Chronic intestinal pseudoobstruction (ORPHA:2978)
A rare and heterogeneous gastroenterological clinical syndrome characterized by recurrent symptoms of intestinal obstruction with radiological features of dilated small or large intestine in absence of any mechanical occlusive lesion. Permanent alterations in neural, muscular, or mesenchymal structures of the intestinal wall or its extrinsic neural control, chronically impair tonic and propulsive motor functions in one or more segments of the gut.
Epidemiology
The incidence of the pediatric form of CIPO has been estimated ≤ 1/40,000 live births. In Japan, the prevalence of CIPO in children < 15 years of age was 1/270,000 and in adults with onset age > 15 years was 1/100,000 and 1/125,000 and the annual incidence was 1/476,000 and 1/435,000 in males and females, respectively.
Clinical description
Patients present with chronic abdominal pain and distention; in between, acute episodes of severe abdominal pain and vomiting suggest a mechanical obstruction. Patients have diarrhea due to small bowel bacterial overgrowth or constipation due to delayed transit. Weight loss results from malabsorption and inadequate food intake.
Etiology
CIPO is often associated with diseases in which treatment and prognosis are those of the underlying condition. In the remaining ''primary'' cases two subgroups can be recognized: those in whom CIPO is caused by an abnormal autoimmune/inflammatory response against neuromuscular structures of the gut and those in whom an inherited or de novo genetic mutation underlies the impairment of muscle, neural, or interstitial cell function. ACTG2 gene variants account for approximately 50% of the genetic cases. Other genes were reported, most of which in single-cases.
Diagnostic methods
Abdominal MRI or CT scan should confirm the chronic dilatation of the small or large intestine and should exclude a mechanical obstruction. Patients should therefore be investigated for the presence of numerous diseases that are associated with CIPO, such as Hirshsprung's disease, mitochondrial or paraneoplastic diseases, for the use of drugs that impair gastrointestinal motility, and for family history of similar symptoms. Esophageal, antroduodenal and anorectal manometry play a supportive role in the diagnosis; low amplitude contractions suggest a myopathic disorder whereas disorganized motor patterns suggest a neuropathic disorder. Full-thickness biopsies are usually not recommended but might be indicated to confirm an ongoing inflammatory visceral neuropathy or myopathy before starting immunotherapies. Genes that should be investigated in the case of CIPO include ACTG2, MYH11 and FLNA. Screening of TYMP and POLG should be considered in case of suspected mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). The genetic screening of FLNA (NM_001110556.1) in the context of CIPO could be limited to exon 1, as pathogenic mutations resulting in a visceral phenotype are confined to the longer isoform, which is specifically expressed in intestinal smooth muscle cells.
Differential diagnosis
The differential diagnosis includes mechanical obstruction, acute colonic pseudoobstruction, enteric dismotility and slow transit constipation.
Antenatal diagnosis
Antenatal diagnosis of the ACTG2 mutation can be proposed when fetal bladder dilation is observed. Antenatal diagnosis of other genes is theoretically possible but has not been reported in the literature. Antenatal diagnosis is possible when a pathogenic variant has been identified in a family member with the disease.
Genetic counseling
Genetic counseling is recommended when cases of chronic intestinal pseudoobstruction are recurrent within the same family or when the physician suspects a genetic etiology.
Management and treatment
Management depends on the cause of the disorder, the extent and location of intestine involved, and the severity of symptoms. General measures include low residue diets, oral and/or enteral nutrition to prevent malnutrition, prokinetic agents (prucalopride), neostigmine or pyridostigmine to reduce intestinal dilatation and cycles of antibiotics to control bacterial overgrowth. Autoimmune/inflammatory forms might benefit from immunosuppressive treatments. Surgery should be avoided except in selected cases; ostomies can provide safe and effective detention of segmental bowel distention. Intestinal transplantation has become a therapeutic option in selected cases.
Prognosis
CIPO is a clinical syndrome characterized by disabling and potentially life-threatening complications over time. Treatment and long-term outcome is heterogeneous and often unsatisfactory.

                            Last update: 
                            June 2024


                            - Expert reviewer(s): 
                            Dr Guido BASILISCO  - Dr Margherita MARCHI