Abstract
Introduction
Hemolytic uremic syndrome (HUS) is a disease group characterized by microangiopathic hemolytic anemia, thrombocytopenia, and kidney injury caused by thrombotic microangiopathy (TMA), a pathology involving endothelial damage in microvessels causing microthrombi. Although often caused by Shiga toxin-producing E. coli (STEC), HUS also has rarer causes including drug-induced, cobalamin C deficiency-mediated, and complement-mediated (CM). We present a case of HUS with difficult diagnostic work-up due to complex patient history and hospital course.
Case Description
A 65-year-old man with multiple myeloma on carfilzomib/pomalidomide/dexamethasone was hospitalized for one day history of fatigue, nausea, vomiting, abdominal pain, diarrhea, and low urine output. Initial laboratory values showed platelets 8,000/uL, hemoglobin 12.5 g/dL, WBC 24,800/uL, creatinine 3.2 mg/dL, BUN 44 mg/dL, and total bilirubin 4.4 mg/dL. Urine studies showed microscopic hematuria and albuminuria (>1313 ug/mg). Blood smear showed reactive leukocytosis, rare platelets, and marked schistocytes. Hemolysis studies showed indirect bilirubin 3.4 mg/dL, haptoglobin <10 mg/dL, LDH 2,995 U/L, and negative direct antiglobulin test. PT, aPTT, and fibrinogen levels were normal, ruling out acute disseminated intravascular coagulation. ADAMTS13 activity was more than 102%, ruling out thrombotic thrombocytopenic purpura. CT scan showed cholecystitis, which was treated with antibiotics and cholecystostomy. He developed anuria and uremia, requiring dialysis. Initial platelet transfusions improved platelet count to 78,000, but it gradually decreased to 37,000. He required multiple RBC transfusions for gradual hemoglobin decrease to 6.7. Repeat laboratory values and blood smears showed persistent hemolysis. Though delayed by ileus, enteric PCR panel was eventually collected; no pathogens were detected. Serum homocysteine and methylmalonic acid levels were normal, ruling out cobalamin C deficiency. Due to high suspicion for CM-HUS, terminal complement blockade treatment with eculizumab was started. Within a few days, the patient's hemoglobin level, platelet count, and hemolysis markers improved. His urine output improved, but he remained dependent on dialysis at discharge. His complement factor H (CFH) autoantibody level (collected prior to eculizumab) later resulted as normal.
Discussion
This case highlights the complexity of managing HUS in patients with multiple potential causes and complications interfering with work-up. The patient had been receiving carfilzomib, which can rarely cause drug-induced TMA. However, this patient's TMA presented suddenly after 10 cycles of carfilzomib, pointing away from drug-induced etiology. Thus, CM-HUS rose to the top of most likely diagnoses. This is caused by genetic or acquired defects in the alternative complement pathway resulting in dysregulation and can be triggered by stressors such as cholecystitis. Detection of CFH autoantibodies and pathologic complement gene mutations can confirm CM-HUS. However, these tests are expensive, take weeks to process, and negative results cannot rule out diagnosis. Because CM-HUS is a clinical diagnosis of exclusion, other HUS causes should be ruled out before starting first-line treatment with complement blockade. Stool STEC testing in this patient was unfortunately delayed from cholecystitis-related ileus, thus delaying treatment. Overall, because of limited understanding of HUS, more research is needed to build evidence-based guidelines for diagnostic work-up and treatment plans, which include risk-benefit analysis for initiating empiric complement blockade.
No relevant conflicts of interest to declare.