Cholestasis of Pregnancy Case File

Cholestasis of Pregnancy Case File

Eugene C.Toy, MD, William E. Seifert, Jr., PHD, Henry W. Strobel, PHD, Konrad P. Harms, MD

❖ CASE 33

A 26-year-old female at 35 weeks gestation presents to the clinic with complaints of generalized itching. Patient reports no rash or skin changes. She denies any change in clothing detergent, soaps, or perfumes. She denies nausea and vomiting and otherwise feels well. On physical exam, there are no rashes apparent on her skin and only some excoriations from itching. Blood work reveals slightly elevated serum transaminase and bilirubin levels.

◆ What is the patient’s likely diagnosis?

◆ What are treatment options?

◆ What is the cause of the patient’s generalized itching?

ANSWERS TO CASE 33: CHOLESTASIS OF PREGNANCY

Summary: A 26-year-old female at 35 weeks gestation with generalized pruritus without a rash and slightly elevated liver transaminases and bilirubin.

◆ Diagnosis: Cholestasis of pregnancy.

◆ Treatment options: Oral antihistamines, cholestyramine, ursodeoxycholic acid.

◆ Etiology of generalized itching: Increased serum bile salts and accumulation of bile salts in the dermis of the skin.

CLINICAL CORRELATION

Cholestasis of pregnancy is a condition in which the normal flow of bile from the gallbladder is impeded, leading to accumulation of bile salts in the body. Generalized itching and, possibly, jaundice may result. It is speculated that the hormones such as estrogen and progesterone, which are elevated in pregnancy, cause a slowing of the gallbladder function, leading to this disorder. Uncomplicated cholestasis is usually diagnosed clinically by generalized itching in a pregnant woman, usually in the third trimester without a rash. Elevated serum levels of bile salts can help to confirm the diagnosis. Elevated bilirubin levels or liver transaminase enzymes may also be seen. The usual treatment includes antihistamine medications for the itching. Some experts recommend ursodeoxycholic acid, a naturally occurring bile acid that seems to improve liver function and may reduce the serum bile acid concentration. More severe cases may require bile salt binders such as cholestyramine or corticosteroids.

APPROACH TO BILE SALTS

Objectives

1. Be able to describe the catabolism and metabolism of bile salts.

2. Biochemical mechanism of action of cholestyramine and ursodeoxycholic acid.

Definitions

Bile acids: The major metabolites of cholesterol, which are synthesized in the liver and stored in the gallbladder for use as emulsifiers in the digestion of lipids. Primary bile acids are those synthesized directly from cholesterol in the liver; Secondary bile acids are metabolites of primary bile acids produced by the action of intestinal bacteria.

Bile salts: The ionized form of bile acids, which is the state that bile acids exist at physiologic conditions.

Cholestyramine: A synthetic, strongly basic anion exchange resin that will strongly bind bile salts when taken orally and prevent their reabsorption in the intestinal tract.

Conjugated bile salts: Bile salts whose carboxylate groups have been enzymatically condensed with the amino groups of either of the amino acids glycine or taurine to form the glyco- or tauroconjugates. This conjugation extends the pH range over which the bile salts are ionized and therefore effective emulsifying agents.

Ursodeoxycholic acid: A naturally occurring bile acid (originally isolated from the bile of bears) that is present in minor concentrations in the bile (approximately 1 to 10 percent). When administered orally, it helps to dissolve cholesterol gallstones.

DISCUSSION

Bile salt molecules secreted by the gallbladder are essential for the emulsification and absorption of fats. They are the salt forms of bile acids, which are the major product of cholesterol catabolism in the liver. Bile salts form micelles as their hydrophobic face contacts the fat (triacylglycerol), and their polar face maintains contact with the aqueous environment. This micelle formation allows water-soluble digestive enzymes to digest the entrapped triacylglycerol molecule, releasing fatty acids that are readily absorbed by the digestive system.

There are two primary bile acids formed in the liver from cholesterol: cholic acid and chenodeoxycholic acid. The formation of bile acids prevents cholesterol accumulation in organs; the body cannot break down the steroid ring of cholesterol. At physiologic pH, bile acids will always be in the form of bile salts. Bile salts are conjugated with glycine or taurine in the liver prior to excretion, forming glyco- or tauroconjugates. Bacterial enzymes present in the intestine produce the secondary bile salts, deoxycholate and lithocholate, by reducing the primary bile salts.

Bile salts perform an important function and are recycled by the body. The body produces 400 mg of bile salts per day from cholesterol; this represents the fate of half of the cholesterol used daily in metabolism (800 mg). However, 20 to 30 g of bile acids is maintained in the enterohepatic circulation. Less than 0.5 g per day is lost to excretion. Bile salts are produced in the liver, stored in the gallbladder, and secreted through the bile duct into the duodenum where they act on triacylglycerol molecules in the intestines. In the gut, the glycine or taurine moiety is removed from the bile salt. It is reabsorbed in the small intestine and returned to the liver for reuse via the portal vein. Bile salts are absorbed by passive diffusion along the entire small intestine, and a specialized Na⁺-bile salt cotransporter is present in the lower ileum.

Intrahepatic cholestasis of pregnancy is a syndrome of unknown etiology characterized by a 100-fold increase in maternal and fetal blood bile salt levels. Bile salts are produced in both the fetal and maternal liver. The fetus transfers the bile salts across the placenta for disposal. When the function of the maternal gallbladder is slowed, bile salts can accumulate in the liver and bloodstream, ultimately resulting in the classical pruritus symptom. It is believed that pregnancy-related hormones may slow bile salt excretion from the gallbladder.

The most successful therapy for cholestasis of pregnancy has been ursodeoxycholic acid (Figure 33-1). Ursodeoxycholic acid is a naturally occurring bile acid, which, when administered, relieves both pruritus and liver function abnormalities. Experimental evidence suggests that it protects hepatocytes and cholangiocytes from bile acid-induced cytotoxicity and improves hepatobiliary excretion. Additionally, it decreases bile salt transfer to the fetus and improves the secretory function of placental trophoblast cells. Ursodeoxycholic acid is recycled through the enterohepatic circulation.

Cholestyramine is another treatment option for cholestasis of pregnancy. It is an oral medication that binds bile salts in the intestine and promotes their excretion in the feces. As this drug is not absorbed, it most likely has little effect on the fetus. Effects on the fetus are still under evaluation. However, cholestyramine can interfere with the absorption of fat soluble vitamins, such as vitamins A, D, E, and K. In rare cases, drug-induced vitamin K deficiency is believed to contribute to hemorrhaging during childbirth.

Figure 33-1. Comparison of the structures of isomers of deoxycholate.

COMPREHENSION QUESTIONS

[33.1] A 18-year-old male with sickle cell anemia develops severe right upper-abdominal pain radiating to his lower right chest and his right flank 36 hours prior to admission to the ER. Twelve hours following the onset of pain, he began to vomit intractably. In the past year he has had several episodes of mild back and lower extremity pain that he attributed to mild sickle cell crises. He reported that the present pain was not like his usual crisis pain. He also reports that his urine is the color of iced tea and his stool now has a light clay color. On examination, his temperature is slightly elevated, and heart rate is rapid. He is exquisitely tender to pressure over his right upper abdomen. The sclerae of his eyes are slightly yellowish in color.

What is the most likely cause of this patient’s symptoms?

A. A cholesterol-rich gallstone

B. A defect in the synthesis of bile acids

C. A defect in heme synthesis

D. A gallstone rich in calcium bilirubinate

E. A sickle cell crisis brought on by overexertion

[33.2] A patient has been on combination statin and cholestyramine therapy to lower his serum cholesterol levels. Prior to any surgery, this patient would be well advised to be supplemented with which of the following?

A. Vitamin A

B. Vitamin B12

C. Vitamin C

D. Vitamin K

E. Linolenic acid

[33.3] A 17-year-old female, whose parents were first cousins, presents to a neurologist because of recurring seizures despite being on anticonvulsive therapy. Nodules that appeared to be fatty deposits were present on her Achilles tendon and several of her joints. Plasma cholesterol concentrations were elevated, and an assay of plasma sterols indicated elevated cholestanol. Cultured skin fibroblasts did not contain any sterol 27-hydroxylase activity. A diagnosis of cerebrotendinous xanthomatosis, a genetic disease inherited in an autosomal fashion, was made. A deficiency in sterol 27-hydroxylase would lead to a decrease in the synthesis of which of the following compounds?

A. Chenodeoxycholate

B. Cortisol

C. 1,25-Dihydroxycholecalciferol

D. Estradiol

E. Testosterone

Answers

[33.1] D. Although a cholesterol-rich gallstone cannot be completely ruled out with the given information, because the patient has experienced several mild sickle cell crises that are accompanied by increased red blood cell destruction, his symptoms are consistent with a gallstone caused by precipitation of calcium salt of bilirubin. Large quantities of bilirubin can overwhelm the ability of the liver to convert it to the more soluble diglucuronide conjugate. As a consequence, the more insoluble unconjugated form enters the bile and is easily precipitated in the presence of calcium ion. If a large stone forms, it can obstruct the bile duct and result in the symptoms exhibited by the patient.

[33.2] D. Cholestyramine binds bile acids strongly so that they cannot be reabsorbed in the intestinal tract, thus increasing the flow of cholesterol to bile acid synthesis and decreasing cholesterol levels in the plasma. However, by binding bile acids, cholestyramine also decreases the absorption of fat-soluble vitamins and fatty acids, which must be taken up in micelles formed with bile acids. Although absorption of vitamin A and linolenic acid may be compromised, the patient needs to be concerned about vitamin K, which is required for blood clot formation.

[33.3] A. The enzyme sterol 27-hydroxylase catalyzes the hydroxylation of carbon 27 of the steroid side chain in the conversion of cholesterol to the primary bile acids. It is a mitochondrial, cytochrome P450 enzyme that has a broad specificity and can act on cholesterol as well as its reduced and hydroxylated metabolites. A deficiency in this enzyme leads to decreased bile acid synthesis and increased conversion of cholesterol to cholestanol.

BIOCHEMISTRY PEARLS

❖ There are two primary bile acids formed in the liver from cholesterol: cholic acid and chenodeoxycholic acid.

❖ Ursodeoxycholic acid has been reported to have good efficacy in treating the symptoms of pregnancy-related cholestasis, relieving both pruritus and liver function abnormalities.

❖ Cholestyramine can interfere with the absorption of fat-soluble vitamins, such as vitamins A, D, E, and K.

References

Brites D. Intrahepatic cholestasis of pregnancy: changes in maternal-fetal bile acid balance and improvement by ursodeoxycholic acid. Ann Hepatol 2002;1(1):20–8. 

Devlin TM, ed. Textbook of Biochemistry with Clinical Correlations, 5th ed. New York: Wiley-Liss, 2002. 

Germain AM, Carvajal JA, Glasinovic JC, et al. Intrahepatic cholestasis of pregnancy: an intriguing pregnancy specific disorder. J Soc Gynecol Investig 2002;9(1):10–14.

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