Introduction to Hemolytic-Uremic Syndrome.

Hemolytic-uremic syndrome (HUS), first described in 1955, is a heterogeneous syndrome characterized by a triad of microangiopathic hemolytic anemia, acute renal failure, and thrombocytopenia. Initially thought to be a sporadic process, it is now recognized as the most common cause of acute renal failure in children.

Pathogenesis:

In D+ HUS, with Shiga toxin-producing E. coli O157:H7 infection, the toxin binds, invades, and causes destruction of colonic epithelial cells, resulting in bloody diarrhea. Presumably because of the inflamed colon allowing transmural absorption, the toxin then enters the blood circulation. There the toxin binds to a glycolipid receptor known as globotriaosylceramide (Gb3), which results in endocytosis of the toxin usually within renal glomerular endothelial cells, and at times, other target organs. The expression of Gb3 receptors appears to be higher in infants and young children, which may in part explain the age-related propensity for developing HUS. Older children and adults have lower numbers of these receptors but may develop HUS whenever the combined effect of lipopolysaccharide and cytokines upregulate the expression of these Gb3 receptors.

Clinical Features:

With STEC infection, the incubation period is typically 3 to 4 days after exposure (range, 1 to 14 days).

Initial signs of symptomatic infection are vomiting, diarrhea, and significant abdominal pain. The diarrhea is often watery like typical viral gastroenteritis for the first 1 to 3 days; then, in most cases (80%), it becomes bloody. Patients are often afebrile. Only 30% have fever and it tends to be low-grade in contrast to that seen with most bacterial enterocolitis. The hemorrhagic colitis resolves completely without any sequelae in most (90-95%) cases. Infection can also be asymptomatic.

When it occurs, the triad of HUS typically follows the onset of diarrhea in 5 to 7 days (range, 1 to 14 days), often just as the colitis is resolving. This time lag may provide an opportunity for potential interventions to prevent renal failure.

Lethargy, irritability, renewed vomiting, pallor, edema, hypertension, and decreased urine output are common. Hypertension occurs about 75% of the time. Renal involvement can be mild with only some microscopic hematuria and proteinuria with normal urine output, or may extend to irreversible renal failure with widespread cortical necrosis. Notably, the presence of diarrhea may mask oliguria. Oliguria occurs in many cases (about 60%) lasting typically about 1 week, with frank anuria (40%) lasting a few days.

Extrarenal manifestations, when present, can include rectal prolapse, toxic megacolon, bowel gangrene, intestinal perforation, colonic stenosis, intussusception, pancreatitis, pancreatic insufficiency (diabetes mellitus), CNS involvement (seizures, cerebral edema, hemiparesis, cranial nerve involvement, cerebral infarction), myocardial dysfunction, congestive heart failure with or without fluid overload, liver injury, and myositis. Most of the cardiovascular involvement in HUS is a result of fluid overload secondary to renal failure. Direct myocardial injury can sometimes occur.

CNS involvement occurs up to 30% of the time, the most common manifestation being seizures.

Often, metabolic derangements (e.g., hyponatremia, uremia) or hypertension are causative, but in some cases the seizures are the result of CNS vascular involvement. The presence of fever and CNS symptoms may make the distinction between HUS and thrombotic thrombocytopenic purpura (TTP) more difficult. TTP is mainly an adult process manifested by neurologic symptoms, fever, and mild renal dysfunction. Bloody diarrhea is uncommon. Both diseases share endothelial cell damage as the inciting event but by different mechanisms. TTP is either due to congenital absence of von Willebrand factor-cleaving protease enzyme (ADAMTS 13) activity or to an acquired antibody directed against this enzyme.

Differential Diagnosis:

The differential diagnosis for HUS would include intussusception, inflammatory bowel disease, sepsis, meningococcemia, disseminated intravascular coagulation, vasculitis, leukemia and other malignancies, post-streptococcal glomerulonephritis, rapidly progressive glomerulonephritis, lupus nephritis, TTP, immune thrombocytopenic purpura (ITP), and immune hemolytic anemia.