hemolytic uremic syndrome
Introduction
Introduction to hemolytic uremic syndrome Gasser (1955) first reported five cases of children with hemolytic anemia, acute renal insufficiency and thrombocytopenia. Later, this type of triple syndrome is called haemolyticuraemicsyndrome (HUS), which is also called microangiopathichemolyticanemia. A typical HUS is a syndrome characterized by abnormal red blood cell morphology, clinically characterized by hemolytic anemia, thrombocytopenia, and acute renal failure. Intrarenal microvascular hemolysis and intravascular coagulation vascular endothelial injury are the central link of all HUS pathogenesis, and also the initial link. Endothelial cell damage can be through inflammatory and non-inflammatory pathways, STEC-derived lipopolysaccharide (LPS) It can activate white blood cells, activate neutrophils to release TNF, IL-1, internal elastic enzymes and oxygen free radicals, stimulate the synthesis of cytokines TNF and IL-1. LPS and cytokines have synergistic effects and can damage endothelial cells, TNF. Or LPS can stimulate the apoptosis of endothelial cells exposed to Stx, causing damage to vascular endothelial cells, damage to renal capillary endothelial cells caused by various reasons, causing fibrin deposition, endothelial cell damage manifested as cell swelling, shedding, endothelial cell damage After exposure to the basement membrane, activation of platelets and localized intravascular thrombosis, on the one hand, due to mechanical damage to red blood cells and platelets, microvascular hemolytic anemia and thrombocytopenia, and on the other hand due to microvascular disease and swelling of endothelial cells, Platelets adhere, aggregate, and form thrombus at the damaged site, causing intrarenal micro Tube thromboembolism, resulting in a sharp decline in glomerular filtration rate, can occur with severe renal cortical necrosis, acute renal failure eventually. basic knowledge The proportion of illness: the incidence rate is about 0.005%-0.009% Susceptible people: no special people Mode of infection: non-infectious Complications: jaundice, diabetes, ataxia, disturbance of consciousness, coma, pulmonary edema
Cause
Causes of hemolytic uremic syndrome
Genetic factors (20%):
HUS is inherited by autosomal recessive or autosomal dominant inheritance. Autosomal recessive inheritance can be more than one year between siblings of the same family. The chance of involvement in children is higher than that of newborns and adults, and the prognosis is poor. The mortality rate is close to 65%. Most patients with autosomal dominant HUS are adult, with recurrent attacks and poor prognosis.
Infection (20%):
(1) Bacteria: Escherichia coli infection of Shiga toxin, resulting in Shiga toxin as-sociated HUS (Stx HUS) accounting for 75%, is the most common type, Escherichia coli secreting Stx ( STEC) secretes Stx1, Stx2 and its derivatives, Shigella dysenteriae, Salmonella, and Pseudomonas infections are also associated with the pathogenesis of HUS. Bacteria such as Streptococcus pneumoniae can react TF antigen on the surface of red blood cells with its own TF antibody. , causing blood cells to aggregate and induce HUS.
(2) Virus: A variety of viruses that may be associated with this disease have been isolated. The incidence of HUS is high after infection by some viruses. Coxsackie virus, ECHO virus, influenza virus, Epstein-Barr virus, mucus virus, etc. Arbovirus, varicella virus, infectious mononucleosis virus, etc.
(3) Others: Rickettsia and mycoplasma infections have also been reported in relation to HUS.
Cancer with HUS (15%):
Some tumors, such as gastric cancer and prostate cancer, are particularly prone to occur when mitomycin C is used to treat adenocarcinoma. The incidence rate is 4%. It usually occurs after 6 to 12 months, often accompanied by acute respiratory distress syndrome. Poor, the mortality rate is as high as 70%. In addition, vinblastine, cisplatin, bleomycin, 5-fluorouracil, bleomycin, etc. can induce HUS.
Drugs or certain chemicals (15%):
In addition to some anti-tumor drugs, contraceptives or other estrogen-containing drugs, penicillin, ampicillin, immunosuppressive agents, cyclosporine, quinine, cocaine, etc. can induce HUS, eat spoiled food, a certain toxin in food It can cause endothelial cell damage directly or indirectly.
Other factors (10%):
Adult HUS is also common in acute hypertension, rheumatic diseases, bone marrow transplantation or kidney transplantation, endocrine and metabolic abnormalities such as prostacyclin deficiency, alpha-tocopherol deficiency, vitamin B12 metabolism abnormalities, etc. can be the predisposing factors of this disease.
Pathogenesis
1. Intrarenal microvascular hemolysis and intravascular coagulation vascular endothelial injury are the central link of all HUS pathogenesis, and also the initial link. Endothelial cell damage can pass through two pathways: inflammation and non-inflammation. STEC-derived lipopolysaccharide (LPS) activates white blood cells, activates neutrophils to release TNF, IL-1, internal elastic enzymes and oxygen free radicals, stimulates the synthesis of cytokines TNF and IL-1. LPS and cytokines have synergistic effects and can damage endothelial cells. TNF or LPS can stimulate the apoptosis of endothelial cells exposed to Stx, causing damage to vascular endothelial cells, damage to renal capillary endothelial cells caused by various causes, causing fibrin deposition, endothelial cell damage manifested as cell swelling, shedding, and endothelium. After cell damage, the basement membrane is exposed, activates platelets and causes local intravascular thrombosis, on the one hand because of red blood cells and platelets are mechanically damaged, resulting in microangiopathic hemolytic anemia and thrombocytopenia, and on the other hand due to microvascular disease and endothelial cells Swelling, platelets adhere to and accumulate at the damaged site, forming a thrombus, causing intrarenal micro Thromboembolism of blood vessels leads to a sharp decline in glomerular filtration rate, renal cortical necrosis can occur in severe cases, and acute renal failure eventually occurs.
2. Stx damage to renal tubular epithelial cells After Stx Escherichia coli infection, Stx enters the blood circulation, binds to the renal endothelial cell glycolipid receptor glycosphingolipid receptor, inhibits endothelial cell protein synthesis, causes cell necrosis or Apoptosis, acute tubulointerstitial injury can lead to acute renal failure.
3. Bacterial toxins and neuraminidase directly damage epithelial cells. Bacterial endotoxin can release cytokine-mediated endothelial cell damage, activate macrophages to increase active oxidative metabolites, activate neutrophils, and increase cell surface receptor expression. It promotes leukocyte aggregation, causes neutrophil-mediated cell damage, and activates complement and platelet activating factor to participate in the pathogenesis.
Neuraminidase is a harmful factor that can damage glomerular capillary endothelial cells and cause disease. Pneumococci can also produce this enzyme.
4. Hemagglutination and fibrinolysis abnormality HUS The balance between thromboxane (TXA2) and platelet activating factor (PAF) and prostacyclin (PGI2) is destroyed, and the damaged vascular endothelial cells in HUS cannot produce PGI2, endothelium. The cell-producing factor of PGI2 is also reduced, the degradation of PGI2 is accelerated, the consumption is increased, the decrease of PGI2 causes the platelet to accumulate, and the adhesion is strengthened, which is beneficial to the deposition of platelets in the damaged glomerular capillary wall. The PAF produced by the kidney can promote platelets. Continuous activation and deposition of platelets in glomerular capillaries promote platelet aggregation and thrombosis, leading to a sharp deterioration of renal function, reduction of plasminogen activator produced by vascular endothelium, thrombosis, and macromolecules produced by vascular endothelium. Vascular von Willebrand Factor (VWF) multimer promotes adhesion of platelets to injured vessel walls and promotes thrombosis.
Recently, studies have concluded that the following factors eventually lead to hypercoagulability, enhanced platelet adhesion and aggregation, and low fibrinolytic activity:
(1) Inflammatory mediators: especially TNF, IL-6, IL-8, involved in endothelial cell injury and activation.
(2) Activation of platelets and blood coagulation processes.
(3) Reduced PGI production in endothelial cells.
(4) Endothelin-endothelium relaxing factor imbalance in endothelial cells.
(5) Lipid peroxide.
(6) Circulating immune complexes and anti-endothelial cell antibodies.
5. Immune mechanism The pathogenesis of HUS may be related to immunity. Most cases of HUS have respiratory or gastrointestinal infections before the onset of HUS, which is consistent with the pathogenesis of antigen-antibody reaction. Some patients have IgA, IgM and C3 decrease in the early stage of the disease. Immunofluorescence of renal tissues revealed deposition of IgM, C3, C1q, properdin and fibrinogen.
6. Pregnancy is easy to cause HUS mechanism. The fibrinogen in the blood circulation of pregnant women, the V, VII, VIII coagulation factors have different degrees of increase, while the fibrinolysis ability is reduced, some complications of pregnancy (abortion, placental abruption) , eclampsia, etc.) due to the release of the thromboplastin (thromboplastin) can cause the activation of blood coagulation mechanism, it is easier to induce intravascular coagulation in pregnant women in the hypercoagulable state, forming a microthrombus in the kidney and causing disease.
7. The pathologically severe glomerulus is congested, infarcted, transparent thrombus can be seen in the capillaries, the lesion is lighter, the capillary wall is thickened, there is eosinophilic, and the glycogen staining is weakly positive. The transparent substance is deposited on the endothelial cells. Mesangial cell proliferation is also evident between the basement membranes. Under electron microscopy, endothelial cell damage is mainly found in glomerular capillaries and renal arterioles. Granular or fibrous electron denses are present between endothelial cells and their basement membranes. The gap, the glomerular capillaries have a large number of platelets, capillaries, subendothelial and mesangial cellulose deposits.
Cellulose-like necrosis occurs in the affected arterioles and interlobular arterial wall, and the exfoliation of endothelial cells can be seen. The interstitial space between fibrin in the thrombus is larger than the cavity formed in the glomerular capillaries. Aneurysm formation, especially in the small arteries of the aorta, renal cortical necrosis can be focal, or involving all.
Prevention
Hemolytic uremic syndrome prevention
The disease is a disease caused by multiple causes, and there is no effective preventive measure for HUS caused by genetic factors. For other causes, the patient should actively treat the primary disease or avoid the application of nephrotoxic drugs to prevent the occurrence of HUS. Progressive increase.
Complication
Hemolytic uremic syndrome complications Complications jaundice diabetes ataxia dysfunction disorder coma pulmonary edema
HUS has a wide range of extrarenal damage, and some are life-threatening, but with the improvement of treatment, the mortality rate has dropped below 10%, and only about 5% of survivors have persistent and severe extrarenal sequelae.
1. Digestive system diseases In addition to the intestinal manifestations mentioned above, there are also: 1 pancreatic disease: the pathological damage of the pancreas is also caused by thrombotic microangiopathy (TMA), which can lead to pancreatic internal and external secretion, but there is clinical pancreatitis. There are not many performers, and 4% to 15% of patients can show temporary or permanent diabetes. 2 liver disease: visible liver enlargement and transaminase increased, occasionally cholestatic jaundice, no reports of chronic liver damage and liver failure, liver biopsy showed small thrombosis, no liver necrosis. 3 gallbladder disease, can occur cholelithiasis, and may be related to rapid hemolysis to form bilirubin calcium salt stones.
2. Central nervous system damage is diverse, there are irritability, lethargy, anxiety, but also hallucinations, delusions, stupor and even coma and other degrees of disturbance of consciousness, examination can be seen tremor, convulsions, hyperreflexia, ataxia, Pakistan Signs of cerebral spinal fluid (+) and cranial nerve damage, cerebrospinal fluid protein quantitative increase, CT and MRI examination can determine the nature and location of the damage.
3. Circulatory system damage can be seen in myocarditis, myocardial infarction, heart failure.
4. Respiratory system damage has pulmonary edema or hemorrhagic infiltration. The autopsy can detect pulmonary microthrombus more than the number of patients with significant primary lung damage.
5. Others such as skin ecchymosis, herpes labialis also occurred. The autoimmune of HUS children found thrombosis in the microvascular system of the adrenal gland, thyroid gland, thymus, lymph nodes, bladder and ovary, but no organ dysfunction associated with these anatomical lesions has been reported.
Symptom
Symptoms of hemolytic uremic syndrome Common symptoms Acute hemolytic uremic syndrome Hematuria bleeding tends proteinuria pale coma azotemia abdominal pain dying blood in the stool
HUS can be ill at any age, but it mainly occurs in young children and children. There is no significant difference in gender, but adults are more likely to be associated with pregnancy. HUS may be associated with pregnancy. Rural areas are more common in cities and are usually sporadic. All have onset, but the peaks in late spring and early summer, the severity of the disease is different, and there are different variability.
1. The prodromal symptoms are typical of prodromal symptoms, with gastrointestinal symptoms as the main manifestations, such as loss of appetite, vomiting, diarrhea, abdominal pain, with moderate fever, a small number of severe bloody stools, 1/3 children with upper respiratory tract infection symptoms, this period Usually 1 to 7 days, then enter the acute phase after 1 to 5 days of asymptomatic period.
2. Acute manifestations Typical manifestations of the acute phase are hemolytic anemia, thrombocytopenia and acute renal failure.
(1) hemolytic anemia: hemolytic anemia manifests a significant reduction in hemoglobin in the short term, the degree of anemia is inconsistent with the severity of acute renal failure, pediatric manifestations are pale, jaundice is generally not obvious, or only the face is lemon yellow, at the beginning of the disease There are repeated hemolytic crisis in 2 weeks, hemoglobin can be reduced by 30 ~ 50g / L within a few hours, check the peripheral blood leukocytes and reticulocytes increased, blood smear can be seen in the shape of red blood cells and red blood cell debris, red blood cells can be triangular, Armor type, thorn type, blood non-binding bilirubin increased, red blood cell life shortened, an average of 3 days, anemia continued to recover after 1 to 3 weeks.
(2) thrombocytopenia: 90% of patients have thrombocytopenia, mainly due to increased peripheral damage, platelet survival time is shortened from normal 7 to 10 days to 1.5 to 5 days, thrombocytopenia generally lasts 7 to 14 days, a small number of recovery Slow, bleeding due to thrombocytopenia, manifested as nosebleeds, bleeding gums, skin blemishes or small hematoma, hematemesis, blood in the stool, hemoptysis, fundus hemorrhage, and even cerebral hemorrhage.
(3) acute renal failure: renal damage leads to acute and severe renal failure, lighter only temporary reduction in urine output, mild renal dysfunction, sometimes called laboratory hemolytic uremic syndrome, severely less Urine type, oliguria can last from 2 days to 8 weeks, urine test has protein, red, white blood cells and casts, and other symptoms of acute renal failure, such as azotemia, hyperkalemia, metabolic acid Poisoning, high blood volume, high blood pressure, etc., due to the large amount of red blood cells destroyed by hemolytic release of uric acid, it is prone to hyperuricemia, and some cases induce congestive heart failure due to severe anemia, oliguria, hypertension, electrolyte imbalance, etc. Abnormalities, sudden cardiac arrest and death, the incidence of chronic renal failure in HUS is 10% to 40%, requiring long-term dialysis treatment to maintain life.
(4) symptoms of the nervous system: HUS can affect the central nervous system, some patients have varying degrees of neuropsychiatric symptoms, such as headache, lethargy, irritability, muscle tremor, convulsions, and even coma, some cases of legacy neurological sequelae, such as Abnormal behavior, learning difficulties, severe mental retardation, and even seizures.
(5) Other manifestations: Invasion of the heart due to myocardial necrosis caused by myocardial microvascular thrombosis, causing heart failure, arrhythmia, severe sudden death, pulmonary microvascular thrombosis can lead to chest tightness, hemoptysis, pulmonary insufficiency and other performance.
3. Variant HUS
(1) Familial HUS: In addition to genetic factors, familial cases may suffer from pathogenic factors in the environment.
(2) Recurrent or recurrent HUS: There are few typical prodromal symptoms in recurrence. The recurrence of adult women often occurs during pregnancy, and the mortality rate is as high as 30%.
(3) Postpartum HUS: There are many symptoms such as flu-like syndrome, vomiting and diarrhea, or urinary tract infection.
The traditional HUS diagnosis is mainly based on clinical, that is, the presence of microvascular hemolytic anemia, thrombocytopenia and renal damage (hematuria, proteinuria and renal insufficiency) can be diagnosed as HUS, but in fact, the clinical manifestations of HUS change, performance is not the same The literature reports that many clinical manifestations of HUS are not typical. For example, anemia and thrombocytopenia can be mild or not present, and there is no clinical manifestation of renal disease. Therefore, the diagnosis of HUS should be understood from the basic pathological changes and pathophysiological aspects of HUS. The occurrence of kidney disease changes plays a decisive role in the diagnosis of HUS.
Examine
Examination of hemolytic uremic syndrome
1. Severe hemolytic anemia can occur repeated hemolysis within a few days to several weeks, reticulocytes increase, medullary red blood cells increase, and hemoglobin decreases.
2. The Coombs test was mostly negative and the erythrocyte enzyme activity was normal.
3. The peripheral blood smear can be seen in the strange shape of red blood cells, helmet-shaped cells and broken red blood cells.
4. Thrombocytopenia is common and lasts for days to weeks.
5. Other
(1) Prothrombin time: Some patients have normal or slightly shortened thromboplastin time, and V or VIII factors are normal or slightly increased; fibrin cleavage products are increased, and ATIII can be decreased.
(2) Serum C3, C4 and CH50 can be decreased: C3 can be deposited in the glomeruli of some patients; serum IgG concentration begins to decrease, while IgA and IgM increase; IgM deposits are often detected in the glomerular mesangial area. Fibrinogen deposition is common.
(3) Urine examination: visible proteinuria, hematuria and tubular urine and BUN increased.
(4) Electrolyte disorders, including serum sodium, bicarbonate and calcium, blood potassium can be high or low, serum cholesterol, triglycerides and phosphorus can be increased.
1. Renal histological examination The basic pathological changes of HUS are thrombotic microangiopathy. The kidney is the main affected organ of HUS. The renal histological examination shows that the kidney is microvascular, which may involve glomerular and renal interstitial arteries. The lesions are characterized by swelling of endothelial cells, enlargement of the subendothelial space leads to thickening of the capillary wall, narrowing of the lumen, fibrin and lipid deposition under the endothelium, red blood cells, platelets and microthrombus in the capillary lumen, mesangial area increase Wide, mesangial cells are lysed or foam-like cells. In some cases, crescents and tendon necrosis may occur. In severe cases, small arteries may be involved, renal cortical necrosis may occur, and lesions of glomeruli may be focally distributed. In addition, glomeruli may be present. Ischemic signs, glomerular GBM thickening, shrinkage, glomerular collapse, cyst thickening, renal interstitial arterioles and small artery endothelial cells proliferating, intimal swelling, tube wall necrosis, lumen narrowing, Some cavities can be seen in the lumen, renal tubules, interstitial lesions are often moderate, severe, and some have tubular necrosis. In the late course of the disease, small arterial fibrosis can be seen, eventually leading to small arterioles and glomeruli. , Hyaline abandoned glomerular, tubular atrophy, and interstitial fibrosis (FIG. 1).
Immunofluorescence examination showed that fibrin was found in most microthrombus. IgM, C3, C1q and properdin deposition were observed on the arterial wall. Electron microscopy showed that glomerular swelling of endothelial cells could be exfoliated from GBM and new along the endothelial cells. The thin basement membrane is formed, and there are cell-like electron-relaxing substances under the endothelium, and the capillary lumen is narrowed, and foam cells containing fat droplets, membranous matrix edema, and even dissolution are seen.
The extent and extent of glomerular and arterial damage can vary depending on the cause, condition, stage of disease, and age of onset. Some scholars have classified HUS kidney lesions into three types:
(1) glomerular damage is the main.
(2) Mainly caused by vascular injury.
(3) Renal cortical necrosis.
These three lesions can also overlap each other. In the same case, glomerular lesions can coexist with severe arterial lesions. The lesions in children are mainly glomerular, vascular lesions are mild, and even the subendothelial space is widened. Adult HUS artery The lesion is more obvious, so the prognosis is not as good as the child.
In addition to kidney involvement, HUS can also affect the central nervous system, gastrointestinal tract, lung, heart and other organs, as well as microvascular embolism and necrotizing lesions.
2. Regular B-ultrasound, X-ray, CT and other inspections.
Diagnosis
Diagnosis and diagnosis of hemolytic uremic syndrome
Diagnostic criteria
1. Basis for severe hemolytic anemia.
2. Thrombocytopenia.
3. Acute renal failure, abnormal urine test such as proteinuria, red, white blood cells and tubular urine.
4. Blood smear has abnormal red blood cells and red blood cell debris, abnormal blood coagulation, prolonged thrombin time, and increased FDP.
5. Renal biopsy confirmed renal microvascular disease, microvascular embolism.
All of the above contribute to the diagnosis of HUS.
Differential diagnosis
Should be noted with the identification of toxic or ischemic acute tubular necrosis, children and adolescents should be differentiated from allergic purpura nephritis, women of childbearing age should be identified with lupus nephritis, HUS with fever and central nervous system symptoms pay attention to thrombotic platelets Reduced purpura (TTP) phase differentiation, both clinically have microvascular hemolytic anemia, thrombocytopenia and renal dysfunction, pathologically have microembolism, but HUS mainly occurs in children, especially infants, microvascular disease Involved in the kidneys. TTP often invades adults, and the lesions are mainly affected by the central nervous system. However, the two diseases may overlap. Others believe that the different manifestations of the same disease are not included in the thrombotic microangiopathy (TMA).
