Hemolytic Uremic Syndrome in Emergency Medicine

Updated: Jan 21, 2015
  • Author: Audrey J Tan, DO; Chief Editor: Steven C Dronen, MD, FAAEM  more...
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Overview

Background

Hemolytic uremic syndrome (HUS) is primarily a disease of infancy and early childhood and is classically characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. In 1955, Gasser et al first described hemolytic uremic syndrome as a self-limited illness associated with a prodrome of diarrhea that resulted in spontaneous recovery. [1] Though the description of this childhood illness has not changed significantly through the years, additional insight into the pathology and disease process have come to light recently.

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Pathophysiology

Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) fall into the broader category of thrombotic microangiopathies (TMA). Thrombotic microangiopathies are characterized by the involvement of widespread occlusive microvascular thromboses resulting in thrombocytopenia, microangiopathic hemolytic anemia, and variable signs and symptoms of end-organ ischemia. Though recent research has revealed that the two disease processes have underlying similarities, hemolytic uremic syndrome and thrombotic thrombocytopenic purpura have historically been considered two separate disease entities.

Two predominant types of HUS are identified: one type involves diarrhea (D+) and the other, D- or atypical, does not.

D+ HUS is the classic form, accounting for 95% of cases of hemolytic uremic syndrome in children. This form of hemolytic uremic syndrome occurs predominantly in children and is preceded by a prodrome of diarrhea, most commonly caused by an infection by shiga-toxin producing Escherichia coli.

Specifically, E coli serotype O157:H7 has been associated with more than 80% of infections leading to hemolytic uremic syndrome. The shiga-like toxin affects endothelial cells and initiates intravascular thrombogenesis. After entering the circulation via the gastrointestinal mucosa, the toxin preferentially localizes to the kidneys, inhibiting protein synthesis and eventually leading to cell necrosis or apoptosis. Endothelial cell damage subsequently potentiates renal microvascular thrombosis by promoting activation of the blood coagulation cascade. Platelet aggregation results in a consumptive thrombocytopenia. Microangiopathic hemolytic anemia results from mechanical damage to red blood cells circulating through partially occluded microcirculation.

E coli O157:H7 is not normally found in human intestinal flora but is present in 1% of healthy cattle. Thus, meat may become contaminated during animal slaughter and processing. The most common form of transmission to children in the United States is ingestion of undercooked meat containing viable bacteria. Ingesting unpasteurized fruits and juices, coming into contact with unchlorinated water, and person-to-person transmission in daycare or long-term care facilities are alternate routes of transmission.

D- HUS accounts for the remaining 5% of cases of hemolytic uremic syndrome and its etiology, age at onset, and clinical presentations are far more varied. Unlike D+ HUS, D- HUS is not preceded by an identifiable gastrointestinal infection. The pathogenesis of D- HUS has been the focus of current research and has, thus far, been associated with complement dysregulation in up to 50% of cases. [2] Specifically, mutations in complement regulatory protein factor H, factor I, or factor B or autoantibodies against factor H have all been implicated. [2] These mutations result in inability to suppress complement activation and for reasons that are not completely understood, the glomerular endothelium is particularly susceptible to these changes.

Clinically, D- HUS has been associated with various nonenteric infections, viruses, drugs, malignancies, transplantation, pregnancy, and other underlying medical conditions such as scleroderma and antiphospholipid syndrome. Infections caused by Streptococcus pneumoniae has been linked to 40% of D- HUS cases. Categories of drugs that have been most frequently associated with D- HUS include anticancer molecules (mitomycin, cisplatin, bleomycin, and gemcitabine), immunotherapeutics (cyclosporine, tacrolimus, OKT3, IFN, and quinidine), and antiplatelet agents (ticlopidine and clopidogrel).

Malignancies found in conjunction with hemolytic uremic syndrome include prostatic, gastric, and pancreatic cancers. Familial forms of D- HUS exist but account for fewer than 3% of cases. Unlike D+ HUS, only 4.7% of D-HUS cases in the United States involve children.

In contrast to hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP) presents with the classic pentad of microangiopathic hemolytic anemia, thrombocytopenia, prominent neurologic symptoms, fever and a milder form of renal failure. The pathophysiology of thrombotic thrombocytopenic purpura is different in that, as opposed to endothelial cell injury, thrombotic thrombocytopenic purpura is thought to be caused by a deficiency in the metalloprotease ADAMTS13, which is involved in the regulation of von Willebrand factor. A lack of this protein results in spontaneous platelet aggregation and the widespread deposition of platelet-rich thrombi in the microvasculature of various organs, most notably the heart, brain, and kidneys.

Current research has demonstrated that, though a deficiency of ADAMTS13 clearly diagnoses thrombotic thrombocytopenic purpura, patients with D- HUS also share this finding. Current research suggests that these two illnesses share a similar pathophysiology and may be variants of the same disease spectrum.

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Epidemiology

Frequency

United States

  • The overall incidence of D+ HUS is estimated to be approximately 2.1 cases per 100,000 persons per year, with a peak incidence in children who are younger than 5 years (6.1 cases per 100,000 per year). The lowest rate is in adults aged 50-59 years (0.5 cases per 100,000 per year). [3]
  • Incidence tends to parallel the seasonal fluctuation of E coli O157:H7 infection, which peaks between June and September. [3]
  • Incidence of D- HUS in children is approximately 2 cases per year per 100,000 total population. [3]

Mortality/Morbidity

See the list below:

  • In D+ HUS, the mortality rate is between 3% and 5%. Older children and adults often have poorer prognoses. Death is nearly always associated with severe extrarenal disease, including severe central nervous system (CNS) involvement. Approximately two thirds of children with D+ HUS require dialysis. [4]
  • In cases of D- HUS, overall mortality rate approaches 26%.

Race

Hemolytic uremic syndrome has no predilection for a specific race.

Sex

Hemolytic uremic syndrome has no predilection for either sex.

Age

See the list below:

  • D+ HUS is typically observed in infants and children, especially those aged 6 months to 4 years.
  • D- HUS is variable in its age of presentation.
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