Abstract. The hemolytic uremic syndrome (HUS) is a disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal failure.
Pathology Patterns Reviews
Hemolytic Uremic Syndrome Revisited Shiga Toxin, Factor H, and Fibrin Generation Douglas P. Blackall, MD,1 and Marisa B. Marques, MD2 Key Words: Factor H; HUS; Hemolytic-uremic syndrome; Microangiopathic hemolytic anemia; Renal failure; Shiga toxin; Thrombotic microangiopathy DOI: 10.1309/06W402EHNGVVB24C
Abstract The hemolytic uremic syndrome (HUS) is a disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. These features reflect the underlying histopathologic lesion: fibrin-rich thrombi that predominate in the renal microvasculature. HUS most commonly affects children younger than 5 years and is associated with Shiga toxin–producing enteric bacteria, the most important of which is Escherichia coli O157:H7. In this setting, HUS is epidemic and also might affect adults, particularly elderly people. Sporadic cases of HUS more commonly occur in adults and are associated with a wide variety of inciting agents and conditions. Although the disease manifestations might be similar and endothelial activation or injury likely represents a common etiologic event, differing responses to therapy suggest different pathogenic mechanisms. As more is understood about the underlying pathogenesis of the diseases that we now lump together as HUS, more efficacious and rational treatment and prevention strategies are likely to follow.
© American Society for Clinical Pathology
The hemolytic uremic syndrome (HUS) is a disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. It was first described by Gasser et al in 1955 and is the most common cause of renal failure in early childhood.1,2 However, all age groups are affected by this disease process, and extrarenal manifestations of the disease may occur (eg, microthrombi in the brain).2 Vascular endothelial injury seems to have a central role in HUS pathogenesis, with resulting fibrin-rich thrombi responsible for the clinical manifestations of the disease.3 Hemolysis occurs as erythrocytes traverse occluded vessels, with schistocytes typically abundant on examination of the peripheral blood smear. Platelets are consumed at sites of vascular injury, resulting in thrombocytopenia. Finally, for reasons that are not completely understood, thrombus formation is most significant and obvious in the kidneys, with resulting renal failure. The clinical manifestations of HUS can be difficult to distinguish from thrombotic thrombocytopenic purpura (TTP). In fact, many have viewed these disorders as an overlap syndrome (TTP-HUS), with the predominant clinical manifestation determining the ascribed diagnosis. 4 Thrombotic microangiopathies with predominant neurologic manifestations might be diagnosed as TTP, while those with primary renal involvement are named HUS. However, the past decade has realized an explosion in our understanding of the pathogenic underpinnings of both illnesses, to the extent that it is becoming possible to differentiate at least 2 distinctive pathologic processes. This is an important consideration because therapy for each is quite distinct. This review focuses on the clinical manifestations of HUS, its laboratory findings and pathogenesis, and the implications for therapy that have resulted from a greater understanding of the disease and its causes. Am J Clin Pathol 2004;121(Suppl 1):S81-S88 DOI: 10.1309/06W402EHNGVVB24C
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Blackall and Marques / HEMOLYTIC UREMIC SYNDROME REVIEW
Case Study A previously healthy 4-year-old girl was admitted to the hospital with a 1-week history of abdominal pain and watery diarrhea. Just before admission, bloody diarrhea was noted. The patient was admitted with a presumptive diagnosis of gastroenteritis and dehydration. Blood and stool cultures were obtained, and the patient was hydrated. Admitting laboratory data were all within defined reference ranges, including a hemoglobin of 12.9 g/dL (129 g/L; reference range, 11.5-13.5 g/dL [115-135 g/L]), a hematocrit of 37.4% (0.37; reference range, 34.0%-40.0% [0.34-0.40]), a platelet count of 306 × 103/µL (306 × 109/L; reference range, 150-400 × 103/µL [150-400 × 109/L]), and a creatinine level of 0.4 mg/dL (35 µmol/L; reference range, 0.1-0.7mg/dL [9-62 µmol/L]). A few days after admission, the patient’s laboratory values began to change: her hemoglobin, hematocrit, and platelet count fell, and her creatinine level rose. At this time, the microbiology laboratory reported a negative blood culture, but a stool culture was positive for Escherichia coli, serotype O157:H7. An enzyme immunoassay also was positive for Shiga toxin. One week after the onset of the patient’s bloody diarrhea, her hemoglobin had fallen to 6.9 g/dL (69 g/L), her hematocrit was 19.5% (0.20), her platelet count was 39 × 103/µL (39 × 109/L), and her creatinine level had risen to 4.9 mg/dL (433 µmol/L). She was also anuric, for which hemodialysis was started. During the next few days, the patient received supportive care and a total of 3 dialysis procedures. Almost immediately, her condition improved as evidenced by a falling creatinine level, a rising platelet count, and stabilized hemoglobin and hematocrit values (although the patient required 1 transfusion of packed RBCs). After a 2-week hospitalization, the patient’s creatinine level and platelet count returned to normal, and she was discharged from the hospital.
Clinical Manifestations The preceding case study represents the classic manifestations of HUS. The most common form of the syndrome is associated with a prodromal diarrhea (D+ HUS) that occurs in healthy young children between 6 months and 5 years of age.1 Initially, the diarrhea is watery but usually evolves to a hemorrhagic colitis. This is followed by evidence of hemolysis (falling hemoglobin and hematocrit values; schistocytes on peripheral blood smear) and thrombocytopenia within 5 to 7 days. Oliguria and anuria may follow several days later. Therapy is largely symptomatic, and the outcome for patients with D+ HUS generally is favorable, although the combined mortality rate and rate of end-stage renal disease is approximately 10%.5 In addition, long-term follow-up of S82 S82
Am J Clin Pathol 2004;121(Suppl 1):S81-S88 DOI: 10.1309/06W402EHNGVVB24C
survivors has demonstrated that 25% will have renal dysfunction (as characterized by a glomerular filtration rate lower than 80 mL/min per 1.73 m 2 ), hypertension, or proteinuria.5 Fortunately, recurrence is uncommon. In contrast with diarrhea-associated HUS, the sporadic, nonprodromal form of HUS is not associated with a preceding diarrhea (D– HUS) and is rare in childhood. This form of HUS has a worse prognosis, is more likely to relapse, and sometimes is associated with a family history of disease.2 In addition, D– HUS is associated with certain drugs (eg, pentostatin, cyclosporine, mitomycin C), various malignant neoplasms (eg, pancreatic and lung cancers), solid organ and bone marrow transplantation, and vasculitic diseases.2 D– HUS is associated with a greater incidence of extrarenal disease (eg, neurologic complications, liver dysfunction, pancreatic and cardiac problems) and might be difficult to distinguish from TTP. Still, the hallmarks of HUS remain the same: microangiopathic hemolytic anemia, thrombocytopenia, and renal failure.
Laboratory Findings HUS is largely a clinical diagnosis supported by laboratory abnormalities that reflect the underlying pathophysiologic process (intravascular fibrin-rich thrombus formation). A nonimmune, schistocytic, hemolytic anemia with prominent polychromatophilia is seen on the blood smear. Biochemical evidence supporting hemolysis also is routinely present, including an elevated lactate dehydrogenase level, a low serum haptoglobin concentration, and an unconjugated hyperbilirubinemia. Thrombocytopenia is a common finding in HUS and directly reflects the underlying pathophysiology (endothelial injury and platelet consumption). However, severe thrombocytopenia (
