Intrahepatic cholestasis of pregnancy ICP also known as Obstretic cholestasis or recurrent jaundice of pregnancy or Pruritus gravidarum, is a cholestatic disorder characterized by pruritus,elevated serum aminotransferases and bile acid levels with onset in the second or third trimester of pregnancy, and spontaneous relief of signs and symptoms within two to three weeks after delivery.
The incidence of ICP varies widely with geographical location and ethnicity. 1 to 2 pregnancies in 1000 are affected by cholestasis. it is most common in South America, particularly in Chile, where the early reports described an overall incidence of 10% with higher rates seen in woman of Araucanian Indian descent.
ICP is more common in the winter months in Finland, Sweden,Chile and Portugal.A higher incidence is seen in twin pregnancies (2.7%vs 0.7%). One study has suggested that it is more common in women over the age of 35 years. there is a higher incidence of gallstones in both affected women and their families. Hepatitis C seropositivity has been reported to be a risk factor for ICP,and may be associated with the early onset of the condition.It has also been suggested that woman with ICP have more severe and prolonged emesis and higher rates of drug sensitivy.
Intrahepatic cholestasis of pregnancy, 2009
DIAGNOSIS AND CLINICAL MANIFESTATION
Diagnosis of ICP may be made in the presence of pruritus without a rash in the absence of other liver disease in a gravid patient beyond 25 week's gestation with the serum elevation of serum BA and /or aminotransferases levels.
- Clinical features
- Pruritus :particulary on the palms of the hands and soles of the feet, is the primary clinical symptom of ICP and is not associated with any specific skin lesions.
- Sleep deprivation, psychological suffering and even suicidal thoughts
- It usually presents in the third trimester, after 30 weeks of gestation, but rare cases developing
as early 6 to 10 weeks has been described.
- Mild jaundice with serum levels of conjugated bilirubin only moderately elevated occurs in 10 to 15% of cases develops 1-4 weeks after the onset of pruritus, but occasionally can be the initial symptom.
- Sub clinical steatorrhea may be seen along with fat malabsorption, which may lead to vitamin K deficiency resulting in a prolonged prothrombin time in postpartum hemorrhage.
- Laboratory findings
The main biochemical alterations are the elevations of serum bile acids and aminotransferase activity.
- Bile Acids levels greater than 10 umol/L are common diagnostic marker 10
- Liver Function Tests (LFTs)
- Aminotransferase (AST,AST) activity can be raised up to 20 times.
- The normal Gamma-glutamyl transferase activity is unusual but indicative of MDR3 gene mutation leading to the increase, of bile acids or of underlying liver disease.
- It is uncommon to have a raised serum bilirubin.
Affected individuals have a defect involving the excretion of bile salts,which lead to increased serum bile acid . These are deposited within the skin, causing intense pruritus.
The cause of ICP is unknown but is thought to be multifactorial with genetic,hormonal and environmental involvement.Family clustering and varying incidence in different geographic regions speaks strongly for a genetic etiology of ICP.
- Genetic factor
- Mutation of the adenosine triphosphate binding cassette,subfamily B,member ABCB4/abcd4 gene also known as Multidrug Resistant Protein 3 (MDR3) which controls secretion of phosphatidylcholine into bile have been found in 15% of cases of ICP.
- Genetic mutation's affecting hepatic bile salt transport molecoles is also associated with progressive familial intrahepatic cholestasis. Changes induced by these genetic mutations lead to an increased sensitivity to Estrogen.
- Genetic changes in the ABCB11 or the ABCB4 (linK) gene can increase a woman's likelihood of developing intrahepatic cholestasis of pregnancy.
The ABCB11 gene provides instructions for making a protein called the bile salt export pump (BSEP). this protein is found in the liver and its main role is to move bile salt out of liver cells,which is important for the normal release of bile.Changes in the ABCB11 gene also associated with the ICP reduce the amount of function of the BSEP protein ,although enough function remains for sufficient bile secretion under most circumstances. Studies show that the hormones Estrogen and Progesterone (and products formed during their breakdown) , which are elevated during pregnancy, further reduce the function of BSEP, resulting in impaired bile secretion and the features of ICP.
The ABCB4 gene provides instructions for making a protein that helps move certain fats called phospolipids across cell membranes and release them into bile. Phospholipids attach to bile acids,
Large amounts of bile acids can be toxic when they are not bound to phospholipids. A mutation in one copy of the ABCB4 gene mildly reduces the amount of ABCB4 protein. Under most circumstances, though , enough protein is available to move an adequate amount of phospholipids out of the liver cells to bind to bile acids. although the mechanism is unclear, the function of the remaining ABCB4 protein appears to be impaired during pregnancy,which may further reduce the movement of phospholipids into bile .The lack of phospholipids available to bind to bile acids leads to a buildup of toxic bile acids that can impair liver function including the regulation of bile flow.
Most women with ICP don't have a genetic change in the ABCB11 or ABCB4 gene.
- Hormonal factors
ICP has been associated with the cholestatic effect of oestradiol metabolites. In particular 17 beta oestradiol glucuronide. Progesterone metabolites, however play an even more important part in its pathogenesis. All steroid, estrogen, progesterone and corticosteroids are incresaed during pregnancy 1,000-fold at term compared with the non pregnant state. Sex hormone exerts cholestatic effects via Inibition of the hepatocellular bile salt export pump; another mechanism for sex hormone interaction involves the association of higher sex hormone levels with impaired sulfation. patients with ICP have a significantly increased ratio of 3 alfa to 3 beta hydroxysteroids and large amounts of mono or disulphated progesterone metabolites excreted in their urine suggest impaired biliary canalicular transporters. The hepatic transport mechanisms for biliary excretion can be saturated by sulfated progesterone metabolites.
- Environmental factors are also though to contribute to the development of ICP. Many patients have more mild recurrence in subsequent pregnancies,which suggests that environmental factors play a role in the development and severity of ICP. For example,limited studies have shown that Selenium deficiency can play a role in ICP. Selenium acts aa a cofactor of several enzymes in the oxidative metabolism in the liver but the role of selenium in bile excretion has yet not be defined. Seasonal variation is also noted, with more severe cases in the winter months. Consultation with a dietician and discussion of timing for subsequent pregnancies is prudent in patients with a history of ICP.
- Risk factor
- Individuals with the sensitivity to estrogen should be monitored closely during pregnancy for signs and symptoms of ICP,especially in the third trimester when the estrogen levels are at their highest.
- Similarly,those with the multiple gestation's are at an increased risk for developing ICP. owing to increased levels of estrogen above those seen with singleton gestation.
- Women whose mother or sisters has Cholestasis, in fact susceptibility is inherited in an autosomal dominant pattern, which mean one copy of the altered gene in each cell is sufficient to increase the risk of developing the disorder.
The primary objective of pharmacologic treatment in ICP is to alleviate maternal symptoms and improve fetal outcome.
Many drug agents have been used in the treatment of ICP. These include Phenobarbital,Hydroxyzine,Glutathione precursor, S-adenosyl methione (SAME),cholestyramine and Dexamethasone. All these agents showed some limited clinical benefit.Ursodeoxycholic acid ( UDCA) remains the drug of choice for the treatment of ICP.
- UDCA at a daily dose ranging from 600-2000 mg was effective at reducing pruritus decreasing the total serum bile acid levels, ALT values and bilirubin levels; and allowing delivery closer to term(37.8+/-0.9 wk 33 +/-7.1 wk).
- UDCA has been shown to Improve impaired ehepatocellular secretion by mainly postranscriptional stimulation off canalicular expression of key transport proteins like the conjugate export pump MRP2 (ABCB2), or the bile salt export pump, BSEP (ABCB11). it has antiapoptotic effects.in addition to effects to UDCA on the maternal liver, UDCA restores the impaired maternal-placental bile acid transport across the trophoblast. This could be mediated by enhanced expression of plasma membrane transporters involved in the excretory role of the placenta and would prevent structural alterations of the trophoblast induced by maternal cholestasis.
- UDCA lowers serum levels of ethinyl-estradiol 17 beta glucuronide ,a major cholestatic metabolite of estrogen.
ICP presents risk to the fetus than to the mother (Fetal outcome ) . ICP increases particularly when associated with fasting serum bile acid levels > 40umol/L the risk of preterm delivery meconium staining of amniotic fluid fetal bradycardia, fetal distress, fetal loss with the associated mortality and morbidity. In addition, the fetus is at an increased risk for stillbirth. Maternal prognosis is good and symptoms resolve rapidly after delivery,accompanied by normalization of serum liver test. ICP recurs during subsequent pregnancies in 45-70% with varying severity of recurrent episodes. The major concern for is for postpartum hemorrhage if her vitamin K levl it is low ,leading to an increase in prothrombin time.