There are many changes in the anatomy and physiology of the female human body during pregnancy. Aside from the profound reproductive system changes, there are also many reversible modifications in other internal organ systems, all of which happen to accommodate the changing needs of the woman throughout the 3 trimesters of pregnancy. The liver changes during pregnancy and predisposes the woman to certain hepatic conditions that could put her and the fetus at increased risk for morbidity or mortality.
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nurse comforting female patient dysfunctional uterine bleeding

Image: “young african nurse comforting female patient in doctor’s office” by
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Physiologic Changes in the Liver during Pregnancy

The human liver is among those in the animal kingdom that does not change in size during pregnancy. Tissue biopsies show that there are not many changes in liver morphology from pregnant women. However, there is a distinct increase in the hepatic arterial and portal venous blood flow as the pregnancy progresses.

Another significant change related to the liver during pregnancy is the upregulation of liver enzymes and proteins. Here are some of the observed changes in serum levels among pregnant women:

  • Alkaline phosphatase – increased due to heat-stable placental alkaline phosphatase isoenzymes.
  • Aspartate transaminase (AST), alanine transaminase, γ-glutamyl transpeptidase (GGT), and bilirubin – decreased.
  • Albumin and serum globulins – concentration decreases but the total amount in the body increases.
  • Leucine aminotranspeptidase – increased due to the presence of pregnancy-specific enzymes with distinct substrate specificities. The presence of this enzyme in non-pregnant individuals denotes liver disease.

Intrahepatic Cholestasis of Pregnancy

Otherwise known as recurrent jaundice of pregnancy, cholestatic hepatosis, or icterus gravidarum. This condition commonly affects women who are pregnant with 2 or more fetuses and is influenced by genetics. It is characterized by itching and jaundice.

Pathogenesis of intrahepatic cholestasis of pregnancy

There is no known cause for intrahepatic cholestasis among pregnant women. However, it has been theorized that mutations in certain genes are implicated in the pathogenesis of the disorder. Some of the genes that are thought to cause the disease when mutated are the following:

  • ABCB4 – expresses multidrug resistance protein 3 which is implicated in progressive familial intrahepatic cholestasis.
  • ABCB11 – a gene that expresses a bile salt pump.
  • ATP8B1 – encodes Farnesoid X receptor and transporting ATPase.

Some drugs are also known to exacerbate bile acid transport dysfunction. An example is an azathioprine, a commonly used anti-rejection medication given for post-transplant patients.

Impaired clearance of bile results in its accumulation in the plasma and is manifested as hyperbilirubinemia. This could regress after delivery but can recur in subsequent pregnancies.

Management of intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis is managed supportively. Itching is controlled by antihistamines and topical emollients. Use of cholestyramine is still under debate as it interferes with the absorption of fat-soluble vitamins needed for the maintenance of pregnancy.

Acute Fatty Liver of Pregnancy

This disorder can also be called acute fatty metamorphosis or acute yellow atrophy. It is the most common cause of acute liver disease among pregnant women. Fat vesicles accumulate in the liver parenchyma and alter the normal functioning of hepatocytes. The liver then appears yellow, soft, greasy, and small.

Pathogenesis of acute fatty liver of pregnancy

Some cases are known to be brought about by recessively inherited mitochondrial abnormalities of fatty acid oxidation. The genes most commonly associated with this defect are responsible for the expression of fatty acid dehydrogenases and consist of the following:

  • G1528C
  • E474Q

Another cause that could contribute to the development of this disorder is the dysfunction of enzymes needed for oxidation of fatty acids. Patients with severe preeclampsia, especially in the presence of HELLP syndrome, are also predisposed to develop acute fatty liver.

Pregnant women with acute fatty liver may have persistent nausea and vomiting, anorexia, abdominal pain, jaundice, hypertension, edema, and proteinuria. There may also be some degree of clotting dysfunction due to the impairment in the synthetic functions of the hepatocytes.

Management of acute fatty liver of pregnancy

Supportive care is critical in the management of pregnant women with acute fatty liver. More often than not, the viability of the fetus is already severely compromised at the time of the diagnosis. If not dead, viable fetuses tolerate labor poorly. Opting for cesarean delivery to shorten the recovery time of the liver can result in more severe complications due to the presence of coagulopathy. For this reason, a trial of labor induction with close fetal monitoring is done.

Most of the time, the liver regresses to its normal state after delivery, although some problems can occur such as transient diabetes insipidus.

Viral Hepatitis in Pregnancy

The availability of preventive and curative measures for viral hepatitis has significantly contributed to the decline of the disease, including in pregnant women. Although not directly hepatotoxic itself, the hepatitis virus can induce several immune reactions that can damage the hepatocytes.

Hepatitis A and E

Both of these viruses are enterically transmitted and can cause subclinical and overt symptoms that are indicative of liver inflammation. However, cases of hepatitis A have declined significantly due to vaccination programs all over the world, especially in developing countries. Hepatitis E, on the other hand, is the most common cause of viral hepatitis and has been implicated in many epidemic outbreaks in developing countries. In rare cases, this virus can cause fulminant hepatitis in pregnant women.

Pregnant patients with this disease are advised to eat a balanced diet and get plenty of rest. Patients with less severe manifestations can be managed on an outpatient basis. These viruses are not teratogenic but can cause preterm birth and neonatal cholestasis.

Hepatitis B and Hepatitis D

Hepatitis B is transmitted by exposure to infected blood or body fluids. It has a long incubation period and can remain asymptomatic for quite some time. Even if symptoms start to manifest they are often nonspecific making it more difficult for diagnosis. Hepatitis B is responsible for almost half of the cases of fulminant hepatitis. In chronically infected individuals, they may remain asymptomatic indefinitely and become carriers of the disease. Although vertical transmission to the fetus is negligible, prophylactic measures are instituted to prevent neonatal infection.

Hepatitis D viruses can only cause infection in the presence of the hepatitis B virus. It can either coexist with hepatitis B or occur secondarily. When both viruses are present morbidity and mortality are significantly increased.

Hepatitis C

Transmission of hepatitis C occurs through blood and body fluids. Patients who are HIV-infected, IV drug users, on hemodialysis, and children born to infected individuals are at an increased risk for the viral infection and should undergo screening. Prenatal screening for high-risk women is also encouraged.

Only a small subset of infected individuals develop specific symptoms such as jaundice. Most patients show only generalized symptoms or remain asymptomatic for quite some time.

The majority of the patients infected with hepatitis C will become chronically infected carriers of the virus. Around a third of them develop liver cirrhosis. However, the prognosis for the disease is generally excellent especially if managed promptly.

Fetal problems such as low birth weight, NICU admission, preterm delivery, and mechanical ventilation have been reported among women who have been infected during pregnancy. However, the high-risk lifestyle associated with hepatitis C infection may also play a crucial part in the development of maternal and fetal complications. Mothers with viremia are more likely to transmit the virus to the fetus.

Unfortunately, there are still no vaccines available against hepatitis C.

Autoimmune Hepatitis in Pregnancy

Identification of the causative agent for various cases of hepatitis is crucial as a treatment for each varies significantly.

In some cases pathogens (virus or another foreign body) can cause hepatic damage without directly insulting the hepatocytes. Damage is achieved once the immune system is engaged to attack the invading agent. Activated T cells are then deployed to the area of invasion and unintentionally attack the surrounding hepatocytes.

Chronic autoimmune hepatitis is more common among women, especially among those who have other autoimmune diseases such as thyroiditis, ulcerative colitis, type 1 diabetes, and rheumatoid arthritis.

Generally, the prognosis for pregnant women with autoimmune hepatitis is good, given that proper measures to control the disease are instituted promptly and consistently. Medications such as corticosteroids may help alleviate the condition.

Non-Alcoholic Fatty Liver Disease in Pregnancy

Non-alcoholic fatty liver disease

Image: “Micrograph of non-alcoholic fatty liver disease (NAFLD)” by Nephron – Own work, License: CC BY-SA 3.0

This condition is also referred to as steatohepatitis, and when uncontrolled, can lead to cirrhosis. It is similar to alcohol-induced liver damage in terms of morphology but without any evidence of alcohol abuse. It usually occurs with other conditions such as type 2 diabetes, obesity, and hyperlipidemia. Although most cases do not show any evidence of abnormal liver enzyme levels, steatosis may be prominent in high-risk patients. Diabetic and obese pregnant women are at higher risk of developing the disease.

Steatohepatitis is part of a continuum that starts with non-alcoholic steatohepatitis and ends with hepatic cirrhosis. Since steatohepatitis is asymptomatic, patients may present with very high levels of aminotransferases when they begin to manifest signs and symptoms.

The primary mode of intervention for pregnant patients with non-alcoholic fatty liver disease is weight loss and control of existing comorbidities such as diabetes and dyslipidemia.

Cirrhosis in Pregnancy

Liver cirrhosis is usually irreversible and is characterized by fibrosis of the liver parenchyma. To compensate, the liver tries to regenerate the areas of fibrosis, forming multiple nodules. Cirrhosis is commonly the endpoint for many liver diseases.

Liver cirrhosis

Image: “Macroscopic image of micronodular (liver) cirrhosis caused by alcohol consumption” by Amadalvarez – Own work, License: CC BY-SA 4.0

  • Laennec cirrhosis – results from chronic alcohol abuse.
  • Postnecrotic cirrhosis – sequelae of hepatitis B and C infection; common among young and pregnant women.
  • Cryptogenic cirrhosis – results from non-alcoholic fatty liver disease.

Manifestations may include jaundice, edema, coagulopathy, metabolic abnormalities, and portal hypertension.

Generally speaking, nonpregnant women who have cirrhosis are infertile. However, if they do get the disorder while pregnant, they generally have poor outcomes. Sequelae can include transient hepatic failure, variceal hemorrhage, preterm delivery, fetal growth restriction, splenic artery aneurysms, and maternal death.

Management of cirrhosis in pregnancy

Pregnant patients with liver cirrhosis are managed the same way as with those who are not pregnant. Screening procedures for the identification of severe complications including the presence of bleeding from esophageal varices are recommended. Portal pressure and esophageal varices are addressed by giving beta blockers. Acute bleeding from varices should be managed promptly.

Acute Acetaminophen Overdose during Pregnancy

The availability of acetaminophen as an over-the-counter medication for fever and pain has contributed to the prevalence of liver damage caused by drug toxicities. Even among pregnant women, acetaminophen is the most commonly used pain reliever. The damage caused by the harmful acetaminophen metabolite N-acetyl-p-benzoquinone imine (NAPQI) causes massive hepatocyte damage, and a subsequent cytokine storm may follow.

Manifestations of acetaminophen toxicity are nonspecific and can include nausea, vomiting, sweating, fatigue, and pallor. The management depends on the dosage of the drug taken and the span of time that has elapsed from ingestion. The most commonly used antidote for acetaminophen toxicity is N-acetylcysteine.

Overview of Liver Diseases of Pregnancy

Hyperemesis gravidarum Intra-hepatic cholestasis of pregnancy Hepatic rupture Pre-eclampsia HELLP syndrome Acute fatty liver disease of pregnancy
N/v and dehydration in first trimester Pruritis and jaundice in 2nd or 3rd trimester Severe abdominal pain in 3rd trimester with shock N/v; HTN, edema, seizures in 2nd or 3rd trimester, seizure makes the progression from pre-eclampsia to eclampsia RUQ pain, n/v, HTN, in 2nd or 3rd trimester Jaundice, RUQ pain, hepatomegaly in 3rd trimester
Bilirubin up to 5 X/ULN or ALT 2-3 X/ULN Bilirubin up to 10 X/ULN, ALT up to 1000 Bilirubin normal, ALT > 100 Bilirubin up to 20 X/ULN, ALT > 1000, low haptoglobin, low platelet count Bilirubin up to 20 X/ULN, ALT > 1000, DIC, elevated ammonia
Treatment: hydration, resolves spontaneously Treatment: Cholestyramine, UDCA, delivery Treatment: immediate surgery Treatment: magnesium, sulfate, delivery Treatment: delivery Treatment: delivery

Review Question

The correct answer can be found below the references.

Which among the following situations indicate that the patient is at high-risk for developing intrahepatic cholestasis should she wish to conceive a child with her partner?

  1. History of IV drug use
  2. Body mass index of 31 and a fasting blood sugar level of 180 mg/dL
  3. Current intake of anti-rejection medications after undergoing kidney transplantation
  4. Fever and malaise hours after eating with friends at a sushi bar
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