Episode 77 - Intrahepatic Cholestasis of Pregnancy - a podcast by Rio Bravo Family Medicine Residency Program

Intrahepatic Cholestasis of Pregnancy (ICP).

Amel and Dr Wonderly discuss the signs, symptoms, and management of ICP. A reminder for alcohol use disorder screening.

Introduction: Screening for alcohol use disorder. 
Written by Hector Arreaza, MD. Reviewed by Jacqueline Uy, MD.

 

Today is December 3, 2021.

Substance misuse occurs in about 20% of patients seen in primary care settings. For example, alcohol-related disorders are present in up to 26% of general clinic patients, “a prevalence rate similar to those for such other chronic diseases as hypertension and diabetes”[1]. The USPSTF recommends screening for unhealthy alcohol use in adults 18 years or older, including pregnant women, and provide those engaged in risky drinking with brief behavioral counseling to reduce alcohol use (this is a Grade B recommendation). This brief introduction is to encourage everyone to screen adults for alcohol use disorder. Let’s start with the basics. 

 

It is important to know the size of a standard drink so you can counsel your patients appropriately. According to the CDC, a standard drink is equal to 14 grams (0.6 ounces) of pure alcohol. Generally, this amount of pure alcohol is found in:

12 ounces of beer (5% alcohol content).

8 ounces of malt liquor (7% alcohol content).

5 ounces of wine (12% alcohol content).

1.5 ounces or a “shot” of 80-proof (40% alcohol content) distilled spirits or liquor (such as gin, rum, vodka, whiskey).

Moderate alcohol drinking means 2 drinks or less in a day for men and 1 drink or less in a day for women. Binge drinking means drinking enough to bring your blood alcohol concentration (BAC) level to 0.08% or more. This may be different in each patient, as humans metabolize alcohol differently, but usually it corresponds to 5 or more drinks on a single occasion for men or 4 or more drinks on a single occasion for women, generally within about 2 hours[2].

 

A good approach to screen for alcohol use disorder is by asking: “Do you sometimes drink alcoholic beverages?”, and then the single screening question, “How many times in the past year have you had 5 or more drinks (men) OR 4 or more drinks (women) in a day?”[3] 

 

The screening is considered positive if the patient answers one or more times a year. If positive, then you may continue your assessment with another tool such as AUDIT. This can be a topic for a whole episode. 

 

For now, we just want to remind you to screen your patients for alcohol use because the prevalence is very high and we as primary care physicians can make a big difference in the prevention and treatment of alcohol misuse in our communities. 

 

This is Rio Bravo qWeek, your weekly dose of knowledge brought to you by the Rio Bravo Family Medicine Residency Program from Bakersfield, California. Our program is affiliated with UCLA, and it’s sponsored by Clinica Sierra Vista, Let Us Be Your Healthcare Home. 

Intrahepatic Cholestasis of Pregnancy (ICP). 

Written by Amel Tabet, MS3, American university of the Caribbean. Discussion with Sally Wonderly, MD; and Hector Arreaza, MD.

What is Intrahepatic Cholestasis of Pregnancy and why does it matter?

As its name implies, Intrahepatic Cholestasis of Pregnancy (ICP) is a multifactorial liver dysfunction in some pregnant women that occurs during their either second or third trimester of pregnancy and resolves spontaneously after parturition. It is defined by the presence of pruritus -- previously called pruritus gravidarum or recurrent jaundice of pregnancy-- and abnormally elevated serum bile acid levels and mildly increased hepatic aminotransferase levels, in the absence of diseases that may yield similar laboratory findings and symptoms. Key symptoms are pruritus, high bile acid and high transaminases. 

How common is ICP?

In the US incidence ranges from 0.32 percent to 5.6 percent, depending on the area. The Los Angeles area has a high incidence compared to other areas in the US. The highest rates in Europe are in Scandinavia. 

It is very frequent in Chile (South America). The indigenous people known as Araucanos have the highest incidence worldwide at 27.6 percent.

Pathogenesis

The pathogenesis of ICP remains unclear. It is mainly attributed to changes in various sex steroid levels but more recent research points towards an etiology that relates to various mutations in the many genes involved in the control of the hepatocellular transport systems such as the ABCB4 gene, which encodes multidrug resistance protein 3 (MDR3) linked to progressive familial intrahepatic cholestasis, errors of the ABCB11 gene that encodes for the bile salt export pump, and more recently on FXR/NR1H4 and PXR/NR1I2 genes that encode for proteins that critically regulate bile acid synthesis and transport, and the transcription of ABCB11 in humans and the role of epigenetics influence by means of methylation of these genes. 

Dangers for mother: Beside the discomfort of pruritus, ICP is transient and of little maternal risk generally. The mother may be uncomfortable but it’s not fatal.

 

Danger to fetus: The elevated bile acids enter the fetal circulation because it crosses the placenta. Bile acids cause major fetal and neonatal complications, such as abnormal intrapartum fetal heart rate and meconium-stained amniotic fluid that can lead to fetal distress and prematurity or intrauterine demise and to neonatal respiratory distress syndrome associated with bile acids entering the lungs.

 

Who is at risk for ICP?

Multifetal pregnancies.

Genetics: There is also a significant genetic influence that leads to variability of incidence by population. In North America, cholestasis is infrequent with an overall incidence approximating 1 case in 500 to 1000 pregnancies. Whereas its rate is high in indigenous women from Chile and Bolivia and nears 5.6 % among Hispanic women in Los Angeles. In other countries, for example Sweden, China, and Israel, the incidence varies from 0.25 to 1.5 %.

Diet and environment can also have an influence. Research has shown an association of ICP with environmental and dietary factors such as seasonal changes of mineral dietary components and with gut-derived endotoxins subsequent to increased gastrointestinal permeability. This complex nature-nurture interaction suggests that ICP is strongly modulated by epigenetic mechanisms.

Liver disease: Women with preexisting liver disease are at risk. Other risks include in vitro fertilization, cholelithiasis, advanced maternal age, and Hepatitis C and fatty liver disease. 

 

History of ICP is an important risk, because it also recurs during subsequent pregnancies in 60 to 70 % of patients.

 

Signs and symptoms:

The main clinical presentation is an often-generalized pruritus in late second or third trimester, that usually starts and predominates on the palms and soles and is worse at night. It could range from mild to intolerable pruritus that may precede laboratory findings by several weeks and evidenced by possible presence of scratch marks and excoriations on physical examination. Jaundice arises in 14 to 25 % of patients and it typically develops 1 to 4 weeks after the onset of itching. Other accompanying symptoms may also occur such as nausea, RUQ pain, steatorrhea, poor appetite and sleep deprivation. Other signs include dark urine, pale stools.

 

Diagnosis:

To establish a diagnosis, careful history taking, physical examination, and laboratory evaluation are performed. Thus, in the absence of any other liver disease, ICP is diagnosed by the presence of pruritus that is associated with elevated total serum bile acid levels, elevated aminotransferases (seldom exceed 250 U/L), hyperbilirubinemia (4 to 5 mg/dL) and elevated alkaline phosphatase. In severe cases that account for 20%, cholestasis manifests as bile acids levels > 40 micromol/L.

Differential diagnosis include: Preeclamptic liver disease, which is ruled out if blood pressure elevation or proteinuria are absent and cholelithiasis and biliary obstruction are excluded by sonography. Moreover, because of mild transaminitis in case of ICP, acute viral hepatitis is an improbable diagnosis. 

Liver biopsy is generally not needed. Even though not necessary for diagnosis, liver biopsy for research purposes, showed occurrence of changes with presence of cholestasis with bile plugs in the hepatocytes and canaliculi of the centrilobular regions, without inflammation or necrosis. These changes were found to fade after delivery with recurrence in successive pregnancies or with estrogen-containing contraceptives.

Management:

Management focuses mainly on reducing maternal discomfort due to pruritus and prevention of more serious fetal outcomes and reduce the risks of prenatal morbidity and mortality. 

For patients that have persistent clinical findings consistent with ICP without any biochemical evidence of ICP, we only treat with antihistamines and topical emollients such as calamine lotion and we perform a weekly evaluation of maternal total serum bile acid (TSBA) level. 

 

In symptomatic patients with positive biochemical evidence of ICP we treat with ursodeoxycholic acid (UDCA) 300 mg BID or TID until delivery. UDCA was found in clinical trials to relieve pruritus, lower bile acid and serum enzyme levels, and to reduce preterm birth, fetal distress, respiratory distress syndrome, and neonatal intensive care unit admission. Along with treatment, we continue the weekly evaluation of the TSBA level with a warranted earlier delivery if TSBA ≥100 micromol/L and the related high risk of stillbirth. 

 

Thus, delivery management is mainly based on the highest TSBA level at any time during pregnancy. 

If TSBA level is <40 micromol/L, delivery is advised at 37 to 38 6/7 weeks (Grade 2C). 

For TSBA within 40-99 micromol/L range, delivery is advised at 36 to 37 weeks (Grade 2C). 

For TSBA ≥100 micromol/L, delivery is recommended at 36 weeks.  

For any patient with worsening liver function tests and relentless symptoms despite treatment, or a prior history of ICP and fetal death before 36 weeks and recurring ICP in the present pregnancy, delivery before 36 weeks is warranted.

 

Postpartum women with persistent clinical symptoms should undergo liver function and TSBA level check and should be referred to liver specialist if unresolved dysfunction. Check liver function tests and bile acids 6-8 weeks after delivery and investigate other causes if these labs are abnormal.

 

There is a risk for recurrence in up to 90% of future pregnancies and it can present with hormonal contraceptives as well. 

 

__________________________

Now we conclude our episode number 77 “Intrahepatic Cholestasis of Pregnancy” or ICP. If you have a pregnant patient who complains of severe pruritus, remember to check total serum bile acids and liver function tests. Elevated bile acids in pregnancy should not be taken lightly. Act promptly and wisely. Delivery may be warranted even before 36 weeks in patients with worsening liver function, unrelenting symptoms or prior ICP with fetal death before 36 weeks. Even without trying, every night you go to bed being a little wiser.

Thanks for listening to Rio Bravo qWeek. If you have any feedback about this podcast, contact us by email RioBravoqWeek@clinicasierravista.org, or visit our website riobravofmrp.org/qweek. This podcast was created with educational purposes only. Visit your primary care physician for additional medical advice. This week we thank Hector Arreaza, Amel Tabet, Sally Wonderly, and Jacqueline Uy. Audio edition: Suraj Amrutia. See you next week! 

 

 

References:

Sullivan Eleanor and Michael Fleming, A Guide to Substance Abuse Services for Primary Care Clinicians, Treatment Improvement Protocol (TIP) Series, U.S. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, www.samhsa.gov,   https://store.samhsa.gov/sites/default/files/SAMHSA_Digital_Download/SMA08-4075_508.pdf

 

Alcohol Questions and Answers, Centers for Disease Control and Prevention, CDC.gov, https://www.cdc.gov/alcohol/faqs.htm#bingeDrinking, accessed on November 16, 2021.

 

Helping Patients Who Drink Too Much: A CLINICIAN’S GUIDE, Updated 2005 Edition, National Institutes of Health, www.nih.gov, 

 

Dermatological Disorders. In: Cunningham F, Leveno KJ, Bloom SL, Dashe JS, Hoffman BL, Casey BM, Spong CY. eds. Williams Obstetrics, 25e. McGraw Hill; 2018. Accessed October 11, 2021. https://accessmedicine-mhmedical-com.aucmed.idm.oclc.org/content.aspx?bookid=1918§ionid=141465503

 

Hashemi N, Ukomado C. Hepatic Complications of Pregnancy. In: Greenberger NJ, Blumberg RS, Burakoff R. eds. CURRENT Diagnosis & Treatment: Gastroenterology, Hepatology, & Endoscopy, 3e. McGraw Hill; 2016. Accessed October 11, 2021. https://accessmedicine-mhmedical-com.aucmed.idm.oclc.org/content.aspx?bookid=1621§ionid=105182308.   

 

Hepatic, Biliary, and Pancreatic Disorders. In: Cunningham F, Leveno KJ, Bloom SL, Dashe JS, Hoffman BL, Casey BM, Spong CY. eds. Williams Obstetrics, 25e. McGraw Hill; 2018. Accessed October 12, 2021. https://accessmedicine-mhmedical-com.aucmed.idm.oclc.org/content.aspx?bookid=1918§ionid=148216133.

 

Intrahepatic cholestasis of pregnancy. Keith D Lindor, Richard H Lee. UpToDate. Sep 2021. https://www.uptodate.com/contents/intrahepatic-cholestasis-of-pregnancy?search=intrahepatic%20cholestasis%20of%20pregnancy&source=search_result&selectedTitle=1~60&usage_type=default&display_rank=1#references    

 

Klauser CK, Saltzman DH. Gastrointestinal Disorders in Pregnancy. In: DeCherney AH, Nathan L, Laufer N, Roman AS. eds. CURRENT Diagnosis & Treatment: Obstetrics & Gynecology, 12e. McGraw Hill; 2019. Accessed October 11, 2021. https://accessmedicine-mhmedical-com.aucmed.idm.oclc.org/content.aspx?bookid=2559§ionid=206962251.

 

Cabrerizo R, Castaño GO, Burgueño AL, Fernández Gianotti T, Gonzalez Lopez Ledesma MM, Flichman D, Pirola CJ, Sookoian S. Promoter DNA methylation of farnesoid X receptor and pregnane X receptor modulates the intrahepatic cholestasis of pregnancy phenotype. PLoS One. 2014 Jan 31;9(1):e87697. doi: 10.1371/journal.pone.0087697. PMID: 24498169; PMCID: PMC3909199. https://pubmed.ncbi.nlm.nih.gov/24498169/

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