The findings highlight the need for genetic testing to diagnose aHUS in complex cases, the researchers said.
The case report, “Atypical Hemolytic Uremic Syndrome (p.Gly1110Ala) with Autoimmune Disease,” was published in the American Journal of Case Reports.
aHUS is characterized by mutations in the complement system, a group of blood proteins that is important for fighting off disease. The presence of mutations is what distinguishes aHUS from typical HUS — which is caused by a bacterial infection — and secondary HUS, which develops as a consequence of autoimmune diseases or organ transplants.
The study describes a 49-year-old woman who was admitted to a hospital in South Korea due to low hemoglobin levels and high levels of bilirubin, which is an indicator of red blood cell damage. The patient also had decreased kidney function. Her symptoms included shortness of breath and swelling in the feet, which had started five days before her medical exam.
The woman had no history of hypertension or diabetes mellitus, but had tested positive for antinuclear antibodies, a type of autoantibody — those attacking the body’s own tissues — found in people with scleroderma.
The initial treatment, for suspected rheumatoid arthritis, another autoimmune disease, was successful in easing such symptoms as finger swelling and intermittent Raynaud’s phenomenon, a condition in which the fingers and toes feel numb, prickly, and frigid in response to cold temperatures or stress.
Her lab test results, combined with elevated blood pressure and the reduced kidney function, suggested that she might have scleroderma renal crisis (SRC) as a result of systemic sclerosis sine scleroderma. People with this rare condition have systemic scleroderma and its typical scarring in their internal organs, but do not have the hallmark skin thickening. Conversely, SRC involves sudden blood pressure increases and acute kidney failure.
“Because of the clinical overlap with aHUS, SRC is suggested as a cause of HUS,” the researchers wrote.
To ensure diagnostic accuracy, the patient also underwent genetic testing. This revealed a new mutation, known as p.Gly1110Ala — a substitution of the amino acid alanine for the amino acid glycine at position 1110 — in the gene coding for the protein complement factor H (CFH).
CFH is a regulator of the complement system, that is, it normally limits the activity of the complement system to protect healthy cells. Mutations in the CFH gene are a well-known cause of aHUS. According to the investigators, the p.Gly1110Ala mutation is expected to result in aHUS.
The fact that aHUS only manifested at age 49 and that the patient had a mutation deemed to induce the disease may support the “two-hit” hypothesis of aHUS development. The gist of this hypothesis is that having a complement-associated mutation — the first “hit” — may not be sufficient to cause the condition. A second “hit” is thereby necessary for clinical signs or symptoms of the disease, which in this case would be renal crisis from systemic sclerosis sine scleroderma.
The woman was treated with CellCept (mycophenolate mofetil), which resolved the ongoing low levels of platelets and red blood cell destruction within two months. However, the woman’s organ damage persisted. As of the study’s completion date, she was receiving regular hemodialysis.
Notably, treatment with Soliris (eculizumab), a therapy that binds to complement protein C5, was not used because the woman had a genetic variation in the C5 gene. That variation was expected to reduce the treatment’s efficacy.
“As illustrated by this case report, the pathogenesis [disease processes] of aHUS is complex, and various etiologies [causes] can coexist in a single patient,” the team concluded.
“When dealing with HUS, it is recommended to check the complement gene mutations, despite pre-existing complement-amplifying conditions like systemic sclerosis sine scleroderma, in the era of compliment-inhibiting therapy, which can improve the outcome and survival of patients,” they said.
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