What are the other Names for this Condition? (Also known as/Synonyms)

• aHUS (Atypical Hemolytic-Uremic Syndrome)
• Complement Dysregulation-Associated aHUS
• Non-Shiga-Like Toxin-Associated Hemolytic-Uremic Syndrome

What is Atypical Hemolytic-Uremic Syndrome? (Definition/Background Information)

• Atypical Hemolytic-Uremic Syndrome (aHUS) is a very rare, life-threatening disorder that is caused by the abnormal activation of complement system. The complement system is part of the immune system that protects the body from infectious organisms
• aHUS is a chronic condition that may affect any individual at any age. The main feature of this condition is the formation of blood clots in the small blood vessels, which is known as systemic thrombotic microangiopathy (or TMA). Any organ may be affected, but the commonly affected organs include the brain, heart, kidney, and gastrointestinal tract
• Atypical Hemolytic-Uremic Syndrome has 3 major features:
  • Hemolytic anemia
  • Decreased platelets (thrombocytopenia)
  • Kidney failure
• Abnormal activation of the complement system in aHUS could be triggered by chemotherapy, infections (bacterial, viral), major transplant surgery, and even pregnancy
• A combination of environmental and genetic factors is reported to cause Atypical Hemolytic-Uremic Syndrome. Mutations in the genes involved in the normal functioning of the complement system are reported to be the cause of aHUS. However, Idiopathic Atypical Hemolytic-Uremic Syndrome could occur even without genetic mutations in an individual, due to unknown cause(s)
• The symptoms of Atypical Hemolytic-Uremic Syndrome could include abdominal pain, low urine output, jaundice, weakness, and abnormal bleeding. The diagnosis of aHUS may involve several tests of the blood, urine, genetic tests, tests for Escherichia coli to eliminate Hemolytic-Uremic Syndrome or HUS (which is caused by the bacterium), etc.
• If left untreated, many complications could arise as a result of aHUS. These might include acute kidney failure, end-stage kidney disease, liver malfunction (leading to jaundice), clot formation leading to damage to the heart (heart attack) and brain (stroke)
• Lifelong treatment and therapy may be required to manage Atypical Hemolytic-Uremic Syndrome, which may involve dialysis, plasma exchange and even a kidney transplant, if necessary
• The prognosis of Atypical Hemolytic-Uremic Syndrome depends upon several factors, the extent of organ damage (particularly kidney damage), and the health status of the individual. Nevertheless, despite intensive and timely treatment, the long-range prognosis of aHUS is unpredictable

Who gets Atypical Hemolytic-Uremic Syndrome? (Age and Sex Distribution)

• Atypical Hemolytic-Uremic Syndrome is a very rare disorder with an estimated incidence of 1: 300,000-500,000 population worldwide
• The condition may affect a wide age range including children and adults. There is no gender preference reported for the occurrence of aHUS
• All racial and ethnic groups are at risk

What are the Risk Factors for Atypical Hemolytic-Uremic Syndrome? (Predisposing Factors)

Atypical Hemolytic-Uremic Syndrome is believed to be influenced by a combination of factors, which may be both genetic and environmental. The following factors may trigger the abnormal activation of the complement system, leading to an individual’s risk of developing aHUS:

• Chemotherapy medications
• Viral and bacterial infections, such as upper respiratory tract or gastrointestinal tract infections
• Major organ transplant such as the liver, kidney, heart, and bone marrow
• Pregnancy and postpartum period

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Atypical Hemolytic-Uremic Syndrome? (Etiology)

Atypical Hemolytic-Uremic Syndrome is caused by mutations in genes that help in normal functioning of complement system. The disorder may be acquired or inherited.

• The abnormal proteins caused by the mutations cause unnecessary activation of the complement system. This activation causes blood clots, which decreases blood supply to vital organs
• Some individuals can be affected by aHUS, even if they do not possess the genetic mutations; this condition is known as Idiopathic Atypical Hemolytic-Uremic Syndrome
• It has been observed that only 20% of the individuals have a family history of aHUS, while nearly 50% are sporadic type (random occurrence) with no family history
• If there is a positive family history, then the condition may be inherited in an autosomal dominant or autosomal recessive manner

Autosomal dominant: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly functioning gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring. 

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children, born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Atypical Hemolytic-Uremic Syndrome?

The signs and symptoms of Atypical Hemolytic-Uremic Syndrome depend upon the organ systems affected. They may include:

• Anemia, causing tiredness, muscle weakness, and fatigue
• Low platelets in blood, which could lead to uncontrolled and abnormal bleeding
• Liver dysfunction, potentially resulting in jaundice with pale and yellow skin
• Kidney dysfunction, causing symptoms of kidney failure, such as decreased urination, abdominal pain, confusion, etc.

How is Atypical Hemolytic-Uremic Syndrome Diagnosed?

A combination of diagnostic tests and correlation with the clinical signs and symptoms may be necessary to ensure an accurate diagnosis of Atypical Hemolytic-Uremic Syndrome. The diagnostic tests performed for aHUS may include:

• Complete physical examination with evaluation of medical history (including family history)
• Testing of blood samples
• Urine test to detect blood and protein in urine samples
• Test for E. coli to rule out typical HUS
• Genetic testing and analysis
• Prenatal exams include amniocentesis and chorionic villus sampling to detect aHUS mutations
• A differential diagnosis may be considered to eliminate similar conditions

What are the possible Complications of Atypical Hemolytic-Uremic Syndrome?

Complications arising from Atypical Hemolytic-Uremic Syndrome may include:

• Acute renal failure
• End-stage renal disease
• Damage to the heart, brain, and liver
  • If blood clots reach the coronary artery, it could result in a heart attack
  • If blood clots affect the brain, it could result in a stroke
• Hypertension
• Thrombotic microangiopathy; serious damage of blood vessels due to formation of blood clots
• Blood disorders: Reduction of blood platelets, destruction of RBCs

How is Atypical Hemolytic-Uremic Syndrome Treated?

An early diagnosis and appropriate prompt and intensive treatment are keys to reducing mortality rates from Atypical Hemolytic-Uremic Syndrome. Often, an individualized treatment plan is required which could include:

• Dialysis
• Plasma therapy, plasma exchange
• Renal transplantation; sometimes a combined liver-kidney transplant is resorted to
• Use of complement inhibitors
• Eculizumab drug, which was approved by the US FDA for the treatment of aHUS in 2011

How can Atypical Hemolytic-Uremic Syndrome be Prevented?

• Atypical Hemolytic-Uremic Syndrome is a serious medical disorder caused by genetic and non-genetic factors in an individual. Thus far, no preventive measures have been reported for aHUS
• When planning for a child, genetic counseling and genetic testing could help individuals having a family history of the condition in making appropriate decisions

What is the Prognosis of Atypical Hemolytic-Uremic Syndrome? (Outcomes/ Resolutions)

• With timely, aggressive and active treatment, Atypical Hemolytic-Uremic Syndrome could be effectively managed and controlled, to some extent. A lifelong management of the condition is required
• Without treatment, aHUS is a fatal condition and the prognosis is poor. The overall death rate from aHUS is around 45% in children and 65% in adults
• Individuals may be continuously affected with kidney-related disorders, such as end-stage renal disease and abnormal kidney function, necessitating dialysis for long durations (often many years)
• In many cases, kidney transplants may become a necessity. However, due to systemic thrombotic microangiopathy, there remains a possibility of failure in 90% of the transplants

Additional and Relevant Useful Information for Atypical Hemolytic-Uremic Syndrome:

• Atypical Hemolytic-Uremic Syndrome should not be confused with ‘typical hemolytic-uremic syndrome‘. Typical HUS is caused by E. coli bacterium infection that produces shiga-like toxins. This condition usually affects children less than 10 years old. The most common symptom of typical HUS is severe diarrhea
• Additionally, aHUS is also known as Non-Shiga-Like Toxin-Associated Hemolytic-Uremic Syndrome
• aHUS is termed as an ‘ultra rare’ condition in the United States