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  Disease summary:

  
  
  
  
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    Hypertensive disorders of pregnancy

    
    
    
    
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      A spectrum of clinical disorders including pre-eclampsia, eclampsia, HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), and pregnancy complicated by hepatic infarction and/or rupture.

      
      
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      Pre-eclampsia complicates approximately 5% of all pregnancies. Many women with pre-eclampsia have mildly abnormal liver function tests, but 5% to 20% of pre-eclamptic pregnancies develop HELLP syndrome.

      
      
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      Risk factors for the development of pre-eclampsia include primiparity, older maternal age, increased body mass index, long birth interval, medical disorders including diabetes mellitus, chronic renal failure and antiphospholipid syndromes, family history of pre-eclampsia, or fetal factors including multiple pregnancy, or the presence of a hydatidiform mole.

      
      
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      Uncomplicated pre-eclampsia is defined as the development of hypertension and proteinuria in pregnancy. Oedema is often seen. Pre-eclampsia can also be associated with abdominal pain, headaches, visual changes, and renal and liver impairment, but the liver impairment is usually mild.

      
      
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      HELLP syndrome is a subgroup of women with pre-eclampsia and is a severe variant of the condition. Hypertension and proteinuria may be absent in up to 15% of women presenting with features of HELLP syndrome. Severe disseminated intravascular coagulation and multiorgan failure can be associated with this condition and lead to significant maternal and fetal morbidity and mortality.

      
      
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      Hepatic hemorrhage or failure occurs in approximately 1% of pregnancies complicated by HELLP syndrome and are associated with significant mortality as fulminant liver failure may result.

      
      
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      All of these conditions are thought to have a common etiology, and result from abnormal placentation early in gestation, when the spiral arteries fail to form low-resistance vessels as they do in normal pregnancy. Diffuse endothelial activation occurs which can result in multiorgan dysfunction later in the course of the pregnancy.

      
      
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      Adverse fetal outcomes associated with hypertensive disorders in pregnancy include intrauterine growth restriction, placental abruption, and intrauterine death.

    
    
    
    
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    Acute fatty liver of pregnancy

    
    
    
    
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      This disorder is a rare and potentially life-threatening condition that occurs in pregnancy and usually presents toward the end of the third trimester.

      
      
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      Liver dysfunction results from microvesicular steatosis (in contrast to macrovesicular steatosis which is seen in other liver disorders such as nonalcoholic fatty liver disease).

      
      
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      More common in primigravidae, in multiple pregnancies, or pregnancies with male fetuses.

      
      
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      Important symptoms that suggest a diagnosis of acute fatty liver of pregnancy (AFLP) include abdominal pain (particularly in the right upper quadrant), nausea, vomiting, and polydipsia on a background of malaise and anorexia.

      
      
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      This disorder is considered part of the same spectrum as pre-eclampsia and HELLP syndrome and so the features may overlap. Severe hypertension or proteinuria is rare, however.

    
    
    
    
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    Intrahepatic cholestasis of pregnancy

    
    
    
    
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      Intrahepatic cholestasis of pregnancy (ICP) is the most frequent cause of cholestasis in pregnancy and is more commonly seen in certain populations (incidence in Chile and Scandinavia is 12% and 1.5%, respectively).

      
      
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      The disorder is characterized by the development of pruritus (in the absence of a rash) which can be severe, and deranged liver function tests, in association with elevated serum bile acid concentration.

      
      
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      It has also been associated with adverse fetal outcomes including meconium-stained amniotic fluid, spontaneous preterm labor, and intrauterine death.

      
      
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      ICP typically presents with pruritus in the third trimester of pregnancy, but has been reported to develop as early as 8 weeks’ gestation. Symptoms such as dark urine, steatorrhea, and jaundice can also develop. Pruritus can develop before biochemical parameters become abnormal, so it is important to repeat the liver function tests and serum bile acid concentration if clinical suspicion persists.

      
      
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      Women with ICP are more likely to have a family history of gallstones and ICP. Some women may have previously developed similar symptoms when taking the oral contraceptive pill. ICP is more common in women who have hepatitis C and the condition can develop earlier in these pregnancies compared to hepatitis C antibody-negative women (mean 29 weeks compared to 34 weeks).

    
    
    
    
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    Differential diagnosis:

    
    
    
    
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      Other nonpregnancy-specific causes for acute liver dysfunction should also be considered including drug-related liver dysfunction (antibiotics, paracetamol), infective causes (exposure to viral hepatitides particularly hepatitis E), structural causes including Budd-Chiari syndrome and choledocholithiasis, or antibody-associated causes such as autoimmune hepatitis or primary biliary cirrhosis.

    
    
    
    
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    Monogenic forms:

    
    
    
    
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      No monogenic forms of HELLP, AFLP, or ICP have been identified.

    
    
    
    
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    Family history:

    
    
    
    
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      The risk of pre-eclampsia in a primigravida is increased three- to fourfold if there is a family history of the condition.

      
      
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      Daughters and siblings of women with ICP have up to a 12-fold increased risk of developing the condition.

    
    
    
    
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    Environmental factors:

    
    
    
    
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      In some populations it has been demonstrated that there is a seasonal variation in the number of cases of ICP. For example, in Portugal more cases were seen in winter months compared to summer.

      
      
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      Investigation of the concentrations of selenium, copper, and zinc has also shown these to be lower in women with ICP.

    
    

  
  

Diagnostic Evaluation

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  A thorough history for symptoms such as

  
  
  
  
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    Abdominal pain (particularly epigastric or right upper quadrant), headaches, visual disturbance (suggestive of pre-eclampsia or HELLP)

    
    
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    Nausea, vomiting, anorexia, malaise, abdominal pain, polyuria, polydipsia (suggestive of AFLP)

    
    
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    Pruritus, most commonly affecting palms and soles, cholestatic symptoms including dark urine or steatorrhea, and systemic symptoms such as anorexia or malaise (suggestive of ICP)

  
  
  
  
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  Drug history—medications associated with cholestasis, symptoms with previous use of oral contraceptive pill, or in vitro fertilization

  
  
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  Clinical assessment including

  
  
  
  
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    Blood pressure and urinalysis

    
    
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    Examination particularly for hepatic tenderness, hepatomegaly, ascites, or encephalopathy

    
    
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    Skin examination to look for other causes of pruritus (rashes, infections such as scabies)

  
  
  
  
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  Blood tests including

  
  
  
  
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    Full blood count (hemolysis or thrombocytopenia may be evident in HELLP; leukocytosis is common in AFLP).

    
    
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    Renal function (acute renal failure can occur in HELLP or AFLP).

    
    
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    Liver function tests are deranged, to differing extents in each disorder (Table 101-1).

    
    
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    Increased serum bile acid concentration in ICP.

    
    
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    Hypoglycemia and abnormal coagulation parameters are associated with AFLP, but coagulopathy is rarely seen in ICP.

    
    
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    Viral serology for hepatitis A, B, C, and E, Epstein-Barr virus, cytomegalovirus, herpes simplex virus, and human immunodeficiency virus.

    
    
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    Liver antibodies including antimitochondrial antibodies (suggestive of primary biliary cirrhosis) and antismooth muscle antibodies.

  
  
  
  
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  Urine analysis for protein-creatinine ratio or 24-hour collection for total protein.

  
  
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  Abdominal ultrasound is performed to exclude other causes of deranged liver function. Gallstones are more commonly seen in parous women and in women with ICP.

Hellp Syndrome

There has been no consensus about diagnostic criteria for HELLP syndrome, and studies have used a variety of measures and thresholds to make the diagnosis. Suggested parameters and thresholds are listed here.

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  Hemolysis

  
  
  
  
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    Microangiopathic hemolytic anemia and schistocytes on film

    
    
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    Elevated lactate dehydrogenase greater than 600 IU/L (>2 × ULN)

    
    
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    Elevated bilirubin

    
    
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    Low haptoglobin

    
    
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    Significant drop in hemoglobin

  
  
  
  
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  Elevated liver enzymes

  
  
  
  
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    Aspartate aminotransferase (AST) greater than 70 IU/L (>2 × ULN)

  
  
  
  
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  Thrombocytopenia

  
  
  
  
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    Platelet count less than 100,000/mm³

  
  

Acute Fatty Liver of Pregnancy