Intrahepatic Cholestasis of Pregnancy

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Diagnosis and reasoning

Pruritus may be a manifestation of a local dermatological condition - or a clue towards underlying systemic disease. Pregnancy adds an additional dimension of complexity, as there are several conditions unique to this time period. Local dermatogical conditions related to pregnancy include pemphigoid gestationis, pruritic urticarial papules and plaques of pregnancy. Those unrelated to pregnancy include xerotic eczema, atopic and contact dermatitis and scabies. The main systemic causes related to pregnancy are acute fatty liver of pregnancy, intrahepatic cholestasis of pregnancy and HELLP syndrome. Important systemic conditions unrelated to pregnancy include liver disorders (such as viral and autoimmune hepatitis) and allergic reactions. The unremarkable physical examination in this patient excludes local causes. While the absence of jaundice does not rule out viral or autoimmune hepatitis, the lack of associated symptoms such as fatigue, abdominal discomfort, nausea and anorexia makes these etiologies unlikely. Acute fatty liver of pregnancy (AFLP) is also unlikely, as these patients are almost always icteric, and far more ill. Features of liver failure are often present. HELLP syndrome is a severe form of preeclampsia. In this patient, the normal blood pressure and absence of urinary proteins makes this diagnosis clinically less likely. Intrahepatic cholestasis of pregnancy (ICP) is mainly characterized by generalized pruritus which is most prominent on the palms and soles. It is a diagnosis of exclusion. Her liver function tests demonstrate mild conjugated hyperbilirubinemia with normal gamma-glutamyl transpeptidase levels. This pattern of findings is suggestive of cholestasis (note that alkaline phosphatase levels may be elevated in pregnancy due to the presence of the placental isoenzyme). In addition, the elevated serum bile acid levels favor the diagnosis of ICP. Her liver transaminases are only minimally elevated, while her clotting profile, full blood count and renal functions are normal. These results exclude HELLP syndrome and AFLP. Note that the liver transaminases are typically elevated into the thousands of units in acute viral hepatitis. In addition, serology excludes chronic viral hepatitis, while her autoimmune screen is unremarkable. Thus, by exclusion, ICP is indeed the diagnosis. Note that a liver biopsy is not required for diagnosis of ICP. Her management should include ursodeoxycholic acid for symptomatic relief of pruritus. and oral vitamin K (as there may be malabsorption of fat soluble vitamins, due to disruption of the enterohepatic circulation of bile acids). Emergency delivery is not indicated in this patient, while there is no indication for N-Acetyl-Cysteine therapy.


Discussion

Intrahepatic cholestasis of pregnancy (ICP) - which is also known as "Obstetric Cholestasis", is a liver disease specific to pregnancy. The incidence varies throughout the world, occurring in only 0.01% of pregnancies in the United States, but in between 5% to 15% of pregnancies in Chile and Bolivia. The etiology is believed to be multifactorial with genetic, hormonal and environmental factors playing significant roles. Women with multiple pregnancies, and/or a family history or a personal history of ICP are at increased risk of developing the condition. The disease typically manifests itself in the second or third trimester and completely resolves after delivery. It is characterized by generalized pruritus which is most pronounced in palms and soles and is worse at night. Skin lesions are absent except for excoriations resulting from scratching. Jaundice is uncommon, but may develop 1 to 4 weeks after the onset of pruritus. Subclinical steatorrhea may also occur with resultant fat and fat soluble vitamin malabsorption (especially vitamin K). The most sensitive biochemical abnormality is elevation of the serum bile acid level, which often reaches 10 to 100 times the normal values (although this is not a universal finding). In addition, this investigation may not be freely available in certain centers and is not essential to confirm the diagnosis. Serum transaminases may increase 2 to 10 fold - reaching even 1000 IU/L in some patients. Gamma glutamyl transferase is usually normal or mildly elevated, while ALP may also be elevated - although interpretation is difficult due to the elevation of the placental isoenzyme during pregnancy. The management is aimed at alleviating maternal symptoms and improving fetal outcome. Ursodeoxycholic acid provides strong symptomatic benefit and has the additional advantage of improving liver functions. Evidence suggests that UDCA acts by improving the impaired hepatocellular secretion of bile; it also restores the impaired bile acid transport across the trophoblast. Topical emollients may also provide slight relief of the pruritus. Daily supplementation of Vitamin K is also important. This will help prevent intra and postpartum hemorrhage due to impaired clotting. Note also that it is prudent to monitor these patients with weekly liver function tests (LFT) and to confirm postpartum normalization of LFT. ICP is associated with an increased risk for intrauterine death, as well as premature delivery, and meconium staining of the amniotic fluid. While the pathogenesis of the fetal complications is still poorly understood, a role for bile acids or toxic metabolites of bile acids has been suggested. Autopsies of the stillborns show signs of acute anoxia with serosal and pulmonary petechial bleeding without intrauterine growth restriction. The majority of intrauterine deaths in singleton pregnancies occur after 37 weeks of gestation - thus a discussion should take place with the patient, regarding induction of labour after this time. The increased risk of maternal and perinatal morbidity from early intervention should be contrasted with the inability to predict stillbirth if the pregnancy continues (especially in patients with severe biochemical abnormalities). The ultimate decision on when or whether to intervene should be taken after careful counseling. The maternal outcome is almost universally favorable, with symptoms typically resolving within a few days following delivery. These patients do not develop long term hepatic sequelae, although ICP may recur in 60% to 70% of subsequent pregnancies. Symptoms may recur with estrogen containing oral contraceptive pills (OCP) and menstruation - therefore OCPs are best avoided in these patients.


Take home messages

  1. ICP is a diagnosis of exclusion.
  2. Elevated serum bile acids are the most sensitive biochemical abnormality for ICP.
  3. The important adverse outcomes include intrauterine death, premature delivery and meconium staining.
  4. Delivery after 37 weeks of gestation should be discussed with the mother.
  5. Maternal vitamin K supplementation should not be neglected.

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  1. AFP: liver disease in pregnancy (1999)
  2. Archives of Dermatology : The Importance of Serum Bile Acid Level Analysis and Treatment With Ursodeoxycholic Acid in Intrahepatic Cholestasis of Pregnancy (2007)
  3. BMJ: Obstetric cholestasis (2002)
  4. Orphanet journal of rare diseases: intrahepatic cholestasis of pregnancy (2007)
  5. RCOG green-top guideline No 43: Obstetric cholestasis (2011)