eMedicine Specialties > Emergency Medicine > Hematology & Oncology

Hemolytic Uremic Syndrome

Audrey J Tan, DO, Staff Physician, Department of Emergency Medicine, State University of New York Downstate Medical Center, Kings County Hospital Center
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

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.

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.

Differential Diagnoses

Workup

Laboratory Studies

• Hemolytic uremic syndrome (HUS) is primarily a clinical diagnosis coupled with consistent laboratory findings.
• Hemolytic uremic syndrome produces a microangiopathic hemolytic anemia with a hemoglobin level that is typically less than 8 g/dL. This is a consistent finding and is necessary to establish the diagnosis.
  • The hallmark of hemolytic uremic syndrome in the peripheral smear is the presence of schistocytes. These consist of fragmented, deformed, irregular, or helmet-shaped RBCs (see Media file 1). They reflect the partial destruction of RBCs that occurs as they traverse vessels partially occluded by platelet and hyaline microthrombi. The peripheral smear may also contain giant platelets. This is due to the reduced platelet survival time resulting from the peripheral consumption/destruction.

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.

• A consumptive coagulopathy is typically not present.
• Thrombocytopenia is noted and is typically mild to moderate in severity with platelet counts of less than 60,000 per mL. In spite of this finding, neither purpura nor active bleeding is typically seen.  
• Prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen are within the reference ranges, thus differentiating hemolytic uremic syndrome and thrombotic thrombocytopenic purpura from disseminated intravascular coagulation (DIC).
• Elevation of lactate dehydrogenase (LDH) and indirect bilirubin levels reflects intravascular hemolysis. Bilirubin rarely exceeds 2-3 mg/dL. Haptoglobin is very low, as it is consumed by free hemoglobin released by the destroyed RBC’.
• Blood urea nitrogen (BUN) and creatinine measurements are markedly elevated. However, there is no correlation between the severity of anemia and the severity of the renal disease.
• Urine, if present, may contain protein and RBCs.
• D-dimer and fibrinogen levels are usually within the reference range.
• The reticulocyte count should be elevated.
• Coombs test results are negative, indicating that the anemia is not immunologically mediated.
• A moderate leukocytosis may be present but rarely more than 20,000 per mL.
• Plasma contains free hemoglobin that can often be observed with the naked eye. The degree correlates with the severity of the anemia.
• Bone marrow reveals erythroid hyperplasia and increased megakaryocytes.
• Blood cultures are negative in E coli –mediated disease since only the shiga-like toxin is circulating in the blood while the organisms remain in the GI lumen.
• Stool cultures typically detect shiga toxin-producing E coli.

Imaging Studies

Imaging studies are not indicated for the diagnosis of hemolytic uremic syndrome unless a viscus perforation is suspected. At that point, plain films or CT will aid in the diagnosis.

Treatment

Emergency Department Care

ED care should focus on supportive management, correction of blood pressure elevation, blood transfusions, and if necessary, arrangement for prompt dialysis.

• Avoid unnecessary use of antibiotics or antimotility agents during diarrheal illness. The use of these agents has been shown to increase the incidence of hemolytic uremic syndrome (HUS) because as motility slows, the gut is exposed to the toxins for a longer period of time. Additionally, antibiotic-induced injury to the bacterial membrane favors the acute release of large amounts of toxins. Use of antibiotics has been shown to increase the risk of full-blown HUS by 17-fold, and thus, the recommendation is to avoid its use, except in cases of sepsis.
• Maintain fluid balance. In light of the diarrheal illness, fluid resuscitation is important, although one must avoid fluid overload. Watch for and treat hyperkalemia. If indicated, treat renal failure aggressively with hemodialysis.
• Treat hypertension with standard antihypertensive agents.
• Plasma exchange (plasmapheresis combined with fresh-frozen plasma replacement) is currently the treatment of choice. Plasma exchange is performed daily until remission is obtained. However, because 85% of children with hemolytic uremic syndrome recover after supportive therapy alone, plasma exchange is generally reserved for the most severe cases.

Consultations

Consult a hematologist and a nephrologist to help manage the case and an intensivist to admit the patient to an ICU setting, if necessary. In severe cases, consider consulting the renal transplant service if renal dysfunction persists.

Medication

Management consists of early dialysis for acute renal failure and general supportive care, including treatment of hypertension.

Refractory cases have been treated with vincristine or cyclosporine A. Steroids are of questionable benefit, as are antiplatelet agents such as aspirin or dipyridamole. Fibrinolytic therapy is not only ineffective but it also increases the risk of bleeding. Platelet transfusions can worsen the patient's status by inducing further organ damage.

Follow-up

Complications

Complications of hemolytic uremic syndrome include the following:

• Hypertension
• Chronic renal failure
• Neurologic dysfunction including seizures, coma, stroke, hemiparesis, and cortical blindness: Severe CNS involvement is associated with significant mortality.
• GI involvement, including any area from the esophagus to the anus: This can include hemorrhagic colitis, bowel necrosis/perforation, or intussusception.
• Cardiac dysfunction, possibly precipitated by uremia and fluid overload
• Complications involving the pancreas are seen in fewer than 10% of patients and can include glucose intolerance. Frank diabetes mellitus is rare.
• Liver complications including hepatomegaly and/or increased serum transaminases levels are not uncommon.
• In severe cases, death may be an inevitable outcome if the disease has progressed too far prior to presentation.

Prognosis

• The overall mortality rate of hemolytic uremic syndrome is 5-15%.
• For unknown reasons, younger children who present in the summer with the typical diarrheal prodrome tend to do better than older children who develop hemolytic uremic syndrome during the colder months of the year.
• Adults with hemolytic uremic syndrome generally have a poorer prognosis than children. In one study, 14% of adults with hemolytic uremic syndrome succumbed to the disease.
• With supportive care, approximately 85% of patients recover and regain normal renal function.
• Patients experiencing D- HUS have a poorer prognosis. 

Miscellaneous

Medicolegal Pitfalls

• Failure to suspect hemolytic uremic syndrome in a child with a recent diarrheal or upper respiratory illness who now presents with azotemia, fever, and hematologic abnormalities.
• Beware of exacerbating hypertension, especially when administering fluids or blood transfusions.

Special Concerns

• Hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP) has been associated with pregnancy. It usually resolves with delivery, although the fetal mortality rate can be high. A genetic predisposition for pregnancy-induced HUS/TTP is suspected. Make sure to distinguish this from the HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count).

Multimedia

Media file 1: 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.

References

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Keywords

hemolytic uremic syndrome, HUS, thrombotic microangiopathy, TMA, acute renal failure, microangiopathic hemolytic anemia, thrombocytopenia, diarrhea, Escherichia coli, E coli, upper respiratory infection, severe renal failure, Escherichia coli serotype O157:H7, Shigella species, Shigella dysenteriae, Salmonella species, Yersinia species, Campylobacter species, verotoxins, varicella, echovirus, coxsackievirus A, coxsackievirus B, Streptococcus pneumoniae, Clostridium difficile, AIDS, cancer, chemotherapeutic agents, mitomycin C, thrombotic thrombocytopenic purpura, TTP, acute diarrheal illness, toxic gastroenteritis, uremia, hypertensive encephalopathy, congestive heart failure, CHF, arrhythmias, pancreatitis, retinal hemorrhage, vitreous hemorrhage, hypertension, oliguria

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.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, William Shapiro, MD, to the development and writing of this article.

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