Case Based Pediatrics For Medical Students and Residents
Department of Pediatrics, University of Hawaii John A. Burns School of Medicine
Chapter XIII.5. Hemolytic Uremic Syndrome
Jonathan K. Marr, MD
March 2002

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This is a 3 year old male who is brought to the ED by his mother when she noted bloody diarrhea earlier in the day. There is no fever, ill contacts, or recent exposures to children with diarrhea. He is noted to be pale. His family had attended a birthday party 7 days prior where the child had consumed hot dogs and hamburgers.

Exam: VS T 37.7, P 150, R 28, BP 100/45, oxygen saturation 100% in RA. Weight 17 kg (75%ile). He is alert but fussy, pale, and non-toxic appearing. His conjunctiva are pale. His TMs are normal. He has no nasal flaring or palatal petechiae. His oral mucosa is moist and his tongue is pale. His neck is supple without adenopathy. His heart has a regular rhythm with tachycardia and a grade III/VI vibratory systolic ejection murmur at the left sternal border without radiation. No heaves, lifts, thrills, rubs, or gallops are present. His lungs are clear with good aeration. His abdomen is flat, soft, and non-tender, with the liver edge palpable 3cm below the RCM. The spleen is non-palpable. His genitalia and anus are normal (no rectal prolapse). His pulses and perfusion are good. There are is no edema, rash, or petechiae.

Labs: CBC: WBC 16,000 with 56% segs, 12% bands, 27% lymphs, 3% eos, 2% basos, hemoglobin 8 mg/dL, hematocrit 24.6, platelet count 75,000; peripheral smear shows schistocytes, helmet cells, and polychromasia. Na 133, K 5.9, Cl 96, bicarbonate 16, BUN 45, creatinine 1.3, glucose 145 mg/dL, Ca 7.8, PO4 7.1, uric acid 7.3, and LDH 300. Coagulation studies are normal.


Hemolytic uremic syndrome (HUS) is a heterogeneous group of similar entities that has been recognized for over 45 years and has been reported from most parts of the world. It is one of the most common causes of acute renal failure in childhood and is defined by a combination of microangiopathic hemolytic anemia, variable degrees of thrombocytopenia, and renal failure (1). Other systems, such as the CNS may be involved.

HUS can be classified in a number of ways, but the most common is the diarrhea-associated (D+ HUS) versus atypical (D- HUS) HUS without diarrhea. The D+ HUS is characterized by a sudden onset of hemolytic anemia, thrombocytopenia, and acute renal failure after prodromal gastrointestinal enteritis. The atypical (D- HUS) is rare in childhood, portends a worse prognosis, is more likely to relapse, and may be associated with a family history of HUS disease. It appears to be associated with certain chemotherapy drugs (cyclosporin and tacrolimus), oral contraceptives, cancer, bone marrow transplantation, Streptococcus pneumoniae infections, and vasculitic diseases (1).

Another common classification used is Shiga-like toxin-associated HUS (Stx HUS), since D+ HUS has been strongly associated with a toxin-producing strain of Escherichia coli O157:H7 (1,2). Historically, Shigatoxin (Stx) is an exotoxin produced by Shigella dysenteriae type I and the term verotoxin is derived from the use of vero (monkey) cells as a cytotoxic assay for the Shigatoxins produced by E. coli O157:H7 (1). Human verotoxin producing E. coli (VTEC) strains produce one or both of the toxins Stx-1 and Stx-2 and are established causes of HUS associated with bloody diarrhea. Other strains of E. coli besides O157:H7 produce shiga toxins; they include E. coli O111, O26:H11, and O103:H2, although they are less commonly found in HUS cases, since their assays are not routinely commercially available (1,2).

Epidemiologically, the most common form of the HUS syndrome (D+ HUS) occurs predominantly in healthy children 6 months to 5 years of age, and has seasonal variation with peaks in the summer and fall (1). Most cases of D+ HUS occurring during epidemics are due to ingestion of contaminated, usually undercooked, ground beef. Approximately 1% of beef cattle in the United States harbor intestinal E. coli O157:H7. The organisms become incorporated during the processing of ground beef that mixes meat from multiple cattle such that one infected animal can contaminate large quantities of ground beef. E. coli O157:H7 can also be acquired by consuming fruits or vegetables contaminated by manure, drinking unpasteurized milk, swimming in contaminated lakes, and person-to-person contact (1).

Stx produced by VTEC is most specifically toxic to cells containing a specialized glycolipid receptor called glycosphingolipid globotriosyl ceramide (Gb3) (2). Glomerular epithelial cells in the renal cortex contain large quantities of Gb3. This explains the predilection for renal cortex lesions and acute renal failure (1). Other areas that contain Gb3 include the CNS and the pancreas.

VTEC also releases lipopolysaccharide (LPS), stimulating WBCs to release inflammatory mediators (TNF-alpha, IL-1, and elastase) that cause endothelial cell detachment, increased procoagulant activity, and release of free radicals causing oxidative cell membrane injury (1). The injury to endothelial cells in renal microvessels results in local intravascular coagulation and a microangiopathic hemolytic anemia with mechanical destruction of erythrocytes and platelets by fibrin strands in narrow vessels (1). Platelet adherence contributes to microthrombi and platelets are consumed when platelet-fibrin thrombi are formed in these injured areas. The capillary lumina are narrowed by endothelial swelling and occlusive thrombi, effectively decreasing blood flow to the glomeruli leading to renal insufficiency and eventually progressing to renal failure.

Clinically, HUS presents with abdominal pain, vomiting, and bloody, mucoid diarrhea. The prodromal phase of the illness varies from 1-15 days before the onset of HUS. Pallor and petechiae occurs within 5-7 days after the onset of the bloody diarrhea. Other signs that may be noted include oliguria, personality changes, and drowsiness. The oliguria found in 60% of patients lasts an average of one week; however 50% of patients, are anuric for an average of 3 days. Most patients are irritable and somnolent. Other findings include behavioral changes, ataxia, dizziness, tremors, and twitching. With progression of the disease, anuria, coma, hemiparesis, cranial nerve dysfunction, cerebral infarcts, seizures, and death can occur. Seizures are reported in 3-5% of cases (2). Active bleeding other than the bloody diarrhea is rare. Hypertension is a common feature of HUS and occurs in 50% of all affected individuals. Possible etiologies for this include fluid overload and increased renin activity (1). Pancreatic insufficiency manifested as transient diabetes mellitus occurs in 4-15% of patients (1,2). Mortality has declined and is between 5-10% during the acute phase. Predictive features associated with poorer long-term outcomes include: severe gastrointestinal prodrome (colitis with rectal prolapse), prolonged duration of anuria, extended duration of dialysis, coma on admission, and high leukocyte count (1). Generalized seizures during the acute phase of the disease are not predictive of death or poor neurological sequelae (1). Age and gender have no consistent correlations on outcome.

The differential diagnosis of early HUS includes: ulcerative colitis, Crohn's disease, appendicitis, intussusception, idiopathic rectal prolapse, gastroenteritis, or acute bacterial endocarditis.

Thrombotic thrombocytopenic purpura (TTP), also known as Moschcowitz's syndrome is similar to HUS with the features of: microangiopathic hemolytic anemia, thrombocytopenia, renal dysfunction, fever, and neurological disturbances (4). It is probable that TTP and HUS represent a similar pathological process, except that TTP is the more serious multisystem disorder with a higher mortality (30-40% within 3 months). The pathophysiologic events involved with TTP are not fully understood but probably involve abnormalities in endothelial composition and unusually large von Willebrand Factor (vWF) multimers in the circulation causing platelet activation with resultant platelet thrombi formation.

Laboratory findings in HUS include a negative Coombs test, normochromic, normocytic anemia with helmet cells, schistocytes, and polychromatophilia on blood smear indicative of hemolysis. Other evidence for hemolysis is an elevated LDH and low serum haptoglobin. An unconjugated hyperbilirubinemia is usually present. The mean hemoglobin is 8 mg/dL. The platelet count is moderately depressed to 50,000, but can be as low as 5,000. Neither the severity nor the duration of the thrombocytopenia correlates with the overall severity of disease. The duration of the thrombocytopenia lasts from 2-3 weeks and there are usually no signs of active bleeding other than the bloody diarrhea. The half-life of infused platelets are shorter, as they are likely taken up by the liver and spleen; furthermore, circulating platelets are dysfunctional. Leukocytosis is present and is nonspecific diagnostically; a recent study, however, found the risk of developing HUS proportional to the initial WBC count (3). Coagulation tests are normal and fibrin split products may be positive.

Signs of renal dysfunction include elevated serum levels of creatinine, potassium, phosphorus, and uric acid which result from decreased glomerular filtration, hemolysis, and transcellular cation shifts (1). Elevations in BUN and creatinine may initially reflect volume depletion because of the diarrhea, but may later be the result of renal failure. Sodium, calcium, and albumin may be low from initial diarrhea losses and later from volume overload because of renal failure. Pancreatic insufficiency is manifested by elevations in amylase and lipase or glucose intolerance.

Histopathology on renal biopsy (not always done unless clinically indicated) demonstrates glomerular lesions of endothelial cell swelling and a widened subendothelial space filled with fibrin-like substances and lipids (1). This results in a thickened capillary wall and reduced capillary lumen. The glomerular basement membrane is intact. Occasionally there may be crescents and signs of necrosis and the glomeruli may be lobulated and resemble membranoproliferative glomerulonephritis (1). Thrombi may occlude arteriolar lumens and there may be tubulointerstitial disease. Fibrin, fibronectin, IgM, and C3 are found by immunofluorescent microscopy along capillary walls, mesangium, and in the subendothelial spaces of capillaries and arterioles (1).

Treatment for HUS is supportive. Dehydration should be corrected, but over hydration should be avoided if oliguric renal failure occurs. Fluids must be limited to insensible losses plus the volume of urine output. Hyperkalemia, hyperphosphatemia, and severe metabolic acidosis may be managed medically. Dialysis is indicated if this fails. Packed red blood cells should be transfused if the hemoglobin falls below 6g/dL or for symptomatic anemia. Platelet transfusions are rarely administered since generalized bleeding is not common; however, they may be indicated before surgical procedures (i.e. catheter placement for hemodialysis or peritoneal dialysis) or active bleeding. Hypertension should be treated to prevent encephalopathy or congestive heart failure. Calcium-channel blockers (nifedipine) or nitroprusside are the medications often recommended to control hypertension.

Peritoneal or hemodialysis should be considered when fluid and electrolyte imbalances cannot be corrected by medical management, or when fluid overload compromises cardiac or pulmonary function. In general, when the BUN exceeds 100 mg/dL, dialysis should be considered even in the absence of fluid and electrolyte imbalances (2). Non-oliguric patients generally do not need dialysis.

Antiplatelet drugs, intravenous immune globulin, anticoagulants, thrombolytic agents, prostacyclin, and corticosteroids have not been found to be beneficial (1,2). Plasma infusion or exchange therapy found to be beneficial in patients with TTP, has not been found to be advantageous in patients with HUS. Plasmapheresis has been of benefit in atypical HUS (D-) when neurological involvement is present (1). Fresh frozen plasma administration may be harmful in patients with HUS (1). Antibiotic therapy during D+ HUS is controversial, after a recent report suggested that the risk of developing HUS may be increased after antibiotic therapy (sulfa-containing and beta-lactam) for E. coli O157:H7 (3). Currently, a chemically synthesized trisaccharide (Synsorb-Pk), was found to bind with high affinity to Stx-1 and Stx-2, and is undergoing human trials in Canada in assessing its value in preventing D+ HUS (1).

Prevention of D+ HUS is most effective by cooking ground beef until the inside is no longer pink. The Food and Drug Administration recommends a minimum internal temperature of 155 degrees F for cooked hamburger. The most effective means of preventing person-to-person spread is supervised handwashing. Infected children must be excluded from day care centers, until they have documented negative stool cultures for E. coli O157:H7.

Prognosis for HUS has improved with the introduction of dialysis. Previously, children with HUS died from fluid overload, metabolic derangements, and uremia. The acute fatality rate ranges from 4-12% and another 5% develop acute renal failure and anuria. End-stage renal disease or chronic renal failure develops in 10-15% of HUS patients (2). 65-85% recover completely, however, a significant number of patients develop renal sequelae (proteinuria, hypertension, and low creatinine clearance) during long-term follow up studies (1).


Questions

1. What is the likely etiology of D+ HUS?

2. What defines HUS?

3. What types of blood cells would be most consistent with a diagnosis of HUS in a 3 year old child with bloody diarrhea?
. . . . . a. Atypical lymphocytes
. . . . . b. Elliptocytes
. . . . . c. Myeloblasts
. . . . . d. Schistocytes
. . . . . e. Spherocytes

4. What is the strongest indication for dialysis?
. . . . . a. Serum sodium of 120
. . . . . b. Initial bicarbonate of 14
. . . . . c. Serum BUN 120 mg/dL
. . . . . d. Initial K of 5.2
. . . . . e. Anuria for 3 days

5. True/False: The severity of hemolysis correlates with degree of renal failure?

6. A 3 year old girl presents with signs and symptoms of intussusception which include crampy intermittent abdominal pain, crying with puffy eyes, currant jelly diarrhea, pallor, dehydration and oliguria. Could this patient have HUS? Explain how all of the findings above could be due to HUS instead.


References

1. Meyers KEC, Kaplan BS. Chapter 50 - Hemolytic-Uremic Syndromes. In: Barratt T, et al (eds). Pediatric Nephrology, fourth edition. 1999, Philadelphia: Lippincott, Williams, & Wilkins, pp. 811-822.

2. Corrigan JJ, et al. Hemolytic-Uremic Syndrome. Pediatr Rev 2001;22(11):365-369.

3. Wong CS, et al. The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections. N Engl J Med 2000;342(26):1930-1936.

4. Banatvala N, et al. The United States National Prospective Hemolytic Uremic Syndrome Study: Microbiologic, Serologic, Clinical, and Epidemiological Findings. J Infect Dis 2001;183:1063-1070.


Answers to questions

1. E. coli O157:H7

2. Microangiopathic hemolytic anemia, thrombocytopenia, and renal failure.

3. d. schistocytes

4. c. serum BUN >100

5. False

6. Crampy abdominal pain (due to colitis), crying with puffy eyes (due to abdominal cramps, fluid retention due to renal failure causing puffy eyes), currant jelly diarrhea (actually bloody diarrhea due to E. coli O157:H7), pallor (due to hemolytic anemia), dehydration (due to diarrhea), oliguria (due to renal failure).


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