Intrahepatic Cholestasis of Pregnancy
Encyclopedia
Intrahepatic cholestasis
of pregnancy (also known as "cholestasis of pregnancy," "jaundice of pregnancy," "obstetric cholestasis," and "prurigo gravidarum") in the United Kingdom
, is a medical condition in which cholestasis
occurs during pregnancy
. It typically presents with troublesome itch
ing and can lead to complications for both mother and fetus.
Itching has long been considered to be a common symptom of pregnancy. The vast majority of times, itching, or pruritus, is a minor annoyance caused by changes to the skin, especially that of the abdomen. However, there are instances when itching is a symptom of ICP. This is usually most intense on the palms of the hands, and the soles of the feet, but can be wide spread.
ICP occurs most commonly in the third trimester, but can begin at any time during the pregnancy. It is also the second most common cause of jaundice
in pregnancy.
Fetal consequences include:
Delivery has been recommended in the 38th week when lung maturity has been established.
. Generally, the itching is localized to the abdomen, legs, palms, and soles, but can be generalized.
Hallmarks of ICP include the following symptoms:
Most common:
Less common:
It is important to note that not all ICP sufferers have all of the above symptoms. For example, Jaundice only occurs in relatively small subset of cases, and in some cases abnormal lab results were not seen until 15 weeks or more after the onset of symptoms.
and genetic factors
are likely to be important in the pathogenesis
of the disease. A number of features of the disease suggest a link to hormones:
Estrogen
Estrogens, and particularly glucuronide
s such as estradiol-17β-D-glucuronide, have been shown to cause cholestasis in animal studies, by reducing bile acid
uptake by hepatocyte
s.
Progesterone
Treatment with progesterone in the third trimester of pregnancy has been shown to be associated with the development of ICP, and levels of metabolites of progesterone, particularly sulfate
d progesterone, are higher in patients with ICP than unaffected women, suggesting that progesterone also has a role in ICP.
, which controls secretion of phosphatidylcholine
into bile, have been found in 15% of cases of ICP.
Genetic mutations affecting hepatic bile salt transport molecules have also been found in patients with progressive familial intrahepatic cholestasis
(PFIC). It has been found that mothers of patients with PFIC have a higher incidence of ICP, suggesting that heterozygote carriers of these mutations are also predisposed to ICP.
In addition to genetic changes to bile salt transport molecules, high levels of estrogen glucuronides have been shown to inhibit the bile salt export pump (BSEP) ABCB11
, and high levels of progesterone to inhibit the ABCB4 (MDR3) phospholipid transporter.
Consequently, both genetic mutations in hepatocyte proteins involved in bile secretion together with inhibition of those proteins by high levels of hormone metabolites in pregnancy may have roles in the pathogenesis of ICP.
To obtain a diagnosis of ICP, there are two LFT and Serum bile acid test. The liver function tests
(LFTs) is a simple blood test, the results of which should be available by the next day. If the ALT
level is elevated, this, plus pruritus of palms and soles, should be treated as diagnostic of ICP (however LFT's are not always elevated in ICP patients). The serum bile acid blood test for ICP is a quantitative measurement of bile salts. The results of this test often take longer to return, but the test is more specific for ICP.
Other problems with the liver that occur in pregnancy should be considered by the treating clinician. These include preeclampsia, the HELLP syndrome, and acute fatty liver of pregnancy. Furthermore, other causes of hepatitis, like hepatitis viruses and certain medications, should also be considered.
If additional blood tests to check clotting function identify a problem, giving Vitamin K
may help avoid the risk of hemorrhage at delivery.
Delivery by 37 completed weeks is considered crucial to fetal outcome , though it does not completely eliminate the risks associated with the condition.
Cholestasis
In medicine, cholestasis is a condition where bile cannot flow from the liver to the duodenum. The two basic distinctions are an obstructive type of cholestasis where there is a mechanical blockage in the duct system such as can occur from a gallstone or malignancy and metabolic types of...
of pregnancy (also known as "cholestasis of pregnancy," "jaundice of pregnancy," "obstetric cholestasis," and "prurigo gravidarum") in the United Kingdom
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
, is a medical condition in which cholestasis
Cholestasis
In medicine, cholestasis is a condition where bile cannot flow from the liver to the duodenum. The two basic distinctions are an obstructive type of cholestasis where there is a mechanical blockage in the duct system such as can occur from a gallstone or malignancy and metabolic types of...
occurs during pregnancy
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
. It typically presents with troublesome itch
Itch
Itch is a sensation that causes the desire or reflex to scratch. Itch has resisted many attempts to classify it as any one type of sensory experience. Modern science has shown that itch has many similarities to pain, and while both are unpleasant sensory experiences, their behavioral response...
ing and can lead to complications for both mother and fetus.
Itching has long been considered to be a common symptom of pregnancy. The vast majority of times, itching, or pruritus, is a minor annoyance caused by changes to the skin, especially that of the abdomen. However, there are instances when itching is a symptom of ICP. This is usually most intense on the palms of the hands, and the soles of the feet, but can be wide spread.
ICP occurs most commonly in the third trimester, but can begin at any time during the pregnancy. It is also the second most common cause of jaundice
Jaundice
Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...
in pregnancy.
Risks if untreated
Maternal consequences include the following:- Itching, which can become intense and debilitating
- Premature labor
- Deranged clotting, which requires Vitamin K
Fetal consequences include:
- Fetal distress
- MeconiumMeconiumMeconium is the earliest stools of an infant. Unlike later feces, meconium is composed of materials ingested during the time the infant spends in the uterus: intestinal epithelial cells, lanugo, mucus, amniotic fluid, bile, and water. Meconium is almost sterile, unlike later feces, is viscous and...
ingestion - Meconium aspiration syndromeMeconium aspiration syndromeMeconium aspiration syndrome is a medical condition affecting newborn infants. It occurs when meconium is present in their lungs during or before delivery...
- Stillbirth
Delivery has been recommended in the 38th week when lung maturity has been established.
Signs and symptoms
Most women with this condition present in third trimester with intense itching without a rashRash
A rash is a change of the skin which affects its color, appearance or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cracked or blistered, swell and may be painful. The causes, and...
. Generally, the itching is localized to the abdomen, legs, palms, and soles, but can be generalized.
Hallmarks of ICP include the following symptoms:
Most common:
- Itching, in particular but not limited to that of the palms of the hands and soles of the feet, without presence of a rash
- Itching that increases in the evening
- Itching that does not respond favorably to anti-histamines or other anti-itch remedies
- Often, elevated LFTLFTLFT may refer to:* Lafayette, Louisiana , United States; Amtrak station code LFT* Lafayette Regional Airport, Louisiana in the USA.* Layer four traceroute, a utility to analyze computer networks* Legacy Family Tree, a genealogy software...
results as well as serum bile acid counts
Less common:
- Darker urine
- Lighter stools
- Increased clotting time (due to possibly associated vitamin K deficiency)
- Fatigue
- Increased nausea
- Decrease in appetite
- Jaundice
- Upper right quadrant pain
It is important to note that not all ICP sufferers have all of the above symptoms. For example, Jaundice only occurs in relatively small subset of cases, and in some cases abnormal lab results were not seen until 15 weeks or more after the onset of symptoms.
Mechanism
The causes of intrahepatic cholestasis of pregnancy are still not fully understood. HormonesSex steroid
Sex steroids, also known as gonadal steroids, are steroid hormones that interact with vertebrate androgen or estrogen receptors. Their effects are mediated by slow genomic mechanisms through nuclear receptors as well as by fast nongenomic mechanisms through membrane-associated receptors and...
and genetic factors
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
are likely to be important in the pathogenesis
Pathogenesis
The pathogenesis of a disease is the mechanism by which the disease is caused. The term can also be used to describe the origin and development of the disease and whether it is acute, chronic or recurrent...
of the disease. A number of features of the disease suggest a link to hormones:
- ICP occurs in the third trimester at the time when hormone levels are at their highest.
- Twin and triplet pregnanciesMultiple birthA multiple birth occurs when more than one fetus is carried to term in a single pregnancy. Different names for multiple births are used, depending on the number of offspring. Common multiples are two and three, known as twins and triplets...
, which are associated with higher hormone levels, show a higher incidence of ICP. - ICP resolves quickly after delivery, when placental hormonePlacentaThe placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
levels drop back to normal. - Older high-dose estrogen oral contraceptive pills could cause features of ICP.
EstrogenEstrogenEstrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
s
Estrogens, and particularly glucuronideGlucuronide
A glucuronide, also known as glucuronoside, is any substance produced by linking glucuronic acid to another substance via a glycosidic bond...
s such as estradiol-17β-D-glucuronide, have been shown to cause cholestasis in animal studies, by reducing bile acid
Bile acid
Bile acids are steroid acids found predominantly in the bile of mammals. Bile salts are bile acids compounded with a cation, usually sodium. In humans, the salts of taurocholic acid and glycocholic acid represent approximately eighty percent of all bile salts. The two major bile acids are cholic...
uptake by hepatocyte
Hepatocyte
A hepatocyte is a cell of the main tissue of the liver. Hepatocytes make up 70-80% of the liver's cytoplasmic mass.These cells are involved in:* Protein synthesis* Protein storage* Transformation of carbohydrates...
s.
ProgesteroneProgesteroneProgesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
Treatment with progesterone in the third trimester of pregnancy has been shown to be associated with the development of ICP, and levels of metabolites of progesterone, particularly sulfateSulfate
In inorganic chemistry, a sulfate is a salt of sulfuric acid.-Chemical properties:...
d progesterone, are higher in patients with ICP than unaffected women, suggesting that progesterone also has a role in ICP.
Genetic factors
Clustering of cases of ICP in families, geographic variation in rates of ICP, and recurrence of ICP in 45-70% of subsequent pregnancies all suggest a genetic component to the disease. Genetic mutations in the hepatocellular transport protein ABCB4 (MDR3)ABCB4
Multidrug resistance protein 3 is a protein that in humans is encoded by the ABCB4 gene. ABCB4 is associated with progressive familial intrahepatic cholestasis type 3.-External links:...
, which controls secretion of phosphatidylcholine
Phosphatidylcholine
Phosphatidylcholines are a class of phospholipids that incorporate choline as a headgroup.They are a major component of biological membranes and can be easily obtained from a variety of readily available sources such as egg yolk or soy beans from which they are mechanically extracted or chemically...
into bile, have been found in 15% of cases of ICP.
Genetic mutations affecting hepatic bile salt transport molecules have also been found in patients with progressive familial intrahepatic cholestasis
Progressive familial intrahepatic cholestasis
Progressive familial intrahepatic cholestasis refers to a group of familial cholestatic conditions caused by defects in biliary epithelial transporters. The clinical presentation usually occurs first in childhood with progressive cholestasis...
(PFIC). It has been found that mothers of patients with PFIC have a higher incidence of ICP, suggesting that heterozygote carriers of these mutations are also predisposed to ICP.
In addition to genetic changes to bile salt transport molecules, high levels of estrogen glucuronides have been shown to inhibit the bile salt export pump (BSEP) ABCB11
ABCB11
ATP-binding cassette, sub-family B member 11 also known as ABCB11 is a protein which in humans is encoded by the ABCB11 gene.- Function :...
, and high levels of progesterone to inhibit the ABCB4 (MDR3) phospholipid transporter.
Consequently, both genetic mutations in hepatocyte proteins involved in bile secretion together with inhibition of those proteins by high levels of hormone metabolites in pregnancy may have roles in the pathogenesis of ICP.
Environmental factors
A number of features of ICP suggest that environmental factors also have a role in the disease:- It has been reported that the incidence of ICP is higher in winter than summer in Sweden, Finland and Chile.
- The incidence of ICP in Chile has dropped from 14% of pregnancies before 1975 to less than 2% in 1997.
- ICP recurs in between 45% and 70% of subsequent pregnancies.
- Low serum seleniumSeleniumSelenium is a chemical element with atomic number 34, chemical symbol Se, and an atomic mass of 78.96. It is a nonmetal, whose properties are intermediate between those of adjacent chalcogen elements sulfur and tellurium...
levels have been linked to ICP, although the role of selenium in bile secretion is not known.
Diagnosis
While most pregnant women experience some itch from time to time, itching on the palms and soles without a visible rash, or persisting severe or extensive itch symptoms should be reported to the midwife or obstetrican.To obtain a diagnosis of ICP, there are two LFT and Serum bile acid test. The liver function tests
Liver function tests
Liver function tests , are groups of clinical biochemistry laboratory blood assays designed to give information about the state of a patient's liver. The parameters measured include PT/INR, aPTT, albumin, billirubin and others...
(LFTs) is a simple blood test, the results of which should be available by the next day. If the ALT
Alanine transaminase
Alanine transaminase or ALT is a transaminase enzyme . It is also called serum glutamic pyruvic transaminase or alanine aminotransferase ....
level is elevated, this, plus pruritus of palms and soles, should be treated as diagnostic of ICP (however LFT's are not always elevated in ICP patients). The serum bile acid blood test for ICP is a quantitative measurement of bile salts. The results of this test often take longer to return, but the test is more specific for ICP.
Other problems with the liver that occur in pregnancy should be considered by the treating clinician. These include preeclampsia, the HELLP syndrome, and acute fatty liver of pregnancy. Furthermore, other causes of hepatitis, like hepatitis viruses and certain medications, should also be considered.
Treatment
Upon diagnosis, most providers will prescribe Ursodeoxycholic Acid. While there is no cure for ICP, and no way to guarantee a successful outcome, studies have shown a slightly better fetal and maternal outcome from administration of Ursodeoxycholic Acid, whereas Cholestyramine appears to only relieve itching.If additional blood tests to check clotting function identify a problem, giving Vitamin K
Vitamin K
Vitamin K is a group of structurally similar, fat soluble vitamins that are needed for the posttranslational modification of certain proteins required for blood coagulation and in metabolic pathways in bone and other tissue. They are 2-methyl-1,4-naphthoquinone derivatives...
may help avoid the risk of hemorrhage at delivery.
Delivery by 37 completed weeks is considered crucial to fetal outcome , though it does not completely eliminate the risks associated with the condition.
See also
- Pruritic Urticarial Papules and Plaques of Pregnancy (PUPPP) an itchy condition of pregnancy that is associated with a rash.
- CholestasisCholestasisIn medicine, cholestasis is a condition where bile cannot flow from the liver to the duodenum. The two basic distinctions are an obstructive type of cholestasis where there is a mechanical blockage in the duct system such as can occur from a gallstone or malignancy and metabolic types of...
- Cholestatic pruritusCholestatic pruritusCholestatic pruritus is the sensation of itch due to nearly any liver disease, but the most commonly associated entities are primary biliary cirrhosis, primary sclerosing cholangitis, obstructive choledocholithiasis, carcinoma of the bile duct, cholestasis , and chronic hepatitis C viral infection...
- List of cutaneous conditions