Chronic intestinal pseudo-obstruction due to β2microglobulin-amyloidosis in a patient on high-flux haemodialysis

Abstract

Dialysis-related amyloidosis (DRA) or β2microglobulin (β2m)-amyloidosis is a disorder caused by the inability to clear a protein called β2m in patients with chronic kidney disease. It results in deposition of β2m as amyloid fibrils, most commonly in bones and joints. Infrequently, visceral organs may be involved. With modern high-flux haemodialysis, DRA has become a rare disease, yet it may occur. We present a case of DRA in an 86-year-old woman. This case is particularly notable for its rare presentation as chronic intestinal pseudo-obstruction. It is of paramount importance to recognise this entity in order to reduce delay in treatment and avoid patients being frustrated not getting a diagnosis.

Background

Dialysis-related amyloidosis (DRA) is characterised by the tissue deposition of β2microglobulin (β2m) in the affected body parts. The exact prevalence of DRA is unknown since biopsy, the conclusive diagnostic test, is rarely performed.¹ β2m is a component of the major histocompatibility complex that is present on cell surfaces. It is normally cleared by glomerular filtrates, with subsequent reabsorption and catabolism in proximal tubules. Tissue deposition of β2m is due to reduced clearance in patients with reduced kidney function.² In addition, the dialysis procedure itself may also mildly stimulate intradialytic β2m-production.³

Most commonly, DRA affects the musculoskeletal system, in particular the bones and joints. Carpal tunnel syndrome due to amyloid deposition is frequently the first manifestation, often relapsing despite surgery.⁴ Visceral involvement is infrequent, however in some patients β2m may also deposit in internal organs, especially blood vessels and the gastrointestinal tract.¹ Deposition of β2m in the blood vessels and interstitium of the gastro-intestinal tract has been associated with abdominal pain, visceral perforation, gastric and colonic dilatation, intestinal necrosis, malabsorption, ischaemic colitis and chronic diarrhoea in patients on long-term haemodialysis.⁵

Case presentation

An 86-year-old woman, known with rheumatoid arthritis (RA) and end stage renal disease (ESRD), was admitted to the emergency room because of a unilateral, dislocated Colles fracture after a fall at her home. Surgical fracture reduction under general anaesthesia was performed on the day of admission. She was treated with only paracetamol for pain relief. She did not receive opioid analgesics. Few hours after surgery, she reported diffuse abdominal pain, nausea and vomiting. Physical examination revealed abdominal distension and tympany. There was a significant reduction of bowel sounds and a mild, diffuse tenderness. In the past 2 years the patient was hospitalised twice because of a similar paralytic ileus. The presumed cause was the temporary intake of opioid analgesics. Both episodes resolved spontaneously after the discontinuation of the analgesics. On admission, she reported to have one bowel movement a day for the last 10 months.

Investigations

A routine blood sample was done on admission and 2 days after surgery. Both showed ESRD and a normocytic anaemia (10.5 g/dL). No other abnormalities were found.

Because symptoms of postoperative ileus remained until 3 days after surgery, a CT of the abdomen was performed. This showed dilatation of the stomach and small intestine in the absence of gas-fluid levels on supine and erect abdominal radiographs (figure 1). A mechanical blockage could not be visualised. There were no signs of constipation or faecal impaction on this imaging. A nasogastric tube was placed and the patient was put on a parenteral nutrition.

Figure 1.

Dilatation of the small intestine (arrow).

However, symptoms of abdominal pain yet worsened. Because of this deterioration, another CT of the abdomen was done 3 days after the initial imaging. On this second CT, gastric dilatation and dilation of the small intestine had resolved, but dilation of the whole large intestine had appeared, except for the sigmoid colon (figure 2). Further work-up with sigmoidoscopy to exclude colorectal neoplasms, however, turned out negative. Colonic biopsies were taken to exclude gastro-intestinal diseases that could cause pseudo-obstruction in this patient. In specific, we wanted to exclude amyloid A (AA) amyloidosis and DRA because the patient respectively suffered from RA and had been on haemodialysis for twelve years because of ESRD. Since gastric dilation had resolved spontaneously, a gastroscopy was done. This showed esophagitis grade D according to Los Angeles Classification. Also, biopsies of stomach and duodenum were taken.

Figure 2.

Dilatation of the large intestine (arrow).

Biopsies of the colon appeared normal, but biopsies of stomach and duodenum were aberrant. Submucosal blood vessels were infiltrated with eosinophilia and Congo-red staining was positive (figure 3). Also, thioflavin T fluorescence was positive (figure 4). These findings confirmed the presence of amyloidosis, of which the vascular deposition was predominantly segmental. The biopsy of the stomach also showed gastric mucosal calcinosis.

Figure 3.

Congo-red staining with deposition of amyloid fibrils in the submuosal blood vessels (arrow).

Figure 4.

Thioflavin T immunofluorescence positive for amyloidosis.

Differential diagnosis

In this case report the patient suffered from recurrent or chronic intestinal pseudo-obstructions (CIPO).

This is a syndrome characterised by signs and symptoms of the small or large bowel in the absence of an anatomic lesion that obstructs the flow of intestinal contents. CIPO is a rare disorder that may be due to an underlying neuropathic or myopathic disorder or abnormality in the interstitial cells of Cajal.⁶ In this case, amyloidosis was the underlying condition that caused CIPO.

However, the type of amyloidosis still had to be determined. First of all, there was the presumption of AA amyloidosis because the patient had a history of RA. However, immunohistochemistry was negative for AA amyloidosis. Also, by direct examination (immunohistochemical staining and direct sequencing) of the amyloid, there was no evidence that the amyloid was light chain-related. So the option of an amyloid light chain (AL) amylodisis was rejected. Third, the hypothesis of transthyretin amyloidosis (ATTR) was made, but transthyertin staining remained negative.

Since AL amyloidosis, AA amyloidosis, ATTR and DRA are the four most common types of amyloidosis, the diagnosis of DRA was formulated per exclusionem.⁷ The fact this patient had been on haemodialysis for 12 years, made this diagnosis very suitable. In addition, some other findings supported the hypothesis of DRA. First, vascular deposition of amyloid was predominantly segmental, which is typical for DRA, and not circumferential, as seen in AL or AA amyloidosis.⁸ Second, the biopsy of the stomach showed gastric mucosal calcinosis, often seen in ESRD (figure 5).⁹

Figure 5.

Detailed image of gastric mucosal calcinosis (arrow).

Serum β2m level had increased to 12 mg/L (normal <1.7 mg/L). However, this finding is not helpful for the diagnosis of DRA, since levels are also elevated among dialysis patients in the absence of DRA.^{10 11} Theoretically, also the underlying rheumatic condition could be a cause of increased serum β2m levels, but the fact this patient had been in remission for more than 30 years, makes this explanation very unlikely.¹²

Anti-β2m serum can be used to identify amyloid fibrils that are made of β2m.^{13 14} In fact, using mouse monoclonal β2m antibodies (ab54810, abcam, Cambridge, Massachusetts, USA), we were able to prove that the amyloid in this case was made of β2m (figure 6). Also, when the type of amyloidosis is unknown, direct identification of the protein by laser microdissection and mass spectrometry-based (LMD-MS) proteomic analysis of a biopsy specimen is an alternative way to characterise the type of amyloid. The validation of this method for commercial purposes has been of particular interest. This approach, which was originally used for the analysis of the proteomics of AL amyloid, has also been validated for AA but not for other types of amyloidosis like DRA.^{15 16} Unfortunately, LMD-MS proteomic analysis is not widespread available, as was in this case.

Figure 6.

Anti-β2m staining with deposition of β2m amyloid fibrils appearing dark brown (arrow).

However, the combination of ESRD, the exclusion of the other most common types of amyloidosis and the finding of gastric mucosal calcinosis and segmental vascular deposition of amyloid, made this case highly suspective for DRA. In the end, using mouse monoclonal β2m antibodies we were able to confirm the diagnosis of DRA.

Treatment

In this case we added haemodiafiltration (HDF) to haemodialysis using a very high flux polysulphone membrane. This treatment lasted 4 hours and was done three times per week using ultrapure dialysis fluid (<0.001 EU/mL).

Outcome and follow-up

Two weeks after starting haemodiafiltration the patient started to feel better and gradually symptoms of pseudo-obstruction disappeared over a period of 2 months. She had good appetite and could restart eating. At present, 1 year later, she is still on HDF. She had a short relapse of intestinal pseudo-obstruction 1 month ago, possibly triggered by intake of opioid analgesics, but recovered quickly after 2 days.

Discussion

DRA is an underestimated condition, often forgotten by healthcare providers. The three most well recognised risk factors for DRA were identified in the 1990s. Dialysis vintage, age, biocompatibility of dialysis solution and membrane were considered the principal risk factors for DRA.¹⁷ Recently is has become clear there’s a fourth risk factor for the development of DRA. Argyropoulos et al showed that residual renal function (RRF) is another major determinant of serum β2M concentrations, even in patients receiving maintenance dialysis. This makes sense because, β2M is cleared by glomerular filtration and subsequent proximal tubular reabsorbed and catabolized. Therefore, decrease in kidney function, and the consequent reduction in RRF, leads to progressive increase in the plasma levels of β2M. As a consequence, the more is the RRF and urine output, the better is the clearance of β2M and the defense against the development of DRA. Therefore, all strategies to maintain the RRF for as long as possible must be put in place. Argyropoulos et al concluded that enhanced dialytic removal of β2M will materially affect the biomarker’s levels only when the residual renal clearance is less than 2 mL/min. In this case report the residual renal clearance was around 1 mL/min, based on a 24 hours urine creatinine clearance.¹⁸

There are only a few case reports of gastro-intestinal involvement in DRA, most of them published during periods when haemodialysis was performed with low-flux membranes that were impermeable to β2m.⁵ Indeed high flux haemodialyzers (HFD) remove β2M much more efficiently than their low-flux counterparts, despite it may happen as proven in this case.² Convective therapies, including HDF and haemofiltration (HF), achieve higher middle molecule clearances relative to high flux dialysis. Average β2M clearance is 48.75 mL/min for conventional HFD, and 87.06 mL/min for convective therapies as HDF and HF. Therefore, being on HDF or HF may result in clinically and statistically significant improvement in total and cardiovascular mortality relative to conventional HFD.¹⁹ In this case the patient responded very well to the change from conventional HD to HDF, in that there did not appear to be further clinical progression of her condition.

In addition, dialysis prescription parameters as well as membrane material are also minor determinants of β2M clearance from the body in renal replacement therapies. In multivariable meta-regression analyses there appeared significantly higher β2M clearance for polyarylethersulfone dialyzers when used for high-flux dialysis and polysulfone membranes in convective therapies. Higher Kuf, blood flow and substitution fluid rates may also provide some benefit independent of the dialysis modality.¹⁹

Considering that kidney transplantation is generally believed to be the optimal form of renal replacement therapy, it is fair to assume that in patients affected by DRA, the best treatment option is renal transplantation. It has been shown that after a number of years, in a patient with a well-functioning renal graft, the amyloid deposits may also regress. In contrast, HFD and convective dialysis therapies can only prevent further storage of amyloid, but do not induce regression of amyloid deposits. Therefore HDF and convective dialysis therapies are merely helpful in delaying disease progression. Unfortunately, many of ESRD patients are not appropriate candidates for transplantation because of comorbid conditions, advanced age and dialysis vintage.²⁰

Patient’s perspective.

I still remember the frustration and feeling of helplessness by not knowing the cause of my symptoms. I wanted to be able to put a name on my illness. However, I was fortunate enough to find the right diagnosis with the help of my doctors. Having a name for my condition has changed a lot for me. There is definitely comfort in knowing what is happening to your body, even if the disease is difficult to treat. For that, I am happy that doctors all over the world could be learning from my case.

Learning points.

• Dialysis-related amyloidosis (DRA) is a caused by the inability to clear β2microglobulin (β2m) in patients with chronic kidney disease, which results in the tissue deposition of the protein as amyloid fibrils.

• DRA affects the musculoskeletal system; however, visceral involvement may also happen.

• Using anti-β2m serum or laser microdissection and mass spectrometry-based proteomic analysis of a biopsy specimen makes histological diagnosis.

• Haemodiafiltration and convective dialysis therapies can delay disease progression

• Kidney transplantation with a well-functioning renal graft is the only therapy that might be able to induce regression of amyloid deposits.