Contributor Disclosures. Please read the Disclaimer at the end of this page. This discovery has had a major impact on identifying the underlying cause of familial HUS, and on the management of these patients, who historically have had a poor prognosis.
The clinical manifestation, diagnosis, and management of complement-mediated HUS will be reviewed here. Complement-mediated thrombotic microangiopathy is also discussed elsewhere. Thrombotic microangiopathy describes a specific pathologic lesion teakbrunt hus which abnormalities in the vessel wall of arterioles and capillaries lead to microvascular thrombosis.
The former, also referred to as typical HUS, primarily resulted from Shiga toxin-producing Escherichia coli STEC infections, and less frequently from Shigella dysenteriae type 1 infection. However, ongoing research has provided a better understanding of the underlying causes of HUS, especially those due to genetic mutations in the alternative pathway of complement [ 2,3 ].
As a result, the following classification has been developed based on pathophysiological considerations and triggering factors [ 4 ]:. Most complement-mediated HUS cases are due to gene mutations of complement factors [ ].
Antibodies to complement proteins have been implicated in the etiology of 6 to 10 percent of patients with complement-mediated HUS [ 10 ]. In addition, patients may have concurrent genetic mutations and antibodies to complement proteins [ 11 ]. Genetic complement disorders — Variants in the following identified genes that encode complement proteins appear to account for at least 50 to 60 percent of non-Shiga toxin-producing E.
It is likely that the percent of noninfectious HUS cases due to a complement disorder will rise with ongoing research identifying new gene variants. In addition, a significant number of patients with complement-mediated HUS have variants of more than one complement protein [ 2,7,10,16 ].
It is important to stress that the penetrance of the disease is low, as less than 20 percent of family members carrying the same variant as the patient with complement-mediated HUS will be affected with the disease [ 17 ]. The risk is higher in the siblings and the offspring of patients than in parents.
Therefore, genetic counselling in aHUS requires the input of trained geneticists and experts who have a comprehensive view of complement biology [ 18 ]. See 'Factor H' below. The proposed mechanism for the development of HUS is a trigger event, such as infection or pregnancy, in a susceptible individual with a gene variant s or antibodies to complement proteins, which leads to uninhibited continuous activation of the alternative pathway resulting in the formation of the membrane attack complex MAC [ 2,12,19 ].
This causes renal endothelium damage leading to activation of the coagulations cascade and thrombotic microangiopathy. See "Complement pathways", section on 'Alternative pathway'. Data from an animal study suggest that C5 activation is important in Boende och Hem pathogenesis of HUS, thus supporting the use of eculizumaba humanized monoclonal antibody to C5 [ 20 ].
See 'Complement blockade eculizumab ' below. Gastrointestinal symptoms diarrhea and vomiting are common as well as relapses, which typically occur within the first two years after initial presentation [ 21,29 ]. These findings suggest that in some patients, multiple "hits" to the complement system may be necessary for the clinical presentation of complement-mediated HUS [ 25,32 ].