Haemolytic Uremic Syndrome (HUS) is a clinical condition that describes the association of haemolytic anaemia and renal impairment along with low platelet count (thrombocytopenia) in infants and young children (Carol Inward, 2008). This condition is more common with infants and young children due to their immunocompromised condition. It usually develops after an infection of the digestive system by a specific strain of E. coli bacterium (E. coli0157:H7), which is found in undercooked food, non-pasteurized dairy products and juices, contaminated water, or contact with an infected person. E. coli is a gram negative bacterium which is commonly found in the intestine of human beings and animals. Most strains of E. coli bacteria are harmless but E. coli0157:H7 stands out as an exception. It is the most common member of the Enter haemorrhagic, Shiga toxin producing organisms (a group of pathogenic E. coli strains). This strain deposits itself in the digestive system and produces toxins that easily enter the bloodstream and start destroying the RBCs present in the blood. The initial symptoms observed for an E. coli infection usually surface in about 3-5 days after an individual consumes anything that contains the bacterium. These symptoms include nausea, vomiting, stomach cramps and bloody diarrhoea. Most cases of HUS are preceded by occurrence of bloody diarrhoea in two thirds of the patients which is characterized by increased levels of blood in the stool accompanied by abdominal cramps, vomiting and the kidney being largely affected. The symptoms of HUS are seen usually 7-10 days after the patient acquires diarrhoea. These include, paleness, fever, small unexplained bruises and nose bleeding (due to loss of platelets i.e. thrombocytopenia), fatigue, decreased flow of urine, jaundice, and swelling of the hands and feet due to hypertension. The prevalence of HUS in the UK, North America and the whole of Europe is 0.7 per 100000 children < 16 years of age. This has been consistent for the last 20 years and the highest incidence of HUS in the world is in Argentina, recorded in 2002, with 12.2 cases per 100000 children < 5 years of age. (R.M. Lynn, et al. 2005).
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CASE PRESENTATION: -
A case of post diarrhoeal HUS with acute renal failure in a 12 year old girl was reported. The very first symptom presented by her was bloody diarrhoea which was probably due to a potential E. coli infection caused by consuming undercooked beef. As a result, she was treated with antibiotics. Furthermore, after hospitalisation she complained of headaches and tiredness, four days after which she went into renal failure.
A complete blood test was conducted on the patient in order to confirm the condition and the test results were as follows:
Blood Component Range in the body Normal range Inference
HB 9.8 g/dl 12-16 Highly Decreased
RBC 3.52 x1012/L 3.8-5.2x1012/L Decreased
WBC 32.5 x 109/L 4-11x109/L Highly Increased
HCT 0.301 0.360-0.380 Decreased
MCV 85fl 80-99fl Normal
PLT 25 x 109/L 150-400x109/L Highly Decreased
BILIRUBIN 175 µmol/L 0-22µmol/L Increased
INR 1.0 0.8-1.2 Normal
APTTr 1.0 1.5-3.5 Slightly Decreased
Courtesy for reference ranges :- (Bekaert S.;2007)
The above test results clearly indicate that that the levels of haemoglobin, red blood cells and platelets are highly decreased and the level of white blood cells are above the normal range. Bilirubin levels are also elevated which show that it is not completely excreted out of the body. The values of International Normalized ratio (INR) and APPTr are more or less normal. The low levels of haemoglobin in the blood indicate possible anaemia and decreased RBC count indicates occurrence of haemolysis in the blood, whereas, the low levels of platelets indicate the condition of thrombocytopenia. Low haemoglobin and RBC count in the blood clearly indicate haemolytic anaemia whereas low platelet count indicates towards thrombocytopenia. Bilirubin levels indicate that the kidney is not functioning properly as the waste products are not eliminated. Therefore, it can be inferred that the patient showed confirmatory reports of haemolytic anaemia, thrombocytopenia and renal failure which altogether are a characteristic of HUS (R.M. Lynn, et al. 2005).
The above test (complete blood count) indicates a suspected condition of HUS which can be confirmed and analysed with some other diagnostic tests.
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In this case, the patient first presented bloody diarrhoea. As E. coli0157:H7 is the most common cause of HUS; the patient can therefore be tested for a potential E. coli infection. The patient's stool sample is tested for the presence of an E coli0157:H7 strain and a positive test result helps confirm HUS. This can be done by plating fresh faecal sample of the patient on sorbitol-Mackonkey agar. This particular type of agar consists of sorbitol and not lactose as a source of carbon. Unlike most of the human faecal E. coli, E. coli 0157:H7 cannot ferment sorbitol after overnight incubation and therefore they are presented as colourless colonies on the agar. (Tarr P. I. et al, 2005)
Fig 1 shows E coli O157:H7 on a sorbitol-MacConkey agar plate. Arrow indicates distinctive colourless E coli O157:H7 colony.
Courtesy: - (Tarr P. I. et al; 2005)
The body normally clears these bacteria within a week and therefore a negative test does not exclude the disease.
Urine tests can be done to confirm the presence of blood or protein in the urine.
Kidney functioning has to be tested for the presence of Uremia or renal failure. This can be done by checking the level of waste fluids in the body that are usually filtered by the kidney. Renal failure or uremia can be confirmed when the level of creatinine in the body rises.
A physical exam can be carried out in order to check for liver or spleen swelling or any kind of nervous system changes. Abnormal changes in the nervous system distinguish HUS from thrombotic thrombocytopenic purpura.
Haemolytic testing can be done to check for elevated bilirubin and lactate dehydrogenase levels and decreased levels of haptoglobin.
Peripheral smears of blood can be tested for the presence of schistocytes (fragmented, deformed and irregular red blood cells) and thrombocytopenia. Presence of schistocytes confirms that the patient is suffering from haemolytic anaemia.
Fig 2: -
FIG 2 shows Peripheral blood film from a patient with HUS. The blood film shows schistocytes: fragmented, irregular, or helmet-shaped red blood cells (arrows) and an immature platelet (p).
Courtesy: - (Elliott J. E.; Robins-Browne M. R.; 2005)
HUS is an entity of abnormalities consisting of haemolytic anaemia, thrombocytopenia and renal failure. Haemolytic anaemia is caused when the blood clots within the capillaries of the body. When the RBC's pass through these clogged capillaries, they are snipped apart and broken. Renal failure occurs when the kidneys are unable to filter the urea and other waste products built up in the bloodstream. The events that lead to HUS start with the consumption of a particular strain of E. coli from contaminated foodstuffs or contaminated water. In this case, HUS was preceded by an episode of bloody diarrhoea caused by an E. coli infection (E. coli0157:H7) that expressed Shiga toxin producing E. coli (verocytotoxins) in the intestine of the patient. The patient was first tested for E. coli infection due to the consumption of undercooked beef. If the beef is not properly cooked for a long time and at the right temperature, it is left uncooked. As a result, bacteria in the food are not completely killed and enter the body of the person who consumes it. This led to the clinical condition of diarrhoea which was bloody. The Shiga toxins in this infection play an essential role in the pathogenesis of HUS. They are of two main types Stx1 and STx2. They consist of an A unit and 5 B units. (Rhodes M. J; 2007) The Shiga toxin producing E. coli (STEC) enters the bloodstream, multiplies rapidly and cause severe damage to the gut epithelium that result in haemorrhagic and ulcerative lesions. The initial binding of the E. coli bacterium with the intestinal epithelium takes place with the help of adhesins (intimin). This becomes an essential step towards the presentation of diarrhoea in the body. This attachment is defined by the dissolution of the brush border at the site of attachment. Adherence to the mucosal surface prevents loss of bacteria and promotes the delivery of toxin into the cell. The onset of diarrhoea and HUS leads to severe tissue injury further generating an immediate inflammatory response through leukocyte activation and cytokine production. Increased levels of macrophages and neutrophils are observed in patients suffering from HUS and it was the same in this case. Shiga toxin pathogens prestimulate the endothelial cells with cytokines such as TNF- α (mediates inflammation and microvascular coagulation), IL-1 β or sodium butyrate which then together act to induce cell injury. This resulted in an increase in the number of glycosphingolipid globotriaosylceramide (Gb3) receptors, type of cell surface receptor. The B unit of Shiga toxins bind to these receptors and gain access to the circulatory system.
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Action of Shiga toxin on susceptible cells
Courtesy: - (Elliott J. E.; Robins-Browne M. R.; 2005)
This binding initiates absorption of the toxin in the intestinal capillaries and the bloodstream. These toxins further attach to the weak receptors on the white blood cells and move towards the kidneys. In the kidneys, these receptors are present on the glomerular endothelial lining. The toxins attach to the receptors and enter the cell's cytoplasm where the A units of Shiga toxins inhibit the synthesis of proteins resulting is cell injury or cell death. This further leads to the activation of blood platelets and the coagulation cascade, forming clots in the tiny blood vessels of the body. As mentioned before, the red blood cells pass through these clogged capillaries and are sheared apart or broken which results in fragmented, lysed, irregularly shaped RBCs in the bloodstream. Furthermore, platelet adhesion and damage in the kidneys lead to thrombocytopenia.
Diagrammatic representation of the mechanisms underlying the pathogenesis of STEC associated Haemolytic Uremic Syndrome.
The above figure explains the sequence of events from the ingestion of STEC to the development of Haemolytic Uremic Syndrome. The numbers from 1-10 define the order of this sequence. Simultaneous events are mentioned in small letters (2a, 2b etc) and the words in italics indicate incomplete or pending data.
Courtesy: - (Proulx F. et al. 2001)
As the patient was suspected of an E. coli infection, she was treated with certain specific antibiotics. Certain antibiotics such as sulfa drugs, beta-lactum antibiotics, trimethropin etc. can be administered to treat the infection (Remuzzi G. and Rugenenti P.; 1995). However, exposure to these antibiotics cause E. coli to release Shiga toxins into the intestine which further leads to apoptosis or cell injury (Wong C. S. et al.; 2000). It can therefore be confirmed that treating the patient with antibiotics for E. coli infection possibly led to the initiation of HUS. Children suffering from an E. coli infection should not be treated with antibiotics for the above mentioned reasons.
HUS is a condition that terminates by the natural course of events and careful supportive care towards the patient is very essential.
To start with, when the patient is diagnosed with bloody diarrhoea, there are chances of acquiring HUS and therefore urgent referral to a specialist pediatric service is important.
In this case, the patient showed bloody diarrhoea, E. coli infection leading to HUS. In order to treat her condition, the following treatment measures could be taken into account.
Intensive Care: - Close observation and supervision in an intensive care unit is very important as it may take weeks or months for the patient to get fully recovered.
Blood Transfusion: - Blood transfusion is necessary to treat severe cases of anaemia. As a lot of RBC's are lysed and destroyed in this particular condition, it becomes necessary for the patient to be transfused with fresh packed red blood cells. Care is taken that the transfusion process is slow due to danger of severe hypertension.
In some cases, the liquid portion of blood (plasma) is filtered to remove the antibodies that are present in the blood or the whole portion is removed and replaced with fresh plasma which is usually donated.
Medication: - Medication is usually given to control the elevated blood pressure which can surface due to loss of blood cells and transfusions.
Nutrition: - Diarrhoea often leads to severe dehydration which causes loss of essential fluids and electrolytes like Na and K from the body. In order to rebalance and rehydrate the body intravenous nutrition becomes necessary (supplying with nutrients through an IV tube). Maintaining normal levels of salt and water in the body can ease the immediate symptoms and help prevent further complications.
Dialysis: - Dialysis is the medical procedure to remove the wastes and additional fluid from the blood. This has to be carried out if the kidneys have stopped functioning and is required in more than half of the patients suffering from Haemolytic Uremic Syndrome. Dialysis was much needed in this case as the patient had eventually gone into renal failure.
Fig 5: -
Diagrammatic representation of the procedure carried out in dialysis.
Courtesy: - (Roy K. M.; 2009)
Currently there are no definite treatment measures for HUS and therefore all the measures are used to treat the symptoms and clinical conditions that lead to HUS. Early diagnosis of the symptoms and pathological conditions may help in the initiation of supportive therapy which may avoid further complications related to the disorder. Also, proper understanding of the condition would help develop future therapeutic strategies for the betterment of individuals suffering from HUS. (Elliott J. E.; Robins-Browne M. R.; 2005). The National Institute of Diabetes and Digestive Kidney Diseases (NIDDK) help and carry out the research to help patients with kidney disorders. It maintains a Pediatric Nephrology Program that looks into the causes, treatments and preventive measures related to disorders of the kidney in children. The KUH division of the department helps many researchers working to find measures of prevention for HUS from developing after the initial infection of the gastrointestinal tract.
The condition can be prevented by avoiding the consumption of contaminated fluids and foodstuffs that can lead to severe infections. Foodstuffs should be thoroughly washed and cooked before ingesting and contact with contaminated water should be avoided.
Full recovery in children with the disorder is expected and without dialysis, up to 40% of those affected by HUS may die, and 80% may present with renal impairment. With proper treatment measures, the death rate falls to 10% or less and that of kidney impairment to 25%. (Wedro B. C.; 2000)