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HUS (Hemolytic-Uremic Syndrome)

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Title: Hemolytic-Uremic Syndrome (HUS)

Hemolytic-uremic syndrome (or haemolytic-uraemic syndrome), abbreviated HUS, is a disease characterized by hemolytic anemia, acute renal failure (uremia) and a low platelet count (thrombocytopenia). It predominantly, but not exclusively, affects children. Most cases are preceded by an episode of diarrhea caused by E. coli O157:H7, which is acquired as a foodborne illness. It is a medical emergency and carries a 5–10% mortality; of the remainder, the majority recover without major consequences but a small proportion develop chronic kidney disease and become reliant on renal replacement therapy. HUS was first defined as a syndrome in 1955.

Signs & Symptoms

In Children

The classic childhood case of HUS occurs after ingestion of a strain of bacteria, usually types of E. coli, that expresses verotoxin (also called shiga-like toxin). Bloody diarrhea typically follows. HUS develops about 5-10 days after onset of diarrhea, with decreased urine output (oliguria), blood in the urine (hematuria), kidney failure, low platelet counts (thrombocytopenia) and destruction of red blood cells (microangiopathic hemolytic anemia). Hypertension is common. In some cases, there are prominent neurologic changes.

In Adults
Adult HUS has similar symptoms and pathology, but is an uncommon outcome of the following: HIV; antiphospholipid syndrome (associated with lupus erythematosus and generalized hypercoagulability); postpartum renal failure; malignant hypertension; scleroderma; and certain drugs, including some chemotherapy drugs and other immunosuppressive agents (mitomycin, ciclosporin, cisplatin and bleomycin).

Atypical Cases
A third category is referred to as familial HUS or atypical HUS (aHUS).

It represents 5-10% of HUS cases and is largely due to mutations in the complement proteins factor H, membrane cofactor protein and factor leading to uncontrolled complement system activation.

Recurrent thromboses result in a high mortality rate.

Most reported HUS cases during the 2011 Escherichia coli O104:H4 outbreak were atypical cases.


HUS is one of the thrombotic microangiopathies, a category of disorders that includes thrombotic thrombocytopenic purpura (TTP).

In the classical form (90% of cases), the STEC toxin enters the bloodstream and causes damage to the body's vascular endothelium. This is especially damaging to the kidney, where the toxin attaches to the glomerular endothelium and initiates a noninflammatory reaction leading to acute renal failure. Moreover, the generalized endothelial damage leads to platelet activation that causes thrombocytopenia (low platelet count). The renal glomerular endothelial cells express a receptor for the toxin.

The consumption of platelets as they adhere to the thrombi lodged in the small vessels typically leads to mild or moderate thrombocytopaenia with a platelet count of less than 60,000 per mL. The typical pathophysiology involves the shiga-toxin binding to proteins on the surface of glomerular endothelium and inactivating a metalloproteinase called ADAMTS13, which is also involved in the closely related thrombotic thrombocytopenic purpura (TTP). Once the ADAMTS13 is disabled, multimers of von Willebrand Factor (vWF) form and initiate platelet activation and cause microthrombi formation. Inhibition of ADAMTS13 causes activated platelets because the large multimers of uncleaved vWF are hyperactive. The arterioles and capillaries of the body become obstructed by the resulting complexes of activated platelets which have adhered to endothelium via large multimeric vWF. The growing thrombi lodged in smaller vessels destroyred blood cells (RBCs) as they squeeze through the narrowed blood vessels, forming schistocytes, or fragments of sheared RBCs. This mechanism, known as microangiopathic hemolysis, has been likened to the effect of a cheesewire or garotte across the vessel lumen. The presence of schistocytes is a key finding that helps to diagnose HUS. Typically, this haemolysis results in a haemoglobin level of less than 80 mg/L.

As in the related condition TTP, reduced blood flow through the narrowed blood vessels of the microvasculature leads to reduced blood flow to vital organs, and ischemia may develop. The kidneys and the central nervous system (brain and spinal cord) are the parts of the body most critically dependent on high blood flow, thus they are the most likely organs to be affected. However, in comparison to TTP, the kidneys tend to be more severely affected in HUS, and the central nervous system is less commonly affected.

In contrast with typical disseminated intravascular coagulation seen with other causes of septicemia and occasionally with advanced cancer, coagulation factors are not consumed in HUS (or TTP) and the coagulation screen, fibrinogen level, and assays for fibrin degradation products such as "D-Dimers", are generally normal despite the low platelet count (thrombocytopenia).

HUS occurs after 2-7% of all E. coli O157:H7 infections. Children and adolescents are commonly affected. Grossly, the kidneys may show patchy or diffuse renal cortical necrosis. Histologically, the glomeruli show thickened and sometimes split capillary walls due largely to endothelial swelling. Large deposits of fibrin-related materials in the capillary lumens, subendothelially, and in the mesangium are also found along with mesangiolysis. Interlobular and afferent arterioles show fibrinoid necrosis and intimal hyperplasia and are often occluded by thrombi.

A somewhat less common form of HUS (~10% of cases) does not follow STEC infection and is thought to result from factor H deficiency (a complement regulatory protein) that results in uncontrolled complement activation after minor endothelialinjury resulting in thrombosis
Clinically, HUS can be very hard to distinguish from thrombotic thrombocytopenic purpura. The laboratory features are almost identical, and not every case of HUS is preceded by diarrhea. HUS is characterized by the triad of hemolytic anemia,thrombocytopenia, and acute renal failure. The only distinguishing feature is that in TTP, fever and neurological symptoms are often present; but this is not always the case. A pericardial friction rub can also sometimes be heard on auscultation (uremic pericarditis). The two conditions are sometimes treated as a single entity called TTP/HUS. However, some dispute this grouping, and TTP is now known to be caused by an acquired defect in the protein ADAMTS13.

The effect of antibiotics in E. coli O157:H7 colitis is controversial. Certain antibiotic may stimulate further verotoxin production and thereby increase the risk of HUS.
 However there is also tentative evidence that some antibiotics likequinolones may decrease the risk of haemolytic uraemic syndrome.

Treatment is generally supportive, with dialysis as needed. Untreated HUS in adults, however, may progress to end-stage organ damage. Platelet transfusion may actually worsen the outcome.

In most children with postdiarrheal HUS, there is a good chance of spontaneous resolution, so observation in a hospital is often all that is necessary, with supportive care such as hemodialysis where indicated. In children with neurological or other nonrenal involvement, and in adult cases, particularly when there is diagnostic uncertainty between HUS and TTP, plasmapheresis (plasma exchange) is the treatment of choice. This is generally performed daily until the platelet count is normal, using fresh frozen plasma as the replacement fluid for the patient's plasma which is removed. Plasmapheresis may reverse the ongoing platelet consumption.

There are case reports of experimental treatments with eculizumab, a monoclonal antibody that blocks part of the complement system, being used to treat congenital atypical hemolytic uremic syndrome, as well as severe shiga-toxin associated hemolytic uremic syndrome.  These have shown promising results.

With aggressive treatment, more than 90% survive the acute phase. About 9% may develop end stage renal disease. About one-third of persons with HUS have abnormal kidney function many years later, and a few require long-term dialysis. Another 8% of persons with HUS have other lifelong complications, such as high blood pressure, seizures, blindness, paralysis, and the effects of having part of their colon removed. The overall mortality rate from HUS is 5-15%. Children and the elderly have a worse prognosis.

Epidemiology & Notable Outbreaks

HUS has a peak incidence between six months and four years of age.

HUS and the E. coli infections which caused it have been the source of much negative publicity for the Food and Drug Administration (FDA), meat industries, and fast-food restaurants since the 1990s, especially in the Jack in the Boxcontaminations. It was also featured in the Robin Cook novel Toxin. In 2006, an epidemic of harmful E. coli emerged in the United States due to contaminated spinach. The known cases have been reported at 183, including 29 cases of HUS. In June, 2009, Nestle Toll House cookie dough was linked to an outbreak of E. coli 0157:H7 in the United States, which sickened 70 people in 30 states.

In May, 2011 an epidemic of bloody diarrhea caused by E. coli O104:H4 contaminated fenugreek seeds hit Germany. Tracing the epidemic revealed more than 4000 cases, with hemolytic-uremic syndrome developing in more than 800 of the cases, with 50 of them resulting in death. Over 90% of the cases were in adults 
(Wikipedia, 2012)