GI in Pregnancy: GI in Pregnancy: Liver Diseases of Pregnancy

0:00Welcome to Board Pearls. This is episode three of six of the GI in Pregnancy chapter, in the Special Populations and Acute or Supportive Care module. This episode is the liver diseases unique to pregnancy. The first patient is a woman itching at thirty-one weeks. Her case shows how intrahepatic cholestasis of pregnancy is recognized and confirmed, why gamma-glutamyl transferase, GGT, stays normal, why one bile acid level separates waiting from delivering, what ursodeoxycholic acid does and doesn't do, why vitamin K is needed, and what the diagnosis means for her next pregnancy and her contraception. Two more women show the third-trimester emergencies whose only cure is delivery. One has HELLP syndrome, hemolysis, elevated liver enzymes, and low platelets, and her case shows how it's defined, graded, and managed. The other has acute fatty liver of pregnancy, and her case shows why it's a fetal enzyme problem, how it's told apart from HELLP, and what sudden shoulder pain after delivery means.

1:00Here's the first patient. A thirty-one-year-old woman is thirty-one weeks pregnant with her second child, and she weighs sixty-eight kilograms. For ten days she's had intense itching, worst at night, mostly on her palms and soles, without rash or jaundice. Her first labs a week ago were normal. In her first pregnancy she remembers itching late in the third trimester that went away after delivery.

1:22She most likely has intrahepatic cholestasis of pregnancy, ICP, a reversible cholestasis of late pregnancy and the most common liver disease unique to pregnancy. It presents in the second or third trimester, typically at twenty-five to thirty-two weeks, with itching that's worse at night and concentrated on the palms and soles. The itching is often the only symptom, and it can come before the labs turn abnormal, so normal labs are repeated when the itching persists, which is why her first normal result doesn't end the workup. Jaundice occurs in only ten to twenty-five percent and always follows the itching, so jaundice first and itching later argues against ICP and widens the search to the emergencies later in this episode.

2:01Her repeat labs make the diagnosis, and total bile acids are the test. Total bile acids above ten micromoles per liter are diagnostic, and one hundred or more defines severe disease. Alkaline phosphatase and 5-prime-nucleotidase rise, but GGT is typically normal. Aspartate aminotransferase, AST, and alanine aminotransferase, ALT, can rise but rarely exceed one thousand, and bilirubin, when raised, is usually below five. A right upper quadrant ultrasound excludes biliary obstruction before the diagnosis is accepted, and hepatitis C serology is checked. Biopsy isn't needed, though it would show centrilobular cholestasis with canalicular bile plugs and no inflammation or necrosis.

2:48Her results show total bile acids of one hundred twelve, an ALT of one hundred ninety, a normal GGT and bilirubin, a normal ultrasound, and negative hepatitis C serology. She has severe ICP. Some of her alkaline phosphatase may be placental, as episode one explains, which is why bile acids rather than alkaline phosphatase make the diagnosis.

3:11The mechanism explains her normal GGT, her hepatitis C test, and her history. Estrogen and progesterone impair bile acid secretion across the canalicular membrane, a transport problem that doesn't injure the ducts, so GGT stays normal. The susceptibility genes encode the canalicular transporters: ABCB11, the bile salt export pump; ABCB4, the phospholipid transporter MDR3; and ATP8B1, the FIC1 translocase. Variants in them can't keep up with the bile acid load of late pregnancy, which is why ICP runs in families and populations, with a United States prevalence of about one to two percent and much higher rates in some Hispanic populations, up to about a quarter of Araucanian Indians in Chile. Hepatitis C raises ICP risk about twentyfold by further impairing transporter function, which is why its serology is part of her workup.

4:09Her bile acid level sets her baby's risk, and one hundred is the number that matters. In a large individual patient data meta-analysis, bile acids below forty carried fetal mortality close to baseline, forty to ninety-nine carried a modestly raised risk, and one hundred or more carried a steep rise in stillbirth, to about three point four percent, the inflection point of the disease. Maternal bile acids cross the placenta and bind muscarinic and bile acid receptors on fetal heart muscle, causing arrhythmia, and toxic hydrophobic bile acids deposit in fetal tissue. Untreated severe ICP carries fetal mortality of eleven to twenty percent, preterm delivery in nineteen to sixty percent, and fetal distress in twenty-two to forty-one percent. At one hundred twelve, her level puts the timing of delivery into the plan, not just her itch.

4:57She starts ursodeoxycholic acid, UDCA, ten to fifteen milligrams per kilogram per day, typically five hundred to two thousand milligrams daily, adjusted to her symptoms. It's hydrophilic, so it displaces the toxic hydrophobic bile acids from the pool and improves canalicular transport, and it crosses the placenta, protecting fetal heart muscle. About three-quarters of patients respond with lower bile acids and less itching. A randomized trial in twenty nineteen showed no improvement in fetal outcomes compared with placebo, but UDCA remains recommended for its clear maternal benefit, and later meta-analyses suggest fetal benefit at higher bile acid levels, where the absolute risk is greatest. At sixty-eight kilograms, her dose is about six hundred eighty to one thousand twenty milligrams a day, raised within that range before it's called a failure. She's told it should ease her itching and may help her baby most at her level, but it doesn't replace the decision about delivery.

5:52Her cholestasis also affects her clotting. It impairs absorption of fat-soluble vitamins and raises the risk of bleeding around delivery, so she's given vitamin K around delivery. Cholestyramine binds bile acids in the gut, but it's poorly tolerated and worsens fat-soluble vitamin malabsorption, so it's reserved for women who can't take UDCA, with extra attention to vitamin K.

6:14Her delivery is timed by the same three bile acid levels. Bile acids of one hundred or more call for delivery at thirty-six to thirty-seven weeks, because the steep rise in stillbirth risk outweighs the lung maturity gained by waiting. Forty to ninety-nine allows delivery at thirty-six to thirty-nine weeks, individualized by symptom control and obstetric factors, and below forty allows delivery at thirty-nine weeks, because fetal risk is close to baseline. At one hundred twelve, she's planned for delivery at thirty-six to thirty-seven weeks, with vitamin K beforehand.

6:47Her diagnosis continues after delivery and into her next pregnancy. Itching and labs resolve within one to two weeks after delivery, so they're rechecked, and labs that don't normalize suggest an underlying liver disease the pregnancy unmasked. ICP recurs in sixty to ninety percent of later pregnancies and with combined hormonal contraceptives, so estrogen-containing contraception is generally avoided. Her itching in her first pregnancy was very likely undiagnosed ICP, making this a recurrence. Severe, recurrent, or early-onset ICP prompts genetic testing of the transporter genes, because some women carry variants of benign recurrent intrahepatic cholestasis or progressive familial intrahepatic cholestasis that affect long-term care, so she's offered testing. In her next pregnancy, bile acids are checked as soon as the itching returns. Women with ICP also carry a higher long-term risk of hepatitis C, nonalcoholic cirrhosis, gallstones and cholecystitis, and nonalcoholic pancreatitis, so she has long-term follow-up.

7:49Now the emergencies. A twenty-six-year-old woman is thirty-four weeks pregnant with her first child, with headache and right upper quadrant and epigastric pain. Her blood pressure is one hundred sixty-four over one hundred twelve with proteinuria. Her platelets are sixty-eight thousand, her AST three hundred forty, and her lactate dehydrogenase, LDH, eight hundred twenty, with schistocytes on smear, a mostly unconjugated bilirubin of one point nine, and a normal glucose.

8:15She has severe preeclampsia with HELLP syndrome. Her hypertension, hemolysis, high liver enzymes, and low platelets point there, but the stage of pregnancy narrows the list first. Hyperemesis belongs to the first trimester, through week twenty. ICP belongs to the second and third trimesters, preeclampsia to after twenty weeks, HELLP to after twenty-two, and acute fatty liver to after twenty-eight. Jaundice in the third trimester is always concerning and prompts evaluation for ICP, preeclampsia or HELLP, acute fatty liver, and viral hepatitis in parallel. At thirty-four weeks, all three emergencies are possible, so her labs have to separate them.

8:55Her blood pressure and proteinuria make the first diagnosis, preeclampsia. Preeclampsia is a blood pressure of one hundred forty over ninety or more, with proteinuria or end-organ dysfunction, after twenty weeks, affecting three to ten percent of pregnancies. It's severe at one hundred sixty over one hundred ten or more, or with any end-organ dysfunction: oliguria, pulmonary edema, neurologic symptoms, persistent epigastric or right upper quadrant pain, liver injury, thrombocytopenia, or fetal growth restriction. The liver is involved in ten to twenty percent. Her pressure, headache, pain, liver injury, and platelets each make her preeclampsia severe.

9:38Her labs then meet HELLP syndrome, the severe end of the same vascular disease, defined by the Tennessee criteria: hemolysis with an LDH of six hundred or more, an AST of seventy or more, and platelets of one hundred thousand or fewer. HELLP affects about one to six in a thousand pregnancies. It develops before delivery in seventy percent and within two weeks after delivery in thirty percent, and a fifth of cases occur without hypertension. The Tennessee classification grades it by platelets, which track bleeding risk at delivery and how intensive management must be: class one is below fifty thousand, with the highest maternal mortality, class two is fifty to one hundred thousand, and class three is one hundred to one hundred fifty thousand. At sixty-eight thousand, she's class two, and her platelets are watched closely.

10:25Her liver is injured through its sinusoids. The placenta's dysfunctional endothelium releases the antiangiogenic factors sFlt-1 and soluble endoglin, which injure the mother's endothelium, causing vasoconstriction and fibrin deposition in small vessels. In the liver, fibrin thrombi in the sinusoids cause obstruction and ischemic necrosis with hemorrhage around the portal tracts. The hemolysis is microangiopathic, red cells fragmenting on fibrin strands, which produces her schistocytes, a low haptoglobin, a high LDH, and a mostly unconjugated bilirubin. Liver enzymes can reach the thousands. Maternal mortality is one to three and a half percent, and perinatal mortality is fifty-six to three hundred sixty-seven per thousand live births.

11:11Her treatment is delivery, because the endothelial injury resolves only when the placenta is removed. Supportive care includes intensive care unit, ICU, monitoring, blood pressure control, magnesium sulfate to prevent seizures, antenatal corticosteroids for lung maturity if delivery is before thirty-two weeks, and platelet transfusion to above forty thousand at delivery or for procedures. At thirty-four weeks, she doesn't meet the rule for antenatal steroids, and with platelets above forty thousand she needs no transfusion unless they fall. So she gets blood pressure control, magnesium, ICU monitoring, and delivery.

11:47Her course after delivery has its own pattern. HELLP can worsen for forty-eight hours after delivery before improving, so worse labs on the first morning aren't a new event. Because thirty percent of cases arise after delivery, right upper quadrant pain and falling platelets in the two weeks after a normal delivery can also be HELLP. It recurs in about seven percent of later pregnancies.

12:09The other emergency is acute fatty liver of pregnancy. A thirty-seven-year-old woman in her third pregnancy is thirty-five weeks pregnant with twins, with a week of nausea, vomiting, abdominal pain, and intense thirst, and she's now jaundiced and confused. Her glucose is forty-eight, her international normalized ratio, INR, two point one, her white count eighteen thousand, her uric acid high, her creatinine rising, and her AST above her ALT, with normal platelets and no schistocytes.

12:41She has acute fatty liver of pregnancy, AFLP, a rare mitochondrial liver failure, occurring in about one in six thousand six hundred to one in twenty thousand pregnancies, at a mean of thirty-six weeks, with rapid jaundice, coagulopathy, hypoglycemia, and lactic acidosis. Her risk factors are typical: she's had several pregnancies and is carrying twins, and the other risk factors are coexisting liver disease of pregnancy and a male fetus.

13:09The cause is in the fetus. The mother is heterozygous and the fetus homozygous for a deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase, LCHAD, so the fetus can't oxidize long-chain fatty acids. They spill into the mother's circulation and overwhelm her liver's mitochondria, producing microvesicular steatosis, mainly in zone three, with preserved architecture and little inflammation. Mitochondrial failure accounts for each of her findings: hypoglycemia from impaired gluconeogenesis, coagulopathy from impaired synthesis, confusion from ammonia accumulation, and lactic acidosis from impaired pyruvate handling.

13:50Her diagnosis is made by the Swansea criteria, six or more features without another explanation: vomiting, abdominal pain, polydipsia or polyuria, raised transaminases, raised bilirubin, renal impairment, encephalopathy, hypoglycemia, coagulopathy, ascites or a bright liver on ultrasound, microvesicular steatosis on biopsy, leukocytosis, or raised urate. The criteria have a positive predictive value of about eighty-five percent and a negative predictive value approaching one hundred percent, so biopsy is usually unnecessary. She has far more than six.

14:27Separating her from the HELLP patient decides how each is managed, and it rests on specific findings. Hypoglycemia, encephalopathy, coagulopathy, polydipsia or polyuria, a high urate, marked leukocytosis, often above fifteen thousand, and an AST above the ALT favor AFLP. Schistocytes, a markedly high LDH, and deep thrombocytopenia favor HELLP. Both cause vomiting, pain, raised transaminases and bilirubin, and renal impairment, and about half of women with AFLP also have features of preeclampsia. Her low glucose and high INR mean a failing liver, not an injured vessel.

15:09Her treatment is delivery, and her diagnosis extends to her twins. Delivery is the only definitive treatment, with ICU support, imaging to exclude hepatic hemorrhage or rupture, and transfer to a transplant center if her liver failure worsens. With timely delivery and support, maternal mortality is now ten to thirty-three percent, an order of magnitude lower than before prompt delivery, which is why AFLP is treated as a delivery emergency. Perinatal mortality remains fifteen to twenty-five percent in contemporary series, and up to about sixty percent when the fetus is LCHAD-deficient. She and her twins undergo LCHAD genetic testing, because an affected infant develops nonketotic hypoglycemic coma with stress or fasting, which is reversible with adequate feeding.

15:56The HELLP patient, after her delivery, illustrates one more complication. Hepatic infarction with subcapsular hematoma or capsular rupture complicates roughly one to two percent of HELLP and severe preeclampsia, and fewer cases of AFLP. It presents with sudden severe abdominal pain, often radiating to the right shoulder or scapula from diaphragmatic irritation, transaminases often above three to six thousand, spiking fevers, and anemia, with mostly right-lobe involvement on computed tomography, CT, or magnetic resonance imaging, MRI.

16:29Sudden right shoulder pain, a falling hemoglobin, and hypotension the day after her delivery would be rupture. It needs aggressive resuscitation with blood products and either surgery or hepatic artery embolization, and maternal mortality is fifty-six to seventy-five percent, with fetal mortality of sixty-two to seventy-seven percent. A stable patient with a contained subcapsular hematoma is managed conservatively, with correction of coagulopathy and serial imaging.

16:58Here are the traps the boards set in these patients. Dismissing nocturnal palm and sole itching because the first labs were normal. Diagnosing ICP without total bile acids, or expecting a raised GGT. Skipping the ultrasound or hepatitis C serology. Waiting past thirty-seven weeks with bile acids of one hundred or more, or delivering a mild case early. Withholding UDCA because a trial didn't show fetal benefit. Forgetting vitamin K before delivery. Starting estrogen contraception after ICP. And forgetting long-term follow-up.

17:32For HELLP and AFLP, the traps are these. Excluding HELLP because the blood pressure is normal, or forgetting it can start after delivery. Forgetting magnesium sulfate. Giving antenatal steroids by reflex after thirty-two weeks. Leaving platelets below forty thousand at delivery. Being alarmed by worse labs in the first forty-eight hours after delivery. Calling AFLP HELLP when the glucose is low and the INR high. Biopsying a patient who meets the Swansea criteria. Forgetting LCHAD testing of the infant. And missing right shoulder pain as hepatic rupture.

18:08So, start to finish. Nocturnal palm and sole itching in the late second or third trimester with total bile acids over ten and a normal GGT is ICP, after obstruction is excluded by ultrasound and hepatitis C is checked, and normal labs are repeated if the itching persists. Delivery comes at thirty-six to thirty-seven weeks for bile acids of one hundred or more, at thirty-six to thirty-nine weeks for forty to ninety-nine, and at thirty-nine weeks below forty. UDCA treats symptoms, vitamin K is given before delivery, the disease resolves within two weeks after delivery, and it recurs in most later pregnancies and with estrogen contraception, so follow-up is long-term.

18:50HELLP is hemolysis with schistocytes and a high LDH, a raised AST, and low platelets, graded by platelet count, usually with hypertension and sometimes after delivery. AFLP is liver failure with hypoglycemia, coagulopathy, encephalopathy, a high urate, and leukocytosis, diagnosed by the Swansea criteria and caused by fetal LCHAD deficiency, so mother and baby are tested. Both need delivery, with magnesium and blood pressure control in HELLP, platelets above forty thousand at delivery, and transplant referral for worsening AFLP. Sudden right upper quadrant or shoulder pain with shock suggests hepatic rupture, which needs resuscitation and surgery or embolization.

19:32Episode four is viral hepatitis in pregnancy.

19:35For the full chapter, the practice vignettes, and the topic-tagged question bank, head to board pearls dot com. You'll find the rest of the series on Apple Podcasts, Spotify, or wherever you listen to podcasts. That brings us to the end of episode three of six of chapter thirty-five, and I'll see you in the next one.