Cite this as: BMJ 2009;338:b200
R Som, foundation year 2 doctor, R Wynne-Simmons, foundation year 2 doctor, J Islam, specialty trainee in medicine, S Lawman, consultant nephrologist
1 Sussex Kidney Unit, Royal Sussex County Hospital, Brighton BN2 5BE
Correspondence to: R Som firstname.lastname@example.org
A 28 year old man presented to the accident and emergency department with central abdominal pain that had lasted just over a day and was "cramping" in nature. He had had bloody diarrhoea for three days, with increasing frequency and amount of blood. He had eaten a chicken sandwich purchased from a canteen the day before the onset of symptoms. There was no history of recent foreign travel or any important medical history.
On examination he was found to be warm and well perfused, and his abdomen was soft, with mild generalised tenderness. On admission his full blood count, renal function and liver function tests were all within normal range.
Three days after admission he had persistent bloody diarrhoea; his haemoglobin concentration had dropped by 40 g/l to 126 g/l. Colonoscopy and biopsies showed acute indeterminate colitis. His white cell count was 23.3x109/l, neutrophils 19.1x106/l, platelets 49x109/l, international normalised ratio 1.0, APTT (activated partial thromboplastin time)1.0, C reactive protein 256 mg/l, urea 19.7 mmol/l, creatinine 530 µmol/l, potassium 4.8 mmol/l, serum lactate dehydrogenase 3452 U/l. He quickly became anuric.
1 What is the diagnosis?
2 What would you expect to find on culture of stool?
3 What would you expect to see on a blood film?
4 What is the differential diagnosis?
5 What two therapeutic procedures might this patient have?
1 Haemolytic uraemic syndrome—diarrhoea positive.
2 Escherichia coli O157:H7.
3 Blood film would show signs of haemolysis—schistocytes, spherocytes, and reticulocytosis.
4 Thrombotic thrombocytopenic purpura.
5 Plasma exchange and dialysis.
The diagnosis of haemolytic uraemic syndrome was supported by a stool culture positive for Escherichia coli O157:H7, a blood film showing fragmented blood cells, a full blood count showing low platelets, and raised lactate dehydrogenase. He may have contracted E coli O157:H7 from the sandwich (though this is impossible to confirm). He needed haemodialysis and a total of 11 plasma exchanges. Renal biopsy showed glomerular intravascular thrombosis in keeping with haemolytic uraemic syndrome and acute tubular necrosis. One week after the diagnosis was made his condition deteriorated; he had several tonic-clonic seizures needing admission to the intensive care unit. After three weeks his clinical condition improved, and he was finally discharged home after a month with normal renal function.
Haemolytic uraemic syndrome is a form of thrombotic microangiopathy first described by Gasser et al,1 characterised by the triad of acute renal failure, haemolytic anaemia, and thrombocytopenia.2 It primarily affects children3 but can occur in adults.4 5
Haemolytic uraemic syndrome is classified as either diarrhoea positive or diarrhoea negative, depending on whether the patient has a diarrhoeal prodrome. The history taking should aim to establish whether the diarrhoea is infective or secondary to inflammatory bowel disease or other forms of colitis, which are important differentials as the diarrhoea may be bloody. In diarrhoea positive haemolytic uraemic syndrome, the diarrhoea is nearly always secondary to infection; therefore a careful travel and diet history is necessary. Abdominal pain should also cause the clinician to consider causes of acute abdomen as differentials.6
The pathophysiology of haemolytic uraemic syndrome is poorly understood. Damage to endothelial cells leads to an increase in proinflammatory and prothrombotic factors.7 Aggregation of platelets causes consumptive thrombocytopenia8 and the formation of microthrombi that are deposited in renal vasculature. These mechanisms reduce platelet count and cause renal failure. This microangiopathology is then responsible for mechanical haemolysis of red blood cells and the subsequent fall in haemoglobin concentration. Thus systemic symptoms may occur because of anaemia, and oliguria and hypertension can result because of rapid decline in renal function.
In diarrhoea negative haemolytic uraemic syndrome the triggers include antibodies, viruses (HIV, for example) and drugs,9 and the history taking and examination should focus on these. This form of the syndrome is less common.8
The diagnosis of haemolytic uraemic syndrome can be made only when haemolytic anaemia, thrombocytopenia, and renal failure are all confirmed.6
Investigations in haemolytic uraemic syndrome SerologyAnaemia secondary to haemolysis
Raised lactase dehydrogenase—confirms haemolysis
Blood film—schistocytes, spherocytes, and reticulocytosis
Urea and creatinine—when both are raised, acute renal failure is indicated
Serum concentrations of complement—possible familial cause24 25
Serum concentrations of drugs—immunosuppressants, for example26 27
MicrobiologicalStool cultures—screen for E coli O157:H7, but also other causes of infective diarrhoea
Blood cultures—screen for E coli O157:H7
HistologicalRenal biopsy—confirms the diagnosis and indicates the prognosis28 29
ImagingRenal ultrasound—check size of kidneys and exclude urinary outflow obstruction as the cause of renal failure
2 Findings on culture of stool
Escherichia coli O157:H7 releases Shiga toxins, triggering endothelial damage that leads to haemolytic uraemic syndrome; it is the commonest cause of the syndrome.6 8 10 The bacterium can be grown from stool and blood cultures.
E coli O157:H7 is transmitted through eating undercooked food, particularly meat. Beef,11 venison, and unpasteurised milk11 have been implicated. The faeco-oral route is another potential mode of transmission.11
3 Expected findings on blood film
On a blood film, schistocytes, spherocytes, and reticulocytosis indicate haemolysis. At a microscopic level, the haemolysis is essentially secondary to mechanical shearing by vessels narrowed by platelet aggregation. Lactate dehydrogenase is released when erythrocytes break down, and therefore a raised serum concentration confirms haemolysis.
4 Main differential diagnosis
A common difficulty is differentiating between haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura (TTP).4 Some clinicians say that the two are on a spectrum of the same disease; others claim that they are two distinct conditions with similar clinical manifestations.5 Those who say they are distinct conditions cite the differing pathophysiology: endothelial damage in haemolytic uraemic syndrome, and the autoimmune process of ADAMTS13 inhibition in TTP.12 13 14
The pathophysiology of secondary TTP is poorly understood, and much work recently has highlighted the importance of von Willebrand factor in haemolytic uraemic syndrome, thus blurring its boundary with TTP.4 5 13
Clinically, there is much overlap. The classic description of TTP is a pentad of microangiopathic haemolytic anaemia, thrombocytopenia, acute renal failure, neurological sequelae, and fever,15 though there are no particular pathognomonic features. Neurological symptoms are thought to be more common in TTP and renal failure more marked in haemolytic uraemic syndrome.16 Renal failure is an essential criterion in the diagnosis of haemolytic uraemic syndrome. This helps to distinguish the two conditions, as does the presence of diarrhoeal prodrome in haemolytic uraemic syndrome.
5 Therapeutic procedures
Few clear guidelines exist for treating haemolytic uraemic syndrome—as management is often at the discretion of the doctor, treatment stratagems vary.17 Fluid balance and electrolyte abnormalities caused by acute renal failure need to be managed, and dialysis is often indicated.
Plasmapheresis has been shown to improve survival and prognosis18 19 and is preferred to plasma infusion because it treats fluid overload20 (large volumes of plasma are needed for therapeutic effects) and because it is an extracorporeal form of treatment.21 22 This is true in both forms of haemolytic uraemic syndrome. Plasmapheresis is contraindicated when the syndrome is secondary to S pneumoniae, as antibodies to Thomsen-Freidenreich antigen circulate in adult plasma.21
The use of antibiotics in haemolytic uraemic syndrome remains controversial. Although E coli O157:H7 has been shown to be vulnerable to certain antibiotics22 there is strong evidence that using antibiotics can worsen haemolytic uraemic syndrome22 and can trigger the syndrome by enhancing release of Shiga toxins.22 23
Cite this as: BMJ 2009;338:b200
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