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Hemolytic-Uremic Syndrome (HUS)

By

David J. Kuter

, MD, DPhil, Harvard Medical School

Last full review/revision Jun 2020| Content last modified Jun 2020
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Hemolytic-uremic syndrome (HUS) is an acute, fulminant disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury. HUS usually occurs in children following an infection, typically with Shiga toxin–producing bacteria (eg, Escherichia coli O157:H7), but may also occur in adults. Diagnosis requires demonstrating characteristic laboratory test abnormalities, including direct antiglobulin test–negative hemolytic anemia. Treatment is supportive care (sometimes including hemodialysis); eculizumab or ravulizumab is rarely indicated.

Pathophysiology

Hemolytic-uremic syndrome, like thrombotic thrombocytopenic purpura (TTP), involves nonimmunologic platelet destruction. Endothelial damage is common. Loose strands of platelets and fibrin are deposited in multiple small vessels and damage passing platelets and red blood cells (RBCs), causing significant thrombocytopenia and anemia (microangiopathic hemolytic anemia). Platelets are also consumed within multiple small thrombi, contributing to the thrombocytopenia.

Multiple organs develop bland platelet–von Willebrand factor (VWF) thrombi localized primarily to arteriocapillary junctions, described as thrombotic microangiopathy. The brain, heart, and kidneys are particularly likely to be affected. The microthrombi do not include RBCs or fibrin (unlike thrombi in disseminated intravascular coagulation) and do not manifest the vessel wall granulocytic infiltration characteristic of vasculitis. Large-vessel thrombi are uncommon.

Etiology

Most cases occur in children and follow

  • Acute infection

Most often (about 90% of cases), the infection is acute hemorrhagic colitis resulting from Shiga toxin–producing bacteria (eg, Escherichia coli O157:H7, or some strains of Shigella dysenteriae). Occasionally the cause is pneumococcal infection and rarely HIV infection.

A small minority of cases are unrelated to infection and involve

  • Dysregulation of the complement system

Complement dysregulation is usually from a mutation in genes controlling complement proteins or factors but sometimes from acquired autoantibodies to certain complement factors. Congenital complement disorders may also increase the risk of hemolytic-uremic sydrome (HUS) following infection.

Symptoms and Signs

Children with Shigatoxin-related hemolytic-uremic sydrome (HUS) usually have a prodrome of vomiting, abdominal pain, and diarrhea (frequently bloody) and often a history of exposure to infection. Patients with pneumococcal-related HUS usually have manifestations of pneumonia, meningitis, or sepsis. Fever does not usually occur. About a week after the prodrome, manifestations of hemolytic anemia, thrombocytopenia and acute kidney injury develop. Complement-mediated HUS does not usually have an infectious prodrome.

Manifestations of ischemia develop with varying severity in multiple organs. Neurologic manifestations occur in about one quarter of patients and include weakness, confusion, and seizures. Kidney injury may produce hematuria, decreased urination or anuria, and/or hypertension. Despite thrombocytopenia, purpura and overt bleeding are uncommon although gastrointestinal tract ischemia may cause significant hemorrhagic colitis, with abdominal pain, nausea, vomiting, and bloody diarrhea. Cardiac involvement may cause arrhythmias.

Diagnosis

  • Complete blood count (CBC) with platelets, peripheral blood smear, direct antiglobulin (Coombs) test, LDH, PT, PTT, fibrinogen

  • Exclusion of other thrombocytopenic disorders

Hemolytic-uremic syndrome is suspected in patients with suggestive symptoms, thrombocytopenia, microangiopathic anemia and signs of acute kidney injury. If the disorder is suspected, urinalysis, peripheral blood smear, reticulocyte count, serum lactic dehydrogenase (LDH), renal function tests, serum bilirubin (direct and indirect), and direct antiglobulin test are done. ADAMTS13 enzyme activity levels may be helpful. This enzyme is a plasma protease that cleaves von Willebrand factor; deficiency causes thrombotic thrombocytopenic purpura (TTP) and decreased ADAMTS13 activity levels may help identify atypical cases of TTP.

The diagnosis is suggested by

  • Thrombocytopenia and anemia

  • Fragmented red blood cells on the blood smear indicative of microangiopathic hemolysis (schistocytes: helmet cells, triangular RBCs, distorted-appearing RBCs)

  • Evidence of hemolysis (falling hemoglobin level, polychromasia, elevated reticulocyte count, elevated serum LDH and bilirubin, reduced haptoglobin)

  • Negative direct antiglobulin test

  • Normal ADAMTS13 activity

Diagnosis of cause

Stool testing (Shiga toxin enzyme-linked immunosorbent assay or specific culture media for E. coli O157:H7) is done in children with diarrhea and also adults who had a prodrome of bloody diarrhea; however, the organism and toxin may have cleared by the time of presentation.

In atypical cases, ie patients who have not had preceding infection or who have recurrent disease, testing for complement factor gene mutations is recommended

Treatment

  • Supportive care, often including hemodialysis

  • For cases involving complement dysregulation, sometimes eculizumab or ravulizumab

Typical diarrhea-associated hemolytic-uremic syndrome in children caused by enterohemorrhagic infection usually spontaneously remits and is treated with supportive care; antibiotics are not used. Over half of patients require renal dialysis. Unlike with thrombotic thrombocytopenic purpura, plasma exchange and corticosteroids are not used.

In patients with HUS caused by complement dysregulation, complement inhibition with eculizumab or ravulizumab can sometimes reverse the kidney failure. Children with known or presumed hereditary deficiency in complement regulatory proteins such as factor H are particularly likely to respond to eculizumab or ravulizumab.

Key Points

  • Platelets and RBCs are destroyed nonimmunologically, leading to thrombocytopenia and anemia; renal failure is common in children and adults with hemolytic-uremic syndrome (HUS).

  • Cause in children is typically hemorrhagic colitis resulting from Shiga toxin–producing bacteria.

  • Less common causes involve complement dysregulation from a variety of inherited and acquired causes

  • Typical diarrhea-associated hemolytic-uremic syndrome in children usually spontaneously remits with supportive care, although over half of affected children require renal dialysis.

  • Complement-mediated HUS may respond to complement inhibition using eculizumab or ravulizumab.

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