aHUS is a rare disease characterized by alternative complement pathway dysregulation which have multiple diverse etiologies. AP-related HUS mentioned in this article constitutes a small group among them [1]. A triggering event starts the inflammatory process on the endothelial cell surface. Fibrin and platelet deposition caused by endothelial cell damage evokes thrombotic microangiopathy and affects all organs and tissues, especially the kidneys [4]. Although the pathogenic mechanism of pancreatitis-related HUS has not been clarified yet, two basic pathologies have been suggested. The first is that the cytokines, interleukin-1, and tumor necrosis factor-α, released during AP directly cause vascular endothelial damage [5]. Another suggested triggering mechanism of AP-related HUS is it is the interaction of pancreatic proteases, which are released into the circulation with pancreatic tissue destruction with coagulation factors [5,6,7]. In healthy people, von Willebrand factor is degraded by ADAMTS13, preventing platelet aggregation [8]. Circulating proteases stimulate endothelial cell release of ultra large von Willebrand factor multimers and prevent the cleavage of these multimers by ADAMTS13, causing thrombus formation from shear stress on the vascular endothelium [5,6,7]. Considering this case and suggested pathogenic pathways, it can be speculated that the severity of AP and inflammation may be the triggering mechanism. However, no relationship was found between the severity of acute pancreatitis and the development of HUS in previous studies [9].
As in our case, development time of AP-related HUS is generally on the 3rd day of the onset of the disease and generally in period when pancreatitis is in resolution. This period between AP and HUS development provides evidence supporting these pathogenic pathways [10]. Due to the lack of available tests at our institution, we could not perform genetic tests to evaluate mutations in complementary regulatory proteins to rule out primary aHUS. However, the presence of still unidentified mutations makes it difficult to explain the etio-pathogenesis of the disease with the result of genetic mutation alone [11]. Sharma et al. in their article, suggested the existence of 3 types for the coexistence of AP and HUS, namely AP-associated secondary HUS, HUS triggered by AP, and TMA associated with HUS and AP. Accordingly, the most common type is AP-associated secondary HUS type of co-existence, had classical risk factors of AP like alcoholism or gall stones. It has been suggested that interleukins, TNF alpha and cytokines cause secondary HUS by causing endothelial damage [12]. Our case can be considered as type 1 coexistance due to the coexistence of gallstones and the age of development of HUS.
Pancreatitis-related HUS was first described in 1978 in an 18-year-old patient, and the etiology of pancreatitis was reported as idiopathic. After that, approximately 30 patients have been reported. The median age of these patients is 39 and the majority of them have alcoholic pancreatitis. To our knowledge, gallstone associated pancreatitis, as in our case, was reported in only four patients, and one of the patients had recurrent HUS [9]. Until now, there has been no reported patient under the age of 18, our case is the youngest age patient reported.
The presence of accompanying neurological symptoms was previously thought to distinguish between HUS and thrombotic thrombocytopenic purpura (TTP), which is a common cause of thrombotic microangiopathy, especially in the adult population. However, it is now known that central nervous system involvement is a common extrarenal complication of HUS especially in children [13]. A normal level of ADAMTS13 activity in a sample taken prior to initiation of plasma therapy safely excludes the diagnosis of thrombotic thrombocytopenic purpura [11]. In 2007, Swisher et al. reported a systemic review in patients with TTP-HUS. In this case series, 4 patients with neurological findings including diplopia, grand mal seizure, hemiparesis, and speech disorder were mentioned. ADAMTS-13 levels were not studied in any of these patients [5]. Although our case experienced temporary vision loss after generalized grand-mal seizure, normal ADAMTS13 activity and level results suggested that this neurological finding was an extrarenal manifestation of HUS in our patient.
Prior to the introduction of Eculizumab, which provides alternative complement system blockade via C5a blockade, plasma therapy was the mainstay of treatment in aHUS cases. Later there have been publications reporting that Eculizumab is much more favorable in this patient group due to its efficacy and low side-effect profile compared to plasma therapy [1, 14]. Due to the high cost of eculizumab and its low availability, especially in developing countries, a consensus guideline for developing countries was published in 2019. It is recommended early PE (not plasma infusion) therapy be continued at a daily rate until hematological remission achievement the absence of Eculizumab. Eculizumab treatment is recommended in the presence of unresponsiveness to PE therapy, life-threatening conditions, complications of PE, and hereditary complement defects [15]. However, there are no prospective, controlled studies to properly evaluate the efficacy of eculizumab in the treatment of secondary HUS cases such as pancreatitis-related HUS. In the reported cases of pancreatitis related HUS, it was observed that those who used eculizumab did not need dialysis therapy and a rapid remission of the disease was achieved [9]. Since our case was a Syrian refugee and had payment problems, we started PE as first-line treatment. Fortunately, the patient responded quickly and completely to PE.
