At a Glance

Hemolytic-uremic syndrome (HUS) is a clinical syndrome characterized by the triad of thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and acute renal failure. This rare, life threatening disease predominantly affects children, mostly younger than five years of age, and is considered the most common cause of sudden short-term acute kidney failure in children.

Although HUS presentation is diverse, the typical initial symptom is an episode of bloody diarrhea caused by Shiga toxin–producing E. coli (serotype O157:H7) usually acquired as a food borne illness. The classic presentation of this medical emergency disorder usually develops within 1 week (range 1-10 days) and may mimic an acute surgical abdomen, such as acute appendicitis or ulcerative colitis before the common triad develops a few days later.

Clinically, there is a great similarity between HUS and thrombotic thrombocytopenic purpura (TTP). Renal involvement is one of the prominent findings in HUS with symptoms ranging from mild hematuria and proteinuria to severe renal failure. Neurological findings, conversely, are less important in this syndrome, and symptoms, such as irritability, seizures or altered mental status, may develop in less than one-third of cases.

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What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

HUS is primarily a clinical diagnosis disorder with characteristic laboratory findings. The hemoglobin level is typically less than 8g/dL with a negative Coomb’s test and elevated reticulocyte count. Thrombocytopenia is often mild to moderate (average of 60 x 103/microL). A moderate leukocytosis may be present but is rarely above 20 x 103/microL.

The presence of schistocytes and helmet cells on the peripheral blood smear is considered one of the significant findings in HUS. Giant platelets may also be seen on the peripheral smear.

A slight increase in indirect bilirubin levels with markedly elevated lactate dehydrogenase (LDH) along with very low to undetectable levels of haptoglobin reflects intravascular hemolysis, which may recur over a several week period.

Coagulation screening tests, prothrombin time (PT) and activated partial thromboplastin time (aPTT), are almost always within the normal limits, as well as fibrinogen and D-dimer levels.

The markedly elevated levels of blood urea nitrogen (BUN) and creatinine reveal the degree of renal involvement. Significant protein and blood can be detected in the urine, if obtainable. Occasionally, red blood cell casts can also be seen in urine sediment.

In case of E. coli, blood cultures are usually negative but stool cultures can typically detect the Shiga toxin-producing E. coli.

What Lab Results Are Absolutely Confirmatory?

  • In addition to the thrombocytopenia, MAHA and the acute renal failure, diagnosis can be confirmed by a positive E. coli or Shiga-toxin stool.

  • Occasionally, intestinal wall thickening found by abdominal CT scan can be helpful.

  • Rarely, a renal biopsy is needed in some uncertain cases.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

There is no correlation between the severity of anemia or the degree of thrombocytopenia and the severity of the renal disease. In addition, petechia, purpura, and/or active bleeding are uncommon features of HUS, despite the significant low platelet count.

This syndrome is more predominant in rural areas with a peak incidence in warmer seasons corresponding to the increased risk of E coli O157:H7 infection and is mostly presented as outbreaks (e.g., 1992 outbreak due to undercooked hamburger contaminated with E. coli). It is, generally, presented in children as gastroenteritis complaints (e.g., abdominal pain or tenderness, nausea or vomiting, fever), whereas affected adults may be asymptomatic.

E. coli O157:H7 is responsible for most of the typical HUS in children in the United States; several cases were reported following either gastrointestinal infections with different bacteria (e.g., shigella and salmonella) or nongastrointestinal infections. E. coli serotype O157:H7 is normally found as an intestinal flora in 1% of healthy cattle. Therefore, the most common form of transmission is by the ingestion of contaminated undercooked meat, unpasteurized milk, or milk products that become affected during processing.

Cases of HUS were also reported after swimming in feces contaminated pools and lakes. Other risk factors include animal to person, or person-to-person transmission. It’s worth mentioning that, for unknown reason, not all people infected with E. coli serotype O157:H7 develop HUS.

Following the intestinal mucosal penetration, the Shiga toxin enters the bloodstream and concentrates in the glomerular space of the kidney. This causes endothelial cell necrosis that will eventually initiate a renal microvascular thrombosis. The growing thrombi will obstruct the vessel lumen, destroy the bypassing red blood cells as they squeeze through the narrowed vessels forming schistocytes, activate platelets that result in a consumptive thrombocytopenia, and reduce the renal blood flow, which may lead to end-organ damage.

Clinically, HUS is classified into two types, depending on the presence of the diarrhea; diarrhea-positive (or typical) HUS (>85%) and diarrhea-negative (or atypical) HUS (10%). The former is more common in children and can be endemic, linked to a common source of infection, and results in bloody diarrhea. Vomiting, low grade fever, and/or minor neurological symptoms may also be present in up to one-third of HUS patients. Acute renal failure is predominant in more than one-half of the cases and manifested clinically by hypertension associated with oliguria and anuria. Almost 50% of these patients may require dialysis during the acute course of the disease with a generally favorable prognosis in restoring renal function. Therefore, a high index of suspicion should be maintained on initial presentation.

Atypical HUS, conversely, occurs sporadically and is mainly seen in adults with existing risk factors, such as familial predisposition (e.g., factor H deficiency; a complement regulatory protein), infections (e.g., E. coli, Streptococcus pneumoniae), pregnancy, or medications (e.g., mitomycin ticlopidine). Although almost 90% of the typical HUS cases recover without permanent damage, atypical HUS patients often experience serious complications with more than 50% requiring chronic dialysis and a mortality rate of about 25%.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Shiga toxins, but not E. coli, are key virulence factors in HUS; therefore, blood culture is typically not helpful in HUS cases.

Identification of enterohemorrhagic E. coli (i.e., O157:H7) by stool culture is essential in HUS diagnosis; however, false-negative results can be seen in some cases, since the bacterial presence in the stool is limited to only a few days.

Diagnostically, it is difficult to differentiate between HUS and TTP because of the clinical and laboratory overlap between these identical disorders. However, patient age, low grade to no fever, presence of diarrhea, more prominent renal involvement, and less neurological findings are all in favor of HUS.

HUS findings can also be mimicked by several other disorders, such as viral or bacterial gastroenteritis, inflammatory bowel disease, ischemic colitis, appendicitis, sepsis, systemic vasculitis, Henoch-Schönlein Purpura, or the pregnancy-associated HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count).

In contrast to the typical disseminated intravascular coagulation (DIC), coagulation factors are not consumed in HUS. Laboratory screening of the traditional coagulation tests (PT and aPTT), fibrinogen level, fibrin degradation products, and D-Dimers are generally normal in HUS, despite thrombocytopenia.