Atypical hemolytic uremic syndrome, or aHUS, is a rare disease that is caused by the abnormal activity of part of the immune system known as the complement cascade.
Such abnormal complement activation leads to increased inflammation and blood clotting in small blood vessels, particularly those in the kidneys. Over time, these small blood vessels can become clogged, leading to kidney damage and, eventually, kidney failure.
Most people with aHUS have inherited mutations in the genes that regulate the function of the complement cascade. However, these inherited mutations do not fully guarantee that a person will develop aHUS. Usually, a trigger event is also necessary. In some cases, aHUS can develop in the absence of any known disease-causing mutation.
How can mutations predispose toward aHUS?
The complement cascade, also known as the complement system, or sometimes just as “complement,” comprises a group of more than 30 proteins found in the blood and other body fluids. Normally, these proteins remain in an inactivated state, but when there is an inflammatory stimulus, such as a disease-causing bacteria or virus, the complement proteins become activated.
Complement activation occurs via a series of sequential events, sort of like a series of dominoes falling down: one activated complement protein activates the next, which in turn activates the next in the signaling cascade. The end result is the activation of a series of proteins with powerful pro-inflammatory and blood clotting activity, which can help fight disease-causing invaders.
Because these proteins are so potent, their activation is tightly regulated by the body to prevent erroneous activation that can damage healthy tissues. Several genes are involved in this regulation. Yet, mutations in these genes can make them less effective at preventing complement activation, which in turn can predispose a person to develop aHUS.
Specific genes whose mutations have been implicated in aHUS include C3, CD46 (MCP), CFB, CFH, CFHR1, CFHR3, CFHR4, CFI, DGKE, and THBD.
Inheritance of aHUS-predisposing mutations
For each of these implicated genes, like most genes, a person inherits two copies — one from each biological parent. Depending on the specific gene and type of mutation, aHUS-predisposing mutations can be inherited either in an autosomal dominant or in an autosomal recessive manner.
Autosomal dominant inheritance means that a person only needs one gene copy to be mutated to develop the disease. In contrast, in autosomal recessive inheritance, both copies of the gene must be mutated in order for the disease to develop.
What can trigger aHUS?
Simply having a mutation, or more than one, that can predispose a person toward developing aHUS does not guarantee that an individual will develop the disease. Typically, a trigger event is necessary.
Generally, anything that can activate the immune system — and, in particular, the complement cascade — can act as a trigger for developing aHUS.
Infections are a common trigger, and many different types of viral, bacterial, fungal, and parasitic infections have been reported to lead to the onset of aHUS. Infections of the upper respiratory system and the digestive system are particularly common disease triggers.
Autoimmune diseases — conditions in which the body’s immune system erroneously attacks healthy tissues — and some types of cancer also can act as triggers for aHUS. Organ and bone marrow transplants also may lead to its onset.
Some kinds of medications also can trigger aHUS, including some immune-modulating medicines — for example, interferon-alpha and -beta — oral contraceptives, and cancer treatments such as cisplatin, mitomycin, and gemcitabine. Recreational drugs, such as cocaine, heroin, and ecstasy, also can be a disease trigger.
Another common trigger for aHUS is pregnancy. Statistics indicate that about one in five women with aHUS will experience disease symptoms during pregnancy.
Does everyone with aHUS have a disease-predisposing mutation?
About 60% of people with aHUS have a disease-predisposing mutation, while the remaining 40% do not.
Sometimes, aHUS can be caused by autoantibodies, or self-targeting antibodies, that block the activity of complement-regulating proteins, ultimately resulting in uncontrolled complement activation.
In other cases, aHUS can be idiopathic, meaning that it has no clear cause.
What is “atypical” about aHUS?
aHUS is specifically characterized by the dysregulation or impairment of the complement pathway. It is called “atypical” in order to differentiate it from other types of hemolytic uremic syndrome (HUS), which have similar symptoms, but different biological causes.
In “typical” HUS, the disease is caused by E. coli bacteria that produce a toxic protein called Shiga toxin. Typical aHUS accounts for more than 90% of HUS cases. Importantly, because it is caused by an infection, typical HUS is often acute in the short term, but responds well to treatment in the long run. In contrast, aHUS is more likely to be chronic and cause long-term health problems.
HUS also can develop as a result of another disease, or due to the use of certain medications, in which case it is deemed as “secondary” HUS. Although it can be difficult to differentiate between aHUS and secondary HUS, the secondary type is not characterized by complement dysregulation.
Last updated: April 13, 2021
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