Atypical haemolytic uremic syndrome secondary to acute pancreatitis: a unique presentation

Abstract

Atypical haemolytic uraemic syndrome (aHUS) is a disease of complement dysregulation and can be fatal if not treated in a timely manner. Although normally associated with triggers such as infection or pregnancy, this case demonstrates acute pancreatitis as the triggering event. The patient’s initial presentation of thrombocytopaenia and acute renal failure was first attributed to a systemic inflammatory response syndrome due to pancreatitis, but with detailed history and further laboratory investigation, we were able to show that patient was having symptoms associated with aHUS. On early recognition of aHUS, this patient was able to receive the proper standard of care with eculizumab and had a full recovery while preventing renal failure. When patients present with thrombocytopaenia and renal failure in acute pancreatitis, we want to ensure physicians keep aHUS on the differential.

Background

Atypical haemolytic uraemic syndrome (aHUS) is an extremely rare, chronic and inflammatory disease caused by dysregulation in the complement system. The resulting microangiopathy can damage multiple organ systems, including the kidneys. aHUS as a result of alcoholic pancreatitis, is seldom reported, but it is important for physicians to recognise HUS/thrombotic thrombocytopenic purpura (TTP) as one of the top causes of acute renal failure among adults with acute pancreatitis, particularly in the setting of anaemia and thrombocytopaenia. Prompt treatment with eculizumab will improve renal function and other systemic manifestations.

Case presentation

A 32-year-old male patient with medical history of recurrent pancreatitis, post-traumatic stress disorder and alcohol abuse presented with a 1-day history of abdominal pain and three to four episodes of non-bilious vomiting. The patient states that he quit drinking 6 months prior to this episode. On presentation, he had normal vital signs with physical examination pertinent for epigastric tenderness. Laboratories were significant for haemoglobin 15.9, white cell count 11×10⁹/L with neutrophilic predominance, platelets 191, creatinine 1.1, normal liver function tests except for a bilirubin of 1.7. Initial lipase was 582 and elevated to 1019 by the end of the first day of admission. CT abdomen/pelvis with contrast demonstrated hepatic steatosis, peripancreatic fluid consistent with acute pancreatitis with an 8 mm pancreatic tail pseudocyst that was chronic; no pseudoaneurysm or splenic vein thrombosis. He was started on supportive management for pancreatitis. By day 2 of admission, his platelet count dropped from 191 to 48, and creatinine elevated from 1.1 to 2.26 with no clinical improvement. Haematology was consulted for further evaluation. Of note, this was his third admission for acute pancreatitis in 1 year. His previous admissions were also complicated by renal failure and thrombocytopaenia. On his last admission, his creatinine acutely rose to 12 within 3–4 days of admission before trending downwards to normal in 3 weeks. He received supportive management for pancreatitis with fluids and opioids without any intervention or dialysis.

Investigations

Peripheral smear on day 1 showed one to two schistocytes per high powered field, lots of burr cells and normal-appearing neutrophils with low platelet count. Patient also had elevated lactate dehydrogenase, low haptoglobin with normal total bilirubin, reticulocyte count and Coombs test. D-dimer was elevated at 4.72 µg/mL, fibrinogen was elevated at 617 mg/dL and ADAMSTS-13 (A Disintegrin And Metalloproteinase with Thrombospondin type 1 motif, 13) activity was low at 59%. Complement levels were elevated at 195 complement activity enzyme units. Though he had a mixed haemolysis picture, his creatinine acutely elevated to 8, and his peripheral smear showed an increase in the number of schistocytes on subsequent days. Since this was the second time he has developed concomitant renal failure with pancreatitis, we suspected he had aHUS, triggered by acute pancreatitis.

We also sent a number of genetic tests to assess mutations in complement regulatory proteins such as factor H, I, CFH, CD46, CFI, C3, CFB, THBD, CFHR1, CFHR5 and DGKE; these were pending at the time of initial workup.

Differential diagnosis

Thrombocytopaenia secondary to systemic inflammatory response syndrome (SIRS): Acute pancreatitis can lead to SIRS, which in turn can cause thrombocytopaenia and acute kidney injury. His presentation was consistent with SIRS especially with no signs of schistocytes on initial peripheral smear. However, acutely worsening renal function on subsequent days with an increase in number of schistocytes is not consistent with SIRS.

Renal failure from contrast-induced nephropathy: Acute contrast-induced nephropathy can be seen 24–48 hours after contrast is given. Typically it lasts 3–7 days. Urinalysis would normally show muddy brown granular and epithelial cell casts and free renal tubular epithelial cells. His urinalysis never showed any casts. There would also not be thrombocytopaenia induced by this which would mean more than one process would be going on at once.

aHUS: Laboratories and peripheral smear were consistent with thrombotic microangiopathy with associated acute renal failure. ADAMSTS-13 level was 59%, with no preceding diarrhoea thus ruling out TTP and Escherichia coli-induced HUS. The patient had a similar presentation with each of his previous pancreatitis episodes. Acute pancreatitis does strongly activate the complement system and with mutations in his complement regulatory proteins, the acute pancreatitis could be the trigger to activate an aHUS flair.

Treatment

After extensive discussion between surgery, nephrology and haematology, it was decided to treat this patient with eculizumab for aHUS. He was given 900 mg weekly for four doses with a plan to stop the drug once he improved. Meningococcal vaccine was administered, and he was started on amoxicillin 500 mg two times per day as prophylaxis.

Outcome and follow-up

The day after the eculizumab was started his creatinine stopped trending upwards, and his platelets started to rise, as seen in figure 1. By the time of discharge, his platelets had elevated from a nadir of 11–510 in just 10 days. In that same time period, his creatinine had decreased to 1.20 from a maximum of 8.51, while in previous admissions it had trended all the way up to 12. During the previous admission, his creatinine continued to rise for 12 days before it peaked, and he was hospitalised for a total of 24 days, whereas during this hospitalisation his creatinine rise stopped after only 5 days, and his hospitalisation only lasted 14. Though an expensive drug, the day’s difference in hospitalisation can make a large difference in cost. As his platelets continued upwards, a kidney biopsy was also obtained. The biopsy did not show any TMA process, but there was complement deposition. Of the complement mutations sent, there was a one heterozygous mutation. When he was seen in clinic 1 month later, he was still recovering from his pancreatitis with nasogastric tube and total parenteral nutrition, but he was feeling much better, had no signs of bleeding and was making good urine. At this point, it was decided to stop the eculizumab after four doses and to only restart it if he had another bout of pancreatitis to help prevent further renal damage.

Figure 1.

Platelet and creatinine over time. First dose of eculizumab given on the 6th day of hospitalization.

Discussion

aHUS is defined by having haemolytic anaemia, thrombocytopaenia and acute kidney injury simultaneously. Patients with aHUS typically have a mutation in complement regulation that once incited by a triggering event can lead to uninhibited activation of complement system leading to the above issues. Trigger events for aHUS are typically infection or pregnancy, but it is possible that pancreatitis could also be one of these events.

There have been only a few reported cases of aHUS caused by acute pancreatitis. Singh et aldescribed a very similar case in which a 32-year-old male patient presented with acute pancreatitis and then developed aHUS which necessitated plasmapheresis.¹ They hypothesised that in either HUS or TTP secondary to pancreatitis the pancreatic proteases modify circulating von Willebrand factor (vWF) molecules enabling spontaneous platelet aggregation. They felt using vWF-cleaving protease (ADAMTS-13) would help differentiate between TTP and aHUS.¹ Prior to this, Swisher et al described five cases of patients who presented with acute pancreatitis and then developed aHUS while hospitalised.² In these cases, no specific underlying mutation was found, but some had deficiencies in ADAMTS-13 activity or disorders of complement regulation. They hypothesised that only when a strong insult such as pancreatitis happened did the disease present. Using this information, we suspect that our patient had some genetic defect in his complement regulatory genes. Since pancreatitis is associated with high levels of complement activity, we hypothesised that when his complement was largely upregulated, any defects in complement regulation would come into play. Our patient had heterozygous missense variant in MCP/CD46 that has been previously associated with aHUS. He also had heterozygous mutations in exon 3 of MMACHC gene. Overall, the results of his genetic panel were equivocal, as the mutations he has have been reported in other cases of aHUS but are not considered pathogenic alone.^{3 4}

For aHUS, current guidelines recommend eculizumab, if this is unavailable then plasma exchange can be considered. There are no evidence-based guidelines to recommend when it is advisable to stop eculizumab therapy, and it is often continued lifelong.⁵ An agreed on minimum treatment time is until renal recovery and help prevent early relapse, which is what we did in our patient.

Patient’s perspective.

It was a huge relief to have a diagnosis. We have children and we were worried about the continued cost of hospitalisations and the possibility of needing dialysis if I continued to have kidney failure. The only worry now is the cost of the drug which we have worked with the physicians and drug companies to help pay.

Learning points.

• Physicians recognise haemolytic uraemic syndrome (HUS)/TTP as one of the potential causes of acute renal failure among adult patients with acute pancreatitis, especially in the setting of anaemia and thrombocytopaenia.

• Prompt treatment with eculizumab will improve renal function and other systemic malfunction.

• Primary atypical HUS is caused by complement dysregulation, and it is important to send for genetic testing.