Approach
Although the disorder is considered to be a severe form of pre-eclampsia, not all patients affected by HELLP syndrome meet the presenting diagnostic criteria for severe pre-eclampsia. In independent studies, severe hypertension initially was absent in 12% to 18% of patients with HELLP syndrome, and in another 15% blood pressure was normal.[5][30][54][55] Likewise, 4% to 14% of patients lacked proteinuria.[1][5] Consequently, all women suspected of pre-eclampsia, including those with non-specific symptoms such as nausea, vomiting, or malaise, should be evaluated for possible HELLP syndrome. Up to 95% of patients with HELLP syndrome eventually express hypertension during the course of therapy.[5]
HELLP syndrome is a serious condition characterised by progressive and sometimes rapid maternal and fetal deterioration.
The diagnoses of thrombotic thrombocytopenic purpura (TTP), haemolytic uraemic syndrome (HUS), acute fatty liver of pregnancy (AFLP), and systemic lupus erythematosus (SLE)-catastrophic antiphospholipid syndrome (CAPS) should always be entertained when considering a diagnosis of HELLP syndrome, particularly in a patient whose presumptive HELLP syndrome is unresponsive to medical management and delivery. Women with TTP, HUS, SLE-CAPS, or AFLP initially considered to have HELLP syndrome incur great risk unless other disease-specific therapy, usually including plasma exchange, is appropriately and timely instituted.
History
Key risk factors include white ethnicity, advanced maternal age, multiparity, obesity, chronic hypertension, diabetes mellitus, autoimmune disorders, abnormal placentation (e.g., molar pregnancy), and a prior pregnancy with pre-eclampsia with or without HELLP syndrome.
Non-specific symptoms may be the only presenting element, but they may indicate significant illness. Common symptoms include headache (in 33% to 61%), nausea and/or vomiting (29% to 84%), generalised malaise (90%), and right upper quadrant (RUQ) or epigastric pain (40% to 100%). Visual disturbances occur in <20% of cases.[1][5][55][56]
Physical examination
On physical examination, two-thirds of patients manifest oedema and hypertension. Tenderness to palpation in the RUQ is common, as are brisk reflexes. Jaundice and bleeding manifestations, such as haematuria, may rarely be present.
Diagnostic criteria
The laboratory diagnostic criteria for HELLP syndrome vary somewhat in the literature, but the following guidelines are commonly used.[1][10][30]
Haemolysis: schistocytes, burr cells, and polychromasia on a peripheral blood smear, are diagnostic; however, peripheral blood smears are not routinely performed in clinical practice. Rather, elevated total and indirect (unconjugated) bilirubin (total bilirubin 20.5 micromol/L [1.2 mg/dL] or more), low serum haptoglobin, and elevated lactate dehydrogenase (LDH) are considered sufficient evidence of haemolysis.
Elevated liver transaminases: aspartate transaminase (AST) or alanine transaminase 70 IU/L or more, or twice the upper limit of normal concentration for either/both analytes not accounted for by alternative diagnoses.
Low platelets: moderate to severe thrombocytopenia (platelet count <100 x 10⁹/L [<100,000/microlitre]).
Although definitions and strict cut-off values are often arbitrary, adherence to widely accepted diagnostic criteria facilitates scientific reporting and communication. This includes assignment of class (1, 2, 3) to facilitate management and compare outcomes.
It is also most important to differentiate HELLP syndrome from TTP, not least because their management is different and the use of plasma exchange in TTP can be lifesaving. An LDH-to-AST ratio that is >22.0 suggests the presence of TTP when access to immediate assay for ADAMTS-13 is unavailable. Rarely, a patient with SLE-CAPS, HUS, or AFLP may meet criteria for HELLP syndrome but not respond to traditional management until plasma exchange is undertaken.[57]
Rarely, patients can present with a clinical and laboratory picture that appears to be pre-eclampsia with HELLP syndrome. Some of these disorders include immune thrombocytopenic purpura, acute pancreatitis/cholecystitis, hypotensive or septic shock, severe folate deficiency, parathyroid adenoma with hypertensive crisis, Wilson's disease, acute myeloid leukaemia, several forms of acute haemolytic anaemia, severe vitamin B12 deficiency, babesiosis, and haemophagocytic lymphohistiocytosis.[15][30][58][59][60][61] When HELLP syndrome fails to respond to recommended therapy (usually with delivery), the presence of one of these other conditions is considered.
Laboratory studies
Initial laboratory studies in all patients with clinical features suspicious for pre-eclampsia or HELLP syndrome should include:
FBC
LFTs (AST, bilirubin, LDH)
Peripheral blood smear
Uric acid, fibrinogen, and prothrombin time/partial thromboplastin time. These are undertaken in the patient with severe disease who might have evidence of advanced renal compromise, placental abruption, or the suspicion of an imitator disorder
Optional studies include serum electrolytes, serum creatinine, and serum glucose.
The pregnant patient meeting the laboratory diagnostic criteria should be considered to have HELLP syndrome regardless of the presence or absence of hypertension, proteinuria, or other clinical signs. Some patients with partial HELLP syndrome may present with only elevated liver enzymes and low platelets ('ELLP') or isolated elevated liver enzymes ('EL').
A decreased haematocrit may or may not be present. While haemolytic anaemia is part of the pathology, patients with HELLP syndrome are frequently haemoconcentrated at baseline, a situation that may mask the haemolysis, at least until later stages of the disease. In each case, if other diagnostic criteria are met, the patient should be considered to have severe pre-eclampsia and be treated accordingly. AST is the dominant transaminase initially released in the peripheral circulation in pre-eclampsia, including in HELLP syndrome.[2]
Not infrequently, serum creatinine is elevated. A urinalysis should be performed in all patients, and proteinuria, caused by increased renal tubular permeability, is found in 66% to 100% of patients.
Major maternal morbidity
The risk of serious maternal morbidity correlates in general with increasingly severe signs, symptoms, and laboratory abnormalities. It is greatest and maternal mortality is most likely when HELLP syndrome deteriorates to the most advanced stage of class 1.[5][30][52] Major maternal morbidity includes the presence in a patient of any one or more of the following by category: cardiopulmonary complications of pulmonary oedema, pleural or pericardial effusion, required intubation with ventilator support, congestive heart failure, myocardial infarction or arrest; haematological/coagulation complications of disseminated intravascular coagulation, or required transfusion of blood products; central nervous system/visual complications of stroke, cerebral oedema, hypertensive encephalopathy, vision loss, posterior reversible encephalopathy syndrome; hepatic complications of subcapsular liver haematoma or rupture; and renal complications if serum creatinine exceeds 1.2 mg/dL with acute tubular necrosis or acute renal failure.
Imaging
Maternal imaging studies are not routinely necessary in HELLP syndrome. However, in the patient with significant RUQ pain and decreased haematocrit in whom liver bleeding as hepatic infarction, haematoma, or rupture is suspected, ultrasound examination (possibly computed tomography or magnetic resonance imaging) is indicated to rule out the presence of hepatic subcapsular haematoma or intraparenchymal haemorrhage.
Fetal biometric and biophysical characteristics should be evaluated as well as gestational age determination, with additional umbilical artery Doppler flow evaluation in the presence of fetal growth restriction. Continuous fetal heart-rate monitoring is advisable where feasible.
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