Dr Liji Thomas, MD
Diagnosis of Typical Hemolytic Uremic Syndrome (HUS)
Hemolytic uremic syndrome (HUS) usually occurs in children following an episode of diarrheal infection caused by STEC strain O157:H7, and occasionally following infection with Shigella dysenterieae or neuraminidase-producing Streptococcus pneumoniae. This is also called typical HUS. Diagnosis of this condition depends upon the clinical features and laboratory evidence of the pathognomonic blood changes.
There is a typical prodromal diarrheal episode. There are no specific signs in the gastroenteritis phase to identify patients who may be at high risk for HUS, but the features to watch for may include:
- Diarrhea (whether bloody or not)
- Abdominal cramps
- Nausea and vomiting
- Rectal prolapse associated with hemorrhagic colitis
The earliest signs of HUS include those of acute renal failure:
Associated complications may be manifested, including CNS complications such as jitteriness, seizures and disorientation.
Laboratory investigations are far more specific, and include:
- Full blood count which shows hemolysis in the form of fragmentation of erythrocytes, seen within a day of acquiring the infection.
- Anemia of the microangiopathic hemolytic type, with a mean hemoglobin concentration of 6g/dL.
- Thrombocytopenia is seen in over 90% of patients with HUS due to platelet sequestration in various end-organ vascular beds, with a count below 50 000/mm3.
- Clotting times are unchanged.
- Leukocytosis is present.
- Reticulocyte count may be increased.
- CRP levels are high.
- Coomb’s test is negative.
- Presence of hematuria on urine analysis. Proteinuria may also be present.
- Acute renal failure shown by renal function tests showing azotemia, as the result of obstruction of renal blood flow by microthrombi in the renal parenchyma.
- Stool cultures should be taken for STEC even though the patient may not be shedding the microbes after the first six days of infection. This will confirm the etiologic diagnosis, which is of public health importance. Stool testing for Shiga toxin is more rapid and reliable.
Diagnosis of Atypical HUS
In the remaining cases, there is no history of diarrhea, and stool cultures as well as Shiga toxin testing are negative. These are called atypical HUS.
Investigations of these patients are similar to the above. However there are certain additional risk factors whose presence needs to be looked for - these are mostly associated with alternative complement pathway dysregulation. One or more of these factors will be detected in approximately 60% of cases. These include:
- Mutations in:
- Complement factor H (CFH)
- Membrane cofactor protein
- Complement factor I
- Complement C3
- Complement factor B (thrombomodulin)
- CFH-related gene 1
- Factor H autoantibodies
In other forms of atypical HUS, the alternative complement pathway is not affected.
Laboratory tests to distinguish between these two categories include:
- Assay of the classical and alternative complement pathway activity
- Measurement of various complement factors C3, C4, H, B and I
- Measurement of anti-CFH IgG autoantibodies
- Assay of ADAMTS 13 activity
- Tests for mutations in the complement-related genes listed above
- Mutation testing of diacyl-glycerol kinase epsilon which is important in the non-complement mediated type of atypical HUS
It is important to distinguish complement-mediated forms of atypical HUS from the second category because only the first type is likely to respond to the administration of the humanized monoclonal anti-complement antibody, eculizumab. The second type should be treated with plasma exchange transfusions first, unless the patient is a child below the age of 2 years. In this subgroup, eculizumab may be the first option due to the general non-feasibility of plasma exchange in such small children.