Chronic intestinal pseudo-obstruction and how to avoid them

CIPO is a severe intestinal motility disorder characterised by radiological evidence of dilated small bowel loops, mimicking mechanical obstruction, denoting the failure of propulsive forces exerted by intestinal peristalsis to overcome the natural resistance to flow.² Although small bowel dilatation with air–fluid levels in radiological studies is a necessary criterion to establish the diagnosis of CIPO, there are no quantitative criteria to define an abnormal bowel diameter. Moreover, in some cases, radiological signs are only present during acute exacerbations (pseudo-obstructive crisis), showing “normal” or “near normal” radiological studies in between. This complicates diagnosis and often delays it by several years after symptom onset.³ On the other hand, CIPO is sometimes overdiagnosed in patients with severe functional digestive symptoms, in the absence of radiological evidence of small bowel dilatation, leading to unnecessary interventions and an increase in morbidity.

To confirm intestinal motility disorder, small bowel (duodenal and/or jejunal) manometry is the gold-standard diagnostic test (Figure 1).⁴ Although not widely available, this test is especially helpful in CIPO when inter-episodic radiology is normal. A normal manometric pattern virtually excludes a severe motility disorder.⁵ Small intestinal manometry may also detect obstructive patterns, which would compel re-evaluation of the patient for a missed mechanical obstruction.⁶

Over the last decade, there have been important advancements in the evaluation of small intestinal motility with novel techniques like high-resolution jejunal manometry,⁷ cine-magnetic resonance imaging (MRI),⁸ and whole-gut transit scintigraphy.⁹ For example, cine-MRI detects differential motor abnormalities in patients with CIPO compared with patients with irritable bowel syndrome (IBS)¹⁰ and has shown promising results¹¹ evaluating the response to prokinetic treatment in patients with CIPO according to different phenotypes. High-resolution jejunal manometry detects specific small bowel motor abnormalities in patients with mitochondriopathies.¹² Nonetheless, these novel diagnostic techniques must all overcome challenges, including procedure standardisation and external validation of results, before they can be applied in standard clinical practice.

Figure 1 | Examples of normal and abnormal small bowel motility by high-resolution jejunal manometry. a | A normal migrating motor complex seen in a healthy subject, characterized by three phases: a period of irregular propagated contractions (phase II), followed by a period of repetitive regular propagated contractions (phase III), and then a period of motor quiescence (phase I). b | A myopathic pattern in a patient with systemic sclerosis. Note the absence of propagated contractions during phase II and the reduced amplitude during phase III. c | A neuropathic pattern in a patient with a mitochondrial disease. Note the abnormal configuration of the propagated contractions during phase III.

CIPO represents the most advanced stage of a wide range of neuro-myopathies that cause gastrointestinal motility dysfunction. It has many etiological mechanisms that involve abnormalities in the function of the enteric nervous system and/ or the enteric smooth muscles.

CIPO can be broadly classified as primary or secondary.¹³ Primary CIPO may be congenital or idiopathic, while secondary CIPO is the end-stage manifestation of gastrointestinal involvement from a well-defined disease, either systemic or localised to the gastrointestinal tract. Primary CIPO is usually diagnosed in childhood and secondary CIPO is more frequent in the adult population.¹⁴ Up to 50% of patients diagnosed with CIPO during adulthood will have an underlying disease subject to specific treatment (neurologic, paraneoplastic, autoimmune, metabolic/endocrine, or infectious diseases, Table 1).¹⁵ Therefore, in adult patients recently diagnosed with CIPO, it is imperative to perform a full diagnostic work-up to search for an underlying aetiology.¹³

Table 1 | Causes of CIPO.

In any patient diagnosed with CIPO during adulthood, once a thorough work-up has ruled out secondary causes, it is important to consider forms of primary CIPO arising from genetic disorders presenting at later stages of life.¹⁶ A thorough family history of relatives with a similar clinical presentation, early deaths, or difficulties thriving may suggest a congenital form of CIPO. However, a lack of family history does not exclude genetic forms of CIPO, since the patient may be the index case of a sporadic mutation. Genome sequencing techniques are now widely available to detect genetic variants associated with CIPO. Two genetic conditions are worth mentioning. Dominant mutations in the smooth muscle actin gene ACTG2 account for up to 50% of primary CIPO in childhood and adulthood.¹⁷ ACTG2 mutations are associated with multivisceral myopathy (urinary tract and/or uterine involvement) and also specific phenotypes (megacystis–microcolon– intestinal hypoperistalsis syndrome and prune-belly syndrome).¹⁸ Another recognised form of recessive primary CIPO is mitochondrial neurogastrointestinal encephalopathy (MNGIE). MNGIE syndrome is caused by mutations in the thymidine phosphorylase gene TYMP. Patients with MNGIE present with neurological signs, such as ptosis, ophthalmoparesis, and peripheral neuropathy, along with objective findings on brain MRI (leukoencephalopathy), highlighting the importance of a thorough neurological examination in all patients with CIPO.

Recognising genetic causes of CIPO, it is useful to provide genetic counselling and also to screen other family members before severe forms develop, particularly with treatment advances like liver transplantation for MNGIE.¹⁹

Another important step in the evaluation of patients with CIPO is histopathological analysis of the intestine. When work-up for an underlying systemic or genetic disorder is negative, a full-thickness small bowel biopsy should be considered to determine the underlying neuromuscular abnormalities.²⁰ Small bowel full-thickness biopsies are obtained by surgery since conventional endoscopic biopsies do not reach the deep neuromuscular layers of the intestine. Although indications for surgery in patients with CIPO should be carefully weighed, particularly in those with an advanced disease or malnutrition, complications from full-thickness biopsies are rare, with the primary concern being prolonged post-operative ileus.²¹

Small intestinal manometry may be useful to decide whether to perform a biopsy, since abnormal motility patterns are strongly associated with abnormal neuromuscular findings on full-thickness biopsies.²² When full-thickness biopsies are considered, the jejunum should be the preferred site of sampling, as it is the segment with the highest diagnostic yield.²¹

The most important motivation for histological analysis of patients with idiopathic CIPO is the potential detection of an inflammatory cell infiltrate in the myenteric plexus (myenteric ganglionitis) and/or adjacent smooth muscle layers (leiomyositis), since inflammatory forms of CIPO may respond to immunosuppressive treatments (Figure 2).²³ High-dose steroids, including azathioprine, intravenous immunoglobulins, and rituximab, have been reported to induce satisfactory recovery in case series and case reports of patients with CIPO secondary to inflammatory neuromyopathies (Figure 3).^24–26

Figure 2 | Full-thickness jejunal biopsy of a patient with an autoimmune form of CIPO associated to myasthenia gravis and achalasia. The histological image shows a lymphocytic CD3+ infiltrate in the myenteric plexus between the circular and longitudinal muscle layers of the small bowel (myenteric ganglionitis). Image courtesy of Dr. S. Landolfi, Pathology Department, Vall d’Hebron University Hospital.

Figure 3 | Abdominal computed tomography (CT) scan images from the same patient shown in Figure 2, with an autoimmune form of CIPO and myenteric ganglionitis by histological analysis. a | note the dilated small bowel before treatment and b | note an improvement of dilatation after treatment with steroids (later tapered to a low-dose maintenance treatment).

During the course of the disease, most patients with CIPO will present with acute exacerbations (acute pseudo-obstructive crisis). Patients with acute exacerbations will often report food intolerance, vomiting, and a distended abdomen.³ Initial management is conservative and involves fasting, intravenous fluid resuscitation, correction of metabolic derangements, and bowel decompression with a nasogastric tube. During acute exacerbations, it is essential to systematically evaluate reversible systemic and metabolic factors that may contribute to abnormal gut motility function. Infections,particularly abdominal sepsis and catheter-related infections in patients receiving total parenteral nutrition, are recognised triggers for acute exacerbations that can worsen dysmotility symptoms. Additionally, adverse effects of medications, such as opioids and anticholinergics, should be considered, and any identified culprit medication should be discontinued. For pain management, it is important to avoid opioids and prioritise other analgesic options. In chronic opioid users, peripherally acting opioid receptor antagonists (PAMORAs), which block gastrointestinal opioid receptors while preserving analgesic effects, can be considered.

Furthermore, electrolyte disturbances and compromised kidney function, primarily attributed to factors like vomiting, dehydration, or third-space fluid sequestration, are frequently encountered and contribute to the perpetuation of abnormal gut motility.Another frequent complication in patients with CIPO is small intestinal bacterial overgrowth (SIBO).²⁷ This should be suspected in patients with symptoms such as flatulence, chronic diarrhoea,and steatorrhoea; deficiencies in fat-soluble vitamins and vitamin B12; or increased folate levels. The treatment of SIBO in patients with small bowel motility disorders involves two main strategies: enhancing gastrointestinal propulsive activity with prokinetic agents and reducing bacterial load by using oral antibiotics. A range of prokinetic drugs and antibiotic regimens to be used in CIPO are summarised in Table 2 and Table 3. Breath levels of hydrogen and methane may be elevated in patients with CIPO during fasting, and therefore glucose or lactulose breath tests are often not useful to guide therapy. In symptomatic patients with severe small intestinal dysmotility, empiric treatment with antibiotics is recommended regardless of breath test results.

Table 2 | Antibiotics used for small intestinal bacterial overgrowth treatment in CIPO.^15,20,26

Table 3 | Prokinetics used for symptom management in CIPO.^20,26,28

At the time of diagnosis, malnutrition is almost invariably present in patients with CIPO.²⁰ During the course of the disease, about one-third of patients with CIPO will need some type of parenteral nutritional support.³ Therefore, nutritional assessment is imperative to improve quality of life and prognosis. A significant lack of data exists regarding nutritional strategies for CIPO, and current practices are primarily based on extrapolated evidence and expert experience.

The effective management of patients with CIPO starts with a systematic and personalised nutritional strategy, which should be tailored to the individual patient by route and quantity. The dietary regimen should focus on maintaining nutritional balance while minimising any adverse impact on digestive symptoms. This task is best undertaken in conjunction with nutritionists and dietitians with experience in motility disorders. Patients should undergo regular anthropometry (weight, BMI), control of eating habits (number of meals, percentage of meal completion), and adequate control of fluid balance; laboratory nutritional measurements should be measured and corrected, as needed.

It is important to remember that eating is psychologically beneficial, therefore, the oral route should be improved and maintained as much as possible. In addition, diet plans and modifications should consider the quantity and composition of essential macro- and micro nutrients, and special attention should be given to excluding specific food components that have the potential to worsen gastrointestinal symptoms (Table 4).

If oral intake is not sufficient to maintain nutrition, enteral or parenteral nutrition should be considered. Enteral feeding should be the next route of choice for all patients, however, patients with CIPO who do not tolerate oral feeding generally have poor tolerance to enteral feeding. Before opting for invasive procedures like percutaneous feeding tube placement, it is advisable to conduct a trial using a nasogastric or nasojejunal feeding tube. In patients with severe malnutrition, significant weight loss,hypoproteinemia despite maximum enteral therapy, electrolyte, and other micro-nutrient deficiencies unresponsive to oral supplementation, parenteral support should be initiated.

Table 4 | Measures to improve oral diet intake in CIPO.

Patients with CIPO have distended bowel loops filled with retained secretions and insoluble gas (composed mainly of swallowed air and by-products of fermentation by SIBO), causing bowel distension and reducing the absorption capacity of the small intestine, which further aggravates the stasis. Bowel distension plays an important role in the genesis of gastrointestinal symptoms and usually progresses over time.³ In cases where chronic bowel distension is associated with invalidating symptoms that do not respond to diet modification and pharmacological treatments, venting techniques to achieve effective bowel decompression are beneficial (Figure 4).

When selecting venting techniques, the timing and characteristics of refractory symptoms play a crucial role. If the refractory symptoms are associated with an exacerbating factor (e.g., sepsis, acute pseudo-obstructive crisis, pharmacological adverse effects) that can be improved, conventional methods like intermittent nasogastric suction, rectal tubes, or colonic decompression may be suitable. Conversely, for patients with chronically poorly controlled symptoms despite maximum medication and good adherence to general measures, more invasive and permanent procedures, such as surgical, radiological or endoscopic gastrostomies, or jejunostomies, should be considered.²⁹ Permanent venting tubes are useful to improve food tolerance and reduce obstructive symptoms, but patients with CIPO have the disadvantage of an increased risk of peristomal leakage of gastric or intestinal content.

Figure 4 | CT scan image of a CIPO patient with a gastrojejunostomy tube placed for venting.

It is important to remember that in most cases, surgery is unable to restore effective gut motility in patients with CIPO. Moreover, unnecessary surgical interventions in patients with CIPO increase the risk of complications, by potentially exacerbating the underlying dysmotility, both acutely through post-operative ileus and chronically due to post-operative adhesions. Regretfully, many patients with CIPO often undergo multiple, non-contributive laparotomies due to a delay in the diagnosis of the motility disorder.³⁰

When patients with CIPO present to the emergency room with symptoms of bowel occlusion, they usually present acute exacerbations (pseudo-obstructive crisis) and conservative management (fasting, intravenous fluid resuscitation, correction of metabolic derangements, and bowel decompression with a nasogastric tube) is warranted and parenteral prokinetics, like erythromycin or neostigmine should be considered (Figure 5).^31,32 Of note, neostigmine infusion should be administered with cardiac monitoring and atropine readily available due to the risk of symptomatic bradycardia. Surgery should only be employed to treat complications such as volvulus, intestinal ischemia, perforation, or peritonitis. Post-operative morbidity is higher in patients with CIPO who undergo intestinal resection compared with patients who receive a conservative approach.³³ In selected cases of end-stage CIPO with intestinal failure and total parenteral nutrition-associated complications, intestinal transplantation is a life-saving option and should be considered on a case-to-case basis.³⁴

Figure 5 | Abdominal X-rays from a patient obtained: a | during an acute pseudo-obstructive episode and b | after resolution with conservative management.