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HELLP Syndrome – a Multisystemic Disorder
Dan Mihu1, Nicolae Costin1, Carmen Mihaela Mihu2, Andrada Seicean3, Rãzvan Ciortea1 1) Clinic of Obstetrics-Gynecology. 2) Department of Histology. 3) 3rd Medical Clinic, University of Medicine and Pharmacy, Cluj-Napoca
HELLP syndrome is a multisystemic disorder with an incidence of 0.17-0.85% of all pregnancies. Its etiopathogenesis is not completely understood. The most widely accepted hypotheses are: a change in the immune feto-maternal balance, platelet aggregation, endothelial dysfunction, arterial hypertension and an inborn error of the fatty acid oxidative metabolism. Hepatic involvement occurs by intravascular fibrin deposition and hypovolemia. Maternofetal complications cause a 6.7-70% perinatal mortality rate and a 1-24% maternal mortality rate. The recognition of HELLP syndrome and the rapid initiation of therapy are required for the improvement of materno-fetal prognosis.
the absence of these disorders. The risk of recurrence in a subsequent pregnancy is estimated at 19-27% (3).
The pathogenesis of HELLP syndrome is not completely understood. Morphopathological lesions in preeclampsia involve a deficient remodeling of maternal vascularization through the placental trophoblast, occurring early during the course of pregnancy. Because trophoblast invasion invariably brings the fetus in contact with the immunocompetent maternal cells, feto-maternal interactions during the course of pregnancy are crucial for the prognosis (4). In the third trimester of pregnancy, there is a remarkable activation of maternal leukocytes in peripheral blood. Fetally derived soluble HLA antigen (sHLA-DR) levels are linked to the activated immunocompetent cells, and are due to an intense immune maternal response to the fetus. Since sHLA-DR molecules are able to induce cell apoptosis, even low sHLADR levels can be important for the regulation of the maternal immune system or for the maintenance of the feto-maternal immune balance during pregnancy (5). In HELLP syndrome, high plasma sHLA-DR levels are found. The syndrome can be considered an acute rejection of the fetal allograft. Moreover, the assessment of sHLA-DR levels can be used for the identification of the patients with preeclampsia at risk of the HELLP syndrome during pregnancy (5). In preeclampsia, there is an abnormal expression of cell adhesion molecules, as well as of the endothelial cell growth factor and its receptor in the trophoblast, causing a uteroplacental vascular insufficiency that will result in an abnormal release and metabolization of nitric oxide, prostaglandins and endothelin in the placental tissue. These changes induce platelet aggregation, endothelial dysfunction and arterial hypertension (6). Transmembrane Fas proteins, which belong to the tumor necrosis factor receptor family (TNFRSF), expressed by T lymphocytes that regulate the invasion of the trophoblast in the myometrium, also play a role. The substitution of a single nucleotide at position 670 of the maternal (not fetal) TNFRSF6 gene
HELLP syndrome - preeclampsia- pregnancy - liver hematoma - diagnosis- therapy
HELLP syndrome is a multisystemic disorder that complicates pregnancy and has a poor prognosis. It was first described by Weinstein in 1982. The acronym is for hemolysis (H), elevated liver enzymes (EL), thrombocytopenia (low platelet count – LP) (1). The name of the syndrome (hell + help) suggests the severity of maternal and fetal prognosis. It occurs in 0.17-0.85% of all pregnancies, and is more frequent in older multiparous Caucasian women. In 70% of the cases, the disorder is diagnosed antepartum: 10% before 27 weeks of gestation (WG), 70% between 27-37 WG, 20% after 37 WG (2). In 30% of cases it is diagnosed postpartum. HELLP syndrome is frequently associated with severe preeclampsia or eclampsia, but can also be diagnosed in
J Gastrointestin Liver Dis December 2007 Vol.16 No 4, 419-424 Address for correspondence: Assoc. Prof. Dan Mihu Clinic of Obstetrics-Gynecology 21 Decembrie Str, no 55-57 Cluj-Napoca, Romania E-mail: firstname.lastname@example.org
Given the recessive autosomal transmission. periportal hemorrhage and fibrin deposits in the hepatic sinusoids. a rare but severe complication. less than 34 WG. the partial thromboplastin time and serum fibrinogen levels are normal in HELLP syndrome. molecular diagnosis is recommended for all pregnant women with HELLP syndrome. preceding the laboratory diagnosis of HELLP syndrome by 1-2 weeks (11). as well as their partners and children (13. 9). plasminogens. with a reserved maternal prognosis (19). cause consumption thrombocytopenia and thrombotic microangiopathy in the HELLP syndrome. Hepatic involvement in pregnant women is more frequent when fetuses have a severe enzymatic deficiency (LCHAD). The prothrombin time. The pathogenesis of liver involvement in HELLP syndrome is unknown. 16). fibrinopeptide A. followed by the formation of a fibrin matrix at the site of the lesion. renal and hematologic disorders. The significantly increased levels of tissue plasminogen activator and plasminogen activator inhibitor-1 (PAI-1) in the context of HELLP syndrome compared to normal pregnancy suggest that platelet activation and the alteration of plasminogen activation are involved in the pathogenesis of this syndrome (9). A reduction in T and B lymphocyte function. A difficult differential diagnosis is with AFLP. The vascular endothelium can be damaged by segmental vasospasm. In the presence of this association.420 Mihu et al results in an increased capacity of maternal lymphocytes to recognize and destroy the trophoblast during invasion of the uterine wall and spiral arteries. The liver pathology is similar to that of the liver in preeclampsia. causing an increase in platelet clearance (8). and renal dysfunction (1. but are usually altered in DIC. a 3-hydroxyacyl metabolite that is produced by the fetus or the placenta. 26). The enzyme responsible for the cleavage of von Willebrand factor multimers ADAMTS13 has also a low level in women with HELLP syndrome compared to healthy pregnant women (10). eclampsia was present in 52%. Importantly. fibrin monomer. hemorrhage or gastrointestinal bleeding may occur. visual disorders and epigastric pain. A mutation allows a long chain fatty acid. associated with hypovolemia. but liver puncture biopsy is rarely performed because of defective coagulation (24). is associated with hemoperitoneum. An association with diabetes insipidus (20) or with antiphospholipid syndrome might be evident (21). but hypoglycemia and prolongation of the prothrombin time are present and the evolution is towards acute liver failure. 2. antiphospholipid antibodies should be searched for (22). once the liver glycogen source has been exhausted (12). In certain cases. Liver capsule rupture. presenting focal hepatocyte necrosis. A complex chain of events is initiated in the liver by intravascular fibrin deposition with sinusoidal obstruction. Most (90%) present a prodrome several days before seeing a doctor. 25. Macrovesicular fatty loading of the liver is different from that of AFLP. An inborn error of fatty acid oxidative metabolism may occur in fetuses born in the context of HELLP syndrome. which results in an insufficient mitochondrial oxidation of fatty acids required for ketogenesis. 2). as well as in the monocyte function. maternal and fetal mortality increase up to 50% (23). Circulating platelets adhere to the damaged or activated endothelium. with vital risk (6. In women with an early onset of preeclampsia. which may result in hepatic rupture. HELLP syndrome should not be considered as a variant of disseminated intravascular coagulation (DIC). The main disorders that should be considered in the differential diagnosis are gastrointestinal and liver diseases. i. which also occurs in multiparous women after 30 WG. D-dimers. Hepatic ischemia causes hepatic infarction. has been found. for those with acute fatty liver of pregnancy (AFLP). . nausea and vomiting. alpha-2 antiplasmin. Diagnosis Clinical picture Onset occurs in the last trimester of pregnancy in 70% of patients. such as antithrombin III. might better differentiate DIC from HELLP syndrome (1. correlated with headache. who have subsequently developed HELLP syndrome (15). altered liver tests. Morphopathological aspect is of microvesicular steatosis. prekallicrein. It has similar manifestations as HELLP syndrome (cytolysis and thrombocytopenia). fibronectin. even if microangiopathic hemolytic anemia is characteristic for both disorders. There are significant differences between these two entities. severe arterial hypertension is not constant and even absent in HELLP syndrome. with the release of von Willebrand factor multimers. In a study performed on 61 patients with HELLP syndrome. Physical examination reveals pain in the right upper abdominal quadrant. vasospasm and accelerated platelet aggregation (6. leading to an increased risk for HELLP syndrome (7). a significant weight gain and generalized edemas. Some patients present a pseudoinfluenza syndrome. pregnant women with these symptoms should undergo paraclinical investigations for HELLP syndrome (4).e. Evaluation of more sensitive markers of DIC. The break of the platelet membrane and the release of arachydonic acid and other vasoactive mediators produce vasoconstriction. and immediately after delivery in the rest of patients (18). Because early diagnosis is crucial. 14). Biological investigation The early diagnosis of HELLP syndrome is based on the detection of hemolysis. complaining of headache and visual disorders. to accumulate at maternal level due to a long chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency (LCHAD). subcapsular hematomas and intraparenchymatous hemorrhage. Hematomas are most frequently present in the right hepatic lobe (75%) (17). Endothelial cell activation. which is demonstrated by a decrease in the liver blood flow on Doppler examination in patients with preeclampsia.
IL8. In pregnant women. The lack of an increase in platelet levels after 96 hours from delivery indicates a severe disorder. independent of blood pressure values and of hemolysis degree. Antithrombin III < 79%. The velocity of the cerebral blood flow is increased (32). Uric acid >7. Liver specimens show a positive reaction with IL-1 β.TNF α and neutrophil elastase antibodies.HELLP Syndrome 421 Hemolysis is evidenced by an increase in lactate dehydrogenase (LDH) levels >600 UI/L and a decrease in serum haptoglobin values. thrombocytes <100. These are negative in patients with AFLP (31). Maternal platelet count decreases immediately after delivery.000100. An increase in the response of platelet calcium to arginin-vasopressin. at values > 3.000/mm3) and class III (100. The sudden increase in diastolic blood pressure over 120 mmHg raises the risk of lethal complications such as hypertensive encephalopathy. Markers of HELLP syndrome with a predictive value are searched for. Serum amyloid A is so far selected. except for severe cases complicated by DIC. Transcranial Doppler US evidences cerebral vascular changes similar to vasospasms. Imaging of the liver Liver imaging is important for the evaluation of subcapsular or intraparenchymal hemorrhage and hepatic rupture.000-150. Thrombocytopenia is the major and early cause of alteration of coagulation in the HELLP syndrome. but the levels of fibrin degradation products. Cortical ischemia can generate . Classification Two classifications for the HELLP syndrome are commonly used (1.8 mg/dl is an independent risk factor for materno-fetal morbidity and mortality (27). Hyaluronic acid levels increase in preeclampsia to > 100 μg/L. which precedes thrombocytopenia and occurs in the first trimester of pregnancy. the hepatic syntheses are maintained. DIC. reaching >100. an invasive procedure. ultrasound (US) and MRI are preferred due to the absence of ionizing radiation. Cerebral complications are rare. being fatal in 50-65% of cases. intrahepatic hematoma. there are two forms: complete (all elements present) and partial HELLP syndrome (one or two elements present). Acceleration of platelet destruction.000/mm3. and an irregular interface between the normal hepatic parenchyma and intrahepatic hematoma corresponding to the capsule rupture site (30). microangiopathy with sinusoidal obstruction causes hepatocyte necrosis responsible for the increase of aspartate aminotransferase (AST) (mean 250 UI/L) and alanine aminotransferase (ALT) levels (26). Fibrin deposits and hyaline deposits are shown by immunofluorescence at the level of liver sinusoids. Transabdominal US evidences intrahepatic hematomas as hypoechogenic structures.000/mm3). Hepatic arteriography.000/mm3). with the possible development of multiple organ failure (27). alteration of prostacyclin production and increased fibrin deposits in the vascular wall. an association with DIC can be considered. a moderate increase in gamma GT. These early sensitive markers of HELLP syndrome can be detected before the increase of serum unconjugated bilirubin level and decrease of hemoglobin values. The increased serum fibronectin levels indicates vascular involvement in preeclampsia. with a worse prognosis (19). D-dimers. but particularly severe. has been reported and proposed as a possible predictor of preeclampsia. However. D-dimers > 4 μg/ml and thrombinantithrombin complexes >26 mg/ml have been proposed as criteria for the induction of delivery in HELLP syndrome (17). Multiple factors are involved in the pathogenesis of thrombocytopenia: vascular endothelial damage. In 30% of cases. then rises starting with day 3 postpartum. The Tennessee System classification is based on the assessment of the following parameters: AST>70 UI/L. can establish the site of hemorrhage and is only performed before arterial embolization (30). increased platelet volumeand megakaryocyte production have also been found. The prothrombin time and the activated partial thromboplastin time (APTT) are normal in early stages. alkaline phosphatase and serum bilirubin is found (26). hypoperfusion). The Mississippi classification relies on the thrombocyte counts: class I (<50. CT is the method of election in the postpartum period (29. being a reliable marker for HELLP syndrome. Accordingly. being markers of secondary fibrinolysis and platelet aggregation. HELLP syndrome might cause both tubular necrosis potentially reversible and cortical necrosis (in most cases with sequelae). platelet activation. Acute liver failure is rare due to the double vascularization of the liver and to its capacity to function under low oxygen uptake conditions. focal parenchymatous necrosis and macrovesicular steatosis can be observed in 1/3 of patients.000/ mm3. Liver biopsy Liver biopsy has a risk of hemorrhage and hepatic rupture.000/mm3 after day 6 postpartum. As hepatic necrosis and intraparenchymal hemorrhage are focal lesions. A few patients present significant renal involvement. LDH >600 UI/L. occlusion of renal arteriole lumens.2).30). The prothrombin time is normal.5 mg/L (28). Renal complications occur at the microvascularization level (vascular thrombosis. When platelet count decreases to less than 50. Periportal hemorrhage. ventricular arrhythmias. Higher α-fetoprotein or human chorionic gonadotropin (HCG) values in the second trimester of pregnancy increase the risk of HELLP syndrome up to 47 times. class II (50. Complications and prognosis Cerebral hemorrhage is the most severe complication. and thrombin-antithrombin complexes are increased. by proteome analysis. CT or MRI can detect hemoperitoneum. Glutathione S transferase π and glutathione S transferase α are early markers of the hemolysis and liver damage.
labor. maternal mortality and morbidity due to the premature detachment of the normally inserted placenta. Treatment should be performed in Intensive Care Units (ICU) with dialysis and ventilatory support in severe cases. If no obstetric complications are present. 34).53). Perinatal infantile mortality varies between 6. heparin. hemorrhagic complications. nitroglycerine or sodium nitroprussiate (in hypertensive crisis). hydralazine. Patient counselling regarding the risk of recurrence of HELLP syndrome for subsequent pregnancies is mandatory. The prognosis of pregnancies complicated by HELLP syndrome depends on early diagnosis and early therapeutic approach (2). immunosuppressive agents. and have severe thrombocytopenia.000 cases. It is characterized by resistance to arginin-vasopressin mediated by high vasopressinase levels. the rupture of Glisson capsule occurs at the lower liver margin.7 and 70%. hemorrhage and shock. Diuretics are not used as a routine because they increase maternal hypovolemia and worsen uteroplacental hypoperfusion (2. Nephrogenic diabetes insipidus is a rare complication. The critical state of the patient is improved after the induction of delivery. and the perinatal mortality can reach 80% (7). Epidural anesthesia can be recommended when the thrombocyte count is higher than 100.000/ mm3. The maternal mortality rate varies from 18 to 86%. Renal failure in HELLP syndrome can be due to coagulation disorders. Plasmapheresis with fresh frozen plasma has been proposed as a therapeutic method in patients who show a progressive increase in bilirubinemia. acute pulmonary edema and hepatic rupture occurred at the same rate. hemorrhage and hematomas. to reduce the risk of necrotic hemorrhagic rectocolitis and intraventricular hemorrhage of the fetus. and prematurity. vaginal delivery is preferred. since it does not improve prognosis (43. even if the Glisson capsule is intact. and microangiopathic thrombosis causes renal dysfunction. serum creatinin. Hypertension in preeclampsia can be treated with i. patient transportation. and 25% thrombocytopenia. Mg sulfate. Obstetric approach The induction of delivery is the only specific therapy in HELLP syndrome. cardiopulmonary. immediate induction of delivery is recommended. calcium channel antagonists. Delivery by cesarean section is required in 60% of cases. its evacuation is not required. and perinatal infantile mortality and morbidity were similar. Therapy The management of patients with preeclampsia and HELLP syndrome is controversial. subfascial drainage may be necessary in order to reduce the risk of hematomas. In pregnant women with a gestational age of more than 34 WG. aspirin in low doses. a consensus of the NIH recommends the use of corticosteroids to accelerate fetal pulmonary maturity. Massive blood transfusions and the correction of coagulopathy with . The conclusion was that steroid therapy should only be administered to very well selected cases. Surgical approach The rupture of a subcapsular liver hematoma followed by shock represents a surgical emergency (52. although the higher risk is for developing preeclampsia (43%) or other complications in a new pregnancy (27). When the hematoma is extensive. 30% show intrauterine growth retardation. intrauterine asphyxia. dialysis. causing sudden epigastric pain. Its incidence is about 8% (27). a small liver hematoma with an intact Glisson capsule is detected. Most frequently. The maternal advantage of corticotherapy was an extension of the time period between hospital admission and the induction of delivery. but has no favorable results in patients with fulminant hemolysis (45. Because of the presence of hepatic hemorrhage and subcapsular hematoma. In the case of cesarean section. 46).000 to 1/ 250. antithrombotic agents. seizures) may induce hepatic rupture. Imaging or paracentesis are diagnostic for intraperitoneal hemorrhage. allowing the delay of delivery. and consists of plasma expanders. If during the cesarean section. Hepatic complications include infarction. Hepatic rupture occurs in 1/40. About 60% of fetuses die intrauterinely. it is recommended to open the capsule and evacuate the hematoma in order to avoid its extension and secondary hepatic rupture (49). fresh frozen plasma. In an analysis performed on 170 patients with HELLP syndrome. The early recognition of HELLP syndrome and the initiation of early therapy are required in order to ensure the favorable evolution of the mother and fetus. Maternal mortality varies between 1 and 24% and can be due to coagulation disorders. antithrombin. hepatic and gastrointestinal disorders (35-37). 44).v. liver palpation. prostacyclin.422 Mihu et al arterial hypertension. The improvement of thrombocytopenia has been more frequently observed for the low doses compared to the high doses (40-42). Severe maternal complications are more frequent when the induction of pregnancy is delayed for more than 12 hours (48). At a gestational age between 24-34 WG. and the fetal advantage was an increase in weight at birth. Patients with atypical forms of preeclampsia or HELLP syndrome should be investigated for antiphospholipid antibodies (38). comparing the dexamethasone group to a control group. Most therapeutic modalities are similar to those applied for severe preeclampsia.51). The increased vasopressinase levels may occur as a result of deficient hepatic metabolization (33. minor trauma (vomiting. central nervous system. anemia and hypotension. steroids. It is caused by the premature detachment of the normally inserted placenta. 4. 47). when there are no coagulation disorders and the bleeding time is normal (50. The administration of corticoids is followed by a rapid improvement of clinical and laboratory parameters. This is also recommended for patients in whom HELLP syndrome persists for more than 72 hours postpartum.
What we have learned about preeclampsia. Liver transplantation is necessary when hemorrhage cannot be arrested during laparotomy or in the context of fulminant liver failure (58). 12. which develops with focal liver involvement. Are clinical symptoms more predictive than laboratory parameters for adverse maternal outcome in HELLP syndrome? Acta Obstet Gynecol Scand 2007. Salama M. Hauth J. Zhou Y. and low platelet count. Espinosa G. Zhao Y. their resection is not required in the same operative time. hemolysis and thrombocytopenia. Branch DW. Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis. Semin Perinatol 2003. 19. Benyo DF. Grosse-Wilde H. 21. 17. fresh frozen plasma and thrombocyte mass are mandatory (7). 94: 48-52. JAMA 2002. 9. Sibai BM. Ginecol Obstet Mex 2007. 75: 224-229. Pereira PL. 3. 11. May WL. The induction of delivery. et al. 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