Practice Essentials
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 kidney injury. [1] The clinical course of HUS can range from subclinical to life threatening, and the presentation may vary depending on the etiology. [2]
HUS has two variants, typical and atypical. Typical HUS is related to bacteria, with more than 90% following a gastrointestinal infection with Shiga toxin–producing Escherichia coli (STEC). Nomenclature for HUS varies throughout the literature: typical HUS is also called classic HUS, STEC-HUS, and diarrhea-positive (D+) HUS.
Atypical HUS (aHUS) is HUS not mediated by Shiga toxin. It is also called diarrhea-negative (D-) or non–diarrhea-associated HUS. Most patients with atypical HUS have mutations in one or more of the genes that encode proteins involved in the alternate pathway of complement, which creates a predisposition to the disorder. Atypical HUS may also be due to development of autoantibodies against complement factor H. [3]
HUS may also be initiated by autoimmune disease, transplantation, cancer, infection (eg, with Streptococcus pneumoniae, influenza virus), pregnancy, or certain cytotoxic drugs. HUS linked to those clinical entities is sometimes designated as secondary HUS. [3] For example, in pneumococcal HUS, S pneumoniae damages endothelial cells in the blood vessels, disturbing local complement homeostasis and producing a thrombogenic state. [4, 5] However, in some cases it may be difficult to determine whether a particular factor is the cause or is the trigger in a patient with an underlying predisposition. [3, 4]
Signs and symptoms of typical HUS include the following::
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Diarrhea, which becomes hemorrhagic in most cases, usually within 1-2 days
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Vomiting
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Fever, in 5-20% of cases
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After 4-6 days, sudden onset of the clinical manifestations of HUS: pallor and shortness of breath from hemolytic anemia, and reduced or absent urine output due to acute kidney injury
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Neurologic symptoms in 33% of patients (eg, irritability, seizures, or altered mental status)
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Diarrhea may improve as the other HUS signs and symptoms begin
Atypical HUS does not typically begin with a gastrointestinal illness. Patients with pneumococcal HUS may have had a recent respiratory illness. Clinical manifestations of atypical HUS are similar to those of typical HUS, although neurologic involvement is more common. See Presentation.
HUS is primarily a clinical diagnosis coupled with consistent laboratory findings, including the following:
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Microangiopathic hemolytic anemia, with a hemoglobin level that is typically less than 8 g/dL
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Schistocytes on the peripheral blood smear
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Mild to moderate thrombocytopenia
See Workup.
Emergency department (ED) care for patients with HUS should focus on the following:
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Supportive management
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Correction of blood pressure elevation
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Red blood cell transfusions
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Arrangement for prompt dialysis, if necessary
The monoclonal antibodies eculizumab and ravulizumab are approved for treatment of atypical HUS. See Treatment and Medication.
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, HUS and TTP 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 HUS 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 HUS. 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. [6] 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. [7] Specifically, mutations in complement regulatory protein factor H, factor I, or factor B or autoantibodies against factor H have all been implicated. [7] 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 the following:
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Anticancer molecules (mitomycin, cisplatin, bleomycin, and gemcitabine)
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Immunotherapeutics (cyclosporine, tacrolimus, OKT3, interferon, and quinidine)
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Antiplatelet agents (ticlopidine and clopidogrel)
Malignancies found in conjunction with HUS 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.
Epidemiology
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). [8]
Incidence tends to parallel the seasonal fluctuation of E coli O157:H7 infection, which peaks between June and September. [8]
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. Incidence of D- HUS in children is approximately 2 cases per year per 100,000 total population. [8]
Hemolytic uremic syndrome has no predilection for a specific race or for either sex.
Prognosis
With supportive care, approximately 85% of patients recover and regain normal renal function. The overall mortality rate of hemolytic uremic syndrome (HUS) is 5-15%. 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. [9] In cases of D- HUS, overall mortality rate approaches 26%.
For unknown reasons, younger children who present in the summer with the typical diarrheal prodrome tend to do better than older children who develop HUS during the colder months of the year.
Adults with HUS generally have a poorer prognosis than children. In one study, 14% of adults with HUS succumbed to the disease. Adults who undergo kidney transplantation because of HUS are at much higher risk of graft loss than patients undergoing transplantation for other reasons. [10] Patients with atypical HUS have a poorer prognosis with high mortality and >50% of patients developing end-stage renal disease. However, since the introduction of eculizumab, these outcomes have greatly improved. [11]
Complications of hemolytic uremic syndrome include the following:
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Hypertension
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Neurologic dysfunction including seizures, coma, stroke, hemiparesis, and cortical blindness: Severe CNS involvement is associated with significant mortality.
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GI involvement, including any area from the esophagus to the anus: This can include hemorrhagic colitis, bowel necrosis/perforation, or intussusception.
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Cardiac dysfunction, possibly precipitated by uremia and fluid overload
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Complications involving the pancreas are seen in fewer than 10% of patients and can include glucose intolerance. Frank diabetes mellitus is rare.
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Liver complications including hepatomegaly and/or increased serum transaminases levels are not uncommon.
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In severe cases, death may be an inevitable outcome if the disease has progressed too far prior to presentation.
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Peripheral smear in hemolytic uremic syndrome (HUS), with findings of microangiopathic hemolytic anemia. Note schistocytes/helmet cells as well as decrease in platelets. Image courtesy of Emma Z. Du, MD.
