eMedicine Specialties > Emergency Medicine > Hematology & Oncology

Hemolytic Uremic Syndrome

Author: Audrey J Tan, DO, Staff Physician, Department of Emergency Medicine, State University of New York Downstate Medical Center, Kings County Hospital Center
Coauthor(s): Mark A Silverberg, MD, FACEP, MMB, Assistant Professor, Assistant Residency Director, Department of Emergency Medicine, State University of New York Downstate College of Medicine; Consulting Staff, Department of Emergency Medicine, Staten Island University Hospital, Kings County Hospital, University Hospital, State University of New York Downstate at Brooklyn
Contributor Information and Disclosures

Updated: Jun 17, 2009

Introduction

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  The description of this childhood illness has not changed significantly through the years.

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.

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

  • In D+ HUS, the mortality rate is less than 10%, although older children and adults often have poorer prognoses.
  • 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

  • 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.

Clinical

History

  • Risk factors for hemolytic uremic syndrome in children include eating rare hamburger, a recent trip to a petting zoo, and visiting a nursing home relative with diarrhea.
  • Children usually present following an acute diarrheal illness. The GI prodrome typically occurs 4-6 days following onset of diarrhea and may mimic ulcerative colitis, various enteric infections, or appendicitis.
  • Diarrhea becomes hemorrhagic in 70% of cases, usually within 1-2 days of onset of diarrhea.
  • Vomiting occurs in 30-60% of cases.
  • Urine output may be reduced or absent.
  • Neurologic symptoms are observed in 33% of patients and may include irritability, seizures, or altered mental status.

Physical

  • Findings of hemolytic uremic syndrome reflect those of the inciting prodromal illness and the end organ in which thrombogenesis is occurring.
  • Fever occurs in 30% of cases.
  • GI bleeding is often noted.
  • GI involvement may lead to symptoms of an acute abdomen, with occasional peritonitis.
  • Cardiac involvement may lead to congestive heart failure (CHF) and arrhythmias.
  • Microinfarcts in the pancreas may cause pancreatitis or rarely, insulin-dependent diabetes mellitus.
  • Ocular involvement may lead to retinal or vitreous hemorrhages.
  • Hypertension and oliguria are typical findings consistent with renal compromise.

Causes

See Pathophysiology.

More on Hemolytic Uremic Syndrome

Overview: Hemolytic Uremic Syndrome
Differential Diagnoses & Workup: Hemolytic Uremic Syndrome
Treatment & Medication: Hemolytic Uremic Syndrome
Follow-up: Hemolytic Uremic Syndrome
Multimedia: Hemolytic Uremic Syndrome
References
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References

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Further Reading

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Contributor Information and Disclosures

Author

Audrey J Tan, DO, Staff Physician, Department of Emergency Medicine, State University of New York Downstate Medical Center, Kings County Hospital Center
Audrey J Tan, DO is a member of the following medical societies: American College of Emergency Physicians and American Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)

Mark A Silverberg, MD, FACEP, MMB, Assistant Professor, Assistant Residency Director, Department of Emergency Medicine, State University of New York Downstate College of Medicine; Consulting Staff, Department of Emergency Medicine, Staten Island University Hospital, Kings County Hospital, University Hospital, State University of New York Downstate at Brooklyn
Mark A Silverberg, MD, FACEP, MMB is a member of the following medical societies: American College of Emergency Physicians, American Medical Association, Council of Emergency Medicine Residency Directors, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Medical Editor

William G Gossman, MD, Associate Clinical Professor of Emergency Medicine, Creighton University School of Medicine; Consulting Staff, Department of Emergency Medicine, Creighton University Medical Center
William G Gossman, MD is a member of the following medical societies: American Academy of Emergency Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Jeffrey L Arnold, MD, FACEP, Chairman, Department of Emergency Medicine, Santa Clara Valley Medical Center
Jeffrey L Arnold, MD, FACEP is a member of the following medical societies: American Academy of Emergency Medicine and American College of Physicians
Disclosure: Nothing to disclose.

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Steven C Dronen, MD, FAAEM, Director of Emergency Services, Director of Chest Pain Center, Department of Emergency Medicine, Ft Sanders Sevier Medical Center
Steven C Dronen, MD, FAAEM is a member of the following medical societies: American Academy of Emergency Medicine and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

 
 
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