]


Epigenetic reductions of DNA repair enzyme expression may likely lead to the genomic and epigenomic instability characteristic of cancer. [ 75 ] [ 76 ] [ 67 ]  As summarized in the articles  Carcinogenesis  and  Neoplasm , for sporadic cancers in general, a deficiency in DNA repair is occasionally due to a mutation in a DNA repair gene, but is much more frequently due to epigenetic alterations that reduce or silence expression of DNA repair genes. [ 77 ]


Epigenetic alterations involved in the development of colorectal cancer may affect a person's response to chemotherapy. [ 78 ]


Consensus molecular subtypes (CMS) classification of colorectal cancer was first introduced in 2015. CMS classification so far has been considered the most robust classification system available for CRC that has a clear biological interpretability and the basis for future clinical stratification and subtype-based targeted interventions. [ 79 ]


A novel Epigenome-based Classification (EpiC) of colorectal cancer was proposed in 2021 introducing 4 enhancer subtypes in people with CRC. Chromatin states using 6 histone marks are characterized to identify EpiC subtypes. A combinatorial therapeutic approach based on the previously introduced consensus molecular subtypes (CMSs) and EpiCs could significantly enhance current treatment strategies. [ 80 ]


Colorectal cancer diagnosis is performed by sampling of areas of the colon suspicious for possible tumor development, typically during colonoscopy or sigmoidoscopy, depending on the location of the lesion. [ 20 ]


A colorectal cancer is sometimes initially discovered on  CT scan . [ 81 ]


Presence of  metastases  is determined by a  CT scan  of the chest, abdomen and pelvis. [ 20 ]  Other potential imaging tests such as  PET  and  MRI  may be used in certain cases. [ 20 ]  MRI is particularly useful to determine local stage of the tumor and to plan the optimal surgical approach. [ 81 ]


MRI is also performed after completion of neoadjuvant chemoradiotherapy to identify patients who achieve complete response. Patients with complete response on both MRI and endoscopy may not require surgical resection and can avoid unnecessary surgical morbidity and complications. [ 82 ]  Patients selected for non-surgical treatment of rectal cancer should have periodic MRI scans, receive physical examinations, and undergo endoscopy procedures to detect any tumor re-growth which can occur in a minority of these patients. When local recurrence occurs, periodic follow up can detect it when it is still small and curable with salvage surgery. In addition, MRI tumor regression grades can be assigned after chemoradiotherapy which correlate with patients' long-term survival outcomes. [ 83 ]


The  histopathologic  characteristics of the  tumor  are reported from the analysis of tissue taken from a biopsy or surgery. A pathology report contains a description of the microscopical characteristics of the tumor tissue, including both tumor cells and how the tumor invades into healthy tissues and finally if the tumor appears to be completely removed. The most common form of colon cancer is  adenocarcinoma , constituting between 95% [ 85 ]  and 98% [ 86 ]  of all cases of colorectal cancer. Other, rarer types include  lymphoma , adenosquamous and  squamous cell carcinoma . Some subtypes are more aggressive. [ 87 ]   Immunohistochemistry  may be used in uncertain cases. [ 88 ]


Staging  of the cancer is based on both radiological and pathological findings. As with most other forms of cancer, tumor staging is based on the  TNM system  which considers how much the initial tumor has spread and the presence of metastases in lymph nodes and more distant organs. [ 20 ]  The AJCC 8th edition was published in 2018. [ 89 ]


It has been estimated that about half of colorectal cancer cases are due to lifestyle factors, and about a quarter of all cases are preventable. [ 90 ]  Increasing surveillance, engaging in physical activity, consuming a diet high in fiber, quitting smoking and limiting alcohol consumption decrease the risk. [ 91 ] [ 92 ]


Lifestyle risk factors with strong evidence include lack of exercise, cigarette smoking, alcohol, and obesity. [ 93 ] [ 94 ] [ 95 ]  The risk of colon cancer can be reduced by maintaining a normal body weight through a combination of sufficient exercise and eating a  healthy diet . [ 96 ]


Current research consistently links eating more red meat and processed meat to a higher risk of the disease. [ 97 ]  Starting in the 1970s, dietary recommendations to prevent colorectal cancer often included increasing the consumption of  whole grains , fruits and vegetables, and reducing the intake of  red meat  and  processed meats . This was based on animal studies and retrospective observational studies. However, large scale prospective studies have failed to demonstrate a significant protective effect, and due to the multiple causes of cancer and the complexity of studying correlations between diet and health, it is uncertain whether any specific dietary interventions will have significant protective effects. [ 98 ] : 432–433  [ 99 ] : 125–126   In 2018 the  National Cancer Institute  stated that "There is no reliable evidence that a diet started in adulthood that is low in fat and meat and high in fiber, fruits, and vegetables reduces the risk of CRC by a clinically important degree." [ 93 ] [ 100 ]


Consuming alcoholic drinks and consuming processed meat both increase the risk of colorectal cancer. [ 101 ]


The 2014 World Health Organization cancer report noted that it has been hypothesized that dietary fiber might help prevent colorectal cancer, but that most studies at the time had not yet studied the correlation. [ 99 ]  A 2019 review, however, found evidence of benefit from dietary fiber and whole grains. [ 102 ]  The  World Cancer Research Fund  listed the benefit of fiber for prevention of colorectal cancer as "probable" as of 2017. [ 103 ]  A 2022  umbrella review  says there is "convincing evidence" for that association. [ 104 ]


Higher physical activity is recommended. [ 21 ] [ 105 ]   Physical exercise  is associated with a modest reduction in colon but not rectal cancer risk. [ 106 ] [ 107 ]  High levels of physical activity reduce the risk of colon cancer by about 21%. [ 108 ]   Sitting  regularly for prolonged periods is associated with higher mortality from colon cancer. Regular exercise does not negate the risk but does lower it. [ 109 ]


Aspirin  and  celecoxib  appear to decrease the risk of colorectal cancer in those at high risk. [ 110 ] [ 111 ]  Aspirin is recommended in those who are 50 to 60 years old, do not have an increased risk of bleeding, and are at risk for cardiovascular disease to prevent colorectal cancer. [ 112 ]  It is not recommended in those at average risk. [ 113 ]


There is tentative evidence for  calcium  supplementation, but it is not sufficient to make a recommendation. [ 114 ]


Adequate  Vitamin D  intake and blood levels are associated with a lower risk of colon cancer. [ 115 ] [ 116 ]


As more than 80% of colorectal cancers arise from  adenomatous polyps , screening for this cancer is effective for both early detection and for prevention. [ 20 ] [ 117 ]  Diagnosis of cases of colorectal cancer through screening tends to occur 2–3 years before diagnosis of cases with symptoms. [ 20 ]  Any polyps that are detected can be removed, usually by  colonoscopy  or  sigmoidoscopy , and thus prevent them from turning into cancer. Screening has the potential to reduce colorectal cancer deaths by 60%. [ 118 ]


The three main screening tests are colonoscopy,  fecal occult blood  testing, and  flexible sigmoidoscopy . Of the three, only sigmoidoscopy cannot screen the  right side of the colon  where 42% of cancers are found. [ 119 ]  Flexible sigmoidoscopy, however, has the best evidence for decreasing the risk of death from any cause. [ 120 ]


Fecal occult blood testing (FOBT) of the stool is typically recommended every two years and can be either  guaiac-based  or  immunochemical . [ 20 ]  If abnormal FOBT results are found, participants are typically referred for a follow-up colonoscopy examination. When done once every 1–2 years, FOBT screening reduces colorectal cancer deaths by 16% and among those participating in screening, colorectal cancer deaths can be reduced up to 23%, although it has not been proven to reduce all-cause mortality. [ 121 ]  Immunochemical tests are accurate and do not require dietary or medication changes before testing. [ 122 ]  However, research in the UK has found that for these immunochemical tests, the threshold for further investigation is set at a point that may miss more than half of bowel cancer cases. The research suggests that the  NHS England's  Bowel Cancer Screening Programme could make better use of the test's ability to provide the exact concentration of blood in faeces (rather than only whether it is above or below a cutoff level). [ 123 ] [ 124 ]


Other options include  virtual colonoscopy  and stool DNA screening testing (FIT-DNA). Virtual colonoscopy via a  CT scan  appears as good as standard colonoscopy for detecting cancers and large adenomas but is expensive, associated with radiation exposure, and cannot remove any detected abnormal growths as standard colonoscopy can. [ 20 ]  Stool DNA screening test looks for  biomarkers  associated with colorectal cancer and precancerous lesions, including altered  DNA  and  blood hemoglobin . A positive result should be followed by  colonoscopy . FIT-DNA has more false positives than FIT and thus results in more adverse effects. [ 10 ]  Further study is required as of 2016 to determine whether a three-year screening interval is correct. [ 10 ]


In the United States, screening is typically recommended between ages 50 and 75 years. [ 10 ] [ 125 ]  The  American Cancer Society  recommends starting at the age of 45. [ 126 ]  For those between 76 and 85 years old, the decision to screen should be individualized. [ 10 ]  For those at high risk, screenings usually begin at around 40. [ 20 ] [ 127 ]


Several screening methods are recommended including stool-based tests every 2 years,  sigmoidoscopy  every 10 years with  fecal immunochemical testing  every two years, and  colonoscopy  every 10 years. [ 125 ]  It is unclear which of these two methods is better. [ 128 ]  Colonoscopy may find more cancers in the first part of the colon, but is associated with greater cost and more complications. [ 128 ]  For people with average risk who have had a high-quality colonoscopy with normal results, the  American Gastroenterological Association  does not recommend any type of screening in the 10 years following the colonoscopy. [ 129 ] [ 130 ]  For people over 75 or those with a life expectancy of less than 10 years, screening is not recommended. [ 131 ]  It takes about 10 years after screening for one out of a 1000 people to benefit. [ 132 ]  The USPSTF list seven potential strategies for screening, with the most important thing being that at least one of these strategies is appropriately used. [ 10 ]


In Canada, among those 50 to 75 years old at normal risk, fecal immunochemical testing or FOBT is recommended every two years or sigmoidoscopy every 10 years. [ 133 ]  Colonoscopy is less preferred. [ 133 ]


Some countries have national colorectal screening programs which offer FOBT screening for all adults within a certain age group, typically starting between ages 50 and 60. Examples of countries with organised screening include the United Kingdom, [ 134 ]  Australia, [ 135 ]  the Netherlands, [ 136 ]  Hong Kong, and Taiwan. [ 137 ]


The UK Bowel Cancer Screening Programme aims to find warning signs in people aged 60 to 74, by recommending a faecal immunochemical test (FIT) every two years. FIT measures blood in faeces, and people with levels above a certain threshold may have bowel tissue examined for signs of cancer. Growths having cancerous potential are removed. [ 138 ] [ 124 ]


The treatment of colorectal cancer can be aimed at cure or palliation. The decision on which aim to adopt depends on various factors, including the person's health and preferences, as well as the stage of the tumor. [ 139 ]  Assessment in multidisciplinary teams is a critical part of determining whether the patient is suitable for surgery or not. [ 140 ]  When colorectal cancer is caught early, surgery can be curative. However, when it is detected at later stages (for which  metastases  are present), this is less likely and treatment is often directed at palliation, to relieve symptoms caused by the tumour and keep the person as comfortable as possible. [ 20 ]


At an early stage, colorectal cancer may be removed during a colonoscopy using one of several techniques, including  endoscopic mucosal resection  or  endoscopic submucosal dissection . [ 5 ]  Endoscopic resection is possible if there is low possibility of lymph node metastasis and the size and location of the tumor make en bloc resection possible. [ 141 ]  For people with localized cancer, the preferred treatment is complete surgical removal with adequate  margins , with the attempt of achieving a cure. The procedure of choice is a partial  colectomy  (or proctocolectomy for rectal lesions) where the affected part of the colon or rectum is removed along with parts of its  mesocolon  and  blood supply  to facilitate removal of draining  lymph nodes . This can be done either by an open  laparotomy  or  laparoscopically , depending on factors related to the individual person and lesion factors. [ 20 ]  The colon may then be reconnected or a person may have a  colostomy . [ 5 ]


If there are only a few metastases in the liver or lungs, these may also be removed.  Chemotherapy  may be used before surgery to shrink the cancer before attempting to remove it. The two most common sites of recurrence of colorectal cancer are the  liver  and  lungs . [ 20 ]  For  peritoneal carcinomatosis   cytoreductive surgery , sometimes in combination with  HIPEC  can be used in an attempt to remove the cancer. [ 142 ]


In both cancer of the  colon  and  rectum ,  chemotherapy  may be used in addition to surgery in certain cases. The decision to add chemotherapy in management of colon and rectal cancer depends on the stage of the disease. [ 143 ]


In Stage I colon cancer, no chemotherapy is offered, and surgery is the definitive treatment. The role of chemotherapy in Stage II colon cancer is debatable, and is usually not offered unless risk factors such as T4 tumor, undifferentiated tumor, vascular and perineural invasion or inadequate lymph node sampling is identified. [ 144 ]  It is also known that the people who carry abnormalities of the mismatch repair genes do not benefit from chemotherapy. For Stage III and Stage IV colon cancer, chemotherapy is an integral part of treatment. [ 20 ]


If cancer has spread to the  lymph nodes  or distant organs, which is the case with Stage III and Stage IV colon cancer respectively, adding chemotherapy agents  fluorouracil ,  capecitabine  or  oxaliplatin  increases life expectancy. If the lymph nodes do not contain cancer, the benefits of chemotherapy are controversial. If the cancer is widely metastatic or unresectable, treatment is then  palliative . Typically in this setting, a number of different chemotherapy medications may be used. [ 20 ]  Chemotherapy drugs for this condition may include  capecitabine ,  fluorouracil ,  irinotecan ,  oxaliplatin  and  UFT . [ 145 ]  The drugs capecitabine and fluorouracil are interchangeable, with capecitabine being an oral medication and fluorouracil being an intravenous medicine. Some specific  regimens  used for CRC are  CAPOX ,  FOLFOX ,  FOLFOXIRI , and  FOLFIRI . [ 146 ]  Antiangiogenic drugs such as  bevacizumab  are often added in first line therapy. [ 147 ]  Another class of drugs used in the second line setting are  epidermal growth factor receptor  inhibitors, of which the three FDA approved ones are  aflibercept ,  cetuximab  and  panitumumab . [ 148 ] [ 149 ]


The primary difference in the approach to low stage rectal cancer is the incorporation of radiation therapy. Often, it is used in conjunction with chemotherapy in a  neoadjuvant  fashion to enable surgical resection, so that ultimately a  colostomy  is not required. However, it may not be possible in low lying tumors, in which case, a permanent colostomy may be required. Stage IV rectal cancer is treated similar to Stage IV colon cancer.


Stage IV colorectal cancer due to  peritoneal carcinomatosis  can be treated using  HIPEC  combined with cytoreductive surgery, in some people. [ 150 ] [ 151 ] [ 152 ]  Also, T4 colorectal cancer can be treated with HIPEC to avoid future relapses. [ 153 ]


While a combination of  radiation  and chemotherapy may be useful for  rectal cancer , [ 20 ]  for some people requiring treatment, chemoradiotherapy can increase acute treatment-related toxicity, and has not been shown to improve survival rates compared to radiotherapy alone, although it is associated with less local recurrence. [ 142 ]  For squamous cell carcinoma of the anal canal, chemoradiation therapy (CRT) with 5-FU and mitomycin C is preferred over radiation alone, offering improved survival outcomes but with increased risks of  acute hematological toxicity . [ 154 ]


The use of radiotherapy in colon cancer is not routine due to the sensitivity of the bowels to radiation. [ 155 ]  Radiation therapy's side effects (and occurrence rates) include acute (27%) and late (17%)  dermatological toxicities , acute (14%) and late (27%)  gastrointestinal toxicities , [ 154 ]  and late  pelvic radiation disease  (1-10%), e.g.,  irreversible lumbosacral plexopathy . [ 156 ]


As with chemotherapy, radiotherapy can be used as a neoadjuvant for clinical stages T3 and T4 for rectal cancer. [ 157 ]  This results in downsizing or downstaging of the tumour, preparing it for surgical resection, and also decreases local recurrence rates. [ 157 ]  For locally advanced rectal cancer, neoadjuvant chemoradiotherapy has become the standard treatment. [ 158 ]  Additionally, when surgery is not possible radiation therapy has been suggested to be an effective treatment against CRC pulmonary metastases, which are developed by 10-15% of people with CRC. [ 159 ]


Immunotherapy  with immune checkpoint inhibitors has been found to be useful for a type of colorectal cancer with  mismatch repair deficiency  and  microsatellite instability . [ 160 ] [ 161 ] [ 162 ]   Pembrolizumab  is approved for advanced CRC tumours that are MMR deficient and have failed usual treatments. [ 163 ]  Most people who do improve, however, still worsen after months or years. [ 161 ]


On the other hand, in a prospective phase 2 study published in June 2022 in The New England Journal of Medicine, 12 patients with Deficient Mismatch Repair (dMMR) stage II or III rectal adenocarcinoma were administered single-agent  dostarlimab , an anti–PD-1 monoclonal antibody, every three weeks for six months. After a median follow-up of 12 months (range, 6 to 25 months), all 12 patients had a complete clinical response with no evidence of tumor on MRI, 18F-fluorodeoxyglucose–positron-emission tomography, endoscopic evaluation, digital rectal examination, or biopsy. Moreover, no patient in the trial needed chemoradiotherapy or surgery, and no patient reported adverse events of grade 3 or higher. However, although the results of this study are promising, the study is small and has uncertainties about long-term outcomes. [ 164 ]


Palliative care  can be used at the same time as the cancer treatment and is recommended for any person who has advanced colon cancer or who has significant symptoms. [ 165 ] [ 166 ]  Involvement of palliative care may be beneficial to improve the quality of life for both the person and his or her family, by improving symptoms, anxiety and preventing admissions to the hospital. [ 167 ]


In people with incurable colorectal cancer, palliative care can consist of procedures that relieve symptoms or complications from the cancer but do not attempt to cure the underlying cancer, thereby improving  quality of life . Surgical options may include non-curative surgical removal of some of the cancer tissue, bypassing part of the intestines, or stent placement. These procedures can be considered to improve symptoms and reduce complications such as bleeding from the tumor, abdominal pain and intestinal obstruction. [ 168 ]  Non-operative methods of symptomatic treatment include radiation therapy to decrease tumor size as well as pain medications. [ 169 ]


In addition to medical intervention, a variety of psychosocial interventions have been implemented to address psychosocial concerns in the context of colorectal cancer. [ 170 ]  Depression and anxiety are highly prevalent in patients diagnosed with CRC, therefore psychosocial interventions can be helpful for alleviating psychological distress. [ 171 ] [ 172 ]  Many patients continue to experience symptoms of anxiety and depression following treatment, regardless of treatment outcome. [ 171 ] [ 173 ]  Societal stigmas associated with colorectal cancer present further psychosocial challenges for CRC patients and their families. [ 174 ] [ 175 ]


Colorectal cancer patients have a 51% higher risk of experiencing depression than individuals without the disease. [ 172 ]  Additionally, CRC patients are at high risk of experiencing severe anxiety, low self-esteem, poor self-concept, and social anxiety. [ 171 ] [ 176 ]


Regardless of treatment outcome, many CRC patients experience ongoing symptoms of anxiety, depression, and distress. [ 171 ]


Survivorship of CRC can involve significant lifestyle adjustments. [ 175 ]  Postoperative afflictions may include stomas, bowel issues, incontinence, odor, and changes to sexual functioning. [ 175 ] [ 176 ]  These changes can result in distorted body image, social anxiety, depression, and distress—all of which contribute to a poorer quality of life. [ 175 ] [ 177 ]


Colorectal cancer is the second leading cause of cancer-related death worldwide. [ 178 ]  Transitioning into palliative care and contending with mortality can be a deeply distressing experience for a CRC patient and their loved ones.


Colorectal cancer is highly stigmatized and can elicit feelings of disgust from  patients, healthcare professionals, family, intimate partners, and the general public. [ 174 ]  Patients with stomas are especially vulnerable to stigmatization due to unavoidable odors, gas, and unpleasant noises from stoma bags. [ 174 ]  Additionally, associated CRC risk factors like poor diet, alcohol consumption, and lack of physical activity prompt negative assumptions of blame and personal responsibility onto CRC patients. [ 175 ]  Judgement from others along with internalized self-blame and embarrassment can negatively affect self-esteem, sociability, and quality of life. [ 175 ]


Face-to-face interventions such as clinician-patient talk therapy, body-mind-spirit practices, and support group sessions have been identified as most effective in reducing anxiety and depression in CRC patients. [ 170 ]  Additionally, journaling exercises and over-the-phone talk therapy sessions have been implemented. [ 170 ]  Though deemed less effective, these non-face-to-face interventions are economically inclusive and have been found to reduce both depression and anxiety in CRC patients. [ 170 ]


The U.S.  National Comprehensive Cancer Network  and  American Society of Clinical Oncology  provide guidelines for the follow-up of colon cancer. [ 179 ] [ 180 ]  A  medical history  and  physical examination  are recommended every 3 to 6 months for 2 years, then every 6 months for 5 years.  Carcinoembryonic antigen  blood level measurements follow the same timing, but are only advised for people with T2 or greater lesions who are candidates for intervention. A  CT-scan  of the chest, abdomen and pelvis can be considered annually for the first 3 years for people who are at high risk of recurrence (for example, those who had poorly differentiated tumors or venous or lymphatic invasion) and are candidates for curative surgery (with the aim to cure). A  colonoscopy  can be done after 1 year, except if it could not be done during the initial staging because of an obstructing mass, in which case it should be performed after 3 to 6 months. If a villous polyp, a polyp >1 centimeter or high-grade dysplasia is found, it can be repeated after 3 years, then every 5 years. For other abnormalities, the colonoscopy can be repeated after 1 year. [ 143 ]


Routine  PET  or  ultrasound scanning ,  chest X-rays ,  complete blood count  or  liver function tests  are not recommended. [ 179 ] [ 180 ]


For people who have undergone curative surgery or adjuvant therapy (or both) to treat non-metastatic colorectal cancer, intense surveillance and close follow-up have not been shown to provide additional survival benefits. [ 181 ]


Exercise may be recommended in the future as secondary therapy to cancer survivors. In epidemiological studies, exercise may decrease colorectal cancer-specific mortality and all-cause mortality. Results for the specific amounts of exercise needed to observe a benefit were conflicting. These differences may reflect differences in tumour biology and the expression of biomarkers. People with tumors that lacked  CTNNB1  expression (β-catenin), involved in  Wnt signalling pathway , required more than 18  Metabolic equivalent  (MET) hours per week, a measure of exercise, to observe a reduction in colorectal cancer mortality. The mechanism of how exercise benefits survival may be involved in immune surveillance and inflammation pathways. In clinical studies, a pro-inflammatory response was found in people with stage II-III colorectal cancer who underwent 2 weeks of moderate exercise after completing their primary therapy. Oxidative balance may be another possible mechanism for benefits observed. A significant decrease in 8-oxo-dG was found in the urine of people who underwent 2 weeks of moderate exercise after primary therapy. Other possible mechanisms may involve metabolic hormone and sex-steroid hormones, although these pathways may be involved in other types of cancers. [ 182 ] [ 183 ]


Another potential biomarker may be  p27 . Survivors with tumors that expressed p27 and performed greater and equal to 18 MET hours per week were found to have reduced colorectal cancer mortality survival compared to those with less than 18 MET hours per week. Survivors without p27 expression who exercised were shown to have worse outcomes. The constitutive activation of  PI3K/AKT/mTOR pathway  may explain the loss of p27 and excess energy balance may up-regulate p27 to stop cancer cells from dividing. [ 183 ]


Physical activity provides benefits to people with non-advanced colorectal cancer. Improvements in aerobic fitness, cancer-related fatigue and health-related quality of life have been reported in the short term. [ 184 ]  However, these improvements were not observed at the level of disease-related mental health, such as anxiety and depression. [ 184 ]


Fewer than 600 genes are linked to outcomes in colorectal cancer. [ 51 ]  These include both unfavorable genes, where high expression is related to poor outcome, for example the  heat shock 70 kDa protein 1 (HSPA1A) , and favorable genes where high expression is associated with better survival, for example the  putative RNA-binding protein 3 (RBM3) . [ 51 ]  The prognosis is also correlated with a poor fidelity of the pre-mRNA splicing apparatus, and thus a high number of deviating alternative splicing. [ 185 ]


The average five-year recurrence rate in people with  colon cancer  where surgery is successful is 5% for  stage  I cancers, 12% in stage II and 33% in stage III. However, depending on the number of risk factors it ranges from 9–22% in stage II and 17–44% in stage III. [ 186 ]  The average five-year recurrence rate in people with  rectal cancer  where surgery is successful is 9% for stage 0  (after pre-treatment)  cancers, 8% for stage I cancers, 18% in stage II and 34% in stage III. Depending on the number of risk factors (0-2) the risk for distant metastasis in  rectal cancer  ranges from 4-11% in stage 0, 6-12% in stage I, 11-28% in stage II and 15-43% in stage III. [ 187 ]


The recurrence rates have decreased over the past decades as a result of improvements in the colorectal cancer management. [ 188 ]  The risk of recurrence after five years of surveillance remain very low. [ 189 ]


In Europe the  five-year survival rate  for colorectal cancer is less than 60%. In the  developed world  about a third of people who get the disease die from it. [ 20 ]


Survival is directly related to detection and the type of cancer involved, but overall is poor for symptomatic cancers, as they are typically quite advanced. Survival rates for early stage detection are about five times that of late stage cancers. People with a tumor that has not breached the  muscularis mucosa  (TNM stage Tis, N0, M0) have a five-year survival rate of 100%, while those with invasive cancer of T1 (within the submucosal layer) or T2 (within the muscular layer) have an average five-year survival rate of approximately 90%. Those with a more invasive tumor yet without node involvement (T3-4, N0, M0) have an average five-year survival rate of approximately 70%. People with positive regional lymph nodes (any T, N1-3, M0) have an average five-year survival rate of approximately 40%, while those with distant metastases (any T, any N, M1) have a poor prognosis and the five year survival ranges from <5 percent to 31 percent. [ 190 ] [ 191 ] [ 192 ] [ 193 ] [ 194 ]


Five-year overall survival (OS)  in rectal cancer after modern  preoperative treatment  and surgery was 90% for stage 0, 86% for stage I, 78% for stage II, and 67% for stage III according to a nationwide, population-based study. [ 187 ]


Whilst the impact of colorectal cancer on those who survive varies greatly there will often be a need to adapt to both physical and psychological outcomes of the illness and its treatment. [ 195 ]  For example, it is common for people to experience incontinence, [ 196 ]  sexual dysfunction, [ 197 ]  problems with stoma care [ 198 ]  and fear of cancer recurrence [ 199 ]  after primary treatment has concluded.


A qualitative systematic review published in 2021 highlighted that there are three main factors influencing adaptation to living with and beyond colorectal cancer: support mechanisms, severity of late effects of treatment and psychosocial adjustment. Therefore, it is essential that people are offered appropriate support to help them better adapt to life following treatment. [ 200 ]


Globally more than 1 million people get colorectal cancer every year [ 20 ]  resulting in about 715,000 deaths as of 2010 up from 490,000 in 1990. [ 201 ]


As of 2012 [update] , it is the second most common cause of cancer in women (9.2% of diagnoses) and the third most common in men (10.0%) [ 14 ] : 16   with it being the fourth most common cause of cancer death after  lung ,  stomach , and  liver cancer . [ 202 ]  It is more common in developed than developing countries. [ 203 ]  Global incidence varies 10-fold, with highest rates in Australia, New Zealand, Europe and the US and lowest rates in Africa and South-Central Asia. [ 204 ]


In 2022, the incidence of colorectal cancer in the United States was anticipated to be about 151,000 adults, including over 106,000 new cases of colon cancer (some 54,000 men and 52,000 women) and about 45,000 new cases of rectal cancer. [ 205 ]  Since the 1980s, the incidence of colorectal cancer decreased, dropping by about 2% annually from 2014 to 2018 in adults aged 50 and older, due mainly to improved screening. [ 205 ]  However, incidence of colorectal cancer has increased in individuals aged 25 to 50. In early 2023, the American Cancer Society (ACS) reported that 20% of diagnoses (of colon cancer) in 2019 were in patients under age 55, which is about double the rate in 1995, and rates of advanced disease increased by about 3% annually in people younger than 50. It predicted that, in 2023, an estimated 19,550 diagnoses and 3,750 deaths would be in people younger than 50. [ 206 ]  Colorectal cancer also disproportionately affects the Black community, where the rates are the highest of any racial/ethnic group in the US. African Americans are about 20% more likely to get colorectal cancer and about 40% more likely to die from it than most other groups. Black Americans often experience greater obstacles to cancer prevention, detection, treatment, and survival, including systemic racial disparities that are complex and go beyond the obvious connection to cancer.


In the UK about 41,000 people a year get colon cancer making it the fourth most common type. [ 207 ]


One in 19 men and one in 28 women in Australia will develop colorectal cancer before the age of 75; one in 10 men and one in 15 women will develop it by 85 years of age. [ 208 ]


In   Papua New Guinea  and other Pacific Island States including the  Solomon Islands , colorectal cancer is a very rare cancer compared to lung, stomach, liver or breast cancer. It is estimated that 8 in 100,000 people are likely to develop colorectal cancer every year, while 24 in 100,000 women are likely to develop breast cancer. [ 209 ]


A diagnosis of colorectal cancer in patients under 50 years of age is referred to as early-onset colorectal cancer (EOCC). [ 178 ] [ 210 ]  Instances of EOCC have increased over the last decade, specifically in patient populations aged 20 to 40 years old throughout North America, Europe, Australia, and China. [ 210 ] [ 211 ]


The incidence of colorectal cancer in younger populations has increased over the last decade. [ 178 ] [ 210 ] [ 211 ]   While advancements in diagnostic procedure may have some impact, reduced likelihood of screening among these populations suggests detection bias is not a major contributor to this trend.  It is more likely that cohort effects are contributing. [ 211 ]


The population experiencing the greatest rise in EOCC cases are men and women aged 20 to 29 years old, with incidence increasing by 7.9% per year between 2004 and 2016. [ 211 ]  Similarly, though less severe, men and women aged 30 to 39 experienced an increase in cases at a rate of 3.4% per year during that same time period. Despite these increases, the mortality rate for colorectal cancer has remained the same. [ 211 ]


Risk factors associated with EOCC are akin to those of all colorectal cancer cases. [ 210 ]  Observed cohort-effects are likely the product of generational shifts in lifestyle and environmental factors. [ 178 ] [ 210 ]


In 2018, the American Cancer Society modified their previous screening guideline for colorectal cancer from age 50 down to age 45 following the recognition of increasing cases of EOCC. [ 211 ]  Individuals under the age of 60 have been identified as most susceptible to non-participation in colorectal cancer screening. [ 212 ]


Rectal cancer has been diagnosed in an Ancient Egyptian  mummy  who had lived in the  Dakhleh Oasis  during the  Ptolemaic period . [ 213 ]


In the United States, March is  colorectal cancer awareness month . [ 118 ]


Preliminary  in-vitro  evidence suggests  lactic acid bacteria  (e.g.,  lactobacilli ,  streptococci  or  lactococci ) may be protective against the development and progression of colorectal cancer through several mechanisms such as  antioxidant  activity,  immunomodulation , promoting  programmed cell death ,  antiproliferative effects , and  epigenetic  modification of cancer cells. [ 214 ]


Constipation  is a  bowel  dysfunction that makes  bowel movements  infrequent or hard to pass. [ 2 ]  The  stool  is often hard and dry. [ 4 ]  Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the bowel movement. [ 3 ]  Complications from constipation may include  hemorrhoids ,  anal fissure  or  fecal impaction . [ 4 ]  The normal frequency of bowel movements in adults is between three per day and three per week. [ 4 ]  Babies often have three to four bowel movements per day while young children typically have two to three per day. [ 8 ]


Constipation has many causes. [ 4 ]  Common causes include slow movement of stool within the colon,  irritable bowel syndrome , and  pelvic floor  disorders. [ 4 ]  Underlying associated diseases include  hypothyroidism ,  diabetes ,  Parkinson's disease ,  celiac disease ,  non-celiac gluten sensitivity ,  vitamin B 12  deficiency ,  colon cancer ,  diverticulitis , and  inflammatory bowel disease . [ 4 ] [ 5 ] [ 6 ] [ 9 ] [ 10 ]  Medications associated with constipation include  opioids , certain  antacids ,  calcium channel blockers , and  anticholinergics . [ 4 ]  Of those taking  opioids  about 90% develop constipation. [ 11 ]  Constipation is more concerning when there is weight loss or  anemia ,  blood is present in the stool , there is a history of inflammatory bowel disease or colon cancer in a person's family, or it is of new onset in someone who is older. [ 12 ]


Treatment of constipation depends on the underlying cause and the duration that it has been present. [ 4 ]  Measures that may help include drinking enough fluids, eating more  fiber , consumption of  honey [ 13 ]  and  exercise . [ 4 ]  If this is not effective,  laxatives  of the  bulk-forming agent ,  osmotic agent ,  stool softener , or  lubricant type  may be recommended. [ 4 ]   Stimulant laxatives  are generally reserved for when other types are not effective. [ 4 ]  Other treatments may include  biofeedback  or in rare cases surgery. [ 4 ]


In the general population rates of constipation are 2–30 percent. [ 7 ]  Among elderly people living in a care home the rate of constipation is 50–75 percent. [ 11 ]  People in the United States spend more than  US$ 250   million  on medications for constipation a year. [ 14 ]


Constipation is a symptom, not a disease. Most commonly, constipation is thought of as infrequent bowel movements, usually fewer than 3 stools per week. [ 15 ] [ 16 ]  However, people may have other complaints as well including: [ 3 ] [ 17 ]


The  Rome III Criteria  are a set of symptoms that help standardize the diagnosis of constipation in various age groups. These criteria help physicians to better define constipation in a standardized manner.


The causes of constipation can be divided into  congenital , primary, and secondary. [ 2 ]  The most common kind is primary and not life-threatening. [ 18 ]  It can also be divided by the age group affected such as children and adults.


Primary or  functional constipation  is defined by ongoing symptoms for greater than six months not due to an underlying cause such as medication  side effects  or an underlying medical condition. [ 2 ] [ 19 ]  It is not associated with abdominal pain, thus distinguishing it from  irritable bowel syndrome . [ 2 ]  It is the most common kind of constipation, and is often multifactorial. [ 18 ] [ 20 ]  In adults, such primary causes include: dietary choices such as insufficient dietary fiber or fluid intake, or behavioral causes such as decreased  physical activity . In children, causes can include diets low in fiber and fluids, underlying medical conditions, and reluctance to go to the bathroom. [ 21 ]  In the elderly, common causes have been attributed to insufficient dietary fiber intake, inadequate fluid intake, decreased  physical activity , side effects of medications,  hypothyroidism , and obstruction by  colorectal cancer . [ 22 ]  Evidence to support these factors however is poor. [ 22 ]


Secondary causes include side effects of medications such as opiates, endocrine and metabolic disorders such as  hypothyroidism , and obstruction such as from  colorectal cancer [ 20 ]  or  ovarian cancer . [ 23 ]   Celiac disease  and  non-celiac gluten sensitivity  may also present with constipation. [ 5 ] [ 24 ] [ 6 ]  Cystocele can develop as a result of chronic constipation. [ 25 ]


Constipation can be caused or exacerbated by a low-fiber diet, low liquid intake, or dieting. [ 17 ] [ 26 ]  Dietary fiber helps to decrease colonic transport time, increases stool bulk but simultaneously softens stool. Therefore, diets low in fiber can lead to primary constipation. [ 20 ]


Many medications have constipation as a side effect. Some include (but are not limited to)  opioids ,  diuretics ,  antidepressants ,  antihistamines ,  antispasmodics ,  anticonvulsants ,  tricyclic antidepressants ,  antiarrythmics ,  beta-adrenoceptor antagonists ,  anti-diarrheals , 5-HT3 receptor antagonists such as  ondansetron , and aluminum  antacids . [ 17 ] [ 27 ]  Certain  calcium channel blockers  such as  nifedipine  and  verapamil  can cause severe constipation due to dysfunction of motility in the  rectosigmoid colon . [ 28 ]  Supplements such as calcium and iron supplements can also have constipation as a notable side effect. [ 29 ] [ 30 ]


Metabolic and endocrine problems which may lead to constipation include:  pheochromocytoma ,  hypercalcemia ,  hypothyroidism ,  hyperparathyroidism ,  porphyria ,  chronic kidney disease ,  pan-hypopituitarism ,  diabetes mellitus , and  cystic fibrosis . [ 17 ] [ 18 ]  Constipation is also common in individuals with muscular and myotonic dystrophy. [ 17 ]


Systemic diseases  that may present with constipation include  celiac disease  and  systemic sclerosis . [ 5 ] [ 24 ] [ 31 ]


Constipation has a number of structural (mechanical, morphological, anatomical) causes, namely through creating space-occupying lesions within the colon that stop the passage of stool, such as  colorectal cancer ,  strictures ,  rectocoles ,  anal sphincter  damage or malformation and post-surgical changes. Extra-intestinal masses such as other malignancies can also lead to constipation from external compression. [ 32 ]


Constipation also has neurological causes, including  anismus ,  descending perineum syndrome ,  desmosis  and  Hirschsprung's disease . [ 7 ]  In infants, Hirschsprung's disease is the most common medical disorder associated with constipation. Anismus occurs in a small minority of persons with chronic constipation or obstructed defecation. [ 33 ]


Spinal cord lesions and neurological disorders such as  Parkinson's disease  and  pelvic floor dysfunction [ 18 ]  can also lead to constipation.


Chagas disease  may cause constipation through the destruction of the  myenteric plexus . [ 34 ] [ 35 ]


Voluntary withholding of the stool is a common cause of constipation. [ 17 ]  The choice to withhold can be due to factors such as fear of pain, fear of public restrooms, or laziness. [ 17 ]  When a child holds in the stool a combination of encouragement,  fluids ,  fiber , and  laxatives  may be useful to overcome the problem. [ 36 ]  Early intervention with withholding is important as this can lead to  anal fissures . [ 37 ]


A number of diseases present at birth  can result in  constipation in children . They are as a group uncommon with Hirschsprung's disease (HD) being the most common. [ 38 ]  There are also congenital structural anomalies that can lead to constipation, including anterior displacement of the anus,  imperforate anus , strictures, and small left colon syndrome. [ 39 ]


The diagnosis is typically made based on a person's description of the symptoms. Bowel movements that are difficult to pass, very firm, or made up of small hard pellets (like those excreted by rabbits) qualify as constipation, even if they occur every day. Constipation is traditionally defined as three or fewer bowel movements per week. [ 15 ]  Other symptoms related to constipation can include bloating,  distension , abdominal pain, headaches, a feeling of fatigue and nervous exhaustion, or a sense of incomplete emptying. [ 40 ]  Although constipation may be a diagnosis, it is typically viewed as a symptom that requires evaluation to discern a cause.


Distinguish between acute (days to weeks) or chronic (months to years) onset of constipation because this information changes the  differential diagnosis . This in the context of accompanied symptoms helps physicians discover the cause of constipation. People often describe their constipation as bowel movements that are difficult to pass, firm stool with lumpy or hard consistency, and excessive straining during bowel movements. Bloating, abdominal  distension , and abdominal pain often accompany constipation. [ 41 ]  Chronic constipation (symptoms present at least three days per month for more than three months) associated with abdominal discomfort is often diagnosed as irritable bowel syndrome (IBS) when no obvious cause is found. [ 42 ]


Poor dietary habits, previous abdominal surgeries, and certain medical conditions can contribute to constipation. Diseases associated with constipation include  hypothyroidism , certain types of  cancer , and  irritable bowel syndrome . Low fiber intake, inadequate amounts of fluids, poor ambulation or immobility, or medications can contribute to constipation. [ 17 ] [ 26 ]  Once the presence of constipation is identified based on a culmination of the symptoms described above, then the cause of constipation should be figured out.


Separating non-life-threatening from serious causes may be partly based on symptoms. For example, colon cancer may be suspected if a person has a family history of colon cancer, fever, weight loss, and rectal bleeding. [ 15 ]  Other alarming signs and symptoms include family or personal history of inflammatory bowel disease, age of onset over 50, change in stool caliber, nausea, vomiting, and neurological symptoms like weakness, numbness and difficulty urinating. [ 41 ]


A physical examination should involve at least an abdominal exam and rectal exam. Abdominal exam may reveal an abdominal mass if there is significant stool burden and may reveal abdominal discomfort.  Rectal examination  gives an impression of the anal sphincter  tone  and whether the lower rectum contains any feces or not. Rectal examination also gives information on the consistency of the stool, the presence of hemorrhoids, blood and whether any  perineal  irregularities are present including skin tags, fissures, anal warts. [ 26 ] [ 17 ] [ 15 ]  Physical examination is done manually by a physician and is used to guide which diagnostic tests to order.


Functional constipation is common and does not warrant diagnostic testing. Imaging and laboratory tests are typically recommended for those with alarm signs or symptoms. [ 15 ]


The laboratory tests performed depends on the suspected underlying cause of the constipation. Tests may include CBC ( complete blood count ), thyroid function tests, serum calcium, serum potassium, etc. [ 17 ] [ 15 ]


Abdominal X-rays  are generally only performed if bowel obstruction is suspected, may reveal extensive impacted fecal matter in the colon, and may confirm or rule out other causes of similar symptoms. [ 26 ] [ 17 ]


Colonoscopy may be performed if an abnormality in the colon like a tumor is suspected. [ 15 ]  Other tests rarely ordered include  anorectal manometry , anal sphincter electromyography, and  defecography . [ 17 ]


Colonic propagating pressure wave sequences (PSs) are responsible for discrete movements of the bowel contents and are vital for normal defecation. Deficiencies in PS frequency, amplitude, and extent of propagation are all implicated in severe defecatory dysfunction (SDD). Mechanisms that can normalize these aberrant motor patterns may help rectify the problem. Recently the novel therapy of  sacral nerve stimulation  (SNS) has been utilized for the treatment of severe constipation. [ 43 ]


The Rome III Criteria for functional constipation must include two or more of the following and present for the past three months, with symptoms starting for at least 6 months prior to diagnosis. [ 15 ]


Constipation is usually easier to prevent than to treat. Following the relief of constipation, maintenance with adequate exercise, fluid intake, and high-fiber diet is recommended. [ 17 ]


A limited number of cases require urgent medical intervention or will result in severe consequences. [ 3 ]


The treatment of constipation should focus on the underlying cause if known. The National Institute of Health and Care Excellence (NICE) break constipation in adults into two categories: chronic constipation of unknown cause, and constipation due to opiates. [ 44 ]


In chronic constipation of unknown cause, the main treatment involves the increased intake of water and fiber (either dietary or as supplements). [ 18 ]  The routine use of laxatives or enemas is discouraged, as having bowel movements may come to be dependent upon their use. [ 45 ]


Soluble fiber supplements such as  psyllium  are generally considered first-line treatment for chronic constipation, compared to insoluble fibers such as wheat bran. Side effects of fiber supplements include bloating, flatulence, diarrhea, and possible  malabsorption  of iron, calcium, and some medications. However, patients with opiate-induced constipation will likely not benefit from fiber supplements. [ 37 ]


If  laxatives  are used,  milk of magnesia  or  polyethylene glycol  are recommended as first-line agents due to their low cost and safety. [ 3 ]  Stimulants should only be used if this is not effective. [ 18 ]  In cases of chronic constipation, polyethylene glycol appears superior to  lactulose . [ 46 ]   Prokinetics  may be used to improve gastrointestinal motility. A number of new agents have shown positive outcomes in chronic constipation; these include  prucalopride [ 47 ]  and  lubiprostone . [ 48 ]   Cisapride  is widely available in third world countries, but has been withdrawn in most of the west. It has not been shown to have a benefit on constipation, while potentially causing cardiac arrhythmias and deaths. [ 49 ]


Enemas  can be used to provide a form of mechanical stimulation. A large volume or high enema [ 50 ]  can be given to cleanse as much of the colon as possible of feces, [ 51 ] [ 52 ]  and the solution administered commonly contains  castile soap  which irritates the colon's lining resulting in increased urgency to defecate. [ 53 ]  However, a low enema is generally useful only for stool in the rectum, not in the intestinal tract. [ 54 ]


Constipation that resists the above measures may require physical intervention such as manual disimpaction (the physical removal of impacted stool using the hands; see  fecal impaction ).


Regular  exercise  can help improve chronic constipation. [ 55 ]


In refractory cases, procedures can be performed to help relieve constipation.  Sacral nerve stimulation  has been demonstrated to be effective in a minority of cases.  Colectomy  with ileorectal  anastomosis  is another intervention performed only in patients known to have a slow colonic transit time and in whom a defecation disorder has either been treated or is not present. [ 3 ]  Because this is a major operation, side effects can include considerable abdominal pain, small bowel obstruction, and post-surgical infections. Furthermore, it has a very variable rate of success and is very case dependent. [ 37 ]


Complications that can arise from constipation include  hemorrhoids ,  anal fissures ,  rectal prolapse , and fecal impaction. [ 17 ] [ 26 ] [ 56 ] [ 57 ]  Straining to pass stool may lead to hemorrhoids. In later stages of constipation, the abdomen may become distended, hard and diffusely tender. Severe cases ("fecal impaction" or  malignant constipation ) may exhibit symptoms of bowel obstruction (nausea,  vomiting , tender abdomen) and  encopresis , where soft stool from the small intestine bypasses the mass of impacted fecal matter in the  colon .


Constipation is the most common chronic gastrointestinal disorder in adults. Depending on the definition employed, it occurs in 2% to 20% of the population. [ 18 ] [ 58 ]  It is more common in women, the elderly and children. [ 58 ]  Specifically constipation with no known cause affects females more often affected than males. [ 59 ]  The reasons it occurs more frequently in the elderly is felt to be due to an increasing number of health problems as humans age and decreased physical activity. [ 19 ]


Since ancient times different societies have published medical opinions about how health care providers should respond to constipation in patients. [ 61 ]  In various times and places, doctors have made claims that constipation has all sorts of medical or social causes. [ 61 ]  Doctors in history have treated constipation in reasonable and unreasonable ways, including use of a  spatula mundani . [ 61 ]


After the advent of the  germ theory of disease  then the idea of "auto-intoxication" entered popular Western thought in a fresh way. [ 61 ]   Enema  as a scientific medical treatment and  colon cleansing  as alternative medical treatment became more common in medical practice. [ 61 ]


Since the 1700s in the West there has been some popular thought that people with constipation have some moral failing with  gluttony  or  laziness . [ 62 ]


Approximately 3% of children have constipation, with girls and boys being equally affected. [ 39 ]  With constipation accounting for approximately 5% of general pediatrician visits and 25% of pediatric gastroenterologist visits, the symptom carries a significant financial impact upon the healthcare system. [ 8 ]  While it is difficult to assess an exact age at which constipation most commonly arises, children frequently experience constipation in conjunction with life-changes. Examples include: toilet training, starting or transferring to a new school, and changes in diet. [ 8 ]  Especially in infants, changes in formula or transitioning from breast milk to formula can cause constipation. The majority of constipation cases are not tied to a medical disease, and treatment can be focused on simply relieving the symptoms. [ 39 ]


The six-week period after pregnancy is called the  postpartum  stage. [ 63 ]  During this time, women are at increased risk of being constipated. Multiple studies estimate the prevalence of constipation to be around 25% during the first 3 months. [ 64 ]  Constipation can cause discomfort for women, as they are still recovering from the delivery process especially if they have had a  perineal tear  or underwent an  episiotomy . [ 65 ]  Risk factors that increase the risk of constipation in this population include: [ 65 ]


Hemorrhoids  are common in pregnancy and also may get exacerbated when constipated. Anything that can cause pain with stooling (hemorrhoids, perineal tear, episiotomy) can lead to constipation because patients may withhold from having a bowel movement so as to avoid pain. [ 65 ]


The pelvic floor muscles play an important role in helping pass a bowel movement. Injury to those muscles by some of the above risk factors (examples- delivering a large child, lengthy second stage of labor, forceps delivery) can result in constipation. [ 65 ]  Enemas may be administered during labor and these can also alter bowel movements in the days after giving birth. [ 63 ]  However, there is insufficient evidence to make conclusions about the effectiveness and safety of laxatives in this group of people. [ 65 ]


Diarrhea  ( American English ), also spelled  diarrhoea  or  diarrhœa  ( British English ), is the condition of having at least three loose, liquid, or watery  bowel movements  in a day. [ 2 ]  It often lasts for a few days and can result in  dehydration  due to fluid loss. [ 2 ]  Signs of dehydration often begin with loss of the normal stretchiness of the skin and irritable behaviour. [ 2 ]  This can progress to decreased  urination ,  loss of skin color , a  fast heart rate , and a  decrease in responsiveness  as it becomes more severe. [ 2 ]  Loose but non-watery  stools  in babies who are exclusively  breastfed , however, are normal. [ 2 ]


The most common cause is an infection of the  intestines  due to a  virus ,  bacterium , or  parasite —a condition also known as  gastroenteritis . [ 2 ]  These infections are often acquired from food or water that has been contaminated by  feces , or directly from another person who is infected. [ 2 ]  The three types of diarrhea are: short duration watery diarrhea, short duration bloody diarrhea, and persistent diarrhea (lasting more than two weeks, which can be either watery or bloody). [ 2 ]  The short duration watery diarrhea may be due to  cholera , although this is rare in the developed world. [ 2 ]  If blood is present, it is also known as  dysentery . [ 2 ]  A number of non-infectious causes can result in diarrhea. [ 5 ]  These include  lactose intolerance ,  irritable bowel syndrome ,  non-celiac gluten sensitivity ,  celiac disease ,  inflammatory bowel disease  such as  ulcerative colitis ,  hyperthyroidism ,  bile acid diarrhea , and a number of medications. [ 5 ] [ 6 ] [ 7 ]  In most cases,  stool cultures  to confirm the exact cause are not required. [ 8 ]


Diarrhea can be prevented by improved  sanitation , clean  drinking water , and  hand washing  with soap. [ 2 ]   Breastfeeding  for at least six months and  vaccination against rotavirus  is also recommended. [ 2 ]   Oral rehydration solution  (ORS)—clean water with modest amounts of salts and  sugar —is the treatment of choice. [ 2 ]   Zinc tablets  are also recommended. [ 2 ]  These treatments have been estimated to have saved 50 million children in the past 25 years. [ 1 ]  When people have diarrhea it is recommended that they continue to eat healthy food, and babies continue to be breastfed. [ 2 ]  If commercial ORS is not available, homemade solutions may be used. [ 9 ]  In those with severe dehydration,  intravenous fluids  may be required. [ 2 ]  Most cases, however, can be managed well with fluids by mouth. [ 10 ]   Antibiotics , while rarely used, may be recommended in a few cases such as those who have bloody diarrhea and a high fever, those with severe  diarrhea following travelling , and those who grow specific bacteria or parasites in their stool. [ 8 ]   Loperamide  may help decrease the number of bowel movements but is not recommended in those with severe disease. [ 8 ]


About 1.7 to 5 billion cases of diarrhea occur per year. [ 2 ] [ 5 ] [ 11 ]  It is most common in  developing countries , where young children get diarrhea on average three times a year. [ 2 ]  Total deaths from diarrhea are estimated at 1.53 million in 2019—down from 2.9 million in 1990. [ 4 ]  In 2012, it was the second most common cause of  deaths in children  younger than five (0.76 million or 11%). [ 2 ] [ 12 ]  Frequent episodes of diarrhea are also a common cause of  malnutrition  and the most common cause in those younger than five years of age. [ 2 ]  Other long term problems that can result include  stunted growth  and poor intellectual development. [ 12 ]


The word diarrhea is from the  Ancient Greek   διάρροια  from  διά   dia  "through" and  ῥέω   rheo  "flow".


Diarrhea  is the spelling in  American English , whereas  diarrhoea  is the spelling in  British English .


Slang terms for the condition include "the runs", "the squirts" (or "squits" in Britain [ 13 ] ) and "the trots". [ 14 ] [ 15 ]


The word is often pronounced as  / ˌ d aɪ ə ˈ r iː ə /   DY -ə- REE -ə .


Diarrhea is defined by the  World Health Organization  as having three or more loose or liquid  stools  per day, or as having more stools than is normal for that person. [ 2 ]


Acute diarrhea is defined as an abnormally frequent discharge of semisolid or fluid fecal matter from the bowel, lasting less than 14 days, by  World Gastroenterology Organization . [ 16 ]  Acute diarrhea that is watery may be known as AWD (Acute Watery Diarrhoea.) [ 17 ]


Secretory diarrhea means that there is an increase in the active secretion, or there is an inhibition of absorption. There is little to no structural damage. The most common cause of this type of diarrhea is a  cholera toxin  that stimulates the secretion of  anions , especially  chloride  ions (Cl – ). Therefore, to maintain a charge balance in the  gastrointestinal tract , sodium (Na + ) is carried with it, along with water. In this type of diarrhea intestinal fluid secretion is  isotonic  with plasma even during fasting. [ 18 ] [ 19 ]  It continues even when there is no oral food intake.