Cholestasis Of Pregnancy

Introduction

Cholestasis of pregnancy or intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease affecting about 0.5% to 0.7% of pregnant women in the second or third trimester of pregnancy, although the onset of symptoms might present earlier. Cholestasis of pregnancy is characterised by maternal pruritus, typically in the palms of the hands and soles of the feet, which gets worse at night, secondary to elevated serum bile acids and abnormal liver function tests. In ICP cases, the rash is absent, but due to ongoing itching, excoriations may be observed at the time of examination.^1,3

Interestingly, about 25% of pregnant women will normally experience itching during pregnancy, but most of them will not have cholestasis during pregnancy. The ICP cases have been linked to foetal complications, including stillbirth, early labour, foetal irregular heartbeats, respiratory distress syndrome and asphyxial events. The onset of maternal symptoms of ICP usually occurs in the third trimester after 30 weeks of pregnancy, but it has been reported as early as 7 weeks also, ICP symptoms resolve spontaneously after delivery.^1,2

Normal bile acid metabolism

Metabolism is the process by which the body changes food and drinks into energy. Cholesterol Breakdown → Bile acid - Cholic acid (CA) & Chenodeoxycholic Acid (CDCA) → conjugation of bile acids with taurine and glycine and form bile salts that are secreted in the intestine → They help in fat digestion in the gut by acting as emulsifiers → Bile salts again deconjugate to form secondary bile acids deoxycholic (DCA) & lithocholic acid (LCA) → Transported back to the liver via enterohepatic circulation.⁴

Causes and risk factors

The cause is multifactorial and includes genetic, hormonal, and exentric causes. Most of the guidelines mentioned personal or family history as a risk factor, with a rate ranging from 40%-92%. Some guidelines discuss multifetal gestation and cholelithiasis as participating factors in ICP. However, all guidelines agreed that viral hepatitis of any type should be considered in diagnosing ICP, particularly in women with symptoms including dark urine, jaundice, or a history of illicit drug use.¹

According to a Swedish study form, high rates of ICP have been reported in women with hepatobiliary pathologies, including pre-pregnancy chronic hepatitis, hepatitis C, and cholelithiasis.¹

Certain individuals are highly sensitive to oestrogen and progesterone hormones due to genetic factors. Genetically, women at risk have elevated amounts of sulphated progesterone metabolites, which may result in the saturation of the hepatic transport system used for the biliary excretion of these compounds. Impaired bile acid metabolism with accumulation of bile acid is linked to foetal complications in the form of stillbirth, preterm birth, foetal distress and meconium. Thus, the underlying cause of ICP is related to high perinatal mortality and morbidity rates.⁴

Several genetic variations have been identified in the hepatobiliary disease process. Hepatobiliary transport proteins, including aminophospholipid transporter, bile salt export pump, and hepatic phospholipid transporter have been involved in familial ICP, in addition to changes in the nuclear hormone receptor farnesoid X have been discussed in white European cohort.¹

ICP is mostly seen in advanced maternal age, pregnancies following in-vitro fertilisation (IVF) and pregnancy with high levels of estrogens and progesterone as multiple pregnancies.⁴

Presentation of ICP

Pruritus without a rash was identified by the guidelines as the primary and characteristic maternal symptom in ICP. This type of pruritus gets worse at night, particularly in the palms and soles, and is possibly associated with sleep disturbances. The itching could be localised or generalised, and in severe cases, excoriation may be detected on examination of the skin, which demonstrates scratch marks and scarring secondary to deep itching.^1,3

Other clinical features may include:^1,3,4

• Skin changes due to yellowish discolouration caused by high bilirubin levels.
• Steatorrhea is the excretion of abnormal fat in stool and may result in vitamin K deficiency secondary to malabsorption of fat-soluble vitamins.
• Anxiety secondary to sleep disturbance
• Discomfort, restlessness and lack of appetite for food.
• Weight loss
• Stomach discomfort 
• Dark urine

Diagnosis of ICP

The diagnosis of ICP relies on the primary characteristic symptoms, elevation of bile acid serum and ruling out other causes of liver diseases linked to cholestasis. Therefore, differential diagnosis of ICP is essential, including biliary obstruction, viral hepatitis, primary biliary cirrhosis and liver diseases specific to pregnancy, e.g., elevated liver enzymes and low platelets syndrome (HELLP), Hemolysis, acute fatty liver of pregnancy and preeclampsia. Also, it is essential to be aware of other skin cases in pregnancy that have pruritus associated with skin rash, besides regular liver function tests and the bile acids are not elevated. 

Raised bile acids and serum are specific parameters and important characteristics of ICP diagnosis. Bile acids include cholic acid (CA) and chenodeoxycholic acid (CDCA). During normal pregnancy, the bile acids should be less than ten umol/l. The CA: CDCA ratio in non pregnant women is 1:1, however, this ratio in ICP is inaccurate for diagnosis. A reliable diagnosis should be made for total bile acids serum and liver function tests, which are enough. 

Classification of ICP

ICP has been classified according to the bile acid levels as follows:

• Mild (10-39 umol/l)
• Moderate (40-99 umol/l)
• Severe (>100 umol/l)

• Liver function tests, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) show mild elevation between 2 and 30-fold upper limit of normal in the majority of ICP cases.  
• Serum Alkaline phosphatase (ALP) is elevated, but it is not a specific ICP test as it is already produced physiologically in high levels from the placenta during pregnancy; thus, it is normally increased during pregnancy.
• The gamma-glutamyl transpeptidase (GGT) levels may be detected at high levels but can be expected. Interestingly, GGT levels may be used to give a clue regarding genetic aetiology, as low GGT levels and high GGT levels can distinguish between certain types of genetic mutations. 
• Skin yellowish discolouration may present in 10% of patients with ICP. 
• Bilirubin, if elevated, is often between 1-5 mg/dl.
• Prothrombin time may be disrupted by fat malabsorption and reduced vitamin K absorption.
• Hence, with these changes in liver functions along with jaundice in pregnancy, a differential diagnosis of liver diseases linked to pregnancy, as well as those unrelated to pregnancy, can be made. A diagnostic combination of laboratory tests, symptoms, signs, imaging techniques, if needed, and detailed medical history should be considered to help the clinician make a reliable diagnosis.⁴

Treatment options

Ursodeoxycholic acid (UDCA) 

Ursodeoxycholic acid (UDCA) is the most common drug used to treat ICP. UDCA is a hydrophilic bile acid that stimulates the synthesis and insertion of bile acid (BA) transporters into the hepatocyte membrane, thus improving BA biliary excretion. Moreover, it plays an important role in reducing foetal BA concentrations.

Clinical studies and research have studied the effect of UDCA vs placebo widely. UDCA has proved in some recent randomised controlled trials (RCTs) to be an effective drug in improving pruritus symptoms in ICP patients. Other RCTs have demonstrated the positive outcomes of UDCA in reducing LFT levels and bile acid levels as well. However, the effect of UDCA on foetal outcomes is still unclear; the latest clinical trials seek to study further UDCA vs placebo direct effect on foetal outcomes in a large cohort of women in the UK.³

Rifampicin

Rifampicin is a second line drug used in combination with UDCA, it is used in women who do not respond to UDCA monotherapy. Studies have demonstrated the positive effect of rifampicin in reducing BA levels and pruritus symptoms when it is combined with UDCA. Rifampicin acts as a pregnane X receptor agonist, thus it can act in cooperation with UDCA.³

Other drug therapies

Other drugs used in ICP include guar gum, S-adenosyl-L-methionine, cholestyramine, activated charcoal and dexamethasone but their use is limited and there is not much supported evidence.³

Management of pregnancy

Timing of delivery

There are no certain studies or guidelines for the optimal timing of delivery of the foetus for women with ICP. However, it is recommended that elective delivery may be of benefit and should be discussed with the mother. In the UK, most ICP cases undergo induction of labour at 37-38 weeks, this aims to balance the effects of prematurity against risk of foetal demise, this would be perfect between 37 & 39 weeks gestation.³

The future health of the mother

Recovery occurs after foetus delivery, and women remain asymptomatic outside of pregnancy. However, there is increased evidence of developing liver diseases in later life, including liver fibrosis, chronic hepatitis, cirrhosis, cholangitis and gallstone disease. After episodic ICP, it is of high importance to advise women about combined oral contraceptives in triggering hepatic impairment, but there are other safe alternatives of contraceptive forms that are recommended.

Moreover, there is a study that demonstrated the possibility of ICP in altering the long-term metabolic health of the foetus. This study was conducted on 16-year-old children of women with ICP found to have elevated levels of adiposity and impaired serum lipid profiles.³

Summary

ICP is a unique pregnancy-related liver disease that occurs mostly in the second or third trimester. The characteristic symptoms of ICP is severe skin itching with no rash along with elevated levels of bile acids. There is a significant illness and death rate of the foetus, such as stillbirth. UDCA is the best treatment option and the drug of choice, which has been proven in several studies to alleviate skin itching and reduce foetal bile acid levels. Close monitoring should be followed to decrease foetal disease and death rates. Thus, early foetal delivery should be considered at 37 weeks. ICP maternal symptoms resolve in the post-delivery period, but there is a high risk of recurrence.