Unusual presentation of Crohn’s disease
- Kate Edwards and
- Karen Yearsley
- Gastroenterology, Nevill Hall Hospital, Abergavenny, UK
- Correspondence to Dr Kate Edwards; kate.edwards8@wales.nhs.uk
Abstract
A previously well 37-year-old woman attended the emergency assessment unit with symptoms of lethargy, breathlessness and peripheral oedema, whereby initial basic investigations revealed an iron deficiency anaemia and serum hypoalbuminaemia. The patient subsequently had multiple admissions to secondary care over a 2-year period due to worsening peripheral and central oedema. Investigations ruled out non-gastrointestinal causes of serum hypoalbuminaemia, such as renal, cardiac and hepatic failures. Gastrointestinal investigations later revealed raised faecal alpha-1 antitrypsin and small bowel ulceration on capsule endoscopy, with a histological diagnosis of Crohn’s disease made after a small bowel wedge resection. This case describes the unusual presentation of Crohn’s disease displaying symptoms primarily of protein-losing enteropathy, an uncommon and under-recognised consequence of inflammatory bowel disease. A review of current literature and the underlying pathophysiology for this rare condition are discussed, particularly in relation to Crohn’s disease.
Background
Protein-losing enteropathy (PLE) is described as an excessive gastrointestinal (GI) protein loss; the subsequent serum hypoalbuminaemia forms a low oncotic pressure state with resultant third spacing of fluid, presenting clinically as peripheral or central oedema.1
There are over 60 documented causes of PLE inclusive of both GI and non-GI pathologies.2 However, PLE remains an uncommon and under-recognised complication of Crohn’s disease.3
Overall, there are three mechanisms through which PLE may develop. These include an increased lymphatic pressure, defects in tight-junction complexes resulting in a ‘leaky gut’, and through macroscopic defects in the intestinal mucosal wall due to erosions and ulcerations; it is this latter pathomechanism which is implicated in the development of PLE in Crohn’s disease.2 4
PLE is diagnosed through measuring the daily faecal clearance of alpha-1 antitrypsin (A1AT), although the underlying disease process driving PLE must also be sought.1 5 The aim of management in PLE involves treating the underlying disease state, in this case Crohn’s disease, and optimising the patient’s nutritional status.3
Despite PLE being associated with multiple diseases, including inflammatory bowel disease, there is still an underappreciation by physicians for this condition, such that PLE does not feature within any British or European guidelines for Crohn’s disease management.6 This lack of awareness indicates that PLE itself is not a primary disease entity, but instead a syndrome which complicates multiple chronic disorders.1
Given there is an accepted strong correlation between serum hypoalbuminaemia and patient mortality,4 this case presents an excellent learning opportunity to inform readers of this uncommon and under-recognised condition. Hence, increased understanding of PLE may promote earlier appropriate investigation and timely management of the underlying primary disease process.
Here an uncommon case of PLE secondary to small bowel Crohn’s disease is reported.
Case presentation
A 37-year-old woman presented to the emergency assessment unit (EAU) with a 4-week history of progressive lethargy and breathlessness. She denied any chest pain, weight loss or change in her bowel habit over the past 6 months. On clinical assessment it was noted that she had peripheral oedema to the knees bilaterally and pale conjunctiva; however, systems examination beyond this was largely unremarkable. The patient had no medical history and took no regular medications. She was a current smoker with a 20-pack year history and worked full time as a teaching assistant. There was no family history of any significant GI disease as far as the patient was aware.
Blood tests on admission revealed a marked microcytic anaemia (haemoglobin of 55 g/L and mean corpuscular volume of 62 fL), with thrombocytosis (platelets of 567 x 109/L) and hypoalbuminaemia (serum albumin of 12 g/L). The patient declined GI investigation at this point, so she received intravenous Ferinject and was discharged on oral iron supplementation. A follow-up appointment with acute physicians 1 month later showed an improvement in haemoglobin to 102 g/dL and no further follow-up was arranged. At this time, coeliac serology using tissue transglutaminase (tTG) antibody was negative and the urine protein to creatinine ratio was within normal limits.
The patient re-presented multiple times over the course of a 2-year period and subsequently underwent a range of investigations to determine the cause of her symptoms.
Investigations
The patient presented 18 months later with worsening symptomatic iron deficiency anaemia (IDA), namely breathlessness and lethargy, and ongoing leg swelling. Subsequent oesophagogastroduodenoscopy (OGD) revealed severe ulcerative gastritis at the pylorus, with impending gastric outlet obstruction (figure 1). Biopsies showed no granulomata but extensive ulceration associated with an acute fibrinopurulent exudate. The patient was commenced on high-dose omeprazole, 40 mg two times per day, and was discharged home given she had no symptoms of gastric outlet obstruction.
Oesophagogastroduodenoscopy image showing severe ulcerative gastritis at the pylorus, with impending gastric outlet obstruction.
Two months later the patient presented for the third time to EAU with ongoing symptoms of IDA. A colonoscopy was performed and reported to be within normal limits, including the terminal ileum. She was subsequently discharged with ongoing oral iron replacement therapy.
A few months later, the patient presented for the fourth time with worsening oedema on her arms, legs and face. Her serum albumin remained low at 10 g/L. She denied any upper or lower GI tract symptoms, with bowels opening two times per day without diarrhoea, bleeding, mucus or tenesmus. She also denied any cardiac symptoms such as orthopnoea or paroxysmal nocturnal dyspnoea. Subsequent cross-sectional imaging revealed bilateral pleural effusions with large-volume ascites and peritoneal thickening. Transthoracic echocardiogram showed overall good left ventricular systolic function and pulmonary artery pressures within normal range.
Repeat biopsies from the pyloric region on OGD reported ulceration with an acute inflammatory exudate, overlying granulation tissue and fibrosis of the submucosa. Further investigations revealed a faecal calprotectin of greater than 600 μg/g and she was found to be deplete of micronutrients inclusive of selenium, zinc, copper plus fat-soluble vitamin A and vitamin D complexes. Ascitic fluid analysis showed reactive mesothelial and inflammatory cells, but no malignant cells. Serum ascitic albumin gradient was 0.6 g/dL, suggestive of an exudative process. Further imaging using magnetic resonance (MR) enterogram showed progressive ascites with diffuse small bowel wall thickening which had progressed over the series, but no focal abnormality was identified.
Soon after, the patient re-presented to the acute medical take for the fifth time with symptoms of small bowel obstruction. Her symptoms settled with conservative management, and nutritional requirements were optimised using parenteral nutrition before progressing to several weeks of nasojejunal feeding. A stool sample for A1AT was sent, which was raised at 1.620 mg/g. Two weeks after discharge the patient had an endoscopically placed small bowel capsule endoscopy (figure 2).
Oesophagogastroduodenoscopy image showing endoscopically placed small bowel capsule endoscopy within the third part of the duodenum.
Pending the results, the patient re-presented to the hospital with acute breathlessness due to pulmonary oedema. Repeat transthoracic echocardiogram revealed a moderate-severe left ventricular impairment, with an ejection fraction of 39%, and a cardiac biopsy ruled out amyloid as a cause of her constellation of symptoms. The patient’s cardiomyopathy, thought to be due to severe serum hypoalbuminaemia, was subsequently treated with intravenous diuretics and ongoing enteral nutritional support.
The results of the small bowel capsule endoscopy revealed multiple areas of significant ulceration associated with luminal stricturing; however, it was noted that the capsule did not enter the caecum (figure 3). As a result, the patient underwent laparoscopic resection of the capsule; during this operation 50 cm of small bowel was noted to have multiple strictures within which the capsule was retained. A wedge resection was undertaken, leaving 290 cm of healthy small bowel. Histology revealed bowel wall thickening with acute patchy inflammation and ulceration into the submucosa, with granulomas observed.
Small bowel capsule endoscopy image showing mucosal ulceration within the small bowel.
Differential diagnosis
The differential diagnoses were vast for both IDA and the patient’s progressive oedematous state; however, there were few differentials that linked both pathologies together.
Individually, the most likely cause of IDA in a young woman such as this patient would be from menstrual blood loss; however, she denied having menorrhagia and was amenorrhoeic for much of this time. Malabsorption due to coeliac disease is another differential; however, this patient’s coeliac serology was normal and duodenal biopsies did not reveal villous atrophy, thus excluding this pathology. Additionally, the patient denied regular use of non-steroidal anti-inflammatory drugs or aspirin when considering an iatrogenic cause of her IDA.
The patient also presented with hypoalbuminaemia and progressively worsening peripheral and central oedema. Initially, nephrotic syndrome was considered as a differential; however, further investigation did not reveal heavy proteinuria. Cardiac dysfunction was also contemplated, but initial transthoracic echocardiogram showed a well-preserved left ventricular systolic function. Also, normal pulmonary pressures were observed, therefore discounting pulmonary hypertension as a cause of the progressive oedema. Likewise, hepatic disease was considered; however, other synthetic liver function tests such as bilirubin and international normalised ratio were normal and cross-sectional imaging revealed normal hepatic parenchyma.
Significant hypoalbuminaemia in conjunction with IDA and thrombocytopaenia gave suspicion to an underlying chronic inflammatory process, likely originating from the GI tract. The histological features of the resected small bowel, in conjunction with a raised faecal A1AT, led us to the diagnosis of small bowel Crohn’s disease, presenting as a PLE.
Treatment
Pending diagnosis, the patient responded well biochemically to a period of nasojejunal enteral feeding, with a documented rise in her serum albumin and correction of the micronutrient and vitamin deficiencies. Currently the patient maintains her nutritional requirements with an oral diet, supplemented with a once daily capsule of Forceval and 6 monthly intramuscular injection of ergocalciferol 300 000 IU. With the diagnosis of small bowel Crohn’s disease in hand, the patient was subsequently initiated on azathioprine 75 mg once daily plus 3 months of metronidazole at a dose of 400 mg three times per day in the immediate postoperative period.
Outcome and follow-up
A repeat MR enterogram 6 months after initial diagnosis showed a radiologically normal small bowel. However, the patient remains moderately symptomatic on target dose azathioprine monotherapy, as confirmed with thiopurine methyltransferase metabolite testing, with a marginally raised faecal calprotectin of 174.6 μg/g, and as such a repeat small bowel capsule endoscopy is currently awaited. Reassuringly, her serum albumin has risen to 45 g/L and follow-up echocardiogram has demonstrated a marked improvement in the left ventricular systolic function, with repeat ejection fraction measured at 63%.
Discussion
PLE is an under-reported syndrome of exorbitant protein loss from the lumen of the GI tract. It was first described by French pathologist Pierre Eugène Ménétrier in 1947, who noted hyperplastic gastric folds in patients with serum hypoalbuminaemia, which later became known as Menetrier’s disease.1 Subsequently PLE is now a recognised consequence of over 60 different diseases inclusive of both GI and non-GI pathologies2 and is often correlated to increased morbidity and mortality in such patients.1
Any serum protein can undergo excess GI clearance in PLE. However, serum proteins with medium or long half-times such as albumin, A1AT, and immunoglobulins IgA, IgM and IgG are commonly involved.4 When describing PLE, the principal serum protein monitored is albumin; the total serum albumin concentration is established by evaluating the rate of hepatic synthesis against its clearance.1 Typically, the rate of albumin synthesis within the liver is 150 mg/kg/day, giving a relatively long half-life of 17.3 days.7 In comparison, catabolism accounts for 90% of daily albumin clearance, with urinary and GI losses accounting for 4% and 6%, respectively.1 However, patients with PLE have far higher GI albumin losses; putting this into perspective, the daily GI clearance must increase by 17 times to reduce the serum albumin concentration by 50%.8 Hence, with its relatively long half-life, even a slow GI loss can have a dramatic effect on reducing the serum albumin concentration.1
There are three recognised pathophysiological mechanisms leading to PLE.2 The first known mechanism is due to increased lymphatic pressure caused by diseases such as congestive cardiac failure, cirrhosis with portal hypertension or systemic lupus erythematous.4 Second, PLE may be caused by conditions such as coeliac disease or Menetrier’s disease, whereby the mucosa is grossly intact but defects in the tight-junction complexes allow excess protein loss through the paracellular spaces into the GI lumen.1 Lastly, and relevant to our case, is the mechanism by which excess protein is lost through the GI tract due to mucosal erosions and ulcerations.
Crohn’s disease is a complex chronic inflammatory condition that can affect any part of the GI tract.6 Macroscopically, Crohn’s disease typically demonstrates ‘skip lesions’ seen as discontinuous areas of disease activity, demonstrating submucosal erosions or ulcerations.6 Histologically, patchy areas of chronic inflammation infiltrating the lamina propria along with non-cryptolytic granulomas are often seen.9 These areas of ulceration signify damage to the mucosal barrier, resulting in an increased permeability and subsequent free passage of proteins from the interstitium into the GI lumen.1 10 In this context, the rate of luminal albumin loss is limited by the normal capillary permeability where the flux is balanced against the interstitial albumin concentration.1 However, in areas of ulceration and breakdown of the lumen epithelial barrier, the interstitial albumin concentration falls dramatically. Therefore, the diffusion gradient between the capillary and interstitium increases, resulting in albumin luminal losses of 1000 mL/day if the whole intestinal mucosal barrier was disrupted.1 Hence, the degree of albumin loss in Crohn’s disease is directly proportional to the amount of intestinal mucosa involved in disease activity, assuming the capillary permeability remains unaffected in regions of epithelial breakdown.1
Crohn’s disease has also been described as causing PLE through the mechanism of increasing lymphatic pressure.2 However, this pathomechanism has since been refuted given that Crohn’s disease only causes focal lymphatic obstruction. As such, the pressure produced is unlikely to result in rupture and subsequent GI lymphatic leak.1 This is further supported by the normal levels of CD4 T cells in patients with Crohn’s disease compared with patients with disease entities causing PLE through increased lymphatic pressure and leakage.11
There are currently no published guidelines for diagnosing and managing PLE in patients with Crohn’s disease.4 A quantitative diagnosis of PLE is primarily made by measuring the GI clearance of A1AT.12 A1AT is resistant to proteolysis, is neither secreted nor absorbed within the intestine, and is of similar molecular weight to albumin (50 kDa and 67 kDa, respectively).1 Therefore, faecal loss of A1AT is deemed comparable with that of albumin, with a normal clearance rate of less than 20 mL in 24 hours.1 5 However, several studies have found a poor correlation between Crohn’s disease activity and the quantitative value of faecal A1AT; a number of patients with clinically quiescent Crohn’s disease have had significant PLE with raised A1AT levels,12 13 rendering A1AT measurement an unreliable marker for Crohn’s disease relapse.14
The clinical manifestation of PLE may vary depending on the underlying chronic disease state. Therefore, it is important that clinicians listen closely to the patient’s symptoms and undertake a full system review.4 Due to serum hypoalbuminaemia and a subsequent low oncotic pressure state, patients often present with generalised peripheral and central oedema as a result of third spacing of fluid.4 This can present as pleural or pericardial effusions, ascites and limb swelling, although macular oedema and retinal detachment have also been described.8 15
Diagnostic work-up to determine the underlying cause of PLE first involves ruling out non-GI causes of serum hypoalbuminaemia, such as cardiac, renal and hepatic system failures.1 Once such pathologies have been eliminated, GI causes of PLE should be considered. Such investigations will include serum IgA tTG antibodies, stool microscopy for bacteria and parasites, and faecal calprotectin, along with endoscopy. If upper GI endoscopy proves normal and the underlying diagnosis is still uncertain, lower GI endoscopy and small bowel imaging with MRI and capsule endoscopy should be undertaken to visualise the remaining GI tract.4
Treatment of PLE focuses largely on reducing activity of the underlying chronic disease state, in this case Crohn’s disease.3 However, PLE is not recognised in any British or European guidelines for Crohn’s disease management, such as the 2019 British Society of Gastroenterology consensus guidelines.6 Furthermore, there is little guidance on how to optimally manage a patient presenting acutely with complications of PLE, such as acute pulmonary oedema or ascites.4
Antitumour necrosis factor (anti-TNF) biologic therapy is a recognised management strategy for Crohn’s disease and is often used acutely to induce remission.6 However, PLE has been implicated in reducing the efficiency of anti-TNF globulin therapy in patients with Crohn’s disease; a study by Klotz et al 16 demonstrated that patients with severely active Crohn’s disease had a reduced serum half-life of the anti-TNF biologic agent infliximab, which also correlated with the degree of serum hypoalbuminaemia. This suggests that patients with greater enteral loss of proteins, including immunoglobulins, correlate with the higher turnover rate of serum anti-TNF globulins.1 Further studies are warranted in patients with Crohn’s disease and PLE to evaluate the relationship between faecal A1AT clearance and serum infliximab half-times; patients with greater faecal A1AT levels may require higher concentrations or more frequent dosing of infliximab to gain disease control.1
Optimisation of the patient’s nutritional status through dietary modifications is also recognised as an important aspect of PLE management.3 17 Acutely, a low-fat and high-protein diet, up to 2–3 g/kg of body weight per day, may be required when GI protein loss is at its greatest.17 If this cannot be achieved through oral diet supplementation, administration of parenteral or enteral nutrition with high amino acid content may be required, taking into account that high protein concentrations can lower luminal oncotic pressures and exacerbate oedema further.8
Additionally, the use of human serum albumin (HSA) as a therapeutic option in PLE is debated. Some studies have suggested the use of HSA in cases of severe serum hypoalbuminaemia18; however, its longer term use for managing PLE has proved ineffective.19 Conversely, other studies have demonstrated that use of HSA is limited to critically unwell patients, with the aim of correcting hypovolaemia rather than improving oncotic pressures.20
Learning points
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Protein-losing enteropathy is a clinical syndrome of excessive luminal protein loss caused by many gastrointestinal and non-gastrointestinal diseases.
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The process by which protein-losing enteropathy develops in the context of Crohn’s disease is due to mucosal erosions and ulcerations, allowing free passage of proteins from the interstitium into the gastrointestinal lumen.
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Currently there are no specific guidelines on the recognition, investigation and management of protein-losing enteropathy, particularly in relation to inflammatory bowel disease.
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The degree of protein-losing enteropathy may be quantified by measuring 24-hour faecal alpha-1 antitrypsin, with a normal value set at less than 20 mL per day.
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Treatment should focus on reducing disease activity of the underlying condition, in this case Crohn’s disease, while also optimising nutrition.
Ethics statements
Footnotes
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Twitter @KateEd89
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Contributors KY was involved in the patient’s management, which is currently ongoing, and highlighted the case as one to write. KY was involved with editing of the case report. KE wrote the case report and undertook a literature search of the subject.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.
References
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