Approach
Historical and examination factors in HUS differ according to type.
Initial investigations
In all patients with suspected HUS, investigations that help establish the diagnosis include complete blood count (CBC), peripheral smear, creatinine, prothrombin time (PT), partial thromboplastin time (PTT), and lactate dehydrogenase (LDH). These should be done as part of the initial evaluation. The presence of significant numbers of red cell fragments on peripheral smear establishes the diagnosis of a thrombotic microangiopathy.
Haptoglobin may also be tested.
Stool culture and stool polymerase chain reaction (PCR)
Most children will have a history of bloody diarrhea, but diarrhea may not be reported in some cases.
In all children a stool culture should be done early in the course of presentation, as delayed collection may show a negative culture result.[29] In children who no longer have diarrhea, a rectal swab can be performed for stool culture and Shiga toxin assay.[30]
PCR assay can detect Shiga toxin 1 and Shiga toxin 2 genes from stool samples and is associated with faster turnaround of results.
Determining the cause
Diagnosing and distinguishing between the various causes of thrombotic microangiopathy is complex.[31]
Hematologic consultation is advised if a patient is suspected to have atypical HUS (aHUS); evaluation of the alternative complement regulatory pathway should be considered in these patients.
Alternative diagnoses that need to be excluded are thrombotic thrombocytopenic purpura (TTP), malignant hypertension, systemic vasculitis, and, in pregnant patients, preeclampsia and HELLP (hemolysis, elevated liver enzyme levels, and a low platelet count) syndrome.[32] An ADAMTS 13 level is useful in distinguishing TTP (more consistently low level in TTP) from HUS.
Further factors in diagnosis depend on the type of HUS.
Evaluation of STEC HUS
Infection with Shiga toxin-producing Escherichia coli (STEC) should be suspected in patients who present with abdominal pain and bloody diarrhea, especially during summer months.[33] The disease is most common in children <5 years of age but can be seen at any age.[7] There may be a known community outbreak of toxicogenic E coli at the time of diagnosis. A history of ingestion of undercooked ground beef, cheese, poultry, vegetables, or water that have been contaminated with E coli is sometimes found.[18]
A CBC, peripheral smear, electrolytes (sodium, potassium, chloride), bicarbonate level, blood urea nitrogen and creatinine, LDH, PT, and PTT should be done as part of initial evaluation. A haptoglobin test is typically low in the setting of hemolysis.
A stool culture, and Shiga toxin assay if possible, should be performed early in the diarrheal illness to detect E coli.[29] Once STEC HUS is confirmed, additional tests including liver function tests, amylase, lipase, and serum glucose, should be performed to evaluate hepatic and pancreatic involvement. Patients with severe abdominal pain may need abdominal imaging such as abdominal and/or KUB (kidneys, ureters, bladder) ultrasound or CT, to look for toxic megacolon, ischemic/necrotic bowel, or bowel perforation.
In patients with central nervous system involvement, head imaging (computed tomography [CT] or magnetic resonance imaging [MRI]) is warranted to look for stroke, abscess, or hemorrhage.
Evaluation of secondary and atypical HUS
Evaluation of patients who present without diarrhea but with anemia, thrombocytopenia, and an elevated creatinine should include an early review of the peripheral blood smear. Historical factors, which may be elicited in secondary HUS, include treatment with cyclosporine, chemotherapy, quinine, and bone marrow transplant; current pregnancy or postpartum status; and a family history of HUS-like syndrome. In sporadic HUS, the inciting factor is not known.
PT and PTT are useful in ruling out other causes of thrombocytopenia, such as disseminated intravascular coagulation.
Tests are available to assess alternative complement pathway abnormalities. Testing for C3, C4, factor H, factor H autoantibody, factor I, factor B, ADAMTS13 activity, membrane attack complex levels, and CH50 can be performed. Genetic testing of complement pathway abnormalities can also be considered.
Evaluation of familial HUS
For patients with a history suggestive of a familial syndrome, abnormalities of the alternative complement regulatory pathway should be suspected. Evaluation should be done as described under sporadic HUS, but in addition, an assessment of the proteins involved in complement regulation should be performed. Evaluation will often require the services of a laboratory specializing in the complement system.[6][15] Some experts have suggested that adult patients who present with a thrombotic microangiopathy but do not have a known secondary cause and who have normal ADAMTS13 levels should be considered to have atypical HUS.[34]
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