Hemolytic-uremic syndrome

Definition

Hemolytic-uremic syndrome (HUS) is a syndrome defined by the presence of acute hemolytic anemia (low red blood cell count caused by the break up of red cells within the blood stream by a person's own immune system), thrombocytopenia (a low number of platelets), and kidney failure. Having these three symptoms all at once can be caused by a number of problems—some by infections, others by genes, and some are still unknown.

Description

About 90% of HUS cases occur in children less than five years of age. In most cases, there is an early phase of diarrhea, followed by the lowered blood counts and the renal failure . Most patients get better after HUS, a few die during the worst stage of the illness, others go on to have life-long kidney disease, and some will progress to having a form of HUS that comes and goes over the rest of their lives. Which patients will have which outcome is not known during the illness.

Many infectious organisms have been thought to play a role as things that may cause HUS outbreaks, such as one E. coli serotype and one Shigella dysenteriae serotype. About 40% of patients who ingest E. coli 0157:H7 (the implicated serotype) will go on to get some form of diarrhea. Of those that develop diarrhea, about 5% will progress to some form of HUS (ranging in strength from mild to fatal). The bacteria linked to HUS have been shown to produce a toxin that gets released into the bloodstream after the organisms invade the colon's mucosal lining. The toxin, once inside of cells, disrupts protein synthesis. The spreading of organisms that make toxins tends to occur through food products.

Many outbreaks of HUS in the United States have occurred over the last several decades. These outbreaks have been linked to various food sources such as hamburger meat that is not cooked enough, apple juice and apple cider that has not been pasteurized, water, fruits, vegetables, and unpasteurized milk. Hamburger meat is the most common way that E. coli spreads. This bacteria is part of the normal flora of cow intestines and it is thought that it gets into the meat during the process of killing and cutting up the cow. When this beef is then not cooked enough to kill the organism, it is able to travel into the human GI (gastro-intestinal) system with ease. The spreading of this disease can also occur with person-to-person contact through a fecal-oral route. Support for this theory includes data from daycare centers that had outbreaks of HUS.

About 10% of cases in children and 50% of cases in adults will be a type of HUS that occurs without diarrhea. Of these cases, some can be linked with other infections, but other cases have no clear cause. Out of these unclear cases, some will be a form of HUS that runs in families. There have been many research studies into families that have many members who have a form of HUS that keeps coming back over the patient's lifetime. Genetic tests of these families have found what may be a gene that can cause some cases of HUS.

Patients with HUS all show signs of making thrombi (blood clots) in small vessels. These thrombi form in kidney blood vessels as well as small arteries all over the body. Thus, clots can cause infarcts (starvation and death) of kidney tissue, brain tissue, the bowel, and other organs.

Genetic profile

While most families that have a form of HUS that passes on the disease in an autosomal recessive pathway, there have been some families with signs of autosomal dominant transmission. Genetic tests have found that a region on chromosome 1q can play a role in the forms of HUS that run in families. The gene for factor H (a protein regulator of the alternate complement pathway) is the leading gene candidate. Molecular proof linking factor H to cases of HUS that occur without diarrhea was first produced in 1998. Since then, screening of patients and families of patients with HUS not linked to a preceding episode of diarrhea have found a subset of patients who have mutated copies of the factor H gene.

Tests that look at different families with an inherited form of HUS have shown that there are many different point mutations within the factor H gene. All of these mutations led to some reduced level of factor H. With this lower level, many researchers have noticed that patients also have reduced levels of a protein called C3. This protein is part of the complement cascade that is supposed to attack bacteria within the body. Patients with low levels of C3 may be at more risk of having very bad problems arise from infections than patients with normal immune systems. Also, the familial form of HUS is most likely a multifactorial disease (i.e. no one gene mutation causes it by itself) that occurs in certain patients who are predisposed to the disorder.

Demographics

The largest number of cases occur in children between the ages of six months and five years of age. The mean age of children who get HUS is four. Within the United States, this disease most often occurs in epidemics, versus an endemic form that is found in other parts of the world. For example, Argentina has a much higher incidence of HUS than America. Interestingly, the rate of E. coli that make the oxins that cause infections is higher in Argentina.

Signs and symptoms

The clinical history most often seen in patients with HUS is of a diarrheal illness that comes before the anemia and renal disease by five to seven days. Some children have symptoms other than diarrhea. These include belly pain, nausea, and throwing up.

When HUS occurs, patients can have many different types of symptoms. Patients tend to have pallor (pale skin), decreased urine output, and fatigue. Even though they tend to have low platelet (the cells that cause blood to clot) counts, they seldom have too much bleeding. About one quarter of patients will have neurologic signs and symptoms that present as seizures, drowsiness, coma, and personality changes. Most of the patients that have HUS with diarrhea will also have hypertension (high blood pressure) that occurs with it. Almost one fifth of patients with HUS will also have some form of pancreatic problems that can lead to the body not making enough insulin and causing diabetes. In some cases, the diabetes may last for the rest of the patient's life.

Kidney problems vary from patient to patient in how severe they may be. Some patients only have lower urine output, but others progress to full kidney failure. In some patients who develop HUS without diarrhea, the onset of renal failure will be more subtle such that they will present with symptoms of volume overload (too much retained fluid).

Diagnosis

The diagnosis of HUS should be considered in patients who present with symptoms of anemia or renal failure who either give a history of diarrhea before it or have certain problems that show up in their lab tests. Patients will always have low red blood cell counts (anemia) with signs of the ongoing break down of red blood cells. On peripheral smear (blood looked at through a microscope), Burr cells can be seen. These are red blood cells with bumps sticking out of the surface of the cell. Also schistocytes (pieces of red blood cells that have been destroyed) can be seen under the microscope which provide clues of the ongoing break down of red blood cells (hemolysis).

Diagnosis of familial HUS will depend on the presence of many cases within one family that are not linked to an outside epidemic. Often, the cases will occur over a stretch of many years. As of yet, there is no genetic or lab test that can tell which people will get familial HUS. Prenatal testing is not yet available either.

Treatment and management

There is no certain treatment for patients with HUS other than supportive care. Many types of treatments have been tried in attempts to reduce the amount of clotting that occurs in small vessels, but with little or no success. Antibiotic treatment for children with diarrhea caused by E. coli tended to raise, instead of lower, the rate of transformation into HUS. Thus, antibiotics tend to not be used for children with diarrhea. They are of little benefit and may be harmful. Treatment of diarrhea in children should consist of supportive care with ample fluids in order to prevent dehydration.

Careful notice must be paid to fluid intake. It is very easy for kidney failure patients to build up too much volume and have problems with their electrolyte levels. Patients with really low red blood cell counts can be given blood transfusions. Those who get severe renal failure may need dialysis treatment to rid their blood of toxins that would have been cleared by the kidneys. These treatments apply to all forms of HUS including HUS with diarrhea, HUS without diarrhea, and familial HUS. In some patients with recurring familial disease, kidney transplants have been tried, but the disease did recur in many patients.

Prognosis

About 10% of children will die during the acute phase of the illness or will be left with chronic renal or brain damage. Most of the deaths during the acute phase occur in children where organs other than the kidneys are also involved (i.e. brain thrombi formation). Long term effects also include diabetes, rectal stricture (narrowing of the rectum caused by fibrous tissue formation), and neurologic deficits (related to strokes). Of children who have HUS with diarrhea (most of the cases), about 1% will have the illness return.

In adults, the death rate is much higher, at 15 to 30%. Also, 30% of those who do not die from HUS will have chronic kidney damage and 25% may go on to have the disease recur. This difference in age-related recurrence rates and outcomes may be due to the fact that a higher number of adults get the form of HUS that begins without diarrhea.

Resources

BOOKS

Nathan, David, et al. "Schistocytic Hemolytic Anemia with Severe Thrombocytopenia." In Nathan and Oski's Hematology of Infancy and Childhood. Philadelphia: W.B. Saunders, 1998.

Siegler, Richard. "Hemolytic Uremic Syndrome/Thrombotic Thrombocytopenic Purpura." In Primer on Kidney Diseases. San Diego, CA: Academic Press, 1998.

PERIODICALS

Landau, Daniel, et al. "Familial Hemolytic Uremic Syndrome Associated with Complement Factor H Deficiency." Journal of Pediatrics 138 (March 2001): 412-417.

Wong, Craig, et al. "The Risk of Hemolytic-Uremic Syndrome After Antibiotic Treatment of Escherichia coli 0157:H7 Infections." New England Journal of Medicine 342, no. 26 (June 2000): 1930-1936.

WEBSITES

"H Factor 1; HF1." Online Mendelian Inheritance in Man.<http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=134370>.

"Hemolytic-Uremic Syndrome; HUS." Online Mendelian Inheritance in Man.<http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=235400>.

Benjamin Morris Greenberg