Factor H, autoimmunity and atypical Hemolytic Uremic Syndrome

The tone of the voice on the phone told me something was wrong. He calmly told me a family member had been taken to the ER the night before and was very sick. His calmness was deceitful. I had no idea someone so close to me may have been dying.

The diagnosis for the time being was Dengue Fever, although tests later would come up negative for the hemorrhagic disease that is similar to Ebola. The presence of symptoms made the diagnosis 'inconclusive'. It wasn't until, after a phone call to my family member about it several years afterward, I later sat up straight in bed at 11:00 at night with what my hubs called a 'House' moment.

What the doctors ignored at the time was the dose of quinine my family member had taken for spasms just hours prior to her admission to the hospital. What was unknown at the time was that my family carries a genetic marker that can create a problem with the complement system - part of our immune system - that can be involved in not only autoimmunity, but a rare syndrome called atypical hemolytic uremic syndrome (HUS) which causes all the mysterious symptoms she had which were stupefying her doctors. The trigger for this syndrome can be any of several things including specific medications... especially quinine.

The genetic anomaly is a defect in the complement factor H gene (CFH). I knew about this gene because genetic testing showed that I am homozygous for the defect - this means I have 2 copies of the defective gene. The gene is responsible for regulating how the complement system works, and a defect in it can mean either a hidden, or overtly obvious defective complement system. Either way, the genetic goof has an extremely high correlation with US as well as autoimmunity and the eye condition macular degeneration. The healthy gene tells the complement system (ie immune system) not to attack the body's own tissue (self). When the gene malfunctions, little or nothing is there to tell the immune system not to attack self, and a chronic inflammatory autoimmune condition results.

When a person with this defect takes the medicine (or any food or drink that contains) quinine, the body can create antibodies against the quinine which has attached itself onto cells. The immune system begins a vicious attack and those cells are destroyed. In my family member's case, this meant many of her organs began to fail starting with her kidneys, and she began to spontaneously bleed - - everywhere. Eyes, nose, mouth bled freely. Under the skin of most of her body was bleeding, turning into huge purple and red bruises. She looked like she'd been in a horrible car accident or beaten within an inch of her life. She vomited "cow pies" of blood, and urinated copious amounts of blood. The pain was so intense she screamed day and night for them to "put me out", until she was too exhausted to cry out anymore. She had neurological symptoms that continue today. Because they didn't know what was happening, the doctors didn't know how to treat it and essentially stood by, ordered tests and watched.

Thankfully, she slowly began to recover, although autoimmunity remains a challenge. They never had an official answer why she got sick with such unique and dangerous symptoms, and because Dengue Fever had been mentioned, she can no longer make her yearly pilgrimage to a tropical place each winter for fear of the disease. She never completely recovered, but she is better.

Had she tested positive for HUS or had it been recognized as such, she could have received treatment that would have shut down her complement system. Years ago, plasma therapy was used to replace the missing factor H. The drug Eculizumab is the suggested treatment at this time, for serious cases or those in
which simple withdrawal of an offending medication is insufficient or plasma therapy is not indicated. Red cell transfusions may have been useful to counter the anemia caused by the destruction of her blood cells and excessive bleeding.

Unfortunately, because testing for HUS didn't occur within a reasonable time of her disease, she will likely never have a concrete answer if that was the cause or not. Antibodies can stay in the bloodstream after the withdrawal of the offending drug for days, week, months... sometimes a year or two. The literature suggests a 're-challenge' of the medicine, but in her case this would likely prove fatal. It has been about 5 years since her illness. We do now know that she carries the genetic defect. When she asked her doctor about it, his answer was "Your family seems to have some strange and unique things going on."

I tell this story because, as autoimmune patients, we need to be aware that there are sometimes very dangerous things that can result from our condition that may be unexpected. Not everyone with autoimmunity is going to have the CFH defective gene or genes, but it is very likely that many do and are not aware of it. It is wise to be aware of HUS and factor H because eliminating triggers can help to prevent a recurrence. Quinine, for example, although no longer sold in the US as a drug, it is available and found in commercially sold foods and drinks. Tonic water is a known source of quinine and is often used by patients with nightly leg cramps. Other triggers for HUS include:

contraceptive pills and estrogens
varicella-zoster virus, strep or other virus
pregnancy and/or delivery
cancer
HIV
combined methylmalonic aciduria and homocystinuria (a vitamin B12 metabolism disorder)
organ transplantation
anti-platelet agents
infection (cold, flu, etc)
inflammatory disorders
medications

Anyone who is suspected of having an attack of aHUS should ask about testing for the most updated list of affected genes: CFH, CFI, MCP, C3, CFB. If results are negative, than a Factor H Immune study is next.


For additional reading:

What is the Complement system?
NEJM
Hemolysis and renal failure in a toddler
Gene Reviews
Oxford Journals