Typical HUS Ingestion of Shiga toxin-producing bacteria -producing
E. coli (STEC) is the organism most commonly responsible for HUS. Typical HUS is caused by ingestion of
bacteria that produce
Shiga toxins, with
Shiga toxin-producing Escherichia coli (STEC) being the most common type and
E. coli O157:H7 the most common
serotype. Once ingested, the bacteria move to the
intestines where they produce the Shiga toxins. The bacteria and toxins damage the mucosal lining of the intestines, and thus are able to gain entry into the circulation. Shiga toxin gains entry to the cell via Gb3 and
endocytosis, it then is transported to the
Golgi apparatus where
furin cleaves the A subunit of the Shiga toxin. One explanation for the greater prevalence of HUS in children and adolescents could be that children have more Gb3 receptors than adults which may be why children are more susceptible to HUS. Cattle, swine, deer, and other mammals do not have GB3 receptors, but can be asymptomatic carriers of Shiga toxin-producing bacteria. Some humans can also be asymptomatic carriers. Once the bacteria colonizes, diarrhea followed by bloody
diarrhea, hemorrhagic colitis, typically follows. Other serotypes of STEC also cause disease, including HUS, as occurred with
E. coli O104:H4, which triggered a 2011 epidemic of STEC-HUS in
Germany.
Thrombosis HUS is one of the
thrombotic microangiopathies, a category of disorders that includes STEC-HUS, aHUS, and
thrombotic thrombocytopenic purpura (TTP). The release of
cytokines and
chemokines (IL-6, IL-8, TNF-α, IL-1β) that are commonly released by Shiga toxin are implicated in
platelet activation and TTP. The presence of
schistocytes is a key finding that helps to diagnose HUS. Shiga toxin directly activates the
alternative complement pathway and also interferes with complement regulation by binding to complement
factor H, an inhibitor of the
complement system. Shiga toxin causes complement-mediated platelet, leukocyte, and endothelial cell activation, resulting in systemic hemolysis, inflammation and thrombosis. Severe clinical complications of TMA have been reported in patients from 2 weeks to more than 44 days after presentation with STEC-HUS, with improvements in clinical condition extending beyond this time frame, suggesting that complement activation persists beyond the acute clinical presentation and for at least 4 months.
Thrombocytopenia and kidney damage The consumption of
platelets as they adhere to the thrombi lodged in the small vessels typically leads to mild or moderate
thrombocytopenia with a platelet count of less than 60,000 per microliter. As in the related condition TTP, reduced blood flow through the narrowed blood vessels of the
microvasculature leads to reduced blood flow to vital organs, and
ischemia may develop. Grossly, the
kidneys may show patchy or diffuse
renal cortical necrosis.
Histologically, the
glomeruli show thickened and sometimes split capillary walls due largely to endothelial swelling. Large deposits of fibrin-related materials in the capillary lumens, subendothelially, and in the
mesangium are also found along with mesangiolysis. Interlobular and afferent arterioles show fibrinoid necrosis and intimal
hyperplasia and are often occluded by thrombi. Early signs of systemic complement-mediated TMA include
thrombocytopenia (platelet count below 150,000 or a decrease from baseline of at least 25%) Despite the use of supportive care, an estimated 33–40% of patients will die or have
end-stage renal disease (ESRD) with the first clinical manifestation of aHUS, and has not been proven effective in any controlled trials. People with aHUS and ESRD have also had to undergo lifelong dialysis, which has a 5-year survival rate of 34–38%. == Diagnosis ==