Characterization of patients with medically unexplained intolerance to enteral feeding treated with home parenteral nutrition: A descriptive cohort study

Abstract

Background and Aims

Dutch intestinal failure centers are increasingly confronted with patients started on total parenteral nutrition because of reported intolerance to enteral feeding without meeting clinical criteria for intestinal failure. This study aimed to describe clinical characteristics, medical consumption, and treatment status of patients with medically unexplained intolerance to enteral feeding treated with home parenteral nutrition.

Methods

We performed a descriptive cohort study in three intestinal failure expert centers in the Netherlands. We identified adult patients on total parenteral nutrition without a medical explanation for intolerance to enteral feeding via an electronic medical record search. We investigated patient characteristics, diagnostic procedures, and treatments these individuals had undergone. We also evaluated the impact of caring for these patients on physicians, using a questionnaire.

Results

78 patients on total parenteral nutrition and with medically unexplained intolerance to enteral feeding were analyzed. Most patients were female (91%), 80% were ≤45 years at the start of gastrointestinal complaints, 63% were on opioids, and in 83% discontinuation of total parenteral nutrition was not achieved. The impact on treating physicians was rated as at least very burdensome.

Conclusion

Treating patients with medically unexplained intolerance to enteral feeding with total parenteral nutrition is challenging for involved professionals in Dutch intestinal failure expert centers. This mainly concerns relatively young, female patients, most using opioids, and weaning off total parenteral nutrition is not successful in most cases. We suggest using caution when initiating total parenteral nutrition in patients with unexplained enteral intolerance before consultation with and/or assessment at an expert center.

INTRODUCTION

Disorders of gut‐brain interaction, previously termed functional gastrointestinal disorders, present a common but complex challenge in clinical practice. Such conditions are associated with reduced quality of life and increased healthcare consumption, particularly when patients report an intolerance to enteral feeding. ¹ In routine practice, intestinal failure expert centers primarily treat patients who require parenteral nutrition because of a reduction of gut function below the minimum necessary for adequate absorption, most commonly in the context of short bowel syndrome, small intestinal dysmotility, intestinal fistulas, or extensive small bowel mucosal disease. ² In such conditions, parenteral nutrition represents a life‐saving therapy. ³

In recent years, and in line with experiences in other European countries, ⁴ , ⁵ Dutch intestinal failure expert centers have seen an increasing number of referrals of patients who were started on total parenteral nutrition because of self‐reported intolerance to enteral feeding without a clear medical explanation. Initiation of total parenteral nutrition in the absence of a well‐defined underlying condition leading to intestinal failure poses a major clinical challenge, particularly given the risks and complications of long‐term parenteral nutrition and the considerable burden on healthcare resources.

Weaning off total parenteral nutrition in patients with medically unexplained intolerance is often difficult and requires full support from patients, their family, or other caregivers. Many of these patients have a history of extensive healthcare use across multiple hospitals, including frequent outpatient visits, repeated hospitalizations, and numerous, sometimes invasive, diagnostic procedures. Managing this patient group can be challenging and may lead to conflicts between patients and healthcare professionals. However, the clinical characteristics, prior medical consumption, and treatment status of patients with medically unexplained intolerance to enteral feeding treated with total parenteral nutrition have not been systematically described at a national level.

To address this knowledge gap, a descriptive cohort study was conducted among adult patients with medically unexplained intolerance to enteral feeding who were treated with home total parenteral nutrition at one of three expert centers in the Netherlands. The aim of this study was to describe the clinical characteristics, medical consumption, and treatment status of this patient population.

METHODS

Study design and patients

We performed a descriptive cohort study of 78 adults with medically unexplained intolerance to enteral feeding who received home parenteral nutrition for at least 6 months at Radboud University Medical Center, University Medical Center Groningen, or Amsterdam University Medical Center between 1997 and 2023. These three centers represent all adult intestinal failure expert centers in the Netherlands.

Patients were included if they were ≥18 years of age, had been treated with home parenteral nutrition for at least 6 months, and had been diagnosed with medically unexplained intolerance to enteral feeding by the treating intestinal failure expert. Patients were excluded if they met the clinical criteria for intestinal failure, defined as a reduction of gut function below the minimum necessary for the absorption of macronutrients and/or water and electrolytes, such that intravenous supplementation is required to maintain health and/or growth. ⁶ The diagnosis of intestinal failure and medically unexplained intolerance to enteral feeding was established by the treating intestinal failure expert at the participating center, based on clinical assessment and review of the available diagnostic work‐up.

The primary outcome was the clinical and demographic characteristics of patients with medically unexplained intolerance to enteral feeding treated with home parenteral nutrition. These characteristics included sex, marital and residential status, educational level, age at symptom onset and first specialist evaluation, presenting gastrointestinal symptoms, bowel complaints, oral intake, complaints in other organ systems, medication use (opioids and psychopharmacological drugs), psychiatric history, employment status, contact with peers, and healthcare‐seeking behavior. Secondary outcomes were prior diagnostic and therapeutic interventions, the clinical course after initiation of total parenteral nutrition, and the reported impact of caring for these patients on the medical team. Clinical course included treatment status at the time of data collection (still under treatment, deceased, referred, or termination of the treatment relationship) and the ability to resume oral and/or enteral feeding.

Study procedures

Physicians at the three intestinal failure expert centers identified patients who met the inclusion criteria. Medical records were retrospectively reviewed between October 2023 and February 2024 to extract data on patient characteristics, diagnostic procedures, treatments, and clinical course. The study did not include a predefined follow‐up period; outcomes reflect information available in the medical records at the time of data extraction. In addition, a cross‐sectional questionnaire was used to assess the perceived impact of caring for this patient population on healthcare professionals. This questionnaire was completed between May and June 2024.

Data collection

The following data were retrospectively collected from the medical records: sex, age, marital status, current housing conditions, educational level, age of first symptoms of intolerance to enteral feeding, primary/major complaint(s) associated with feeding intolerance, time between first symptoms and initiation of total parenteral nutrition, amount of oral intake, complaints related to other organ systems, use of opiates and/or psychotropic medication, psychiatric medical history, contact with peers, current or past employment, diagnostics and treatments that were performed to evaluate and treat enteral feeding intolerance, and clinical course after initiating total parenteral nutrition.

Information on oral intake was obtained from the medical record and was based on available documentation, including dietary records, dietitian reports, or physician estimates. The timing of this assessment varied between the patients.

Questionnaire evaluating the impact on healthcare professionals

This questionnaire was developed by the study authors to assess the perceived impact of this patient population on physicians. The survey included eight questions scored on a 5‐point Likert scale (1 = never, 5 = always for questions 1–7, 1 = not at all, 5 = extremely for Question 8). The questionnaire was neither formally validated nor pilot‐tested. The questionnaire is included in Figure S1.

Statistical analysis

Baseline characteristics and questionnaire results were summarized using descriptive statistics. Continuous variables were presented as mean with standard deviation or median with interquartile range if not normally distributed. Categorical variables were presented as numbers and percentages. All statistical analyses were performed using IBM SPSS Statistics for Windows, version 29.0 (IBM Corp.).

Ethical approval

Our study was approved by the Radboud University Medical Center research ethics committee (protocol number: 2022‐15983) and adhered to the principles of the Declaration of Helsinki. Written informed consent was waived as the research poses no more than minimal risks to the participants.

RESULTS

Patient characteristics

During the study period, 536 patients were treated with home parenteral nutrition across the three participating centers. Of these, 78 patients met the inclusion criteria and were included in the analysis (Figure S2). The median (IQR) age at the start of total parenteral nutrition was 37 (29–50) years. The median (IQR) duration of total parenteral nutrition was 6 (2–9) years. Further clinical characteristics of the study population are presented in Table 1.

Table 1.

Characteristics of adult patients with medically unexplained intolerance to enteral feeding and treated with home parenteral nutrition.

Characteristics	N = 78
Female, No. (%)	71 (91.0)
Marital status, No. (%)
Relationship (including marriage, registered partnership)	44 (56.4)
Single	31 (39.7)
Unknown	3 (3.85)
Residential status, No. (%)
Living with a partner with or without children	38 (48.7)
Living alone with or without children	26 (33.3)
Living with parents or guardians	11 (14.1)
Living in a care facility	1 (1.28)
Unknown	2 (2.56)
Education level, No. (%)
Secondary school	12 (15.4)
Vocational education	16 (20.5)
Higher education/university	22 (28.2)
Unknown	28 (35.9)
Age at start intolerance to enteral feeding, No. (%)
≤25 years	28 (35.9)
26–45 years	34 (43.6)
≥46 years	16 (20.5)
Age at first evaluation medical specialist, No. (%)
≤25 years	28 (35.9)
26–45 years	34 (43.6)
≥46 years	16 (20.5)
Major complaint, No.(%)a
Nausea, bloating, vomiting	55 (70.5)
(Abdominal) pain	50 (64.1)
Other	4 (5.13)
Other bowel complaints before start HPN, No. (%)a
None	9 (11.5)
Diarrhea	18 (23.1)
Constipation	59 (75.6)
Bloated abdomen/flatulence	13 (16.7)
Time between start complaints and start date HPN, No. (%)
<1 year	10 (12.8)
1–5 years	37 (47.4)
>5 years	31 (39.7)
Oral intake, in addition to HPN, No. (%)
Small amounts of solid food and liquids	38 (48.7)
Liquids only (including water)	34 (43.6)
Nihil (including only sips of water)	5 (6.41)
Unknown	1 (1.28)
Complaints in other organ systems, No. (%)	39 (50.0)
Use of opioids, No. (%)	49 (62.8)
Use of psychopharmacological drugs, No. (%)	26 (33.3)
Presence of significant psychiatric medical history, No. (%)	31 (39.7)
Reported psychiatric diagnosis, No. (%)
Eating disorders	13 (16.7)
Depressive disorders	11 (14.1)
Somatic symptom and related disorder	4 (5.12)
Personality disorders	4 (5.12)
Trauma‐ and stressor related disorders	4 (5.12)
Anxiety disorders	2 (2.56)
Autism spectrum disorders	2 (2.56)
Other psychiatric disorders	2 (2.56)
Substance‐related and addictive disorders	1 (1.28)
Functional complaints in other organ systems, No. (%)a
None	39 (50.0)
Urologic	10 (12.8)
Gynaecologic	1 (1.28)
Neurologic	14 (17.9)
Pain	11 (14.1)
Other	17 (21.8)
Employment status, No. (%)
Disability	46 (58.9)
Unemployed	14 (17.9)
Unknown	9 (11.5)
Employed	5 (6.41)
Student	4 (5.12)
Attitude in self‐proposing medical diagnoses or solutions, No. (%)
Active	45 (57.7)
Neutral	28 (35.9)
Passive	5 (6.41)
Number of patients insisting on medically unnecessary procedures, No. (%)	38 (48.7)
Contact with peers, No. (%)
Yes, via knowledge network	2 (2.56)
Yes, via online forums/websites/(social) media	23 (29.5)
No	2 (2.56)
Unknown	51 (65.4)

^a Multiple answers were possible. HPN; home parenteral nutrition.

The category “other” for major complaints in Table 1 included dumping‐like symptoms, nonspecific dysphagia‐like symptoms, intolerance to tube feeding with early satiety and vomiting, and underweight in the context of an eating disorder.

Complaints in other organ systems were reported in 50% of patients (Table 1) and included a heterogeneous group of comorbidities and prior medical conditions, such as osteoporosis, chronic obstructive pulmonary disease, renal insufficiency, thyroid disorders, cardiovascular disease, prior abdominal surgery (including appendectomy, cholecystectomy, gastric banding, and Scopinaro procedure), and thromboembolic events.

The “other” category for functional complaints in other organ systems in Table 1 mainly included functional or unexplained symptoms affecting multiple disciplines, including otorhinolaryngological (unexplained aphonia and functional voice disorders), neurological (functional neurological symptoms, unexplained gait disturbances, headache, and sensory symptoms), internal medicine (including unexplained hypoglycemia and postural orthostatic tachycardia syndrome), ophthalmological, and cardiovascular complaints.

Diagnostics, treatment, and clinical course

Table 2 presents the diagnostics tests performed, prescribed treatment, and clinical course of the 78 enrolled patients. Other treatments not included in the Table were surgery for superior mesenteric artery syndrome (N = 1), recurrent admissions for constipation and the need for laxatives in a clinical setting (N = 1), Roux‐en‐Y Gastric Bypass for gastroparesis (N = 1), and one Roux‐en‐Y reversal surgery. In 83% of patients, discontinuation of total parenteral nutrition was not achieved.

Table 2.

Diagnostics, treatment, and clinical course of adult patients with medically unexplained intolerance to enteral feeding and treated with home parenteral nutrition.

	N = 78
Started with TPN before referral to an expert center, No. (%)	34 (43.5)
Number of centres where treatment took place before referral to expert centre, No. (%)
0	6 (7.69)
1	28 (35.9)
2	20 (25.6)
3	14 (17.9)
>3	8 (10.3)
Unknown	2 (2.56)
Number of diagnostics per patient, median (IQR)	6.0 (4.8, −8.0)
Diagnostics performed, No. (%)a
Upper endoscopy	65 (83.3)
Gastric emptying scintigraphy	53 (67.9)
Abdominal CT	49 (62.8)
Abdominal, oesophageal, stomach X‐ray	42 (53.8)
Colonoscopy	40 (51.2)
Antroduodenal manometry	39 (50.0)
MRI enterography	32 (41.0)
Abdominal ultrasound	29 (37.2)
X‐ray colonic transit study	21 (26.9)
Orocaecal transit time	20 (25.6)
Oesophageal manometry	19 (24.4)
Hydrogen breath test (glucose, lactose, lactulose)	17 (21.8)
Defecography	14 (17.9)
Capsule endoscopy	9 (11.5)
Anorectal manometry	8 (10.3)
Diagnostic laparoscopy or ‐tomy	6 (7.69)
(Food) allergy screening	6 (7.69)
Barostat (stomach, rectum)	5 (6.41)
pH impedance monitoring	4 (5.13)
Treatments performed, No. (%)a
Nasogastric or nasoduodenal tube	54 (69.2)
PEG tube	42 (53.8)
PEG‐J tube	32 (41.0)
Surgical jejunostomy	24 (30.7)
Bowel ostomy	24 (30.7)
Bowel surgery	23 (29.5)
Nasojejunal tube	19 (24.4)
Transanal irrigation	14 (17.9)
PEJ tube	12 (15.4)
PRG tube	9 (11.5)
Chait tube	3 (3.85)
G‐POEM surgery	2 (2.56)
No previous treatment	1 (1.28)
Other	4 (5.13)
Psychiatry or psychology consult, No. (%)b	54 (69.2)
Clinical course, No. (%)a
Still under treatment in expert center	64 (82.1)
Deceased	9 (11.5)
Referred to other specialist or center	3 (3.85)
Referred back to general practitioner or referring center	1 (1.28)
Termination of treatment relationship	1 (1.28)
Ability to restart enteral feeding, No. (%)
No, chronic TPN	65 (83.3)
Yes, with enteral feeding	5 (6.41)
Yes, with oral feeding on a normal diet	4 (5.13)
Yes, with oral feeding on a modified diet	2 (2.56)
TPN and oral or enteral feeding	2 (2.56)
Cause of death, No. (%)
Palliative management by discontinuing TPN	5 (6.41)
Not related to feeding problems	3 (3.85)
Due to complications of treatment	1 (1.28)

Abbreviations: CT, computed tomography; G‐POEM, gastric peroral endoscopic myotomy; MRI, magnetic resonance imaging; PEG, percutaneous endoscopic gastrostomy; PEG‐J, percutaneous endoscopic gastrojejunostomy; PEJ, percutaneous endoscopic jejunostomy; PRG, percutaneous radiologic gastrostomy; TPN, total parenteral nutrition.

^a Multiple answers were possible.

^b Psychology or psychiatry involvement could also mean a one‐time consultation.

Impact on treating physicians

Seven physicians (100% response rate) from the intestinal failure expert centers completed the questionnaire. Figure S3 summarizes the results for each question. All physicians rated patient care as at least very burdensome.

DISCUSSION

In recent years, both in the Netherlands and in other countries, ⁴ an increase in patients reporting a severe intolerance to enteral nutrition without a medical explanation, despite extensive diagnostics or even surgical interventions, has been observed. Management of such patients is challenging, and even more so in those with critical weight loss, when medical teams are urged by patients or referring physicians to initiate total parenteral nutrition despite the absence of a clear underlying condition. Given the risks and complications associated with long‐term total parenteral nutrition support ³ and the strain that such treatment puts on healthcare resources, there is an unmet need to better understand and characterize this group. The present study represents a first attempt to describe patients with medically unexplained intolerance to enteral feeding who were treated with home parenteral nutrition in the Netherlands, from the perspective of three intestinal failure expert centers.

Our study identified several characteristics of this population that, in the absence of available data in the literature, require corroboration from an international perspective. First, the cohort almost exclusively comprised female patients (91%). This preponderance contrasts with the 61% female representation in the general chronic intestinal failure population. ⁷ Second, with a median age at total parenteral nutrition initiation of 37 years, this cohort is considerably younger than most intestinal failure patients with a benign underlying disease (55 years). ² This finding suggests an earlier onset of symptoms and potentially prolonged dependence on specialized nutritional support in case alternative management approaches remain unsuccessful. Third, opioid use in patients from this cohort was substantially higher (63%) compared with the 44% reported in chronic home parenteral nutrition patients with non‐cancer‐related pain. ⁸ Finally, our cohort included a relatively high number of patients with a psychiatric medical history (40%), particularly concerning diagnoses within the spectrum of eating disorders (13 patients). These findings emphasize the importance of psychiatric evaluation in patients with unexplained feeding intolerance.

In addition to patient characteristics, the present study provides insight into the burden of caring for this patient population. All participating physicians from the three intestinal failure expert centers in the Netherlands rated the care of patients with medically unexplained intolerance to enteral nutrition as at least very burdensome. Currently, no data are available on the impact of caring for the general intestinal failure population on healthcare professionals.

Limitations and strengths

While this study provides valuable clinical and observational insights, several limitations should be acknowledged. First, this study was initiated in response to observations from clinical practice and discussions among Dutch intestinal failure teams, which led to data collection across various centers. Differences in data collection methods may have led to variability in the collected data, potentially resulting in inconsistencies or missing information. Some variables were based on narrative documentation and clinical judgement in the medical record, which may have introduced misclassification. Moreover, although we aimed to acquire all available information, the retrospective nature of this study may have led to missing data, such as underreporting of medical consumption, as not all information may have been documented in the medical records. Patients often have a long medical journey, and not all relevant information is always available at referral. Also, the study did not include a predefined follow‐up period, and therefore, outcomes were based on information available in the medical records at the time of data extraction. Additionally, we may have underestimated the number of these patients in our centers, as they might have been misdiagnosed with intestinal failure. Moreover, the descriptive design and the absence of a matched comparative cohort do not allow causal or comparative conclusions. Nevertheless, this data set provides a foundation for further research, and we hope that future prospective studies can address these limitations.

Finally, while we included specific questions regarding the impact of these patients on healthcare providers, we did not use validated questionnaires. However, to our knowledge, there is no questionnaire that encompasses all of the detailed questions we sought to address here.

Despite its limitations, this study also has notable strengths. For instance, it represents nationwide data from all adult intestinal failure centers in the Netherlands. Also, by describing this cohort, we aim to raise awareness and provide clinical data to identify these patients at an early stage. By systematically describing this patient population, we aim to support earlier and more objective recognition based on empirical data, rather than on individual clinical impressions. This may be particularly relevant given the high proportion of female patients in this cohort, as increased awareness may help to reduce potential bias in clinical decision‐making. For the future, given the early onset of the reported intolerance to enteral feeding, it would be interesting to link these data to the pediatric intestinal failure population.

CONCLUSION

Home parenteral nutrition is a life‐saving therapy in patients with intestinal failure. The present descriptive cohort study provides a national overview of patients with medically unexplained intolerance to enteral feeding who were treated with home parenteral nutrition. The study population predominantly consists of relatively young female patients who more frequently use opioids and place a substantial burden on healthcare professionals in intestinal failure expert centers.

The findings highlight the complexity of clinical decision‐making in patients with medically unexplained intolerance to enteral feeding and underline the importance of early referral to intestinal failure expert centers. Early involvement of multidisciplinary teams, including psychiatric assessment, may help to avoid inappropriate initiation of home parenteral nutrition and support the development of alternative management strategies.

AUTHOR CONTRIBUTIONS

J. Korzilius: investigation; methodology; formal analysis; visualization; writing—original draft. E. Limonard: investigation; writing—review and editing. A. Simon: investigation; writing—review and editing. F. van der Heide: investigation; writing—review and editing. G. Bouma: writing—review and editing. I. Keuning: writing—review and editing. E. Grein: writing—review and editing. T. van den Heuvel: writing—review and editing. D. Keszthelyi: writing—review and editing. G. Dijkstra: conceptualization; methodology; investigation; writing—review and editing. M. Serlie: conceptualization; methodology; investigation; writing—review and editing. G. Wanten: conceptualization; methodology; investigation; writing—review and editing.

CONFLICT OF INTEREST STATEMENT

None declared.

Supporting information

Revised supplementary file.

DATA AVAILABILITY STATEMENT

Data described in the manuscript will be made available upon request pending application and approval by the corresponding author.